Stuart Goodman, MD, PhD

All Publications

• The advantages and shortcomings of stem cell therapy for enhanced bone healing. Tissue engineering. Part C, Methods Chow, S. K., Gao, Q., Pius, A., Morita, M., Ergul, Y. S., Murayama, M., Shinohara, I., Cekuc, M. S., Ma, C., Susuki, Y., Goodman, S. B. 2024

  Abstract

  This review explores the regenerative potential of key progenitor cell types and therapeutic strategies to improve healing of complex fractures and bone defects. We define, summarize, and discuss the differentiation potential of totipotent, pluripotent, and multipotent stem cells, emphasizing the advantages and shortcomings of cell therapy for bone repair and regeneration. The fundamental role of mesenchymal stem cells (MSCs) is highlighted due to their multipotency to differentiate into the key lineage cells including osteoblasts, osteocytes, and chondrocytes, which are crucial for bone formation and remodeling. Hematopoietic stem cells (HSCs) also play a significant role; immune cells such as macrophages and T cells modulate inflammation and tissue repair. Osteoclasts are multi-nucleated cells that are important to bone remodeling. Vascular progenitor cells are critical to oxygen and nutrient supply. The dynamic interplay among these lineages and their microenvironment is essential for effective bone restoration. Therapies involving cells that are more than "minimally manipulated" are controversial and include embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). ESCs, derived from early-stage embryos, possess pluripotent capabilities and have shown promise in preclinical studies for bone healing. iPSCs, reprogrammed from somatic cells, offer personalized medicine applications and can differentiate into various tissue-specific cell lines. Minimally manipulative cell therapy approaches such as the use of concentrated bone marrow aspirate (BMAC), exosomes, and various biomaterials for local delivery are explored for their effectiveness in bone regeneration. BMAC, which contains mostly immune cells but few mesenchymal and vascular progenitors, probably improves bone healing by facilitating paracrine mediated intercellular communication. Exosome isolation harnesses the biological signals and cellular byproducts that are a primary source for cell crosstalk and activation. Safe, efficacious, and cost-effective strategies to enhance bone healing using novel cellular therapies are part of a changing paradigm to modulate the inflammatory, repair and regenerative pathways to achieve earlier more robust tissue healing and improved physical function.

  View details for DOI 10.1089/ten.TEC.2024.0252

  View details for PubMedID 39311464

• Author Correction: Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration. Nature communications Andrew, T. W., Koepke, L. S., Wang, Y., Lopez, M., Steininger, H., Struck, D., Boyko, T., Ambrosi, T. H., Tong, X., Sun, Y., Gulati, G. S., Murphy, M. P., Marecic, O., Tevlin, R., Schallmoser, K., Strunk, D., Seita, J., Goodman, S. B., Yang, F., Longaker, M. T., Yang, G. P., Chan, C. K. 2024; 15 (1): 8030

  View details for DOI 10.1038/s41467-024-51829-1

  View details for PubMedID 39271692

• The interactions of macrophages, lymphocytes, and mesenchymal stem cells during bone regeneration. Bone & joint research Murayama, M., Chow, S. K., Lee, M. L., Young, B., Ergul, Y. S., Shinohara, I., Susuki, Y., Toya, M., Gao, Q., Goodman, S. B. 2024; 13 (9): 462-473

  Abstract

  Bone regeneration and repair are crucial to ambulation and quality of life. Factors such as poor general health, serious medical comorbidities, chronic inflammation, and ageing can lead to delayed healing and nonunion of fractures, and persistent bone defects. Bioengineering strategies to heal bone often involve grafting of autologous bone marrow aspirate concentrate (BMAC) or mesenchymal stem cells (MSCs) with biocompatible scaffolds. While BMAC shows promise, variability in its efficacy exists due to discrepancies in MSC concentration and robustness, and immune cell composition. Understanding the mechanisms by which macrophages and lymphocytes - the main cellular components in BMAC - interact with MSCs could suggest novel strategies to enhance bone healing. Macrophages are polarized into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, and influence cell metabolism and tissue regeneration via the secretion of cytokines and other factors. T cells, especially helper T1 (Th1) and Th17, promote inflammation and osteoclastogenesis, whereas Th2 and regulatory T (Treg) cells have anti-inflammatory pro-reconstructive effects, thereby supporting osteogenesis. Crosstalk among macrophages, T cells, and MSCs affects the bone microenvironment and regulates the local immune response. Manipulating the proportion and interactions of these cells presents an opportunity to alter the local regenerative capacity of bone, which potentially could enhance clinical outcomes.

  View details for DOI 10.1302/2046-3758.139.BJR-2024-0122.R1

  View details for PubMedID 39237112

• Harnessing immunomodulation to combat sarcopenia: current insights and possible approaches. Immunity & ageing : I & A Zhang, N., Zhai, L., Wong, R. M., Cui, C., Law, S. W., Chow, S. K., Goodman, S. B., Cheung, W. H. 2024; 21 (1): 55

  Abstract

  Sarcopenia is a complex age-associated syndrome of progressive loss of muscle mass and strength. Although this condition is influenced by many factors, age-related changes in immune function including immune cell dynamics, and chronic inflammation contribute to its progression. The complex interplay between the immune system, gut-muscle axis, and autophagy further underscores their important roles in sarcopenia pathogenesis. Immunomodulation has emerged as a promising strategy to counteract sarcopenia. Traditional management approaches to treat sarcopenia including physical exercise and nutritional supplementation, and the emerging technologies of biophysical stimulation demonstrated the importance of immunomodulation and regulation of macrophages and T cells and reduction of chronic inflammation. Treatments to alleviate low-grade inflammation in older adults by modulating gut microbial composition and diversity further combat sarcopenia. Furthermore, some pharmacological interventions, nano-medicine, and cell therapies targeting muscle, gut microbiota, or autophagy present additional avenues for immunomodulation in sarcopenia. This narrative review explores the immunological underpinnings of sarcopenia, elucidating the relationship between the immune system and muscle during ageing. Additionally, the review discusses new areas such as the gut-muscle axis and autophagy, which bridge immune system function and muscle health. Insights into current and potential approaches for sarcopenia management through modulation of the immune system are provided, along with suggestions for future research directions and therapeutic strategies. We aim to guide further investigation into clinical immunological biomarkers and identify indicators for sarcopenia diagnosis and potential treatment targets to combat this condition. We also aim to draw attention to the importance of considering immunomodulation in the clinical management of sarcopenia.

  View details for DOI 10.1186/s12979-024-00458-9

  View details for PubMedID 39103919

  View details for PubMedCentralID 3118623

• The Influence of an Unexpected Symbolic Gift on Postoperative Arthroplasty Patients' Press Ganey Scores. The Journal of arthroplasty Lee, J. J., Mitchell, A. R., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2024

  Abstract

  INTRODUCTION: Hospitals use Press Ganey surveys to evaluate patient satisfaction. The goal of our study was to evaluate whether surgeon-driven gifting to patients post-operatively affects Press Ganey Survey responses.METHODS: There were 1,468 patients undergoing arthroplasty at our institution who were randomized to receive a thank you gift, a small bouquet of flowers, and a note from their provider after surgery, or nothing for completing their pre-operative arthroplasty registry questionnaire. Press Ganey surveys were sent to patients who received and did not receive flowers immediately after their hospital stay and after the patients' first post-operative visit. Scores were reported as the mean score and the fraction of responses with a top-box rating. One-sided student t-tests and Fischer Exact tests were used to assess statistical significance.RESULTS: Hospital Discharge Patients who received flowers had higher Press Ganey survey scores than patients who did not receive flowers. For example, for "Physician's concerns for questions," they had higher scores (mean difference: 3.7 ± 1.6 points, P = 0.012) and a 9% higher top-box rating (P = 0.032). For "Staff attitude towards visitors," they also had higher scores (mean difference: 2.8 ± 1.3 points, P = 0.019) and a 7% higher top-box rating (P = 0.049). First Follow-up Patients who received flowers had a higher top-box rating for "Concern provider showed for questions" and "Amount of time provider spent with you" by 6% (P = 0.046) and 11% (P = 0.009), respectively. They also had higher scores for "Information provider gave about medications" (mean difference: 4.0 ± 1.6 points, P = 0.009) and 11% higher top-box rating (P = 0.006).DISCUSSION: Press Ganey Surveys were higher in orthopaedic patients who received bouquets of flowers from their arthroplasty surgeons compared to patients who did not. At follow-up, improved Press Ganey scores persisted if the patient received flowers. The gift of flowers generates patient loyalty to their surgeon.

  View details for DOI 10.1016/j.arth.2024.07.018

  View details for PubMedID 39025277

• T cells and macrophages jointly modulate osteogenesis of mesenchymal stromal cells. Journal of biomedical materials research. Part A Murayama, M., Shinohara, I., Toya, M., Susuki, Y., Lee, M. L., Young, B., Gao, Q., Chow, S. K., Goodman, S. B. 2024

  Abstract

  Approximately 5%-10% of fractures go on to delayed healing and nonunion, posing significant clinical, economic, and social challenges. Current treatment methods involving open bone harvesting and grafting are associated with considerable pain and potential morbidity at the donor site. Hence, there is growing interest in minimally invasive approaches such as bone marrow aspirate concentrate (BMAC), which contains mesenchymal stromal cells (MSCs), macrophages (Mφ), and T cells. However, the use of cultured or activated cells for treatment is not yet FDA-approved in the United States, necessitating further exploration of optimal cell types and proportions for effective bone formation. As our understanding of osteoimmunology advances, it has become apparent that factors from anti-inflammatory Mφ (M2) promote bone formation by MSCs. Additionally, M2 Mφ promote T helper 2 (Th2) cells and Treg cells, both of which enhance bone formation. In this study, we investigated the interactions among MSCs, Mφ, and T cells in bone formation and explored the potential of subsets of BMAC. Coculture experiments were conducted using primary MSCs, Mφ, and CD4+ T cells at specific ratios. Our results indicate that nonactivated T cells had no direct influence on osteogenesis by MSCs, while coculturing MSCs with Mφ and T cells at a ratio of 1:5:10 positively impacted bone formation. Furthermore, higher numbers of T cells led to increased M2 polarization and a higher proportion of Th2 cells in the early stages of coculture. These findings suggest the potential for enhancing bone formation by adjusting immune and mesenchymal cell ratios in BMAC. By understanding the interactions and effects of immune cells on bone formation, we can develop more effective strategies and protocols for treating bone defects and nonunions. Further studies are needed to investigate these interactions in vivo and explore additional factors influencing MSC-based therapies.

  View details for DOI 10.1002/jbm.a.37771

  View details for PubMedID 38963690

• The outcome of revision total hip arthroplasty for instability. The bone & joint journal Apinyankul, R., Hong, C., Hwang, K. L., Burket Koltsov, J. C., Amanatullah, D. F., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2024; 106-B (5 Supple B): 105-111

  Abstract

  Instability is a common indication for revision total hip arthroplasty (THA). However, even after the initial revision, some patients continue to have recurrent dislocation. The aim of this study was to assess the risk for recurrent dislocation after revision THA for instability.Between 2009 and 2019, 163 patients underwent revision THA for instability at Stanford University Medical Center. Of these, 33 (20.2%) required re-revision due to recurrent dislocation. Cox proportional hazard models, with death and re-revision surgery for periprosthetic infection as competing events, were used to analyze the risk factors, including the size and alignment of the components. Paired t-tests or Wilcoxon signed-rank tests were used to assess the outcome using the Veterans RAND 12 (VR-12) physical and VR-12 mental scores, the Harris Hip Score (HHS) pain and function, and the Hip disability and Osteoarthritis Outcome score for Joint Replacement (HOOS, JR).The median follow-up was 3.1 years (interquartile range 2.0 to 5.1). The one-year cumulative incidence of recurrent dislocation after revision was 8.7%, which increased to 18.8% at five years and 31.9% at ten years postoperatively. In multivariable analysis, a high American Society of Anesthesiologists (ASA) grade (hazard ratio (HR) 2.72 (95% confidence interval (CI) 1.13 to 6.60)), BMI between 25 and 30 kg/m2 (HR 4.31 (95% CI 1.52 to 12.27)), the use of specialized liners (HR 5.39 (95% CI 1.97 to 14.79) to 10.55 (95% CI 2.27 to 49.15)), lumbopelvic stiffness (HR 6.03 (95% CI 1.80 to 20.23)), and postoperative abductor weakness (HR 7.48 (95% CI 2.34 to 23.91)) were significant risk factors for recurrent dislocation. Increasing the size of the acetabular component by > 1 mm significantly decreased the risk of dislocation (HR 0.89 (95% CI 0.82 to 0.96)). The VR-12 physical and HHS (pain and function) scores improved significantly at mid term.Patients requiring revision THA for instability are at risk of recurrent dislocation. Higher ASA grades, being overweight, a previous lumbopelvic fusion, the use of specialized liners, and postoperative abductor weakness are significant risk factors.

  View details for DOI 10.1302/0301-620X.106B5.BJJ-2023-0726.R1

  View details for PubMedID 38688516

• Correction: Pius et al. Effects of Aging on Osteosynthesis at Bone-Implant Interfaces. Biomolecules 2024, 14, 52. Biomolecules Pius, A. K., Toya, M., Gao, Q., Lee, M. L., Ergul, Y. S., Chow, S. K., Goodman, S. B. 2024; 14 (3)

  Abstract

  Max L. Lee was not included as an author in the original publication [...].

  View details for DOI 10.3390/biom14030340

  View details for PubMedID 38540803

• Targeting an inflammation-amplifying cell population can attenuate osteoarthritis-associated pain. Arthritis research & therapy Pandey, A., Singla, M., Geller, A., Goodman, S. B., Bhutani, N. 2024; 26 (1): 53

  Abstract

  BACKGROUND: Understanding of pain in osteoarthritis, its genesis, and perception is still in its early stages. Identification of precise ligand-receptor pairs that transduce pain and the cells and tissues in which they reside will elucidate new therapeutic approaches for pain management. Our recent studies had identified an inflammation-amplifying (Inf-A) cell population that is expanded in human OA cartilage and is distinctive in the expression of both IL1R1 and TNF-R2 receptors and active Jnk signaling cascade.METHODS: In this study, we have tested the function of the cartilage-resident IL1R1+TNF-R2+ Inf-A cells in OA. We have identified that the IL1R1+TNF-R2+ Inf-A cells expand in aged mice as well as after anterior cruciate ligament tear upon tibia loading and OA initiation in mice. We targeted and modulated the Jnk signaling cascade in InfA through competitive inhibition of Jnk signaling in mice and human OA explants and tested the effects on joint structure and gait in mice.RESULTS: Modulation of Jnk signaling led to attenuation of inflammatory cytokines CCL2 and CCL7 without showing any structural improvements in the joint architecture. Interestingly, Jnk inhibition and lowered CCL2 and 7 are sufficient to significantly improve the gait parameters in treated PTOA mice demonstrating reduced OA-associated pain. Consistent with the mice data, treatment with JNK inhibitor did not improve human OA cartilage explants.CONCLUSION: These studies demonstrate that Inf-A, an articular-cartilage resident cell population, contributes to pain in OA via secretion of CCL2 and 7 and can be targeted via inhibition of Jnk signaling.

  View details for DOI 10.1186/s13075-024-03284-y

  View details for PubMedID 38368390

• Assessing Ability for ChatGPT to Answer Total Knee Arthroplasty-Related Questions. The Journal of arthroplasty Magruder, M. L., Rodriguez, A., Wong, C. H., Erez, O., Piuzzi, N. S., Scuderi, G. R., Slover, J., Oh, J. H., Schwarzkopf, R., Chen, A. F., Iorio, R., Goodman, S. B., Mont, M. A. 2024

  Abstract

  Artificial intelligence (AI) in the field of orthopaedics has been a topic of increasing interest and opportunity in recent years. Its applications are widespread both for physicians and patients, including use in clinical decision-making, in the operating room, and in research. In this study, we aimed to assess the quality of ChatGPT answers when asked questions related to total knee arthroplasty (TKA).ChatGPT prompts were created by turning 15 of the American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guidelines into questions. An online survey was created, which included screenshots of each prompt and answers to the 15 questions. Surgeons were asked to grade ChatGPT answers from 1 to 5 based on their characteristics: 1) Relevance; 2) Accuracy; 3) Clarity; 4) Completeness; 5) Evidence-based; and 6) Consistency. There were eleven Adult Joint Reconstruction fellowship-trained surgeons who completed the survey. Questions were subclassified based on the subject of the prompt: 1) risk factors, 2) implant/Intraoperative, and 3) pain/functional outcomes. The average and standard deviation for all answers, as well as for each subgroup, were calculated. Inter-rater reliability (IRR) was also calculated.All answer characteristics were graded as being above average (i.e., a score > 3). Relevance demonstrated the highest scores (4.43±0.77) by surgeons surveyed, and consistency demonstrated the lowest scores (3.54±1.10). ChatGPT prompts in the Risk Factors group demonstrated the best responses, while those in the Pain/Functional Outcome group demonstrated the lowest. The overall IRR was found to be 0.33 (poor reliability), with the highest IRR for relevance (0.43) and the lowest for evidence-based (0.28).ChatGPT can answer questions regarding well-established clinical guidelines in TKA with above-average accuracy but demonstrates variable reliability. This investigation is the first step in understanding large language model (LLM) AIs like ChatGPT and how well they perform in the field of arthroplasty.

  View details for DOI 10.1016/j.arth.2024.02.023

  View details for PubMedID 38364879

• Additively manufactured Ti-Ta-Cu alloys for the next-generation load-bearing implants. International journal of extreme manufacturing Bandyopadhyay, A., Mitra, I., Ciliveri, S., Avila, J. D., Dernell, W., Goodman, S. B., Bose, S. 2024; 6 (1): 015503

  Abstract

  Bacterial colonization of orthopedic implants is one of the leading causes of failure and clinical complexities for load-bearing metallic implants. Topical or systemic administration of antibiotics may not offer the most efficient defense against colonization, especially in the case of secondary infection, leading to surgical removal of implants and in some cases even limbs. In this study, laser powder bed fusion was implemented to fabricate Ti3Al2V alloy by a 1:1 weight mixture of CpTi and Ti6Al4V powders. Ti-Tantalum (Ta)-Copper (Cu) alloys were further analyzed by the addition of Ta and Cu into the Ti3Al2V custom alloy. The biological, mechanical, and tribo-biocorrosion properties of Ti3Al2V alloy were evaluated. A 10 wt.% Ta (10Ta) and 3 wt.% Cu (3Cu) were added to the Ti3Al2V alloy to enhance biocompatibility and impart inherent bacterial resistance. Additively manufactured implants were investigated for resistance against Pseudomonas aeruginosa and Staphylococcus aureus strains of bacteria for up to 48 h. A 3 wt.% Cu addition to Ti3Al2V displayed improved antibacterial efficacy, i.e. 78%-86% with respect to CpTi. Mechanical properties for Ti3Al2V-10Ta-3Cu alloy were evaluated, demonstrating excellent fatigue resistance, exceptional shear strength, and improved tribological and tribo-biocorrosion characteristics when compared to Ti6Al4V. In vivo studies using a rat distal femur model revealed improved early-stage osseointegration for alloys with 10 wt.% Ta addition compared to CpTi and Ti6Al4V. The 3 wt.% Cu-added compositions displayed biocompatibility and no adverse inflammatory response in vivo. Our results establish the Ti3Al2V-10Ta-3Cu alloy's synergistic effect on improving both in vivo biocompatibility and microbial resistance for the next generation of load-bearing metallic implants.

  View details for DOI 10.1088/2631-7990/ad07e7

  View details for PubMedID 38021398

  View details for PubMedCentralID PMC10654690

• Sex differences of NF-κB-targeted therapy for mitigating osteoporosis associated with chronic inflammation of bone. Bone & joint research Toya, M., Kushioka, J., Shen, H., Utsunomiya, T., Hirata, H., Tsubosaka, M., Gao, Q., Chow, S. K., Zhang, N., Goodman, S. B. 2024; 13 (1): 28-39

  Abstract

  Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice.We used a murine model of chronic inflammation induced by continuous intramedullary delivery of lipopolysaccharide-contaminated polyethylene particles (cPE) using an osmotic pump. Specimens were evaluated using micro-CT and histomorphometric analyses. Sex-specific osteogenic and osteoclastic differentiation potentials were also investigated in vitro, including alkaline phosphatase, Alizarin Red, tartrate-resistant acid phosphatase staining, and gene expression using reverse transcription polymerase chain reaction (RT-PCR).Local delivery of NF-κB decoy ODN in vivo increased osteogenesis in males, but not females, in the presence of chronic inflammation induced by cPE. Bone resorption activity was decreased in both sexes. In vitro osteogenic and osteoclastic differentiation assays during inflammatory conditions did not reveal differences among the groups. Receptor activator of nuclear factor kappa Β ligand (Rankl) gene expression by osteoblasts was significantly decreased only in males when treated with ODN.We demonstrated that NF-κB decoy ODN increased osteogenesis in male mice and decreased bone resorption activity in both sexes in preclinical models of chronic inflammation. NF-κB signalling could be a therapeutic target for chronic inflammatory diseases involving bone, especially in males.

  View details for DOI 10.1302/2046-3758.131.BJR-2023-0040.R3

  View details for PubMedID 38194999

• Preclinical models for studying corticosteroid-induced osteonecrosis of the femoral head JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS Tsubosaka, M., Maruyama, M., Lui, E., Kushioka, J., Toya, M., Gao, Q., Shen, H., Li, X., Chow, S., Zhang, N., Yang, Y., Goodman, S. B. 2024; 112 (1)

  View details for DOI 10.1002/jbm.b.35360

  View details for Web of Science ID 001129268300001

• Preclinical models for studying corticosteroid-induced osteonecrosis of the femoral head. Journal of biomedical materials research. Part B, Applied biomaterials Tsubosaka, M., Maruyama, M., Lui, E., Kushioka, J., Toya, M., Gao, Q., Shen, H., Li, X., Chow, S. K., Zhang, N., Yang, Y. P., Goodman, S. B. 2024; 112 (1): e35360

  Abstract

  Nontraumatic osteonecrosis of the femoral head (ONFH) is a refractory condition that commonly results in femoral head collapse and degenerative arthritis of the hip. In the early stages, surgical procedures for hip preservation, including core decompression (CD), have been developed to prevent progressive collapse of the femoral head. Optimization of bone regeneration and biological augmentation may further enhance the therapeutic efficacy of CD for ONFH. Thus, combining CD with cell-based therapy has recently been proposed. In fact, patients treated with cell-based therapy using autologous bone marrow concentrate demonstrate improved survivorship of the femoral head, compared with conventional CD alone. Preclinical research studies to investigate adjunctive therapies for CD often utilize the rabbit model of corticosteroid-induced ONFH. Mesenchymal stem cells (MSCs) are known to promote osteogenesis and angiogenesis, and decrease inflammation in bone. Local drug delivery systems have the potential to achieve targeted therapeutic effects by precisely controlling the drug release rate. Scaffolds can provide an osteoconductive structural framework to facilitate the repair of osteonecrotic bone tissue. We focused on the combination of both cell-based and scaffold-based therapies for bone tissue regeneration in ONFH. We hypothesized that combining CD and osteoconductive scaffolds would provide mechanical strength and structural cell guidance; and that combining CD and genetically modified (GM) MSCs to express relevant cytokines, chemokines, and growth factors would promote bone tissue repair. We developed GM MSCs that overexpress the anti-inflammatory, pro-reconstructive cytokines platelet-derived growth factor-BB to provide MSCs with additional benefits and investigated the efficacy of combinations of these GM MSCs and scaffolds for treatment of ONFH in skeletally mature male New Zealand white rabbits. In the future, the long-term safety, efficacy, durability, and cost-effectiveness of these and other biological and mechanical treatments must be demonstrated for the patients affected by ONFH.

  View details for DOI 10.1002/jbm.b.35360

  View details for PubMedID 38247252

• Effects of Aging on Osteosynthesis at Bone-Implant Interfaces. Biomolecules Pius, A. K., Toya, M., Gao, Q., Ergul, Y. S., Chow, S. K., Goodman, S. B. 2023; 14 (1)

  Abstract

  Joint replacement is a common surgery and is predominantly utilized for treatment of osteoarthritis in the aging population. The longevity of many of these implants depends on bony ingrowth. Here, we provide an overview of current techniques in osteogenesis (inducing bone growth onto an implant), which is affected by aging and inflammation. In this review we cover the biologic underpinnings of these processes as well as the clinical applications. Overall, aging has a significant effect at the cellular and macroscopic level that impacts osteosynthesis at bone-metal interfaces after joint arthroplasty; potential solutions include targeting prolonged inflammation, preventing microbial adhesion, and enhancing osteoinductive and osteoconductive properties.

  View details for DOI 10.3390/biom14010052

  View details for PubMedID 38254652

• The 2023 Orthopaedic Research Society's International Consensus Meeting on musculoskeletal infection: Summary from the host immunity section. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Schwarz, E. M., Archer, N. K., Atkins, G. J., Bentley, K. a., Botros, M., Cassat, J. E., Chisari, E., Coraça-Huber, D. C., Daiss, J. L., Gill, S. R., Goodman, S. B., Harro, J., Hernandez, C. J., Ivashkiv, L. B., Kates, S. L., Marques, C. N., Masters, E. A., Muthukrishnan, G., Owen, J. R., Raafat, D., Saito, M., Veis, D. J., Xie, C. 2023

  Abstract

  Musculoskeletal infections (MSKI), which are a major problem in orthopedics, occur when the pathogen eludes or overwhelms the host immune system. While effective vaccines and immunotherapies to prevent and treat MSKI should be possible, fundamental knowledge gaps in our understanding of protective, nonprotective, and pathogenic host immunity are prohibitive. We also lack critical knowledge of how host immunity is affected by the microbiome, implants, prior infection, nutrition, antibiotics, and concomitant therapies, autoimmunity, and other comorbidities. To define our current knowledge of these critical topics, a Host Immunity Section of the 2023 Orthopaedic Research Society MSKI International Consensus Meeting (ICM) proposed 78 questions. Systematic reviews were performed on 15 of these questions, upon which recommendations with level of evidence were voted on by the 72 ICM delegates, and another 12 questions were voted on with a recommendation of "Unknown" without systematic reviews. Two questions were transferred to another ICM Section, and the other 45 were tabled for future consideration due to limitations of available human resources. Here we report the results of the voting with internet access to the questions, recommendations, and rationale from the systematic reviews. Eighteen questions received a consensus vote of ≥90%, while nine recommendations failed to achieve this threshold. Commentary on why consensus was not achieved on these questions and potential ways forward are provided to stimulate specific funding mechanisms and research on these critical MSKI host defense questions.

  View details for DOI 10.1002/jor.25758

  View details for PubMedID 38102985

• Primary Total Hip Arthroplasty in Juvenile Idiopathic Arthritis: Survivorship after a Median Follow-up of 12 Years. The Journal of arthroplasty Warren, S. I., Hwang, K. L., Lee, J. J., Murrietta, A., Koltsov, J. C., Goodman, S. B. 2023

  Abstract

  Juvenile idiopathic arthritis (JIA) is a chronic inflammatory condition of childhood that frequently affects the hip. Total hip arthroplasty (THA) in JIA can be challenging due to the patient's young age, small proportion, complex anatomy, and bone loss. Outcome data is limited.We reviewed prospectively collected data in 57 JIA patients (83 hips) who underwent THA between 1986 and 2020 by a single surgeon. The median patient age at surgery was 26 years (range, 14 to 62). Reoperation-free survival was assessed via the cumulative incidence function, accounting for the competing risk of death. Relationships between patient and implant factors and survivorship were evaluated by stratification of the cumulative incidence function and Gray's tests. Wilcoxon signed rank tests were used to assess the preoperative to latest postoperative change in patient reported outcomes measures (PROMs).At a median (interquartile range) of 12 (4, 20) years follow-up, 13 (16%) patients underwent reoperation, most commonly for polyethylene wear and osteolysis (7 hips). The estimated incidence of 10-, 20-, and 30-year revision (95% confidence interval) were 11.3% (4.5, 21.6%), 18.5% (8.9, 30.9%), and 40.6% (19.4, 60.9%), respectively. There were no differences in survival based on patient age, sex, implant fixation method, polyethylene type, or thickness. All PROMs improved from preoperative to latest follow up.Primary THA is a durable and effective treatment for JIA patients with severe hip involvement and results in major improvements in pain and function. We did not identify any factors predictive of failure.

  View details for DOI 10.1016/j.arth.2023.12.021

  View details for PubMedID 38104785

• Host and Microbial Characteristics Associated with Recurrent Prosthetic Joint Infections. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Hampton, J. P., Zhou, J. Y., Kameni, F. N., Espiritu, J. R., Manasherob, R., Cheung, E., Miller, M. D., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2023

  Abstract

  Approximately 20% of patients after resection arthroplasty and antibiotic spacer placement for prosthetic joint infection develop repeat infections, requiring an additional antibiotic spacer before definitive reimplantation. The host and bacterial characteristics associated with the development of recurrent infection is poorly understood. A case-control study was conducted for 106 patients with intention to treat by two-stage revision arthroplasty for prosthetic joint infection at a single institution between 2009-2020. Infection was defined according to the 2018 Musculoskeletal Infection Society criteria. Thirty-nine cases ("recurrent-PJI") received at least two antibiotic spacers before clinical resolution of their infection, and 67 controls ("single-PJI") received a single antibiotic cement spacer prior to infection-free prosthesis reimplantation. Patient demographics, McPherson host grade, and culture results including antibiotic susceptibilities were compared. Fifty-two (78%) single-PJI and 32 (82%) recurrent-PJI patients had positive intraoperative cultures at the time of their initial spacer procedure. The odds of polymicrobial infections were 11-fold higher among recurrent-PJI patients, and the odds of significant systemic compromise (McPherson host-grade C) were more than double. Recurrent-PJI patients were significantly more likely to harbor Staphylococcus aureus. We found no differences between cases and controls in pathogen resistance to the six most tested antibiotics. Among recurrent-PJI patients, erythromycin-resistant infections were more prevalent at the final than initial spacer, despite no erythromycin exposure. Our findings suggest that McPherson host grade, polymicrobial infection, and S. aureus infection are key indicators of secondary or persistent joint infection following resection arthroplasty and antibiotic spacer placement, while bacterial resistance does not predict infection-related arthroplasty failure. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jor.25768

  View details for PubMedID 38093490

• C-C Motif Chemokine Ligand 2 Enhances Macrophage Chemotaxis, Osteogenesis, and Angiogenesis during the Inflammatory Phase of Bone Regeneration. Biomolecules Shinohara, I., Tsubosaka, M., Toya, M., Lee, M. L., Kushioka, J., Murayama, M., Gao, Q., Li, X., Zhang, N., Chow, S. K., Matsumoto, T., Kuroda, R., Goodman, S. B. 2023; 13 (11)

  Abstract

  Local cell therapy has recently gained attention for the treatment of joint diseases and fractures. Mesenchymal stem cells (MSCs) are not only involved in osteogenesis and angiogenesis, but they also have immunomodulatory functions, such as inducing macrophage migration during bone regeneration via macrophage crosstalk. C-C motif chemokine ligand 2 (CCL2), a known inflammatory mediator, is associated with the migration of macrophages during inflammation. This study examined the utility of CCL2 as a therapeutic target for local cell therapy. Using lentiviral vectors for rabbit MSCs, genetically modified CCL2 overexpressing MSCs were generated. Osteogenic differentiation assays were performed using MSCs with or without macrophages in co-culture, and cell migration assays were also performed. Additionally, co-cultures were performed with endothelial cells (ECs), and angiogenesis was evaluated using a tube formation assay. Overexpression of CCL2 did not affect bone formation under monoculture conditions but promoted chemotaxis and osteogenesis when co-cultured with macrophages. Furthermore, CCL2-overexpression promoted tube formation in co-culture with ECs. These results suggest that CCL2 induces macrophage chemotaxis and osteogenesis by promoting crosstalk between MSCs and macrophages; CCL2 also stimulates ECs to induce angiogenesis. These findings indicate that CCL2 may be a useful therapeutic target for local cell therapy in areas of bone loss.

  View details for DOI 10.3390/biom13111665

  View details for PubMedID 38002347

• Polylactide Degradation Activates Immune Cells by Metabolic Reprogramming. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Maduka, C. V., Alhaj, M., Ural, E., Habeeb, O. M., Kuhnert, M. M., Smith, K., Makela, A. V., Pope, H., Chen, S., Hix, J. M., Mallett, C. L., Chung, S., Hakun, M., Tundo, A., Zinn, K. R., Hankenson, K. D., Goodman, S. B., Narayan, R., Contag, C. H. 2023: e2304632

  Abstract

  Polylactide (PLA) is the most widely utilized biopolymer in medicine. However, chronic inflammation and excessive fibrosis resulting from its degradation remain significant obstacles to extended clinical use. Immune cell activation has been correlated to the acidity of breakdown products, yet methods to neutralize the pH have not significantly reduced adverse responses. Using a bioenergetic model, delayed cellular changes are observed that are not apparent in the short-term. Amorphous and semi-crystalline PLA degradation products, including monomeric l-lactic acid, mechanistically remodel metabolism in cells leading to a reactive immune microenvironment characterized by elevated proinflammatory cytokines. Selective inhibition of metabolic reprogramming and altered bioenergetics both reduce these undesirable high cytokine levels and stimulate anti-inflammatory signals. The results present a new biocompatibility paradigm by identifying metabolism as a target for immunomodulation to increase tolerance to biomaterials, ensuring safe clinical application of PLA-based implants for soft- and hard-tissue regeneration, and advancing nanomedicine and drug delivery.

  View details for DOI 10.1002/advs.202304632

  View details for PubMedID 37737614

• Friend or foe? Inflammation and the foreign body response to orthopedic biomaterials. Journal of biomedical materials research. Part A Gibon, E., Takakubo, Y., Zwingenberger, S., Gallo, J., Takagi, M., Goodman, S. B. 2023

  Abstract

  The use of biomaterials and implants for joint replacement, fracture fixation, spinal stabilization and other orthopedic indications has revolutionized patient care by reliably decreasing pain and improving function. These surgical procedures always invoke an acute inflammatory reaction initially, that in most cases, readily subsides. Occasionally, chronic inflammation around the implant develops and persists; this results in unremitting pain and compromises function. The etiology of chronic inflammation may be specific, such as with infection, or be unknown. The histological hallmarks of chronic inflammation include activated macrophages, fibroblasts, T cell subsets, and other cells of the innate immune system. The presence of cells of the adaptive immune system usually indicates allergic reactions to metallic haptens. A foreign body reaction is composed of activated macrophages, giant cells, fibroblasts, and other cells often distributed in a characteristic histological arrangement; this reaction is usually due to particulate debris and other byproducts from the biomaterials used in the implant. Both chronic inflammation and the foreign body response have adverse biological effects on the integration of the implant with the surrounding tissues. Strategies to mitigate chronic inflammation and the foreign body response will enhance the initial incorporation and longevity of the implant, and thereby, improve long-term pain relief and overall function for the patient. The seminal research performed in the laboratory of Dr. James Anderson and co-workers has provided an inspirational and driving force for our laboratory's work on the interactions and crosstalk among cells of the mesenchymal, immune, and vascular lineages, and orthopedic biomaterials. Dr. Anderson's delineation of the fundamental biologic processes and mechanisms underlying acute and chronic inflammation, the foreign body response, resolution, and eventual functional integration of implants in different organ systems has provided researchers with a strategic approach to the use of biomaterials to improve health in numerous clinical scenarios.

  View details for DOI 10.1002/jbm.a.37599

  View details for PubMedID 37656958

• TET1 regulates skeletal stem cell (SSC) mediated cartilage regeneration. Arthritis & rheumatology (Hoboken, N.J.) Pandey, A., Hoover, M., Singla, M., Bedi, Y., Storaci, H., Goodman, S. B., Chan, C., Bhutani, N. 2023

  Abstract

  Adult skeletal stem cells (SSC) give rise to chondrocytes, osteocytes and stromal cells as progeny have been shown to contribute to cartilage regeneration in Osteoarthritis (OA). Understanding extrinsic and intrinsic regulators of SSC fate and function can therefore identify putative candidate factors to enhance cartilage regeneration. This study explores how the DNA hydroxymethylase, TET1 regulates SSC function in OA.We investigated the differences in SSC lineage tree and differentiation potential in neonatal and adult Tet1 +/+ and Tet1-/- mice, with and without injury and upon OA induction and progression. Using RNA-seq, the transcriptomic differences between SSC and Bone, cartilage and stromal progenitor cells (BCSP) were identified in Tet1 +/+ mice and Tet1-/- mice.Loss of Tet1 skewed the SSC lineage tree by expanding the SSC pool and enhanced the chondrogenic potential of SSC and BCSP. Tet1 inhibition led to enhanced chondrogenesis in in human SSC and chondroprogenitors (CP) isolated from human cartilage. Importantly, TET1 inhibition in vivo in late stages of a mouse model of Osteoarthritis (OA) led to increased cartilage regeneration. Transcriptomic analyses of SSC and BCSP lacking Tet1 revealed pathway alterations in TGFβ signaling, melatonin degradation and cartilage development associated genes. Lastly, we report that use of hormone melatonin can dampen inflammation and improve cartilage health.While Tet1 is a broad epigenetic regulator, Melatonin can mimic the ability of TET1 inhibition to enhance the chondrogenic ability of skeletal stem cells. Melatonin administration has the potential to be an attractive stem cell based therapy for cartilage regeneration.

  View details for DOI 10.1002/art.42678

  View details for PubMedID 37610277

• Glycolytic reprogramming in macrophages and MSCs during inflammation. Frontiers in immunology Li, X., Shen, H., Zhang, M., Teissier, V., Huang, E. E., Gao, Q., Tsubosaka, M., Toya, M., Kushioka, J., Maduka, C. V., Contag, C. H., Chow, S. K., Zhang, N., Goodman, S. B. 2023; 14: 1199751

  Abstract

  Dysregulated inflammation is associated with many skeletal diseases and disorders, such as osteolysis, non-union of fractures, osteonecrosis, osteoarthritis and orthopaedic infections. We previously showed that continuous infusion of lipopolysaccharide (LPS) contaminated polyethylene particles (cPE) caused prolonged inflammation and impaired bone formation. However, the metabolic and bioenergetic processes associated with inflammation of bone are unknown. Mitochondria are highly dynamic organelles that modulate cell metabolism and orchestrate the inflammatory responses that involve both resident and recruited cells. Glycolytic reprogramming, the shift from oxidative phosphorylation (OXPHOS) to glycolysis causes inappropriate cell activation and function, resulting in dysfunctional cellular metabolism. We hypothesized that impaired immunoregulation and bone regeneration from inflammatory states are associated with glycolytic reprogramming and mitochondrial dysfunction in macrophages (Mφ) and mesenchymal stromal cells (MSCs).We used the Seahorse XF96 analyzer and real-time qPCR to study the bioenergetics of Mφ and MSCs exposed to cPE. To understand the oxygen consumption rate (OCR), we used Seahorse XF Cell Mito Stress Test Kit with Seahorse XF96 analyzer. Similarly, Seahorse XF Glycolytic Rate Assay Kit was used to detect the extracellular acidification rate (ECAR) and Seahorse XF Real-Time ATP Rate Assay kit was used to detect the real-time ATP production rates from OXPHOS and glycolysis. Real-time qPCR was performed to analyze the gene expression of key enzymes in glycolysis and mitochondrial biogenesis. We further detected the gene expression of proinflammatory cytokines in Mφ and genes related to cell differentiation in MSC during the challenge of cPE.Our results demonstrated that the oxidative phosphorylation of Mφ exposed to cPE was significantly decreased when compared with the control group. We found reduced basal, maximal and ATP-production coupled respiration rates, and decreased proton leak in Mφ during challenge with cPE. Meanwhile, Mφ showed increased basal glycolysis and proton efflux rates (PER) when exposed to cPE. The percentage (%) of PER from glycolysis was higher in Mφ exposed to cPE, indicating that the contribution of the glycolytic pathway to total extracellular acidification was elevated during the challenge of cPE. In line with the results of OCR and ECAR, we found Mφ during cPE challenge showed higher glycolytic ATP (glycoATP) production rates and lower mitochondrial ATP (mitoATP) production rates which is mainly from OXPHOS. Interestingly, MSCs showed enhanced glycolysis during challenge with cPE, but no significant changes in oxygen consumption rates (OCR). In accordance, seahorse assay of real-time ATP revealed glycoATP rates were elevated while mitoATP rates showed no significant differences in MSC during challenge with cPE. Furthermore, Mφ and MSCs exposed to cPE showed upregulated gene expression levels of glycolytic regulators and Mφ exposed to cPE expressed higher levels of pro-inflammatory cytokines.This study demonstrated the dysfunctional bioenergetic activity of bone marrow-derived Mφ and MSCs exposed to cPE, which could impair the immunoregulatory properties of cells in the bone niche. The underlying molecular defect related to disordered mitochondrial function could represent a potential therapeutic target during the resolution of inflammation.

  View details for DOI 10.3389/fimmu.2023.1199751

  View details for PubMedID 37675119

  View details for PubMedCentralID PMC10477714

• Del1 Is a Growth Factor for Skeletal Progenitor Cells in the Fracture Callus. Biomolecules Sun, Y., Boyko, T., Marecic, O., Struck, D., Mann, R. K., Andrew, T. W., Lopez, M., Tong, X., Goodman, S. B., Yang, F., Longaker, M. T., Chan, C. K., Yang, G. P. 2023; 13 (8)

  Abstract

  Failure to properly form bone or integrate surgical implants can lead to morbidity and additional surgical interventions in a significant proportion of orthopedic surgeries. While the role of skeletal stem cells (SSCs) in bone formation and repair is well-established, very little is known about the factors that regulate the downstream Bone, Cartilage, Stromal, Progenitors (BCSPs). BCSPs, as transit amplifying progenitor cells, undergo multiple mitotic divisions to expand the pool of lineage committed progenitors allowing stem cells to preserve their self-renewal and stemness. Del1 is a protein widely expressed in the skeletal system, but its deletion led to minimal phenotype changes in the uninjured mouse. In this paper, we demonstrate that Del1 is a key regulator of BCSP expansion following injury. In Del1 knockout mice, there is a significant reduction in the number of BCSPs which leads to a smaller callus and decreased bone formation compared with wildtype (WT) littermates. Del1 serves to promote BCSP proliferation and prevent apoptosis in vivo and in vitro. Moreover, exogenous Del1 promotes proliferation of aged human BCSPs. Our results highlight the potential of Del1 as a therapeutic target for improving bone formation and implant success. Del1 injections may improve the success of orthopedic surgeries and fracture healing by enhancing the proliferation and survival of BCSPs, which are crucial for generating new bone tissue during the process of bone formation and repair.

  View details for DOI 10.3390/biom13081214

  View details for PubMedID 37627279

• CCL2 promotes osteogenesis by facilitating macrophage migration during acute inflammation. Frontiers in cell and developmental biology Toya, M., Zhang, N., Tsubosaka, M., Kushioka, J., Gao, Q., Li, X., Chow, S. K., Goodman, S. B. 2023; 11: 1213641

  Abstract

  Novel minimally invasive strategies are needed to obtain robust bone healing in complex fractures and bone defects in the elderly population. Local cell therapy is one potential option for future treatment. Mesenchymal stromal cells (MSCs) are not only involved in osteogenesis but also help direct the recruitment of macrophages during bone regeneration via MSC-macrophage crosstalk. The C-C motif chemokine ligand 2 (CCL2) is an inflammatory chemokine that is associated with the migration of macrophages and MSCs during inflammation. This study investigated the use of CCL2 as a therapeutic target for local cell therapy. MSCs and macrophages were isolated from 10 to 12 week-old BALB/c male mice. Genetically modified CCL2 over-expressing MSCs were produced using murine CCL2-secreting pCDH-CMV-mCCL2-copGFP expressing lentivirus vector. Osteogenic differentiation assays were performed using MSCs with or without macrophages in co-culture. Cell migration assays were also performed. MSCs transfected with murine CCL2-secreting pCDH-CMV-mCCL2-copGFP expressing lentivirus vector showed higher levels of CCL2 secretion compared to unaltered MSCs (p < 0.05). Genetic manipulation did not affect cell proliferation. CCL2 did not affect the osteogenic ability of MSCs alone. However, acute (1 day) but not sustained (7 days) stimulation with CCL2 increased the alizarin red-positive area when MSCs were co-cultured with macrophages (p < 0.001). Both recombinant CCL2 (p < 0.05) and CCL2 released from MSCs (p < 0.05) facilitated macrophage migration. We demonstrated that acute CCL2 stimulation promoted subsequent osteogenesis in co-culture of MSCs and macrophages. Acute CCL2 stimulation potentially facilitates osteogenesis during the acute inflammatory phase of bone healing by directing local macrophage migration, fostering macrophage-MSC crosstalk, and subsequently, by activating or licensing of MSCs by macrophage pro-inflammatory cytokines. The combination of CCL2, MSCs, and macrophages could be a potential strategy for local cell therapy in compromised bone healing.

  View details for DOI 10.3389/fcell.2023.1213641

  View details for PubMedID 37457301

  View details for PubMedCentralID PMC10348816

• Purification and functional characterization of novel human skeletal stem cell lineages. Nature protocols Hoover, M. Y., Ambrosi, T. H., Steininger, H. M., Koepke, L. S., Wang, Y., Zhao, L., Murphy, M. P., Alam, A. A., Arouge, E. J., Butler, M. G., Takematsu, E., Stavitsky, S. P., Hu, S., Sahoo, D., Sinha, R., Morri, M., Neff, N., Bishop, J., Gardner, M., Goodman, S., Longaker, M., Chan, C. K. 2023

  Abstract

  Human skeletal stem cells (hSSCs) hold tremendous therapeutic potential for developing new clinical strategies to effectively combat congenital and age-related musculoskeletal disorders. Unfortunately, refined methodologies for the proper isolation of bona fide hSSCs and the development of functional assays that accurately recapitulate their physiology within the skeleton have been lacking. Bone marrow-derived mesenchymal stromal cells (BMSCs), commonly used to describe the source of precursors for osteoblasts, chondrocytes, adipocytes and stroma, have held great promise as the basis of various approaches for cell therapy. However, the reproducibility and clinical efficacy of these attempts have been obscured by the heterogeneous nature of BMSCs due to their isolation by plastic adherence techniques. To address these limitations, our group has refined the purity of individual progenitor populations that are encompassed by BMSCs by identifying defined populations of bona fide hSSCs and their downstream progenitors that strictly give rise to skeletally restricted cell lineages. Here, we describe an advanced flow cytometric approach that utilizes an extensive panel of eight cell surface markers to define hSSCs; bone, cartilage and stromal progenitors; and more differentiated unipotent subtypes, including an osteogenic subset and three chondroprogenitors. We provide detailed instructions for the FACS-based isolation of hSSCs from various tissue sources, in vitro and in vivo skeletogenic functional assays, human xenograft mouse models and single-cell RNA sequencing analysis. This application of hSSC isolation can be performed by any researcher with basic skills in biology and flow cytometry within 1-2 days. The downstream functional assays can be performed within a range of 1-2 months.

  View details for DOI 10.1038/s41596-023-00836-5

  View details for PubMedID 37316563

  View details for PubMedCentralID 6568007

• Glycolytic reprogramming underlies immune cell activation by polyethylene wear particles. Biomaterials advances Maduka, C. V., Habeeb, O. M., Kuhnert, M. M., Hakun, M., Goodman, S. B., Contag, C. H. 2023; 152: 213495

  Abstract

  Primary total joint arthroplasties (TJAs) are widely and successfully applied reconstructive procedures to treat end-stage arthritis. Nearly 50% of TJAs are now performed in young patients, posing a new challenge: performing TJAs which last a lifetime. The urgency is justified because subsequent TJAs are costlier and fraught with higher complication rates, not to mention the toll taken on patients and their families. Polyethylene particles, generated by wear at joint articulations, drive aseptic loosening by inciting insidious inflammation associated with surrounding bone loss. Down modulating polyethylene particle-induced inflammation enhances integration of implants to bone (osseointegration), preventing loosening. A promising immunomodulation strategy could leverage immune cell metabolism, however, the role of immunometabolism in polyethylene particle-induced inflammation is unknown. Our findings reveal that immune cells exposed to sterile or contaminated polyethylene particles show fundamentally altered metabolism, resulting in glycolytic reprogramming. Inhibiting glycolysis controlled inflammation, inducing a pro-regenerative phenotype that could enhance osseointegration.

  View details for DOI 10.1016/j.bioadv.2023.213495

  View details for PubMedID 37301057

• Bone regeneration in inflammation with aging and cell-based immunomodulatory therapy. Inflammation and regeneration Kushioka, J., Chow, S. K., Toya, M., Tsubosaka, M., Shen, H., Gao, Q., Li, X., Zhang, N., Goodman, S. B. 2023; 43 (1): 29

  Abstract

  Aging of the global population increases the incidence of osteoporosis and associated fragility fractures, significantly impacting patient quality of life and healthcare costs. The acute inflammatory reaction is essential to initiate healing after injury. However, aging is associated with "inflammaging", referring to the presence of systemic low-level chronic inflammation. Chronic inflammation impairs the initiation of bone regeneration in elderly patients. This review examines current knowledge of the bone regeneration process and potential immunomodulatory therapies to facilitate bone healing in inflammaging.Aged macrophages show increased sensitivity and responsiveness to inflammatory signals. While M1 macrophages are activated during the acute inflammatory response, proper resolution of the inflammatory phase involves repolarizing pro-inflammatory M1 macrophages to an anti-inflammatory M2 phenotype associated with tissue regeneration. In aging, persistent chronic inflammation resulting from the failure of M1 to M2 repolarization leads to increased osteoclast activation and decreased osteoblast formation, thus increasing bone resorption and decreasing bone formation during healing.Inflammaging can impair the ability of stem cells to support bone regeneration and contributes to the decline in bone mass and strength that occurs with aging. Therefore, modulating inflammaging is a promising approach for improving bone health in the aging population. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that may benefit bone regeneration in inflammation. Preconditioning MSCs with pro-inflammatory cytokines affects MSCs' secretory profile and osteogenic ability. MSCs cultured under hypoxic conditions show increased proliferation rates and secretion of growth factors. Resolution of inflammation via local delivery of anti-inflammatory cytokines is also a potential therapy for bone regeneration in inflammaging. Scaffolds containing anti-inflammatory cytokines, unaltered MSCs, and genetically modified MSCs can also have therapeutic potential. MSC exosomes can increase the migration of MSCs to the fracture site and enhance osteogenic differentiation and angiogenesis.In conclusion, inflammaging can impair the proper initiation of bone regeneration in the elderly. Modulating inflammaging is a promising approach for improving compromised bone healing in the aging population.

  View details for DOI 10.1186/s41232-023-00279-1

  View details for PubMedID 37231450

  View details for PubMedCentralID 2880220

• Bioenergetic Profile Of Mesenchymal Stromal Cells And Macrophages In The Presence Of An Inflammatory Stimulus In A 3D Model Teissier, V., Gao, Q., Shen, H., Li, J., Li, X., Huang, E., Kushioka, J., Toya, M., Tsubosaka, M., Hirata, H., Alizadeh, H., Maduka, C., Zhang, N., Contag, C., Yang, Y. P., Goodman, S. B. MARY ANN LIEBERT, INC. 2023

  View details for Web of Science ID 001120356800285

• Selecting a High-dose Antibiotic-laden Cement Knee Spacer. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Hollyer, I., Ivanov, D., Kappagoda, S., Lowenberg, D. W., Goodman, S. B., Amanatullah, D. F. 2023

  Abstract

  Periprosthetic infection (PJI) after total knee arthroplasty (TKA) remains a common and challenging problem for joint replacement surgeons and patients. Once the diagnosis of PJI has been made, patient goals and characteristics and the infection timeline dictate treatment. Most commonly, this involves a two-stage procedure with removal of all implants, debridement, and placement of a static or dynamic antibiotic spacer. Static spacers are commonly indicated for older, less healthy patients that would benefit from soft tissue rest after initial debridement. Mobile spacers are typically used in younger, healthier patients to improve quality of life and reduce soft tissue contractures during antibiotic spacer treatment. Spacers are highly customizable with regard to antibiotic choice, cement variety, and spacer design, each with reported advantages, drawbacks, and indications that will be covered in this article. While no spacer has yet to be demonstrated as superior to any other, the modern arthroplasty surgeon must be familiar with the available modalities to optimize treatment for each patient. Here we propose a treatment algorithm to assist surgeons in deciding on treatment for PJI after TKA. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jor.25570

  View details for PubMedID 37127938

• Sex Differences Of Nf-κB-targeted Therapy For Mitigating Chronic Inflammation In Bone Toya, M., Kushioka, J., Shen, H., Utsunomiya, T., Huang, E., Hirata, H., Tsubosaka, M., Gao, Q., Teissier, V., Li, X., Zhang, N., Goodman, S. B. MARY ANN LIEBERT, INC. 2023

  View details for Web of Science ID 001120356800181

• Arthroplasty for femoral neck fractures is at risk for under restoration of lateral femoral offset. Hip international : the journal of clinical and experimental research on hip pathology and therapy Shah, H. N., Barrett, A. A., Finlay, A. K., Arora, P., Bellino, M. J., Bishop, J. A., Gardner, M. J., Miller, M. D., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2023: 11207000231169914

  Abstract

  PURPOSE: The aim of the study was to determine the restoration of hip biomechanics through lateral offset, leg length, and acetabular component position when comparing non-arthroplasty surgeons (NAS) to elective arthroplasty surgeons (EAS).METHODS: 131 patients, with a femoral neck fracture treated with a THA by 7 EAS and 20 NAS, were retrospectively reviewed. 2 blinded observers measured leg-length discrepancy, femoral offset, and acetabular component position. Multivariate logistic regression models examined the association between the surgeon groups and restoration of lateral femoral, acetabular offset, leg length discrepancy, acetabular anteversion, acetabular position, and component size, while adjusting for surgical approach and spinal pathology.RESULTS: NAS under-restored 4.8mm of lateral femoral offset (43.9±8.7mm) after THA when compared to the uninjured side (48.7±7.1mm, p=0.044). NAS were at risk for under-restoring lateral femoral offset when compared to EAS (p=0.040). There was no association between lateral acetabular offset, leg length, acetabular position, or component size and surgeon type.CONCLUSIONS: Lateral femoral offset is at risk for under-restoration after THA for femoral neck fractures, when performed by surgeons that do not regularly perform elective THA. This indicates that lateral femoral offset is an under-appreciated contributor to hip instability when performing THA for a femoral neck fracture. Lateral femoral offset deserves as much attention and awareness as acetabular component position since a secondary analysis of our data reveal that preoperative templating and intraoperative imaging did not prevent under-restoration.

  View details for DOI 10.1177/11207000231169914

  View details for PubMedID 37128124

• Metabolic profile of mesenchymal stromal cells and macrophages in the presence of polyethylene particles in a 3D model. Stem cell research & therapy Teissier, V., Gao, Q., Shen, H., Li, J., Li, X., Huang, E. E., Kushioka, J., Toya, M., Tsubosaka, M., Hirata, H., Alizadeh, H. V., Maduka, C. V., Contag, C. H., Yang, Y. P., Zhang, N., Goodman, S. B. 2023; 14 (1): 99

  Abstract

  Continuous cross talk between MSCs and macrophages is integral to acute and chronic inflammation resulting from contaminated polyethylene particles (cPE); however, the effect of this inflammatory microenvironment on mitochondrial metabolism has not been fully elucidated. We hypothesized that (a) exposure to cPE leads to impaired mitochondrial metabolism and glycolytic reprogramming and (b) macrophages play a key role in this pathway.We cultured MSCs with/without uncommitted M0 macrophages, with/without cPE in 3-dimensional gelatin methacrylate (3D GelMA) constructs/scaffolds. We evaluated mitochondrial function (membrane potential and reactive oxygen species-ROS production), metabolic pathways for adenosine triphosphate (ATP) production (glycolysis or oxidative phosphorylation) and response to stress mechanisms. We also studied macrophage polarization toward the pro-inflammatory M1 or the anti-inflammatory M2 phenotype and the osteogenic differentiation of MSCs.Exposure to cPE impaired mitochondrial metabolism of MSCs; addition of M0 macrophages restored healthy mitochondrial function. Macrophages exposed to cPE-induced glycolytic reprogramming, but also initiated a response to this stress to restore mitochondrial biogenesis and homeostatic oxidative phosphorylation. Uncommitted M0 macrophages in coculture with MSC polarized to both M1 and M2 phenotypes. Osteogenesis was comparable among groups after 21 days.This work confirmed that cPE exposure triggers impaired mitochondrial metabolism and glycolytic reprogramming in a 3D coculture model of MSCs and macrophages and demonstrated that macrophages cocultured with MSCs undergo metabolic changes to maintain energy production and restore homeostatic metabolism.

  View details for DOI 10.1186/s13287-023-03260-4

  View details for PubMedID 37085909

  View details for PubMedCentralID PMC10122387

• Assessment of Team Dynamics and Operative Efficiency in Hip and Knee Arthroplasty. JAMA surgery Cousins, H. C., Cahan, E. M., Steere, J. T., Maloney, W. J., Goodman, S. B., Miller, M. D., Huddleston, J. I., Amanatullah, D. F. 2023

  Abstract

  Surgical team communication is a critical component of operative efficiency. The factors underlying optimal communication, including team turnover, role composition, and mutual familiarity, remain underinvestigated in the operating room.To assess staff turnover, trainee involvement, and surgeon staff preferences in terms of intraoperative efficiency.Retrospective analysis of staff characteristics and operating times for all total joint arthroplasties was performed at a tertiary academic medical center by 5 surgeons from January 1 to December 31, 2018. Data were analyzed from May 1, 2021, to February 18, 2022. The study included cases with primary total hip arthroplasties (THAs) and primary total knee arthroplasties (TKAs) comprising all primary total joint arthroplasties performed over the 1-year study interval.Intraoperative turnover among nonsurgical staff, presence of trainees, and presence of surgeon-preferred staff.Incision time, procedure time, and room time for each surgery. Multivariable regression analyses between operative duration, presence of surgeon-preferred staff, and turnover among nonsurgical personnel were conducted.A total of 641 cases, including 279 THAs (51% female; median age, 64 [IQR, 56.3-71.5] years) and 362 TKAs (66% [238] female; median age, 68 [IQR, 61.1-74.1] years) were considered. Turnover among circulating nurses was associated with a significant increase in operative duration in both THAs and TKAs, with estimated differences of 19.6 minutes (SE, 3.5; P < .001) of room time in THAs and 14.0 minutes (SE, 3.1; P < .001) of room time in TKAs. The presence of a preferred anesthesiologist or surgical technician was associated with significant decreases of 26.5 minutes (SE, 8.8; P = .003) of procedure time and 12.6 minutes (SE, 4.0; P = .002) of room time, respectively, in TKAs. The presence of a surgeon-preferred vendor was associated with a significant increase in operative duration in both THAs (26.3 minutes; SE, 7.3; P < .001) and TKAs (29.6 minutes; SE, 9.6; P = .002).This study found that turnover among operative staff is associated with procedural inefficiency. In contrast, the presence of surgeon-preferred staff may facilitate intraoperative efficiency. Administrative or technologic support of perioperative communication and team continuity may help improve operative efficiency.

  View details for DOI 10.1001/jamasurg.2023.0168

  View details for PubMedID 36947044

  View details for PubMedCentralID PMC10034665

• Improving Biocompatibility for Next Generation of Metallic Implants. Progress in materials science Bandyopadhyay, A., Mitra, I., Goodman, S. B., Kumar, M., Bose, S. 2023; 133

  Abstract

  The increasing need for joint replacement surgeries, musculoskeletal repairs, and orthodontics worldwide prompts emerging technologies to evolve with healthcare's changing landscape. Metallic orthopaedic materials have a shared application history with the aerospace industry, making them only partly efficient in the biomedical domain. However, suitability of metallic materials in bone tissue replacements and regenerative therapies remains unchallenged due to their superior mechanical properties, eventhough they are not perfectly biocompatible. Therefore, exploring ways to improve biocompatibility is the most critical step toward designing the next generation of metallic biomaterials. This review discusses methods of improving biocompatibility of metals used in biomedical devices using surface modification, bulk modification, and incorporation of biologics. Our investigation spans multiple length scales, from bulk metals to the effect of microporosities, surface nanoarchitecture, and biomolecules such as DNA incorporation for enhanced biological response in metallic materials. We examine recent technologies such as 3D printing in alloy design and storing surface charge on nanoarchitecture surfaces, metal-on-metal, and ceramic-on-metal coatings to present a coherent and comprehensive understanding of the subject. Finally, we consider the advantages and challenges of metallic biomaterials and identify future directions.

  View details for DOI 10.1016/j.pmatsci.2022.101053

  View details for PubMedID 36686623

• Abrieb bei Metall-Metall-Gleitpaarungen : Was haben wir aus den letzten Jahrzehnten gelernt? Orthopadie (Heidelberg, Germany) Knecht, C., Polakof, L., Behrens, J., Goodman, S. B. 2023

  Abstract

  Metal-on-metal (MoM) bearing hip arthroplasty saw increasing utilization and peaked in the 1990s and early 2000s. Although the linear and volumetric wear rate for aMoM bearings was lower than its polyethylene counterpart, metal ion particles were found to be approximately 10 *smaller and 500 *higher in quantity compared to polyethylene wear debris. Research into these articulations have demonstrated their relationship to the formation of lymphocyte-mediated adverse local tissue reactions. The work-up for metal particle-associated conditions (metallosis) includes athorough patient history and physical examination, blood laboratory studies for metal ion concentrations, and advanced imaging studies including magnetic resonance imaging (MRI). The treatment of metallosis and adverse local tissue reactions ranges from close serial observation to extensive debridement and full revision of arthroplasty components, when indicated.

  View details for DOI 10.1007/s00132-023-04346-w

  View details for PubMedID 36820850

• Using Microphysiological System for the Development of Treatments for Joint Inflammation and Associated Cartilage Loss-A Pilot Study. Biomolecules Makarczyk, M. J., Hines, S., Yagi, H., Li, Z. A., Aguglia, A. M., Zbikowski, J., Padget, A. M., Gao, Q., Bunnell, B. A., Goodman, S. B., Lin, H. 2023; 13 (2)

  Abstract

  Osteoarthritis (OA) is a painful and disabling joint disease affecting millions worldwide. The lack of clinically relevant models limits our ability to predict therapeutic outcomes prior to clinical trials, where most drugs fail. Therefore, there is a need for a model that accurately recapitulates the whole-joint disease nature of OA in humans. Emerging microphysiological systems provide a new opportunity. We recently established a miniature knee joint system, known as the miniJoint, in which human bone-marrow-derived mesenchymal stem cells (hBMSCs) were used to create an osteochondral complex, synovial-like fibrous tissue, and adipose tissue analogs. In this study, we explored the potential of the miniJoint in developing novel treatments for OA by testing the hypothesis that co-treatment with anti-inflammation and chondroinducing agents can suppress joint inflammation and associated cartilage degradation. Specifically, we created a "synovitis"-relevant OA model in the miniJoint by treating synovial-like tissues with interleukin-1β (IL-1β), and then a combined treatment of oligodeoxynucleotides (ODNs) suppressing the nuclear factor kappa beta (NF-κB) genetic pathway and bone morphogenic protein-7 (BMP-7) was introduced. The combined treatment with BMP-7 and ODNs reduced inflammation in the synovial-like fibrous tissue and showed an increase in glycosaminoglycan formation in the cartilage portion of the osteochondral complex. For the first time, this study demonstrated the potential of the miniJoint in developing disease-modifying OA drugs. The therapeutic efficacy of co-treatment with NF-κB ODNs and BMP-7 can be further validated in future clinical studies.

  View details for DOI 10.3390/biom13020384

  View details for PubMedID 36830751

• Complications, Implant Survivorships, and Functional Outcomes of Conversion Total Knee Arthroplasty with Prior Hardware. The Journal of arthroplasty Apinyankul, R., Hui, A. Y., Hwang, K., Segovia, N. A., Amanatullah, D. F., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2023

  Abstract

  End-stage knee osteoarthritis with retained peri-articular hardware is a frequent scenario. Conversion total knee arthroplasty (TKA) leads to excellent outcomes, but poses unique challenges. The evidence supporting retention vs. removal of hardware during TKA is controversial.Patients who underwent TKA with prior hardware between January 2009 and December 2019 were identified. A total of 148 patients underwent TKA with prior hardware. Mean follow-up was 60 months (range, 24 to 223). Univariate and multivariable analyses were used to study correlations among factors and surgical-related complications, prosthesis failures, and functional outcomes.The complication rate was 28 of 148 (18.9%). The use of a quadriceps snips in addition to a medial parapatellar arthrotomy was associated with a higher complication (Odds ratio (OR) 20.7, p < 0.05), implant failures (OR 13.9, p < 0.05), and lower Veteran Rand 12 Mental Score (VR-12 MS) (-14.8, p < 0.05). Hardware removal vs. retention and use of single vs. multiple incisions were not associated with complications or prosthesis failures. Removal of all hardware was associated with significantly higher (+7.3, p < 0.05) VR-12 MS compared to retention of all hardware.TKA with prior hardware was associated with more complications, implant failures, and lower VR-12 MS when a more constrained construct or quadriceps snip was performed. This probably reflects the level of difficulty of the procedure, rather than the surgical approach used. Hardware removal or retention was not associated with complications or implant failures; however, removal rather than retention of all prior hardware is associated with increased general health outcomes.

  View details for DOI 10.1016/j.arth.2023.01.049

  View details for PubMedID 36758842

• Creation of a Knee Joint-on-a-Chip for Modeling Joint Diseases and Testing Drugs. Journal of visualized experiments : JoVE Makarcyzk, M. J., Li, Z. A., Yu, I., Yagi, H., Zhang, X., Yocum, L., Li, E., Fritch, M. R., Gao, Q., Bunnell, B. A., Goodman, S. B., Tuan, R. S., Alexander, P. G., Lin, H. 2023

  Abstract

  The high prevalence of debilitating joint diseases like osteoarthritis (OA) poses a high socioeconomic burden. Currently, the available drugs that target joint disorders are mostly palliative. The unmet need for effective disease-modifying OA drugs (DMOADs) has been primarily caused by the absence of appropriate models for studying the disease mechanisms and testing potential DMOADs. Herein, we describe the establishment of a miniature synovial joint-mimicking microphysiological system (miniJoint) comprising adipose, fibrous, and osteochondral tissue components derived from human mesenchymal stem cells (MSCs). To obtain the three-dimensional (3D) microtissues, MSCs were encapsulated in photocrosslinkable methacrylated gelatin before or following differentiation. The cell-laden tissue constructs were then integrated into a 3D-printed bioreactor, forming the miniJoint. Separate flows of osteogenic, fibrogenic, and adipogenic media were introduced to maintain the respective tissue phenotypes. A commonly shared stream was perfused through the cartilage, synovial, and adipose tissues to enable tissue crosstalk. This flow pattern allows the induction of perturbations in one or more of the tissue components for mechanistic studies. Furthermore, potential DMOADs can be tested via either "systemic administration" through all the medium streams or "intraarticular administration" by adding the drugs to only the shared "synovial fluid"-simulating flow. Thus, the miniJoint can serve as a versatile in vitro platform for efficiently studying disease mechanisms and testing drugs in personalized medicine.

  View details for DOI 10.3791/64186

  View details for PubMedID 36779602

• Stereochemistry Determines Immune Cellular Responses to Polylactide Implants. ACS biomaterials science & engineering Maduka, C. V., Alhaj, M., Ural, E., Kuhnert, M. M., Habeeb, O. M., Schilmiller, A. L., Hankenson, K. D., Goodman, S. B., Narayan, R., Contag, C. H. 2023

  Abstract

  Repeating l- and d-chiral configurations determine polylactide (PLA) stereochemistry, which affects its thermal and physicochemical properties, including degradation profiles. Clinically, degradation of implanted PLA biomaterials promotes prolonged inflammation and excessive fibrosis, but the role of PLA stereochemistry is unclear. Additionally, although PLA of varied stereochemistries causes differential immune responses in vivo, this observation has yet to be effectively modeled in vitro. A bioenergetic model was applied to study immune cellular responses to PLA containing >99% l-lactide (PLLA), >99% d-lactide (PDLA), and a 50/50 melt-blend of PLLA and PDLA (stereocomplex PLA). Stereocomplex PLA breakdown products increased IL-1β, TNF-α, and IL-6 protein levels but not MCP-1. Expression of these proinflammatory cytokines is mechanistically driven by increases in glycolysis in primary macrophages. In contrast, PLLA and PDLA degradation products selectively increase MCP-1 protein expression. Although both oxidative phosphorylation and glycolysis are increased with PDLA, only oxidative phosphorylation is increased with PLLA. For each biomaterial, glycolytic inhibition reduces proinflammatory cytokines and markedly increases anti-inflammatory (IL-10) protein levels; differential metabolic changes in fibroblasts were observed. These findings provide mechanistic explanations for the diverse immune responses to PLA of different stereochemistries and underscore the pivotal role of immunometabolism in the biocompatibility of biomaterials applied in medicine.

  View details for DOI 10.1021/acsbiomaterials.2c01279

  View details for PubMedID 36634351

• The efficiency of genetically modified mesenchymal stromal cells combined with a functionally graded scaffold for bone regeneration in corticosteroid-induced osteonecrosis of the femoral head in rabbits. Journal of biomedical materials research. Part A Tsubosaka, M., Maruyama, M., Lui, E., Moeinzadeh, S., Huang, E. E., Kushioka, J., Hirata, H., Jain, C., Storaci, H. W., Chan, C., Toya, M., Gao, Q., Teissier, V., Shen, H., Li, X., Zhang, N., Matsumoto, T., Kuroda, R., Goodman, S. B., Yang, Y. P. 2023

  Abstract

  Core decompression (CD) with mesenchymal stromal cells (MSCs) is an effective therapy for early-stage osteonecrosis of the femoral head (ONFH). Preconditioning of MSCs, using inflammatory mediators, is widely used in immunology and various cell therapies. We developed a three-dimensional printed functionally graded scaffold (FGS), made of beta-TCP and PCL, for cell delivery at a specific location. The present study examined the efficacy of CD treatments with genetically modified (GM) MSCs over-expressing PDGF-BB (PDGF-MSCs) or GM MSCs co-over-expressing IL-4 and PDGF-BB and preconditioned for three days of exposure to lipopolysaccharide and tumor necrosis factor-alpha (IL-4-PDGF-pMSCs) using the FGS for treating steroid-induced ONFH in rabbits. We compared CD without cell-therapy, with IL-4-PDGF-pMSCs alone, and with FGS loaded with PDGF-MSCs or IL-4-PDGF-pMSCs. For the area inside the CD, the bone volume in the CD alone was higher than in both FGS groups. The IL-4-PDGF-pMSCs alone and FGS+PDGF-MSCs reduced the occurrence of empty lacunae and improved osteoclastogenesis. There was no significant difference in angiogenesis among the four groups. The combined effect of GM MSCs or pMSCs and the FGS was not superior to the effect of each alone. To establish an important adjunctive therapy for CD for early ONFH in the future, it is necessary and essential to develop an FGS that delivers biologics appropriately and provides structural and mechanical support.

  View details for DOI 10.1002/jbm.a.37495

  View details for PubMedID 36606330

• MegaPro, a clinically translatable nanoparticle for in vivo tracking of stem cell implants in pig cartilage defects. Theranostics Suryadevara, V., Hajipour, M. J., Adams, L. C., Aissaoui, N. M., Rashidi, A., Kiru, L., Theruvath, A. J., Huang, C., Maruyama, M., Tsubosaka, M., Lyons, J. K., Wu, W. E., Roudi, R., Goodman, S. B., Daldrup-Link, H. E. 2023; 13 (8): 2710-2720

  Abstract

  Rationale: Efficient labeling methods for mesenchymal stem cells (MSCs) are crucial for tracking and understanding their behavior in regenerative medicine applications, particularly in cartilage defects. MegaPro nanoparticles have emerged as a potential alternative to ferumoxytol nanoparticles for this purpose. Methods: In this study, we employed mechanoporation to develop an efficient labeling method for MSCs using MegaPro nanoparticles and compared their effectiveness with ferumoxytol nanoparticles in tracking MSCs and chondrogenic pellets. Pig MSCs were labeled with both nanoparticles using a custom-made microfluidic device, and their characteristics were analyzed using various imaging and spectroscopy techniques. The viability and differentiation capacity of labeled MSCs were also assessed. Labeled MSCs and chondrogenic pellets were implanted into pig knee joints and monitored using MRI and histological analysis. Results: MegaPro-labeled MSCs demonstrated shorter T2 relaxation times, higher iron content, and greater nanoparticle uptake compared to ferumoxytol-labeled MSCs, without significantly affecting their viability and differentiation capacity. Post-implantation, MegaPro-labeled MSCs and chondrogenic pellets displayed a strong hypointense signal on MRI with considerably shorter T2* relaxation times compared to adjacent cartilage. The hypointense signal of both MegaPro- and ferumoxytol-labeled chondrogenic pellets decreased over time. Histological evaluations showed regenerated defect areas and proteoglycan formation with no significant differences between the labeled groups. Conclusion: Our study demonstrates that mechanoporation with MegaPro nanoparticles enables efficient MSC labeling without affecting viability or differentiation. MegaPro-labeled cells show enhanced MRI tracking compared to ferumoxytol-labeled cells, emphasizing their potential in clinical stem cell therapies for cartilage defects.

  View details for DOI 10.7150/thno.82620

  View details for PubMedID 37215574

• Clinical Assessments of Fracture Healing and Basic Science Correlates: Is There Room for Convergence? Current osteoporosis reports Lopas, L. A., Shen, H., Zhang, N., Jang, Y., Tawfik, V. L., Goodman, S. B., Natoli, R. M. 2022

  Abstract

  PURPOSE OF REVIEW: The purpose of this review is to summarize the clinical and basic science methods used to assess fracture healing and propose a framework to improve the translational possibilities.RECENT FINDINGS: Mainstays of fracture healing assessment include clinical examination, various imaging modalities, and assessment of function. Pre-clinical studies have yielded insight into biomechanical progression as well as the genetic, molecular, and cellular processes of fracture healing. Efforts are emerging to identify early markers to predict impaired healing and possibly early intervention to alter these processes. Despite of the differences in clinical and preclinical research, opportunities exist to unify and improve the translational efforts between these arenas to develop and optimize our ability to assess and predict fracture healing, thereby improving the clinical care of these patients.

  View details for DOI 10.1007/s11914-022-00770-7

  View details for PubMedID 36534307

• Revision hip arthroplasty using a modular, cementless femoral stem: long-term follow-up. The Journal of arthroplasty Valtanen, R. S., Hwang, K. L., Amanatullah, D. F., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2022

  Abstract

  BACKGROUND: As the number of primary total hip arthroplasty (THA) cases increase, so does the demand for revision operations. However, long-term follow-up data for revision THA is lacking.METHODS: A retrospective review was completed of patients who underwent revision THA at a single institution between January 2002 and October 2007 using a cementless modular stem. Patient demographic, clinical, and radiographic data was collected. Preoperative and postoperative patient reported outcome (PRO) scores were compared at a minimum of fourteen-year follow-up.RESULTS: Eighty-four patients (89 hips) with a median age of 69 years (range, 28 to 88) at operation were included. Indications for revision included aseptic loosening (84.2%), infection (12.4%), and periprosthetic fracture (3.4%). Twenty-two hips sustained at least one complication: intraoperative fracture (7.9%), dislocation (6.7%), prosthetic joint infection (4.5%), deep venous thrombosis (3.4%), late periprosthetic fracture (2.2%). There were no modular junction complications. Eight patients underwent reoperations; only three involved the stem. Thirty-eight patients (45%) were deceased prior to final follow-up without known reoperations. Twenty-seven patients (32%) were lost to follow-up. Twenty-one patients (23%) were alive at minimum fourteen-year follow-up. Complete PROs were available for nineteen patients (range, 14 to 18.5 years follow-up). Significant improvement was seen in UCLA Activity, VR-12 physical, HOOS, JR., and HHS pain and function scores.CONCLUSION: Challenges of long-term follow-up include patient migration, an unwillingness to travel for re-examination, medical comorbidities, advanced age, and death. The cementless modular revision stem demonstrated long-term clinical success and remains a safe and reliable option for complex revision operations.

  View details for DOI 10.1016/j.arth.2022.12.018

  View details for PubMedID 36535440

• Experimental models to study osteoarthritis pain and develop therapeutics. Osteoarthritis and cartilage open Riewruja, K., Makarczyk, M., Alexander, P. G., Gao, Q., Goodman, S. B., Bunnell, B. A., Gold, M. S., Lin, H. 2022; 4 (4): 100306

  Abstract

  Pain is the predominant symptom of osteoarthritis (OA) that drives patients to seek medical care. Currently, there are no pharmacological treatments that can reverse or halt the progression of OA. Safe and efficacious medications for long-term management of OA pain are also unavailable. Understanding the mechanisms behind OA pain generation at onset and over time is critical for developing effective treatments. In this narrative review, we first summarize our current knowledge on the innervation of the knee joint, and then discuss the molecular mechanism(s) currently thought to underlie OA pain. In particular, we focus on the contribution of each joint component to the generation of pain. Next, the current experimental models for studying OA pain are summarized, and the methods to assess pain in rodents are presented. The potential application of emerging microphysiological systems in OA pain research is especially highlighted. Lastly, we discuss the current challenge in standardizing models and the selection of appropriate systems to address specific questions.

  View details for DOI 10.1016/j.ocarto.2022.100306

  View details for PubMedID 36474784

• The Environmental Impact of Orthopaedic Surgery. The Journal of bone and joint surgery. American volume Saleh, J. R., Mitchell, A., Kha, S. T., Outterson, R., Choi, A., Allen, L., Chang, T., Ladd, A. L., Goodman, S. B., Fox, P., Chou, L. 2022

  Abstract

  ➤: There are a growing number of opportunities within the field of orthopaedic surgery to address climate change and investigate ways to promote sustainability.➤: Orthopaedic surgeons can take a proactive role in addressing climate change and its impacts within the areas of operating-room waste, carbon emissions from transportation and implant manufacturing, anesthetic gases, and water usage.➤: Future studies are needed to further these initiatives on quantifying and decreasing environmental impact and furthering sustainable use of our resources.

  View details for DOI 10.2106/JBJS.22.00548

  View details for PubMedID 36574633

• Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration. Nature communications Andrew, T. W., Koepke, L. S., Wang, Y., Lopez, M., Steininger, H., Struck, D., Boyko, T., Ambrosi, T. H., Tong, X., Sun, Y., Gulati, G. S., Murphy, M. P., Marecic, O., Telvin, R., Schallmoser, K., Strunk, D., Seita, J., Goodman, S. B., Yang, F., Longaker, M. T., Yang, G. P., Chan, C. K. 2022; 13 (1): 6491

  Abstract

  Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell's ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.

  View details for DOI 10.1038/s41467-022-34063-5

  View details for PubMedID 36310174

• Outcome of the Wagner Cone femoral component for difficult anatomical conditions during total hip arthroplasty. International orthopaedics Lawson, K., Hwang, K. L., Montgomery, S., Amanatullah, D. F., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2022

  Abstract

  PURPOSE: Total hip arthroplasty (THA) in patients with small or unusual proximal femoral anatomy is challenging due to sizing issues, control of version, and implant fixation. The Wagner Cone is a monoblock, fluted, tapered stem with successful outcomes for these patients; however, there is limited information on subsidence, a common finding with cementless stems.METHODS: We retrospectively reviewed our cases using the modified Wagner Cone (Zimmer, Warsaw, IN) implanted over a 13-year period (2006-2019) in patients with small or abnormal proximal femoral anatomy. We performed 144 primary THAs in 114 patients using this prosthesis. Mean follow-up was 4.5±3.4years (range, 1-13years). Common reasons for implantation were hip dysplasia (52%) and osteoarthritis in patients with small femoral proportions (22%). Analysis of outcomes included assessment of stem subsidence and stability.RESULTS: Survival was 98.6% in aseptic cases; revision-free survival was 97.9%. Femoral subsidence occurred in 84 cases (58%). No subsidence progressed after 3months. Of those that subsided, the mean distance was 2.8±2.0mm. There was less subsidence in stems that stabilized prior to sixweeks (2.2±1.4mm) compared to those that continued until 12weeks (3.9±1.6, p=0.02). Harris Hip, UCLA, and WOMAC scores significantly improved from pre-operative evaluation (p<0.001*, p<0.003*, p≪0.001*); there was no difference in outcome between patients with and without subsidence (p=0.430, p=0.228, p=0.147).CONCLUSION: The modified Wagner Cone demonstrates excellent clinical outcomes in patients with challenging proximal femoral anatomy. Subsidence is minor, stops by 3months, and does not compromise clinical outcome.

  View details for DOI 10.1007/s00264-022-05608-6

  View details for PubMedID 36224431

• Relationship of Aging, Inflammation, and Skeletal Stem Cells and Their Effects on Fracture Repair. Current osteoporosis reports Goodnough, L. H., Goodman, S. B. 2022

  Abstract

  PURPOSE OF REVIEW: This review summarizes recent investigations into the cellular and molecular effects of skeletal aging on the inflammatory response and stem cell function after fracture.RECENT FINDINGS: Proper regulation of the inflammatory phase of fracture healing is essential. Aging is associated with chronic inflammation, which inhibits bone formation and promotes bone resorption. Osteogenic differentiation and anti-senescence pathways in skeletal stem cells are impaired in geriatric fractures. As the population ages, fragility fractures will continue to represent a significant clinical problem, which will require innovative clinical solutions. Skeletal stem cells in geriatric individuals demonstrate defects in anti-senescence pathways that lead to impaired osteogenic differentiation in vitro in humans. Small molecule-based therapies can partially reverse the aging phenotype. In the future, molecular- or cell-based therapies modulating either inflammatory cells or skeletal stem cells represent potential therapeutic targets to augment contemporary fracture healing interventions in osteoporotic or aging individuals.

  View details for DOI 10.1007/s11914-022-00742-x

  View details for PubMedID 36129609

• Isolated Versus Full Component Revision In Total Knee Arthroplasty For Aseptic Loosening. The Journal of arthroplasty Apinyankul, R., Hwang, K., Segovia, N. A., Amanatullah, D. F., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2022

  Abstract

  Revision of both femoral and tibial components of a total knee arthroplasty (TKA) for aseptic loosening has favorable outcomes. Revision of only one loose component with retention of others has shorter operative time and lower cost, however, implant survivorship and clinical outcomes of these different operations are unclear.Between January 2009 and December 2019, a consecutive cohort of revision TKA were reviewed. Univariate and multivariable analyses were used to study correlations among factors and surgical related complications, time to prosthesis failure, and functional outcomes (University of California Los Angeles (UCLA), Knee Society (KS) functional, Knee osteoarthritis and outcome score for joint replacement (KOOS JR), Veterans RAND 12 (VR-12) physical, and VR-12 mental).A total of 238 patients underwent revision TKA for aseptic loosening. The mean follow-up time was 61 months (range 25 to 152). Ten of the 105 patients (9.5%) who underwent full revision (both femoral and tibial components) and 18 of the 133 (13.5%) who underwent isolated revision had subsequent prosthesis failure [Hazard ratio (HR) 0.67, p = 0.343]. The factor analysis of type of revision (full or isolated revision) did not demonstrate a significant difference between groups in terms of complications, implant failures, and times to failure. Metallosis was related to early time to failure [HR 10.11, p < 0.001] and iliotibial band release was associated with more complications (Odds ratio (OR) 9.87, p = 0.027). Preoperative symptoms of instability were associated with the worst improvement in UCLA score. Higher American Society of Anesthesiologists (ASA) and higher Charlson Comorbidity Index (CCI) were related with worse VR-12 physical (-30.5, p = 0.008) and KOOS JR (-4.2, p = 0.050) scores, respectively.Isolated and full component revision TKA for aseptic loosening do not differ with respect to prosthesis failures, complications, and clinical results at 5 years. Poor ASA status, increased comorbidities, instability, and a severe bone defect are related to worse functional improvement.

  View details for DOI 10.1016/j.arth.2022.09.006

  View details for PubMedID 36099937

• The Impact of Extended Trochanteric Osteotomy with Cerclage Fixation in Revision Total Hip Arthroplasty for Prosthetic Joint Infection. The Journal of arthroplasty Whittaker, M. J., Arora, P., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2022

  Abstract

  BACKGROUND: An extended trochanteric osteotomy (ETO) is a powerful tool for femoral component revision. There is limited evidence that directly supports its use in the setting of a prosthetic joint infection (PJI). Cerclage fixation raises the theoretical concern for persistent infection.METHODS: The institutional database included 76 ETOs for revision arthroplasty between January 1, 2008 and December 31, 2019. The cohort was divided based on indication for femoral component revision: PJI versus aseptic revision. The PJI group was subdivided based on second stage exchange versus retention of initial cerclage fixation. Operative time, estimated blood loss, complications, and rate of repeat revision surgery were evaluated.RESULTS: Forty-nine patients (64%) underwent revision for PJI and 27 patients (36%) underwent aseptic revision. There was no significant difference in operative times (p = 0.082), postoperative complications (p = 0.258), or rate of repeat revision surgery (p = 0.322) between groups. Of the 49 patients in the PJI group, 40 (82%) retained cerclage fixation while 9 (18%) had cerclage exchange. Cerclage exchange did not significantly impact operative time (p = 0.758), blood loss (p = 0.498), rate of repeat revision surgery (p = 0.302), or postoperative complications (p = 0.253) including infection (p = 0.639).CONCLUSION: An ETO remains a powerful tool for femoral component removal, even in the presence of a PJI. A multi-institutional investigation would be required to validate observed trends toward better infection control with cerclage exchange. Cerclage exchange did not appear to increase operative time, blood loss, or postoperative complication rates.

  View details for DOI 10.1016/j.arth.2022.08.041

  View details for PubMedID 36067886

• Differential dynamics of bone graft transplantation and mesenchymal stem cell therapy during bone defect healing in a murine critical size defect. Journal of orthopaedic translation Huang, E. E., Zhang, N., Ganio, E. A., Shen, H., Li, X., Ueno, M., Utsunomiya, T., Maruyama, M., Gao, Q., Su, N., Yao, Z., Yang, F., Gaudilliere, B., Goodman, S. B. 2022; 36: 64-74

  Abstract

  Background: A critical size bone defect is a clinical scenario in which bone is lost or excised due to trauma, infection, tumor, or other causes, and cannot completely heal spontaneously. The most common treatment for this condition is autologous bone grafting to the defect site. However, autologous bone graft is often insufficient in quantity or quality for transplantation to these large defects. Recently, tissue engineering methods using mesenchymal stem cells (MSCs) have been proposed as an alternative treatment. However, the underlying biological principles and optimal techniques for tissue regeneration of bone using stem cell therapy have not been completely elucidated.Methods: In this study, we compare the early cellular dynamics of healing between bone graft transplantation and MSC therapy in a murine chronic femoral critical-size bone defect. We employ high-dimensional mass cytometry to provide a comprehensive view of the differences in cell composition, stem cell functionality, and immunomodulatory activity between these two treatment methods one week after transplantation.Results: We reveal distinct cell compositions among tissues from bone defect sites compared with original bone graft, show active recruitment of MSCs to the bone defect sites, and demonstrate the phenotypic diversity of macrophages and T cells in each group that may affect the clinical outcome.Conclusion: Our results provide critical data and future directions on the use of MSCs for treating critical size defects to regenerate bone.Translational Potential of this article: This study showed systematic comparisons of the cellular and immunomodulatory profiles among different interventions to improve the healing of the critical-size bone defect. The results provided potential strategies for designing robust therapeutic interventions for the unmet clinical need of treating critical-size bone defects.

  View details for DOI 10.1016/j.jot.2022.05.010

  View details for PubMedID 35979174

• A Physician Assistant Is Associated With Higher Patient Satisfaction With Outpatient Orthopedic Surgery ORTHOPEDICS Korth, M., Lu, L. Y., Finlay, A. K., Kamal, R. N., Goodman, S. B., Maloney, W. J., Amanatullah, D. F., Huddleston, J. I. 2022; 45 (5): E252-E256

  Abstract

  Patient satisfaction is increasingly used to assess the quality of care and determine physician reimbursement. Patient characteristics influence patient satisfaction, but the effect of physician practice parameters on satisfaction has not been studied in detail. Outpatient satisfaction scores from 11,059 patients who rated 24 orthopedic surgeons from a single institution were studied. Practice-related parameters were collected in a provider-reported survey. Univariate logistic regressions were used to test the associations between each provider characteristic and the likelihood of receiving a 5-star rating on a selection of 16 Press Ganey patient satisfaction questions. The presence of a physician assistant in the clinic positively affected the 5-star rating for all but 1 of the patient satisfaction questions examined, including overall satisfaction (odds ratio [OR], 1.38; 95% CI, 1.03-1.85; P=.031); the likelihood of being recommended to others (OR, 1.57; 95% CI, 1.16-2.14; P=.004); and friendliness/courtesy (OR, 1.58; 95% CI, 1.17-2.13; P=.003). However, having a fellow or nurse practitioner in the clinic, treating children, productivity (measured as total relative value units), taking trauma call, and provider distance from home were not associated with higher scores for any of the Press Ganey patient satisfaction questions. Having a physician assistant in the clinic is an actionable, practice-specific characteristic that positively affects patient satisfaction on many levels and may ultimately improve the perception of care. [Orthopedics. 2022;45(5):e252-e256.].

  View details for DOI 10.3928/01477447-20220511-04

  View details for Web of Science ID 001124810800004

  View details for PubMedID 35576483

• Therapeutic effects of MSCs, genetically modified MSCs, and NFkB-inhibitor on chronic inflammatory osteolysis in aged mice. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Kushioka, J., Toya, M., Shen, H., Hirata, H., Zhang, N., Huang, E., Tsubosaka, M., Gao, Q., Teissier, V., Li, X., Utsunomiya, T., Goodman, S. B. 2022

  Abstract

  The number of total joint replacements is increasing, especially in elderly patients, and so too are implant-related complications such as prosthesis loosening. Wear particles from the prosthesis induce a chronic inflammatory reaction and subsequent osteolysis, leading to the need for revision surgery. This study investigated the therapeutic effect of NF-kB decoy oligodeoxynucleotides (ODN), mesenchymal stem cells (MSCs), and genetically-modified NF-kB sensing interleukin-4 over-secreting MSCs (IL4-MSCs) on chronic inflammation in aged mice. The model was generated by continuous infusion of contaminated polyethylene particles into the intramedullary space of the distal femur of aged mice (15-17-month-old) for six weeks. Local delivery of ODN showed increased bone mineral density (BMD), decreased osteoclast-like cells, increased alkaline phosphatase (ALP)-positive area, and increased M2/M1 macrophage ratio. Local injection of MSCs and IL4-MSCs significantly decreased osteoclast-like cells and increased the M2/M1 ratio, with a greater trend for IL4-MSCs than MSCs. MSCs significantly increased ALP-positive area and BMD values compared to the control. The IL4-MSCs demonstrated higher values for both ALP-positive area and BMD. These findings demonstrated the therapeutic effects of ODN, MSCs, and IL4-MSCs on chronic inflammatory osteolysis in aged mice. The two MSC-based therapies were more effective than ODN in increasing the M2/M1 macrophage ratio, reducing bone resorption, and increasing bone formation. Specifically, MSCs were more effective in increasing bone formation, and IL4-MSCs were more effective in mitigating inflammation. This study suggests potential therapeutic strategies for treating wear particle-associated inflammatory osteolysis after arthroplasty in the elderly. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jor.25434

  View details for PubMedID 36031590

• Synovial joint-on-a-chip for modeling arthritis: progress, pitfalls, and potential. Trends in biotechnology Li, Z. A., Sant, S., Cho, S. K., Goodman, S. B., Bunnell, B. A., Tuan, R. S., Gold, M. S., Lin, H. 2022

  Abstract

  Disorders of the synovial joint, such as osteoarthritis (OA) and rheumatoid arthritis (RA), afflict a substantial proportion of the global population. However, current clinical management has not been focused on fully restoring the native function of joints. Organ-on-chip (OoC), also called a microphysiological system, which typically accommodates multiple human cell-derived tissues/organs under physiological culture conditions, is an emerging platform that potentially overcomes the limitations of current models in developing therapeutics. Herein, we review major steps in the generation of OoCs for studying arthritis, discuss the challenges faced when these novel platforms enter the next phase of development and application, and present the potential for OoC technology to investigate the pathogenesis of joint diseases and the development of efficacious therapies.

  View details for DOI 10.1016/j.tibtech.2022.07.011

  View details for PubMedID 35995600

• Facilitation Of Bone Defect Healing By IL-4 Over- expressing MSCs Goodman, S. B., Zhang, N., Ueno, M., Yang, F. MARY ANN LIEBERT, INC. 2022: 80-81

  View details for Web of Science ID 000848131900086

• Aberrant Expression of COX-2 and FOXG1 in Infrapatellar Fat Pad-Derived ASCs from Pre-Diabetic Donors. Cells O'Donnell, B. T., Monjure, T. A., Al-Ghadban, S., Ives, C. J., L'Ecuyer, M. P., Rhee, C., Romero-Lopez, M., Li, Z., Goodman, S. B., Lin, H., Tuan, R. S., Bunnell, B. A. 2022; 11 (15)

  Abstract

  Osteoarthritis (OA) is a degenerative joint disease resulting in limited mobility and severe disability. Type II diabetes mellitus (T2D) is a weight-independent risk factor for OA, but a link between the two diseases has not been elucidated. Adipose stem cells (ASCs) isolated from the infrapatellar fat pad (IPFP) may be a viable regenerative cell for OA treatment. This study analyzed the expression profiles of inflammatory and adipokine-related genes in IPFP-ASCs of non-diabetic (Non-T2D), pre-diabetic (Pre-T2D), and T2D donors. Pre-T2D ASCs exhibited a substantial decrease in levels of mesenchymal markers CD90 and CD105 with no change in adipogenic differentiation compared to Non-T2D and T2D IPFP-ASCs. In addition, Cyclooxygenase-2 (COX-2), Forkhead box G1 (FOXG1) expression and prostaglandin E2 (PGE2) secretion were significantly increased in Pre-T2D IPFP-ASCs upon stimulation by interleukin-1 beta (IL-1β). Interestingly, M1 macrophages exhibited a significant reduction in expression of pro-inflammatory markers TNFα and IL-6 when co-cultured with Pre-T2D IPFP-ASCs. These data suggest that the heightened systemic inflammation associated with untreated T2D may prime the IPFP-ASCs to exhibit enhanced anti-inflammatory characteristics via suppressing the IL-6/COX-2 signaling pathway. In addition, the elevated production of PGE2 by the Pre-T2D IPFP-ASCs may also suggest the contribution of pre-diabetic conditions to the onset and progression of OA.

  View details for DOI 10.3390/cells11152367

  View details for PubMedID 35954211

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial (vol 153, pg 303, 2018) JAMA SURGERY Hah, J., Mackey, S. C., Schmidt, P. 2022; 157 (6): 553

  View details for DOI 10.1001/jamasurg.2022.1392

  View details for Web of Science ID 000809213600033

• Efficacy of Periarticular Multimodal Analgesic Injection Containing High-Dose Ketorolac versus Triamcinolone in Early Postoperative Total Knee Arthroplasty: A Randomized Controlled Trial SURGICAL TECHNOLOGY INTERNATIONAL-INTERNATIONAL DEVELOPMENTS IN SURGERY AND SURGICAL RESEARCH Apinyankul, R., Lilakhunakon, K., Vechvitvarakul, M., Witayakom, W., Goodman, S. B. 2022; 40

  View details for Web of Science ID 001001091900007

• Efficacy of Periarticular Multimodal Analgesic Injection Containing High-Dose Ketorolac versus Triamcinolone in Early Postoperative Total Knee Arthroplasty: A Randomized Controlled Trial. Surgical technology international Apinyankul, R., Lilakhunakon, K., Witayakom, W., Vechvitvarakul, M., Goodman, S. B. 2022; 40

  Abstract

  INTRODUCTION: Periarticular multimodal analgesic injection associates with less postoperative (post-op) pain after total knee arthroplasty (TKA) with less opioid consumption. The combination of additives and dosage are various and controversial. Evidence of ketorolac compared to triamcinolone as an additive is limited in terms of efficacy and safety.MATERIALS AND METHODS: Fifty-six patients with unilateral TKA were randomized to receive either 60mg ketorolac or 80mg triamcinolone acetonide as cocktail additives in periarticular injection. Significant threshold was considered if the adjusted mean difference of morphine consumption was greater than 3mg at any timepoint. The primary outcomes were morphine consumptions at immediate post-op, 24 hour (h), 48h, and 72h post-op. Pain visual analogue scale (VAS), knee range of motion, straight leg raising ability, and adverse events were secondary outcomes.RESULTS: Adjusted mean differences (ketorolac-triamcinolone) in morphine consumption were -0.4, 2.5, 2.6, and 2.3mg at given timepoints without significance. No difference observed in pain VAS at rest and during motion, post-op knee extension, and straight leg raising ability. However, post-op knee flexion was significantly higher in triamcinolone group at any timepoints (mean differences 10.3, 10.6, and 9.7, respectively, p<0.05).CONCLUSIONS: Periarticular analgesic injection containing 60mg ketorolac provided similar analgesic efficacy and early functional recovery compared with 80mg triamcinolone acetonide. However, triamcinolone may benefit over ketorolac in early post-op knee flexion.

  View details for PubMedID 35453173

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial (vol 153, pg 303, 2018) JAMA SURGERY Hah, J., Mackey, S. C., Schmidt, P. 2022

  View details for DOI 10.1001/jamasurg.2017.4915

  View details for Web of Science ID 000784959200002

• Human Mesenchymal Stem Cell-Derived Miniature Joint System for Disease Modeling and Drug Testing. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Li, Z., Lin, Z., Liu, S., Yagi, H., Zhang, X., Yocum, L., Romero-Lopez, M., Rhee, C., Makarcyzk, M. J., Yu, I., Li, E. N., Fritch, M. R., Gao, Q., Goh, K. B., O'Donnell, B., Hao, T., Alexander, P. G., Mahadik, B., Fisher, J. P., Goodman, S. B., Bunnell, B. A., Tuan, R. S., Lin, H. 2022: e2105909

  Abstract

  Diseases of the knee joint such as osteoarthritis (OA) affect all joint elements. An in vitro human cell-derived microphysiologica system capable of simulating intraarticular tissue crosstalk is desirable for studying etiologies/pathogenesis of joint diseases and testing potential therapeutics. Herein, a human mesenchymal stem cell-derived miniature joint system (miniJoint) is generated, in which engineered osteochondral complex, synovial-like fibrous tissue, and adipose tissue are integrated into a microfluidics-enabled bioreactor. This novel design facilitates different tissues communicating while still maintaining their respective phenotypes. The miniJoint exhibits physiologically relevant changes when exposed to interleukin-1beta mediated inflammation, which are similar to observations in joint diseases in humans. The potential of the miniJoint in predicting in vivo efficacy of drug treatment is confirmed by testing the "therapeutic effect" of the nonsteroidal anti-inflammatory drug, naproxen, as well as four other potential disease-modifying OA drugs. The data demonstrate that the miniJoint recapitulates complex tissue interactions, thus providing a robust organ chip model for the study of joint pathology and the development of novel therapeutic interventions.

  View details for DOI 10.1002/advs.202105909

  View details for PubMedID 35436042

• A Review of Biomimetic Topographies and Their Role in Promoting Bone Formation and Osseointegration: Implications for Clinical Use. Biomimetics (Basel, Switzerland) Berger, M. B., Slosar, P., Schwartz, Z., Cohen, D. J., Goodman, S. B., Anderson, P. A., Boyan, B. D. 2022; 7 (2)

  Abstract

  The use of metallic and polymeric materials for implants has been increasing over the past decade. This trend can be attributed to a variety of factors including a significant increase in basic science research focused on implant material characteristics and how various surface modifications may stimulate osseointegration and, ultimately, fusion. There are many interbody fusion devices and dental implants commercially available; however, detailed information about their surface properties, and the effects that various materials and surface modifications may have on osteogenesis, is lacking in the literature. While the concept of bone-implant osseointegration is a relatively recent addition to the spine fusion literature, there is a comparatively large body of literature related to dental implants. The purpose of this article is to summarize the science of surface modified bone-facing implants, focusing on biomimetic material chemistry and topography of titanium implants, to promote a better understanding of how these characteristics may impact bone formation and osseointegration. This manuscript has the following aspects: highlights the role of titanium and its alloys as potent osteoconductive bioactive materials; explores the importance of biomimetic surface topography at the macro-, micro- and nano-scale; summarizes how material surface design can influence osteogenesis and immune responses in vitro; focuses on the kinds of surface modifications that play a role in the process. Biomimetic surface modifications can be varied across many clinically available biomaterials, and the literature supports the hypothesis that those biomaterial surfaces that exhibit physical properties of bone resorption pits, such as roughness and complex hierarchical structures at the submicron and nanoscale, are more effective in supporting osteoblast differentiation in vitro and osteogenesis in vivo.

  View details for DOI 10.3390/biomimetics7020046

  View details for PubMedID 35466263

• Novel Techniques and Future Perspective for Investigating Critical-Size Bone Defects. Bioengineering (Basel, Switzerland) Huang, E. E., Zhang, N., Shen, H., Li, X., Maruyama, M., Utsunomiya, T., Gao, Q., Guzman, R. A., Goodman, S. B. 2022; 9 (4)

  Abstract

  A critical-size bone defect is a challenging clinical problem in which a gap between bone ends will not heal and will become a nonunion. The current treatment is to harvest and transplant an autologous bone graft to facilitate bone bridging. To develop less invasive but equally effective treatment options, one needs to first have a comprehensive understanding of the bone healing process. Therefore, it is imperative to leverage the most advanced technologies to elucidate the fundamental concepts of the bone healing process and develop innovative therapeutic strategies to bridge the nonunion gap. In this review, we first discuss the current animal models to study critical-size bone defects. Then, we focus on four novel analytic techniques and discuss their strengths and limitations. These four technologies are mass cytometry (CyTOF) for enhanced cellular analysis, imaging mass cytometry (IMC) for enhanced tissue special imaging, single-cell RNA sequencing (scRNA-seq) for detailed transcriptome analysis, and Luminex assays for comprehensive protein secretome analysis. With this new understanding of the healing of critical-size bone defects, novel methods of diagnosis and treatment will emerge.

  View details for DOI 10.3390/bioengineering9040171

  View details for PubMedID 35447731

• EFFICACY OF PRECONDITIONED OR GENETICALLY MODIFIED IL4-SECRETING MESENCHYMAL STROMAL CELLS IN A MODEL OF STEROID-ASSOCIATED OSTEONECROSIS OF THE FEMORAL HEAD IN RABBITS Goodman, S., Maruyama, M., Moeinzadeh, S., Guzman, R., Takagi, M., Yang, Y. MARY ANN LIEBERT, INC. 2022: S30

  View details for Web of Science ID 000821187300099

• AN INNERVATED SYNOVIUM-CARTILAGE CHIP FOR MODELING JOINT INFLAMMATION AND ASSOCIATED PAIN Li, Z., Makarcyzk, M. J., Moy, J. K., Yu, I., Liu, F., Gao, Q., Cho, S., Weber, D. J., Bunnell, B. A., Goodman, S. B., Gold, M. S., Lin, H. MARY ANN LIEBERT, INC. 2022: S505

  View details for Web of Science ID 000821187302237

• Treatment of Critical Size Femoral Bone Defects with Biomimetic Hybrid Scaffolds of 3D Plotted Calcium Phosphate Cement and Mineralized Collagen Matrix. International journal of molecular sciences Culla, A. C., Vater, C., Tian, X., Bolte, J., Ahlfeld, T., Bretschneider, H., Pape, A., Goodman, S. B., Gelinsky, M., Zwingenberger, S. 2022; 23 (6)

  Abstract

  To treat critical-size bone defects, composite materials and tissue-engineered bone grafts play important roles in bone repair materials. The purpose of this study was to investigate the bone regenerative potential of hybrid scaffolds consisting of macroporous calcium phosphate cement (CPC) and microporous mineralized collagen matrix (MCM). Hybrid scaffolds were synthetized by 3D plotting CPC and then filling with MCM (MCM-CPC group) and implanted into a 5 mm critical size femoral defect in rats. Defects left empty (control group) as well as defects treated with scaffolds made of CPC only (CPC group) and MCM only (MCM group) served as controls. Eight weeks after surgery, micro-computed tomography scans and histological analysis were performed to analyze the newly formed bone, the degree of defect healing and the activity of osteoclasts. Mechanical stability was tested by 3-point-bending of the explanted femora. Compared with the other groups, more newly formed bone was found within MCM-CPC scaffolds. The new bone tissue had a clamp-like structure which was fully connected to the hybrid scaffolds and thereby enhanced the biomechanical strength. Together, the biomimetic hybrid MCM-CPC scaffolds enhanced bone defect healing by improved osseointegration and their differentiated degradation provides spatial effects in the process of critical-bone defect healing.

  View details for DOI 10.3390/ijms23063400

  View details for PubMedID 35328820

• Ageing attenuates bone healing by mesenchymal stem cellsin a microribbon hydrogelwith a murine long bone critical-size defect model. Immunity & ageing : I & A Hirata, H., Zhang, N., Ueno, M., Barati, D., Kushioka, J., Shen, H., Tsubosaka, M., Toya, M., Lin, T., Huang, E., Yao, Z., Wu, J. Y., Zwingenberger, S., Yang, F., Goodman, S. B. 2022; 19 (1): 14

  Abstract

  BACKGROUND: Despite the high incidence of fractures and pseudoarthrosis in the aged population, a potential role for the use of mesenchymal stem cells (MSCs) in the treatment of bone defects in elderly patients has not been elucidated. Inflammation and the innate immune system, including macrophages, play crucial roles in the differentiation and activation of MSCs. We have developed lentivirus-transduced interleukin 4 (IL4) over-expressing MSCs (IL4-MSCs) to polarize macrophages to an M2 phenotype to promote bone healing in an established young murine critical size bone defect model. In the current study, we explore the potential of IL4-MSCs in aged mice.METHODS: A 2mm femoral diaphyseal bone defect was created and fixed with an external fixation device in 15- to 17-month-old male and female BALB/c mice. Microribbon (RB) scaffolds (Sc) with or without encapsulation of MSCs were implanted in the defect sites. Accordingly, the mice were divided into three treatment groups: Sc-only, Sc+MSCs, and Sc+IL4-MSCs. Mice were euthanized six weeks after the surgery; subsequently, MicroCT (CT), histochemical and immunohistochemical analyses were performed.RESULTS: CT analysis revealed that bone formation was markedly enhanced in the IL4-MSC group. Compared with the Sc-only, the amount of new bone increased in the Sc+MSCs and Sc+IL4-MSC groups. However, no bridging of bone was observed in all groups. H&E staining showed fibrous tissue within the defect in all groups. Alkaline phosphatase (ALP) staining was increased in the Sc+IL4-MSC group. The Sc+IL4-MSCs group showed a decrease in the number of M1 macrophages and an increase in the number of M2 macrophages, with a significant increase in the M2/M1 ratio.DISCUSSION: IL4 promotes macrophage polarization to an M2 phenotype, facilitating osteogenesis and vasculogenesis. The addition of IL4-MSCs in the RB scaffold polarized macrophages to an M2 phenotype and increased bone formation; however, complete bone bridging was not observed in any specimens. These results suggest that IL4-MSCs are insufficient to heal a critical size bone defect in aged mice, as opposed to younger animals. Additional therapeutic strategies are needed in this challenging clinical scenario.

  View details for DOI 10.1186/s12979-022-00272-1

  View details for PubMedID 35279175

• The 2021 Association Research Circulation Osseous Classification for Early-Stage Osteonecrosis of the Femoral Head-CT Based Study. The Journal of arthroplasty Koo, K., Mont, M. A., Cui, Q., Hines, J., Yoon, B., Novicoff, W., Lee, Y. J., Cheng, E. Y., Drescher, W., Hernigou, P., Kim, S., Sugano, N., Zhao, D., Ha, Y., Goodman, S. B., Sakai, T., Jones, L. C., Lee, M. S., Yamamoto, T., Lee, Y., Kang, Y., Burgess, J., Chen, D., Quinlan, N., Xu, J. Z., Park, J., Kim, H. 2022

  Abstract

  BACKGROUND: The Association Research Circulation Osseous (ARCO) developed a novel classification for early-stage (pre-collapse) osteonecrosis of the femoral head (ONFH). We hypothesized that the novel classification is more reliable and valid when compared to previous three classifications: Steinberg, modified Kerboul, and Japanese Investigation Committee classifications.METHODS: In the novel classification, necrotic lesions were classified into three types: Type 1 is a small lesion, where the lateral necrotic margin is medial to the femoral head apex; Type 2 is a medium-sized lesion, with the lateral necrotic margin being between the femoral head apex and the lateral acetabular edge; and Type 3 is a large lesion, which extends outside the lateral acetabular edge. In a derivation cohort of 40 early-stage osteonecrotic hips based on CT imaging, reliabilities were evaluated using kappa coefficients, and validities to predict future femoral head collapse by chi square tests and receiver operating characteristic curve analyses. The predictability for future collapse was also evaluated in a validation cohort of 104 early-stage ONFH.RESULTS: In the derivation cohort, inter-observer reliability (k=0.545) and intra-observer agreement (63 to 100%) of the novel method were higher than the other three classifications. The novel classification system was best able to predict future collapse (p<0.05) and had the best discrimination between non-progressors and progressors in both the derivation cohort (AUC =0.692[0.522-0.863], p<0.05) and the validation cohort (AUC=0.742[0.644-0.841], p=2.46x10-5).CONCLUSIONS: This novel classification is a highly reliable and valid method of those examined. ARCO recommends using this method as a unified classification for early-stage ONFH.

  View details for DOI 10.1016/j.arth.2022.02.009

  View details for PubMedID 35151809

• Macrophage Polarization and the Osteoimmunology of Periprosthetic Osteolysis. Current osteoporosis reports Goodman, S. B., Gibon, E., Gallo, J., Takagi, M. 2022

  Abstract

  PURPOSE OF REVIEW: Joint replacement has revolutionized the treatment of end-stage arthritis. We highlight the key role of macrophages in the innate immune system in helping to ensure that the prosthesis-host interface remains biologically robust.RECENT FINDINGS: Osteoimmunology is of great interest to researchers investigating the fundamental biological and material aspects of joint replacement. Constant communication between cells of the monocyte/macrophage/osteoclast lineage and the mesenchymal stem cell-osteoblast lineage determines whether a durable prosthesis-implant interface is obtained, or whether implant loosening occurs. Tissue and circulating monocytes/macrophages provide local surveillance of stimuli such as the presence of byproducts of wear and can quickly polarize to pro- and anti-inflammatory phenotypes to re-establish tissue homeostasis. When these mechanisms fail, periprosthetic osteolysis results in progressive bone loss and painful failure of mechanical fixation. Immune modulation of the periprosthetic microenvironment is a potential intervention to facilitate long-term durability of prosthetic interfaces.

  View details for DOI 10.1007/s11914-022-00720-3

  View details for PubMedID 35133558

• Staging Bilateral Total Knee Arthroplasties Reduces Alignment Outliers. The Journal of arthroplasty Follett, M. A., Arora, P., Maloney, W. J., Goodman, S. B., Huddleston, J. I., Amanatullah, D. F. 1800

  Abstract

  PURPOSE: Patients frequently present with bilateral symptomatic knee osteoarthritis and request simultaneous total knee arthroplasties (TKAs). Technical differences between simultaneous and staged TKAs could affect clinical and radiographic outcomes. We hypothesized staged TKAs would have fewer mechanical alignment outliers than simultaneous TKAs.METHODS: We reviewed 87 simultaneous and 72 staged TKAs with at least 2 years of follow-up. Radiographic assessment was done using standing long leg and lateral radiographs of the knee. Coronal and sagittal measurements were performed by four blinded observers on two separate occasions with an intra-observer agreement of 0.95 and inter-observer of 0.92.RESULTS: The first simultaneous knee had no difference in the probability of establishing the mechanical axis outside 3° of neutral (45%) compared to the first staged knee (54%, p = 0.337). However, the second simultaneous knee (49%) was more likely to establish the axis outside mechanical neutral compared to the second staged knee (28%; Odds Ratio (OR): 2.54, Confidence Interval (CI): 1.31 - 4.94, p = 0.006). There was an increased risk of deep venous thrombosis with staged TKA (OR: 2.96, CI: 1.28 - 6.84, p = 0.011), but other perioperative complication rates were not significantly different. There were no clinically significant differences in range of motion or Knee Society Score.CONCLUSION: There is a significantly increased risk of establishing the second knee outside mechanical neutral during a simultaneous TKA compared to staged bilateral TKAs, possibly related to a number of surgeon- and system-related factors. The impact on clinical outcomes and radiographic loosening may become significant in long-term follow up.

  View details for DOI 10.1016/j.arth.2022.01.003

  View details for PubMedID 35017050

• Sex differences in the therapeutic effect of unaltered versus NFkappaB sensing IL-4 over-expressing mesenchymal stromal cells in a murine model of chronic inflammatory bone loss. Frontiers in bioengineering and biotechnology Shen, H., Kushioka, J., Toya, M., Utsunomiya, T., Hirata, H., Huang, E. E., Tsubosaka, M., Gao, Q., Li, X., Teissier, V., Zhang, N., Goodman, S. B. 2022; 10: 962114

  Abstract

  Wear particles from joint arthroplasties induce chronic inflammation associated with prolonged upregulation of nuclear factor kappa-B (NF-kappaB) signaling in macrophages and osteoclasts, which leads to osteolysis and implant loosening. Mesenchymal stromal cell (MSC)-based therapy showed great potential for immunomodulation and mitigation of osteolysis in vivo, especially in the chronic phase of inflammation. We previously generated genetically modified MSCs that secrete the anti-inflammatory cytokine interleukin 4 (IL-4) in response to NF-kappaB activation (NFkappaB-IL-4 MSCs). However, whether the impact of sexual difference in the internal environment can alter the therapeutic effects of IL-4 over-secreting MSCs that simultaneously mitigate prolonged inflammation and enhance bone formation remains unknown. This study investigated the therapeutic effects of unaltered MSCs versus NFkappaB-IL-4 MSCs in mitigating chronic inflammation and enhancing bone formation in male and female mice. The murine model was established by continuous infusion of polyethylene particles contaminated with lipopolysaccharide (cPE) into the medullary cavity of the distal femur for 6 weeks to induce chronic inflammation. Unaltered MSCs or NFkappaB-IL-4 MSCs were infused into the femoral intramedullary cavity in sex-matched groups beginning 3 weeks after primary surgery. Femurs were harvested at 6 weeks, and bone marrow density was measured with micro-computational tomography. Numbers of osteoclast-like cells, osteoblasts, and macrophages were evaluated with histochemical and immunofluorescence staining. cPE infusion resulted in severe bone loss at the surgery site, increased tartrate-resistant acid phosphatase positive osteoclasts and M1 pro-inflammatory macrophages, and decreased alkaline phosphatase expression. MSC-based therapy effectively decreased local bone loss and polarized M1 macrophages into an M2 anti-inflammatory phenotype. In females, unaltered MSCs demonstrated a larger impact in enhancing the osteogenesis, but they demonstrated similar anti-inflammatory effects compared to NFkappaB-IL-4 MSCs. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments in a sexually dimorphic manner, which could be an efficacious therapeutic strategy for treatment of periprosthetic osteolysis in both genders.

  View details for DOI 10.3389/fbioe.2022.962114

  View details for PubMedID 36046680

• Dental Pulp-Derived Stem Cells Are as Effective as Bone Marrow-Derived Mesenchymal Stromal Cells When Implanted into a Murine Critical Bone Defect. Current stem cell research & therapy Vater, C., Männel, C., Bolte, J., Tian, X., Goodman, S. B., Zwingenberger, S. 2022

  Abstract

  Background While bone marrow-derived mesenchymal stromal cells (BM-MSCs) have been used for many years in bone tissue engineering applications, the procedure still has drawbacks such as painful collection methods and damage to the donor site. Dental pulp-derived stem cells (DPSCs) are readily accessible, occur in high amounts and show a high proliferation and differentiation capability. Therefore, DPSCs may be a promising alternative for BM-MSCs to repair bone defects. Objective The aim of this study was to investigate the bone regenerative potential of DPSCs in comparison to BM-MSCs in vitro and in vivo. Methods In vitro investigations included analysis of cell doubling time as well as proliferation and osteogenic differentiation. For the in vivo study 36 male NMRI nude mice were randomized into 3 groups: 1) control (cell-free mineralized collagen matrix (MCM) scaffold), 2) MCM + DPSCs and 3) MCM + BM-MSCs. Critical size 2 mm bone defects were created at the right femur of each mouse and stabilized by an external fixator. After 6 weeks animals were euthanized and microcomputed tomography scans (µCT) and histological analyses were performed. Results In vitro DPSCs showed a 2-fold lower population doubling time and a 9-fold higher increase in proliferation when seeded onto MCM scaffolds as compared to BM-MSCs, but DPSCs showed a significantly lower osteogenic capability than BM-MSCs. In vivo, the healing of the critical bone defect in NMRI nude mice was comparable among all groups. Conclusions Pre-seeding of MCM scaffolds with DPSCs and BM-MSCs did not enhance bone defect healing.

  .

  View details for DOI 10.2174/1574888X17666220215100732

  View details for PubMedID 35168511

• Notching of the Neck After Acetabular Constraint Necessitating Femoral Component Revision. Arthroplasty today Bonano, J. C., Bala, A., Chen, F., Amanatullah, D. F., Goodman, S. B. 2021; 12: 32-35

  Abstract

  A 75-year-old woman who had previously undergone a left revision total hip arthroplasty with the use of a constrained acetabular liner presented with recurrent dislocation of the hip. Intraoperatively, there was metallic staining of the hip capsule and significant notching of the femoral neck, consistent with impingement of the intact locking ring, necessitating stem revision. Constrained acetabular liners have high failure rates due to intraprosthetic impingement, but to our knowledge, failure due to notching of the femoral component and metallosis from repeated impingement has not been described. Surgeons should be aware of this potential mode of failure.

  View details for DOI 10.1016/j.artd.2021.09.007

  View details for PubMedID 34761091

• Macrophages Modulate the Function of MSC- and iPSC-Derived Fibroblasts in the Presence of Polyethylene Particles. International journal of molecular sciences Gao, Q., Li, Z., Rhee, C., Xiang, S., Maruyama, M., Huang, E. E., Yao, Z., Bunnell, B. A., Tuan, R. S., Lin, H., Gold, M. S., Goodman, S. B. 2021; 22 (23)

  Abstract

  Fibroblasts in the synovial membrane secrete molecules essential to forming the extracellular matrix (ECM) and supporting joint homeostasis. While evidence suggests that fibroblasts contribute to the response to joint injury, the outcomes appear to be patient-specific and dependent on interactions between resident immune cells, particularly macrophages (Mphis). On the other hand, the response of Mphis to injury depends on their functional phenotype. The goal of these studies was to further explore these issues in an in vitro 3D microtissue model that simulates a pathophysiological disease-specific microenvironment. Two sources of fibroblasts were used to assess patient-specific influences: mesenchymal stem cell (MSC)- and induced pluripotent stem cell (iPSC)-derived fibroblasts. These were co-cultured with either M1 or M2 Mphis, and the cultures were challenged with polyethylene particles coated with lipopolysaccharide (cPE) to model wear debris generated from total joint arthroplasties. Our results indicated that the fibroblast response to cPE was dependent on the source of the fibroblasts and the presence of M1 or M2 Mphis: the fibroblast response as measured by gene expression changes was amplified by the presence of M2 Mphis. These results demonstrate that the immune system modulates the function of fibroblasts; furthermore, different sources of differentiated fibroblasts may lead to divergent results. Overall, our research suggests that M2 Mphis may be a critical target for the clinical treatment of cPE induced fibrosis.

  View details for DOI 10.3390/ijms222312837

  View details for PubMedID 34884641

• Effect on Osteogenic Differentiation of Genetically Modified IL4 or PDGF-BB Over-Expressing and IL4-PDGF-BB Co-Over-Expressing Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro. Bioengineering (Basel, Switzerland) Tsubosaka, M., Maruyama, M., Huang, E. E., Zhang, N., Utsunomiya, T., Gao, Q., Shen, H., Li, X., Kushioka, J., Hirata, H., Yao, Z., Yang, Y. P., Goodman, S. B. 2021; 8 (11)

  Abstract

  The use of genetically modified (GM) mesenchymal stromal cells (MSCs) and preconditioned MSCs (pMSCs) may provide further opportunities to improve the outcome of core decompression (CD) for the treatment of early-stage osteonecrosis of the femoral head (ONFH). GM interleukin-4 (IL4) over-expressing MSCs (IL4-MSCs), platelet-derived growth factor (PDGF)-BB over-expressing MSCs (PDGF-BB-MSCs), and IL4-PDGF-BB co-over-expressing MSCs (IL4-PDGF-BB-MSCs) and their respective pMSCs were used in this in vitro study and compared with respect to cell proliferation and osteogenic differentiation. IL4-MSCs, PDGF-BB-MSCs, IL4-PDGF-BB-MSCs, and each pMSC treatment significantly increased cell proliferation compared to the MSC group alone. The percentage of Alizarin red-stained area in the IL4-MSC and IL4-pMSC groups was significantly lower than in the MSC group. However, the percentage of Alizarin red-stained area in the PDGF-BB-MSC group was significantly higher than in the MSC and PDGF-BB-pMSC groups. The percentage of Alizarin red-stained area in the IL4-PDGF-BB-pMSC was significantly higher than in the IL4-PDGF-BB-MSC group. There were no significant differences in the percentage of Alizarin red-stained area between the MSC and IL4-PDGF-BB-pMSC groups. The use of PDGF-BB-MSCs or IL4-PDGF-BB-pMSCs increased cell proliferation. Furthermore, PDGF-BB-MSCs promoted osteogenic differentiation. The addition of GM MSCs may provide a useful supplementary cell-based therapy to CD for treatment of ONFH.

  View details for DOI 10.3390/bioengineering8110165

  View details for PubMedID 34821731

• Applying Deep Learning to Quantify Empty Lacunae in Histologic Sections of Osteonecrosis of the Femoral Head. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Lui, E., Maruyama, M., Guzman, R. A., Moeinzadeh, S., Pan, C., Pius, A. K., Quig, M. S., Wong, L. E., Goodman, S. B., Yang, Y. P. 2021

  Abstract

  Osteonecrosis of the femoral head (ONFH) is a disease in which inadequate blood supply to the subchondral bone causes death of cells in the bone marrow. Decalcified histology and assessment of the percentage of empty lacunae are used to quantify the severity of ONFH. However, the current clinical practice of manually counting cells is a tedious and inefficient process. We utilized the power of artificial intelligence by training an established deep convolutional neural network framework, Faster-RCNN, to automatically classify and quantify osteocytes (healthy and pyknotic) and empty lacunae in 135 histology images. The adjusted correlation coefficient between the trained cell classifier and the ground truth was R = 0.98. The methods detailed in this work significantly reduced the manual effort of cell counting in ONFH histological samples and can be translated to other fields of image quantification. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jor.25201

  View details for PubMedID 34676596

• CORR Insights: Highly Crosslinked Polyethylene Liners Have Negligible Wear at 10 Years: A Radiostereometric Analysis Study. Clinical orthopaedics and related research Goodman, S. B. 2021

  View details for DOI 10.1097/CORR.0000000000002014

  View details for PubMedID 34652288

• The effect of genetically modified platelet-derived growth factor-BB over-expressing mesenchymal stromal cells during core decompression for steroid-associated osteonecrosis of the femoral head in rabbits. Stem cell research & therapy Guzman, R. A., Maruyama, M., Moeinzadeh, S., Lui, E., Zhang, N., Storaci, H. W., Tam, K., Huang, E. E., Utsunomiya, T., Rhee, C., Gao, Q., Yao, Z., Yang, Y. P., Goodman, S. B. 2021; 12 (1): 503

  Abstract

  BACKGROUND: Approximately one third of patients undergoing core decompression (CD) for early-stage osteonecrosis of the femoral head (ONFH) experience progression of the disease, and subsequently require total hip arthroplasty (THA). Thus, identifying adjunctive treatments to optimize bone regeneration during CD is an unmet clinical need. Platelet-derived growth factor (PDGF)-BB plays a central role in cell growth and differentiation. The aim of this study was to characterize mesenchymal stromal cells (MSCs) that were genetically modified to overexpress PDGF-BB (PDGF-BB-MSCs) in vitro and evaluate their therapeutic effect when injected into the bone tunnel at the time of CD in an in vivo rabbit model of steroid-associated ONFH.METHODS: In vitro studies: Rabbit MSCs were transduced with a lentivirus vector carrying the human PDGF-BB gene under the control of either the cytomegalovirus (CMV) or phosphoglycerate (PGK) promoter. The proliferative rate, PDGF-BB expression level, and osteogenic differentiation capacity of unmodified MSCs, CMV-PDGF-BB-MSCs, and PGK-PDGF-BB-MSCs were assessed. In vivo studies: Twenty-four male New Zealand white rabbits received an intramuscular (IM) injection of methylprednisolone 20mg/kg. Four weeks later, the rabbits were divided into four groups: the CD group, the hydrogel [HG, (a collagen-alginate mixture)] group, the MSC group, and the PGK-PDGF-BB-MSC group. Eight weeks later, the rabbits were sacrificed, their femurs were harvested, and microCT, mechanical testing, and histological analyses were performed.RESULTS: In vitro studies: PGK-PDGF-BB-MSCs proliferated more rapidly than unmodified MSCs (P<0.001) and CMV-PDGF-BB-MSCs (P<0.05) at days 3 and 7. CMV-PDGF-BB-MSCs demonstrated greater PDGF-BB expression than PGK-PDGF-BB-MSCs (P<0.01). However, PGK-PDGF-BB-MSCs exhibited greater alkaline phosphatase staining at 14days (P<0.01), and osteogenic differentiation at 28days (P=0.07) than CMV-PDGF-BB-MSCs. In vivo: The PGK-PDGF-BB-MSC group had a trend towards greater bone mineral density (BMD) than the CD group (P=0.074). The PGK-PDGF-BB-MSC group demonstrated significantly lower numbers of empty lacunae (P<0.001), greater osteoclast density (P<0.01), and greater angiogenesis (P<0.01) than the other treatment groups.CONCLUSION: The use of PGK-PDGF-BB-MSCs as an adjunctive treatment with CD may reduce progression of osteonecrosis and enhance bone regeneration and angiogenesis in the treatment of early-stage ONFH.

  View details for DOI 10.1186/s13287-021-02572-7

  View details for PubMedID 34526115

• Nonoperative and Operative Bone and Cartilage Regeneration and Orthopaedic Biologics of the Hip: An Orthoregeneration Network (ON) Foundation Hip Review. Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association Hernigou, J., Verdonk, P., Homma, Y., Verdonk, R., Goodman, S. B., Hernigou, P. 2021

  Abstract

  Orthoregeneration is defined as a solution for orthopedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and optimally, provide an environment for tissue regeneration. Options include: drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electro-magnetic stimuli. The goal of regenerative medicine is to enhance the healing of tissue after musculoskeletal injuries as both isolated treatment and adjunct to surgical management, using novel therapies to improve recovery and outcomes. Various orthopaedic biologics (orthobiologics) have been investigated for the treatment of pathology involving the hip, including osteonecrosis (aseptic necrosis) involving bone marrow, bone, and cartilage, and chondral injuries involving articular cartilage, synovium, and bone marrow. Promising and established treatment modalities for osteonecrosis include non-weight bearing; pharmacological treatments including low molecular-weight heparin, prostacyclin, statins, bisphophonates, and denosumab, a receptor activator of nuclear factor-kB ligand (RANKL) inhibitor; extracorporeal shock wave therapy; pulsed electromagnetic fields; core decompression surgery; cellular therapies including bone marrow aspirate (BMA) comprising mesenchymal stromal cells (MSCs aka mesenchymal stem cells) and bone marrow autologous concentrate (BMAC), with or without expanded or cultured cells, and possible addition of bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF); and arterial perfusion of MSCs which may be combined with addition of carriers or scaffolds including autologous MSCs cultured with beta-tricalcium phosphate (b-TCP) ceramics associated with a free vascularized fibula. Promising and established treatment modalities for chondral lesions include autologous platelet-rich plasma (PRP); hyaluronic acid (HA); MSCs (in expanded or non-expanded form) derived from bone marrow or other sources such as fat, placenta, umbilical cord blood, synovial membrane, and cartilage; microfrature or microfracture augmented with membrane containing MSCs, collagen, HA, or synthetic polymer; mosaicpasty; one-stage autologous cartilage translation (ACT) or two-stage ACT using three-dimensional spheroids; and autologous cartilage grafting; chondral flap repair, or flap fixation with fibrin glue. Hip pain is catastrophic in young patients, and promising therapies offer an alternative to premature arthroplasty. This may address both physical and psychological components of pain the goal is to avoid or postpone an artificial joint. LEVEL OF EVIDENCE: Level V, expert opinion. Hip Orthoregeneration for Osteonecrosis and Chondral Defects.

  View details for DOI 10.1016/j.arthro.2021.08.032

  View details for PubMedID 34506886

• Single-cell Profiling of B and T Cell Repertoire and Gene Expression in the RA Synovium Reveals Tissue Specific Clonal Expansion Meednu, N., Wagner, A., Dunlap, G., Zhang, F., Jonsson, A., Wei, K., Utz, P., Robinson, W., Maecker, H., James, J., Guthridge, J., Bridges, S., Bykerk, V., Donlin, L., Goodman, S., DiCarlo, E., Ritchlin, C., Tabechian, D., Lederer, J., Gravallese, E., McGeachy, M., Firestein, G., Boyle, D., Gregersen, P., Horowitz, D., Perlman, H., Mandelin, A., Bathon, J., Geraldino--Pardilla, L., Hughes, L., Holers, V., Deane, K., Moreland, L., Filer, A., Pitzalis, C., Forbess, L., Ben-Artzi, A., Salomon-Escoto, K., Raychaudhuri, S., Brenner, M., Rao, D., McDavid, A., Anolik, J., Medicines, A. WILEY. 2021: 951-952

  View details for Web of Science ID 000744545201215

• Use of Total Hip Arthroplasty in Patients Under 21 Years Old: A US Population Analysis Gibbons, J., Kahlenberg, C., Jannat--Khah, D., Goodman, S., Mandl, L., Sculco, P., Goodman, S., Figgie, M., Mehta, B. WILEY. 2021: 3396-3399

  View details for Web of Science ID 000744545206192

• Use of Total Hip Arthroplasty in Patients Under 21 Years Old: A US Population Analysis. The Journal of arthroplasty Kahlenberg, C. A., Gibbons, J. A., Jannat-Khah, D. P., Goodman, S. M., Mandl, L. A., Sculco, P. K., Goodman, S. B., Figgie, M. P., Mehta, B. Y. 2021

  Abstract

  BACKGROUND: The purpose of this study is to evaluate trends in the use of total hip arthroplasty (THA) in the United States in patients under 21 years of age. Specifically, we examined the frequency of THA in this patient population over the past 2 decades, the epidemiologic characteristics of patients under 21 who underwent THA, and the characteristics of the hospitals where these procedures were performed.METHODS: We retrospectively reviewed the Kids' Inpatient Database, an inpatient US national weighted sample of hospital admissions in patients under 21 from approximately 4200 hospitals in 46 states. We queried the database using Current Procedural Terminology codes for elective and non-elective primary THA for the years 2000-2016. We utilized the International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes to determine primary diagnoses.RESULTS: The weighted total number of THAs performed in patients under 21 in the Kids' Inpatient Database increased from 347 in 2000 to 551 in 2016. The most common diagnoses were osteonecrosis, osteoarthritis, and inflammatory arthritis. The frequency of THA for osteonecrosis increased from 24% in 2000 to 38% in 2016, while the frequency of THA for inflammatory arthritis decreased from 27% in 2000 to 4% in2016.CONCLUSION: The number of THAs in patients under 21 in the United States has increased over the past 2 decades and these procedures are increasingly performed in urban teaching hospitals. The decrease in THA for inflammatory arthritis in this population likely reflects improvements in medical management during the study period.

  View details for DOI 10.1016/j.arth.2021.08.004

  View details for PubMedID 34456091

• The efficacy of lapine preconditioned or genetically modified IL4 over-expressing bone marrow-derived mesenchymal stromal cells in corticosteroid-associated osteonecrosis of the femoral head in rabbits. Biomaterials Maruyama, M., Moeinzadeh, S., Guzman, R. A., Zhang, N., Storaci, H. W., Utsunomiya, T., Lui, E., Huang, E. E., Rhee, C., Gao, Q., Yao, Z., Takagi, M., Yang, Y. P., Goodman, S. B. 2021; 275: 120972

  Abstract

  Cell-based therapy for augmentation of core decompression (CD) using mesenchymal stromal cells (MSCs) is a promising treatment for early stage osteonecrosis of the femoral head (ONFH). Recently, the therapeutic potential for immunomodulation of osteogenesis using preconditioned (with pro-inflammatory cytokines) MSCs (pMSCs), or by the timely resolution of inflammation using MSCs that over-express anti-inflammatory cytokines has been described. Here, pMSCs exposed to tumor necrosis factor-alpha and lipopolysaccharide for 3 days accelerated osteogenic differentiation in vitro. Furthermore, injection of pMSCs encapsulated with injectable hydrogels into the bone tunnel facilitated angiogenesis and osteogenesis in the femoral head in vivo, using rabbit bone marrow-derived MSCs and a model of corticosteroid-associated ONFH in rabbits. In contrast, in vitro and in vivo studies demonstrated that genetically-modified MSCs that over-express IL4 (IL4-MSCs), established by using a lentiviral vector carrying the rabbit IL4 gene under the cytomegalovirus promoter, accelerated proliferation of MSCs and decreased the percentage of empty lacunae in the femoral head. Therefore, adjunctive cell-based therapy of CD using pMSCs and IL4-MSCs may hold promise to heal osteonecrotic lesions in the early stage ONFH. These interventions must be applied in a temporally sensitive fashion, without interfering with the mandatory acute inflammatory phase of bone healing.

  View details for DOI 10.1016/j.biomaterials.2021.120972

  View details for PubMedID 34186237

• Osteonecrosis of the Femoral Head: an Updated Review of ARCO on Pathogenesis, Staging and Treatment. Journal of Korean medical science Hines, J. T., Jo, W. L., Cui, Q., Mont, M. A., Koo, K. H., Cheng, E. Y., Goodman, S. B., Ha, Y. C., Hernigou, P., Jones, L. C., Kim, S. Y., Sakai, T., Sugano, N., Yamamoto, T., Lee, M. S., Zhao, D., Drescher, W., Kim, T. Y., Lee, Y. K., Yoon, B. H., Baek, S. H., Ando, W., Kim, H. S., Park, J. W. 2021; 36 (24): e177

  Abstract

  Non-traumatic osteonecrosis of the femoral head (ONFH) usually affects adults younger than 50 years and frequently leads to femoral head collapse and subsequent arthritis of the hip. It is becoming more prevalent along with increasing use of corticosteroids for the adjuvant therapy of leukemia and other myelogenous diseases as well as management of organ transplantation. This review updated knowledge on the pathogenesis, classification criteria, staging system, and treatment of ONFH.

  View details for DOI 10.3346/jkms.2021.36.e177

  View details for PubMedID 34155839

• Diagnosis and Treatment of Femoral Head Osteonecrosis: A Protocol for Development of Evidence-Based Clinical Practice Guidelines SURGICAL TECHNOLOGY INTERNATIONAL-INTERNATIONAL DEVELOPMENTS IN SURGERY AND SURGICAL RESEARCH Cheng, E. Y., Cui, Q., Goodman, S. B., Ando, W., Baek, S., Bakker, C., Drescher, W., Hernigou, P., Jones, L. C., Kim, H., Kim, S., Kim, T., Ha, Y., Koo, K., Lee, M. S., Mont, M. A., Reichert, I., Sakai, T., Salem, H. S., Sierra, R. J., Stronach, B., Sugano, N., Yamamoto, T., Yoon, B., Zhao, D. 2021; 38

  View details for Web of Science ID 000661729000045

• Concentrated autologous bone marrow aspirate is not "stem cell" therapy in the repair of nonunions and bone defects. Biomaterials and biosystems Goodman, S. B., Zwingenberger, S. 2021; 2: 100017

  Abstract

  Autogenous bone grafting is the gold standard for replacing large bone defects. Due to limitations in the quantity and quality of harvested bone from the iliac crest, and the potential associated morbidity, the technique of cell grafting has been developed. Autogenous bone marrow aspirate is concentrated (so called BMAC) and delivered locally to the intended site with minimally invasive techniques. However, there are only about 1 in 30,000 Colony Forming Unit-Fibroblast (CFU-F) progenitor cells in unconcentrated iliac crest aspirate. Current techniques for cell concentration only increase these numbers by about 5-fold. Thus, BMAC is not equivalent to "stem cell therapy".

  View details for DOI 10.1016/j.bbiosy.2021.100017

  View details for PubMedID 36824655

  View details for PubMedCentralID PMC9934489

• Diagnosis and Treatment of Femoral Head Osteonecrosis: A Protocol for Development of Evidence-Based Clinical Practice Guidelines. Surgical technology international Cheng, E. Y., Cui, Q., Goodman, S. B., Ando, W., Baek, S., Bakker, C., Drescher, W., Hernigou, P., Jones, L. C., Kim, H., Kim, S., Kim, T., Ha, Y., Koo, K., Lee, M. S., Mont, M. A., Reichert, I., Sakai, T., Salem, H. S., Sierra, R. J., Stronach, B., Sugano, N., Yamamoto, T., Yoon, B., Zhao, D. 2021; 38

  Abstract

  INTRODUCTION: There are many treatment options for patients who have osteonecrosis of the femoral head (ONFH) and management strategies vary widely both among and within individual countries. Although many researchers have attempted to elucidate the optimal strategies for managing this disease, the lack of large-scale randomized control trials and the lack of agreement on disease staging have curtailed the development of clear-cut guidelines.MATERIALS AND METHODS: The Association Research Circulation Osseous (ARCO) group sought to address three questions for the management of patients who have ONFH: 1) What imaging studies are most sensitive and specific for the diagnostic evaluation of patients who have ONFH?; 2) What is the best treatment strategy for preventing disease progression in patients who have pre-collapse lesions?; and 3) What is the best treatment strategy for patients who have post-collapse disease? The Patient, Intervention, Comparison, and Outcome (PICO) format was used to formulate the search strategy for each research question. A systematic review will be performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. ARCO participants have been allocated to three groups, each representing one of the PICO questions. After qualitative and quantitative analysis of the data extracted from studies pertaining to each of the three research questions, a set of evidence-based clinical practice guidelines will be proposed for the management of patients who have ONFH.DISCUSSION: It is not always clear which treatment method is optimal for the management of ONFH. Thus, many surgeons have developed and performed various procedures based on patient-specific factors. As there is no consensus on the optimal treatment for various stages of disease, it was clear that developing evidence-based clinical practice guidelines would provide more structure and uniformity to management of these patients. Therefore, the results of this systematic review will lead to the development guidelines that may improve patient-care strategies and result in better outcomes for patients who have ONFH.

  View details for PubMedID 34043232

• Perioperative Statin Use May Reduce Postoperative Arrhythmia Rates After Total Joint Arthroplasty. The Journal of arthroplasty Bonano, J. C., Aratani, A. K., Sambare, T. D., Goodman, S. B., Huddleston, J. I., Maloney, W. J., Burk, D. R., Aaronson, A. J., Finlay, A. K., Amanatullah, D. F. 2021

  Abstract

  BACKGROUND: Postoperative arrhythmias are associated with increased morbidity and mortality in total joint arthroplasty (TJA) patients. HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) decrease atrial fibrillation rates after cardiac surgery, but it is unknown if this cardioprotective effect is maintained after joint reconstruction surgery. We aim to determine if perioperative statin use decreases the incidence of 90-day postoperative arrhythmias in patients undergoing primary TJA.METHODS: We performed a single-center retrospective cohort study in which 231 primary TJA patients (109 hips, 122 knees) received simvastatin 80 mg daily during their hospitalization as part of a single surgeon's standard postoperative protocol. This cohort was matched to 966 primary TJA patients (387 hips and 579 knees) that did not receive simvastatin. New-onset arrhythmias (bradycardia, atrial fibrillation/tachycardia/flutter, paroxysmal supraventricular tachycardia, and ventricular tachycardia) and complications (readmissions, thromboembolism, infection, and dislocation) within 90 days of the procedure were documented. Categorical variables were analyzed using Fisher's exact tests. Our study was powered to detect a 3% difference in arrhythmia rates.RESULTS: Within 90 days postoperatively, arrhythmias occurred in 1 patient (0.4%) who received a perioperative statin, 39 patients (4.0%) who did not receive statins (P= .003), and 24 patients (4.2%) who were on outpatient statins (P= .005). This is 10-fold reduction in the relative risk of developing a postoperative arrhythmia within 90 days of arthroplasty and an absolute risk reduction of 3.6%.CONCLUSION: Treating as few as 28 patients with perioperative simvastatin prevents one new cardiac arrhythmia within 90 days in statin-naive patients undergoing TJA.

  View details for DOI 10.1016/j.arth.2021.05.022

  View details for PubMedID 34127349

• Effect of porosity of a functionally-graded scaffold for the treatment of corticosteroid-associated osteonecrosis of the femoral head in rabbits. Journal of orthopaedic translation Maruyama, M., Pan, C., Moeinzadeh, S., Storaci, H. W., Guzman, R. A., Lui, E., Ueno, M., Utsunomiya, T., Zhang, N., Rhee, C., Yao, Z., Takagi, M., Goodman, S. B., Yang, Y. P. 2021; 28: 90–99

  Abstract

  Background/Objective: Core decompression (CD) with scaffold and cell-based therapies is a promising strategy for providing both mechanical support and regeneration of the osteonecrotic area for early stage osteonecrosis of the femoral head (ONFH). We designed a new 3D printed porous functionally-graded scaffold (FGS) with a central channel to facilitate delivery of transplanted cells in a hydrogel to the osteonecrotic area. However, the optimal porous structural design for the FGS for the engineering of bone in ONFH has not been elucidated. The aim of this study was to fabricate and evaluate two different porous structures (30% or 60% porosity) of the FGSs in corticosteroid-associated ONFH in rabbits.Methods: Two different FGSs with 30% or 60% porosity containing a 1-mm central channel were 3D printed using polycaprolactone and beta-tricalcium phosphate. The FGS was 3-mm diameter and 32-mm length and was composed of three segments: 1-mm in length for the non-porous proximal segment, 22-mm in length for the porous (30% versus 60%) middle segment, and 9-mm in length for the 15% porous distal segment. Eighteen male New Zealand White rabbits were given a single dose of 20​mg/kg methylprednisolone acetate intramuscularly. Four weeks later, rabbits were divided into three groups: the CD group, the 30% porosity FGS group, and the 60% porosity FGS group. In the CD group, a 3-mm diameter drill hole was created into the left femoral head. In the FGS groups, a 30% or 60% porosity implant was inserted into the bone tunnel. Eight weeks postoperatively, femurs were harvested and microCT, mechanical, and histological analyses were performed.Results: The actual porosity and pore size of the middle segments were 26.4%​±​2.3% and 699​±​56​mum in the 30% porosity FGS, and 56.0%​±​4.5% and 999​±​71​mum in the 60% porosity FGS, respectively using microCT analysis. Bone ingrowth ratio in the 30% porosity FGS group was 73.9%​±​15.8%, which was significantly higher than 39.5%​±​13.0% in the CD group on microCT (p​<​0.05). Bone ingrowth ratio in the 60% porosity FGS group (61.3%​±​30.1%) showed no significant differences compared to the other two groups. The stiffness at the bone tunnel site in the 30% porosity FGS group was 582.4​±​192.3​N/mm3, which was significantly higher than 338.7​±​164.6​N/mm3 in the 60% porosity FGS group during push-out testing (p​<​0.05). Hematoxylin and eosin staining exhibited thick and mature trabecular bone around the porous FGS in the 30% porosity FGS group, whereas thinner, more immature trabecular bone was seen around the porous FGS in the 60% porosity FGS group.Conclusion: These findings indicate that the 30% porosity FGS may enhance bone regeneration and have superior biomechanical properties in the bone tunnel after CD in ONFH, compared to the 60% porosity FGS.Translation potential statement: The translational potential of this article: This FGS implant holds promise for improving outcomes of CD for early stage ONFH.

  View details for DOI 10.1016/j.jot.2021.01.002

  View details for PubMedID 33816112

• The Effects of Macrophage Phenotype on Osteogenic Differentiation of MSCs in the Presence of Polyethylene Particles BIOMEDICINES Gao, Q., Rhee, C., Maruyama, M., Li, Z., Shen, H., Zhang, N., Utsunomiya, T., Huang, E., Yao, Z., Bunnell, B. A., Lin, H., Tuan, R. S., Goodman, S. B. 2021; 9 (5)

  View details for DOI 10.3390/biomedicines9050499

  View details for Web of Science ID 000653426000001

• MSC-BASED THERAPY MITIGATES WEAR PARTICLE-INDUCED CHRONIC INFLAMMATION AND ASSOCIATED BONE LOSS IN MICE Zhang, N., Utsunomiya, T., Lin, T. D., Kohno, Y., Ueno, M., Maruyama, M., Huang, E., Rhee, C., Gao, Q., Guzman, R. A., Yao, Z., Goodman, S. B. ELSEVIER SCI LTD. 2021: S34-S35

  View details for Web of Science ID 000650965900029

• The Effects of Macrophage Phenotype on Osteogenic Differentiation of MSCs in the Presence of Polyethylene Particles. Biomedicines Gao, Q., Rhee, C., Maruyama, M., Li, Z., Shen, H., Zhang, N., Utsunomiya, T., Huang, E. E., Yao, Z., Bunnell, B. A., Lin, H., Tuan, R. S., Goodman, S. B. 2021; 9 (5)

  Abstract

  Wear debris generated from the bearing surfaces of joint arthroplasties leads to acute and chronic inflammation, which is strongly associated with implant failure. Macrophages derived from monocytes recruited to the local tissues have a significant impact on bone healing and regeneration. Macrophages can adopt various functional phenotypes. While M1 macrophages are pro-inflammatory, M2 macrophages express factors important for tissue repair. Here, we established a 3D co-culture system to investigate how the immune system influences the osteogenic differentiation of mesenchymal stem cells (MSCs) in the presence of micron-sized particles. This system allowed for the simulation of an inflammatory reaction via the addition of Lipopolysaccharide-contaminated polyethylene particles (cPE) and the characterization of bone formation using micro-CT and gene and protein expression. Co-cultures of MSCs with M2 macrophages in the presence of cPE in a 3D environment resulted in the increased expression of osteogenic markers, suggesting facilitation of bone formation. In this model, the upregulation of M2 macrophage expression of immune-associated genes and cytokines contributes to enhanced bone formation by MSCs. This study elucidates how the immune system modulates bone healing in response to an inflammatory stimulus using a unique 3D culture system.

  View details for DOI 10.3390/biomedicines9050499

  View details for PubMedID 34062822

• 3D Printing in alloy design to improve biocompatibility in metallic implants. Materials today (Kidlington, England) Mitra, I., Bose, S., Dernell, W. S., Dasgupta, N., Eckstrand, C., Herrick, J., Yaszemski, M. J., Goodman, S. B., Bandyopadhyay, A. 2021; 45: 20-34

  Abstract

  3D Printing (3DP) or additive manufacturing (AM) enables parts with complex shapes, design flexibility, and customization opportunities for defect specific patient-matched implants. 3DP or AM also offers a design platform that can be used to innovate novel alloys for application-specific compositional modifications. In medical applications, the biological response from a host tissue depends on a biomaterial's structural and compositional properties in the physiological environment. Application of 3DP can pave the way towards manufacturing innovative metallic implants, combining structural variations at different length scales and tailored compositions designed for specific biological responses. This study shows how 3DP can be used to design metallic alloys for orthopedic and dental applications with improved biocompatibility using in vitro and in vivo studies. Titanium (Ti) and its alloys are used extensively in biomedical devices due to excellent fatigue and corrosion resistance and good strength to weight ratio. However, Ti alloys' in vivo biological response is poor due to its bioinert surface. Different coatings and surface modification techniques are currently being used to improve the biocompatibility of Ti implants. We focused our efforts on improving Ti's biocompatibility via a combination of tantalum (Ta) chemistry in Ti, the addition of designed micro-porosity, and nanoscale surface modification to enhance both in vitro cytocompatibility and early stage in vivo osseointegration, which was studied in rat and rabbit distal femur models.

  View details for DOI 10.1016/j.mattod.2020.11.021

  View details for PubMedID 34220288

  View details for PubMedCentralID PMC8248902

• 3D Printing in alloy design to improve biocompatibility in metallic implants MATERIALS TODAY Mitra, I., Bose, S., Dernell, W. S., Dasgupta, N., Eckstrand, C., Herrick, J., Yaszemski, M. J., Goodman, S. B., Bandyopadhyay, A. 2021; 45: 20-34

  View details for DOI 10.1016/j.mattod.2020.11.021

  View details for Web of Science ID 000659957300007

• Cell spheroids are as effective as single cells suspensions in the treatment of critical-sized bone defects. BMC musculoskeletal disorders Findeisen, L., Bolte, J., Vater, C., Petzold, C., Quade, M., Muller, L., Goodman, S. B., Zwingenberger, S. 2021; 22 (1): 401

  Abstract

  BACKGROUND: Due to their multilineage potential and high proliferation rate, mesenchymal stem cells (MSC) indicate a sufficient alternative in regenerative medicine. In comparison to the commonly used 2-dimensional culturing method, culturing cells as spheroids stimulates the cell-cell communication and mimics the in vivo milieu more accurately, resulting in an enhanced regenerative potential. To investigate the osteoregenerative potential of MSC spheroids in comparison to MSC suspensions, cell-loaded fibrin gels were implanted into murine critical-sized femoral bone defects.METHODS: After harvesting MSCs from 4 healthy human donors and preculturing and immobilizing them in fibrin gel, cells were implanted into 2mm murine femoral defects and stabilized with an external fixator. Therefore, 26 14- to 15-week-old nu/nu NOD/SCID nude mice were randomized into 2 groups (MSC spheroids, MSC suspensions) and observed for 6weeks. Subsequently, micro-computed tomography scans were performed to analyze regenerated bone volume and bone mineral density. Additionally, histological analysis, evaluating the number of osteoblasts, osteoclasts and vessels at the defect side, were performed. Statistical analyzation was performed by using the Student's t-test and, the Mann-Whitney test. The level of significance was set at p=0.05.RESULTS: muCT-analysis revealed a significantly higher bone mineral density of the MSC spheroid group compared to the MSC suspension group. However, regenerated bone volume of the defect side was comparable between both groups. Furthermore, no significant differences in histological analysis between both groups could be shown.CONCLUSION: Our in vivo results reveal that the osteo-regenerative potential of MSC spheroids is similar to MSC suspensions.

  View details for DOI 10.1186/s12891-021-04264-y

  View details for PubMedID 33941144

• Articulating vs Static Spacers for Native Knee Infection in the Setting of Degenerative Joint Disease. Arthroplasty today Hooper, J., Arora, P., Kappagoda, S., Huddleston, J. I., Goodman, S. B., Amanatullah, D. F. 2021; 8: 138–44

  Abstract

  Background: Patients with advanced knee arthritis who develop a septic joint are not adequately treated with irrigation and debridement and intravenous antibiotics because of antecedent cartilage damage. The gold standard treatment has been a 2-stage approach. The periprosthetic joint infection literature has demonstrated the superiority of articulating spacers, and metal-on-poly (MOP) spacers are being used with increasing frequency. The purpose of this study was to compare the postoperative outcomes of patients with infected, arthritic knees treated by a 2-stage approach to those of patients who received single-stage treatment with a MOP spacer.Methods: Sixteen patients with native knee septic arthritis treated with an antibiotic spacer between 1998 and 2019 were reviewed. Demographic data, clinical data, knee motion, Knee Society score, Timed-Up-and-Go, and pain scores were collected. Survivorship of final implants was compared.Results: Six of 16 knees (38%) received single-stage treatment, and 10 received 2-stage treatment (62%). Five of 6 MOP spacers (83%) were retained at a mean follow-up of 3 ± 1.2 years. Nine of 10 (90%) receiving static spacers had subsequent reconstruction, with 9 (100%) surviving at mean follow-up of 7 ± 3.2 years. The patients who received MOP spacers trended toward greater terminal flexion, higher Knee Society score, and faster Timed-Up-and-Go at final follow-up.Conclusion: Infection in a native, arthritic knee may be effectively treated using single-stage MOP spacer. Postoperative outcomes of single-stage MOP spacers compare favorably to staged static spacers and with those undergoing revision surgery for other indications. Longer follow-up is needed to evaluate durability of MOP spacers.

  View details for DOI 10.1016/j.artd.2021.01.009

  View details for PubMedID 33748374

• Suppression of NF-kappaB-induced chronic inflammation mitigates inflammatory osteolysis in the murine continuous polyethylene particle infusion model. Journal of biomedical materials research. Part A Utsunomiya, T., Zhang, N., Lin, T., Kohno, Y., Ueno, M., Maruyama, M., Huang, E., Rhee, C., Yao, Z., Goodman, S. B. 2021

  Abstract

  Wear particle-associated bone loss (periprosthetic osteolysis) constrains the longevity of total joint arthroplasty (TJA). Wear particles induce a prolonged upregulation of nuclear factor kappa B (NF-kappaB) signaling in macrophages and osteoclasts. Synthetic double-stranded oligodeoxynucleotides (ODNs) can prevent the binding of NF-kappaB to the promoter regions of targeted genes and inhibit genetic activation. We tested the hypothesis that polyethylene-particle induced chronic inflammatory bone loss could be suppressed by local delivery of NF-kappaB decoy ODNs in murine in vivo model. Polyethylene particles were continuously infused into the medullary cavity of the distal femur for 6weeks to induce chronic inflammation, and micro-computational tomography and immunohistochemical analysis were performed. Particle-induced chronic inflammation resulted in lower BMD values, an increase in osteoclastogenesis and nuclear translocation of p65, a prolonged M1 pro-inflammatory macrophage phenotype, and a decrease of M2 anti-inflammatory macrophage phenotype. Delayed timing of local infusion of NF-kappaB decoy ODN for the last 3weeks reversed polyethylene-particle associated chronic inflammatory bone loss and facilitated bone healing. This study demonstrated that polyethylene-particle associated chronic inflammatory osteolysis can be effectively modulated via interference with the NF-kappaB pathway; this minimally invasive intervention could potentially be an efficacious therapeutic strategy for periprosthetic osteolysis after TJA.

  View details for DOI 10.1002/jbm.a.37175

  View details for PubMedID 33779115

• A dysfunctional TRPV4-GSK3beta pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity. Nature biomedical engineering Agarwal, P., Lee, H., Smeriglio, P., Grandi, F., Goodman, S., Chaudhuri, O., Bhutani, N. 2021

  Abstract

  Changes in the composition and viscoelasticity of the extracellular matrix in load-bearing cartilage influence the proliferation and phenotypes of chondrocytes, and are associated with osteoarthritis. However, the underlying molecular mechanism is unknown. Here we show that the viscoelasticity of alginate hydrogels regulates cellular volume in healthy human chondrocytes (with faster stress relaxation allowing cell expansion and slower stress relaxation restricting it) but not in osteoarthritic chondrocytes. Cellular volume regulation in healthy chondrocytes was associated with changes in anabolic gene expression, in the secretion of multiple pro-inflammatory cytokines, and in the modulation of intracellular calcium regulated by the ion-channel protein transient receptor potential cation channel subfamily V member 4 (TRPV4), which controls the phosphorylation of glycogen synthase kinase 3beta (GSK3beta), an enzyme with pleiotropic effects in osteoarthritis. A dysfunctional TRPV4-GSK3beta pathway in osteoarthritic chondrocytes rendered the cells unable to respond to environmental changes in viscoelasticity. Our findings suggest strategies for restoring chondrocyte homeostasis in osteoarthritis.

  View details for DOI 10.1038/s41551-021-00691-3

  View details for PubMedID 33707778

• Modified Kerboul Angle Predicts Outcome of Core Decompression With or Without Additional Cell Therapy. The Journal of arthroplasty Boontanapibul, K., Huddleston, J. I., Amanatullah, D. F., Maloney, W. J., Goodman, S. B. 2021

  Abstract

  BACKGROUND: Core decompression is the most common procedure for early-stage osteonecrosis of the femoral head (ONFH). This study investigated outcomes of core decompression with/without bone marrow aspirate concentrate (BMAC), based on the Kerboul combined necrotic angles using magnetic resonance imaging.METHODS: We reviewed 66 patients (83 hips) with early ONFH, Association Research Circulation Osseous stages I-IIIa, who underwent core decompression alone (26 patients, 33 hips) or in combination with BMAC (40 patients, 50 hips). Survival rate and progressive collapse were analyzed using the Kaplan-Meier method, and conversion to total hip arthroplasty (THA) was evaluated. Subgroup analyses based on the modified Kerboul angle were performed: grade I (<200°), grade II (200°-249°), grade III (250°-299°), and grade IV (≥300°).RESULTS: Mean follow-up was 36±23 months. Femoral head collapse with BMAC (16 hips, 32%) was significantly lower than without BMAC (19 hips, 58%, P= .019). Conversion THA was significantly lower with BMAC (28%) than without (58%, P= .007). Survival rates among groups showed significant differences (P= .017). In grade I, 0/12 hips with BMAC collapsed while 3/9 (33%) without BMAC collapsed (P= .063); in grade II, 2/16 hips (12%) with BMAC collapsed while 7/13 (54%) without BMAC collapsed (P= .023). There was no significant difference in collapse with (64%) or without (82%) BMAC in grade III-IV hips (P= .256).CONCLUSION: Core decompression with/without BMAC had a high failure rate, by increasing disease progression and the necessity for THA, for combined necrotic angles >250°. In our study, addition of BMAC had more reliable outcomes than isolated core decompression for precollapse ONFH if the combined necrotic angles were <250°.

  View details for DOI 10.1016/j.arth.2021.01.075

  View details for PubMedID 33618954

• Management of Morbidity and Mortality in a New Zealand White Rabbit Model of Steroid-Induced Osteonecrosis of the Femoral Head COMPARATIVE MEDICINE Casey, K. M., Gore, F., Vilches-Moure, J. G., Maruyama, M., Goodman, S. B., Yang, Y., Baker, S. W. 2021; 71 (1): 86–98

  Abstract

  Steroid-induced osteonecrosis of the femoral head (SONFH) is a condition documented in humans and animals exposed to chronic steroid administration. The rabbit has become a preferred animal model for investigating the pathogenesis and treatment of SONFH due to its shared femoral vascular anatomy with human patients, relative size of the femoral head, and general fecundity. However, morbidity and mortality are frequent during the steroid induction period, prior to surgical manipulation. These problems are poorly reported and inadequately described in the literature. In this study, we report the clinical, gross, and histopathologic findings of New Zealand white (NZW) rabbits undergoing the steroid induction phase of the SONFH model. Severe weight loss (>30%), lipemia, hypercholesterolemia, hyperglycemia, and elevations in ALT and AST were consistent findings across all rabbits, although these changes did not differentiate asymptomatic rabbits from those that became clinically symptomatic or died. Euthanized and spontaneously deceased rabbits exhibited hepatomegaly, hepatic lipidosis/glycogenosis, and hepatocellular necrosis, in addition to a lipid-rich and proteinaceous thoracic effusion. A subset of rabbits developed opportunistic pulmonary infections with Bordetella bronchiseptica and Escherichia coli and small intestine infections with Lawsonia intracellularis superimposed on hepatic and thoracic disease. Together, these findings allowed us to establish a clinical decision-making flowchart that reduced morbidities and mortalities in a subsequent cohort of SONFH rabbits. Recognition of these model-associated morbidities is critical for providing optimal clinical care during the disease induction phase of SONFH.

  View details for DOI 10.30802/AALAS-CM-20-000071

  View details for Web of Science ID 000620257900005

  View details for PubMedID 33500020

  View details for PubMedCentralID PMC7898173

• Current Models for Development of Disease-Modifying Osteoarthritis Drugs. Tissue engineering. Part C, Methods Makarczyk, M. J., Gao, Q., He, Y., Li, Z., Gold, M. S., Hochberg, M., Bunnell, B., Tuan, R. S., Goodman, S. B., Lin, H. 2021

  Abstract

  Osteoarthritis (OA) is a painful and disabling disease that affects millions of people worldwide. Symptom-alleviating treatments exist, although none with long-term efficacy. Furthermore, there are currently no disease-modifying OA drugs (DMOADs) with demonstrated efficacy in OA patients, which is, in part, attributed to a lack of full understanding of the pathogenesis of OA. The inability to translate findings from basic research to clinical applications also highlights the deficiencies in the available OA models at simulating the clinically relevant pathologies and responses to treatments in humans. In this review, the current status in the development of DMOADs will be first presented, with special attention to those in Phase II-IV clinical trials. Next, current in vitro, ex vivo, and in vivo OA models are summarized and the respective advantages and disadvantages of each are highlighted. Notably, the development and application of microphysiological or tissue-on-a-chip systems for modeling OA in humans are presented and the issues that need to be addressed in the future are discussed. Microphysiological systems should be given serious consideration for their inclusion in the DMOAD development pipeline, both for their ability to predict drug safety and efficacy in human clinical trials at present, as well as for their potential to serve as a test platform for personalized medicine.

  View details for DOI 10.1089/ten.TEC.2020.0309

  View details for PubMedID 33403944

• PDGF-BB and IL-4 co-overexpression is a potential strategy to enhance mesenchymal stem cell-based bone regeneration. Stem cell research & therapy Zhang, N. n., Lo, C. W., Utsunomiya, T. n., Maruyama, M. n., Huang, E. n., Rhee, C. n., Gao, Q. n., Yao, Z. n., Goodman, S. B. 2021; 12 (1): 40

  Abstract

  Mesenchymal stem cell (MSC)-based therapy has the potential for immunomodulation and enhancement of tissue regeneration. Genetically modified MSCs that over-express specific cytokines, growth factors, or chemokines have shown great promise in pre-clinical studies. In this regard, the anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory M2 phenotype; M2 macrophages mitigate chronic inflammation and enhance osteogenesis by MSC lineage cells. However, exposure to IL-4 prematurely inhibits osteogenesis of MSCs in vitro; furthermore, IL-4 overexpressing MSCs inhibit osteogenesis in vivo during the acute inflammatory period. Platelet-derived growth factor (PDGF)-BB has been shown to enhance osteogenesis of MSCs with a dose-dependent effect.In this study, we generated a lentiviral vector that produces PDGF-BB under a weak promoter (phosphoglycerate kinase, PGK) and lentiviral vector producing IL-4 under a strong promoter (cytomegalovirus, CMV). We infected MSCs with PDGF-BB and IL-4-producing lentiviral vectors separately or in combination to investigate cell proliferation and viability, protein expression, and the capability for osteogenesis.PDGF-BB and IL-4 co-overexpression was observed in the co-infected MSCs and shown to enhance cell proliferation and viability, and osteogenesis compared to IL-4 overexpressing MSCs alone.Overexpression of PDGF-BB together with IL-4 mitigates the inhibitory effect of IL-4 on osteogenesis by IL-4 overexpressing MSCS. PDGF-BB and IL-4 overexpressing MSCs may be a potential strategy to facilitate osteogenesis in scenarios of both acute and chronic inflammation.

  View details for DOI 10.1186/s13287-020-02086-8

  View details for PubMedID 33413614

• Return to work and productivity loss after surgery: A health economic evaluation. International journal of surgery (London, England) M Hah, J., Lee, E., Shrestha, R., Pirrotta, L., Huddleston, J., Goodman, S., Amanatullah, D. F., Dirbas, F. M., Carroll, I. R., Schofield, D. 2021: 106100

  Abstract

  We aimed to identify preoperative psychosocial factors associated with return-to-work (RTW) and the associated cost of productivity loss due to work absenteeism following surgery. Research demonstrates a high economic burden from productivity loss after surgery, but the comparative cost of productivity loss relative to income across different operations has not been examined.A mixed surgical cohort recruited for a randomized controlled trial were prospectively followed for up to two years following surgery with daily phone assessments to three months, weekly assessments thereafter to six months, then monthly assessments thereafter to determine RTW status, opioid use and pain.183 of 207 (88.3%) patients in paid employment prior to surgery, who provided at least one day of follow-up, were included in this analysis. The average cost of productivity loss due to work absenteeism was $13 761 (median $9064). Patients who underwent total knee replacement incurred the highest income loss. Medical claims filed before surgery were significantly associated with relative income loss (AOR 5.09; 95% CI 1.73-14.96; p < 0.01) and delayed postoperative RTW. Elevated preoperative PTSD symptoms were associated with delayed RTW (HR 0.78; 95%CI 0.63-0.96; p-value = 0.02) while male gender (HR 1.63; 95%CI 1.11-2.38; p-value = 0.01) was associated with faster postoperative RTW.Surgery places a high economic burden on individuals due to postoperative productivity loss. Multidisciplinary approaches, such as pathways, that facilitate the operation and recovery may mitigate the economic consequences for patients, employers, and the healthcare system.

  View details for DOI 10.1016/j.ijsu.2021.106100

  View details for PubMedID 34600123

• Objective Activity Parameters Track Patient-Specific Physical Recovery Trajectories After Surgery and Link With Individual Preoperative Immune States. Annals of surgery Fallahzadeh, R., Verdonk, F., Ganio, E., Culos, A., Stanley, N., Marić, I., Chang, A. L., Becker, M., Phongpreecha, T., Xenochristou, M., De Francesco, D., Espinosa, C., Gao, X., Tsai, A., Sultan, P., Tingle, M., Amanatullah, D. F., Huddleston, J. I., Goodman, S. B., Gaudilliere, B., Angst, M. S., Aghaeepour, N. 2021

  Abstract

  The longitudinal assessment of physical function with high temporal resolution at a scalable and objective level in patients recovering from surgery is highly desirable to understand the biological and clinical factors that drive the clinical outcome. However, physical recovery from surgery itself remains poorly defined and the utility of wearable technologies to study recovery after surgery has not been established.Prolonged postoperative recovery is often associated with long-lasting impairment of physical, mental, and social functions. While phenotypical and clinical patient characteristics account for some variation of individual recovery trajectories, biological differences likely play a major role. Specifically, patient-specific immune states have been linked to prolonged physical impairment after surgery. However, current methods of quantifying physical recovery lack patient specificity and objectivity.Here, a combined high-fidelity accelerometry and state-of-the-art deep immune profiling approach was studied in patients undergoing major joint replacement surgery. The aim was to determine whether objective physical parameters derived from accelerometry data can accurately track patient-specific physical recovery profiles (suggestive of a 'clock of postoperative recovery'), compare the performance of derived parameters with benchmark metrics including step count, and link individual recovery profiles with patients' preoperative immune state.The results of our models indicate that patient-specific temporal patterns of physical function can be derived with a precision superior to benchmark metrics. Notably, six distinct domains of physical function and sleep are identified to represent the objective temporal patterns: "activity capacity" and "moderate and overall activity" (declined immediately after surgery); "sleep disruption and sedentary activity" (increased after surgery); "overall sleep", "sleep onset", and "light activity" (no clear changes were observed after surgery). These patterns can be linked to individual patients' preoperative immune state using cross-validated canonical-correlation analysis. Importantly, the pSTAT3 signal activity in M-MDSCs predicted a slower recovery.Accelerometry-based recovery trajectories are scalable and objective outcomes to study patient-specific factors that drive physical recovery.

  View details for DOI 10.1097/SLA.0000000000005250

  View details for PubMedID 35129529

• Mesenchymal Stem Cells and NF-κB Sensing Interleukin-4 Over-Expressing Mesenchymal Stem Cells Are Equally Effective in Mitigating Particle-Associated Chronic Inflammatory Bone Loss in Mice. Frontiers in cell and developmental biology Zhang, N., Utsunomiya, T., Lin, T., Kohno, Y., Ueno, M., Maruyama, M., Huang, E., Rhee, C., Yao, Z., Goodman, S. B. 2021; 9: 757830

  Abstract

  Wear particles from total joint arthroplasties (TJAs) induce chronic inflammation, macrophage infiltration and lead to bone loss by promoting bone destruction and inhibiting bone formation. Inhibition of particle-associated chronic inflammation and the associated bone loss is critical to the success and survivorship of TJAs. The purpose of this study is to test the hypothesis that polyethylene particle induced chronic inflammatory bone loss could be suppressed by local injection of NF-κB sensing Interleukin-4 (IL-4) over-expressing MSCs using the murine continuous polyethylene particle infusion model. The animal model was generated with continuous infusion of polyethylene particles into the intramedullary space of the femur for 6 weeks. Cells were locally injected into the intramedullary space 3 weeks after the primary surgery. Femurs were collected 6 weeks after the primary surgery. Micro-computational tomography (μCT), histochemical and immunohistochemical analyses were performed. Particle-infusion resulted in a prolonged pro-inflammatory M1 macrophage dominated phenotype and a decrease of the anti-inflammatory M2 macrophage phenotype, an increase in TRAP positive osteoclasts, and lower alkaline phosphatase staining area and bone mineral density, indicating chronic particle-associated inflammatory bone loss. Local injection of MSCs or NF-κB sensing IL-4 over-expressing MSCs reversed the particle-associated chronic inflammatory bone loss and facilitated bone healing. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments, which could be an efficacious therapeutic strategy for periprosthetic osteolysis.

  View details for DOI 10.3389/fcell.2021.757830

  View details for PubMedID 34722543

  View details for PubMedCentralID PMC8551755

• Provider Personal and Demographic Characteristics and Patient Satisfaction in Orthopaedic Surgery. Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews Lu, L. Y., Sharabianlou Korth, M. J., Cheng, R. Z., Finlay, A. K., Kamal, R. N., Goodman, S. B., Maloney, W. J., Huddleston, J. I., Amanatullah, D. F. 2021; 5 (4)

  Abstract

  INTRODUCTION: Patient satisfaction has increasingly been used to assess physician performance and quality of care. Although there is evidence that patient satisfaction is associated with patient-reported health outcomes and communication-related measures, there is debate over the use of patient satisfaction in reimbursement policy. Patient characteristics that influence satisfaction have been studied, but the effects of personal and demographic characteristics of physicians on patient satisfaction have yet to be explored.METHODS: Outpatient satisfaction scores from 11,059 patients who rated 25 orthopaedic surgeons from a single institution were studied. In this study, we sought to explore the relationship between nonmodifiable physician characteristics, such as sex and race, and patient satisfaction with outpatient orthopaedic surgery care, as expressed in the Press Ganey Satisfaction Scores. Univariate logistic regression models were used to test the associations between each provider characteristic and patient satisfaction on the Press Ganey patient satisfaction questionnaire.RESULTS: Three nonmodifiable physician personal and demographic characteristics were markedly associated with lower patient satisfaction scores across overall satisfaction, communication, and empathy domains: (1) female gender, (2) Asian ethnicity, and (3) being unmarried. Asian ethnicity reduced the odds of receiving a 5-star rating for likelihood to recommend the provider by nearly 40%, but none of these nonmodifiable physician personal and demographic characteristics affected the likelihood to recommend the practice.DISCUSSION: Sex, ethnicity, and marital status are nonmodifiable provider characteristics, each associated with markedly lower odds of receiving a 5-star rating on Press Ganey patient satisfaction survey. These data reveal inherent patient biases that negatively affect physician-patient interactions and may exacerbate the lack of diversity in orthopaedic surgery. More research is necessary before using patient satisfaction ratings to evaluate surgeons or as quality measures that affect reimbursement policies.

  View details for DOI 10.5435/JAAOSGlobal-D-20-00198

  View details for PubMedID 33835991

• Different Effects of Intramedullary Injection of Mesenchymal Stem Cells During the Acute vs. Chronic Inflammatory Phase on Bone Healing in the Murine Continuous Polyethylene Particle Infusion Model. Frontiers in cell and developmental biology Utsunomiya, T., Zhang, N., Lin, T., Kohno, Y., Ueno, M., Maruyama, M., Rhee, C., Huang, E., Yao, Z., Goodman, S. B. 2021; 9: 631063

  Abstract

  Chronic inflammation is a common feature in many diseases of different organ systems, including bone. However, there are few interventions to mitigate chronic inflammation and preserve host tissue. Previous in vitro studies demonstrated that preconditioning of mesenchymal stem cells (pMSCs) using lipopolysaccharide and tumor necrosis factor-alpha polarized macrophages from a pro-inflammatory to an anti-inflammatory phenotype and increased osteogenesis compared to unaltered MSCs. In the current study, we investigated the local injection of MSCs or pMSCs during the acute versus chronic inflammatory phase in a murine model of inflammation of bone: the continuous femoral intramedullary polyethylene particle infusion model. Chronic inflammation due to contaminated polyethylene particles decreased bone mineral density and increased osteoclast-like cells positively stained with leukocyte tartrate resistant acid phosphatase (TRAP) staining, and resulted in a sustained M1 pro-inflammatory macrophage phenotype and a decreased M2 anti-inflammatory phenotype. Local injection of MSCs or pMSCs during the chronic inflammatory phase reversed these findings. Conversely, immediate local injection of pMSCs during the acute inflammatory phase impaired bone healing, probably by mitigating the mandatory acute inflammatory reaction. These results suggest that the timing of interventions to facilitate bone healing by modulating inflammation is critical to the outcome. Interventions to facilitate bone healing by modulating acute inflammation should be prudently applied, as this phase of bone healing is temporally sensitive. Alternatively, local injection of MSCs or pMSCs during the chronic inflammatory phase may be a potential intervention to mitigate the adverse effects of contaminated particles on bone.

  View details for DOI 10.3389/fcell.2021.631063

  View details for PubMedID 33816480

• Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model. Frontiers in bioengineering and biotechnology Ueno, M., Zhang, N., Hirata, H., Barati, D., Utsunomiya, T., Shen, H., Lin, T., Maruyama, M., Huang, E., Yao, Z., Wu, J. Y., Zwingenberger, S., Yang, F., Goodman, S. B. 2021; 9: 755964

  Abstract

  Mesenchymal stem cell (MSC)-based therapy and novel biomaterials are promising strategies for healing of long bone critical size defects. Interleukin-4 (IL-4) over-expressing MSCs within a gelatin microribbon (RB) scaffold was previously shown to enhance the bridging of bone within a critical size femoral bone defect in male Balb/c mice. Whether sex differences affect the healing of this bone defect in conjunction with different treatments is unknown. In this study, we generated 2-mm critical-sized femoral diaphyseal bone defects in 10-12-week-old female and male Balb/c mice. Scaffolds without cells and with unmodified MSCs were implanted immediately after the primary surgery that created the bone defect; scaffolds with IL-4 over-expressing MSCs were implanted 3days after the primary surgery, to avoid the adverse effects of IL-4 on the initial inflammatory phase of fracture healing. Mice were euthanized 6weeks after the primary surgery and femurs were collected. MicroCT (CT), histochemical and immunohistochemical analyses were subsequently performed of the defect site. RB scaffolds with IL-4 over-expressing MSCs enhanced bone healing in both female and male mice. Male mice showed higher measures of bone bridging and increased alkaline phosphatase (ALP) positive areas, total macrophages and M2 macrophages compared with female mice after receiving scaffolds with IL-4 over-expressing MSCs. Female mice showed higher Tartrate-Resistant Acid Phosphatase (TRAP) positive osteoclast numbers compared with male mice. These results demonstrated that sex differences should be considered during the application of MSC-based studies of bone healing.

  View details for DOI 10.3389/fbioe.2021.755964

  View details for PubMedID 34738008

• Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis. Frontiers in immunology Qiu, J., Wu, B., Goodman, S. B., Berry, G. J., Goronzy, J. J., Weyand, C. M. 2021; 12: 652771

  Abstract

  Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.

  View details for DOI 10.3389/fimmu.2021.652771

  View details for PubMedID 33868292

• ARCO Consensus on the Pathogenesis of Non-traumatic Osteonecrosis of the Femoral Head. Journal of Korean medical science Cui, Q. n., Jo, W. L., Koo, K. H., Cheng, E. Y., Drescher, W. n., Goodman, S. B., Ha, Y. C., Hernigou, P. n., Jones, L. C., Kim, S. Y., Lee, K. S., Lee, M. S., Lee, Y. J., Mont, M. A., Sugano, N. n., Taliaferro, J. n., Yamamoto, T. n., Zhao, D. n. 2021; 36 (10): e65

  Abstract

  Osteonecrosis of the femoral head (ONFH) is a devastating disease frequently leading to femoral head collapse and hip arthritis. Specifically, non-traumatic ONFH primarily affects young and middle-aged adults. Although compromised local circulation of the femoral head seems to be pathognomonic for the disease, the pathogenesis is perplexing and continues to be an area of scrutiny and research. Comprehension of the pathogenesis is of crucial importance for developing and guiding treatments for the disease. Therefore, we provide an up-to-date consensus on the pathogenesis of non-traumatic ONFH.

  View details for DOI 10.3346/jkms.2021.36.e65

  View details for PubMedID 33724736

• Response to Letter to the Editor on "Diagnosis of Osteonecrosis of the Femoral Head: Too Little, Too Late, and Independent of Etiology". The Journal of arthroplasty Boontanapibul, K. n., Steere, J. T., Amanatullah, D. F., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2021; 36 (2): e12–e13

  View details for DOI 10.1016/j.arth.2020.09.037

  View details for PubMedID 33446355

• Encapsulated Mesenchymal Stromal Cell Microbeads Promote Endogenous Regeneration of Osteoarthritic Cartilage Ex Vivo. Advanced healthcare materials Sahu, N. n., Agarwal, P. n., Grandi, F. n., Bruschi, M. n., Goodman, S. n., Amanatullah, D. n., Bhutani, N. n. 2021: e2002118

  Abstract

  The anti-inflammatory secretome of mesenchymal stromal cells (MSCs) is lucrative for the treatment of osteoarthritis (OA), a disease characterized by low-grade inflammation. However, the precise effects of the MSC secretome on patient-derived OA tissue is lacking. To investigate these effects, alginate encapsulated MSCs are co-cultured with patient-derived OA cartilage explants for 8 days. Proteoglycan distribution in OA cartilage explants examined by Safranin O staining is markedly improved when cultured with MSC microbeads as compared to control OA explants cultured alone. Total sulfated glycosaminoglycan (sGAG) content in OA explants is significantly increased upon co-culture with MSC microbeads on day 8. The sGAG released into the culture media is unchanged by the presence of MSC microbeads, suggesting de novo sGAG synthesis in OA explants. Co-culture with MSC microbeads increased the DNA content and Ki67+ cells in OA explants, indicating proliferation. An increase in secreted cytokines IL-10, HGF, and sFAS assessed by multiplex cytokine assay, increased TIMP1 levels, and reduction in percent apoptotic cells in OA explants is noted. Together, data demonstrates that paracrine factors secreted by alginate encapsulated MSCs microbeads in response to OA cartilage, create an anabolic, proliferative, and anti-apoptotic microenvironment inducing endogenous regeneration in clinically relevant, patient-derived OA cartilage.

  View details for DOI 10.1002/adhm.202002118

  View details for PubMedID 33434393

• Efficacy of motivational-interviewing and guided opioid tapering support for patients undergoing orthopedic surgery (MI-Opioid Taper): A prospective, assessor-blind, randomized controlled pilot trial. EClinicalMedicine Hah, J. M., Trafton, J. A., Narasimhan, B., Krishnamurthy, P., Hilmoe, H., Sharifzadeh, Y., Huddleston, J. I., Amanatullah, D., Maloney, W. J., Goodman, S., Carroll, I., Mackey, S. C. 2020; 28: 100596

  Abstract

  Background: Postoperative opioid use can lead to chronic use and misuse. Few studies have examined effective approaches to taper postoperative opioid use while maintaining adequate analgesia.Methods: This randomized, assessor-blinded, pilot trial of postoperative motivational interviewing and guided opioid tapering support (MI-Opioid Taper) added to usual care (UC) enrolled patients undergoing total hip or knee arthroplasty at a single U.S. academic medical center. MI-Opioid Taper involved weekly (to seven weeks) and monthly (to one year) phone calls until patient-reported opioid cessation. Opioid tapering involved 25% weekly dose reductions. The primary feasibility outcome was study completion in the group to which participants were randomized. The primary efficacy outcome, time to baseline opioid use, was the first of five consecutive days of return to baseline preoperative dose. Intention-to-treat analysis with Cox proportional hazards regression was adjusted for operation. ClinicalTrials.gov registration: NCT02070003.Findings: From November 26, 2014, to April 27, 2018, 209 patients were screened, and 104 patients were assigned to receive MI-Opioid Taper (49 patients) or UC only (55 patients). Study completion after randomization was similar between groups (96.4%, 53 patients receiving UC, 91.8%, 45 patients receiving MI-Opioid Taper). Patients receiving MI-Opioid Taper had a 62% increase in the rate of return to baseline opioid use after surgery (HR 1.62; 95%CI 1.06-2.46; p=003). No trial-related adverse events occurred.Interpretation: In patients undergoing total joint arthroplasty, MI-Opioid Taper is feasible and future research is needed to establish the efficacy of MI-Opioid Taper to promote postoperative opioid cessation.Funding: National Institute on Drug Abuse.

  View details for DOI 10.1016/j.eclinm.2020.100596

  View details for PubMedID 33294812

• Articular cartilage regeneration by activated skeletal stem cells. Nature medicine Murphy, M. P., Koepke, L. S., Lopez, M. T., Tong, X., Ambrosi, T. H., Gulati, G. S., Marecic, O., Wang, Y., Ransom, R. C., Hoover, M. Y., Steininger, H., Zhao, L., Walkiewicz, M. P., Quarto, N., Levi, B., Wan, D. C., Weissman, I. L., Goodman, S. B., Yang, F., Longaker, M. T., Chan, C. K. 2020

  Abstract

  Osteoarthritis (OA) is a degenerative disease resulting in irreversible, progressive destruction of articular cartilage1. The etiology of OA is complex and involves a variety of factors, including genetic predisposition, acute injury and chronic inflammation2-4. Here we investigate the ability of resident skeletal stem-cell (SSC) populations to regenerate cartilage in relation to age, a possible contributor to the development of osteoarthritis5-7. We demonstrate that aging is associated with progressive loss of SSCs and diminished chondrogenesis in the joints of both mice and humans. However, a local expansion of SSCs could still be triggered in the chondral surface of adult limb joints in mice by stimulating a regenerative response using microfracture (MF) surgery. Although MF-activated SSCs tended to form fibrous tissues, localized co-delivery of BMP2 and soluble VEGFR1 (sVEGFR1), a VEGF receptor antagonist, in a hydrogel skewed differentiation of MF-activated SSCs toward articular cartilage. These data indicate that following MF, a resident stem-cell population can be induced to generate cartilage for treatment of localized chondral disease in OA.

  View details for DOI 10.1038/s41591-020-1013-2

  View details for PubMedID 32807933

• Adipose Tissue-Derived Stem Cells Retain Their Adipocyte Differentiation Potential in Three-Dimensional Hydrogels and Bioreactors . Biomolecules O'Donnell, B. T., Al-Ghadban, S., Ives, C. J., L'Ecuyer, M. P., Monjure, T. A., Romero-Lopez, M., Li, Z., Goodman, S. B., Lin, H., Tuan, R. S., Bunnell, B. A. 2020; 10 (7)

  Abstract

  Osteoarthritis (OA) is a common joint disorder with a significant economic and healthcare impact. The knee joint is composed of cartilage and the adjoining bone, a synovial capsule, the infrapatellar fat pad (IPFP), and other connective tissues such as tendons and ligaments. Adipose tissue has recently been highlighted as a major contributor to OA through strong inflammation mediating effects. In this study, methacrylated gelatin (GelMA) constructs seeded with adipose tissue-derived mesenchymal stem cells (ASCs) and cultured in a 3D printed bioreactor were investigated for use in microphysiological systems to model adipose tissue in the knee joint. Four patient-derived ASC populations were seeded at a density of 20 million cells/mL in GelMA. Live/Dead and boron-dipyrromethene/4',6-diamidino-2-phenylindole (BODIPY/DAPI) staining of cells within the constructs demonstrated robust cell viability after 28 days in a growth (control) medium, and robust cell viability and lipid accumulation in adipogenic differentiation medium. qPCR gene expression analysis and protein analysis demonstrated an upregulated expression of key adipogenesis-associated genes. Overall, these data indicate that ASCs retain their adipogenic potential when seeded within GelMA hydrogels and cultured within perfusion bioreactors, and thus can be used in a 3D organ-on-a-chip system to study the role of the IPFP in the pathobiology of the knee OA.

  View details for DOI 10.3390/biom10071070

  View details for PubMedID 32709032

• Thermal Oxide Layer Enhances Crystallinity and Mechanical Properties for Plasma-Sprayed Hydroxyapatite Biomedical Coatings. ACS applied materials & interfaces Bose, S., Ke, D., Vu, A. A., Bandyopadhyay, A., Goodman, S. B. 2020

  Abstract

  The stability of plasma-sprayed hydroxyapatite (HA) coatings on metallic implants in vivo remains a significant challenge for load-bearing orthopedic implants despite their excellent mechanical and osteoconductive properties. This study focuses on oxide layer formation on the surface of Ti6Al4V samples through furnace heating at 600, 700, and 800 °C for 10 min for optimization of the most effective oxide layer to increase plasma coating crystallinity and improve plasma coating bond strength with the metal surface. The 800 °C heat treatment shows an effective oxide layer which increases coating crystallinity from 64 to 75% and coating adhesive bond strength from 25.9 ± 2.3 to 30.7 ± 1.1 MPa, while simultaneously reducing the dissolution rate of HA coatings. The addition of biologically relevant dopants, MgO and SiO2, show negligible effects on crystallinity and adhesive bond strength on plasma-sprayed HA coatings and additionally show an enhancement effect on osteoblast proliferation and differentiation. Moreover, the inclusion of these additivess shows an increase in osteogenesis in a rat distal femur model after 6 and 10 weeks of implantation. Overall, this study provides a direct solution to improve the crystallinity, adhesive bond strength, and osteogenic properties of plasma-sprayed HA coatings on orthopedic implants that is more manufacturable and translational from research to an industrial scale.

  View details for DOI 10.1021/acsami.0c05035

  View details for PubMedID 32530603

• Modulation of the Inflammatory Response and Bone Healing. Frontiers in endocrinology Maruyama, M., Rhee, C., Utsunomiya, T., Zhang, N., Ueno, M., Yao, Z., Goodman, S. B. 2020; 11: 386

  Abstract

  The optimal treatment for complex fractures and large bone defects is an important unsolved issue in orthopedics and related specialties. Approximately 5-10% of fractures fail to heal and develop non-unions. Bone healing can be characterized by three partially overlapping phases: the inflammatory phase, the repair phase, and the remodeling phase. Eventual healing is highly dependent on the initial inflammatory phase, which is affected by both the local and systemic responses to the injurious stimulus. Furthermore, immune cells and mesenchymal stromal cells (MSCs) participate in critical inter-cellular communication or crosstalk to modulate bone healing. Deficiencies in this inter-cellular exchange, inhibition of the natural processes of acute inflammation, and its resolution, or chronic inflammation due to a persistent adverse stimulus can lead to impaired fracture healing. Thus, an initial and optimal transient stage of acute inflammation is one of the key factors for successful, robust bone healing. Recent studies demonstrated the therapeutic potential of immunomodulation for bone healing by the preconditioning of MSCs to empower their immunosuppressive properties. Preconditioned MSCs (also known as "primed/ licensed/ activated" MSCs) are cultured first with pro-inflammatory cytokines (e.g., TNFα and IL17A) or exposed to hypoxic conditions to mimic the inflammatory environment prior to their intended application. Another approach of immunomodulation for bone healing is the resolution of inflammation with anti-inflammatory cytokines such as IL4, IL10, and IL13. In this review, we summarize the principles of inflammation and bone healing and provide an update on cellular interactions and immunomodulation for optimal bone healing.

  View details for DOI 10.3389/fendo.2020.00386

  View details for PubMedID 32655495

  View details for PubMedCentralID PMC7325942

• Modulation of the Inflammatory Response and Bone Healing FRONTIERS IN ENDOCRINOLOGY Maruyama, M., Rhee, C., Utsunomiya, T., Zhang, N., Ueno, M., Yao, Z., Goodman, S. B. 2020; 11

  View details for DOI 10.3389/fendo.2020.00386

  View details for Web of Science ID 000543904600001

• Recent Advances in Total Joint Replacement. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Goodman, S., Wimmer, M. A., Ploeg, H. 2020

  Abstract

  Joint Replacement (JR) is one of the most successful and cost-effective surgical procedures of all medical subspecialties. JR has been shown to reliably decrease pain and restore mobility and function in patients with end-stage arthritis. As the mean age of our general population continues to increase, so will the number of JRs worldwide. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jor.24734

  View details for PubMedID 32410264

• Genetically modified il-4 over-expressing mscs enhance bone healing Ueno, M., Utsunomiya, T., Kohno, Y., Maruyama, M., Zhang, N., Lin, T. D., Yao, Z., Zwingenberger, S., Yang, F., Goodman, S. B. ELSEVIER SCI LTD. 2020: S178

  View details for Web of Science ID 000536174900406

• Injection of mscs mitigates particle associated chronic inflammation of bone Utsunomiya, T., Zhang, N., Lin, T. D., Kohno, Y., Ueno, M., Maruyama, M., Yao, Z., Goodman, S. B. ELSEVIER SCI LTD. 2020: S178–S179

  View details for Web of Science ID 000536174900407

• Macrophage Effects on Mesenchymal Stem Cell Osteogenesis in a Three-Dimensional in vitro Bone Model. Tissue engineering. Part A Romero-Lopez, M., Li, Z., Rhee, C., Maruyama, M., Pajarinen, J., O'Donnell, B., Lin, T., Lo, C., Hanlon, J., Dubowitz, R., Yao, Z., Bunnell, B. A., Lin, H., Tuan, R., Goodman, S. B. 2020

  Abstract

  As musculoskeletal disorders continue to increase globally, there is an increased need for novel, in vitro models to efficiently study human bone physiology in the context of both healthy and diseased conditions. For these models, the inclusion of innate immune cells is critical. Specifically, signaling factors generated from macrophages play key roles in the pathogenesis of many musculoskeletal processes and diseases, including fracture, osteoarthritis, infection, etc. In this study, we aim to engineer three-dimensional (3D) and macrophage-encapsulated bone tissues in vitro, to model cell behavior, signaling, and other biological activities in vivo, in comparison to current two-dimensional (2D) models. We first investigated and optimized 3D culture conditions for macrophages, and then co-cultured macrophages with mesenchymal stem cells (MSCs) which were induced to undergo osteogenic differentiation to examine the effect of macrophage on new bone formation. Seeded within a 3D hydrogel scaffold fabricated from photocrosslinked methacrylated gelatin, macrophages maintained high viability and were polarized toward an M1 or M2 phenotype. In co-cultures of macrophages and human MSCs, MSCs displayed immunomodulatory activities by suppressing M1 and enhancing M2 macrophage phenotypes. Lastly, addition of macrophages, regardless of polarization state, increased MSC osteogenic differentiation, compared to MSCs alone, with pro-inflammatory M1 macrophages enhancing new bone formation most effectively. In summary, this study illustrates the important roles that macrophage signaling and inflammation play in bone tissue formation.

  View details for DOI 10.1089/ten.TEA.2020.0041

  View details for PubMedID 32312178

• Nontraumatic Osteonecrosis of the Femoral Head: Where Do We Stand Today?: A 5-Year Update. The Journal of bone and joint surgery. American volume Mont, M. A., Salem, H. S., Piuzzi, N. S., Goodman, S. B., Jones, L. C. 2020

  View details for DOI 10.2106/JBJS.19.01271

  View details for PubMedID 32282421

• Selective screw fixation is associated with early failure of primary acetabular components for aseptic loosening. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Henry Goodnough, L., Bonano, J. C., Finlay, A. K., Aggarwal, V., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2020

  Abstract

  Selective augmentation of the acetabular component with screws during primary total hip arthroplasty (THA) assumes that the surgeon can detect when an acetabular component needs added stability. In contrast, non-selective screw users do not alter their practice based on their interpretation of stability and either use screws all or none of the time. We aimed to determine the effect of selective screw use on aseptic acetabular component loosening. We retrospectively reviewed aseptic failures of THA acetabular components. We compared the survivorship of selective to non-selective supplementation of acetabular fixation with screws, and compared time to revision, obesity and selective screw use. Selective screw use (n=16) was associated with earlier acetabular component aseptic loosening (median 1.9 years; interquartile range (IQR) 1.1-5.0) compared to non-selective screw use (n=22; median 5.6 years; IQR 2.0- 15.3, p = 0.010). Selective screw use was independently associated with earlier revision after adjusting for patient obesity. Obesity was associated with selective screw use in 50% of the cases versus 14% of non-selective cases (OR 6.3 CI 1.2-25.2, p = 0.028), possibly reflecting the increased difficulty in achieving acetabular component stability in this and other settings with compromised bone. Surgeons should carefully assess component stability at time of primary THA. If the acetabulum is not stable, the addition of screws alone may not be sufficient for acetabular component stability. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jor.24649

  View details for PubMedID 32157712

• Reimbursement and Complications in Outpatient vs Inpatient Unicompartmental Arthroplasty. The Journal of arthroplasty Bosch, L. C., Bala, A., Denduluri, S. K., Maloney, W. J., Huddleston, J. I., Goodman, S. B., Amanatullah, D. F. 2020

  Abstract

  BACKGROUND: Increasing utilization of unicompartmental knee arthroplasty (UKA) has driven a greater push for outpatient treatment and cost containment in the setting of bundled payments. The purpose of this study is to evaluate utilization trends of inpatient vs outpatient UKA, index episode and 90-day reimbursement, and any differences in medical or surgical complications.METHODS: The PearlDiver database was employed to identify all inpatient and outpatient UKAs performed between 2007 and 2016 with 2-year follow-up. Patients were matched by age, gender, and Elixhauser Comorbidity Index. We tracked index procedure and global period reimbursement, 90-day medical and surgical complications, and 2-year surgical complications.RESULTS: The reimbursement and utilization cohort included 3181 outpatient and 5490 inpatient UKAs. Outpatient UKA and overall utilization of UKA increased over the study period. Mean index reimbursement of inpatient UKA was $2486.16 higher per procedure (P < .001) while mean global period reimbursement was $2782.13 higher per inpatient procedure (P < .001). Ninety-day medical complications including postoperative anemia (P < .001), transfusion (P= .024), and arrhythmia (P= .004) were more common with inpatient UKAs, whereas surgical wound complications (P= .001) and operative debridement (P= .028) were more common among outpatient UKAs. Outpatient UKA was not associated with an increased risk of periprosthetic joint infection (P > .05), aseptic loosening (P > .05), or revision surgery (P > .05) when compared to inpatient UKA.CONCLUSION: Outpatient UKA utilization is increasing and is associated with decreased reimbursement compared to inpatient UKA without increased risk of major medical complications, although it is associated with increased risk of wound complication and need for operative debridement at 90 days.

  View details for DOI 10.1016/j.arth.2020.02.063

  View details for PubMedID 32220483

• Increased NF-kappa B Activity in Osteoprogenitor-Lineage Cells Impairs the Balance of Bone Versus Fat in the Marrow of Skeletally Mature Mice REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE Lin, T., Pajarinen, J., Kohno, Y., Nabeshima, A., Lu, L., Nathan, K., Yao, Z., Wu, J. Y., Goodman, S. 2020; 6 (1): 69–77

  View details for DOI 10.1007/s40883-019-00112-7

  View details for Web of Science ID 000519367200007

• Increased NF-kB activity in osteoprogenitor-lineage cells impairs the balance of bone versus fat in the marrow of skeletally mature mice. Regenerative engineering and translational medicine Lin, T., Pajarinen, J., Kohno, Y., Nabeshima, A., Lu, L., Nathan, K., Yao, Z., Wu, J. Y., Goodman, S. 2020; 6: 69-77

  Abstract

  "Senile osteoporosis" is defined as significant aging-associated bone loss, and is accompanied by increased fat in the bone marrow. The proportion of adipocytes in bone marrow is inversely correlated with bone formation, and is associated with increased risk of fracture. NF-κB is a transcription factor that functions as a master regulator of inflammation and bone remodeling. NF-κB activity increases during aging; furthermore, constitutive activation of NF-κB significantly impairs skeletal development in neonatal mice. However, the effects of NF-κB activation using a skeletally mature animal model have not been examined. In the current study, an osteoprogenitor (OP)-specific, doxycycline-regulated NF-κB activated transgenic mouse model (iNF-κB/OP) was generated to investigate the role of NF-κB in bone remodeling in skeletally mature mice. Reduced osteogenesis in the OP-lineage cells isolated from iNF-κB/OP mice was only observed in the absence of doxycycline in vitro. Bone mineral density in the metaphyseal regions of femurs and tibias was reduced in iNF-κB/OP mice. No significant differences in bone volume fraction and cortical bone thickness were observed. Osmium-stained bone marrow fat was increased in epiphyseal and metaphyseal areas in the tibias of iNF-κB/OP mice. These findings suggest that targeting NF-κB activity as a therapeutic strategy may improve bone healing and prevent aging-associated bone loss in aged patients.

  View details for DOI 10.1007/s40883-019-00112-7

  View details for PubMedID 32377560

  View details for PubMedCentralID PMC7202559

• Modifying MSC Phenotype to Facilitate Bone Healing: Biological Approaches. Frontiers in bioengineering and biotechnology Goodman, S. B., Lin, T. n. 2020; 8: 641

  Abstract

  Healing of fractures and bone defects normally follows an orderly series of events including formation of a hematoma and an initial stage of inflammation, development of soft callus, formation of hard callus, and finally the stage of bone remodeling. In cases of severe musculoskeletal injury due to trauma, infection, irradiation and other adverse stimuli, deficient healing may lead to delayed or non-union; this results in a residual bone defect with instability, pain and loss of function. Modern methods of mechanical stabilization and autologous bone grafting are often successful in achieving fracture union and healing of bone defects; however, in some cases, this treatment is unsuccessful because of inadequate biological factors. Specifically, the systemic and local microenvironment may not be conducive to bone healing because of a loss of the progenitor cell population for bone and vascular lineage cells. Autologous bone grafting can provide the necessary scaffold, progenitor and differentiated lineage cells, and biological cues for bone reconstruction, however, autologous bone graft may be limited in quantity or quality. These unfavorable circumstances are magnified in systemic conditions with chronic inflammation, including obesity, diabetes, chronic renal disease, aging and others. Recently, strategies have been devised to both mitigate the necessity for, and complications from, open procedures for harvesting of autologous bone by using minimally invasive aspiration techniques and concentration of iliac crest bone cells, followed by local injection into the defect site. More elaborate strategies (not yet approved by the U.S. Food and Drug Administration-FDA) include isolation and expansion of subpopulations of the harvested cells, preconditioning of these cells or inserting specific genes to modulate or facilitate bone healing. We review the literature pertinent to the subject of modifying autologous harvested cells including MSCs to facilitate bone healing. Although many of these techniques and technologies are still in the preclinical stage and not yet approved for use in humans by the FDA, novel approaches to accelerate bone healing by modifying cells has great potential to mitigate the physical, economic and social burden of non-healing fractures and bone defects.

  View details for DOI 10.3389/fbioe.2020.00641

  View details for PubMedID 32671040

  View details for PubMedCentralID PMC7328340

• Knee or Spine Surgery First? A Survey of Treatment Order for Patients With Concurrent Degenerative Knee and Lumbar Spinal Disorders. The Journal of arthroplasty Goodman, S. B., Lachiewicz, P. F., Liu, N. n., Wood, K. B. 2020

  Abstract

  Total knee arthroplasty (TKA) and lumbar spine surgery have been reported to affect the outcomes of each other. There is insufficient evidence to guide the choice of treatment order for patients with both disorders that are equally symptomatic.Five clinical scenarios of concurrent, advanced, degenerative knee and lumbar spinal disorders were designed to survey surgeons' choices of treatment order and rationale. The spinal disorder was consistently degenerative lumbar spinal stenosis, but the knee conditions varied to include (1) osteoarthritis (OA) with varus deformity, (2) OA with valgus deformity, (3) rheumatoid arthritis with a severe flexion contracture, (4) OA without deformity, and (5) bilateral OA with windswept deformities. The survey was distributed to selected clinical members of the Knee Society and Scoliosis Research Society in North America. The surgeons' choices were compared among the 5 scenarios, and their comments were analyzed using text-mining.Responses were received from 42 of 74 (57%) knee arthroplasty surgeons and 55 of 100 (55%) spine surgeons. The percentages of knee arthroplasty surgeons recommending "TKA first" differed significantly among scenarios: 29%, 79%, 55%, 7%, and 81% for scenarios 1 through 5, respectively (P < .001). A similar pattern was noted for the spine surgeons.For patients with concurrent degenerative knee and lumbar spinal disorders, the severity and type of knee deformity influenced the preference of treatment order in both specialties. Severe valgus deformity and windswept deformities of the knee would drive the decision toward "TKA first."

  View details for DOI 10.1016/j.arth.2020.03.018

  View details for PubMedID 32247672

• Inflammation, Bone Healing and Osteonecrosis: From Bedside to Bench. Journal of inflammation research Goodman, S. B., Maruyama, M. 2020; 13: 913–23

  Abstract

  Osteonecrosis of the epiphyseal and metaphyseal regions of major weight-bearing bones of the extremities is a condition that is associated with local death of bone cells and marrow in the afflicted compartment. Chronic inflammation is a prominent feature of osteonecrosis. If the persistent inflammation is not resolved, this process will result in progressive collapse and subsequent degenerative arthritis. In the pre-collapse stage of osteonecrosis, attempt at joint preservation rather than joint replacement in this younger population with osteonecrosis is a major clinical objective. In this regard, core decompression, with/without local injection of bone marrow aspirate concentrate (BMAC), is an accepted and evidence-based method to help arrest the progression and improve the outcome of early-stage osteonecrosis. However, some patients do not respond favorably to this treatment. Thus, it is prudent to consider strategies to mitigate chronic inflammation concurrent with addressing the deficiencies in osteogenesis and vasculogenesis in order to save the affected joint. Interestingly, the processes of inflammation, osteonecrosis, and bone healing are highly inter-related. Therefore, modulating the biological processes and crosstalk among cells of the innate immune system, the mesenchymal stem cell-osteoblast lineage and others are important to providing the local microenvironment for resolution of inflammation and subsequent repair. This review summarizes the clinical and biologic principles associated with osteonecrosis and provides potential cutting-end strategies for modulating chronic inflammation and facilitating osteogenesis and vasculogenesis using local interventions. Although these studies are still in the preclinical stages, it is hoped that safe, efficacious, and cost-effective interventions will be developed to save the host's natural joint.

  View details for DOI 10.2147/JIR.S281941

  View details for PubMedID 33223846

• Interleukin-4 repairs wear particle induced osteolysis by modulating macrophage polarization and bone turnover. Journal of biomedical materials research. Part A Pajarinen, J. n., Lin, T. n., Nabeshima, A. n., Sato, T. n., Gibon, E. n., Jämsen, E. n., Khan, T. N., Yao, Z. n., Goodman, S. B. 2020

  Abstract

  Periprosthetic osteolysis remains as a major complication of total joint replacement surgery. Modulation of macrophage polarization with interleukin-4 (IL-4) has emerged as an effective means to limit wear particle-induced osteolysis. The aim of this study was to evaluate the efficacy of local IL-4 delivery in treating preexisting particle-induced osteolysis. To this end, recently established 8 week modification of murine continuous femoral intramedullary particle infusion model was utilized. Subcutaneous infusion pumps were used to deliver polyethylene (PE) particles into mouse distal femur for 4 weeks to induce osteolysis. IL-4 was then added to the particle infusion for another 4 weeks. This delayed IL-4 treatment (IL-4 Del) was compared to IL-4 delivered continuously (IL-4 Cont) with PE particles from the beginning and to the infusion of particles alone for 8 weeks. Both IL-4 treatments were highly effective in preventing and repairing preexisting particle-induced bone loss as assessed by μCT. Immunofluorescence indicated a significant reduction in the number of F4/80 + iNOS + M1 macrophages and increase in the number of F4/80 + CD206 + M2 macrophages with both IL-4 treatments. Reduction in the number of tartrate resistant acid phosphatase + osteoclasts and increase in the amount of alkaline phosphatase (ALP) + osteoblasts was also observed with both IL-4 treatments likely explaining the regeneration of bone in these samples. Interesting, slightly more bone formation and ALP + osteoblasts were seen in the IL-4 Del group than in the IL-4 Cont group although these differences were not statistically significant. The study is a proof of principle that osteolytic lesions can be repaired via modulation of macrophage polarization.

  View details for DOI 10.1002/jbm.a.37142

  View details for PubMedID 33340244

• Guidelines for clinical diagnosis and treatment of osteonecrosis of the femoral head in adults (2019 version). Journal of orthopaedic translation Zhao, D. n., Zhang, F. n., Wang, B. n., Liu, B. n., Li, L. n., Kim, S. Y., Goodman, S. B., Hernigou, P. n., Cui, Q. n., Lineaweaver, W. C., Xu, J. n., Drescher, W. R., Qin, L. n. 2020; 21: 100–110

  Abstract

  Osteonecrosis of the femoral head (ONFH) is a common and refractory disease in orthopaedic clinics. The number of patients with ONFH is increasing worldwide every year. There are an estimated 8.12 million patients with nontraumatic osteonecrosis in China alone. Treatment of nontraumatic osteonecrosis has always been a clinical challenge for orthopaedic surgeons. To further standardize diagnosis and treatment of ONFH, these guidelines provide not only basic diagnosis, treatment, and evaluation systems for ONFH but also expert advice and standards in many aspects, including epidemiology, aetiology, diagnostic criteria, pathological staging, prevention and treatment options, and postoperative rehabilitation. The aetiological factors of ONFH can currently be divided into two major categories: traumatic and nontraumatic; however, the specific pathological mechanism of ONFH is not completely clear. Currently, the staging system of ONFH formulated by the Association Research Circulation Osseous is widely used in clinical practice. Based on the changes in the intraosseous blood supply at different stages, the corresponding nonsurgical and surgical treatments are recommended, and when there are risk factors for possible ONFH, certain preventive measures to avoid the occurrence of osteonecrosis are recommended. These guidelines provide brief classification criteria and treatment regimen for osteonecrosis. Specification of the aetiology, treatment plan based on comprehensive consideration of the different stages of osteonecrosis, hip function, age, and occupation of the patients are important steps in diagnosis and developing treatment strategies.New advances in the epidemiology, etiology, pathophysiology, imaging, diagnosis and treatment of ONFH have been renewed in this revision. This guideline can be used for reference by orthopedic professionals and researchers, and for standardized diagnosis and treatment management under the clinical guidance, which is conducive to the prevention, treatment and further research of ONFH, improving the diagnosis and treatment level, making patients' symptoms under good control, and improving their quality of life.

  View details for DOI 10.1016/j.jot.2019.12.004

  View details for PubMedID 32309135

  View details for PubMedCentralID PMC7152793

• The routine use of synovial alpha-defensin is not necessary. The bone & joint journal Amanatullah, D. F., Cheng, R. Z., Huddleston Iii, J. I., Maloney, W. J., Finlay, A. K., Kappagoda, S. n., Suh, G. A., Goodman, S. B. 2020; 102-B (5): 593–99

  Abstract

  To establish the utility of adding the laboratory-based synovial alpha-defensin immunoassay to the traditional diagnostic work-up of a prosthetic joint infection (PJI).A group of four physicians evaluated 158 consecutive patients who were worked up for PJI, of which 94 underwent revision arthroplasty. Each physician reviewed the diagnostic data and decided on the presence of PJI according to the 2014 Musculoskeletal Infection Society (MSIS) criteria (yes, no, or undetermined). Their initial randomized review of the available data before or after surgery was blinded to each alpha-defensin result and a subsequent randomized review was conducted with each result. Multilevel logistic regression analysis assessed the effect of having the alpha-defensin result on the ability to diagnose PJI. Alpha-defensin was correlated to the number of synovial white blood cells (WBCs) and percentage of polymorphonuclear cells (%PMN).Intraobserver reliability and interobserver agreement did not change when the alpha-defensin result was available. Positive alpha-defensin results had greater synovial WBCs (mean 31,854 cells/μL, SD 32,594) and %PMN (mean 93.0%, SD 5.5%) than negative alpha-defensin results (mean 974 cells/μL, SD 3,988; p < 0.001 and mean 39.4% SD 28.6%; p < 0.001). Adding the alpha-defensin result did not alter the diagnosis of a PJI using preoperative (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.14 to 1.88; p = 0.315) or operative (OR 0.52, CI 0.18 to 1.55; p = 0.242) data when clinicians already decided that PJI was present or absent with traditionally available testing. However, when undetermined with traditional preoperative testing, alpha-defensin helped diagnose (OR 0.44, CI 0.30 to 0.64; p < 0.001) or rule out (OR 0.41, CI 0.17 to 0.98; p = 0.044) PJI. Of the 27 undecided cases with traditional testing, 24 (89%) benefited from the addition of alpha-defensin testing.The laboratory-based synovial alpha-defensin immunoassay did not help diagnose or rule out a PJI when added to routine serologies and synovial fluid analyses except in cases where the diagnosis of PJI was unclear. We recommend against the routine use of alpha-defensin and suggest using it only when traditional testing is indeterminate. Cite this article: Bone Joint J 2020;102-B(5):593-599.

  View details for DOI 10.1302/0301-620X.102B5.BJJ-2019-0473.R3

  View details for PubMedID 32349594

• Preoperative Factors Associated with Remote Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: Post Hoc Analysis of a Perioperative Gabapentin Trial. Journal of pain research Hah, J. M., Hilmoe, H. n., Schmidt, P. n., McCue, R. n., Trafton, J. n., Clay, D. n., Sharifzadeh, Y. n., Ruchelli, G. n., Hernandez Boussard, T. n., Goodman, S. n., Huddleston, J. n., Maloney, W. J., Dirbas, F. M., Shrager, J. n., Costouros, J. G., Curtin, C. n., Mackey, S. C., Carroll, I. n. 2020; 13: 2959–70

  Abstract

  Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use.In this post hoc analysis of a randomized, double-blind, placebo-controlled trial of perioperative gabapentin vs active placebo, 410 patients aged 18-75 years, undergoing diverse operations underwent preoperative assessments of pain, opioid use, substance use, and psychosocial variables. After surgery, a modified Brief Pain Inventory was administered over the phone daily up to 3 months, weekly up to 6 months, and monthly up to 2 years after surgery. Pain and opioid cessation were defined as the first of 5 consecutive days of 0 out of 10 pain or no opioid use, respectively.Overall, 36.1%, 19.8%, and 9.5% of patients continued to report pain, and 9.5%, 2.4%, and 1.7% reported continued opioid use at 3, 6, and 12 months after surgery. Preoperative pain at the future surgical site (every 1-point increase in the Numeric Pain Rating Scale; HR 0.93; 95% CI 0.87-1.00; P=0.034), trait anxiety (every 10-point increase in the Trait Anxiety Inventory; HR 0.79; 95% CI 0.68-0.92; P=0.002), and a history of delayed recovery after injury (HR 0.62; 95% CI 0.40-0.96; P=0.034) were associated with delayed pain cessation. Preoperative opioid use (HR 0.60; 95% CI 0.39-0.92; P=0.020), elevated depressive symptoms (every 5-point increase in the Beck Depression Inventory-II score; HR 0.88; 95% CI 0.80-0.98; P=0.017), and preoperative pain outside of the surgical site (HR 0.94; 95% CI 0.89-1.00; P=0.046) were associated with delayed opioid cessation, while perioperative gabapentin promoted opioid cessation (HR 1.37; 95% CI 1.06-1.77; P=0.016).Separate risk factors for prolonged post-surgical pain and opioid use indicate that preoperative risk stratification for each outcome may identify patients needing personalized care to augment universal protocols for perioperative pain management and conservative opioid prescribing to improve long-term outcomes.

  View details for DOI 10.2147/JPR.S269370

  View details for PubMedID 33239904

  View details for PubMedCentralID PMC7680674

• IL-4 Overexpressing Mesenchymal Stem Cells within Gelatin-Based Microribbon Hydrogels Enhance Bone Healing in a Murine Long Bone Critical-size Defect Model. Journal of biomedical materials research. Part A Ueno, M. n., Lo, C. W., Barati, D. n., Conrad, B. n., Lin, T. n., Kohno, Y. n., Utsunomiya, T. n., Zhang, N. n., Maruyama, M. n., Rhee, C. n., Huang, E. n., Romero-Lopez, M. n., Tong, X. n., Yao, Z. n., Zwingenberger, S. n., Yang, F. n., Goodman, S. B. 2020

  Abstract

  Mesenchymal stem cell (MSC)-based therapy is a promising strategy for bone repair. Furthermore, the innate immune system, and specifically macrophages, play a crucial role in the differentiation and activation of MSCs. The anti-inflammatory cytokine IL-4 converts pro-inflammatory M1 macrophages into a tissue regenerative M2 phenotype, which enhances MSC differentiation and function. We developed lentivirus-transduced IL-4 over-expressing MSCs (IL-4 MSCs) that continuously produce IL-4 and polarize macrophages toward an M2 phenotype. In the current study, we investigated the potential of IL-4 MSCs delivered using a macroporous gelatin-based microribbon (μRB) scaffold for healing of critical size long bone defects in Mice. IL-4 MSCs within μRBs enhanced M2 marker expression without inhibiting M1 marker expression in the early phase, and increased macrophage migration into the scaffold. Six weeks after establishing the bone defect, IL-4 MSCs within μRBs enhanced bone formation and helped bridge the long bone defect. IL-4 MSCs delivered using macroporous μRB scaffold is potentially a valuable strategy for the treatment of critical size long bone defects. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbm.a.36982

  View details for PubMedID 32363683

• Initial Presentation and Progression of Secondary Osteonecrosis of the Knee. The Journal of arthroplasty Boontanapibul, K. n., Steere, J. T., Amanatullah, D. F., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2020

  Abstract

  Early detection and intervention are critical to maintaining the native articular cartilage before collapse in secondary osteonecrosis of the knee (SOK). We conducted a retrospective study documenting the initial stage of presentation and the progression of SOK.Our database was reviewed for patients younger than 65 years of age diagnosed with atraumatic SOK between 2002 and 2018. Demographic data, plain radiographs as well as MRI at initial evaluation, and initial treatment were classified and analyzed.One hundred four patients with 164 knees were identified. Mean age was 39 ± 16 years. Females (64%) with bilateral disease (58%) predominated. Seventy-five percent of patients had a history of corticosteroid use, of which 41% were diagnosed with hematologic malignancy and lupus. Fifteen percent of patients had a history of ethanol abuse. At initial presentation, 55% of patients were diagnosed with Ficat-Arlet stage I/II, while 45% were diagnosed with Ficat-Arlet stage III/IV. We found a significant difference in the mean age of patients at early stage of SOK with corticosteroid use (31 ± 12 years of age) when compared to ethanol use (43 ± 13 years of age, P = .02). Treatments included observation (57%), joint preservation surgery (20%), and total knee arthroplasty (23%).Nearly half of patients presented at late stage compromising the potential for joint preservation. The difference in age of referral by over a decade, based on etiology of SOK, suggests a strong provider-based referral or screening bias may be present. Hence, a multidisciplinary approach to earlier detection and referral may be a more effective strategy for preventing the progression of SOK.

  View details for DOI 10.1016/j.arth.2020.05.020

  View details for PubMedID 32527695

• Outcomes of Cemented Total Knee Arthroplasty for Secondary Osteonecrosis of the Knee. The Journal of arthroplasty Boontanapibul, K. n., Amanatullah, D. F., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2020

  Abstract

  Secondary osteonecrosis of the knee (SOK) generally occurs in relatively young patients; at advanced stages of SOK, the only viable surgical option is total knee arthroplasty (TKA). We conducted a retrospective study to investigate implant survivorship, clinical and radiographic outcomes, and complications of contemporary cemented bicompartmental TKA with/without patellar resurfacing for SOK.Thirty-eight cemented TKAs in 27 patients with atraumatic SOK, mean age 43 years (17 to 65), were retrospectively reviewed. Seventy-four percent had a history of corticosteroid use, and 18% had a history of alcohol abuse. Patellar osteonecrosis was coincidentally found in six knees (16%), and all were asymptomatic without joint collapse. The mean followup was 7 years (2 to 12). Knee Society Score (KSS) and radiographic outcomes were evaluated at 6 weeks, 1 year, then every 2 to 3 years.Ninety-two percent had implant survivorship free from revision with significant improvement in KSS. Causes of revision included aseptic tibial loosening (one), deep infection (one), and instability with patellofemoral issues (one). Four of six cases also with patellar osteonecrosis received resurfacing, including one with periprosthetic patellar fracture after minor trauma, with satisfactory clinical results after conservative treatment. None of the unrevised knees had progressive radiolucent lines or evidence of loosening. An unresurfaced patella, use of a stem extension or a varus-valgus constrained prosthesis constituted 18%, 8% and 3%, respectively.Cemented TKAs with selective stem extension in patients with SOK had satisfactory implant survivorship and reliable outcomes. Secondary osteonecrosis of the patella should be carefully evaluated prior to operation.

  View details for DOI 10.1016/j.arth.2020.08.061

  View details for PubMedID 33011011

• Diagnosis of Osteonecrosis of the Femoral Head: Too Little, Too Late, and Independent of Etiology. The Journal of arthroplasty Boontanapibul, K. n., Steere, J. T., Amanatullah, D. F., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2020

  Abstract

  Joint preservation is more effective in early-stage osteonecrosis of the femoral head (ONFH); thus, prompt diagnosis when the femoral head is still salvageable is important. We report a 20-year retrospective study that summarizes age at presentation, etiology, and Association Research Circulation Osseous stage at diagnosis.Our database was reviewed to identify patients younger than 65 years of age who were diagnosed with atraumatic ONFH between 1998 and 2018. Demographic characteristics of patients were evaluated and categorized into different subgroups.Four hundred thirteen patients were identified. At initial presentation, 23% were diagnosed with early-stage ONFH, while 77% were diagnosed with late-stage ONFH. Forty-nine percent had a history of corticosteroid use, of which 13% were diagnosed with hematologic malignancy and 8% were diagnosed with lupus. Ethanol abuse, idiopathic, sickle cell disease, and human immunodeficiency virus were present in 11%, 30%, 3%, and 3%, respectively. The mean age of patients with corticosteroid use (40 ± 14 years) was significantly younger than ethanol use (46 ± 11 years, P = .014) and idiopathic causes (48 ± 11 years, P < .001), but significantly older than sickle cell disease (32 ± 11 years, P = .031). There was no difference in the age of presentation for early-stage and late-stage ONFH by etiology.Nearly 80% of the patients presented with late-stage ONFH. Hence, we have a narrow window of opportunity for hip preservation surgery before femoral head collapse. A multidisciplinary approach to improve screening awareness for early detection by focusing on the etiologic identification and patient education might reduce the incidence of hip arthroplasty in young patients.

  View details for DOI 10.1016/j.arth.2020.04.092

  View details for PubMedID 32456965

• The efficacy of core decompression for steroidassociated osteonecrosisof the femoral head in rabbits. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Maruyama, M. n., Lin, T. n., Kaminow, N. I., Thio, T. n., Storaci, H. W., Pan, C. C., Yao, Z. n., Takagi, M. n., Goodman, S. B., Yang, Y. P. 2020

  Abstract

  Although core decompression (CD) is often performed in the early stages of osteonecrosis of the femoral head (ONFH), the procedure does not always prevent subsequent deterioration and the effects of CD are not fully clarified.The aim of this study was to evaluate the efficacy of CD for steroid associated ONFH in rabbits.Twelve male and twelve female New Zealand rabbits were injected intramuscularly 20 mg/kg of methylprednisolone once and were divided into the disease control and CD groups. In the disease control group, rabbits had no treatment and were euthanized at 12 weeks post-injection. In the CD group, rabbits underwent left femoral CD at 4 weeks post-injection and were euthanized 8 weeks postoperatively. The left femurs were collected to perform morphological, biomechanical and histological analysis.Bone mineral density and bone volume fraction in the femoral head in the CD group were significantly higher than in the disease control group. However, no difference in the mechanical strength was observed between the two groups. Histological analysis showed thatalkaline phosphatase and CD31 positive cells significantly increased in the males after CD treatment. The number of empty lacunae in the surrounding trabecular bone was significantly higher in the CD group.The current study indicated that CD improved the morphological properties, but did not improve the mechanical strength in the femoral headat early stage ONFH.These data suggest the need for additional biological, mechanical strategies,and therapeutic windows to improve the outcome of early stage steroid associated ONFH. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jor.24888

  View details for PubMedID 33095462

• Strontium enhances BMP-2 mediated bone regeneration in a femoral murine bone defect model JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS Quade, M., Vater, C., Schlootz, S., Bolte, J., Langanke, R., Bretschneider, H., Gelinsky, M., Goodman, S. B., Zwingenberger, S. 2020; 108 (1): 174–82

  View details for DOI 10.1002/jbm.b.34376

  View details for Web of Science ID 000500822700018

• Inhibition of TET1 prevents the development of osteoarthritis and reveals the 5hmC landscape that orchestrates pathogenesis. Science translational medicine Smeriglio, P. n., Grandi, F. C., Davala, S. n., Masarapu, V. n., Indelli, P. F., Goodman, S. B., Bhutani, N. n. 2020; 12 (539)

  Abstract

  Osteoarthritis (OA) is a degenerative disease of the joint, which results in pain, loss of mobility, and, eventually, joint replacement. Currently, no disease-modifying drugs exist, partly because of the multiple levels at which cartilage homeostasis is disrupted. Recent studies have highlighted the importance of epigenetic dysregulation in OA, sparking interest in the epigenetic modulation for this disease. In our previous work, we characterized a fivefold increase in cytosine hydroxymethylation (5hmC), an oxidized derivative of cytosine methylation (5mC) associated with gene activation, accumulating at OA-associated genes. To test the role of 5hmC in OA, here, we used a mouse model of surgically induced OA and found that OA onset was accompanied by a gain of ~40,000 differentially hydroxymethylated sites before the notable histological appearance of disease. We demonstrated that ten-eleven-translocation enzyme 1 (TET1) mediates the 5hmC deposition because 98% of sites enriched for 5hmC in OA were lost in Tet1-/- mice. Loss of TET1-mediated 5hmC protected the Tet1-/- mice from OA development, including degeneration of the cartilage surface and osteophyte formation, by directly preventing the activation of multiple OA pathways. Loss of TET1 in human OA chondrocytes reduced the expression of the matrix metalloproteinases MMP3 and MMP13 and multiple inflammatory cytokines. Intra-articular injections of a dioxygenases inhibitor, 2-hydroxyglutarate, on mice after surgical induction of OA stalled disease progression. Treatment of human OA chondrocytes with the same inhibitor also phenocopied TET1 loss. Collectively, these data demonstrate that TET1-mediated 5hmC deposition regulates multiple OA pathways and can be modulated for therapeutic intervention.

  View details for DOI 10.1126/scitranslmed.aax2332

  View details for PubMedID 32295898

• Single-cell mass cytometry reveals cross-talk between inflammation-dampening and inflammation-amplifying cells in osteoarthritic cartilage Science Advances Grandi, F. ., Baskar, R., Smeriglio, P., Murkherjee, S., Indelli, P., F. Amanatullah, D., Goodman, S., Chu, C., Bendall , S., Bhutani, N. 2020; 6 (11)

  View details for DOI 10.1126/sciadv.aay5352

• Tumor Necrosis Factor Primes and Metal Particles Activate the NLRP3 Inflammasome in Human Primary Macrophages. Acta biomaterialia Jämsen, E. n., Pajarinen, J. n., Kouri, V. P., Rahikkala, A. n., Goodman, S. B., Manninen, M. n., Nordström, D. C., Eklund, K. K., Nurmi, K. n. 2020

  Abstract

  Aseptic loosening of total joint replacements is driven by a macrophage-mediated inflammatory reaction to implant-derived wear particles. Phagocytosis of implant debris has been suggested to activate the NLRP3 inflammasome leading to secretion of interleukin (IL)-1β. However, factors and molecular mechanisms driving the particle-induced inflammasome activation are yet to be fully elucidated. In this study, we investigated the inflammasome response of human primary macrophages to titanium, chromium, and molybdenum particles in vitro. We observed that particles alone were not sufficient to induce IL-1β secretion, but an additional priming signal-such as bacterial lipopolysaccharide (LPS)-was required to license the inflammasome activation. By using specific inhibitors against the inflammasome signaling pathway, we demonstrate that the particle-induced IL-1β secretion depended upon activation of the NLRP3 inflammasome. We further hypothesized that tumor necrosis factor (TNF) could substitute for LPS as a priming signal, and found that particle stimulation together with preceding TNF treatment resulted in inflammasome-dependent IL-1β production as well. Our results show that the NLRP3 inflammasome mediates wear particle responses in human primary macrophages, and its activation does not necessarily require the presence of bacterial components, but can be induced under aseptic conditions by TNF priming. Statement of Significance This study was conducted to elucidate the molecular mechanisms of metal particle-induced IL-1β secretion in human primary macrophages. Production of this pro-inflammatory mediator from wear particle-activated macrophages has been associated with increased bone loss around total joint replacements-a condition eventually requiring revision surgery. Our results confirm that together with a co-stimulatory priming signal, particles of common implant metals elicit macrophage-mediated IL-1β secretion through activation of the NLRP3 inflammasome pathway. We also present a concept of TNF priming in this context, demonstrating that the particle-related IL-1β secretion can take place in a truly sterile environment. Thus, inhibition of inflammasome signaling appears a means to prevent wear particle-induced inflammation and development of peri-prosthetic osteolysis.

  View details for DOI 10.1016/j.actbio.2020.03.017

  View details for PubMedID 32194260

• Reply to Letter to the Editor on "Mental Health Status Improves Following Total Knee Arthroplasty". The Journal of arthroplasty Horst, P. K., Barrett, A. A., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2020

  View details for DOI 10.1016/j.arth.2020.05.067

  View details for PubMedID 32571590

• Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY Lin, Z., Li, Z., Li, E. N., Li, X., Del Duke, C. J., Shen, H., Hao, T., Bunnell, B. A., Goodman, S. B., Alexander, P. G., Tuan, R. S., Lin, H. 2019; 7

  View details for DOI 10.3389/fbioe.2019.00411

  View details for Web of Science ID 000504972600001

• Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs. Frontiers in bioengineering and biotechnology Lin, Z., Li, Z., Li, E. N., Li, X., Del Duke, C. J., Shen, H., Hao, T., O'Donnell, B., Bunnell, B. A., Goodman, S. B., Alexander, P. G., Tuan, R. S., Lin, H. 2019; 7: 411

  Abstract

  Osteoarthritis (OA) is a chronic disease mainly characterized by degenerative changes in cartilage, but other joint elements such as bone are also affected. To date, there are no disease-modifying OA drugs (DMOADs), owing in part to a deficiency of current models in simulating OA pathologies and etiologies in humans. In this study, we aimed to develop microphysiological osteochondral (OC) tissue chips derived from human induced pluripotent stem cells (iPSCs) to model the pathologies of OA. We first induced iPSCs into mesenchymal progenitor cells (iMPCs) and optimized the chondro- and osteo-inductive conditions for iMPCs. Then iMPCs were encapsulated into photocrosslinked gelatin scaffolds and cultured within a dual-flow bioreactor, in which the top stream was chondrogenic medium and the bottom stream was osteogenic medium. After 28 days of differentiation, OC tissue chips were successfully generated and phenotypes were confirmed by real time RT-PCR and histology. To create an OA model, interleukin-1β (IL-1β) was used to challenge the cartilage component for 7 days. While under control conditions, the bone tissue promoted chondrogenesis and suppressed chondrocyte terminal differentiation of the overlying chondral tissue. Under conditions modeling OA, the bone tissue accelerated the degradation of chondral tissue which is likely via the production of catabolic and inflammatory cytokines. These findings suggest active functional crosstalk between the bone and cartilage tissue components in the OC tissue chip under both normal and pathologic conditions. Finally, a selective COX-2 inhibitor commonly prescribed drug for OA, Celecoxib, was shown to downregulate the expression of catabolic and proinflammatory cytokines in the OA model, demonstrating the utility of the OC tissue chip model for drug screening. In summary, the iPSC-derived OC tissue chip developed in this study represents a high-throughput platform applicable for modeling OA and for the screening and testing of candidate DMOADs.

  View details for DOI 10.3389/fbioe.2019.00411

  View details for PubMedID 31921815

  View details for PubMedCentralID PMC6930794

• The 2019 Revised Version of Association Research Circulation Osseous Staging System of Osteonecrosis of the Femoral Head. The Journal of arthroplasty Yoon, B., Mont, M. A., Koo, K., Chen, C., Cheng, E. Y., Cui, Q., Drescher, W., Gangji, V., Goodman, S. B., Ha, Y., Hernigou, P., Hungerford, M. W., Iorio, R., Jo, W., Jones, L. C., Khanduja, V., Kim, H. K., Kim, S., Kim, T., Lee, H. Y., Lee, M. S., Lee, Y., Lee, Y. J., Nakamura, J., Parvizi, J., Sakai, T., Sugano, N., Takao, M., Yamamoto, T., Zhao, D. 2019

  Abstract

  BACKGROUND: The Association Research Circulation Osseous (ARCO) presents the 2019 revised staging system of osteonecrosis of the femoral head (ONFH) based on the 1994 ARCO classification.METHODS: In October 2018, ARCO established a task force to revise the staging system of ONFH. The task force involved 29 experts who used a web-based survey for international collaboration. Content validity ratios for each answer were calculated to identify the levels of agreement. For the rating queries, a consensus was defined when more than 70% of the panel members scored a 4 or 5 rating on a 5-point scale.RESULTS: Response rates were 93.1%-100%, and through the 4-round Delphi study, the 1994 ARCO classification for ONFH was successfully revised. The final consensus resulted in the following 4-staged system: stage I-X-ray is normal, but either magnetic resonance imaging or bone scan is positive; stage II-X-ray is abnormal (subtle signs of osteosclerosis, focal osteoporosis, or cystic change in the femoral head) but without any evidence of subchondral fracture, fracture in the necrotic portion, or flattening of the femoral head; stage III-fracture in the subchondral or necrotic zone as seen on X-ray or computed tomography scans. This stage is further divided into stage IIIA (early, femoral head depression ≤2 mm) and stage IIIB (late, femoral head depression >2 mm); and stage IV-X-ray evidence of osteoarthritis with accompanying joint space narrowing, acetabular changes, and/or joint destruction. This revised staging system does not incorporate the previous subclassification or quantitation parameters, but the panels agreed on the future development of a separate grading system for predicting disease progression.CONCLUSION: A staging system has been developed to revise the 1994 ARCO classification for ONFH by an expert panel-based Delphi survey. ARCO approved and recommends this revised system as a universal staging of ONFH.

  View details for DOI 10.1016/j.arth.2019.11.029

  View details for PubMedID 31866252

• Guest Editorial: The Current Use of Biologics and Cellular Therapies in Orthopaedics: Are We Going Down the Right Path? Clinical orthopaedics and related research Manner, P. A., Goodman, S. B. 2019

  View details for DOI 10.1097/CORR.0000000000001068

  View details for PubMedID 31764317

• Osteogenic ability of rat bone marrow concentrate is at least as efficacious as mesenchymal stem cells in vitro JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS Kohno, Y., Lin, T., Pajarinen, J., Romero-Lopez, M., Maruyama, M., Huang, J., Nathan, K., Yao, Z., Goodman, S. B. 2019; 107 (8): 2500–2506

  View details for DOI 10.1002/jbm.b.34340

  View details for Web of Science ID 000488626300005

• Statin use is associated with less postoperative cardiac arrhythmia after total hip arthroplasty HIP INTERNATIONAL Chen, M. J., Bala, A., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Aaronson, A. J., Amanatullah, D. F. 2019; 29 (6): 618–23

  View details for DOI 10.1177/1120700018816091

  View details for Web of Science ID 000487029700010

• Response to Letter to the Editor on "Total Knee Arthroplasty Has Positive Effect on Patients With Low Mental Health Scores". The Journal of arthroplasty Horst, P. K., Barrett, A. A., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2019

  View details for DOI 10.1016/j.arth.2019.10.047

  View details for PubMedID 31785963

• Inflammation and Bone Repair: From Particle Disease to Tissue Regeneration. Frontiers in bioengineering and biotechnology Goodman, S. B., Pajarinen, J., Yao, Z., Lin, T. 2019; 7: 230

  Abstract

  When presented with an adverse stimulus, organisms evoke an immediate, pre-programmed, non-specific innate immune response. The purpose of this reaction is to maintain the organism's biological integrity and function, mitigate or eradicate the injurious source, and re-establish tissue homeostasis. The initial stage of this protective reaction is acute inflammation, which normally reduces or terminates the offending stimulus. As the inflammatory reaction recedes, the stage of tissue repair and regeneration follows. If the above sequence of events is perturbed, reconstitution of normal biological form and function will not be achieved. Dysregulation of these activities may result in incomplete healing, fibrosis, or chronic inflammation. Our laboratory has studied the reaction to wear particles from joint replacements as a paradigm for understanding the biological pathways of acute and chronic inflammation, and potential translational treatments to reconstitute lost bone. As inflammation is the cornerstone for healing in all anatomical locations, the concepts developed have relevance to tissue engineering and regenerative medicine in all organ systems. To accomplish our goal, we developed novel in vitro and in vivo models (including the murine femoral continuous intramedullary particle infusion model), translational strategies including modulation of macrophage chemotaxis and polarization, and methods to interfere with key transcription factors NFκB and MyD88. We purposefully modified MSCs to facilitate bone healing in inflammatory scenarios: by preconditioning the MSCs, and by genetically modifying MSCs to first sense NFκB activation and then overexpress the anti-inflammatory pro-regenerative cytokine IL-4. These advancements provide significant translational opportunities to enhance healing in bone and other organs.

  View details for DOI 10.3389/fbioe.2019.00230

  View details for PubMedID 31608274

  View details for PubMedCentralID PMC6761220

• Inflammation and Bone Repair: From Particle Disease to Tissue Regeneration FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY Goodman, S. B., Pajarinen, J., Yao, Z., Lin, T. 2019; 7

  View details for DOI 10.3389/fbioe.2019.00230

  View details for Web of Science ID 000487523100001

• Cell-Based and Scaffold-Based Therapies for Joint Preservation in Early-Stage Osteonecrosis of the Femoral Head: A Review of Basic Research. JBJS reviews Maruyama, M., Lin, T., Pan, C., Moeinzadeh, S., Takagi, M., Yang, Y. P., Goodman, S. B. 2019

  View details for DOI 10.2106/JBJS.RVW.18.00202

  View details for PubMedID 31503099

• Effect of Aging on the Macrophage Response to Titanium Particles. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Jamsen, E., Pajarinen, J., Lin, T., Lo, C., Nabeshima, A., Lu, L., Nathan, K., Eklund, K. K., Yao, Z., Goodman, S. B. 2019

  Abstract

  Macrophage-mediated inflammatory reaction to implant wear particles drives bone loss around total joint replacements (TJR). Although most TJR recipients are elderly, studies linking wear particle-activated macrophages and peri-implant osteolysis have not taken into account the multiple effects that aging has on the innate immune system and, in particular, on macrophages. To address this, we compared the wear particle responses of bone marrow macrophages obtained from young (2-month) and aged (18-month) mice. Macrophages were polarized to M0, M1, or M2 phenotypes in vitro, challenged with titanium particles, and their inflammatory response was characterized at multiple time points by qRT-PCR and ELISA. In addition, age-dependent changes in activation of transcription factor NF-kappaB were analyzed by a lentiviral vector-based luciferase reporter system. The particle stimulation experiment was further repeated using human primary macrophages isolated from blood donors of different ages. We found that the pro-inflammatory responses were generally higher in macrophages obtained from young mice, but differences between the age groups remained small and of uncertain biological significance. Noteworthily, M2 polarization effectively suppressed the particle-induced inflammation in both young and aged macrophages. These results suggest that aging of the innate immune system per se plays no significant role in the response of macrophages to titanium particles, whereas induction of M2 polarization appears a promising strategy to limit macrophage-mediated inflammation regardless of age. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jor.24461

  View details for PubMedID 31498470

• Total Knee Arthroplasty Has A Positive Effect on Patients With Low Mental Health Scores. The Journal of arthroplasty Horst, P. K., Barrett, A. A., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2019

  Abstract

  BACKGROUND: The purpose of this study is to determine the impact of total knee arthroplasty (TKA) on mental health.METHODS: A total of 205 patients who underwent primary TKA with baseline and 1-year postoperative Short Form-12 Mental Component Score (MCS) were included in this retrospective analysis. Eighty-five (41%) patients had a preoperative MCS less than 50 points, while 120 (59%) patients had a preoperative MCS over 50 points. Two groups were assigned to the patients based on their preoperative MCS: low MCS <50 and high MCS >50.RESULTS: A preoperative MCS less than 50 points was predictive of greater improvement in MCS at 1 year after TKA (P < .001). Patients with low MCS improved by a mean of 10.6 points from 39.1 ± 8.6 points preoperatively to mean of 49.7 ± 10.7 points 1 year after TKA (P < .001). Patients with a high MCS decreased by a mean of 3.5 points from 60.01 ± 6.0 points preoperatively to mean of 56.6 ± 6.8 points 1 year after TKA (P < .001). This remained higher than the postoperative MCS of the patients with a low MCS, 49.7 ± 10.7 (P < .001). The patients with a high MCS had greater improvement in the Short Form-12-Physical domain (14.8 points) than the patients with a low MCS (9.2 points, P < .001).CONCLUSION: Patients with lower baseline mental health had greater improvement in postoperative mental health following TKA than patients with higher baseline mental health. Low preoperative MCS was associated with less improvement in patient-reported outcome measures. Patients with lower baseline mental health scores before TKA benefit mentally and physically from the procedure.

  View details for DOI 10.1016/j.arth.2019.08.033

  View details for PubMedID 31522853

• Treating Titanium Particle-Induced Inflammation with Genetically Modified NF-κB Sensing IL-4 Secreting or Preconditioned Mesenchymal Stem Cells in Vitro. ACS biomaterials science & engineering Kohno, Y., Lin, T., Pajarinen, J., Jämsen, E., Romero-Lopez, M., Maruyama, M., Lo, C. W., Ueno, M., Nathan, K., Yao, Z., Goodman, S. B. 2019; 5 (6): 3032-3038

  Abstract

  Titanium and titanium-based alloys are widely used in orthopaedic implants. Total joint replacement is very successful; however, the foreign body response and chronic inflammation caused by implant-derived biomaterial debris still remain as unsolved issues. Aseptic loosening accompanied by wear debris-induced osteolysis (bone loss) is one of the most frequent causes for late failure and revision surgery. Mesenchymal stem cells (MSCs) and IL-4 may be possible treatment strategies because of their immunomodulatory properties. We investigated the efficacy of novel MSC-based treatments on immunomodulation and osteogenic differentiation in an innovative cell coculture model of titanium particle-induced inflammation in the periprosthetic tissues. MSCs and macrophages were collected from the bone marrow of Balb/c mice. Both MSCs and macrophages (representing endogenous cells at the periprosthetic tissue) were seeded on the bottom wells of the 24-well transwell plates. We generated genetically modified NF-κB sensing IL-4 secreting MSCs (inflammatory responsive MSCs) and MSCs preconditioned by lipopolysaccharide and TNF-α to further enhance their immunomodulatory function. These modified MSCs (representing exogenous therapeutic cells implanted to the periprosthetic tissue) were seeded on the upper chambers of the transwell plates. These cocultures were then exposed to titanium particles for 7 days. NF-κB sensing IL-4 secreting MSCs showed strong immunomodulation (significantly reduced TNF-α and induced Arg1 expression) and promoted early osteogenesis (significantly induced Runx2, ALP, and β-catenin as well as reduced Smurf2 expression) at day 7. IL-4 secreting MSCs also decreased TNF-α protein secretion as early as day 3 and increased IL-1ra protein secretion at day 7, suggesting efficacious immunomodulation of particle-induced inflammation. Preconditioned MSCs did not show significant immunomodulation in this short-term experiment, but ALP and β-catenin expression were significantly induced at day 7. Our results suggest that genetically modified IL-4 secreting MSCs and preconditioned MSCs have the potential to optimize bone regeneration in inflammatory conditions including periprosthetic osteolysis.

  View details for DOI 10.1021/acsbiomaterials.9b00560

  View details for PubMedID 32391436

  View details for PubMedCentralID PMC7207059

• CORR Insights: How Does Mortality Risk Change Over Time After Hip and Knee Arthroplasty? Clinical orthopaedics and related research Goodman, S. B. 2019; 477 (6): 1422–23

  View details for DOI 10.1097/CORR.0000000000000724

  View details for PubMedID 31136445

• American Association of Hip and Knee Surgeons, Hip Society, and Knee Society Position Statement on Biologics for Advanced Hip and Knee Arthritis JOURNAL OF ARTHROPLASTY Browne, J. A., Nho, S. J., Goodman, S. B., Della Valle, C. J. 2019; 34 (6): 1051–52

  Abstract

  Pigmented villonodular synovitis (PVNS) is a locally destructive histiocytic proliferation most commonly occurring in the knee. Extensive local joint destruction can indicate the need for a total knee arthroplasty (TKA). The objective of this study is to evaluate PVNS of the knee as a risk factor for complication after TKA.Patients who underwent TKA with a diagnosis of PVNS of the knee from 2007 to 2016 were identified in a national private payer insurance database. Complication rates for emergency room visits, readmission, revision, stiffness, infection, and death were calculated and compared to a control population of patients who received TKA for osteoarthritis (OA).Four hundred fifty-three patients were diagnosed with PVNS of the knee and underwent TKA during the time period and compared with a matched control cohort of 1812 patients who underwent TKA for OA. The rate of revision TKA at 2 years, emergency room visits, readmission, and death did not differ between the PVNS group and the control cohort. The PVNS group had stiffness at 1 year compared to the OA group (6.84% vs 4.69%, odds ratio 1.48, P = .023). The infection rate at 2 years was 3.31% in the PVNS group and 1.55% in the OA group (odds ratio 1.73, P = .011).The complication rates for TKA in patients with a diagnosis of PVNS of the knee have not been previously demonstrated. These patients have a higher rate of stiffness and infection when compared to a control cohort, so they may have a more complicated postoperative course.

  View details for DOI 10.1016/j.arth.2019.03.068

  View details for Web of Science ID 000468307600002

  View details for PubMedID 30266323

• Stem Cells and Platelet-Rich Plasma Injections for Advanced Hip and Knee Arthritis: Enthusiasm Outpaces Science JOURNAL OF ARTHROPLASTY Browne, J. A., Nho, S. J., Goodman, S. B., Callaghan, J. J., Della Valle, C. J. 2019; 34 (6): 1049–50

  View details for DOI 10.1016/j.arth.2019.03.074

  View details for Web of Science ID 000468307600001

• Improved Range of Motion and Patient-Reported Outcome Scores With Fixed-Bearing Revision Total Knee Arthroplasty for Suboptimal Axial Implant Rotation JOURNAL OF ARTHROPLASTY Amanatullah, D. E., Lichstein, P. M., Lundergan, W. G., Wong, W. W., Maloney, W. J., Goodman, S. B., Huddleston, J. I. 2019; 34 (6): 1174–78

  View details for DOI 10.1016/j.arth.2019.02.007

  View details for Web of Science ID 000468307600024

• Hip or spine surgery first? A SURVEY OF TREATMENT ORDER FOR PATIENTS WITH CONCURRENT DEGENERATIVE HIP AND SPINAL DISORDERS Liu, N., Goodman, S. B., Lachiewicz, P. F., Wood, K. B. BRITISH EDITORIAL SOC BONE JOINT SURGERY. 2019: 37–44

  View details for Web of Science ID 000469965700007

• Two-step stem cell therapy improves bone regeneration compared to concentrated bone marrow therapy JOURNAL OF ORTHOPAEDIC RESEARCH Bolte, J., Vater, C., Culla, A., Ahlfeld, T., Nowotny, J., Kasten, P., Disch, A. C., Goodman, S. B., Gelinsky, M., Stiehler, M., Zwingenberger, S. 2019; 37 (6): 1318–28

  View details for DOI 10.1002/jor.24215

  View details for Web of Science ID 000470781400014

• Treating Titanium Particle-Induced Inflammation with Genetically Modified NF-kappa B Sensing IL-4 Secreting or Preconditioned Mesenchymal Stem Cells in Vitro ACS BIOMATERIALS SCIENCE & ENGINEERING Kohno, Y., Lin, T., Pajarinen, J., Jamsen, E., Romero-Lopez, M., Maruyama, M., Lo, C., Ueno, M., Nathan, K., Yao, Z., Goodman, S. B. 2019; 5 (6): 3032–38

  View details for DOI 10.1021/acsbiomaterials.9b00560

  View details for Web of Science ID 000471212300033

• Computer Navigation vs Conventional Total Hip Arthroplasty: AMedicare Database Analysis. The Journal of arthroplasty Montgomery, B. K., Bala, A., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2019

  Abstract

  BACKGROUND: Computer-assisted surgery (CAS) is applied to total hip arthroplasty (THA) in an attempt to optimize implant positioning. The effect of CAS on postoperative complications after THA remains unknown. Our study aims to assess the change in complication rates when CAS is used in THA.METHODS: The Medicare database was studied from 2005 to 2012. All THAs performed with CAS were identified. A total of 64,944 THAs were identified, including 5412 CAS-THAs and 59,532 conventional THAs. Medical and surgical adverse events were collected at various time points.RESULTS: CAS-THA was not associated with a decreased rate of dislocation at 30 days (1.0% vs 1.2%; odds ratio [OR], 1.14; P= .310), 90 days (1.1% vs 1.4%; OR, 1.23; P= .090), or 2 years (2.3% vs 2.3%; OR, 1.01; P= .931). CAS-THA was associated with a significantly higher rate of periprosthetic fracture at 30 days (0.4% vs 0.6%; OR, 1.46; P= .040) as well as revision THA at 30 days (1.0% vs 1.4%; OR, 1.43; P= .003) and 90 days (1.2% vs 1.7%; OR, 1.42; P < .002) when compared to conventional THA. CAS-THA was associated with a significantly lower rate of deep vein thrombosis and pulmonary embolism when compared to conventional THA at all time points (P < .05).CONCLUSION: Administrative coding data fail to demonstrate any clinically significant reduction in short-term adverse events with CAS-THA. Further study is warranted to evaluate whether the purported benefits of CAS result in a reduction of the adverse events after THA.

  View details for DOI 10.1016/j.arth.2019.04.063

  View details for PubMedID 31176561

• IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis ELIFE Wang, Q., Lepus, C. M., Raghu, H., Reber, L. L., Tsai, M. M., Wong, H. H., von Kaeppler, E., Lingampalli, N., Bloom, M. S., Hu, N., Elliott, E. E., Oliviero, F., Punzi, L., Giori, N. J., Goodman, S. B., Chu, C. R., Sokolove, J., Fukuoka, Y., Schwartz, L. B., Galli, S. J., Robinson, W. H. 2019; 8

  View details for DOI 10.7554/eLife.39905

  View details for Web of Science ID 000467895900001

• Bone Regeneration by Controlled Release of Bone Morphogenetic Protein-2: A Rabbit Spinal Fusion Chamber Molecular Study TISSUE ENGINEERING PART A Hu, T., Naidu, M., Yang, Z., Lam, W., Kumarsing, R., Ren, X., Ng, F., Wang, M., Liu, L., Tan, K., Kwok, K., Goodman, S. B., Goh, J., Wong, H. 2019

  View details for DOI 10.1089/ten.tea.2018.0281

  View details for Web of Science ID 000466514000001

• Venous thromboprophylaxis after total hip arthroplasty: aspirin, warfarin, enoxaparin, or factor Xa inhibitors? Hip international : the journal of clinical and experimental research on hip pathology and therapy Bala, A., Murasko, M. J., Burk, D. R., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2019: 1120700019841600

  Abstract

  INTRODUCTION: Debate over the ideal agent for venous thromboembolism (VTE) prophylaxis after total hip arthroplasty (THA) has led to changes in prescribing trends of commonly used agents. We investigate variation in utilisation and the differences in VTE incidence and bleeding risk in primary THA after administration of aspirin, warfarin, enoxaparin, or factor Xa inhibitors.METHODS: 8829 patients were age/sex matched from a large database of primary THAs performed between 2007 and 2016. Utilisation was calculated using compound annual growth rate. Incidence of postoperative deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding-related complications, postoperative anaemia, and transfusion were identified at 2weeks, 30days, 6weeks, and 90days.RESULTS: Aspirin use increased by 33%, enoxaparin by 7%, and factor Xa inhibitors by 31%. Warfarin use decreased by 1%. Factor Xa inhibitors (1.7%) and aspirin (1.7%) had the lowest incidence of DVT followed by enoxaparin (2.6%), and warfarin (3.7%) at 90days. Factor Xa inhibitors (12%) and aspirin (12%) had the lowest incidence of blood transfusion followed by warfarin (15%) and enoxaparin (17%) at 90 days. There was no difference in incidence of blood transfusion or bleeding-related complications nor any detectable difference in symptomatic PE incidence.CONCLUSIONS: The utilisation of aspirin and factor Xa inhibitors increased over time. Aspirin and factor Xa inhibitors provided improved DVT prophylaxis with lower rates of postoperative anaemia compared to enoxaparin and warfarin.

  View details for DOI 10.1177/1120700019841600

  View details for PubMedID 30990095

• Strontium enhances BMP-2 mediated bone regeneration in a femoral murine bone defect model. Journal of biomedical materials research. Part B, Applied biomaterials Quade, M., Vater, C., Schlootz, S., Bolte, J., Langanke, R., Bretschneider, H., Gelinsky, M., Goodman, S. B., Zwingenberger, S. 2019

  Abstract

  The application of strontium is one option for the clinical treatment of osteoporosis-a disease characterized by reduced bone density and quality-in order to reduce the risk of vertebral and nonvertebral fractures. Unlike other drugs used in osteoporosis therapy, strontium shows a dual effect on bone metabolism by attenuating cellular resorption and simultaneously enhancing new bone tissue formation. Current concerns regarding the systemic application of highly dosed strontium ranelate led to the development of strontium-modified scaffolds based on mineralized collagen (MCM) capable to release biologically active Sr2+ ions directly at the fracture site. In this study, we investigated the regenerative potential of these scaffolds. For in vitro investigations, human mesenchymal stromal cells were cultivated on the scaffolds for 21days (w/ and w/o osteogenic supplements). Biochemical analysis revealed a significant promoting effect on proliferation rate and osteogenic differentiation on strontium-modified scaffolds. In vivo, scaffolds were implanted in a murine segmental bone defect model-partly additionally functionalized with the osteogenic growth factor bone morphogenetic protein 2 (BMP-2). After 6 weeks, bridging calluses were obtained in BMP-2 functionalized scaffolds; the quality of the newly formed bone tissue by means of morphological scores was clearly enhanced in strontium-modified scaffolds. Histological analysis revealed increased numbers of osteoblasts and blood vessels, decreased numbers of osteoclasts, and significantly enhanced mechanical properties. These results indicate that the combined release of Sr2+ ions and BMP-2 from the biomimetic scaffolds is a promising strategy to enhance bone regeneration, especially in patients suffering from osteoporosis. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B, 2019.

  View details for PubMedID 30950569

• Stem Cells and Platelet-Rich Plasma Injections for Advanced Hip and Knee Arthritis: Enthusiasm Outpaces Science. The Journal of arthroplasty Browne, J. A., Nho, S. J., Goodman, S. B., Callaghan, J. J., Della Valle, C. J. 2019

  View details for PubMedID 31000403

• American Association of Hip and Knee Surgeons, Hip Society, and Knee Society Position Statement on Biologics for Advanced Hip and Knee Arthritis. The Journal of arthroplasty Browne, J. A., Nho, S. J., Goodman, S. B., Della Valle, C. J. 2019

  View details for PubMedID 31005436

• Preconditioned or IL4-Secreting Mesenchymal Stem Cells Enhanced Osteogenesis at Different Stages TISSUE ENGINEERING PART A Lin, T., Kohno, Y., Huang, J., Romero-Lopez, M., Maruyama, M., Ueno, M., Pajarinen, J., Nathan, K., Yao, Z., Yang, F., Wu, J. Y., Goodman, S. B. 2019

  View details for DOI 10.1089/ten.tea.2018.0292

  View details for Web of Science ID 000462509800001

• Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery: Secondary Analysis of a Randomized Clinical Trial. JAMA network open Hah, J. M., Cramer, E., Hilmoe, H., Schmidt, P., McCue, R., Trafton, J., Clay, D., Sharifzadeh, Y., Ruchelli, G., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J. G., Curtin, C., Mackey, S. C., Carroll, I. 2019; 2 (3): e190168

  Abstract

  Importance: Acute postoperative pain is associated with the development of persistent postsurgical pain, but it is unclear which aspect is most estimable.Objective: To identify patient clusters based on acute pain trajectories, preoperative psychosocial characteristics associated with the high-risk cluster, and the best acute pain predictor of remote outcomes.Design, Setting, and Participants: A secondary analysis of the Stanford Accelerated Recovery Trial randomized, double-blind clinical trial was conducted at a single-center, tertiary, referral teaching hospital. A total of 422 participants scheduled for thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, or shoulder arthroscopy were enrolled between May 25, 2010, and July 25, 2014. Data analysis was performed from January 1 to August 1, 2018.Interventions: Patients were randomized to receive gabapentin (1200 mg, preoperatively, and 600 mg, 3 times a day postoperatively) or active placebo (lorazepam, 0.5 mg preoperatively, inactive placebo postoperatively) for 72 hours.Main Outcomes and Measures: A modified Brief Pain Inventory prospectively captured 3 surgical site pain outcomes: average pain and worst pain intensity over the past 24 hours, and current pain intensity. Within each category, acute pain trajectories (first 10 postoperative pain scores) were compared using a k-means clustering algorithm. Fifteen descriptors of acute pain were compared as predictors of remote postoperative pain resolution, opioid cessation, and full recovery.Results: Of the 422 patients enrolled, 371 patients (≤10% missing pain scores) were included in the analysis. Of these, 146 (39.4%) were men; mean (SD) age was 56.67 (11.70) years. Two clusters were identified within each trajectory category. The high pain cluster of the average pain trajectory significantly predicted prolonged pain (hazard ratio [HR], 0.63; 95% CI, 0.50-0.80; P<.001) and delayed opioid cessation (HR, 0.52; 95% CI, 0.41-0.67; P<.001) but was not a predictor of time to recovery in Cox proportional hazards regression (HR, 0.89; 95% CI, 0.69-1.14; P=.89). Preoperative risk factors for categorization to the high average pain cluster included female sex (adjusted relative risk [ARR], 1.36; 95% CI, 1.08-1.70; P=.008), elevated preoperative pain (ARR, 1.11; 95% CI, 1.07-1.15; P<.001), a history of alcohol or drug abuse treatment (ARR,1.90; 95% CI, 1.42-2.53; P<.001), and receiving active placebo (ARR, 1.27; 95% CI, 1.03-1.56; P=.03). Worst pain reported on postoperative day 10 was the best predictor of time to pain resolution (HR, 0.83; 95% CI, 0.78-0.87; P<.001), opioid cessation (HR, 0.84; 95% CI, 0.80-0.89; P<.001), and complete surgical recovery (HR, 0.91; 95% CI, 0.86-0.96; P<.001).Conclusions and Relevance: This study has shown a possible uniform predictor of remote postoperative pain, opioid use, and recovery that can be easily assessed. Future work is needed to replicate these findings.Trial Registration: ClinicalTrials.gov Identifier: NCT01067144.

  View details for PubMedID 30821824

• Factors Associated With Acute Pain Estimation, Postoperative Pain Resolution, Opioid Cessation, and Recovery Secondary Analysis of a Randomized Clinical Trial JAMA NETWORK OPEN Hah, J. M., Cramer, E., Hilmoe, H., Schmidt, P., McCue, R., Trafton, J., Clay, D., Sharifzadeh, Y., Ruchelli, G., Goodman, S., Huddleston, J., Maloney, W. J., Dirbas, F. M., Shrager, J., Costouros, J. G., Curtin, C., Mackey, S. C., Carroll, I. 2019; 2 (3)

  View details for DOI 10.1001/jamanetworkopen.2019.0168

  View details for Web of Science ID 000465424000048

• Mesenchymal stem cell-macrophage crosstalk and bone healing BIOMATERIALS Pajarinen, J., Lin, T., Gibon, E., Kohno, Y., Maruyama, M., Nathan, K., Lu, L., Yao, Z., Goodman, S. B. 2019; 196: 80–89

  View details for DOI 10.1016/j.biomaterials.2017.12.025

  View details for Web of Science ID 000459527700007

• Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation FASEB JOURNAL Lin, T., Pajarinen, J., Kohno, Y., Huang, J., Maruyama, M., Romero-Lopez, M., Nathan, K., Yao, Z., Goodman, S. B. 2019; 33 (3): 4203–11

  View details for DOI 10.1096/fj.201801845R

  View details for Web of Science ID 000459794800088

• Osteogenic ability of rat bone marrow concentrate is at least as efficacious as mesenchymal stem cells in vitro. Journal of biomedical materials research. Part B, Applied biomaterials Kohno, Y., Lin, T., Pajarinen, J., Romero-Lopez, M., Maruyama, M., Huang, J., Nathan, K., Yao, Z., Goodman, S. B. 2019

  Abstract

  Cell therapy using bone marrow concentrate (BMC) or purified and expanded mesenchymal stem cells (MSCs) has been shown to have a promising osteogenic capacity. However, few studies have directly compared their relative osteogenic ability. The aim of this study was to compare the osteogenic ability of BMC isolated by density gradient centrifugation with bone marrow-derived MSCs in vitro using the cells of 3-month-old Sprague-Dawley rats. The isolated cells were seeded onto 24-well plates (1*105 cells/well) and cultured in control growth media, osteogenic media with dexamethasone, or media without dexamethasone (which simulated the in vivo tissue environment). Alkaline phosphatase activity at week 2, osteocalcin using quantitative real-time polymerase chain reaction at week 4, and Alizarin red staining at week 4 were evaluated. In the osteogenic media with dexamethasone, BMC showed equivalent (osteocalcin) or even greater (Alizarin red staining) osteogenic ability compared to MSCs, suggesting that cross-talk among various cells in the BMC leads to greater osteogenesis. Furthermore, in the osteogenic media without dexamethasone, BMC showed equivalent (osteocalcin) or a trend for greater (Alizarin red staining) bone formation than MSCs alone. Our results suggest that BMC has at least comparable bone regeneration potential to MSCs. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: 00B: 000-000, 2019.

  View details for PubMedID 30779478

• Improved Range of Motion and Patient-Reported Outcome Scores With Fixed-Bearing Revision Total Knee Arthroplasty for Suboptimal Axial Implant Rotation. The Journal of arthroplasty Amanatullah, D. F., Lichstein, P. M., Lundergan, W. G., Wong, W. W., Maloney, W. J., Goodman, S. B., Huddleston, J. I. 2019

  Abstract

  BACKGROUND: Suboptimal implant rotation has consequences with respect to knee kinematics and clinical outcomes. We evaluated the functional outcomes of revision total knee arthroplasty (TKA) for poor axial implant rotation.METHODS: We retrospectively reviewed 42 TKAs undergoing aseptic revision for poor axial implant rotation. We assessed improvements in Knee Society Score (KSS) and final range of motion (ROM). Subgroup analyses were performed for preoperative instability and stiffness, as well as the number of components revised and level of implant constraint used.RESULTS: Revision for poor axial rotation in isolation improved KSS from 52 ± 22 to 84 ± 25 (P < .001), and flexion increased from 105 ± 21° to 115 ± 13° (P = .001). Revision in the setting of instability significantly improved the KSS (P < .001) but did not affect ROM (P = .172). Revision in the setting of stiffness significantly improved both KSS (P < .001) and ROM (P = .002). There was no statistically significant difference between the postoperative KSS (P = .889) and final knee flexion (P = .629) with single- or both-component revision TKA for isolated poor axial rotation or between the postoperative KSS (P = .956) and final knee flexion (P = .541) with or without the use of higher constraint during revision TKA for isolated poor axial rotation.CONCLUSION: Revision TKA for poor axial alignment improves clinical outcomes scores and functional ROM.

  View details for PubMedID 30853158

• Bone Regeneration by Controlled Release of BMP-2: A Rabbit Spinal Fusion Chamber Molecular Study. Tissue engineering. Part A Hu, T., Naidu, M., Yang, Z., Lam, W. M., Ramruttun, K. A., Ren, X. F., Ng, F., Wang, M., Liu, L., Tan, K. C., Kwok, K. T., Goodman, S. B., Goh, J., Wong, H. K. 2019

  Abstract

  Recombinant human bone morphogenetic protein (rhBMP-2) has been widely used in spine fusion surgery. However, high doses of rhBMP-2 delivered with absorbable collagen sponge (ACS) has led to inflammation-related adverse conditions. Polyelectrolyte complex (PEC) control release carrier can substantially reduce the rhBMP-2 dose and complication without compromising fusion. The molecular events underlying controlled release and their effects on spinal fusion remains unknown. In this study, a rabbit interbody spinal fusion chamber was designed to provide a controlled environment for profiling molecular events during the fusion process. Study groups included Group 1, PEC with 100g rhBMP-2; Group 2, ACS with 100g rhBMP-2; Group 3, ACS with 300g rhBMP-2; Group 4, autologous bone graft and Group 5, empty chamber. Manual palpation, CT and histological analysis showed that Group 1 and 3 achieved bone fusion, while the other groups showed no signs of fusion. Gene expression profiling showed robust induction of osteogenic markers in Groups 1 and 3, with modulated early induction of inflammatory genes in the PEC group. Delivery of 100g rhBMP-2 with ACS (Group 2) resulted in less upregulation of osteogenic genes, increased inflammatory genes expression, and upregulation of osteoclastic genes compared to Group 1. These results suggest that the manner of BMP-2 release at the interbody spinal defect site could dictate the balance of in-situ osteogenic and anti-osteogenic activities, affecting fusion outcomes. The molecular evidence supports PEC for sustained release of BMP-2 for spinal interbody fusion, and the feasibility of employing this novel interbody spinal fusion chamber for future molecular studies.

  View details for PubMedID 30727849

• Editorial Comment: 2018 Hip Society Proceedings CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B. 2019; 477 (2): 295–96

  View details for DOI 10.1097/CORR.0000000000000602

  View details for Web of Science ID 000472544900009

• Cytotoxicity of drugs injected into joints in orthopaedics BONE & JOINT RESEARCH Busse, P., Vater, C., Stiehler, M., Nowotny, J., Kasten, P., Bretschneider, H., Goodman, S. B., Gelinsky, M., Zwingenberger, S. 2019; 8 (2): 41–48

  View details for DOI 10.1302/2046-3758.82.BJR-2018-0099.R1

  View details for Web of Science ID 000460173700001

• Cytotoxicity of drugs injected into joints in orthopaedics. Bone & joint research Busse, P., Vater, C., Stiehler, M., Nowotny, J., Kasten, P., Bretschneider, H., Goodman, S. B., Gelinsky, M., Zwingenberger, S. 2019; 8 (2): 41-48

  Abstract

  Intra-articular injections of local anaesthetics (LA), glucocorticoids (GC), or hyaluronic acid (HA) are used to treat osteoarthritis (OA). Contrast agents (CA) are needed to prove successful intra-articular injection or aspiration, or to visualize articular structures dynamically during fluoroscopy. Tranexamic acid (TA) is used to control haemostasis and prevent excessive intra-articular bleeding. Despite their common usage, little is known about the cytotoxicity of common drugs injected into joints. Thus, the aim of our study was to investigate the effects of LA, GC, HA, CA, and TA on the viability of primary human chondrocytes and tenocytes in vitro.Human chondrocytes and tenocytes were cultured in a medium with three different drug dilutions (1:2; 1:10; 1:100). The following drugs were used to investigate cytotoxicity: lidocaine hydrochloride 1%; bupivacaine 0.5%; triamcinolone acetonide; dexamethasone 21-palmitate; TA; iodine contrast media; HA; and distilled water. Normal saline served as a control. After an incubation period of 24 hours, cell numbers and morphology were assessed.Using LA or GC, especially triamcinolone acetonide, a dilution of 1:100 resulted in only a moderate reduction of viability, while a dilution of 1:10 showed significantly fewer cell counts. TA and CA reduced viability significantly at a dilution of 1:2. Higher dilutions did not affect viability. Notably, HA showed no effects of cytotoxicity in all drug dilutions.The toxicity of common intra-articular injectable drugs, assessed by cell viability, is mainly dependent on the dilution of the drug being tested. LA are particularly toxic, whereas HA did not affect cell viability.Cite this article: P. Busse, C. Vater, M. Stiehler, J. Nowotny, P. Kasten, H. Bretschneider, S. B. Goodman, M. Gelinsky, S. Zwingenberger. Cytotoxicity of drugs injected into joints in orthopaedics. Bone Joint Res 2019;8:41-48. DOI: 10.1302/2046-3758.82.BJR-2018-0099.R1.

  View details for DOI 10.1302/2046-3758.82.BJR-2018-0099.R1

  View details for PubMedID 30915209

  View details for PubMedCentralID PMC6397327

• Suboptimal patellofemoral alignment is associated with poor clinical outcome scores after primary total knee arthroplasty ARCHIVES OF ORTHOPAEDIC AND TRAUMA SURGERY Narkbunnam, R., Electricwala, A. J., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2019; 139 (2): 249–54

  View details for DOI 10.1007/s00402-018-3073-z

  View details for Web of Science ID 000458199700013

• Editorial Comment: 2018 Hip Society Proceedings. Clinical orthopaedics and related research Goodman, S. B. 2019; 477 (2): 295–96

  View details for PubMedID 30794218

• Hematopoietic PBX-interacting protein mediates cartilage degeneration during the pathogenesis of osteoarthritis NATURE COMMUNICATIONS Ji, Q., Xu, X., Kang, L., Xu, Y., Xiao, J., Goodman, S. B., Zhu, X., Li, W., Liu, J., Gao, X., Yan, Z., Zheng, Y., Wang, Z., Maloney, W. J., Ye, Q., Wang, Y. 2019; 10

  View details for DOI 10.1038/s41467-018-08277-5

  View details for Web of Science ID 000456010800010

• Hematopoietic PBX-interacting protein mediates cartilage degeneration during the pathogenesis of osteoarthritis. Nature communications Ji, Q., Xu, X., Kang, L., Xu, Y., Xiao, J., Goodman, S. B., Zhu, X., Li, W., Liu, J., Gao, X., Yan, Z., Zheng, Y., Wang, Z., Maloney, W. J., Ye, Q., Wang, Y. 2019; 10 (1): 313

  Abstract

  Osteoarthritis (OA) has been recognized as the most common chronic age-related disease. Cartilage degeneration influences OA therapy. Here we report that hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP) is essential for OA development. Elevated HPIP levels are found in OA patients. Col2a1-CreERT2/HPIPf/f mice exhibit obvious skeletal abnormalities compared with their HPIPf/f littermates. HPIP deficiency in mice protects against developing OA. Moreover, intra-articular injection of adeno-associated virus carrying HPIP-specific short hairpin RNA in vivo attenuates OA histological signs. Notably, in vitro RNA-sequencing and chromatin immunoprecipitation sequencing profiles identify that HPIP modulates OA cartilage degeneration through transcriptional activation of Wnt target genes. Mechanistically, HPIP promotes the transcription of Wnt targets by interacting with lymphoid enhancer binding factor 1 (LEF1). Furthermore, HPIP potentiates the transcriptional activity of LEF1 and acetylates histone H3 lysine 56 in the promoters of Wnt targets, suggesting that HPIP is an attractive target in OA regulatory network.

  View details for PubMedID 30659184

• Preconditioned or IL4-Secreting Mesenchymal Stem Cells Enhanced Osteogenesis at Different Stages. Tissue engineering. Part A Lin, T., Kohno, Y., Huang, J., Romero-Lopez, M., Maruyama, M., Ueno, M., Pajarinen, J., Nathan, K., Yao, Z., Yang, F., Wu, J., Goodman, S. B. 2019

  Abstract

  Chronic inflammation-associated bone diseases involve continuous destruction and impaired regeneration of bone. Mesenchymal stem cell (MSC)-based therapy has great potential to modulate inflammatory responses and enhance tissue regeneration. We previously showed that lipopolysaccharide [LPS] plus TNF preconditioned MSCs or genetically modified inflammation-sensing (driven by NFB activation) IL4-secreting MSCs enhanced immunomodulation of macrophages to the more desired tissue repaired M2 type. In the current study, the paracrine regulation of therapeutic MSCs on the pro-inflammatory response and osteogenesis of macrophage-MSC co-cultures (representing endogenous cells) was examined using an in vitro transwell system. In the co-cultures, IL4-secreting MSCs decreased TNF and iNOS expression, and increased Arginase 1 and CD206 expression in the presence of LPS-contaminated polyethylene particles. The preconditioned MSCs decreased TNF and CD206 expression in the bottom MSC-macrophage co-cultures in the presence of contaminated particles. In osteogenesis assays, IL4-secreting MSCs decreased ALP expression, but increased alizarin red staining in the presence of contaminated particles. The preconditioned MSCs increased ALP and osteocalcin expression, and had no significant effect on alizarin red staining. These results suggest that potential treatments using preconditioned MSCs at an earlier stage, or IL4-secreting MSCs at a later stage could enhance bone regeneration in inflammatory conditions including periprosthetic osteolysis.

  View details for PubMedID 30652628

• 2-step stem cell therapy improves bone regeneration compared to concentrated bone marrow therapy. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Bolte, J., Vater, C., Culla, A. C., Ahlfeld, T., Nowotny, J., Kasten, P., Disch, A. C., Goodman, S. B., Gelinsky, M., Stiehler, M., Zwingenberger, S. 2019

  Abstract

  Adult stem cells are a promising tool to positively influence bone regeneration. Concentrated bone marrow therapy entails isolating osteoprogenitor cells during surgery with, however, only low cells yield. Two step stem cell therapy requires an additional harvesting procedure but generates high numbers of progenitor cells that facilitate osteogenic pre-differentiation. To further improve bone regeneration, stem cell therapy can be combined with growth factors from platelet rich plasma (PRP) or its lysate (PL) to potentially fostering vascularization. The aim of this study was to investigate the effects of bone marrow concentrate (BMC), osteogenic pre-differentiation of mesenchymal stromal cells (MSCs) and PL on bone regeneration and vascularization. Bone marrow from 4 different healthy human donors was used for either generation of BMC or for isolation of MSCs. Seventy-two mice were randomized to 6 groups (Control, PL, BMC, BMC+PL, pre-differentiated MSCs, pre-differentiated MSCs+PL). The influence of PL, BMC and pre-differentiated MSCs was investigated systematically in a 2mm femoral bone defect model. After a 6-week follow-up, the pre-differentiated MSCs+PL group showed the highest bone volume, highest grade of histological defect healing and highest number of bridged defects with measurable biomechanical stiffness. Using expanded and osteogenically pre-differentiated MSCs for treatment of a critical-size bone defect was favorable with regards to bone regeneration compared to treatment with cells from BMC. The addition of PL alone had no significant influence; therefore the role of PL for bone regeneration remains unclear. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30628121

• Angiotensin receptor blockade mimics the effect of exercise on recovery after orthopaedic trauma by decreasing pain and improving muscle regeneration. The Journal of physiology Tawfik, V. L., Quarta, M. n., Paine, P. n., Forman, T. E., Pajarinen, J. n., Takemura, Y. n., Goodman, S. B., Rando, T. A., Clark, J. D. 2019

  Abstract

  Our tibial fracture orthopaedic injury model in mice recapitulates the major manifestations of complex trauma including nociceptive sensitization, bone fracture, muscle fibrosis and muscle fibre loss. Delayed exercise after complex orthopaedic trauma results in decreased muscle fibrosis and improved pain Losartan, an angiotensin-receptor blocker with antifibrotic abilities, recapitulates the effect of exercise on post-injury recovery and may provide an enhanced recovery option for those who are unable to exercise after injury ABSTRACT: Chronic pain and disability after limb injury are major public health problems. Early mobilization after injury improves functional outcomes for patients but when and how to implement rehabilitation strategies remains a clinical challenge. Additionally, whether the beneficial effects of exercise can be reproduced using pharmacological tools remains unknown and may benefit patients who are unable to exercise due to immobilization. We developed a murine model of orthopaedic trauma combining tibia fracture and pin fixation with muscle damage. Behavioral measures included mechanical nociceptive thresholds and distances run on exercise wheels. Bone healing was quantified using microCT scanning, and muscle fibre size distribution and fibrosis were followed using immunohistochemistry. We found that the model provided robust mechanical allodynia, fibrosis and a shift to smaller average muscle fibre size lasting up to 5 weeks from injury. We also observed that allowing "late" (weeks 1-2) rather than "early" (weeks 0-1) exercise after injury resulted in greater overall running activity and greater reversal of allodynia. In parallel, the late running paradigm was associated with reduced muscle fibrosis, earlier increase in muscle fibre diameter and a short-term benefit in reducing callus volume. Providing the anti-fibrotic angiotensin receptor blocker losartan to mice in drinking water reduced both allodynia and muscle fibrosis. Combining losartan and late exercise provided no additional benefit. We conclude that early healing after orthopaedic trauma must be allowed prior to the initiation of exercise to achieve optimal pain, functional and physiological outcomes and that losartan is a viable candidate for translational studies. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1113/JP278991

  View details for PubMedID 31784993

• Periprosthetic Osteolysis: Mechanisms, Prevention and Treatment. Journal of clinical medicine Goodman, S. B., Gallo, J. n. 2019; 8 (12)

  Abstract

  Clinical studies, as well as in vitro and in vivo experiments have demonstrated that byproducts from joint replacements induce an inflammatory reaction that can result in periprosthetic osteolysis (PPOL) and aseptic loosening (AL). Particle-stimulated macrophages and other cells release cytokines, chemokines, and other pro-inflammatory substances that perpetuate chronic inflammation, induce osteoclastic bone resorption and suppress bone formation. Differentiation, maturation, activation, and survival of osteoclasts at the bone-implant interface are under the control of the receptor activator of nuclear factor kappa-Β ligand (RANKL)-dependent pathways, and the transcription factors like nuclear factor κB (NF-κB) and activator protein-1 (AP-1). Mechanical factors such as prosthetic micromotion and oscillations in fluid pressures also contribute to PPOL. The treatment for progressive PPOL is only surgical. In order to mitigate ongoing loss of host bone, a number of non-operative approaches have been proposed. However, except for the use of bisphosphonates in selected cases, none are evidence based. To date, the most successful and effective approach to preventing PPOL is usage of wear-resistant bearing couples in combination with advanced implant designs, reducing the load of metallic and polymer particles. These innovations have significantly decreased the revision rate due to AL and PPOL in the last decade.

  View details for DOI 10.3390/jcm8122091

  View details for PubMedID 31805704

• Diagnosis and Management of Implant Debris-Associated Inflammation. Expert review of medical devices Goodman, S. B., Gallo, J. n., Gibon, E. F., Takagi, M. n. 2019

  Abstract

  Introduction: Total joint replacement is one of the most common, safe and efficacious operations in all of surgery. However, one major long-standing and unresolved issue is the adverse biological reaction to byproducts of wear from the bearing surfaces and modular articulations. These inflammatory reactions are mediated by the innate and adaptive immune systems.Areas Covered: We review the etiology and pathophysiology of implant debris-associated inflammation, the clinical presentation and detailed work-up of these cases, and the principles and outcomes of non-operative and operative management. Furthermore, we suggest future strategies for prevention and novel treatments of implant related adverse biological reactions.Expert Commentary: The generation of byproducts from joint replacements is inevitable, due to repetitive loading of the implants. A clear understanding of the relevant biological principles, clinical presentations, investigative measures and treatments for implant-associated inflammatory reactions and periprosthetic osteolysis will help identify and treat patients with this issue earlier and more effectively. Although progressive implant-associated osteolysis is currently a condition that is treated surgically, with further research, it is hoped that non-operative biological interventions could prolong the lifetime of joint replacements that are otherwise functional and still salvageable.

  View details for DOI 10.1080/17434440.2020.1702024

  View details for PubMedID 31810395

• The Cost of Malnutrition in Total Joint Arthroplasty. The Journal of arthroplasty Bala, A. n., Ivanov, D. V., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2019

  Abstract

  Malnutrition is a known risk factor for complications and adverse outcomes after elective total joint arthroplasty (TJA), but little is known about the burden this risk factor places on the healthcare system. The purpose of this study was to evaluate the 90-day impact of malnutrition on medical and surgical complications and understand the increase in global reimbursements associated with TJA in malnourished patients.We queried a combined private-payer and Medicare database from 2007 to 2016 for TJA using International Classification of Diseases, 9th revision and Current Procedural Terminology codes. Patients with serum albumin level of <3.5 g/dL were gender, age, and mean Elixhauser Comorbidity Index matched against a cohort with a normal serum albumin level. Odds ratios and confidence intervals were calculated for complications at 90 days postoperatively. Mean index and 90-day global reimbursements were calculated for the two matched groups and compared using P-values.3053 protein malnourished patients receiving TJA were identified, and 12,202 matched protein nourished patients receiving TJA served as controls. At 90 days, the malnourished groups had increased risk for failure of multiple organ systems, periprosthetic joint infection, and reoperation. The mean 90-day increase in reimbursement was $3875 associated with performing a TJA on a protein malnourished patient (P < .001).This study demonstrates an association between malnourished patients and postoperative complications as well as significantly increased reimbursements. Understanding the reimbursement increases at 90 days for TJA in protein malnourished patients is important in the era of bundled payments.

  View details for DOI 10.1016/j.arth.2019.11.018

  View details for PubMedID 31879158

• Biomaterials in Orthopaedics ENCYCLOPEDIA OF BIOMEDICAL ENGINEERING, VOL 1 Gibon, E., Goodman, S. B., Narayan, R. 2019: 301–7

  View details for DOI 10.1016/B978-0-12-801238-3.11032-3

  View details for Web of Science ID 000517437200026

• Optimization and characterization of calcium phosphate transfection in mesenchymal stem cells. Tissue engineering. Part C, Methods Lo, C. W., Lin, T. H., Ueno, M. n., Romero-Lopez, M. n., Maruyama, M. n., Kohno, Y. n., Rhee, C. n., Yao, Z. n., Pérez-Cruz, M. n., Meyer, E. n., Goodman, S. B. 2019

  Abstract

  Mesenchymal stem cells (MSCs) have been used as a therapy to modulate diverse biological processes. To fulfill the requirements for different MSC therapies, safe and effective gene transfer methods for MSCs are critical. Calcium phosphate transfection is an inexpensive and well-described method without discernible biosafety issues; however, an optimal protocol has not been developed for MSCs. In this report, we optimized the protocol of calcium phosphate transfection for murine MSCs, and compared this protocol with other gene transfer methods in different strains of mice and in human cells. We found that transfection efficiency and cell viability showed an inverse relationship depending on serum concentration during the process of calcium phosphate transfection, in which 2% serum was chosen in the optimized protocol. The optimized protocol of calcium phosphate transfection showed a fine balance between efficiency (about 70-80%) and viability (doubling original cell number) compared to other methods. Human MSCs were more resistant to this protocol (about 30% efficiency) compared with murine MSCs. Moreover, MSC potential for osteogenesis, adipogenesis, and chondrogenesis was not affected by calcium phosphate transfection. Finally, MSCs transfected with the luciferase gene were injected into the murine distal femoral bone marrow cavity to monitor gene expression overtime in vivo. MSCs in the bone marrow environment showed extended expression of the luciferase that was transfected by calcium phosphate. This report provides an optimized protocol for calcium phosphate transfection for murine MSCs and characterizes gene over-expression in MSCs in the in vitro and in vivo environments.

  View details for DOI 10.1089/ten.TEC.2019.0147

  View details for PubMedID 31441373

• Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex. Bone & joint research Nathan, K. n., Lu, L. Y., Lin, T. n., Pajarinen, J. n., Jämsen, E. n., Huang, J. F., Romero-Lopez, M. n., Maruyama, M. n., Kohno, Y. n., Yao, Z. n., Goodman, S. B. 2019; 8 (10): 481–88

  Abstract

  Up to 10% of fractures result in undesirable outcomes, for which female sex is a risk factor. Cellular sex differences have been implicated in these different healing processes. Better understanding of the mechanisms underlying bone healing and sex differences in this process is key to improved clinical outcomes. This study utilized a macrophage-mesenchymal stem cell (MSC) coculture system to determine: 1) the precise timing of proinflammatory (M1) to anti-inflammatory (M2) macrophage transition for optimal bone formation; and 2) how such immunomodulation was affected by male versus female cocultures.A primary murine macrophage-MSC coculture system was used to demonstrate the optimal transition time from M1 to M2 (polarized from M1 with interleukin (IL)-4) macrophages to maximize matrix mineralization in male and female MSCs. Outcome variables included Alizarin Red staining, alkaline phosphatase (ALP) activity, and osteocalcin protein secretion.We found that 96 hours of M1 phenotype in male cocultures allowed for maximum matrix mineralization versus 72 hours in female cocultures. ALP activity and osteocalcin secretion were also enhanced with the addition of IL-4 later in male versus female groups. The sex of the cells had a statistically significant effect on the optimal IL-4 addition time to maximize osteogenesis.These results suggest that: 1) a 72- to 96-hour proinflammatory environment is critical for optimal matrix mineralization; and 2) there are immunological differences in this coculture environment due to sex. Optimizing immunomodulation during fracture healing may enhance and expedite the bone regeneration response. These findings provide insight into precise immunomodulation for enhanced bone healing that is sex-specific.Cite this article: K. Nathan, L. Y. Lu, T. Lin, J. Pajarinen, E. Jämsen, J-F. Huang, M. Romero-Lopez, M. Maruyama, Y. Kohno, Z. Yao, S. B. Goodman. Precise immunomodulation of the M1 to M2 macrophage transition enhances mesenchymal stem cell osteogenesis and differs by sex. Bone Joint Res 2019;8:481-488. DOI: 10.1302/2046-3758.810.BJR-2018-0231.R2.

  View details for DOI 10.1302/2046-3758.810.BJR-2018-0231.R2

  View details for PubMedID 31728188

  View details for PubMedCentralID PMC6825050

• Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 1: Glucocorticoid-Associated Osteonecrosis JOURNAL OF ARTHROPLASTY Yoon, B., Jones, L. C., Chen, C., Cheng, E. Y., Cui, Q., Drescher, W., Fukushima, W., Gangji, V., Goodman, S. B., Ha, Y., Hernigou, P., Hungerford, M., Iorio, R., Jo, W., Khanduja, V., Kim, H., Kim, S., Kim, T., Lee, H., Lee, M. S., Lee, Y., Lee, Y., Mont, M. A., Sakai, T., Sugano, N., Takao, M., Yamamoto, T., Koo, K. 2019; 34 (1): 163-+

  View details for DOI 10.1016/j.arth.2018.09.005

  View details for Web of Science ID 000452539200028

• Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 2: Alcohol-Associated Osteonecrosis JOURNAL OF ARTHROPLASTY Yoon, B., Jones, L. C., Chen, C., Cheng, E. Y., Cui, Q., Drescher, W., Fukushima, W., Gangji, V., Goodman, S. B., Ha, Y., Hernigou, P., Hungerford, M., Iorio, R., Jo, W., Khanduja, V., Kim, H., Kim, S., Kim, T., Lee, H., Lee, M. S., Lee, Y., Lee, Y., Mont, M. A., Sakai, T., Sugano, N., Takao, M., Yamamoto, T., Koo, K. 2019; 34 (1): 169-+

  View details for DOI 10.1016/j.arth.2018.09.006

  View details for Web of Science ID 000452539200029

• IgE-mediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis. eLife Wang, Q. n., Lepus, C. M., Raghu, H. n., Reber, L. L., Tsai, M. M., Wong, H. H., von Kaeppler, E. n., Lingampalli, N. n., Bloom, M. S., Hu, N. n., Elliott, E. E., Oliviero, F. n., Punzi, L. n., Giori, N. J., Goodman, S. B., Chu, C. R., Sokolove, J. n., Fukuoka, Y. n., Schwartz, L. B., Galli, S. J., Robinson, W. H. 2019; 8

  Abstract

  Osteoarthritis is characterized by articular cartilage breakdown, and emerging evidence suggests that dysregulated innate immunity is likely involved. Here, we performed proteomic, transcriptomic, and electron microscopic analyses to demonstrate that mast cells are aberrantly activated in human and murine osteoarthritic joint tissues. Using genetic models of mast cell deficiency, we demonstrate that lack of mast cells attenuates osteoarthritis in mice. Using genetic and pharmacologic approaches, we show that the IgE/FcεRI/Syk signaling axis is critical for the development of osteoarthritis. We find that mast cell-derived tryptase induces inflammation, chondrocyte apoptosis, and cartilage breakdown. Our findings demonstrate a central role for IgE-dependent mast cell activation in the pathogenesis of osteoarthritis, suggesting that targeting mast cells could provide therapeutic benefit in human osteoarthritis.This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

  View details for PubMedID 31084709

• Does Bariatric Surgery Normalize Risks After Total Knee Arthroplasty? Administrative Medicare Data. Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews Meller, M. M., Goodman, S. n., Gonzalez, M. H., Lau, E. n. 2019; 3 (12)

  Abstract

  Patients with morbid obesity, defined as body mass index of greater than 40 kg/m2, are being referred for weight loss and bariatric surgery before being accepted for a total knee arthroplasty (TKA). Previous studies have identified the risks associated with doing a TKA in an individual with an increased body mass index. We now present data identifying the same risks in individuals who have undergone bariatric surgery before submitting to TKA.(1) Has the bariatric surgery improved the risk profile for the subsequent TKA? (2) Does the type of bariatric procedure matter?A retrospective cohort study was conducted of patients who underwent bariatric surgery followed by TKA using Medicare hospital claims data. A study was undertaken using the Current Procedure Terminology codes and International Classification of Diseases-9 and International Classification of Diseases-10 for bariatric surgery. These identified entries were then cross-referenced to individuals who later underwent TKA, identified by CPT 27447, between 2004 and 2016. Twelve different types of complications which occurred in the 90-day period after the TKA were analyzed.Postbariatric bypass surgery patients showed a markedly elevated risk in most complications examined. In each category, the type of previous gastric surgery had notable differences in the post-TKA complication profile. In the implant failure category, the data demonstrated an even greater risk after a gastric bypass. When postbariatric patients were compared with morbidly obese individuals who had not undergone bariatric surgery, the hazard ratios (HRs) were markedly elevated for death (HR 1.47/bypass), implant failure (HR 1.58/sleeve), and pneumonia (HR 1.68/bypass).(1) Submitting to bariatric surgery is not sufficient to normalize risks. (2) The type of previous bariatric procedure is associated with the type of complications encountered. (3) We were unable to attribute TKA to bariatric failures. (4) Health systems and health care providers should be cautious in withholding care for patients with morbid obesity.

  View details for DOI 10.5435/JAAOSGlobal-D-19-00102

  View details for PubMedID 32072123

  View details for PubMedCentralID PMC7004493

• Hip or spine surgery first? The bone & joint journal Liu, N. n., Goodman, S. B., Lachiewicz, P. F., Wood, K. B. 2019; 101-B (6_Supple_B): 37–44

  Abstract

  Patients may present with concurrent symptomatic osteoarthritis (OA) of the hip and degenerative disorders of the lumbar spine, with surgical treatment being indicated for both. Whether arthroplasty of the hip or spinal surgery should be performed first remains uncertain.Clinical scenarios were devised for a survey asking the preferred order of surgery and the rationale for this decision for five fictional patients with both OA of the hip and degenerative lumbar disorders. These were symptomatic OA of the hip and: 1) lumbar spinal stenosis with neurological claudication; 2) lumbar degenerative spondylolisthesis with leg pain; 3) lumbar disc herniation with leg weakness; 4) lumbar scoliosis with back pain; and 5) thoracolumbar disc herniation with myelopathy. This survey was sent to 110 members of The Hip Society and 101 members of the Scoliosis Research Society. The choices of the surgeons were compared among scenarios and between surgical specialties using the chi-squared test. The free-text comments were analyzed using text-mining.Responses were received from 51 hip surgeons (46%) and 37 spine surgeons (37%). The percentages of hip surgeons recommending 'hip first' differed significantly among scenarios: 59% for scenario 1; 73% for scenario 2; 47% for scenario 3; 47% for scenario 4; and 10% for scenario 5 (p < 0.001). The percentages of spine surgeons recommending 'hip first' were 49% for scenario 1; 70% for scenario 2; 19% for scenario 3; 78% for scenario 4; and 0% for scenario 5. There were significant differences between the groups for scenarios 3 (more hip surgeons recommended 'hip first'; p = 0.012) and 4 (more hip surgeons recommended 'spine first'; p = 0.006).In patients with coexistent OA of the hip and degenerative disorders of the spine, the question of 'hip or spinal surgery first' elicits relatively consistent answers in some clinical scenarios, but remains controversial in others, even for experienced surgeons. The nature of neurological symptoms can influence surgeons' decision-making. Cite this article: Bone Joint J 2019;101-B(6 Supple B):37-44.

  View details for DOI 10.1302/0301-620X.101B6.BJJ-2018-1073.R1

  View details for PubMedID 31146559

• CORR Insights®: CORR® ORS Richard A. Brand Award: Disruption in Peroxisome Proliferator-Activated Receptor- γ (PPARG) Increases Osteonecrosis Risk Through Genetic Variance and Pharmacologic Modulation. Clinical orthopaedics and related research Goodman, S. B. 2019

  View details for DOI 10.1097/CORR.0000000000000789

  View details for PubMedID 31107340

• Tracking Cell Transplants in Femoral Osteonecrosis with Magnetic Resonance Imaging: A Proof-of-Concept Study in Patients CLINICAL CANCER RESEARCH Theruvath, A. J., Nejadnik, H., Muehe, A. M., Gassert, F., Lacayo, N. J., Goodman, S. B., Daldrup-Link, H. E. 2018; 24 (24): 6223–29

  View details for DOI 10.1158/1078-0432.CCR-18-1687

  View details for Web of Science ID 000453267600016

• Statin use is associated with less postoperative cardiac arrhythmia after total hip arthroplasty. Hip international : the journal of clinical and experimental research on hip pathology and therapy Chen, M. J., Bala, A., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Aaronson, A. J., Amanatullah, D. F. 2018: 1120700018816091

  Abstract

  INTRODUCTION:: While statins have been found to reduce postoperative atrial fibrillation after cardiac surgery, little is known about their use in total hip arthroplasty (THA). This study investigated if statins would similarly reduce postoperative arrhythmias in patients undergoing THA.METHODS:: We queried a large Medicare and private-payer database from 2005 to 2012 and identified 12,075 patients who were on a statin prior to THA. We then age and sex matched 34,446 non-statin users who underwent THA. Baseline comorbidities and postoperative complications were obtained and assessed via standard descriptive statistics.RESULTS:: The statin users had more preoperative comorbidities including congestive heart failure, valvular heart disease, pulmonary and renal disease, diabetes, hypertension, obesity, and anaemia (all p values < 0.001). Postoperatively, the statin users had a statistically higher 90-day incidence of transfusion, acute renal failure, heart failure, pneumonia, and sepsis/shock. All new-onset cardiac arrhythmia was significantly less frequent in the statin group at 2weeks (3.88% vs. 4.72%, p < 0.001), 30days (4.47% vs. 5.29%, p < 0.001), and 90days (5.44% vs. 6.31%, p = 0.001) postoperative. There was no difference in the frequency of venous thromboembolism, myocardial infarction, postoperative anaemia, or bleeding at 90days postoperative.DISCUSSION:: Despite being medically sicker at baseline with multiple risk factors for atrial fibrillation compared to the non-statin users, the statin users displayed a consistently lower occurrence of postoperative cardiac arrhythmia in this retrospective cohort study. Statins may therefore be beneficial in the preoperative optimisation of medically complex patients undergoing THA.

  View details for PubMedID 30526117

• Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology Lin, T., Pajarinen, J., Kohno, Y., Huang, J., Maruyama, M., Romero-Lopez, M., Nathan, K., Yao, Z., Goodman, S. B. 2018: fj201801845R

  Abstract

  Mesenchymal stem cell (MSC)-mediated immunomodulation affects both innate and adaptive immune systems. These responses to environmental cues, such as pathogen-associated molecular patterns, damage-associated molecular patterns, or proinflammatory cytokines, are crucial for resolution of inflammation, as well as successful tissue healing and regeneration. We observed that intermittent, repeated exposure of MSCs to LPS induced stronger NF-kappaB activation than singular stimulation. A similar phenomenon, named innate immune memory or trained immunity, has been reported with macrophages. However, the potential regulation of "immune memory" in nonclassic immune cells, such as MSCs, has not been reported. In the current study, we chose IFN-gamma plus TNF-alpha restimulation-induced iNOS expression as a model of MSC activation, because IFN-gamma and TNF-alpha play crucial roles in MSC-mediated immunomodulation. The iNOS expression was enhanced in LPS-trained MSCs, 3 d after a washout period following primary stimulation. LPS-trained MSCs enhanced the anti-inflammatory (arginase 1 and CD206) marker expression, but decreased the proinflammatory marker (TNF-alpha, IL-1beta, iNOS, and IL-6) expression using an MSC-macrophage coculture model. In contrast, LPS-trained MSCs demonstrated a defective regulation on CD4 T-cell proliferation. Mechanistic studies suggested that histone methylation and the JNK pathway are involved in LPS-trained immunomodulation in MSCs. Our results demonstrate differential immunomodulatory effects of trained MSCs on macrophages and T cells. These immunomodulatory consequences are critical, because they will have a major impact on current MSC-based cell therapies.-Lin, T., Pajarinen, J., Kohno, Y., Huang, J.-F., Maruyama, M., Romero-Lopez, M., Nathan, K., Yao, Z., Goodman, S. B. Trained murine mesenchymal stem cells have anti-inflammatory effect on macrophages, but defective regulation on T-cell proliferation.

  View details for PubMedID 30521384

• The effects of a functionally-graded scaffold and bone marrow-derived mononuclear cells on steroid-induced femoral head osteonecrosis BIOMATERIALS Maruyama, M., Nabeshima, A., Pan, C., Behn, A. W., Thio, T., Lin, T., Pajarinen, J., Kawai, T., Takagi, M., Goodman, S. B., Yang, Y. 2018; 187: 39–46

  View details for DOI 10.1016/j.biomaterials.2018.09.030

  View details for Web of Science ID 000449446000005

• Erratum to: Can a Conical Implant Successfully Address Complex Anatomy in Primary THA? Radiographs and Hip Scores at Early Followup. Clinical orthopaedics and related research Zhang, G., Goodman, S. B., Maloney, W. J., Huddleston, J. I. 2018; 476 (12): 2458

  View details for PubMedID 30427315

• Proximal Femoral Shape Changes the Risk of a Leg Length Discrepancy After Primary Total Hip Arthroplasty JOURNAL OF ARTHROPLASTY Lim, Y., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2018; 33 (12): 3699–3703

  View details for DOI 10.1016/j.arth.2018.08.008

  View details for Web of Science ID 000450300700019

• Can a Conical Implant Successfully Address Complex Anatomy in Primary THA? Radiographs and Hip Scores at Early Followup (vol 474, pg 459, 2016) CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Zhang, G., Goodman, S. B., Maloney, W. J., Huddleston, J. I. 2018; 476 (12): 2458

  View details for DOI 10.1097/CORR.0000000000000540

  View details for Web of Science ID 000457619900027

• Suboptimal patellofemoral alignment is associated with poor clinical outcome scores after primary total knee arthroplasty. Archives of orthopaedic and trauma surgery Narkbunnam, R., Electricwala, A. J., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2018

  Abstract

  BACKGROUND: Proper patellofemoral alignment is an important goal in total knee arthroplasty (TKA). Acceptable patellar alignment is defined as patellar tilt less than or equal to 5° and patellar displacement less than or equal to 5mm. Previous studies reported an incidence of post-operative patellar malalignment in TKA from 7 to 35%. However, correlation between patellar malalignment and clinical outcome after TKA remains unclear. The purpose of the present study was to evaluate the effect of patellar tilt and displacement on the clinical outcome of TKA.METHODS: A retrospective review of 138 primary TKAs with a minimum of 2 year follow-up is reported. Pre-operative and post-operative mechanical axis, patellar tilting angle and patellar displacement were measured. Clinical outcomes were evaluated by the knee functional scores including the Knee Society Score (KSS), Knee injury and Osteoarthritis Outcome Score (KOOS), and Western Ontario McMaster University Osteoarthritis Index (WOMAC) at final follow-up.RESULTS: Forty-two (30%) primary TKAs had suboptimal patellofemoral alignment with a patellar tilt angle greater than 5° or lateral patellar displacement of more than 5mm. There was no statistical difference in pre-operative mechanical axis, pre-operative patellar tilt angle, or pre-operative lateral patellar displacement between the primary TKAs with proper patellofemoral alignment and those with suboptimal alignment. Patients with post-operative patellar tilt or displacement had clinically significant reductions in KSS, KOOS, and WOMAC when compared with patients without post-operative patellar tilt or displacement. The odds of having a fair or poor post-operative result, an odds ratio of 3.4 (95% CI 1.6-7.2) for KSS, 6.4 (95% CI 2.9-14.2) for KOOS, and 5.9 (95% CI 2.6-13.5) for WOMAC, were associated with suboptimal patellofemoral alignment.CONCLUSION: Establishing proper patellofemoral alignment remains an essential goal of primary TKA. There is a strong association between suboptimal post-operative patellofemoral alignment and poor clinical outcome scores after primary TKA.

  View details for PubMedID 30483917

• Strategies for Weight Reduction Prior to Total Joint Arthroplasty JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME Chen, M. J., Bhowmick, S., Beseler, L., Schneider, K. L., Kahan, S. I., Morton, J. M., Goodman, S. B., Amanatullah, D. F. 2018; 100 (21)

  View details for DOI 10.2106/JBJS.18.00020

  View details for Web of Science ID 000449435200015

• Strategies for Weight Reduction Prior to Total Joint Arthroplasty. The Journal of bone and joint surgery. American volume Chen, M. J., Bhowmick, S., Beseler, L., Schneider, K. L., Kahan, S. I., Morton, J. M., Goodman, S. B., Amanatullah, D. F. 2018; 100 (21): 1888–96

  View details for PubMedID 30399084

• Effect of Computer Navigation on Complication Rates Following Unicompartmental Knee Arthroplasty JOURNAL OF ARTHROPLASTY Chona, D., Bala, A., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. E. 2018; 33 (11): 3437-+

  View details for DOI 10.1016/j.arth.2018.06.030

  View details for Web of Science ID 000446993500014

• NF kappa B sensing IL-4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Lin, T., Kohno, Y., Huang, J., Romero-Lopez, M., Pajarinen, J., Maruyama, M., Nathan, K., Yao, Z., Goodman, S. B. 2018; 106 (10): 2744–52

  View details for DOI 10.1002/jbm.a.36504

  View details for Web of Science ID 000448177600018

• Surgery Before Subspecialty Referral for Periprosthetic Knee Infection Reduces the Likelihood of Infection Control CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Song, S., Goodman, S. B., Suh, G., Finlay, A. K., Huddleston, J. I., Maloney, W. J., Amanatullah, D. F. 2018; 476 (10): 1995–2002

  View details for DOI 10.1097/CORR.0000000000000423

  View details for Web of Science ID 000452515700021

• Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 2: Alcohol-Associated Osteonecrosis. The Journal of arthroplasty Yoon, B., Jones, L. C., Chen, C., Cheng, E. Y., Cui, Q., Drescher, W., Fukushima, W., Gangji, V., Goodman, S. B., Ha, Y., Hernigou, P., Hungerford, M., Iorio, R., Jo, W., Khanduja, V., Kim, H., Kim, S., Kim, T., Lee, H. Y., Lee, M. S., Lee, Y., Lee, Y. J., Mont, M. A., Sakai, T., Sugano, N., Takao, M., Yamamoto, T., Koo, K. 2018

  Abstract

  BACKGROUND: Although alcohol is a leading risk factor for osteonecrosis of the femoral head (ONFH) and its prevalence reportedly ranges from 20% to 45%, there are no unified classification criteria for this subpopulation. In 2015, Association Research Circulation Osseous decided to develop classification criteria for alcohol-associated ONFH.METHODS: In June of 2017, Association Research Circulation Osseous formed a task force to conduct a Delphi survey. The task force invited 28 experts in osteonecrosis/bone circulation from 8 countries. Each round of the Delphi survey included questionnaires, analysis of replies, and feedback reports to the panel. After 3 rounds of the survey, consensus was reached on the classification criteria. The response rates for the 3 Delphi rounds were 100% (round 1), 96% (round 2), and 100% (round 3).RESULTS: The consensus on the classification criteria of alcohol-associated ONFH included the following: (1) patients should have a history of alcohol intake >400 mL/wk (320 g/wk, any type of alcoholic beverage) of pure ethanol for more than 6 months; (2) ONFH should be diagnosed within 1 year after alcohol intake of this dose; and (3) patients should not have other risk factor(s).CONCLUSION: ARCO-established classification criteria to standardize clinical studies concerning AA-ONFH.

  View details for PubMedID 30348559

• Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 1: Glucocorticoid-Associated Osteonecrosis. The Journal of arthroplasty Yoon, B., Jones, L. C., Chen, C., Cheng, E. Y., Cui, Q., Drescher, W., Fukushima, W., Gangji, V., Goodman, S. B., Ha, Y., Hernigou, P., Hungerford, M., Iorio, R., Jo, W., Khanduja, V., Kim, H., Kim, S., Kim, T., Lee, H. Y., Lee, M. S., Lee, Y., Lee, Y. J., Mont, M. A., Sakai, T., Sugano, N., Takao, M., Yamamoto, T., Koo, K. 2018

  Abstract

  BACKGROUND: Glucocorticoid usage, a leading cause of osteonecrosis of the femoral head (ONFH), and its prevalence was reported in 25%-50% of non-traumatic ONFH patients. Nevertheless, there have been no unified criteria to classify glucocorticoid-associated ONFH (GA-ONFH). In 2015, the Association Research Circulation Osseous addressed the issue of developing a classification scheme.METHODS: In June 2017, a task force was set up to conduct a Delphi survey concerning ONFH. The task force invited 28 experts in osteonecrosis/bone circulation from 8 countries. Each round of the Delphi survey consists of questionnaires, analysis of replies, and feedback reports to the panel. After 3 rounds of the survey, the panel reached a consensus on the classification criteria. The response rates were 100% (Round 1), 96% (Round 2), and 100% (Round 3), respectively.RESULTS: The consensus on the classification criteria of GA-ONFH included the following: (1) patients should have a history of glucocorticoid use >2 g of prednisolone or its equivalent within a 3-month period; (2) osteonecrosis should be diagnosed within 2 years after glucocorticoid usage, and (3) patients should not have other risk factor(s) besides glucocorticoids.CONCLUSION: Association Research Circulation Osseous established classification criteria to standardize clinical studies concerning GA-ONFH.

  View details for PubMedID 30348552

• Identification of the Human Skeletal Stem Cell. Cell Chan, C. K., Gulati, G. S., Sinha, R., Tompkins, J. V., Lopez, M., Carter, A. C., Ransom, R. C., Reinisch, A., Wearda, T., Murphy, M., Brewer, R. E., Koepke, L. S., Marecic, O., Manjunath, A., Seo, E. Y., Leavitt, T., Lu, W., Nguyen, A., Conley, S. D., Salhotra, A., Ambrosi, T. H., Borrelli, M. R., Siebel, T., Chan, K., Schallmoser, K., Seita, J., Sahoo, D., Goodnough, H., Bishop, J., Gardner, M., Majeti, R., Wan, D. C., Goodman, S., Weissman, I. L., Chang, H. Y., Longaker, M. T. 2018; 175 (1): 43

  Abstract

  Stem cell regulation and hierarchical organization ofhuman skeletal progenitors remain largely unexplored. Here, we report the isolation of a self-renewing and multipotent human skeletal stem cell (hSSC) that generates progenitors of bone, cartilage, and stroma, but not fat. Self-renewing and multipotent hSSCs are present in fetal and adult bones and can also be derived from BMP2-treated human adipose stroma (B-HAS) and induced pluripotent stem cells (iPSCs). Gene expression analysis of individual hSSCs reveals overall similarity between hSSCs obtained from different sources and partially explains skewed differentiation toward cartilage in fetal and iPSC-derived hSSCs. hSSCs undergo local expansion in response to acute skeletal injury. In addition, hSSC-derived stroma can maintain human hematopoietic stem cells (hHSCs) in serum-free culture conditions. Finally, we combine gene expression and epigenetic data of mouse skeletal stem cells (mSSCs) and hSSCs to identify evolutionarily conserved and divergent pathways driving SSC-mediated skeletogenesis. VIDEO ABSTRACT.

  View details for PubMedID 30241615

• The effects of a functionally-graded scaffold and bone marrow-derived mononuclear cells on steroid-induced femoral head osteonecrosis. Biomaterials Maruyama, M., Nabeshima, A., Pan, C., Behn, A. W., Thio, T., Lin, T., Pajarinen, J., Kawai, T., Takagi, M., Goodman, S. B., Yang, Y. P. 2018; 187: 39–46

  Abstract

  Osteonecrosis of the femoral head (ONFH) is a debilitating disease that may progress to femoral head collapse and subsequently, degenerative arthritis. Although injection of bone marrow-derived mononuclear cells (BMMCs) is often performed with core decompression (CD) in the early stage of ONFH, these treatments are not always effective in prevention of disease progression and femoral head collapse. We previously described a novel 3D printed, customized functionally-graded scaffold (FGS) that improved bone growth in the femoral head after CD in a normal healthy rabbit, by providing structural and mechanical guidance. The present study demonstrates similar results of the FGS in a rabbit steroid-induced osteonecrosis model. Furthermore, the injection of BMMCs into the CD decreased the osteonecrotic area in the femoral head. Thus, the combination of FGS and BMMC provides a new therapy modality that may improve the outcome of CD for early stage of ONFH by providing both enhanced biological and biomechanical cues to promote bone regeneration in the osteonecrotic area.

  View details for PubMedID 30292940

• Identification of the Human Skeletal Stem Cell CELL Chan, C. F., Gulati, G. S., Sinha, R., Tompkins, J., Lopez, M., Carter, A. C., Ransom, R. C., Reinisch, A., Wearda, T., Murphy, M., Brewer, R. E., Koepke, L. S., Marecic, O., Manjunath, A., Seo, E., Leavitt, T., Lu, W., Allison Nguyen, Conley, S. D., Salhotra, A., Ambrosi, T. H., Borrelli, M. R., Siebel, T., Chan, K., Schallmoser, K., Seita, J., Sahoo, D., Goodnough, H., Bishop, J., Gardner, M., Majeti, R., Wan, D. C., Goodman, S., Weissman, I. L., Chang, H. Y., Longaker, M. T. 2018; 175 (1): 43-+

  View details for DOI 10.1016/j.cell.2018.07.029

  View details for Web of Science ID 000445120000013

• Tracking Cell Transplants in Femoral Osteonecrosis with Magnetic Resonance Imaging: A Proof of Concept Study in Patients. Clinical cancer research : an official journal of the American Association for Cancer Research Theruvath, A. J., Nejadnik, H., Muehe, A. M., Gassert, F., Lacayo, N. J., Goodman, S. B., Daldrup-Link, H. E. 2018

  Abstract

  PURPOSE: Osteonecrosis (ON) is a devastating complication of high dose corticosteroid therapy in cancer patients. Core decompression for prevention of bone collapse has been recently combined with the delivery of autologous concentrated bone marrow aspirates. The purpose of our study was to develop an imaging test for the detection of transplanted bone marrow cells in ON lesions.EXPERIMENTAL DESIGN: In a prospective proof-of-concept clinical trial (NCT02893293), we performed serial MR imaging studies of nine hip joints of seven ON patients before and after core decompression. 24-48hours prior to the surgery, we injected ferumoxytol nanoparticles intravenously to label cells in normal bone marrow with iron oxides. During the surgery, iron labeled bone marrow cells were aspirated from the iliac crest, concentrated and then injected into the decompression track. Following surgery, patients received follow-up MRI up to 6 months after bone marrow cell transplantation.RESULTS: Iron labeled cells could be detected in the access canal by a dark (negative) signal on T2*-weighted MR images. T2* relaxation times of iron labeled cell transplants were significantly lower compared to unlabeled cell transplants of control patients who were not injected with ferumoxytol (P = 0.02). Clinical outcomes of patients who received ferumoxytol-labeled or unlabeled cell transplants were not significantly different (P = 1), suggesting that the added ferumoxytol administration did not negatively affect bone repair.CONCLUSIONS: This immediately clinically applicable imaging test could become a powerful new tool to monitor the effect of therapeutic cells on bone repair outcomes after corticosteroid-induced osteonecrosis.

  View details for PubMedID 30224340

• Periprosthetic Bacterial Biofilm and Quorum Sensing JOURNAL OF ORTHOPAEDIC RESEARCH Mooney, J. A., Pridgen, E. M., Manasherob, R., Suh, G., Blackwell, H. E., Barron, A. E., Bollyky, P. L., Goodman, S. B., Amanatullah, D. F. 2018; 36 (9): 2331–39

  View details for DOI 10.1002/jor.24019

  View details for Web of Science ID 000443808900002

• A Tissue Engineering Approach for Treating Early Osteonecrosis of the Femoral Head REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE Goodman, S. B. 2018; 4 (3): 162–66

  View details for DOI 10.1007/s40883-018-0058-y

  View details for Web of Science ID 000445496200006

• Surgery Before Subspecialty Referral for Periprosthetic Knee Infection Reduces the Likelihood of Infection Control. Clinical orthopaedics and related research Song, S. Y., Goodman, S. B., Suh, G., Finlay, A. K., Huddleston, J. I., Maloney, W. J., Amanatullah, D. F. 2018

  Abstract

  BACKGROUND: Failure to control a periprosthetic joint infection (PJI) often leads to referral of the patient to a tertiary care institution. However, there are no data regarding the effect of prior surgical intervention for PJI on subsequent infection control.QUESTIONS/PURPOSES: (1) Is the likelihood of 2-year infection-free survival worse if an initial surgery for PJI was performed before referral to a tertiary care center when compared with after referral for definitive treatment? (2) Is the likelihood of identifying a causal organism during PJI worse if the initial surgery for PJI was performed before referral to a tertiary care center when compared with after referral for definitive treatment? (3) We calculated how many patients are harmed by the practice of surgically attempting to treat PJI before referral to a tertiary care center when compared with treatment after referral to a tertiary care center for definitive treatment.METHODS: Among 179 patients (182 TKAs) who were referred for PJI between 2004 and 2014, we retrospectively studied 160 patients (163 TKAs) who had a minimum of 2 years of followup after surgical treatment or had failure of treatment within 2 years. Nineteen TKAs (19 patients) were excluded from the study; 13 patients (7%) had < 2-year followup, three patients had infected periprosthetic fractures, and three patients had infected extensor mechanism reconstruction. Eighty-six patients (88 TKAs, two bilateral [54%]) had no surgical treatment before referral to our institution for PJI management, and 75 patients (75 TKAs [46%]) had PJI surgery before referral. The mean followup was 2.4 ± 1.2 years for patients with PJI surgery before referral and 2.8 ± 1.3 years for patients with no surgery before referral (p = 0.065). Infection-free survival was defined as prosthesis retention without further surgical intervention or antibiotic suppression. During the period, further surgical intervention generally was performed after failure of irrigation and debridement, a one- or two-stage procedure, or between stages of a two-stage reimplantation without documentation of an eradiated infection, and antibiotic suppression generally was used when patients were not medically sound for surgical intervention or definitive implants were placed after the second of a two-stage procedure with positive cultures; these criteria were applied similarly to all patients during this time period in both study groups. Endpoints were assessed using a longitudinally maintained institutional database, and the treating surgeons were not involved in data abstraction. Relative and absolute risk reductions with 95% confidence intervals (CIs) as well as a Kaplan-Meier survival curve with a Cox proportional hazard model were used to evaluate survival adjusting for significant covariates. The number needed to harm is calculated as the number needed to treat. It is the reciprocal of the absolute risk reduction or production by an intervention.RESULTS: The cumulative infection-free survival rate of TKAs at 2 years or longer was worse when PJI surgery was performed before referral to a tertiary center (80%; 95% CI, 69%-87%) compared with when no PJI surgery was performed before referral (94%; 95% CI, 87%-98%; log-rank test p = 0.006). Additionally, PJI surgery before referral resulted in a lower likelihood of causative microorganism identification (52 of 75 [69%]) compared with patients having surgery at the tertiary center (77 of 88 [88%]; odds ratio, 2.71; 95% CI, 1.28-4.70; p = 0.006). With regard to the infection-free survival rate of TKAs, the number needed to harm was 7.0 (95% CI, 4.1-22.5), meaning the referral of less than seven patients to a tertiary care center for definitive surgical management of PJI before intervention at the referring hospital prevents one infection-related failure. With regard to the culture negativity in PJI, the number needed to harm was 5.5 (95% CI, 3.3-16.7), meaning the referral of less than six patients to a tertiary care institution for PJI before surgery at the outside hospital prevents the diagnosis of one culture-negative infection.CONCLUSIONS: Surgical treatment of a PJI before referral for subspecialty surgical management increases the risk of failure of subsequent surgical management. The prevalence of culture-negative PJI was much higher if surgery was attempted before referral to a tertiary care center when compared with referral before treatment. This suggests that surgical treatment of PJI before referral to a treating center with specialized expertise in PJI compromises the infection-free survival and impacts infecting organism isolation.LEVEL OF EVIDENCE: Level III, therapeutic study.

  View details for PubMedID 30179927

• Proximal Femoral Shape Changes the Risk of a Leg Length Discrepancy After Primary Total Hip Arthroplasty. The Journal of arthroplasty Lim, Y. W., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2018

  Abstract

  BACKGROUND: To evaluate how canal morphology affects the technical aspects of total hip arthroplasty, we investigated the effects of femoral cortical index (FCI) on the re-establishment of leg length at the conclusion of surgery.METHODS: We retrospectively reviewed age, gender, body mass index, and radiographs of 516 patients with osteoarthritis or osteonecrosis who underwent unilateral cementless primary total hip arthroplasty between 2008 and 2015. Patients were divided into level of FCI and leg length discrepancy (LLD). Each cohort was compared in terms of demographics and LLD. One-way analysis of variance and Kruskal-Wallis test were used.RESULTS: The mean FCI and LLD were 0.6 ± 0.1 and 3.5 ± 6.3 mm, respectively. Utilization of an extended offset stem was highest with Dorr type A and B hips (P= .001). High FCI increased the risk of lengthening (P= .017) and low FCI increased the risk of shortening (P= .005).CONCLUSION: A high FCI increases the probability of a leg length increase and a low FCI increases the probability of a leg length decrease. Surgeons might consider informing patients in advance of possible variation in leg length depending on the patients' proximal femoral shape and bony quality.

  View details for PubMedID 30173942

• NFkappaB sensing IL-4 secreting mesenchymal stem cells mitigate the proinflammatory response of macrophages exposed to polyethylene wear particles. Journal of biomedical materials research. Part A Lin, T., Kohno, Y., Huang, J., Romero-Lopez, M., Pajarinen, J., Maruyama, M., Nathan, K., Yao, Z., Goodman, S. B. 2018

  Abstract

  Total joint replacement is a highly effective treatment for patients with end-stage arthritis. Proinflammatory macrophages (M1) mediate wear particle-associated inflammation and bone loss. Anti-inflammatory macrophages (M2) help resolve tissue damage and favor bone regeneration. Mesenchymal stem cell (MSC)-based therapy mitigates the M1 dominated inflammatory reaction and favorably modulates the bone remodeling process. In the current study, the immunomodulating ability of (1) unmodified MSCs, (2) MSCs preconditioned by NFkappaB stimulating ligands [lipopolysaccharide (LPS) plus TNFalpha], and (3) genetically modified MSCs that secrete IL-4 as a response to NFkappaB activation (NFkappaB-IL4) was compared in a macrophage/MSC co-culture system. Sterile or LPS-contaminated ultra-high molecular weight polyethylene particles were used to induce the proinflammatory responses in the macrophages. Contaminated particles induced M1 marker expression (TNFalpha, IL1beta, and iNOS), while NFkappaB-IL4 MSCs modulated the macrophages from an M1 phenotype into a more favorable M2 phenotype (Arginase 1/Arg 1 and CD206 high). The IL4 secretion by NFkappaB-IL4 MSCs was significantly induced by the contaminated particles. The induction of Arg 1 and CD206 in macrophages via the preconditioned or naive MSCs was negligible when compared with NFkappaB-IL4 MSC. Our findings indicated that NFkappaB-IL4 MSCs have the "on-demand" immunomodulatory ability to mitigate wear particle-associated inflammation with minimal adverse effects. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2018.

  View details for PubMedID 30084534

• Transplanted interleukin-4--secreting mesenchymal stromal cells show extended survival and increased bone mineral density in the murine femur. Cytotherapy Lin, T., Pajarinen, J., Kohno, Y., Maruyama, M., Romero-Lopez, M., Huang, J., Nathan, K., Khan, T. N., Yao, Z., Goodman, S. B. 2018

  Abstract

  BACKGROUND: Mesenchymal stromal cell (MSC)-based therapy has great potential to modulate chronic inflammation and enhance tissue regeneration. Crosstalk between MSC-lineage cells and polarized macrophages is critical for bone formation and remodeling in inflammatory bone diseases. However, the translational application of this interaction is limited by the short-term viability of MSCs after cell transplantation.METHODS: Three types of genetically modified (GM) MSCs were created: (1) luciferase-expressing reporter MSCs; (2) MSCs that secrete interleukin (IL)-4 either constitutively; and (3) MSCs that secrete IL-4 as a response to nuclear factor kappa-light-chain-enhancer of activated B cell (NFkappaB) activation. Cells were injected into the murine distal femoral bone marrow cavity. MSC viability and bone formation were examined in vivo. Cytokine secretion was determined in a femoral explant organ culture model.RESULTS: The reporter MSCs survived up to 4 weeks post-implantation. No difference in the number of viable cells was found between high (2.5 * 106) and low (0.5 * 106) cell-injected groups. Injection of 2.5 * 106 reporter MSCs increased local bone mineral density at 4 weeks post-implantation. Injection of 0.5 * 106 constitutive IL-4 or NFkappaB-sensing IL-4-secreting MSCs increased bone mineral density at 2 weeks post-implantation. In the femoral explant organ culture model, LPS treatment induced IL-4 secretion in the NFkappaB-sensing IL-4-secreting MSC group and IL-10 secretion in all the femur samples. No significant differences in tumor necrosis factor (TNF)alpha and IL-1beta secretion were observed between the MSC-transplanted and control groups in the explant culture.DISCUSSION: Transplanted GM MSCs demonstrated prolonged cell viability when transplanted to a compatible niche within the bone marrow cavity. GM IL-4-secreting MSCs may have great potential to enhance bone regeneration in disorders associated with chronic inflammation.

  View details for PubMedID 30077567

• Transplanted interleukin-4-secreting mesenchymal stromal cells show extended survival and increased bone mineral density in the murine femur CYTOTHERAPY Lin, T., Pajarinen, J., Kohno, Y., Maruyama, M., Romero-Lopez, M., Huang, J., Nathan, K., Khan, T. N., Yao, Z., Goodman, S. B. 2018; 20 (8): 1028–36

  View details for DOI 10.1016/j.jcyt.2018.06.009

  View details for Web of Science ID 000443716400005

• Systematic characterization of 3D-printed PCL/β-TCP scaffolds for biomedical devices and bone tissue engineering: influence of composition and porosity. Journal of materials research Bruyas, A., Lou, F., Stahl, A. M., Gardner, M., Maloney, W., Goodman, S., Yang, Y. P. 2018; 33 (14): 1948-1959

  Abstract

  This work aims at providing guidance through systematic experimental characterization, for the design of 3D printed scaffolds for potential orthopaedic applications, focusing on fused deposition modeling (FDM) with a composite of clinically available polycaprolactone (PCL) and β-tricalcium phosphate (β-TCP). First, we studied the effect of the chemical composition (0% to 60% β-TCP/PCL) on the scaffold's properties. We showed that surface roughness and contact angle were respectively proportional and inversely proportional to the amount of β-TCP, and that degradation rate increased with the amount of ceramic. Biologically, the addition of β-TCP enhanced proliferation and osteogenic differentiation of C3H10. Secondly, we systematically investigated the effect of the composition and the porosity on the 3D printed scaffold mechanical properties. Both an increasing amount of β-TCP and a decreasing porosity augmented the apparent Young's modulus of the 3D printed scaffolds. Third, as a proof-of-concept, a novel multi-material biomimetic implant was designed and fabricated for potential disk replacement.

  View details for DOI 10.1557/jmr.2018.112

  View details for PubMedID 30364693

  View details for PubMedCentralID PMC6197810

• Systematic characterization of 3D-printed PCL/beta-TCP scaffolds for biomedical devices and bone tissue engineering: Influence of composition and porosity JOURNAL OF MATERIALS RESEARCH Bruyas, A., Lou, F., Stahl, A. M., Gardner, M., Maloney, W., Goodman, S., Yang, Y. 2018; 33 (14): 1948–59

  View details for DOI 10.1557/jmr.2018.112

  View details for Web of Science ID 000440179300003

• Low intrapatient variability of histomorphological findings in periprosthetic tissues from revised metal/ceramic on polyethylene joint arthroplasties JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS Vaculova, J., Gallo, J., Hurnik, P., Motyka, O., Goodman, S. B., Dvorackova, J. 2018; 106 (5): 2008–18

  Abstract

  The type of tissue response to implant by-products can be determined by examination of periprosthetic tissues. However, little is known about the most suitable location for tissue sampling. The main goal of this study was to evaluate the extent of variability in tissue response in relation to location of tissue sampling, implant fixation, age and sex in total joint arthroplasties with metal-on-polyethylene or ceramic-on-polyethylene bearing pairs. We processed 236 histology slides from 21 patients and focused on the association between the location of tissue samples and histological features. The presence of the synovial hyperplasia showed a significant association with the particular sampling site. A higher density of high endothelial cell venules was seen in the samples from around the joint, and polyethylene particles were more abundant in noncemented TJA but both findings did not show statistically significant association with the sampling site. The results showed a relatively small variance in the tissue response to prosthetic by-products among tissues sampled from the same patient. Our findings indicate that tissue samples retrieved from similar distance from around the TJA during the revision operation show comparable results of histological analysis. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2008-2018, 2018.

  View details for DOI 10.1002/jbm.b.33990

  View details for Web of Science ID 000435443500037

  View details for PubMedID 29044940

• The biological basis for concentrated iliac crest aspirate to enhance core decompression in the treatment of osteonecrosis INTERNATIONAL ORTHOPAEDICS Goodman, S. B. 2018; 42 (7): 1705–9

  View details for DOI 10.1007/s00264-018-3830-1

  View details for Web of Science ID 000436405000036

• Early-stage osteonecrosis of the femoral head: where are we and where are we going in year 2018? INTERNATIONAL ORTHOPAEDICS Larson, E., Jones, L. C., Goodman, S. B., Koo, K., Cui, Q. 2018; 42 (7): 1723–28

  Abstract

  Osteonecrosis of the femoral head (ONFH) is a devastating condition affecting relatively young patients whereby the femoral head is necrotic, resulting in significant pain, articular surface collapse, and eventual osteoarthritis. This condition has been highly associated with chronic steroid use, alcoholism, and hip trauma, as well as other less common conditions. Without intervention, this condition has a high likelihood of progressing and developing into end-stage osteoarthritis. Unfortunately, ONFH is difficult to diagnose on plain radiographs in the early stages of the disease, and often requires more advanced imaging modalities such as MRI in order to fully assess for early degeneration. Providers, therefore, must have a high index of suspicion when a younger patient presents with hip pain and negative X-rays. Unfortunately, in patients whose femoral heads have already collapsed, joint-preserving procedures are not effective, and total hip arthroplasty remains the most reliable long-term treatment. Multiple treatments have been pursued to address osteonecrosis in patients whose femoral head have not yet collapsed, but the results of these treatments are mixed. The most promising of these interventions to date is core decompression with the use of concentrated bone marrow aspirate to improve the healing potential of the femoral head. Further studies including randomized clinical trials are necessary in order to assess the effectiveness of this therapy, the best possible source of cells and the best method of implantation in order to further improve results in those with pre-collapse ONFH.

  View details for PubMedID 29619500

• Effect of Computer Navigation on Complication Rates Following Unicompartmental Knee Arthroplasty. The Journal of arthroplasty Chona, D., Bala, A., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2018

  Abstract

  BACKGROUND: We evaluated whether the complication and revision rates of unicompartmental knee arthroplasty (UKA) performed with intraoperative computer-based navigation differ from standard UKAs performed without intraoperative computer-based navigation.METHODS: A Medicare database containing administrative claims data from 2005 to 2014 was queried. Patients who underwent a single UKA and had a minimum of 2 years of follow-up were included in the study. Data from 1025 UKAs performed with navigation were compared against 9228 age and gender-matched UKAs performed without it. Postoperative complications were identified using International Classification of Diseases, Ninth Revision, codes and evaluated at 30 days, 90 days, and 2 years.RESULTS: Orthopedic complications after UKA are rare, and the use of navigation did not affect the rate of conversion to total knee arthroplasty at 2-year follow-up (3.8% in navigated UKAs vs 4.7% in standard UKAs, P= .218). There were also no significant differences in the rates of knee arthrotomy at 2-year follow-up (1.3% in navigated UKAs vs 1.6% in standard UKAs, P= .379). The rates of deep vein thrombosis at 90-day follow-up did not significantly differ between the 2 groups (1.4% in navigated UKAs vs 2.0% in standard UKAs, P= .157).CONCLUSION: This is one of the first studies to use a large cohort to compare outcomes in computer-assisted surgery-UKA against standard UKAs without navigation. The results, particularly that there was not a difference in the rate of conversion to total knee arthroplasty, are directly relevant to clinical decision-making when surgeons are considering employing navigation during UKA.

  View details for PubMedID 30033063

• Cryptotanshinone Protects Cartilage against Developing Osteoarthritis through the miR-106a-5p/GLIS3 Axis MOLECULAR THERAPY-NUCLEIC ACIDS Ji, Q., Qi, D., Xu, X., Xu, Y., Goodman, S. B., Kang, L., Song, Q., Fan, Z., Maloney, W. J., Wang, Y. 2018; 11: 170–79

  Abstract

  Cryptotanshinone (CTS) has emerged as an anti-inflammatory agent in osteoarthritis (OA). However, the molecular mechanism underlying its potent therapeutic effect on OA remains largely unknown. MicroRNAs (miRNAs) act as crucial regulators in maintaining cartilage homeostasis. To investigate whether CTS protects against developing OA through regulation of miRNAs, we examined the potential CTS-mediated miRNA molecules using microarray analysis. We found that CTS significantly promoted miR-106a-5p expression in chondrocytes. Using the OA mouse model created by anterior cruciate ligament transection, we revealed that intra-articular injection of miR-106a-5p agomir attenuated OA. In addition, miR-106a-5p inhibited GLI-similar 3 (GLIS3) production by directly targeting the 3' untranslated region. CTS promoted miR-106a-5p expression through recruitment of a member of the paired box (PAX) family of transcription factors, PAX5, to the miR-106a-5p promoter. Inhibition of PAX5 mimicked the effect of miR-106a-5p and abolished the CTS ability to regulate miR-106a-5p expression. In OA patients, miR-106-5p is downregulated which is accompanied by downregulation of PAX5 and upregulation of GLIS3. Collectively, these data highlight that the PAX5/miR-106a-5p/GLIS3 axis acts as a novel pleiotropic regulator in CTS-mediated OA cartilage protection, suggesting that miR-106a-5p and PAX5 activation and GLIS3 inhibition might be useful and attractive for therapeutic strategies to treat OA patients.

  View details for PubMedID 29858052

• Protocol-Driven Revision for Stiffness After Total Knee Arthroplasty Improves Motion and Clinical Outcomes. The Journal of arthroplasty Hug, K. T., Amanatullah, D. F., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2018

  Abstract

  BACKGROUND: Stiffness after revision total knee arthroplasty (TKA) is a difficult problem without a well-defined treatment algorithm. The purpose of this study was to evaluate the results of revision TKA for stiffness within the context of differential component replacement.METHODS: Consecutive patients who underwent revision TKA were retrospectively identified and included those who received debridement and polyethylene liner exchange alone, revision of only one of the femoral or tibial fixed components, or revision of all components. Preoperative and postoperative range of motion and Knee Society score (KSS) were collected.RESULTS: Sixty-nine knees were included in the study group with a mean follow-up of 43 months (range, 12-205 months). The mean prerevision flexion contracture of 17° improved to 5° after surgical intervention (P < .001). Similarly, mean flexion and motion arc improved from 70° to 92° and from 53° to 87°, respectively (P < .001). Mean KSS knee scores improved from 42 to 70 and KSS function scores improved from 41 to 68 (P < .001). Mean arc of motion improved by 45° in patients who underwent complete component revision, 32° with component retention, and 29° with single component revision (P= .046). KSS knee scores improved by 34, 25, and 28 points in these respective groups (P= .049). KSS function scores improved by 33, 27, and 25 points (P= .077).CONCLUSION: Revision surgery with or without component revision can improve motion and function in patients with stiffness after TKA. Complete component revision may offer the largest improvements in these outcome measures in properly selected patients.

  View details for DOI 10.1016/j.arth.2018.05.013

  View details for PubMedID 29859726

• miR-223-3p Inhibits Human Osteosarcoma Metastasis and Progression by Directly Targeting CDH6 MOLECULAR THERAPY Ji, Q., Xu, X., Song, Q., Xu, Y., Tai, Y., Goodman, S. B., Bi, W., Xu, M., Jiao, S., Maloney, W. J., Wang, Y. 2018; 26 (5): 1299–1312

  Abstract

  Cadherin-6 (CDH6) is aberrantly expressed in cancer and closely associated with tumor progression. However, the functions of CDH6 in human osteosarcoma and the molecular mechanisms underlying CDH6 in osteosarcoma oncogenesis remain poorly understood. In this work, we assessed the role of CDH6 in human osteosarcoma and identified that the expression of CDH6 was closely related with the overall survival and poor prognosis of osteosarcoma patients. MicroRNAs (miRNAs) have been implicated as important epigenetic regulators during the progression of osteosarcoma. Using dual-luciferase reporter assays, we showed that miR-223-3p suppresses CDH6 expression by directly binding to the 3' UTR of CDH6. miR-223-3p overexpression significantly inhibited cell invasion, migration, growth, and proliferation by suppressing the CDH6 expression in vivo and in vitro. Besides, CDH6 overexpression in the miR-223-3p-transfected osteosarcoma cells effectively rescued the inhibition of cell invasion, migration, growth, and proliferation mediated by miR-223-3p. Additionally, Kaplan-Meier analysis suggests that the expression of miR-223-3p predicts favorable clinical outcomes for osteosarcoma patients. Moreover, the expression of miR-223-3p was downregulated in osteosarcoma patients and was negatively associated with the expression of CDH6. Collectively, these data highlight that miR-223-3p/CDH6 axis is an important novel pleiotropic regulator and could early predict the metastatic potential in human osteosarcoma treatments.

  View details for PubMedID 29628305

• Are New Technologies Being Introduced and Adopted Appropriately in Orthopedic Practice? ORTHOPEDICS Goodman, S. B. 2018; 41 (3): 126–27

  View details for DOI 10.3928/01477447-20180501-05

  View details for Web of Science ID 000432834800025

  View details for PubMedID 29767808

• Obesity Is Independently Associated With Early Aseptic Loosening in Primary Total Hip Arthroplasty JOURNAL OF ARTHROPLASTY Goodnough, L. H., Finlay, A. K., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2018; 33 (3): 882–86

  Abstract

  Obesity affects millions of patients in the United States and is associated with several complications after total hip arthroplasty (THA). The effect of obesity on the rate and mode of primary THA failure remains poorly understood, especially given other potentially confounding patient characteristics. We hypothesized that, among patients with a failed primary THA, obesity is independently associated with aseptic loosening and a higher rate of early revision.Six hundred eighty-four consecutive cases with failed THA referred to a single academic center for revision during a 10-year period were retrospectively reviewed. Multivariate logistic regression analysis was used to test the independent association between obesity and the timing as well as cause of THA failure.The rate of primary THA failure before 5 years was 48.8% in obese and 37.1% in nonobese patients (odds ratio [OR] = 1.57, P = .010). Primary THA failure before 5 years was more likely with increasing body mass index (BMI) (BMI: 35-40 kg/m2, OR = 2.31, P = .008; BMI >40 kg/m2, OR = 2.51, P = .049). The rate of primary THA failure for aseptic loosening before 5 years was 30% in obese and 18% in nonobese patients (OR = 1.88, P = .023). Obesity was not a risk for revision for infection, whereas an American Society of Anesthesiologists class ≥3 was independently associated with primary THA failure for infection (OR = 2.33, P < .001).Among patients with a failed THA, comorbidities may account for the risk of revision due to infection in obese patients. Obesity is independently associated with early primary THA failure for aseptic loosening.

  View details for DOI 10.1016/j.arth.2017.09.069

  View details for Web of Science ID 000425893000046

  View details for PubMedID 29089226

• Customized, degradable, functionally graded scaffold for potential treatment of early stage osteonecrosis of the femoral head JOURNAL OF ORTHOPAEDIC RESEARCH Kawai, T., Shanjani, Y., Fazeli, S., Behn, A. W., Okuzu, Y., Goodman, S. B., Yang, Y. P. 2018; 36 (3): 1002–11

  Abstract

  Osteonecrosis of the femoral head (ONFH) is a debilitating disease that results in progressive collapse of the femoral head and subsequent degenerative arthritis. Few treatments provide both sufficient mechanical support and biological cues for regeneration of bone and vascularity when the femoral head is still round and therefore salvageable. We designed and 3D printed a functionally graded scaffold (FGS) made of polycaprolactone (PCL) and β-tricalcium phosphate (β-TCP) with spatially controlled porosity, degradation, and mechanical strength properties to reconstruct necrotic bone tissue in the femoral head. The FGS was designed to have low porosity segments (15% in proximal and distal segments) and a high porosity segment (60% in middle segment) according to the desired mechanical and osteoconductive properties at each specific site after implantation into the femoral head. The FGS was inserted into a bone tunnel drilled in rabbit femoral neck and head, and at 8 weeks after implantation, the tissue formation as well as scaffold degradation was analyzed. Micro-CT analysis demonstrated that the FGS-filled group had a significantly higher bone ingrowth ratio compared to the empty-tunnel group, and the difference was higher at the distal low porosity segments. The in vivo degradation rate of the scaffold was higher in the proximal and distal segments than in the middle segment. Histological analysis of both non-decalcified and calcified samples clearly indicated new bone ingrowth and bone marrow-containing bone formation across the FGS. A 3D printed PCL-β-TCP FGS appears to be a promising customized resorbable load-bearing implant for treatment of early stage ONFH. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1002-1011, 2018.

  View details for PubMedID 28782831

• The biological basis for concentrated iliac crest aspirate to enhance core decompression in the treatment of osteonecrosis. International orthopaedics Goodman, S. B. 2018

  Abstract

  Core decompression is a surgical procedure that is capable of salvaging the patient's own natural joint, if the operation is performed in the early stages of osteonecrosis, in which the articular surface has not collapsed. The addition of concentrated cells, aspirated from the iliac crest, to the core tract has been shown to enhance the viability of the femoral head, although large, prospective, randomized, blinded multicentre studies are lacking. The rationale for adding these cells to the core decompression tract is to provide osteoprogenitor and vascular progenitor cells to the area of decompressed dead bone, in order to facilitate tissue regeneration and repair. It has become increasingly evident that vast discrepancies exist in different series in regard to the criteria for patient selection, the surgical technique of core decompression, the methods for harvesting, processing, and injecting the cells, and the methodology for determining success or failure in a specific patient cohort. This paper reviews the salient points relevant to the treatment of osteonecrosis by core decompression with addition of concentrated iliac crest aspirates and poses important questions regarding the future successful application of this technique.

  View details for PubMedID 29435623

• Editorial Comment: 2017 Hip Society Proceedings CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B. 2018; 476 (2): 214–15

  View details for PubMedID 29529649

• Immunohistochemical Analysis of Inflammatory Rheumatoid Synovial Tissues Using Anti-Human Podoplanin Monoclonal Antibody Panel. Monoclonal antibodies in immunodiagnosis and immunotherapy Suzuki, T., Takakubo, Y., Oki, H., Liu, X., Honma, R., Naganuma, Y., Goodman, S. B., Kaneko, M. K., Kato, Y., Takagi, M. 2018; 37 (1): 12–19

  Abstract

  Podoplanin (PDPN) is a transmembrane sialoglycoprotein, which is expressed in several normal tissues and malignant tumors. Although PDPN expression in rheumatoid arthritis (RA) has been reported, the role of PDPN in RA and other arthritic conditions has not been fully elucidated. In this study, we examined PDPN expression in inflammatory synovial tissues using an anti-human PDPN (hPDPN) monoclonal antibody (mAb) panel to select the most useful one for evaluation of synovitis. Synovial tissue samples were obtained from 11 RA patients and 9 osteoarthritis (OA) patients undergoing joint surgery. PDPN-positive cells were immunostained by a panel of PDPN mAbs (NZ-1, LpMab-3, LpMab-7, LpMab-10, LpMab-12, LpMab-13, and LpMab-17), followed by cell grading of inflammation and cell counting of PDPN-positivity by a quantitative analyzer. Immunohistochemistry showed that PDPN was markedly expressed in both macrophage-like type A and fibroblast-like type B lining cells of the hyperplastic synovial lining cell layer, and macrophages and fibroblasts in the stroma of RA. Among anti-PDPN mAbs, LpMab-12 showed the highest score. In inflammatory OA synovium, PDPN expression was also detectable. Although LpMab-12 also showed the highest score in OA, the difference was not statistically significant. The inflammatory synovitis score of RA was significantly higher than that of OA. PDPN was expressed in inflammatory lining cells and sublining stroma of RA and OA synovium. In the seven anti-hPDPN antibodies examined, LpMab-12 was the most stainable antibody for PDPN in RA synovitis. Thus, LpMab-12 for PDPN has a possible and promising specific biomarker for evaluating synovitis in RA and inflammatory OA.

  View details for PubMedID 29377768

• Particle disease really does exist An evidence based rebuttal to Dr. Mjoberg's opinion letter ACTA ORTHOPAEDICA Pajarinen, J., Gallo, J., Takagi, M., Goodman, S. B. 2018; 89 (1): 133–36

  View details for PubMedID 29143557

• Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials Pajarinen, J., Lin, T., Gibon, E., Kohno, Y., Maruyama, M., Nathan, K., Lu, L., Yao, Z., Goodman, S. B. 2018

  Abstract

  Recent research has brought about a clear understanding that successful fracture healing is based on carefully coordinated cross-talk between inflammatory and bone forming cells. In particular, the key role that macrophages play in the recruitment and regulation of the differentiation of mesenchymal stem cells (MSCs) during bone regeneration has been brought to focus. Indeed, animal studies have comprehensively demonstrated that fractures do not heal without the direct involvement of macrophages. Yet the exact mechanisms by which macrophages contribute to bone regeneration remain to be elucidated. Macrophage-derived paracrine signaling molecules such as Oncostatin M, Prostaglandin E2 (PGE2), and Bone Morphogenetic Protein-2 (BMP2) have been shown to play critical roles; however the relative importance of inflammatory (M1) and tissue regenerative (M2) macrophages in guiding MSC differentiation along the osteogenic pathway remains poorly understood. In this review, we summarize the current understanding of the interaction of macrophages and MSCs during bone regeneration, with the emphasis on the role of macrophages in regulating bone formation. The potential implications of aging to this cellular cross-talk are reviewed. Emerging treatment options to improve facture healing by utilizing or targeting MSC-macrophage crosstalk are also discussed.

  View details for PubMedID 29329642

• Implant-Associated Bacterial Biofilm and Quorum Sensing in Periprosthetic Joint Infections. Journal of orthopaedic research : official publication of the Orthopaedic Research Society Mooney, J. A., Pridgen, E. M., Manasherob, R. n., Suh, G. n., Blackwell, H. E., Barron, A. E., Bollyky, P. L., Goodman, S. B., Amanatullah, D. F. 2018

  Abstract

  Periprosthetic joint infection (PJI) continues to be a common complication after total knee arthroplasty and total hip arthroplasty leading to severe morbidity and mortality. With an aging population and increasing prevalence of total joint replacement procedures, the burden of PJI will be felt not only by individual patients, but in increased healthcare costs. Current treatment of PJI is inadequate resulting in incredibly high failure rates. This is believed to be largely mediated by the presence of bacterial biofilms. These polymicrobial bacterial colonies form within secreted extracellular matrices, adhering to the implant surface and local tissue. The biofilm architecture is believed to play a complex and critical role in a variety of bacterial processes including nutrient supplementation, metabolism, waste management, and antibiotic and immune resistance. The establishment of these biofilms relies heavily on the quorum sensing communication systems utilized by bacteria. Early stage research into disrupting bacterial communication by targeting quorum sensing show promise for future clinical applications. However, prevention of the biofilm formation via early forced induction of the biofilm forming process remains yet unexplored. This article is protected by copyright. All rights reserved.

  View details for PubMedID 29663554

• Corrigendum to Outcome of 4 Surgical Treatments for Wear and Osteolysis of Cementless Acetabular Components [The Journal of Arthroplasty 32 (2017) 2799-2805]. The Journal of arthroplasty Narkbunnam, R., Amanatullah, D. F., Electricwala, A. J., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2018; 33 (1): 308

  View details for DOI 10.1016/j.arth.2017.10.001

  View details for PubMedID 29107500

• Production of GFP and Luciferase-Expressing Reporter Macrophages for In Vivo Bioluminescence Imaging REPORTER GENE IMAGING: METHODS AND PROTOCOLS Pajarinen, J., Lin, T., Goodman, S. B., Dubey, P. 2018; 1790: 99–111

  View details for DOI 10.1007/978-1-4939-7860-1_8

  View details for Web of Science ID 000448886300009

• Outcome of 4 Surgical Treatments for Wear and Osteolysis of Cementless Acetabular Components (vol 32, pg 2799, 2017) JOURNAL OF ARTHROPLASTY Narkbunnam, R., Amanatullah, D. F., Electricwala, A. J., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2018; 33 (1): 308

  View details for DOI 10.1016/j.arth.2017.10.001

  View details for Web of Science ID 000418761100061

• Metal-on-metal total hip arthroplasty is not associated with cardiac disease BONE & JOINT JOURNAL Goodnough, L. H., Bala, A., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2018; 100B (1): 28–32

  Abstract

  Many case reports and small studies have suggested that cobalt ions are a potential cause of cardiac complications, specifically cardiomyopathy, after metal-on-metal (MoM) total hip arthroplasty (THA). The impact of metal ions on the incidence of cardiac disease after MoM THA has not been evaluated in large studies. The aim of this study was to compare the rate of onset of new cardiac symptoms in patients who have undergone MoM THA with those who have undergone metal-on-polyethylene (MoP) THA.Data were extracted from the Standard Analytics Files database for patients who underwent MoM THA between 2005 and 2012. Bearing surface was selected using International Classification of Diseases ninth revision codes. Patients with a minimum five-year follow-up were selected. An age and gender-matched cohort of patients who underwent MoP THA served as a comparison group. New diagnoses of cardiac disease were collected during the follow-up period. Comorbidities and demographics were identified and routine descriptive statistics were used.We identified 29 483 patients who underwent MoM THA and 24 175 matched patients who underwent MoP THA. Both groups had a mean Charlson comorbidity index score of 4. There were no statistically significant differences in 30 of 31 pre-existing comorbidities. Patients undergoing MoM THA had a slightly lower incidence of cardiac failure compared with those undergoing MoP THA at three years (6.60% versus 7.06%, odds ratio (OR) 0.93, 95% confidence interval (CI) 0.87 to 0.99) and four years (8.73% versus 9.49%, OR 0.91, 95% CI 0.86 to 0.97) postoperatively, with no difference in the incidence of new cardiac failure in between the groups at five years. There was no statistically significant difference in the incidence of arrhythmia, myocardial infarction and cardiomyopathy at any time between the two groups.MoM THA is not associated with cardiac complications. Initial reports may have represented individual instances of cardiac disease in patients with a failing MoM articulation rather than an emerging epidemiological trend. Cite this article: Bone Joint J 2018;100-B:28-32.

  View details for PubMedID 29305447

• Production of GFP and Luciferase-Expressing Reporter Macrophages for In Vivo Bioluminescence Imaging. Methods in molecular biology (Clifton, N.J.) Pajarinen, J., Lin, T., Goodman, S. B. 2018; 1790: 99–111

  Abstract

  Macrophages have emerged as crucial regulators of tissue homeostasis, inflammation, and tissue regeneration. In vivo bioluminescence imaging could offer a powerful tool to study many poorly understood aspects of macrophage biology. Thus, we recently developed a straightforward method for the production of large numbers of green fluorescent protein (GFP) and firefly luciferase (fLUC)-expressing reporter macrophages for various in vivo bioluminescence imaging applications. Lentivirus vector containing the GFP/fLUC reporter gene is produced and mouse bone marrow macrophages are isolated following established protocols. Macrophages are then exposed to the lentivirus in the presence of 10muM cyclosporine for 24h. After a 24-h recovery period, the transduction is repeated. Three days after the second infection the cells are ready to be used in vivo. Following this cyclosporine-mediated double infection strategy up to 60% of the macrophages express GFP in flow cytometry. The macrophages maintain their ability to polarize to M1 and M2 phenotypes and, when injected to the systemic circulation of a mouse model, reporter cells are both easily detectable with BLI and migrate to a local site of inflammation. These GFP/fLUC-expressing reporter macrophages could prove to be useful tools to study the role of macrophages in health and disease.

  View details for PubMedID 29858786

• Perioperative Pain Management for Total Knee Arthroplasty: Need More Focus on the Forest and Less on the Trees. Anesthesiology Webb, C. A., Madison, S. n., Goodman, S. B., Mariano, E. R., Horn, J. L. 2018; 128 (2): 420–21

  View details for PubMedID 29337751

• Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis STEM CELL RESEARCH & THERAPY Lin, T., Pajarinen, J., Nabeshima, A., Lu, L., Nathan, K., Jamsen, E., Yao, Z., Goodman, S. B. 2017; 8

  View details for DOI 10.1186/s13287-017-0730-z

  View details for Web of Science ID 000417519200003

• Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis. Stem cell research & therapy Lin, T., Pajarinen, J., Nabeshima, A., Lu, L., Nathan, K., Jämsen, E., Yao, Z., Goodman, S. B. 2017; 8 (1): 277

  Abstract

  Mesenchymal stem cells (MSCs) are capable of immunomodulation and tissue regeneration, highlighting their potential translational application for treating inflammatory bone disorders. MSC-mediated immunomodulation is regulated by proinflammatory cytokines and pathogen-associated molecular patterns such as lipopolysaccharide (LPS). Previous studies showed that MSCs exposed to interferon gamma (IFN-γ) and the proinflammatory cytokine tumor necrosis factor alpha (TNF-α) synergistically suppressed T-cell activation.In the current study, we developed a novel preconditioning strategy for MSCs using LPS plus TNF-α to optimize the immunomodulating ability of MSCs on macrophage polarization.Preconditioned MSCs enhanced anti-inflammatory M2 macrophage marker expression (Arginase 1 and CD206) and decreased inflammatory M1 macrophage marker (TNF-α/IL-1Ra) expression using an in-vitro coculture model. Immunomodulation of MSCs on macrophages was significantly increased compared to the combination of IFN-γ plus TNF-α or single treatment controls. Increased osteogenic differentiation including alkaline phosphate activity and matrix mineralization was only observed in the LPS plus TNF-α preconditioned MSCs. Mechanistic studies showed that increased prostaglandin E2 (PGE2) production was associated with enhanced Arginase 1 expression. Selective cyclooxygenase-2 inhibition by Celecoxib decreased PGE2 production and Arginase 1 expression in cocultured macrophages.The novel preconditioned MSCs have increased immunomodulation and bone regeneration potential and could be applied to the treatment of inflammatory bone disorders including periprosthetic osteolysis, fracture healing/nonunions, and osteonecrosis.

  View details for DOI 10.1186/s13287-017-0730-z

  View details for PubMedID 29212557

  View details for PubMedCentralID PMC5719931

• Patient Satisfaction After Total Knee Arthropliasty A Realistic or Imaginary Goal? ORTHOPEDIC CLINICS OF NORTH AMERICA Gibon, E., Goodman, M. J., Goodman, S. B. 2017; 48 (4): 421-+

  Abstract

  This article summarizes the current literature regarding patient satisfaction after total knee arthroplasty. In 10% to 15% of cases, the operation has not met the patients' expectations. The causes of this dissatisfaction are multifactorial, and include patient-related factors, details related to the surgical procedure and prosthesis chosen, perioperative factors, and factors associated with nursing and general medical care. However, surgeons must bear the brunt of patients' dissatisfaction. This dissatisfaction erodes the doctor-patient relationship, and may have implications in an emerging health care economy in which doctors and hospitals are reimbursed based on both clinical outcome and patient satisfaction.

  View details for PubMedID 28870303

• Response to Letter to the Editor on "Weight Gain After Primary Total Knee Arthroplasty is Associated With Accelerated Time to Revision for Aseptic Loosening" JOURNAL OF ARTHROPLASTY Lim, C. T., Goodman, S. B., Huddleston, J. I., Harris, A. S., Bhowmick, S., Maloney, W. J., Amanatullah, D. F. 2017; 32 (10): 3258

  View details for PubMedID 28705544

• An evidence-based guide to the treatment of osteonecrosis of the femoral head BONE & JOINT JOURNAL Chughtai, M., Piuzzi, N. S., Khlopas, A., Jones, L. C., Goodman, S. B., Mont, M. A. 2017; 99B (10): 1267–79

  Abstract

  Non-traumatic osteonecrosis of the femoral head is a potentially devastating condition, the prevalence of which is increasing. Many joint-preserving forms of treatment, both medical and surgical, have been developed in an attempt to slow or reverse its progression, as it usually affects young patients. However, it is important to evaluate the best evidence that is available for the many forms of treatment considering the variation in the demographics of the patients, the methodology and the outcomes in the studies that have been published, so that it can be used effectively. The purpose of this review, therefore, was to provide an up-to-date, evidence-based guide to the management, both non-operative and operative, of non-traumatic osteonecrosis of the femoral head. Cite this article: Bone Joint J 2017;99-B:1267-79.

  View details for PubMedID 28963146

• miR-216a inhibits osteosarcoma cell proliferation, invasion and metastasis by targeting CDK14 CELL DEATH & DISEASE Ji, Q., Xu, X., Li, L., Goodman, S. B., Bi, W., Xu, M., Xu, Y., Fan, Z., Maloney, W. J., Ye, Q., Wang, Y. 2017; 8: e3103

  Abstract

  Osteosarcoma (OS) has emerged as the most common primary musculoskeletal malignant tumour affecting children and young adults. Cyclin-dependent kinases (CDKs) are closely associated with gene regulation in tumour biology. Accumulating evidence indicates that the aberrant function of CDK14 is involved in a broad spectrum of diseases and is associated with clinical outcomes. MicroRNAs (miRNAs) are crucial epigenetic regulators in the development of OS. However, the essential role of CDK14 and the molecular mechanisms by which miRNAs regulate CDK14 in the oncogenesis and progression of OS have not been fully elucidated. Here we found that CDK14 expression was closely associated with poor prognosis and overall survival of OS patients. Using dual-luciferase reporter assays, we also found that miR-216a inhibits CDK14 expression by binding to the 3'-untranslated region of CDK14. Overexpression of miR-216a significantly suppressed cell proliferation, migration and invasion in vivo and in vitro by inhibiting CDK14 production. Overexpression of CDK14 in the miR-216a-transfected OS cells effectively rescued the suppression of cell proliferation, migration and invasion caused by miR-216a. In addition, Kaplan-Meier analysis indicated that miR-216a expression predicted favourable clinical outcomes for OS patients. Moreover, miR-216a expression was downregulated in OS patients and was negatively associated with CDK14 expression. Overall, these data highlight the role of the miR-216a/CDK14 axis as a novel pleiotropic modulator and demonstrate the associated molecular mechanisms, thus suggesting the intriguing possibility that miR-216a activation and CDK14 inhibition may be novel and attractive therapeutic strategies for treating OS patients.

  View details for PubMedID 29022909

• Tissue-Invasive T Cells in Rheumatoid Arthritis Weyand, C. M., Shen, Y., Li, Y., Matteson, E. L., Goodman, S., Goronzy, J. WILEY. 2017

  View details for Web of Science ID 000411824106206

• Inflammation, ageing, and bone regeneration JOURNAL OF ORTHOPAEDIC TRANSLATION Gibon, E., Lu, L. Y., Nathan, K., Goodman, S. B. 2017; 10: 28–35

  Abstract

  Bone healing involves complex biological pathways and interactions among various cell types and microenvironments. Among them, the monocyte-macrophage-osteoclast line-age and the mesenchymal stem cell-osteoblast lineage are critical, in addition to an initial inflammatory microenvironment. These cellular interactions induce the necessary inflammatory milieu and provide the cells for bone regeneration and immune modulation. Increasing age is accompanied with a rise in the basal state of inflammation, potentially impairing osteogenesis.Translational research has shown multiple interactions between inflammation, ageing, and bone regeneration. This review presents recent, relevant considerations regarding the effects of inflammation and ageing on bone healing.

  View details for PubMedID 29094003

• Inflammation and its resolution and the musculoskeletal system JOURNAL OF ORTHOPAEDIC TRANSLATION Gallo, J., Raska, M., Kriegova, E., Goodman, S. B. 2017; 10: 52–67

  Abstract

  Inflammation, an essential tissue response to extrinsic/intrinsic damage, is a very dynamic process in terms of complexity and extension of cellular and metabolic involvement. The aim of the inflammatory response is to eliminate the pathogenic initiator with limited collateral damage of the inflamed tissue, followed by a complex tissue repair to the preinflammation phenotype. Persistent inflammation is a major contributor to the pathogenesis of many musculoskeletal diseases including ageing-related pathologies such as osteoporosis, osteoarthritis, and sarcopaenia. Understanding the mechanisms of inflammation and its resolution is therefore critical for the development of effective regenerative, and therapeutic strategies in orthopaedics.

  View details for PubMedID 28781962

• Inflammation and the musculoskeletal system JOURNAL OF ORTHOPAEDIC TRANSLATION Goodman, S. B., Qin, L. 2017; 10: A1–A2

  View details for PubMedID 29662763

• Danger of frustrated sensors: Role of Toll-like receptors and NOD-like receptors in aseptic and septic inflammations around total hip replacements JOURNAL OF ORTHOPAEDIC TRANSLATION Takagi, M., Takakubo, Y., Pajarinen, J., Naganuma, Y., Oki, H., Maruyama, M., Goodman, S. B. 2017; 10: 68–85

  Abstract

  The innate immune sensors, Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), can recognize not only exogenous pathogen-associated molecular patterns (PAMPs), but also endogenous molecules created upon tissue injury, sterile inflammation, and degeneration. Endogenous ligands are called damage-associated molecular patterns (DAMPs), and include endogenous molecules released from activated and necrotic cells as well as damaged extracellular matrix. TLRs and NLRs can interact with various ligands derived from PAMPs and DAMPs, leading to activation and/or modulation of intracellular signalling pathways. Intensive research on the innate immune sensors, TLRs and NLRs, has brought new insights into the pathogenesis of not only various infectious and rheumatic diseases, but also aseptic foreign body granuloma and septic inflammation of failed total hip replacements (THRs). In this review, recent knowledge is summarized on the innate immune system, including TLRs and NLRs and their danger signals, with special reference to their possible role in the adverse local host response to THRs.

  View details for PubMedID 29130033

• The effect of desflurane versus propofol anesthesia on postoperative delirium in elderly obese patients undergoing total knee replacement: A randomized, controlled, double-blinded clinical trial. Journal of clinical anesthesia Tanaka, P., Goodman, S., Sommer, B. R., Maloney, W., Huddleston, J., Lemmens, H. J. 2017; 39: 17-22

  Abstract

  The goal of this study was to investigate the incidence of delirium, wake-up times and early post-operative cognitive decline in one hundred obese elderly patients undergoing total knee arthroplasty.Prospective randomized trial.Operating room, postoperative recovery area, hospital wards.100 obese patients (ASA II and III) undergoing primary total knee replacement under general anesthesia with a femoral nerve block catheter.Patients were prospectively randomized to maintenance anesthesia with either propofol or desflurane.The primary endpoint assessed by a blinded investigator was delirium as measured by the Confusion Assessment Method. Secondary endpoints were wake-up times and a battery of six different tests of cognitive function.Four of the 100 patients that gave informed consent withdrew from the study. Of the remaining 96 patients, 6 patients did not complete full CAM testing. Preoperative pain scores, durations of surgery and anesthesia, and amount of intraoperative fentanyl were not different between groups. One patient in the propofol group developed delirium compared to zero in desflurane. One patient in desflurane group developed a confused state not characterized as delirium. Fifty percent of the patients exhibited a 20% decrease in the results of at least one cognitive test on the first 2days after surgery, with no difference between groups. There were no differences in the time to emergence from anesthesia, incidence of postoperative nausea and vomiting, and length of postanesthesia care unit (PACU) stay between the two groups.In conclusion we found a low incidence of delirium but significant cognitive decline in the first 48h after surgery. In this relatively small sample size of a hundred patients there was no difference in the incidence of postoperative delirium, early cognitive outcomes, or wake up times between the desflurane or propofol group.

  View details for DOI 10.1016/j.jclinane.2017.03.015

  View details for PubMedID 28494898

• Continuous Femoral Nerve Catheters Decrease Opioid-Related Side Effects and Increase Home Disposition Rates Among Geriatric Hip Fracture Patients. Journal of orthopaedic trauma Arsoy, D., Gardner, M. J., Amanatullah, D. F., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Bishop, J. A. 2017; 31 (6): e186-e189

  Abstract

  To evaluate the effect of continuous femoral nerve catheter (CFNC) for postoperative pain control in geriatric proximal femur fractures compared with standard analgesia (SA) treatment.Retrospective comparative study.Academic Level 1 trauma center.We retrospectively identified 265 consecutive geriatric hip fracture patients who underwent surgical treatment.One hundred forty-nine patients were treated with standard analgesia without nerve catheter whereas 116 patients received an indwelling CFNC.Daily average preoperative and postoperative pain scores, daily morphine equivalent consumption, opioid-related side effects and discharge disposition.Patients with CFNC patients reported lower average pain scores preoperatively (1.9 ± 1.7 for CFNC vs. 4.7 ± 2 for SA; P < 0.0001), on postoperative day 1 (1.5 ± 1.6 for CFNC vs. 3 ± 1.7 for SA; P < 0.0001) and postoperative day 2 (1.2 ± 1.5 for CFNC vs. 2.6 ± 2.1 for SA; P < 0.0001). CFNC group consumed 39% less morphine equivalents on postoperative day 1 (4.4 ± 5.8 mg for CFNC vs. 7.2 ± 10.8 mg for SA; P = 0.005) and 50% less morphine equivalent on postoperative day 2 (3.4 ± 4.4 mg for CFNC vs. 6.8 ± 13 mg for SA; P = 0.105). Patients with CFNC had a lower rate of opioid-related side effects compared with patients with SA (27.5% for CFNC vs. 47% for SA; P = 0.001). More patients with CFNC were discharged to home with or without health services than patients with SA (15% for CFNC vs. 6% for SA; P = 0.023).Continuous femoral nerve catheter decreased daily average patient-reported pain scores, narcotic consumption while decreasing the rate of opioid-related side effects. Patients with CFNC were discharged to home more frequently.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

  View details for DOI 10.1097/BOT.0000000000000854

  View details for PubMedID 28538458

• Venous Thromboembolism Prophylaxis After TKA: Aspirin, Warfarin, Enoxaparin, or Factor Xa Inhibitors? Clinical orthopaedics and related research Bala, A., Huddleston, J. I., Goodman, S. B., Maloney, W. J., Amanatullah, D. F. 2017

  Abstract

  There is considerable debate regarding the ideal agent for venous thromboembolism (VTE) prophylaxis after TKA. Numerous studies and meta-analyses have yet to provide a clear answer and often omit one or more of the commonly used agents such as aspirin, warfarin, enoxaparin, and factor Xa inhibitors.Using a large database analysis, we asked: (1) What are the differences in VTE incidence in primary TKA after administration of aspirin, warfarin, enoxaparin, or factor Xa inhibitors? (2) What are the differences in bleeding risk among these four agents? (3) How has use of these agents changed with time?We queried a combined Humana and Medicare database between 2007 and Quarter 1 of 2016, and identified all primary TKAs performed using ICD-9 and Current Procedural Terminology codes. All patients who had any form of antiplatelet or anticoagulation prescribed within 1 year before TKA were excluded from our study cohort. We then identified patients who had either aspirin, warfarin, enoxaparin, or factor Xa inhibitors prescribed within 2 weeks of primary TKA. Each cohort was matched by age and sex. Elixhauser comorbidities and Charlson Comorbidity Index for each group were calculated. We identified 1016 patients with aspirin, and age- and sex-matched 6096 patients with enoxaparin, 6096 patients with warfarin, and 5080 patients with factor Xa inhibitors. Using ICD-9 codes, with the understanding that patients at greater risk may have had more-attentive surveillance, the incidence of postoperative deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding-related complications (bleeding requiring surgical intervention, hemorrhage, hematoma, hemarthrosis), postoperative anemia, and transfusion were identified at 2 weeks, 30 days, 6 weeks, and 90 days postoperatively. A four-way chi-squared test was used to determine statistical significance. Utilization was calculated using compound annual growth rate.There was a difference in the incidence of DVT at 90 days (p < 0.01). Factor Xa inhibitors (2.9%) had the lowest incidence of DVT followed by aspirin (3.0%) and enoxaparin (3.5%), and warfarin (4.8%). There was a difference in the incidence of PE at 90 days (p < 0.01). Factor Xa inhibitors (0.9%) had the lowest incidence of PE followed by enoxaparin (1.1%), aspirin (1.2%), and warfarin (1.6%). There was a difference in the incidence of postoperative anemia at 90 days (p < 0.01). Aspirin (19%) had the lowest incidence of postoperative anemia followed by warfarin (22%), enoxaparin (23%), and factor Xa inhibitors (23%). There was a difference in the incidence of a blood transfusion at 90 days (p < 0.01). Aspirin (7%) had the lowest incidence of a blood transfusion followed by factor Xa inhibitors (9%), warfarin (12%), and enoxaparin (13%). There were no differences in bleeding-related complications (p = 0.81) between the groups. Aspirin use increased at a compound annual growth rate of 30%, enoxaparin at 3%, and factor Xa inhibitors at 43%, while warfarin use decreased at a compound annual growth rate of -3%.Factor Xa inhibitors had the highest growth in utilization during our study period, followed by aspirin, when compared with enoxaparin and warfarin. When selected for the right patient, factor Xa inhibitors provided improved VTE prophylaxis compared with enoxaparin and warfarin, with a lower rate of blood transfusion. Aspirin provided comparable VTE prophylaxis compared with factor Xa inhibitors with improved VTE prophylaxis compared with enoxaparin and warfarin with the lowest risk of bleeding.Level III, therapeutic study.

  View details for DOI 10.1007/s11999-017-5394-6

  View details for PubMedID 28569372

• Radiographic scoring system for the evaluation of stability of cementless acetabular components in the presence of osteolysis BONE & JOINT JOURNAL Narkbunnam, R., Amanatullah, D. F., Electricwala, A. J., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2017; 99-B (5): 601-606

  Abstract

  The stability of cementless acetabular components is an important factor for surgical planning in the treatment of patients with pelvic osteolysis after total hip arthroplasty (THA). However, the methods for determining the stability of the acetabular component from pre-operative radiographs remain controversial. Our aim was to develop a scoring system to help in the assessment of the stability of the acetabular component under these circumstances.The new scoring system is based on the mechanism of failure of these components and the location of the osteolytic lesion, according to the DeLee and Charnley classification. Each zone is evaluated and scored separately. The sum of the individual scores from the three zones is reported as a total score with a maximum of 10 points. The study involved 96 revision procedures which were undertaken for wear or osteolysis in 91 patients between July 2002 and December 2012. Pre-operative anteroposterior pelvic radiographs and Judet views were reviewed. The stability of the acetabular component was confirmed intra-operatively.Intra-operatively, it was found that 64 components were well-fixed and 32 were loose. Mean total scores in the well-fixed and loose components were 2.9 (0 to 7) and 7.2 (1 to 10), respectively (p < 0.001). In hips with a low score (0 to 2), the component was only loose in one of 33 hips (3%). The incidence of loosening increased with increasing scores: in those with scores of 3 and 4, two of 19 components (10.5%) were loose; in hips with scores of 5 and 6, eight of 19 components (44.5%) were loose; in hips with scores of 7 or 8, 13 of 17 components (70.6%) were loose; and for hips with scores of 9 and 10, nine of nine components (100%) were loose. Receiver-operating-characteristic curve analysis demonstrated very good accuracy (area under the curve = 0.90, p < 0.001). The optimal cutoff point was a score of ≥ 5 with a sensitivity of 0.79, and a specificity of 0.87.There was a strong correlation between the scoring system and the probability of loosening of a cementless acetabular component. This scoring system provides a clinically useful tool for pre-operative planning, and the evaluation of the outcome of revision surgery for patients with loosening of a cementless acetabular component in the presence of osteolysis. Cite this article: Bone Joint J 2017;99-B:601-6.

  View details for DOI 10.1302/0301-620X.99B5.BJJ-2016-0968.R1

  View details for PubMedID 28455468

• A Randomized Trial of Perioperative Gabapentin to Promote Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort Hah, J., Mackey, S., Efron, B., Mccue, R., Goodman, S., Curtin, C., Carroll, I. LIPPINCOTT WILLIAMS & WILKINS. 2017: 813–17

  View details for Web of Science ID 000412683000420

• Cortical Strut Allograft Support of Modular Femoral Junctions During Revision Total Hip Arthroplasty JOURNAL OF ARTHROPLASTY Lim, C. T., Amanatullah, D. F., Huddleston, J. I., Hwang, K. L., Maloney, W. J., Goodman, S. B. 2017; 32 (5): 1586-1592

  Abstract

  There is risk of junction failure when using modular femoral stems for revision total hip arthroplasty (THA), especially with loss of bone stock in the proximal femur. Using a cortical strut allograft may provide additional support of a modular femoral construct in revision THA.We reviewed prospectively gathered clinical and radiographic data for 28 revision THAs performed from 2004 to 2014 using cementless modular femoral components with cortical strut allograft applied to supplement proximal femoral bone loss: 5 (18%) were fluted taper designs and 23 (82%) were porous cylindrical designs All the patients had a Paprosky grade IIIA or greater femoral defect. The mean follow-up was 5.4 ± 3.9 years.The Harris Hip Scores improved from 26 ± 10 points preoperatively to 71 ± 10 points at final follow-up (P < .001). The Western Ontario McMaster Universities Osteoarthritis Index scores improved from 45 ± 12 points preoperatively to 76 ± 12 points at final follow-up (P < .001). Eighty-nine percent (25 hips) of all revision or conversion THAs were in place at final follow-up. Three (11%) patients underwent reoperations, 2 for infection and 1 for periprosthetic fracture. There was no statistical significant change in femoral component alignment (P = .161) at final follow-up. Mean subsidence was 1.8 ± 1.3 mm at final follow-up. Femoral diameter increased from initial postoperative imaging to final follow-up imaging by a mean of 9.1 ± 5.1 mm (P < .001) and cortical width increased by a mean of 4.5 ± 2.2 mm (P < .001). Twenty-seven hips (96%) achieved union between the cortical strut allograft and the host femur.The use of a modular femoral stem in a compromised femur with a supplementary cortical strut allgraft is safe and provides satisfactory clinical and radiological outcomes.

  View details for DOI 10.1016/j.arth.2016.12.011

  View details for Web of Science ID 000401132100033

• Use of Cortical Strut Allograft After Extended Trochanteric Osteotomy in Revision Total Hip Arthroplasty JOURNAL OF ARTHROPLASTY Lim, C. T., Amanatullah, D. F., Huddleston, J. I., Hwang, K. L., Maloney, W. J., Goodman, S. B. 2017; 32 (5): 1599-1605

  Abstract

  Cortical strut allografts restore bone stock and improve postoperative clinical scores after revision total hip arthroplasty (THA). However, use of a cortical strut allograft is implicated in delayed healing of an extended trochanteric osteotomy (ETO). To date, there are no reports directly comparing ETO with or without cortical strut allografts.We reviewed prospectively gathered data on 50 revision THAs performed from 2004-2014 using an ETO. We compared the demographic, radiological, and clinical outcome of patients with (16 hips) and without (34 hips) cortical strut allograft after an ETO.There were no significant differences in Western Ontario McMaster Universities Osteoarthritis Index or Harris Hip Score between the ETOs with and without a cortical strut allograft. Fifteen of the ETOs (94%) with a cortical strut allograft and 31 of the ETOs (91%) without a cortical strut allograft were in situ at final follow-up (P = 1.000). A higher proportion hips with cortical strut allograft (100%, 16 patients) had preoperative Paprosky grade bone loss more than IIIA compared to those without allograft (29%, 10 patients) (P < .001). There were no differences in femoral stem subsidence (P = .207), alignment (P = .934), or migration of the osteotomized fragment (P = .171). Fourteen of the ETOs (88%) in patients with cortical strut allograft united compared to 34 ETOs (100%) in patients without allograft (P = .095).Our study shows that the use of cortical strut allograft during revision THA with ETO does not reduce the rate of union, radiological or clinical outcomes.

  View details for DOI 10.1016/j.arth.2016.12.002

  View details for Web of Science ID 000401132100035

• CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis ANNALS OF THE RHEUMATIC DISEASES Raghu, H., Lepus, C. M., Wang, Q., Wong, H. H., Lingampalli, N., Oliviero, F., Punzi, L., Giori, N. J., Goodman, S. B., Chu, C. R., Sokolove, J. B., Robinson, W. H. 2017; 76 (5)

  Abstract

  While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis.Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains.Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA.Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.

  View details for DOI 10.1136/annrheumdis-2016-210426

  View details for Web of Science ID 000398387200022

• Outcome of 4 Surgical Treatments for Wear and Osteolysis of Cementless Acetabular Components. journal of arthroplasty Narkbunnam, R., Amanatullah, D. F., Electriwala, A. J., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2017

  Abstract

  Loosening and periprosthetic osteolysis are some of the most common long-term complications after hip arthroplasty. The decision-making process and surgical treatment options are controversial.We retrospectively reviewed 96 acetabular revisions (91 patients) performed between 2002 and 2012, with a minimum of 2 years of follow-up and a mean of 5.7 years of follow-up. Clinical outcome was assessed using the Harris Hip Score. The size and location of osteolytic lesions were evaluated using the preoperative radiographs; healing of the defects was categorized using a standardized protocol.Thirty-three (34.4%) hips had isolated liner exchanges (ILEs), 10 (10.4%) hips had cemented liners into well-fixed shells (CLS), 45 (46.9%) hips had full acetabular revisions (FARs), and 8 (8.3%) hips had revision with a roof ring/antiprotrusio cage (RWC). All procedures showed significant improvement in Harris Hip Score after revision (P ≤ .001). Fifteen patients had moderate residual pain (pain score ≤20): 8 (24%) ILE, 3 (30%) CLS, and 4 (9%) FAR. Complete bone defect healing after grafting was lower with acetabular component retention procedures (ILE and CLS; 27%) compared with full acetabular component revision procedures (FAR and RWC; 57%). Fifteen patients underwent reoperation: 3 ILE, 1 CLS, 8 FAR, and 3 RWC.Acetabular component retention demonstrates a low risk of reoperation; however, residual pain and limited potential for bone graft incorporation are a concern. FAR is technically challenging and may have an elevated risk of reoperation; however, higher degrees of bone graft incorporation and satisfactory clinical outcome can be expected.

  View details for DOI 10.1016/j.arth.2017.04.028

  View details for PubMedID 28587888

• Mesenchymal stem cells in the aseptic loosening of total joint replacements. Journal of biomedical materials research. Part A Pajarinen, J., Lin, T., Nabeshima, A., Jämsen, E., Lu, L., Nathan, K., Yao, Z., Goodman, S. B. 2017; 105 (4): 1195-1207

  Abstract

  Peri-prosthetic osteolysis remains as the main long-term complication of total joint replacement surgery. Research over four decades has established implant wear as the main culprit for chronic inflammation in the peri-implant tissues and macrophages as the key cells mediating the host reaction to implant-derived wear particles. Wear debris activated macrophages secrete inflammatory mediators that stimulate bone resorbing osteoclasts; thus bone loss in the peri-implant tissues is increased. However, the balance of bone turnover is not only dictated by osteoclast-mediated bone resorption but also by the formation of new bone by osteoblasts; under physiological conditions these two processes are tightly coupled. Increasing interest has been placed on the effects of wear debris on the cells of the bone-forming lineage. These cells are derived primarily from multipotent mesenchymal stem cells (MSCs) residing in bone marrow and the walls of the microvasculature. Accumulating evidence indicates that wear debris significantly impairs MSC-to-osteoblast differentiation and subsequent bone formation. In this review, we summarize the current understanding of the effects of biomaterial implant wear debris on MSCs. Emerging treatment options to improve initial implant integration and treat developing osteolytic lesions by utilizing or targeting MSCs are also discussed. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1195-1207, 2017.

  View details for DOI 10.1002/jbm.a.35978

  View details for PubMedID 27977880

• Mesenchymal stem cells homing to improve bone healing JOURNAL OF ORTHOPAEDIC TRANSLATION Lin, W., Xu, L., Zwingenberger, S., Gibon, E., Goodman, S. B., Li, G. 2017; 9: 19–27

  Abstract

  Cell therapy continues to attract growing interest as a promising approach to treat a variety of diseases. Mesenchymal stem cells (MSCs) have been one of the most intensely studied candidates for cell therapy. Since the homing capacity of MSCs is an important determinant of effective MSC-based therapy, the enhancement of homing efficiency is essential for optimizing the therapeutic outcome. Furthermore, trafficking of endogenous MSCs to damaged tissues, also referred to as endogenic stem cell homing, and the subsequent participation of MSCs in tissue regeneration are considered to be a natural self-healing response. Therefore, strategies to stimulate and reinforce the mobilisation and homing of MSCs have become a key point in regenerative medicine. The current review focuses on advances in the mechanisms and factors governing trafficking of MSCs, and the relationship between MSC mobilisation and skeletal diseases, providing insights into strategies for their potential translational implications.

  View details for PubMedID 29662796

• Total hip arthroplasty using a monobloc cementless femoral stem for patients with childhood Perthes' disease BONE & JOINT JOURNAL Lee, K. H., Jo, W., Ha, Y. C., Lee, Y. K., Goodman, S. B., Koo, K. H. 2017; 99B (4): 440-444

  Abstract

  Modular or custom-made femoral components have been preferred for total hip arthroplasty (THA) in patients with a history of Perthes' disease because of the distortion in the anatomy of the proximal femur. However, it has not been established whether a monobloc cementless stem will fit the distorted proximal femur or whether the results of the procedure are satisfactory in this group of patients.We reviewed 68 consecutive patients who had undergone THA for childhood Perthes' disease between June 2003 and December 2008. There were 35 men and 33 women with a mean age of 48 years (16 to 73) at the time of index arthroplasty. Their mean body mass index was 24.4 (18.3 to 32.9). Of the 68 hips, 32 were classified as Stulberg class III and 36 as class IV. The mean pre-operative shortening of the affected leg was 17.2 mm (5 to 34). The minimum follow-up was five years (mean 8.5 years; 5.2 to 10).An intra-operative calcar fracture occurred in eight hips (11.8%) and was successfully treated by cerclage wiring. The mean stem version was 14.6° (-2.3 to 30; standard deviation (sd) 7.3). The mean acetabular component abduction was 40.2° (23.7 to 56.0; sd 6.5) and the mean anteversion 28.3° (6.4 to 43.0; sd 7.6), respectively. The mean follow-up was 8.5 years (5.2 to 10). No dislocations occurred and no hips were revised during the course of the study. At final follow-up, the mean Harris Hip Score was 91 points (59 to 100) and the mean University of California, Los Angeles activity score was 3.2 (2 to 8).Monobloc cementless stems reliably restore the anatomy in Perthes' disease at THA without the need for custom-made or modular implants. Cite this article: Bone Joint J 2017;99-B:440-444.

  View details for DOI 10.1302/0301-620X.99B4.BJJ-2016-0259.R1

  View details for Web of Science ID 000399328900005

• Total hip arthroplasty using a monobloc cementless femoral stem for patients with childhood Perthes' disease. bone & joint journal Lee, K. H., Jo, W., Ha, Y. C., Lee, Y. K., Goodman, S. B., Koo, K. H. 2017; 99-B (4): 440-444

  Abstract

  Modular or custom-made femoral components have been preferred for total hip arthroplasty (THA) in patients with a history of Perthes' disease because of the distortion in the anatomy of the proximal femur. However, it has not been established whether a monobloc cementless stem will fit the distorted proximal femur or whether the results of the procedure are satisfactory in this group of patients.We reviewed 68 consecutive patients who had undergone THA for childhood Perthes' disease between June 2003 and December 2008. There were 35 men and 33 women with a mean age of 48 years (16 to 73) at the time of index arthroplasty. Their mean body mass index was 24.4 (18.3 to 32.9). Of the 68 hips, 32 were classified as Stulberg class III and 36 as class IV. The mean pre-operative shortening of the affected leg was 17.2 mm (5 to 34). The minimum follow-up was five years (mean 8.5 years; 5.2 to 10).An intra-operative calcar fracture occurred in eight hips (11.8%) and was successfully treated by cerclage wiring. The mean stem version was 14.6° (-2.3 to 30; standard deviation (sd) 7.3). The mean acetabular component abduction was 40.2° (23.7 to 56.0; sd 6.5) and the mean anteversion 28.3° (6.4 to 43.0; sd 7.6), respectively. The mean follow-up was 8.5 years (5.2 to 10). No dislocations occurred and no hips were revised during the course of the study. At final follow-up, the mean Harris Hip Score was 91 points (59 to 100) and the mean University of California, Los Angeles activity score was 3.2 (2 to 8).Monobloc cementless stems reliably restore the anatomy in Perthes' disease at THA without the need for custom-made or modular implants. Cite this article: Bone Joint J 2017;99-B:440-444.

  View details for DOI 10.1302/0301-620X.99B4.BJJ-2016-0259.R1

  View details for PubMedID 28385931

• Revision Hip Arthroplasty Using a Modular, Cementless Femoral Stem: Intermediate-Term Follow-Up JOURNAL OF ARTHROPLASTY Sivananthan, S., Lim, C., Narkbunnam, R., Sox-Harris, A., Huddleston, J. I., Goodman, S. B. 2017; 32 (4): 1245-1249

  Abstract

  Modular femoral stem provides flexibility in femoral reconstruction, ensuring improved "fit and fill". However, there are risks of junction failure and corrosion, as well as cost concerns in the use of modular femoral stems.We reviewed prospectively-gathered clinical and radiographic data on revision total hip arthroplasties (THAs) performed from 2001-2007 using modular, cementless femoral component performed by the 2 senior authors. Patients with a minimum follow-up of 7 years were included in this study.Sixty-four patients (68 hips) with a median age of 68 ± 14 years (range 40-92 years) at revision THA were included. The median follow-up was 11.0 ± 1.8 years (range 7-14). Harris hip score, femoral stem subsidence, and stem osseointegration were recorded. The Harris hip score improved from an average of 38.1-80.1 (P < .01). Five hips had one or more dislocations. Seven patients underwent reoperations, 3 of which did not involve the stem. Four stems required revision because of infection, recurrent dislocation, or suboptimal implant position. Survival rates for any reasons and revision for femoral stems were 90% and 94%, respectively, at the most recent follow-up. Four stems subsided more than 5 mm, but established stable osseointegration thereafter. Seven nonloose stems (10.2%) demonstrated radiolucent lines in Gruen zones 1 and 7. No complications regarding the modular junction were encountered.Modular, cementless, extensively porous-coated femoral components have demonstrated intermediate-term clinical and radiographic success. Initial distal intramedullary fixation ensures stability, and proximal modularity further maximizes fit and fill.

  View details for DOI 10.1016/j.arth.2016.10.033

  View details for Web of Science ID 000401125600036

• Pro-inflammatory M1 macrophages promote osteogenesis by mesenchymal stem cells via the COX-2-prostaglandin E2 pathway. Journal of orthopaedic research Lu, L. Y., Loi, F., Nathan, K., Lin, T., Pajarinen, J., Gibon, E., Nabeshima, A., Cordova, L., Jämsen, E., Yao, Z., Goodman, S. B. 2017

  Abstract

  Bone fractures are among the most common orthopaedic problems that affect individuals of all ages. Immediately after injury, activated macrophages dynamically contribute to and regulate an acute inflammatory response that involves other cells at the injury site, including mesenchymal stem cells (MSCs). These macrophages and MSCs work in concert to modulate bone healing. In this study, we co-cultured undifferentiated M0, pro-inflammatory M1, and anti-inflammatory M2 macrophages with primary murine MSCs in vitro to determine the cross-talk between polarized macrophages and MSCs and their effects on osteogenesis. After 4 weeks of co-culture, MSCs grown with macrophages, especially M1 macrophages, had enhanced bone mineralization compared to MSCs grown alone. The level of bone formation after 4 weeks of culture was closely associated with prostaglandin E2 (PGE2) secretion early in osteogenesis. Treatment with celecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, significantly reduced bone mineralization in all co-cultures but most dramatically in the M1-MSC co-culture. We also found that the presence of macrophages reduced the secretion of osteoprotegerin (OPG), the decoy RANKL receptor, suggesting that macrophages may indirectly modulate osteoclast activity in addition to enhancing bone formation. Taken together, these findings suggest that an initial pro-inflammatory phase modulated by M1 macrophages promotes osteogenesis in MSCs via the COX-2-PGE2 pathway. Understanding the complex interactions between macrophages and MSCs provide opportunities to optimize bone healing and other regenerative processes via modulation of the inflammatory response. This study provides one possible biological mechanism for the adverse effects of non-steroidal anti-inflammatory drugs on fracture healing and bone regeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

  View details for DOI 10.1002/jor.23553

  View details for PubMedID 28248001

• The Direct Anterior Approach is Associated With Early Revision Total Hip Arthroplasty. journal of arthroplasty Eto, S., Hwang, K., Huddleston, J. I., Amanatullah, D. F., Maloney, W. J., Goodman, S. B. 2017; 32 (3): 1001-1005

  Abstract

  The direct anterior approach for total hip arthroplasty (THA) has generated increased interest recently. The purpose of this study was to compare the duration to failure and reasons for revision of primary THA performed elsewhere and subsequently revised at our institution after the direct anterior vs other nonanterior surgical approaches to the hip.All primary THAs performed elsewhere and referred to our institution for revision were divided into the direct anterior approach (30 cases) or nonanterior approach groups (100 cases, randomly selected from 453 cases) based on the original surgical approach. Because all primary direct anterior THAs were originally performed after 2004 to eliminate temporal bias, we identified a subset of the nonanterior group in which the primary THA was performed after 2004 (known as the recent nonanterior group, 100 cases, randomly selected from 169 available cases).The mean duration from primary to revision THA was 3.0 ± 2.7 years (direct anterior approach), 12.0 ± 8.8 years (nonanterior approach), and 3.6 ± 2.8 years (recent nonanterior), respectively. There was a significant difference in time to revision between the direct anterior and nonanterior approach groups (P < .001). Aseptic loosening of the stem was significantly more frequent with the direct anterior approach group (9/30, 30.0%) when compared with the nonanterior group (8/100, 8.0%, P = .007) and the recent nonanterior group (7/100, 7.0%, P = .002).Revision of the femoral component for aseptic loosening is more commonly associated with the direct anterior approach in our referral practice.

  View details for DOI 10.1016/j.arth.2016.09.012

  View details for PubMedID 27843039

• Weight Gain After Primary Total Knee Arthroplasty Is Associated With Accelerated Time to Revision for Aseptic Loosening. journal of arthroplasty Lim, C. T., Goodman, S. B., Huddleston, J. I., Harris, A. H., Bhowmick, S., Maloney, W. J., Amanatullah, D. F. 2017

  Abstract

  Obesity is a major health problem worldwide and is associated with complications after total knee arthroplasty (TKA). It remains unknown whether a change in body mass index (BMI) after primary TKA affects the reasons for revision TKA or the time to revision TKA.A total of 160 primary TKAs referred to an academic tertiary center for revision TKA were retrospectively stratified according to change in BMI from the time of their primary TKA to revision TKA. The association between change in BMI and time to revision was also analyzed according to indication for revision of TKA using Pearson's chi-square test.The mean change in BMI from primary to revision TKA was 0.82 ± 3.5 kg/m(2). Maintaining a stable weight after primary TKA was protective against late revision TKA for any reason (P = .004). Patients who failed to reduce their BMI were revised for aseptic loosening earlier, at less than 5 years (P = .020), whereas those who reduced their BMI were revised later, at over 10 years (P = .004).Maintaining weight after primary TKA is protective against later revision TKA for any reason but failure to reduce weight after primary TKA is a risk factor for early revision TKA for aseptic loosening and osteolysis. Orthopedic surgeons should recommend against weight gain after primary TKA to reduce the risk of an earlier revision TKA in the event that a revision TKA is indicated.

  View details for DOI 10.1016/j.arth.2017.02.026

  View details for PubMedID 28318864

• Mutant CCL2 protein coating mitigates wear particle-induced bone loss in a murine continuous polyethylene infusion model BIOMATERIALS Nabeshima, A., Pajarinen, J., Lin, T., Jiang, X., Gibon, E., Cordova, L. A., Loi, F., Lu, L., Jamsen, E., Egashira, K., Yang, F., Yao, Z., Goodman, S. B. 2017; 117: 1-9

  Abstract

  Wear particle-induced osteolysis limits the long-term survivorship of total joint replacement (TJR). Monocyte/macrophages are the key cells of this adverse reaction. Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) is the most important chemokine regulating trafficking of monocyte/macrophages in particle-induced inflammation. 7ND recombinant protein is a mutant of CCL2 that inhibits CCL2 signaling. We have recently developed a layer-by-layer (LBL) coating platform on implant surfaces that can release biologically active 7ND. In this study, we investigated the effect of 7ND on wear particle-induced bone loss using the murine continuous polyethylene (PE) particle infusion model with 7ND coating of a titanium rod as a local drug delivery device. PE particles were infused into hollow titanium rods with or without 7ND coating implanted in the distal femur for 4 weeks. Specific groups were also injected with RAW 264.7 as the reporter macrophages. Wear particle-induced bone loss and the effects of 7ND were evaluated by microCT, immunohistochemical staining, and bioluminescence imaging. Local delivery of 7ND using the LBL coating decreased systemic macrophage recruitment, the number of osteoclasts and wear particle-induced bone loss. The development of a novel orthopaedic implant coating with anti-CCL2 protein may be a promising strategy to mitigate peri-prosthetic osteolysis.

  View details for DOI 10.1016/j.biomaterials.2016.11.039

  View details for PubMedID 27918885

• Editorial Comment: 2016 Hip Society Proceedings CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B. 2017; 475 (2): 334–35

  View details for PubMedID 27620803

• Response to Letter to the Editor on 'Tibiofemoral Dislocation After Total Knee Arthroplasty' JOURNAL OF ARTHROPLASTY Jethanandani, R. G., Maloney, W. J., Huddleston, J. I., Goodman, S. B., Amanatullah, D. F. 2017; 32 (2): 700-700

  View details for DOI 10.1016/j.arth.2016.10.021

  View details for PubMedID 27865569

• Decreased osteogenesis in mesenchymal stem cells derived from the aged mouse is associated with enhanced NF-?B activity. Journal of orthopaedic research Lin, T., Gibon, E., Loi, F., Pajarinen, J., Córdova, L. A., Nabeshima, A., Lu, L., Yao, Z., Goodman, S. B. 2017; 35 (2): 281-288

  Abstract

  Aging is associated with significant bone loss and delayed fracture healing. NF-κB activation is highly correlated with inflammatory-associated bone diseases including infection, wear particle exposure, and chronic inflammation during natural aging processes. The critical roles of NF-κB in both the pro-inflammatory response and osteoclast-mediated bone resorption have been well defined. However, the biological effects of NF-κB activation in mesenchymal stem cell (MSC)-mediated bone formation remain largely unknown. In the current study, bone marrow-MSCs were isolated from young (8 weeks old) and aged (72 weeks old) mice. NF-κB activity in MSCs at basal levels and under different biological conditions were determined by our recently established lentiviral vector-based luciferase reporter assay. We found that NF-κB activity was increased in aged MSCs at basal levels or when exposed to low dose (10 or 100 ng/ml) lipopolysaccharide (LPS); this effect was not seen when the cells were exposed to higher dose (1 μg/ml) LPS. During osteogenesis, NF-κB activity was increased in aged MSCs at weeks 1 and 2, but showed no significant difference at week 3. Both Smurf2 and TAZ, the NF-κB target genes that regulate osteogenic differentiation, were increased in aged MSCs. In addition, the expression of RANKL was dramatically increased, and OPG was decreased in aged MSCs. Our findings suggest that targeting NF-κB activity in MSCs has the potential to modulate aging-associated bone loss, or enhance bone-healing in aged patients. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:281-288, 2017.

  View details for DOI 10.1002/jor.23270

  View details for PubMedID 27105133

• Correlations between macrophage polarizing cytokines, inflammatory mediators, osteoclast activity, and toll-like receptors in tissues around aseptically loosened hip implants JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Jamsen, E., Kouri, V., Ainola, M., Goodman, S. B., Nordstrom, D. C., Eklund, K. K., Pajarinen, J. 2017; 105 (2): 454-463

  Abstract

  Aseptic loosening and osteolysis of joint replacements are driven by macrophage-mediated inflammatory reactions to implant-derived wear debris, but many aspects of these events remain poorly characterized. To better understand the relationships among inflammatory and chemotactic mediators, macrophage phenotype and polarizing cytokines, osteoclast activity, and Toll-like receptors (TLRs) in the pathogenesis of aseptic loosening, we determined how the relative expressions of these factors in the peri-implant tissues correlate to each other and to the life span of the implants using Pearson correlation. The expression of pro-inflammatory mediators and chemokines showed positive correlations among themselves, and with TLR4. Furthermore, M1-polarizing IFN-γ showed positive correlations with a number of pro-inflammatory and chemotactic mediators, whereas M2-polarizing IL-4 showed no such association. IL-8 expression significantly correlated with early time to revision. Similar trends were observed for TNF-α, IFN-γ and CCL3, while the opposite was detected for IL-4. However, none of the inflammatory mediators correlated with the markers of osteoclast activity or the RANKL/OPG ratio. The results highlight the importance of the inflammatory mediators, IFN-γ and TLR4 in the pathogenesis of aseptic loosening; increased pro-inflammatory status was associated with early time to revision, whereas IL-4 correlated with longer implant survival. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbm.a.35913

  View details for Web of Science ID 000392506300011

• NF-?B as a Therapeutic Target in Inflammatory-Associated Bone Diseases. Advances in protein chemistry and structural biology Lin, T., Pajarinen, J., Lu, L., Nabeshima, A., Cordova, L. A., Yao, Z., Goodman, S. B. 2017; 107: 117-154

  Abstract

  Inflammation is a defensive mechanism for pathogen clearance and maintaining tissue homeostasis. In the skeletal system, inflammation is closely associated with many bone disorders including fractures, nonunions, periprosthetic osteolysis (bone loss around orthopedic implants), and osteoporosis. Acute inflammation is a critical step for proper bone-healing and bone-remodeling processes. On the other hand, chronic inflammation with excessive proinflammatory cytokines disrupts the balance of skeletal homeostasis involving osteoblastic (bone formation) and osteoclastic (bone resorption) activities. NF-κB is a transcriptional factor that regulates the inflammatory response and bone-remodeling processes in both bone-forming and bone-resorption cells. In vitro and in vivo evidences suggest that NF-κB is an important potential therapeutic target for inflammation-associated bone disorders by modulating inflammation and bone-remodeling process simultaneously. The challenges of NF-κB-targeting therapy in bone disorders include: (1) the complexity of canonical and noncanonical NF-κB pathways; (2) the fundamental roles of NF-κB-mediated signaling for bone regeneration at earlier phases of tissue damage and acute inflammation; and (3) the potential toxic effects on nontargeted cells such as lymphocytes. Recent developments of novel inhibitors with differential approaches to modulate NF-κB activity, and the controlled release (local) or bone-targeting drug delivery (systemic) strategies, have largely increased the translational application of NF-κB therapy in bone disorders. Taken together, temporal modulation of NF-κB pathways with the combination of recent advanced bone-targeting drug delivery techniques is a highly translational strategy to reestablish homeostasis in the skeletal system.

  View details for DOI 10.1016/bs.apcsb.2016.11.002

  View details for PubMedID 28215222

• Smoking is associated with earlier time to revision of total knee arthroplasty. The Knee Lim, C. T., Goodman, S. B., Huddleston, J. I., Harris, A. H., Bhowmick, S. n., Maloney, W. J., Amanatullah, D. F. 2017

  Abstract

  Smoking is associated with early postoperative complications, increased length of hospital stay, and an increased risk of revision after total knee arthroplasty (TKA). However, the effect of smoking on time to revision TKA is unknown.A total of 619 primary TKAs referred to an academic tertiary center for revision TKA were retrospectively stratified according to the patient smoking status. Smoking status was then analyzed for associations with time to revision TKA using a Chi square test. The association was also analyzed according to the indication for revision TKA.Smokers (37/41, 90%) have an increased risk of earlier revision for any reason compared to non-smokers (274/357, 77%, p=0.031). Smokers (37/41, 90%) have an increased risk of earlier revision for any reason compared to ex-smokers (168/221, 76%, p=0.028). Subgroup analysis did not reveal a difference in indication for revision TKA (p>0.05).Smokers are at increased risk of earlier revision TKA when compared to non-smokers and ex-smokers. The risk for ex-smokers was similar to that of non-smokers. Smoking appears to have an all-or-none effect on earlier revision TKA as patients who smoked more did not have higher risk of early revision TKA. These results highlight the need for clinicians to urge patients not to begin smoking and encourage smokers to quit smoking prior to primary TKA.

  View details for PubMedID 28797880

• Femoral Nerve Catheters Improve Home Disposition and Pain in Hip Fracture Patients Treated With Total Hip Arthroplasty. The Journal of arthroplasty Arsoy, D. n., Huddleston, J. I., Amanatullah, D. F., Giori, N. J., Maloney, W. J., Goodman, S. B. 2017

  Abstract

  Opioids have been the mainstay of treatment in the physiologically young geriatric hip fracture patient undergoing total hip arthroplasty (THA). However opioid-related side effects increase morbidity. Regional anesthesia may provide better analgesia, while decreasing opioid-related side effects. The goal of this study was to examine the effect of perioperative continuous femoral nerve blockade with regards to pain scores, opioid-related side effects and posthospital disposition in hip fracture patients undergoing THA.Twenty-nine consecutive geriatric hip fracture patients (22 women/7 men) underwent THA. Average follow-up was 8.3 months (6 weeks-39 months). Fifteen patients were treated with standard analgesia (SA). Fourteen patients received an ultrasound-guided insertion of a femoral nerve catheter after radiographic confirmation of a hip fracture. All complications and readmissions that occurred within 6 weeks of surgery were noted.Continuous femoral nerve catheter (CFNC) patients were discharged home more frequently than SA patients (43% for CFNC vs 7% for SA; P = .023). CFNC patients reported lower average pain scores preoperatively (P < .0001), on postoperative day 1 (P = .005) and postoperative day 2 (P = .037). Preoperatively, CFNC patients required 61% less morphine equivalent (P = .007). CFNC patients had a lower rate of opioid-related side effects compared with SA patients (7% vs 47%; P = .035).CFNC patients were discharged to home more frequently. Use of a CFNC decreased daily average patient-reported pain scores, preoperative opioid usage, and opioid-related side effects after THA for hip fracture. Based on these data, we recommend routine use of perioperative CFNC in hip fracture patients undergoing THA.

  View details for PubMedID 28641968

• Implants for Joint Replacement of the Hip and Knee MATERIALS AND DEVICES FOR BONE DISORDERS Gallo, J., Gibon, E., Goodman, S. B., Bose, S., Bandyopadhyay, A. 2017: 119–96

  View details for Web of Science ID 000413677700005

• 100% Clean and renewable wind, water, and sunlight all-sector energy roadmaps for 139 countries of the world JOULE Jacobson, M. Z., Delucchi, M. A., Bauer, Z. A., Goodman, S. C., Chapman, W. E., Cameron, M. A., et al 2017; 1 (1): 108-121

  View details for DOI 10.1016/j.joule.2017.07.005

• Murine Model of Progressive Orthopaedic Wear Particle Induced Chronic Inflammation and Osteolysis. Tissue engineering. Part C, Methods Pajarinen, J. n., Nabeshima, A. n., Lin, T. H., Sato, T. n., Gibon, E. n., Jämsen, E. n., Lu, L. n., Nathan, K. n., Yao, Z. n., Goodman, S. B. 2017

  Abstract

  Periprosthetic osteolysis and subsequent aseptic loosening of total joint replacements are driven by byproducts of wear released from the implant. Wear particles cause macrophage mediated inflammation that culminates with periprosthetic bone loss. Most current animal models of particle- induced osteolysis are based on the acute inflammatory reaction induced by wear debris, which is distinct from the slowly progressive clinical scenario. To address this limitation we previously developed a murine model of periprosthetic osteolysis that is based on slow continuous delivery of wear particles into the murine distal femur over a period of 4 weeks. The particle delivery was accomplished by using subcutaneously implanted osmotic pumps and tubing, and a hollow titanium rod press-fit into the distal femur. In this study we report a modification of our prior model in which particle delivery is extended to 8 weeks to better mimic the progressive development of periprosthetic osteolysis and to allow the assessment of interventions in a setting where the chronic particle induced osteolysis is already present at the initiation of the treatment. Compared to 4 week samples extending the particle delivery to 8 weeks significantly exacerbated the local bone loss observed with µCT and the amount of both peri-implant F4/80+ macrophages and TRAP+ osteoclasts detected with immunohistochemical and histochemical stainings. Furthermore systemic recruitment of reporter macrophages to peri-implant tissues observed with bioluminescence imaging continued even at the later stages of particle induced inflammation. This modified model system could provide new insights into the mechanisms of chronic inflammatory bone loss and be particularly useful in assessing the efficacy of treatments in a setting that resembles the clinical scenario of developing periprosthetic osteolysis more closely than currently existing model systems.

  View details for PubMedID 28978284

• CCL2, CCL5 and IGF-1 Participate in The Immunomodulation of Osteogenesis during M1/M2 Transition In Vitro. Journal of biomedical materials research. Part A Córdova, L. A., Loi, F. n., Lin, T. H., Gibon, E. n., Pajarinen, J. n., Nabeshima, A. n., Lu, L. n., Yao, Z. n., Goodman, S. B. 2017

  Abstract

  The modulation of macrophage phenotype from pro-inflammatory (M1) to tissue healing (M2) via exogenous addition of interleukin-4 (IL-4) facilitates osteogenesis; however, the molecular mediators underlying this phenomenon remain unknown. This study characterizes the IL-4-dependent paracrine crosstalk between macrophages and osteoprogenitors and its effect on osteogenesis in vitro. Primary murine M1 were co-cultured with MC3T3 cells (M1-MC3T3) in both transwell plates and direct co-cultures. To modulate M1 to M2, M1-MC3T3 were treated with IL-4 (20ng/mL) at day 3 after seeding (M1+IL-4-MC3T3). Selected molecular targets were assessed at days 3 and 6 after seeding at protein and mRNA levels. Mineralization was assessed at day 21. Transwell M1+IL-4-MC3T3 significantly enhanced the secretion of CCL2/MCP-1, IGF-1 and to a lesser degree, CCL5/RANTES at day 6. At day 3, alkaline phosphatase (Alpl) was up-regulated in direct M1-MC3T3. At day 6, Smurf2 and Insulin growth factor-1 (Igf-1) were down-regulated and up-regulated respectively in direct M1+IL-4-MC3T3. Finally, M1+IL-4-MC3T3 increased bone matrix mineralization compared with MC3T3 cells in transwell, but this was significantly less than M1-MC3T3. Taken together, macrophage subtypes enhanced the osteogenesis in transwell setting and the transition from M1 to M2 was associated with an increase in bone anabolic factors CCL2/MCP-1, CCL5/RANTES and IGF-1 in vitro. This article is protected by copyright. All rights reserved.

  View details for PubMedID 28782174

• Orthopaedic Wear Particle-induced Bone Loss and Exogenous Macrophage Infiltration is mitigated by Local Infusion of NF-κB Decoy Oligodeoxynucleotide. Journal of biomedical materials research. Part A Lin, T. n., Pajarinen, J. n., Nabeshima, A. n., Córdova, L. A., Loi, F. n., Gibon, E. n., Lu, L. n., Nathan, K. n., Jämsen, E. n., Yao, Z. n., Goodman, S. B. 2017

  Abstract

  Excessive production of wear particles from total joint replacements (TJRs) induces chronic inflammation, macrophage infiltration, and consequent bone loss (periprosthetic osteolysis). This inflammation and bone remodeling are critically regulated by the transcription factor NF-κB. We previously demonstrated that inhibition of NF-κB signaling by using the decoy oligodeoxynucleotide (ODN) mitigates polyethylene wear particle-induced bone loss using in vitro and in vivo models. However, the mechanisms of NF-κB decoy ODN action, and in particular its impact on systemic macrophage recruitment, remain unknown. In the current study, this systemic macrophage infiltration was examined in our established murine femoral continuous particle infusion model. RAW264.7 murine macrophages expressing a luciferase reporter gene were injected into the systemic circulation. Quantification of bioluminescence showed that NF-κB decoy ODN reduced the homing of these reporter macrophages into the distal femurs exposed to continuous particle delivery. Particle-induced reduction in bone mineral density at the distal diaphysis of the femur was also mitigated by infusion of decoy ODN. Histological staining showed that the decoy ODN infusion decreased osteoclast and macrophage numbers, but had no significant effects on osteoblasts. Local infusion of NF-κB decoy ODN reduced systemic macrophage infiltration and mitigated particle-induced bone loss, thus providing a potential strategy to treat periprosthetic osteolysis. This article is protected by copyright. All rights reserved.

  View details for PubMedID 28782280

• Establishment of NF-κB sensing and interleukin-4 secreting mesenchymal stromal cells as an "on-demand" drug delivery system to modulate inflammation. Cytotherapy Lin, T. n., Pajarinen, J. n., Nabeshima, A. n., Lu, L. n., Nathan, K. n., Yao, Z. n., Goodman, S. B. 2017

  Abstract

  Chronic inflammation is associated with up-regulation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and excessive inflammatory cytokine secretion by M1 macrophages. The anti-inflammatory cytokine interleukin (IL)-4 converts pro-inflammatory M1 macrophages into an anti-inflammatory and tissue-regenerative M2 phenotype, thus reducing inflammation and enhancing tissue regeneration. We have generated NF-κB responsive, or constitutively active IL-4 expression lentiviral vectors transduced into murine bone marrow-derived mesenchymal stromal cells (MSCs). MSCs with a constitutively active IL-4 expression vector produced large quantities of IL-4 continuously, whereas IL-4 secretion was significantly induced by lipopolysaccharide (LPS) in the NF-κB sensing MSCs. In contrast, LPS had no effect on MSCs with IL-4 secretion driven by a constitutively active promoter. We also found that intermittent and continuous LPS treatment displayed distinct NF-κB activation profiles, and this regulation was independent of IL-4 signaling. The supernatant containing IL-4 from the LPS-treated MSCs suppressed M1 marker (inducible nitric oxide synthase [iNOS] and tumor necrosis factor alpha [TNFα]) expression and enhanced M2 marker (Arginase 1, CD206 and IL1 receptor antagonist [IL1Ra]) expression in primary murine macrophages. The IL-4 secretion at the basal, non-LPS induced level was sufficient to suppress TNFα and enhance Arginase 1 at a lower level, but had no significant effects on iNOS, CD206 and IL1Ra expression. Finally, IL-4 secretion at basal or LPS-induced levels significantly suppressed osteogenic differentiation of MSCs. Our findings suggest that the IL-4 secreting MSCs driven by NF-κB sensing or constitutive active promoter have great potential for mitigating the effects of chronic inflammation and promoting earlier tissue regeneration.

  View details for PubMedID 28739167

• Reconstruction of Disrupted Extensor Mechanism After Total Knee Arthroplasty. The Journal of arthroplasty Lim, C. T., Amanatullah, D. F., Huddleston, J. I., Harris, A. H., Hwang, K. L., Maloney, W. J., Goodman, S. B. 2017

  Abstract

  Disruption of the extensor mechanism after total knee arthroplasty (TKA) is a debilitating complication that results in extension lag, limited range of motion, difficulty in walking, frequent falls, and chronic pain. This study presents the clinical and radiographic results of reconstruction after extensor mechanism disruption in TKA patients.Consecutive patients with allograft reconstruction of extensor mechanism after TKA were identified retrospectively from an academic tertiary center for revision TKA.Sixteen patients with a mean age of 61 ± 14 years at extensor mechanism reconstruction with a minimum of 2-year follow-up were included. The mean follow-up was 3.3 ± 2.2 years. Knee Society score (KSS), before and at final follow-up extension lag, range of motion, and radiographic change in patellar height were reviewed. There were statistically significant improvements between preoperative and final follow-up KSS (P < .001; KSS for pain, preoperative 40 ± 14 points to final follow-up 67 ± 15 points [P < .001]; KSS for function, preoperative 26 ± 21 points to final follow-up 48 ± 25 points [P < .001]). The extension lag was also reduced from 35° ± 16° preoperatively to 14° ± 18° (P < .001) at final follow-up. There was an average proximal patellar migration of 8 ± 10 mm. Five (31%) cases had an extensor lag of >30° or revision surgery for repeat extensor mechanism reconstruction, infection, or arthrodesis.Our 10-year experience using allografts during extensor mechanism reconstruction demonstrates reasonable outcomes, but failures are to be anticipated in approximately one-third of patients.

  View details for PubMedID 28634096

• Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial. JAMA surgery Hah, J. n., Mackey, S. C., Schmidt, P. n., McCue, R. n., Humphreys, K. n., Trafton, J. n., Efron, B. n., Clay, D. n., Sharifzadeh, Y. n., Ruchelli, G. n., Goodman, S. n., Huddleston, J. n., Maloney, W. J., Dirbas, F. M., Shrager, J. n., Costouros, J. n., Curtin, C. n., Carroll, I. n. 2017

  Abstract

  Guidelines recommend using gabapentin to decrease postoperative pain and opioid use, but significant variation exists in clinical practice.To determine the effect of perioperative gabapentin on remote postoperative time to pain resolution and opioid cessation.A randomized, double-blind, placebo-controlled trial of perioperative gabapentin was conducted at a single-center, tertiary referral teaching hospital. A total of 1805 patients aged 18 to 75 years scheduled for surgery (thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, and shoulder arthroscopy) were screened. Participants were enrolled from May 25, 2010, to July 25, 2014, and followed up for 2 years postoperatively. Intention-to-treat analysis was used in evaluation of the findings.Gabapentin, 1200 mg, preoperatively and 600 mg, 3 times a day postoperatively or active placebo (lorazepam, 0.5 mg) preoperatively followed by inactive placebo postoperatively for 72 hours.Primary outcome was time to pain resolution (5 consecutive reports of 0 of 10 possible levels of average pain at the surgical site on the numeric rating scale of pain). Secondary outcomes were time to opioid cessation (5 consecutive reports of no opioid use) and the proportion of participants with continued pain or opioid use at 6 months and 1 year.Of 1805 patients screened for enrollment, 1383 were excluded, including 926 who did not meet inclusion criteria and 273 who declined to participate. Overall, 8% of patients randomized were lost to follow-up. A total of 202 patients were randomized to active placebo and 208 patients were randomized to gabapentin in the intention-to-treat analysis (mean [SD] age, 56.7 [11.7] years; 256 (62.4%) women and 154 (37.6%) men). Baseline characteristics of the groups were similar. Perioperative gabapentin did not affect time to pain cessation (hazard ratio [HR], 1.04; 95% CI, 0.82-1.33; P = .73) in the intention-to-treat analysis. However, participants receiving gabapentin had a 24% increase in the rate of opioid cessation after surgery (HR, 1.24; 95% CI, 1.00-1.54; P = .05). No significant differences were noted in the number of adverse events as well as the rate of medication discontinuation due to sedation or dizziness (placebo, 42 of 202 [20.8%]; gabapentin, 52 of 208 [25.0%]).Perioperative administration of gabapentin had no effect on postoperative pain resolution, but it had a modest effect on promoting opioid cessation after surgery. The routine use of perioperative gabapentin may be warranted to promote opioid cessation and prevent chronic opioid use. Optimal dosing and timing of perioperative gabapentin in the context of specific operations to decrease opioid use should be addressed in further research.clinicaltrials.gov Identifier: NCT01067144.

  View details for PubMedID 29238824

• Elevated Body Mass Index Is Associated With Early Total Knee Revision for Infection JOURNAL OF ARTHROPLASTY Electricwala, A. J., Jethanandani, R. G., Narkbunnam, R., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2017; 32 (1): 252-255

  Abstract

  Obesity affects over half a billion people worldwide, including one-third of men and women in the United States. Obesity is associated with higher postoperative complication rates after total knee arthroplasty (TKA). It remains unknown whether obese patients progress to revision TKA faster than nonobese patients.A total of 666 consecutive primary TKAs referred to an academic tertiary care center for revision TKA were retrospectively stratified according to body mass index (BMI), reason for revision TKA, and time from primary to revision TKA.When examining primary TKAs referred for revision TKA, increasing BMI adversely affected the mean time to revision TKA. The percent of referred TKAs revised by 5 years was 54% for a normal BMI, 64% for an overweight patient, 71% for an obese class I patient, 68% for an obese class II patient, and 73% for a morbidly obese patient. There was a significant difference in time to revision TKA between patients with normal BMI and elevated BMI (P = .005). There was a significant increase in early revision TKA for infection in patients with an elevated BMI (54%, 74/138) when compared with the normal BMI patients (24%, 8/33, P < .003, relative risk ratio = 2.3, absolute risk = 30%, number needed to treat = 3.3). There was no significant increase in acute, early, midterm, or late revision TKA for aseptic loosening and/or osteolysis, instability, stiffness, or other causes between patients with normal BMI and elevated BMI.An elevated BMI is a risk factor for early referral to a tertiary care center for revision TKA. Specifically, orthopedic surgeons should convey to overweight and obese patients that they have at least a 130% increased relative risk and a 30% absolute risk of revision TKA for an early infection if referred for revision TKA. Patient expectations and counseling as well as reimbursement should account for the greater risks when performing a TKA on patients with an elevated BMI.

  View details for DOI 10.1016/j.arth.2016.05.071

  View details for PubMedID 27421585

• Cortical Strut Allograft Support of Modular Femoral Junctions During Revision Total Hip Arthroplasty. journal of arthroplasty Lim, C. T., Amanatullah, D. F., Huddleston, J. I., Hwang, K. L., Maloney, W. J., Goodman, S. B. 2016

  Abstract

  There is risk of junction failure when using modular femoral stems for revision total hip arthroplasty (THA), especially with loss of bone stock in the proximal femur. Using a cortical strut allograft may provide additional support of a modular femoral construct in revision THA.We reviewed prospectively gathered clinical and radiographic data for 28 revision THAs performed from 2004 to 2014 using cementless modular femoral components with cortical strut allograft applied to supplement proximal femoral bone loss: 5 (18%) were fluted taper designs and 23 (82%) were porous cylindrical designs All the patients had a Paprosky grade IIIA or greater femoral defect. The mean follow-up was 5.4 ± 3.9 years.The Harris Hip Scores improved from 26 ± 10 points preoperatively to 71 ± 10 points at final follow-up (P < .001). The Western Ontario McMaster Universities Osteoarthritis Index scores improved from 45 ± 12 points preoperatively to 76 ± 12 points at final follow-up (P < .001). Eighty-nine percent (25 hips) of all revision or conversion THAs were in place at final follow-up. Three (11%) patients underwent reoperations, 2 for infection and 1 for periprosthetic fracture. There was no statistical significant change in femoral component alignment (P = .161) at final follow-up. Mean subsidence was 1.8 ± 1.3 mm at final follow-up. Femoral diameter increased from initial postoperative imaging to final follow-up imaging by a mean of 9.1 ± 5.1 mm (P < .001) and cortical width increased by a mean of 4.5 ± 2.2 mm (P < .001). Twenty-seven hips (96%) achieved union between the cortical strut allograft and the host femur.The use of a modular femoral stem in a compromised femur with a supplementary cortical strut allgraft is safe and provides satisfactory clinical and radiological outcomes.

  View details for DOI 10.1016/j.arth.2016.12.011

  View details for PubMedID 28130016

• Use of Cortical Strut Allograft After Extended Trochanteric Osteotomy in Revision Total Hip Arthroplasty. journal of arthroplasty Lim, C. T., Amanatullah, D. F., Huddleston, J. I., Hwang, K. L., Maloney, W. J., Goodman, S. B. 2016

  Abstract

  Cortical strut allografts restore bone stock and improve postoperative clinical scores after revision total hip arthroplasty (THA). However, use of a cortical strut allograft is implicated in delayed healing of an extended trochanteric osteotomy (ETO). To date, there are no reports directly comparing ETO with or without cortical strut allografts.We reviewed prospectively gathered data on 50 revision THAs performed from 2004-2014 using an ETO. We compared the demographic, radiological, and clinical outcome of patients with (16 hips) and without (34 hips) cortical strut allograft after an ETO.There were no significant differences in Western Ontario McMaster Universities Osteoarthritis Index or Harris Hip Score between the ETOs with and without a cortical strut allograft. Fifteen of the ETOs (94%) with a cortical strut allograft and 31 of the ETOs (91%) without a cortical strut allograft were in situ at final follow-up (P = 1.000). A higher proportion hips with cortical strut allograft (100%, 16 patients) had preoperative Paprosky grade bone loss more than IIIA compared to those without allograft (29%, 10 patients) (P < .001). There were no differences in femoral stem subsidence (P = .207), alignment (P = .934), or migration of the osteotomized fragment (P = .171). Fourteen of the ETOs (88%) in patients with cortical strut allograft united compared to 34 ETOs (100%) in patients without allograft (P = .095).Our study shows that the use of cortical strut allograft during revision THA with ETO does not reduce the rate of union, radiological or clinical outcomes.

  View details for DOI 10.1016/j.arth.2016.12.002

  View details for PubMedID 28110850

• CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis. Annals of the rheumatic diseases Raghu, H., Lepus, C. M., Wang, Q., Wong, H. H., Lingampalli, N., Oliviero, F., Punzi, L., Giori, N. J., Goodman, S. B., Chu, C. R., Sokolove, J. B., Robinson, W. H. 2016

  Abstract

  While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis.Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains.Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA.Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.

  View details for DOI 10.1136/annrheumdis-2016-210426

  View details for PubMedID 27965260

• Revision Hip Arthroplasty Using a Modular, Cementless Femoral Stem: Intermediate-Term Follow-Up. journal of arthroplasty Sivananthan, S., Lim, C., Narkbunnam, R., Sox-Harris, A., Huddleston, J. I., Goodman, S. B. 2016

  Abstract

  Modular femoral stem provides flexibility in femoral reconstruction, ensuring improved "fit and fill". However, there are risks of junction failure and corrosion, as well as cost concerns in the use of modular femoral stems.We reviewed prospectively-gathered clinical and radiographic data on revision total hip arthroplasties (THAs) performed from 2001-2007 using modular, cementless femoral component performed by the 2 senior authors. Patients with a minimum follow-up of 7 years were included in this study.Sixty-four patients (68 hips) with a median age of 68 ± 14 years (range 40-92 years) at revision THA were included. The median follow-up was 11.0 ± 1.8 years (range 7-14). Harris hip score, femoral stem subsidence, and stem osseointegration were recorded. The Harris hip score improved from an average of 38.1-80.1 (P < .01). Five hips had one or more dislocations. Seven patients underwent reoperations, 3 of which did not involve the stem. Four stems required revision because of infection, recurrent dislocation, or suboptimal implant position. Survival rates for any reasons and revision for femoral stems were 90% and 94%, respectively, at the most recent follow-up. Four stems subsided more than 5 mm, but established stable osseointegration thereafter. Seven nonloose stems (10.2%) demonstrated radiolucent lines in Gruen zones 1 and 7. No complications regarding the modular junction were encountered.Modular, cementless, extensively porous-coated femoral components have demonstrated intermediate-term clinical and radiographic success. Initial distal intramedullary fixation ensures stability, and proximal modularity further maximizes fit and fill.

  View details for DOI 10.1016/j.arth.2016.10.033

  View details for PubMedID 27923596

• Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nature nanotechnology Zanganeh, S., Hutter, G., Spitler, R., Lenkov, O., Mahmoudi, M., Shaw, A., Pajarinen, J. S., Nejadnik, H., Goodman, S., Moseley, M., Coussens, L. M., Daldrup-Link, H. E. 2016; 11 (11): 986-994

  Abstract

  Until now, the Food and Drug Administration (FDA)-approved iron supplement ferumoxytol and other iron oxide nanoparticles have been used for treating iron deficiency, as contrast agents for magnetic resonance imaging and as drug carriers. Here, we show an intrinsic therapeutic effect of ferumoxytol on the growth of early mammary cancers, and lung cancer metastases in liver and lungs. In vitro, adenocarcinoma cells co-incubated with ferumoxytol and macrophages showed increased caspase-3 activity. Macrophages exposed to ferumoxytol displayed increased mRNA associated with pro-inflammatory Th1-type responses. In vivo, ferumoxytol significantly inhibited growth of subcutaneous adenocarcinomas in mice. In addition, intravenous ferumoxytol treatment before intravenous tumour cell challenge prevented development of liver metastasis. Fluorescence-activated cell sorting (FACS) and histopathology studies showed that the observed tumour growth inhibition was accompanied by increased presence of pro-inflammatory M1 macrophages in the tumour tissues. Our results suggest that ferumoxytol could be applied 'off label' to protect the liver from metastatic seeds and potentiate macrophage-modulating cancer immunotherapies.

  View details for DOI 10.1038/nnano.2016.168

  View details for PubMedID 27668795

• Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis. Immunity Li, Y., Shen, Y., Hohensinner, P., Ju, J., Wen, Z., Goodman, S. B., Zhang, H., Goronzy, J. J., Weyand, C. M. 2016; 45 (4): 903-916

  Abstract

  Immune aging manifests with a combination of failing adaptive immunity and insufficiently restrained inflammation. In patients with rheumatoid arthritis (RA), T cell aging occurs prematurely, but the mechanisms involved and their contribution to tissue-destructive inflammation remain unclear. We found that RA CD4(+) T cells showed signs of aging during their primary immune responses and differentiated into tissue-invasive, proinflammatory effector cells. RA T cells had low expression of the double-strand-break repair nuclease MRE11A, leading to telomeric damage, juxtacentromeric heterochromatin unraveling, and senescence marker upregulation. Inhibition of MRE11A activity in healthy T cells induced the aging phenotype, whereas MRE11A overexpression in RA T cells reversed it. In human-synovium chimeric mice, MRE11A(low) T cells were tissue-invasive and pro-arthritogenic, and MRE11A reconstitution mitigated synovitis. Our findings link premature T cell aging and tissue-invasiveness to telomere deprotection and heterochromatin unpacking, identifying MRE11A as a therapeutic target to combat immune aging and suppress dysregulated tissue inflammation.

  View details for DOI 10.1016/j.immuni.2016.09.013

  View details for PubMedID 27742546

• Tibiofemoral Dislocation After Total Knee Arthroplasty. journal of arthroplasty Jethanandani, R. G., Maloney, W. J., Huddleston, J. I., Goodman, S. B., Amanatullah, D. F. 2016; 31 (10): 2282-2285

  Abstract

  Tibiofemoral dislocation after total knee arthroplasty (TKA) is a rare complication. Published case reports describe fewer than 6 patients, making conclusions about the etiology, epidemiology, complications, and treatment of tibiofemoral dislocation difficult. This case series highlights common demographic features, potential causes, and difficulties during the management of tibiofemoral dislocations after TKA.Between 2005 and 2014, 14 patients presented to our institution with a tibiofemoral dislocation. Patients were excluded if they had patellofemoral dislocation or subluxation without a tibiofemoral dislocation. We retrospectively reviewed patient demographics, time to first dislocation, number of dislocations, time to surgical intervention, complications, and potential etiologies of tibiofemoral dislocation.Twelve of 14 patients were female. Their mean body mass index was 33 ± 10 kg/m(2). Thirteen of 14 patients had a mean of 2.0 ± 1.4 dislocations. Four patients dislocated due to polyethylene damage and 5 due to ligamentous incompetence. Twelve of 14 patients required open surgical intervention. Complications in this patient population were common with 3 cases of infection, 7 cases of multiple dislocation, 2 cases of popliteal artery laceration, 1 case receiving a fusion, and 1 case receiving an amputation.Patients with tibiofemoral dislocation after TKA are predominantly obese, female, and have a high risk for complications. They dislocate predominantly because of polyethylene damage or ligamentous incompetence. Re-dislocation is common if treated with closed reduction alone.

  View details for DOI 10.1016/j.arth.2016.03.010

  View details for PubMedID 27084503

• Correlations between macrophage polarizing cytokines, inflammatory mediators, osteoclast activity, and toll-like receptors in tissues around aseptically loosened hip implants. Journal of biomedical materials research. Part A Jämsen, E., Kouri, V., Ainola, M., Goodman, S. B., Nordström, D. C., Eklund, K. K., Pajarinen, J. 2016

  Abstract

  Aseptic loosening and osteolysis of joint replacements are driven by macrophage-mediated inflammatory reactions to implant-derived wear debris, but many aspects of these events remain poorly characterized. To better understand the relationships among inflammatory and chemotactic mediators, macrophage phenotype and polarizing cytokines, osteoclast activity, and Toll-like receptors (TLRs) in the pathogenesis of aseptic loosening, we determined how the relative expressions of these factors in the peri-implant tissues correlate to each other and to the life span of the implants using Pearson correlation. The expression of pro-inflammatory mediators and chemokines showed positive correlations among themselves, and with TLR4. Furthermore, M1-polarizing IFN-γ showed positive correlations with a number of pro-inflammatory and chemotactic mediators, whereas M2-polarizing IL-4 showed no such association. IL-8 expression significantly correlated with early time to revision. Similar trends were observed for TNF-α, IFN-γ and CCL3, while the opposite was detected for IL-4. However, none of the inflammatory mediators correlated with the markers of osteoclast activity or the RANKL/OPG ratio. The results highlight the importance of the inflammatory mediators, IFN-γ and TLR4 in the pathogenesis of aseptic loosening; increased pro-inflammatory status was associated with early time to revision, whereas IL-4 correlated with longer implant survival. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbm.a.35913

  View details for PubMedID 27669374

• The effect of local IL-4 delivery or CCL2 blockade on implant fixation and bone structural properties in a mouse model of wear particle induced osteolysis. Journal of biomedical materials research. Part A Sato, T., Pajarinen, J., Behn, A., Jiang, X., Lin, T., Loi, F., Yao, Z., Egashira, K., Yang, F., Goodman, S. B. 2016; 104 (9): 2255-2262

  Abstract

  Modulation of macrophage polarization and prevention of CCL2-induced macrophage chemotaxis are emerging strategies to reduce wear particle induced osteolysis and aseptic total joint replacement loosening. In this study, the effect of continuous IL-4 delivery or bioactive implant coating that constitutively releases a protein inhibitor of CCL2 signaling (7ND) on particle induced osteolysis were studied in the murine continuous femoral intramedullary particle infusion model. Polyethylene particles with or without IL-4 were infused into mouse distal femurs implanted with hollow titanium rods using subcutaneous infusion pumps. In another experimental group, particles were infused into the femur through a 7ND coated rod. After four weeks, fixation of the implant was assessed using a pullout test. The volume of trabecular bone and the geometry of the local cortical bone were assessed by µCT and the corresponding structural properties of the cortical bone determined by torsional testing. Continuous IL-4 delivery led to increased trabecular bone volume as well as enhanced local bone geometry and structural properties, while 7ND implant coating did not have effect on these parameters. The results suggest that local IL-4 treatment is a promising strategy to mitigate wear particle induced osteolysis. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbm.a.35759

  View details for PubMedID 27114284

• Emperor's new clothes: Is particle disease really infected particle disease? JOURNAL OF ORTHOPAEDIC RESEARCH Wasko, M. K., Goodman, S. B. 2016; 34 (9): 1497–1504

  Abstract

  Aseptic loosening remains the most significant long-term complication of total hip replacement. The current paradigm points to an inflammatory response to wear particles as its main trigger. Recently, there have been increasing numbers of positive bacterial isolates reported among patients with clinically absent infection. This paper reviews existing evidence on possible involvement of bacteria and microbial-associated molecular patterns in the pathology of so-called "aseptic loosening." © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1497-1504, 2016.

  View details for PubMedID 27175824

• Obesity is Associated With Early Total Hip Revision for Aseptic Loosening JOURNAL OF ARTHROPLASTY Electricwala, A. J., Narkbunnam, R., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2016; 31 (9): S217-S220

  Abstract

  Obesity affects more than half a billion people worldwide, including one-third of men and women in the United States. Obesity is associated with higher postoperative complication rates after total hip arthroplasty (THA). It remains unknown whether obese patients progress to revision THA faster than nonobese patients.A total of 257 consecutive primary THAs referred to an academic tertiary care center for revision THA were retrospectively stratified according to preoperative body mass index (BMI), reason for revision THA, and time from primary to revision THA.When examining primary THAs referred for revision THA, increasing BMI adversely affected the mean time to revision THA. The percentage of primary THAs revised at 5 years was 25% for a BMI of 18-25, 38% for a BMI of 25-30, 56% for a BMI of 30-35, 73% for a BMI of 35-40, and 75% for a BMI of greater than 40 (P < .001). The percentage of primary THAs revised at 15 years was 70%, 82%, 87%, 94%, and 100%, respectively (P < .001). A significant increase in early revision THA for aseptic loosening/osteolysis in obese patients (56%, 23/41) when compared with the nonobese patients (12%, 10/83, P < .001, relative risk ratio = 4.7).Preoperative BMI influences the time of failure of primary THAs referred to an academic tertiary care for revision THA as well as the mechanism of failure. Specifically, obesity increased in the relative risk of early revision THA due to aseptic loosening/osteolysis by 4.7 fold.

  View details for DOI 10.1016/j.arth.2016.02.073

  View details for Web of Science ID 000382208900046

• The effect of SDF-1 on low dose BMP-2 mediated bone regeneration by release from heparinized mineralized collagen type I matrix scaffolds in a murine critical size bone defect model JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Zwingenberger, S., Langanke, R., Vater, C., Lee, G., Niederlohmann, E., Sensenschmidt, M., Jacobi, A., Bernhardt, R., Muders, M., Rammelt, S., Knaack, S., Gelinsky, M., Guenther, K., Goodman, S. B., Stiehler, M. 2016; 104 (9): 2126-2134

  Abstract

  The treatment of critical size bone defects represents a challenge. The growth factor bone morphogenetic protein 2 (BMP-2) is clinically established but has potentially adverse effects when used at high doses. The aim of this study was to evaluate if stromal derived factor-1 alpha (SDF-1α) and BMP-2 released from heparinized mineralized collagen type I matrix (MCM) scaffolds have a cumulative effect on bone regeneration. MCM scaffolds were functionalized with heparin, loaded with BMP-2 and/or SDF-1α and implanted into a murine critical size femoral bone defect (control group, low dose BMP-2 group, low dose BMP-2 + SDF-1α group, and high dose BMP-2 group). After 6 weeks, both the low dose BMP-2 + SDF-1α group (5.8 ± 0.6 mm³, p = 0.0479) and the high dose BMP-2 group (6.5 ± 0.7 mm³, p = 0.008) had a significantly increased regenerated bone volume compared to the control group (4.2 ± 0.5 mm³). There was a higher healing score in the low dose BMP-2 + SDF-1α group (median grade 8; Q1-Q3 7-9; p = 0.0357) than in the low dose BMP-2 group (7; Q1-Q3 5-9) histologically. This study showed that release of BMP-2 and SDF-1α from heparinized MCM scaffolds allows for the reduction of the applied BMP-2 concentration since SDF-1α seems to enhance the osteoinductive potential of BMP-2. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2126-2134, 2016.

  View details for DOI 10.1002/jbm.a.35744

  View details for Web of Science ID 000380728900002

• Obesity is Associated With Early Total Hip Revision for Aseptic Loosening. journal of arthroplasty Electricwala, A. J., Narkbunnam, R., Huddleston, J. I., Maloney, W. J., Goodman, S. B., Amanatullah, D. F. 2016; 31 (9): 217-220

  Abstract

  Obesity affects more than half a billion people worldwide, including one-third of men and women in the United States. Obesity is associated with higher postoperative complication rates after total hip arthroplasty (THA). It remains unknown whether obese patients progress to revision THA faster than nonobese patients.A total of 257 consecutive primary THAs referred to an academic tertiary care center for revision THA were retrospectively stratified according to preoperative body mass index (BMI), reason for revision THA, and time from primary to revision THA.When examining primary THAs referred for revision THA, increasing BMI adversely affected the mean time to revision THA. The percentage of primary THAs revised at 5 years was 25% for a BMI of 18-25, 38% for a BMI of 25-30, 56% for a BMI of 30-35, 73% for a BMI of 35-40, and 75% for a BMI of greater than 40 (P < .001). The percentage of primary THAs revised at 15 years was 70%, 82%, 87%, 94%, and 100%, respectively (P < .001). A significant increase in early revision THA for aseptic loosening/osteolysis in obese patients (56%, 23/41) when compared with the nonobese patients (12%, 10/83, P < .001, relative risk ratio = 4.7).Preoperative BMI influences the time of failure of primary THAs referred to an academic tertiary care for revision THA as well as the mechanism of failure. Specifically, obesity increased in the relative risk of early revision THA due to aseptic loosening/osteolysis by 4.7 fold.

  View details for DOI 10.1016/j.arth.2016.02.073

  View details for PubMedID 27108056

• The effect of SDF-1a on low dose BMP-2 mediated bone regeneration by release from heparinized mineralized collagen type I matrix scaffolds in a murine critical size bone defect model. Journal of biomedical materials research. Part A Zwingenberger, S., Langanke, R., Vater, C., Lee, G., Niederlohmann, E., Sensenschmidt, M., Jacobi, A., Bernhardt, R., Muders, M., Rammelt, S., Knaack, S., Gelinsky, M., Günther, K., Goodman, S. B., Stiehler, M. 2016; 104 (9): 2126-2134

  Abstract

  The treatment of critical size bone defects represents a challenge. The growth factor bone morphogenetic protein 2 (BMP-2) is clinically established but has potentially adverse effects when used at high doses. The aim of this study was to evaluate if stromal derived factor-1 alpha (SDF-1α) and BMP-2 released from heparinized mineralized collagen type I matrix (MCM) scaffolds have a cumulative effect on bone regeneration. MCM scaffolds were functionalized with heparin, loaded with BMP-2 and/or SDF-1α and implanted into a murine critical size femoral bone defect (control group, low dose BMP-2 group, low dose BMP-2 + SDF-1α group, and high dose BMP-2 group). After 6 weeks, both the low dose BMP-2 + SDF-1α group (5.8 ± 0.6 mm³, p = 0.0479) and the high dose BMP-2 group (6.5 ± 0.7 mm³, p = 0.008) had a significantly increased regenerated bone volume compared to the control group (4.2 ± 0.5 mm³). There was a higher healing score in the low dose BMP-2 + SDF-1α group (median grade 8; Q1-Q3 7-9; p = 0.0357) than in the low dose BMP-2 group (7; Q1-Q3 5-9) histologically. This study showed that release of BMP-2 and SDF-1α from heparinized MCM scaffolds allows for the reduction of the applied BMP-2 concentration since SDF-1α seems to enhance the osteoinductive potential of BMP-2. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2126-2134, 2016.

  View details for DOI 10.1002/jbm.a.35744

  View details for PubMedID 27060915

• NF-?B decoy oligodeoxynucleotide mitigates wear particle-associated bone loss in the murine continuous infusion model. Acta biomaterialia Lin, T., Pajarinen, J., Sato, T., Loi, F., Fan, C., Córdova, L. A., Nabeshima, A., Gibon, E., Zhang, R., Yao, Z., Goodman, S. B. 2016; 41: 273-281

  Abstract

  Total joint replacement is a cost-effective surgical procedure for patients with end-stage arthritis. Wear particle-induced chronic inflammation is associated with the development of periprosthetic osteolysis. Modulation of NF-κB signaling in macrophages, osteoclasts, and mesenchymal stem cells could potentially mitigate this disease. In the current study, we examined the effects of local delivery of decoy NF-κB oligo-deoxynucleotide (ODN) on wear particle-induced bone loss in a murine continuous femoral particle infusion model. Ultra-high molecular weight polyethylene particles (UHMWPE) with or without lipopolysaccharide (LPS) were infused via osmotic pumps into hollow titanium rods placed in the distal femur of mice for 4 weeks. Particle-induced bone loss was evaluated by μCT, and immunohistochemical analysis of sections from the femur. Particle infusion alone resulted in reduced bone mineral density and trabecular bone volume fraction in the distal femur. The decoy ODN reversed the particle-associated bone volume fraction loss around the implant, irrespective of the presence of LPS. Particle-infusion with LPS increased bone mineral density in the distal femur compared with particle-infusion alone. NF-κB decoy ODN reversed or further increased the bone mineral density in the femur (3-6mm from the distal end) exposed to particles alone or particles plus LPS. NF-κB decoy ODN also inhibited macrophage infiltration and osteoclast number, but had no significant effects on osteoblast numbers in femurs exposed to wear particles and LPS. Our study suggests that targeting NF-κB activity via local delivery of decoy ODN has great potential to mitigate wear particle-induced osteolysis.Total joint replacement is a cost-effective surgical procedure for patients with end-stage arthritis. Chronic inflammation is crucial for the development of wear particle-associated bone loss. Modulation of NF-κB signaling in macrophages (pro-inflammatory cells), osteoclasts (bone-resorbing cells), and osteoblasts (bone-forming cells) could potentially mitigate this disease. Here we demonstrated that local delivery of decoy NF-κB oligo-deoxynucleotide (ODN) mitigated ultra-high molecular weight polyethylene (UHMWPE) wear particleinduced bone loss in a clinically relevant murine model. The protective effects of decoy ODN was associated with reduced macrophage infiltration and osteoclast activation, but had no significant effects on osteoblast numbers. Our study suggests that targeting NF-κB activity via local delivery of decoy ODN has great potential to mitigate wear particle-induced bone loss.

  View details for DOI 10.1016/j.actbio.2016.05.038

  View details for PubMedID 27260104

• Cytokines as a predictor of clinical response following hip arthroscopy: minimum 2-year follow-up. Journal of hip preservation surgery Shapiro, L. M., Safran, M. R., Maloney, W. J., Goodman, S. B., Huddleston, J. I., Bellino, M. J., Scuderi, G. J., Abrams, G. D. 2016; 3 (3): 229-235

  Abstract

  Hip arthroscopy in patients with osteoarthritis has been shown to have suboptimal outcomes. Elevated cytokine concentrations in hip synovial fluid have previously been shown to be associated with cartilage pathology. The purpose of this study was to determine whether a relationship exists between hip synovial fluid cytokine concentration and clinical outcomes at a minimum of 2 years following hip arthroscopy. Seventeen patients without radiographic evidence of osteoarthritis had synovial fluid aspirated at time of portal establishment during hip arthroscopy. Analytes included fibronectin-aggrecan complex as well as a multiplex cytokine array. Patients completed the modified Harris Hip Score, Western Ontario and McMaster Universities Arthritis Index and the International Hip Outcomes Tool pre-operatively and at a minimum of 2 years following surgery. Pre and post-operative scores were compared with a paired t-test, and the association between cytokine values and clinical outcome scores was performed with Pearson's correlation coefficient with an alpha value of 0.05 set as significant. Sixteen of seventeen patients completed 2-year follow-up questionnaires (94%). There was a significant increase in pre-operative to post-operative score for each clinical outcome measure. No statistically significant correlation was seen between any of the intra-operative cytokine values and either the 2-year follow-up scores or the change from pre-operative to final follow-up outcome values. No statistically significant associations were seen between hip synovial fluid cytokine concentrations and 2-year follow-up clinical outcome assessment scores for those undergoing hip arthroscopy.

  View details for DOI 10.1093/jhps/hnw013

  View details for PubMedID 27583163

• Hip arthroplasty for treatment of advanced osteonecrosis: comprehensive review of implant options, outcomes and complications. Orthopedic research and reviews Waewsawangwong, W., Ruchiwit, P., Huddleston, J. I., Goodman, S. B. 2016; 8: 13-29

  Abstract

  Surgical treatment for late stage (post-collapse) osteonecrosis of the femoral head is controversial. In these situations, the outcome of joint preservation procedures is poor. There are several arthroplasty options for late-stage disease. The clinical outcomes of hemiarthroplasty and hemiresurfacing are unpredictable because of progressive acetabular cartilage degeneration. Total hip resurfacing may be associated with further vascular insult to the femoral head and early failure of the implant. Total hip replacement with metal-on-conventional polyethylene bearing surfaces has been the gold standard, but implant survivorship is limited in young active patients due to wear and osteolysis. Newer alternative bearing surfaces may have improved wear characteristics, but their durability must be confirmed in longer-term studies.

  View details for DOI 10.2147/ORR.S35547

  View details for PubMedID 30774467

  View details for PubMedCentralID PMC6209358

• The biological response to orthopaedic implants for joint replacement: Part I: Metals. Journal of biomedical materials research. Part B, Applied biomaterials Gibon, E., Amanatullah, D. F., Loi, F., Pajarinen, J., Nabeshima, A., Yao, Z., Hamadouche, M., Goodman, S. B. 2016

  Abstract

  Joint replacement is a commonly performed, highly successful orthopaedic procedure, for which surgeons have a large choice of different materials and implant designs. The materials used for joint replacement must be both biologically acceptable to minimize adverse local tissue reactions, and robust enough to support weight bearing during common activities of daily living. Modern joint replacements are made from metals and their alloys, polymers, ceramics, and composites. This review focuses on the biological response to the different biomaterials used for joint replacement. In general, modern materials for joint replacement are well tolerated by the body as long as they are in bulk (rather than in particulate or ionic) form, are mechanically stable and noninfected. If the latter conditions are not met, the prosthesis will be associated with an acute/chronic inflammatory reaction, peri-prosthetic osteolysis, loosening and failure. This article (Part 1 of 2) is dedicated to the use of metallic devices in orthopaedic surgery including the associated biological response to metallic byproducts is a review of the basic science literature regarding this topic. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2016.

  View details for DOI 10.1002/jbm.b.33734

  View details for PubMedID 27328111

• Aging Affects Bone Marrow Macrophage Polarization: Relevance to Bone Healing. Regenerative engineering and translational medicine Gibon, E., Loi, F., Córdova, L. A., Pajarinen, J., Lin, T., Lu, L., Nabeshima, A., Yao, Z., Goodman, S. B. 2016; 2 (2): 98-104

  Abstract

  Macrophages are an important component of the inflammatory cascade by initiating and modulating the processes leading to tissue regeneration and bone healing. Depending on the local environment, macrophages can be polarized into M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes. In order to assess the effects of aging on macrophage function, bone marrow macrophage polarization using primary bone marrow macrophages (BMMs) from young (8 weeks old) and aged (72 weeks old) wild-type male C57BL/6J mice was analyzed. Fluorescence-activated cell sorting (FACS) analysis (CD11b, iNOS, CD206), qRT-PCR (iNOS, TNF-α, CD206, Arginase 1), and ELISA (TNF-α, IL-1ra) were performed to compare the M1 and M2 phenotypic markers in young and aged mouse macrophages. Once M1 and M2 macrophage phenotypes were confirmed, the results showed that TNF-α mRNA was significantly upregulated in aged M1s after interferon gamma (INF-γ) exposure. Arginase 1 and CD206 mRNA expression were still upregulated with IL4 stimulation in aged macrophages, but to a lesser extend than those from younger animals. TNF-α secretion was also significantly increased in aged M1s compared to young M1s, following lipopolysaccharide (LPS) exposure. However, the IL-1ra secretion did not increase accordingly in aged mice. The results demonstrate that, compared to younger animals, aging of bone marrow derived macrophages increases the resting levels of oxidative stress, and the ratios of pro- to anti-inflammatory markers. These age-related changes in macrophage polarization may explain in part the attenuated response to adverse stimuli and delay in processes such as fracture healing seen in the elderly.Bone healing is a complex process that involves both biological and mechanical factors. Macrophages are key cells that regulate the events involved in bone healing, especially the initial inflammatory phase. In this biological cascade of events, macrophages present as different functional phenotypes including uncommitted (M0), pro-inflammatory (M1), and anti-inflammatory (M2), a process called macrophage polarization. A clear understanding of the effects of aging on macrophage polarization is critical to modulating adverse events such as fractures, atraumatic bone loss, and tissue regeneration in an aging population.

  View details for DOI 10.1007/s40883-016-0016-5

  View details for PubMedID 28138512

• The Biologic Response to Bearing Materials. Orthopaedic knowledge online Gibon, E., Goodman, S. B. 2016; 14 (6)

  Abstract

  Total joint arthroplasty (TJA) is a common and highly successful orthopaedic procedure for which surgeons can use different bearing materials. The materials used for TJA must be both biocompatible to minimize adverse local tissue reactions and robust enough to support weight bearing during common daily activities. Modern bearing materials for TJA are made from metals and their alloys, polymers, and ceramics. The orthopaedic surgeon should be knowledgeable about the biologic response to the different bearing materials used for TJA, as well as the wear by-products generated.

  View details for PubMedID 29104715

• INTRODUCTION OF NEW TECHNOLOGIES IN ORTHOPAEDIC SURGERY JBJS REVIEWS Goodman, S. B., Mihalko, W. M., Anderson, P. A., Sale, K., Bozic, K. J. 2016; 4 (5)

  Abstract

  The introduction of new devices, biologics, and combination products to the orthopaedic marketplace is increasing rapidly. The majority of these new technologies obtain clearance to market by demonstrating substantial equivalence to a predicate (previously approved device) according to the U.S. Food and Drug Administration (FDA) 510(k) process. Surgeons play a critical role in the introduction of new technologies to patients and must take a leadership role in promoting safe, efficacious, appropriate, and cost-effective care, especially for operative procedures. Surgeons should monitor and document their patients' clinical outcomes and adverse events when using new technology, to ensure that the new technology is performing as desired.

  View details for PubMedID 27490218

• Inflammation, fracture and bone repair. Bone Loi, F., Córdova, L. A., Pajarinen, J., Lin, T., Yao, Z., Goodman, S. B. 2016; 86: 119-130

  Abstract

  The reconstitution of lost bone is a subject that is germane to many orthopaedic conditions including fractures and non-unions, infection, inflammatory arthritis, osteoporosis, osteonecrosis, metabolic bone disease, tumors, and periprosthetic particle-associated osteolysis. In this regard, the processes of acute and chronic inflammation play an integral role. Acute inflammation is initiated by endogenous or exogenous adverse stimuli, and can become chronic in nature if not resolved by normal homeostatic mechanisms. Dysregulated inflammation leads to increased bone resorption and suppressed bone formation. Crosstalk amongst inflammatory cells (polymorphonuclear leukocytes and cells of the monocyte-macrophage-osteoclast lineage) and cells related to bone healing (cells of the mesenchymal stem cell-osteoblast lineage and vascular lineage) is essential to the formation, repair and remodeling of bone. In this review, the authors provide a comprehensive summary of the literature related to inflammation and bone repair. Special emphasis is placed on the underlying cellular and molecular mechanisms, and potential interventions that can favorably modulate the outcome of clinical conditions that involve bone repair.

  View details for DOI 10.1016/j.bone.2016.02.020

  View details for PubMedID 26946132

• The biological response to orthopedic implants for joint replacement. II: Polyethylene, ceramics, PMMA, and the foreign body reaction. Journal of biomedical materials research. Part B, Applied biomaterials Gibon, E., Córdova, L. A., Lu, L., Lin, T., Yao, Z., Hamadouche, M., Goodman, S. B. 2016

  Abstract

  Novel evidence-based prosthetic designs and biomaterials facilitate the performance of highly successful joint replacement (JR) procedures. To achieve this goal, constructs must be durable, biomechanically sound, and avoid adverse local tissue reactions. Different biomaterials such as metals and their alloys, polymers, ceramics, and composites are currently used for JR implants. This review focuses on (1) the biological response to the different biomaterials used for TJR and (2) the chronic inflammatory and foreign-body response induced by byproducts of these biomaterials. A homeostatic state of bone and surrounding soft tissue with current biomaterials for JR can be achieved with mechanically stable, infection free and intact (as opposed to the release of particulate or ionic byproducts) implants. Adverse local tissue reactions (an acute/chronic inflammatory reaction, periprosthetic osteolysis, loosening and subsequent mechanical failure) may evolve when the latter conditions are not met. This article (Part 2 of 2) summarizes the biological response to the non-metallic materials commonly used for joint replacement including polyethylene, ceramics, and polymethylmethacrylate (PMMA), as well as the foreign body reaction to byproducts of these materials. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2016.

  View details for DOI 10.1002/jbm.b.33676

  View details for PubMedID 27080740

• Multifunctional coatings to simultaneously promote osseointegration and prevent infection of orthopaedic implants. Biomaterials Raphel, J., Holodniy, M., Goodman, S. B., Heilshorn, S. C. 2016; 84: 301-314

  Abstract

  The two leading causes of failure for joint arthroplasty prostheses are aseptic loosening and periprosthetic joint infection. With the number of primary and revision joint replacement surgeries on the rise, strategies to mitigate these failure modes have become increasingly important. Much of the recent work in this field has focused on the design of coatings either to prevent infection while ignoring bone mineralization or vice versa, to promote osseointegration while ignoring microbial susceptibility. However, both coating functions are required to achieve long-term success of the implant; therefore, these two modalities must be evaluated in parallel during the development of new orthopaedic coating strategies. In this review, we discuss recent progress and future directions for the design of multifunctional orthopaedic coatings that can inhibit microbial cells while still promoting osseointegration.

  View details for DOI 10.1016/j.biomaterials.2016.01.016

  View details for PubMedID 26851394

• Aging, inflammation, stem cells, and bone healing STEM CELL RESEARCH & THERAPY Gibon, E., Lu, L., Goodman, S. B. 2016; 7

  Abstract

  Complex interactions among cells of the monocyte-macrophage-osteoclast lineage and the mesenchymal stem cell-osteoblast lineage play a major role in the pathophysiology of bone healing. Whereas the former lineage directs inflammatory events and bone resorption, the latter represents a source of cells for bone regeneration and immune modulation. Both of these lineages are affected by increasing age, which is associated with higher baseline levels of inflammatory mediators, and a significant reduction in osteogenic capabilities. Given the above, fracture healing, osteoporosis, and other related events in the elderly present numerous challenges, which potentially could be aided by new therapeutic approaches to modulate both inflammation and bone regeneration.

  View details for DOI 10.1186/s13287-016-0300-9

  View details for Web of Science ID 000372580800001

  View details for PubMedCentralID PMC4804630

• Engineered protein coatings to improve the osseointegration of dental and orthopaedic implants. Biomaterials Raphel, J., Karlsson, J., Galli, S., Wennerberg, A., Lindsay, C., Haugh, M. G., Pajarinen, J., Goodman, S. B., Jimbo, R., Andersson, M., Heilshorn, S. C. 2016; 83: 269-282

  Abstract

  Here we present the design of an engineered, elastin-like protein (ELP) that is chemically modified to enable stable coatings on the surfaces of titanium-based dental and orthopaedic implants by novel photocrosslinking and solution processing steps. The ELP includes an extended RGD sequence to confer bio-signaling and an elastin-like sequence for mechanical stability. ELP thin films were fabricated on cp-Ti and Ti6Al4V surfaces using scalable spin and dip coating processes with photoactive covalent crosslinking through a carbene insertion mechanism. The coatings withstood procedures mimicking dental screw and hip replacement stem implantations, a key metric for clinical translation. They promoted rapid adhesion of MG63 osteoblast-like cells, with over 80% adhesion after 24 h, compared to 38% adhesion on uncoated Ti6Al4V. MG63 cells produced significantly more mineralization on ELP coatings compared to uncoated Ti6Al4V. Human bone marrow mesenchymal stem cells (hMSCs) had an earlier increase in alkaline phosphatase activity, indicating more rapid osteogenic differentiation and mineral deposition on adhesive ELP coatings. Rat tibia and femur in vivo studies demonstrated that cell-adhesive ELP-coated implants increased bone-implant contact area and interfacial strength after one week. These results suggest that ELP coatings withstand surgical implantation and promote rapid osseointegration, enabling earlier implant loading and potentially preventing micromotion that leads to aseptic loosening and premature implant failure.

  View details for DOI 10.1016/j.biomaterials.2015.12.030

  View details for PubMedID 26790146

• Removal of Well-Fixed Cementless Acetabular Components in Revision Total Hip Arthroplasty. Orthopedics Adelani, M. A., Goodman, S. B., Maloney, W. J., Huddleston, J. I. 2016; 39 (2): e280-4

  Abstract

  The Zimmer Explant Acetabular Cup Removal System (Warsaw, Indiana) has been touted as a superior method for removing well-fixed cementless acetabular components while minimizing bone loss; however, no comparative data support this. This study compares bone loss following the removal of well-fixed acetabular components with Aufranc gouges and with the Explant System. A review of 623 revision total hip arthroplasties (THAs) at the authors' institution between 2002 and 2013 identified cases involving the revision of well-fixed cementless hemispherical acetabular components for any reason except infection. Twenty-four cases using Aufranc gouges and 27 cases using the Explant System were included. The following surrogates for bone loss were used: (1) the difference between the initial acetabular component outer diameter (OD) and the final reamer OD; (2) the difference between the initial acetabular component OD and the new acetabular component OD; and (3) the use of impaction bone grafting. A 2-tailed Wilcoxon-Mann-Whitney test was used to assess the difference in bone loss between the 2 groups. The use of bone grafting was compared between the groups with the chi-square test. The median differences between the initial acetabular component and the final reamer (P=.004), as well as between the initial and new acetabular components (P=.002), were 2 mm less with the Explant System. Hips in the Aufranc group were more likely to have bone grafting (54% vs 26%; P=.04). These results suggest less bone loss when removing well-fixed acetabular components with the Zimmer Explant System compared with Aufranc gouges. [Orthopedics. 2016; 39(2):e280-e284.].

  View details for DOI 10.3928/01477447-20160129-04

  View details for PubMedID 26840697

• Can a Conical Implant Successfully Address Complex Anatomy in Primary THA? Radiographs and Hip Scores at Early Followup CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Zhang, Q., Goodman, S. B., Maloney, W. J., Huddleston, J. I. 2016; 474 (2): 459-464

  Abstract

  Total hip arthroplasty (THA) in patients with small or abnormal proximal femoral anatomy is challenging as a result of complex anatomic deformities in the hip. It is unclear which stem is the most appropriate for these patients. One possible implant design that may help meet this need is the modified Wagner Cone prosthesis, whose design consists of monoblock cone with splines; however, to our knowledge, no clinical results have been published using this implant.We evaluated the hip scores and radiographic results (including signs of osseointegration and subsidence) of complex primary THA using the modified Wagner Cone cementless femoral component in patients with small or abnormal proximal femoral anatomic proportions.Between 2006 and 2011, we performed 59 THAs on patients whose femoral geometry precluded the use of standard-sized implants. Of these, 49 (83%) received the modified Wagner Cone prosthesis. During this time, our indications for use of the Wagner Cone implant in such patients included: femoral neck retroversion, excessive anteversion of the femoral neck, or small proximal femora not suitable for standard implants. Of those, 40 patients with 49 THAs were available for radiographic and clinical followup at a minimum of 3 years, and no patients were lost to followup. The diagnosis included developmental dysplasia of hip (22 patients, 28 hips), secondary trauma or posttuberculosis osteoarthritis (nine patients, 10 hips), and hip disease secondary to other disorders (eight patients, nine hips) and osteonecrosis (one patients, two hips). Two versions of the stem with 135° (28 hips) or 125° (21 hips) neck angle versions were used to reestablish normal hip biomechanics. Version angle was chosen based on preoperative templating. Cementless cups with screws were used for the acetabulum. Mean followup was 4 years (range, 3-7 years). Study endpoints were the Harris hip score and radiographic evaluations by a surgeon not involved in the clinical care of the patients (QZ); radiographic analysis included evaluating for the presence or absence of signs of osseointegration (including Engh's criteria) and subsidence.The Harris hip score improved from a mean of 41 ± 9 preoperatively to a mean of 85 ± 10 at last followup (p < 0.01). The mean vertical subsidence was 1.5 ± 1.1 mm. Radiographic evaluation demonstrated stability (no further subsidence) of all implants at last followup. Endosteal spot welds were found in 32 hips (65%). No progressive radiolucencies were observed. One patient (one hip) underwent revision surgery as a result of late infection; no other revisions were performed.The modified Wagner Cone femoral stem has provided improvements in hip scores and promising short-term radiographic results at short-term followup in complex cementless THA associated with abnormal or small femoral anatomical proportions in which standard implants are inappropriate. Longer followup will be needed to see if these results endure. Randomized trials are needed to determine the optimal stem design for these patients.Level IV, therapeutic study.

  View details for DOI 10.1007/s11999-015-4480-x

  View details for Web of Science ID 000368021900033

  View details for PubMedCentralID PMC4709298

• Is There a Benefit to Modularity in 'Simpler' Femoral Revisions? Clinical orthopaedics and related research Huddleston, J. I., Tetreault, M. W., Yu, M., Bedair, H., Hansen, V. J., Choi, H. R., Goodman, S. B., Sporer, S. M., Della Valle, C. J. 2016; 474 (2): 415-20

  Abstract

  Modular revision femoral components allow the surgeon to make more precise intraoperative adjustments in anteversion and sizing, which may afford lower dislocation rates and improved osseointegration, but may not offer distinct advantages when compared with less expensive monoblock revision stems.We compared modular and monoblock femoral components for revision of Paprosky Type I to IIIA femoral defects to determine (1) survivorship of the stems; and (2) complications denoted as intraoperative fracture, dislocation, or failure of osseointegration.Between 2004 and 2010, participating surgeons at three centers revised 416 total hip arthroplasties (THAs) with Paprosky Type I to IIIA femoral defects. Of those with minimum 2-year followup (343 THAs, mean followup 51 ± 13 months), 150 (44%) were treated with modular stems and 193 (56%) were treated with monoblock, cylindrical, fully porous-coated stems. During this time, modular stems were generally chosen when there was remodeling of the proximal femur into retroversion and/or larger canal diameters (usually > 18 mm). A total of 27 patients died (6%) with stems intact before 2 years, 46 THAs (13%) were lost to followup before 2 years for reasons other than death, and there was no differential loss to followup between the study groups. The modular stems included 101 with a cylindrical distal geometry (67%) and 49 with a tapered geometry (33%). Mean age (64 versus 68 years), percentage of women (53% versus 47%), and body mass index (31 versus 30 kg/m(2)) were not different between the two cohorts, whereas there was trend toward a slightly greater case complexity in the modular group (55% versus 65% Type 3a femoral defects, p = 0.06). Kaplan-Meier survivorship was calculated for the endpoint of aseptic revision. Proportions of complications in each cohort (dislocation, intraoperative fracture, and failure of osseointegration) were compared.Femoral component rerevision for any reason (including infection) was greater (OR, 2.01; 95% CI, 1.63-2.57; p = 0.03) in the monoblock group (27 of 193 [14%]) compared with the modular cohort (10 of 150 [7%]). Femoral component survival free from aseptic rerevision was greater in the modular group with 91% survival (95% CI, 89%-95%) at 9 years compared with 86% survival (95% CI, 83%-88%) for the monoblock group in the same timeframe. There was no difference in the proportion of mechanically relevant aseptic complications (30 of 193 [16%] in the monoblock group versus 34 of 150 [23%] in the modular group, p = 0.10; OR, 1.47; 95% CI, 0.86-2.53). There were more intraoperative fractures in the modular group (17 of 150 [11%] versus nine of 193 [5%]; OR, 2.2; 95% CI, 1.68-2.73; p = 0.02). There were no differences in the proportions of dislocation (13 of 193 [7%] monoblock versus 14 of 150 [9%] modular; OR, 0.96; 95% CI, 0.67-1.16; p = 0.48) or failure of osseointegration (eight of 193 [4%] monoblock versus three of 150 [2%] modular; OR, 1.92; 95% CI, 0.88-2.84; p = 0.19) between the two groups with the number of hips available for study.Although rerevisions were less common in patients treated with modular stems, aseptic complications such as intraoperative fractures were more common in that group, and the sample was too small to evaluate corrosion-related or fatigue concerns associated with modularity. We cannot therefore conclude from this that one design is superior to the other. Larger studies and pooled analyses will need to be performed to answer this question, but we believe modularity should be avoided in more straightforward cases if possible.Level III, therapeutic study.

  View details for DOI 10.1007/s11999-015-4474-8

  View details for PubMedID 26245164

  View details for PubMedCentralID PMC4709297

• Can a Conical Implant Successfully Address Complex Anatomy in Primary THA? Radiographs and Hip Scores at Early Followup. Clinical orthopaedics and related research Zhang, Q., Goodman, S. B., Maloney, W. J., Huddleston, J. I. 2016; 474 (2): 459-64

  Abstract

  Total hip arthroplasty (THA) in patients with small or abnormal proximal femoral anatomy is challenging as a result of complex anatomic deformities in the hip. It is unclear which stem is the most appropriate for these patients. One possible implant design that may help meet this need is the modified Wagner Cone prosthesis, whose design consists of monoblock cone with splines; however, to our knowledge, no clinical results have been published using this implant.We evaluated the hip scores and radiographic results (including signs of osseointegration and subsidence) of complex primary THA using the modified Wagner Cone cementless femoral component in patients with small or abnormal proximal femoral anatomic proportions.Between 2006 and 2011, we performed 59 THAs on patients whose femoral geometry precluded the use of standard-sized implants. Of these, 49 (83%) received the modified Wagner Cone prosthesis. During this time, our indications for use of the Wagner Cone implant in such patients included: femoral neck retroversion, excessive anteversion of the femoral neck, or small proximal femora not suitable for standard implants. Of those, 40 patients with 49 THAs were available for radiographic and clinical followup at a minimum of 3 years, and no patients were lost to followup. The diagnosis included developmental dysplasia of hip (22 patients, 28 hips), secondary trauma or posttuberculosis osteoarthritis (nine patients, 10 hips), and hip disease secondary to other disorders (eight patients, nine hips) and osteonecrosis (one patients, two hips). Two versions of the stem with 135° (28 hips) or 125° (21 hips) neck angle versions were used to reestablish normal hip biomechanics. Version angle was chosen based on preoperative templating. Cementless cups with screws were used for the acetabulum. Mean followup was 4 years (range, 3-7 years). Study endpoints were the Harris hip score and radiographic evaluations by a surgeon not involved in the clinical care of the patients (QZ); radiographic analysis included evaluating for the presence or absence of signs of osseointegration (including Engh's criteria) and subsidence.The Harris hip score improved from a mean of 41 ± 9 preoperatively to a mean of 85 ± 10 at last followup (p < 0.01). The mean vertical subsidence was 1.5 ± 1.1 mm. Radiographic evaluation demonstrated stability (no further subsidence) of all implants at last followup. Endosteal spot welds were found in 32 hips (65%). No progressive radiolucencies were observed. One patient (one hip) underwent revision surgery as a result of late infection; no other revisions were performed.The modified Wagner Cone femoral stem has provided improvements in hip scores and promising short-term radiographic results at short-term followup in complex cementless THA associated with abnormal or small femoral anatomical proportions in which standard implants are inappropriate. Longer followup will be needed to see if these results endure. Randomized trials are needed to determine the optimal stem design for these patients.Level IV, therapeutic study.

  View details for DOI 10.1007/s11999-015-4480-x

  View details for PubMedID 26245165

  View details for PubMedCentralID PMC4709298

• Lipoteichoic acid modulates inflammatory response in macrophages after phagocytosis of titanium particles through Toll-like receptor 2 cascade and inflammasomes. Journal of biomedical materials research. Part A Naganuma, Y., Takakubo, Y., Hirayama, T., Tamaki, Y., Pajarinen, J., Sasaki, K., Goodman, S. B., Takagi, M. 2016; 104 (2): 435-444

  Abstract

  Toll-like receptor 2 (TLR2) and nucleotide-binding and oligomerization domain-like receptors with a pyrin domain 3 (NLRP3) inflammasomes have been presumed to participate in the pathogenesis of aseptic implant loosening. The aim of this study is to analyze the cellular localization of TLR2 and NLRP3 inflammasomes in the periprosthetic tissue from aseptically loose hip implants as well as the expression of these molecules in macrophages stimulated in vitro with titanium particles (Ti) coated with lipoteichoic acid (LTA). Using immunohistochemistry, immunoreactivity of TLR2 and NLRP3 inflammasomes was found in macrophages within the foreign body granulomatosis. Using RAW264.7 cells, stimulation with Ti increased mRNA levels of TLR2 and TNF-α. Stimulation with LTA-coated Ti enhanced mRNA levels of NLRP3 and IL-1β, whereas, reinforced secretion of IL-1β was not detected in spite of marked release of TNF-α. Finally, the same cells with silenced Irak2, an adaptor protein in the TLR2 cascade, suppressed this NLRP3 upregulation. This study suggests that TLR2 and NLRP3 inflammasomes are factors involved in cross-talk mediating the foreign body type response to wear particles. In addition, discrepant behavior in the release between TNF-α and IL-1β release may explain the variable pathomechanisms of aseptic implant loosening without acute inflammatory reactions. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbm.a.35581

  View details for PubMedID 26440284

• Editorial Comment: 2015 Hip Society Proceedings CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B. 2016; 474 (2): 319–20

  View details for DOI 10.1007/s11999-015-4586-1

  View details for Web of Science ID 000368021900009

  View details for PubMedID 26463563

  View details for PubMedCentralID PMC4709325

• Is There a Benefit to Modularity in 'Simpler' Femoral Revisions? CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Huddleston, J. I., Tetreault, M. W., Yu, M., Bedair, H., Hansen, V. J., Choi, H., Goodman, S. B., Sporer, S. M., Della Valle, C. J. 2016; 474 (2): 415-420

  Abstract

  Modular revision femoral components allow the surgeon to make more precise intraoperative adjustments in anteversion and sizing, which may afford lower dislocation rates and improved osseointegration, but may not offer distinct advantages when compared with less expensive monoblock revision stems.We compared modular and monoblock femoral components for revision of Paprosky Type I to IIIA femoral defects to determine (1) survivorship of the stems; and (2) complications denoted as intraoperative fracture, dislocation, or failure of osseointegration.Between 2004 and 2010, participating surgeons at three centers revised 416 total hip arthroplasties (THAs) with Paprosky Type I to IIIA femoral defects. Of those with minimum 2-year followup (343 THAs, mean followup 51 ± 13 months), 150 (44%) were treated with modular stems and 193 (56%) were treated with monoblock, cylindrical, fully porous-coated stems. During this time, modular stems were generally chosen when there was remodeling of the proximal femur into retroversion and/or larger canal diameters (usually > 18 mm). A total of 27 patients died (6%) with stems intact before 2 years, 46 THAs (13%) were lost to followup before 2 years for reasons other than death, and there was no differential loss to followup between the study groups. The modular stems included 101 with a cylindrical distal geometry (67%) and 49 with a tapered geometry (33%). Mean age (64 versus 68 years), percentage of women (53% versus 47%), and body mass index (31 versus 30 kg/m(2)) were not different between the two cohorts, whereas there was trend toward a slightly greater case complexity in the modular group (55% versus 65% Type 3a femoral defects, p = 0.06). Kaplan-Meier survivorship was calculated for the endpoint of aseptic revision. Proportions of complications in each cohort (dislocation, intraoperative fracture, and failure of osseointegration) were compared.Femoral component rerevision for any reason (including infection) was greater (OR, 2.01; 95% CI, 1.63-2.57; p = 0.03) in the monoblock group (27 of 193 [14%]) compared with the modular cohort (10 of 150 [7%]). Femoral component survival free from aseptic rerevision was greater in the modular group with 91% survival (95% CI, 89%-95%) at 9 years compared with 86% survival (95% CI, 83%-88%) for the monoblock group in the same timeframe. There was no difference in the proportion of mechanically relevant aseptic complications (30 of 193 [16%] in the monoblock group versus 34 of 150 [23%] in the modular group, p = 0.10; OR, 1.47; 95% CI, 0.86-2.53). There were more intraoperative fractures in the modular group (17 of 150 [11%] versus nine of 193 [5%]; OR, 2.2; 95% CI, 1.68-2.73; p = 0.02). There were no differences in the proportions of dislocation (13 of 193 [7%] monoblock versus 14 of 150 [9%] modular; OR, 0.96; 95% CI, 0.67-1.16; p = 0.48) or failure of osseointegration (eight of 193 [4%] monoblock versus three of 150 [2%] modular; OR, 1.92; 95% CI, 0.88-2.84; p = 0.19) between the two groups with the number of hips available for study.Although rerevisions were less common in patients treated with modular stems, aseptic complications such as intraoperative fractures were more common in that group, and the sample was too small to evaluate corrosion-related or fatigue concerns associated with modularity. We cannot therefore conclude from this that one design is superior to the other. Larger studies and pooled analyses will need to be performed to answer this question, but we believe modularity should be avoided in more straightforward cases if possible.Level III, therapeutic study.

  View details for DOI 10.1007/s11999-015-4474-8

  View details for Web of Science ID 000368021900025

  View details for PubMedCentralID PMC4709297

• Lipoteichoic acid modulates inflammatory response in macrophages after phagocytosis of titanium particles through Toll-like receptor 2 cascade and inflammasomes JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Naganuma, Y., Takakubo, Y., Hirayama, T., Tamaki, Y., Pajarinen, J., Sasaki, K., Goodman, S. B., Takagi, M. 2016; 104 (2): 435-444

  Abstract

  Toll-like receptor 2 (TLR2) and nucleotide-binding and oligomerization domain-like receptors with a pyrin domain 3 (NLRP3) inflammasomes have been presumed to participate in the pathogenesis of aseptic implant loosening. The aim of this study is to analyze the cellular localization of TLR2 and NLRP3 inflammasomes in the periprosthetic tissue from aseptically loose hip implants as well as the expression of these molecules in macrophages stimulated in vitro with titanium particles (Ti) coated with lipoteichoic acid (LTA). Using immunohistochemistry, immunoreactivity of TLR2 and NLRP3 inflammasomes was found in macrophages within the foreign body granulomatosis. Using RAW264.7 cells, stimulation with Ti increased mRNA levels of TLR2 and TNF-α. Stimulation with LTA-coated Ti enhanced mRNA levels of NLRP3 and IL-1β, whereas, reinforced secretion of IL-1β was not detected in spite of marked release of TNF-α. Finally, the same cells with silenced Irak2, an adaptor protein in the TLR2 cascade, suppressed this NLRP3 upregulation. This study suggests that TLR2 and NLRP3 inflammasomes are factors involved in cross-talk mediating the foreign body type response to wear particles. In addition, discrepant behavior in the release between TNF-α and IL-1β release may explain the variable pathomechanisms of aseptic implant loosening without acute inflammatory reactions. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbm.a.35581

  View details for Web of Science ID 000368271600011

• The effects of immunomodulation by macrophage subsets on osteogenesis in vitro STEM CELL RESEARCH & THERAPY Loi, F., Cordova, L. A., Zhang, R., Pajarinen, J., Lin, T., Goodman, S. B., Yao, Z. 2016; 7

  Abstract

  Bone formation and remodeling are influenced by the inflammatory state of the local microenvironment. In this regard, macrophages are postulated to play a crucial role in modulating osteogenesis. However, the differential effects of macrophage subsets and their plasticity on bone formation are currently unknown.Polarized primary murine macrophages and preosteoblastic MC3T3 cells were co-cultured to investigate the effect of non-activated M0, pro-inflammatory M1, and tissue-regenerative M2 macrophages on the osteogenic ability of MC3T3-E1 cells in vitro. Furthermore, to model the physiological transition from inflammation to tissue regeneration, M1-MC3T3 co-cultures were treated with interleukin-4 (IL-4) at different time points to modulate the M1 phenotype towards M2. Macrophage phenotypic markers were assessed by flow cytometry and enzyme-linked immunosorbent assay. A time course study of osteogenic markers at different time points was conducted: alkaline phosphatase (ALP) mRNA levels were evaluated at week 1, ALP activity and osteocalcin and osteopontin mRNA levels at week 2, and matrix mineralization and osteocalcin and osteopontin protein concentrations at week 3. Supernatant collected 72 hours after seeding or IL-4 treatment, whichever was later, was analyzed for oncostatin M, a cytokine released by macrophages that has been recognized to enhance osteogenesis. Unpaired t test or one-way ANOVA with Tukey's or Dunnett's post hoc tests were used for statistical comparison of the groups.Co-culture with any of the macrophage subtypes increased the osteogenic ability of MC3T3 cells as indicated by increases in ALP activity and matrix mineralization. Increased ALP activity, osteocalcin concentration, and matrix mineralization demonstrated that osteogenesis by M1-MC3T3 co-cultures was further enhanced by macrophage phenotype modulation to M2 via IL-4 treatment 72 hours after seeding. Increased oncostatin M protein concentration in untreated M1-MC3T3 co-cultures and M1-MC3T3 co-cultures treated with IL-4 at 72 hours correlated with greater ALP activity and matrix mineralization.These results suggest that a transient inflammatory phase is crucial for enhanced bone formation. Macrophage plasticity may offer new strategies for modulating the local inflammatory microenvironment with the aim of potentially enhancing bone repair.

  View details for DOI 10.1186/s13287-016-0276-5

  View details for Web of Science ID 000368576600001

• Treatment of Periprosthetic Knee Infection With a Two-stage Protocol Using Static Spacers CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Lichstein, P., Su, S., Hedlund, H., Suh, G., Maloney, W. J., Goodman, S. B., Huddleston, J. I. 2016; 474 (1): 120-125

  Abstract

  Two-stage exchange arthroplasty is a standard approach for treating total knee arthroplasty periprosthetic joint infection in the United States, but whether this should be performed with a static antibiotic spacer or an articulating one that allows range of motion before reimplantation remains controversial. It is unclear if the advantages of articulating spacers (easier surgical exposure during reimplantation and improved postoperative flexion) outweigh the disadvantages of increased cost and complexity in the setting of similar rates of infection eradication.The purposes of this study were (1) to determine the ultimate range of motion; and (2) to determine the proportion of patients who remained free of infection at a minimum 2 years after treatment with static antibiotic spacers as part of a two-stage revision TKA for the treatment of periprosthetic joint infection.Between 1999 and 2011, we treated 121 patients with chronically infected TKAs, of whom three had medical comorbidities precluding a two-stage exchange, four had died before 2-year followup for reasons other than the surgical intervention, and seven were lost to followup. The remaining 107 patients (109 knees; 53 men and 54 women) were treated using a two-stage approach with static spacers and are evaluated here at a mean of 3.7 years (range, 2.0-9.8 years); no patients were treated with articulating spacers during this study period. Twenty-five percent (27 of 109) of the organisms isolated the first-stage procedure were resistant to methicillin and/or vancomycin. Median age at the time of reimplantation was 67 years (range, 42-89 years). Range of motion was measured by an independent physical therapist with a standard goniometer. Knee Society knee and function scores were calculated before the first stage and at the 2-year mark. Because many of these patients were treated before consensus definitions of infection were established, we made the diagnosis of infection (and established that a patient was believed to be free of infection) using the approaches prevalent at that time, which generally included presence of a sinus tract communicating directly with the implant, two positive tissue cultures, or a combination of cultures, fluid analysis, and serology.Postoperatively, 67 knees had full extension and no patients had a flexion contracture > 10°. Median flexion was 100° (range, 60°-139°). Thirty-nine knees had postoperative flexion > 120°. Ninety-four percent of patients were clinically free of infection at last followup.Our two-stage exchange protocol with static spacers yielded comparable flexion and infection eradication when compared with other recent studies that have used articulating spacers. The large proportion of resistant organisms is alarming. Future multicenter studies should compare static with articulating spacers and should evaluate both cost and efficacy, because our study suggests that adequate range of motion can be achieved without the added cost of the articulating spacer.Level IV, therapeutic study.

  View details for DOI 10.1007/s11999-015-4443-2

  View details for Web of Science ID 000368022600023

  View details for PubMedCentralID PMC4686492

• Treatment of Periprosthetic Knee Infection With a Two-stage Protocol Using Static Spacers. Clinical orthopaedics and related research Lichstein, P., Su, S., Hedlund, H., Suh, G., Maloney, W. J., Goodman, S. B., Huddleston, J. I. 2016; 474 (1): 120-5

  Abstract

  Two-stage exchange arthroplasty is a standard approach for treating total knee arthroplasty periprosthetic joint infection in the United States, but whether this should be performed with a static antibiotic spacer or an articulating one that allows range of motion before reimplantation remains controversial. It is unclear if the advantages of articulating spacers (easier surgical exposure during reimplantation and improved postoperative flexion) outweigh the disadvantages of increased cost and complexity in the setting of similar rates of infection eradication.The purposes of this study were (1) to determine the ultimate range of motion; and (2) to determine the proportion of patients who remained free of infection at a minimum 2 years after treatment with static antibiotic spacers as part of a two-stage revision TKA for the treatment of periprosthetic joint infection.Between 1999 and 2011, we treated 121 patients with chronically infected TKAs, of whom three had medical comorbidities precluding a two-stage exchange, four had died before 2-year followup for reasons other than the surgical intervention, and seven were lost to followup. The remaining 107 patients (109 knees; 53 men and 54 women) were treated using a two-stage approach with static spacers and are evaluated here at a mean of 3.7 years (range, 2.0-9.8 years); no patients were treated with articulating spacers during this study period. Twenty-five percent (27 of 109) of the organisms isolated the first-stage procedure were resistant to methicillin and/or vancomycin. Median age at the time of reimplantation was 67 years (range, 42-89 years). Range of motion was measured by an independent physical therapist with a standard goniometer. Knee Society knee and function scores were calculated before the first stage and at the 2-year mark. Because many of these patients were treated before consensus definitions of infection were established, we made the diagnosis of infection (and established that a patient was believed to be free of infection) using the approaches prevalent at that time, which generally included presence of a sinus tract communicating directly with the implant, two positive tissue cultures, or a combination of cultures, fluid analysis, and serology.Postoperatively, 67 knees had full extension and no patients had a flexion contracture > 10°. Median flexion was 100° (range, 60°-139°). Thirty-nine knees had postoperative flexion > 120°. Ninety-four percent of patients were clinically free of infection at last followup.Our two-stage exchange protocol with static spacers yielded comparable flexion and infection eradication when compared with other recent studies that have used articulating spacers. The large proportion of resistant organisms is alarming. Future multicenter studies should compare static with articulating spacers and should evaluate both cost and efficacy, because our study suggests that adequate range of motion can be achieved without the added cost of the articulating spacer.Level IV, therapeutic study.

  View details for DOI 10.1007/s11999-015-4443-2

  View details for PubMedID 26280681

  View details for PubMedCentralID PMC4686492

• The Role of Macrophages in the Biological Reaction to Wear Debris from Artificial Joints. Journal of long-term effects of medical implants Nich, C. n., Takakubo, Y. n., Pajarinen, J. n., Gallo, J. n., Konttinen, Y. T., Takagi, M. n., Goodman, S. B. 2016; 26 (4): 303–9

  Abstract

  Normal usage of total joint replacements results in the production of wear debris and other byproducts. In particular, polyethylene particles are heavily involved in the stimulation of local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone resorption (osteolysis), and eventually implant loosening. As sentinels of the innate immune system, cells of the monocyte/macrophage lineage initiate the inflammatory cascade that lead to osteolysis. The biological processes involved are complex, based on the unique properties of the monocytes/macrophages, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The interaction with wear debris triggers the release of pro-inflammatory factors such as tumor necrosis factor-α, interleukin-1, and others; pro-osteoclastic factors such as RANKL; and chemokines such as MCP-1 and MIP-1, all of which are crucial to the recruitment, migration, differentiation, and ultimately activation of bone-resorbing osteoclasts. In parallel, other distinct macrophage populations inhibit inflammation and mitigate its consequences on the bone-implant interface. Here, the role of the monocyte/macrophage cell lineage in the initiation and maintenance of the host inflammatory response to wear debris and subsequent periprosthetic osteolysis is presented.

  View details for PubMedID 29199615

• Hip arthroplasty for treatment of advanced osteonecrosis: comprehensive review of implant options, outcomes and complications ORTHOPEDIC RESEARCH AND REVIEWS Waewsawangwong, W., Ruchiwit, P., Huddleston, J. I., Goodman, S. B. 2016; 8: 13–29

  View details for DOI 10.2147/ORR.S35547

  View details for Web of Science ID 000386440200001

• Comprehensive Operative Note Templates for Primary and Revision Total Hip and Knee Arthroplasty. The open orthopaedics journal Electricwala, A. J., Amanatullah, D. F., Narkbunnam, R. I., Huddleston, J. I., Maloney, W. J., Goodman, S. B. 2016; 10: 725-731

  Abstract

  Adequate preoperative planning is the first and most crucial step in the successful completion of a revision total joint arthroplasty. The purpose of this study was to evaluate the availability, adequacy and accuracy of operative notes of primary surgeries in patients requiring subsequent revision and to construct comprehensive templates of minimum necessary information required in the operative notes to further simplify re-operations, if they should become necessary.The operative notes of 144 patients (80 revision THA's and 64 revision TKA's) who underwent revision total joint arthroplasty at Stanford Hospital and Clinics in the year 2013 were reviewed. We assessed the availability of operative notes and implant stickers prior to revision total joint arthroplasty. The availability of implant details within the operative notes was assessed against the available surgical stickers for adequacy and accuracy. Statistical comparisons were made using the Fischer-exact test and a P-value of less than 0.05 was considered statistically significant.The primary operative note was available in 68 of 144 revisions (47%), 39 of 80 revision THAs (49%) and 29 of 66 revision TKAs (44%, p = 0.619). Primary implant stickers were available in 46 of 144 revisions (32%), 26 of 80 revision THAs (32%) and 20 of 66 revision TKAs (30%, p = 0.859). Utilizing the operative notes and implant stickers combined identified accurate primary implant details in only 40 of the 80 revision THAs (50%) and 34 of all 66 revision TKAs (52%, p = 0.870).Operative notes are often unavailable or fail to provide the necessary information required which makes planning and execution of revision hip and knee athroplasty difficult. This emphasizes the need for enhancing the quality of operative notes and records of patient information. Based on this information, we provide comprehensive operative note templates for primary and revision total hip and knee arthroplasty.

  View details for DOI 10.2174/1874325001610010725

  View details for PubMedID 28144382

• Aging, inflammation, stem cells, and bone healing. Stem cell research & therapy Gibon, E., Lu, L., Goodman, S. B. 2016; 7 (1): 44-?

  Abstract

  Complex interactions among cells of the monocyte-macrophage-osteoclast lineage and the mesenchymal stem cell-osteoblast lineage play a major role in the pathophysiology of bone healing. Whereas the former lineage directs inflammatory events and bone resorption, the latter represents a source of cells for bone regeneration and immune modulation. Both of these lineages are affected by increasing age, which is associated with higher baseline levels of inflammatory mediators, and a significant reduction in osteogenic capabilities. Given the above, fracture healing, osteoporosis, and other related events in the elderly present numerous challenges, which potentially could be aided by new therapeutic approaches to modulate both inflammation and bone regeneration.

  View details for DOI 10.1186/s13287-016-0300-9

  View details for PubMedID 27006071

  View details for PubMedCentralID PMC4804630

• The effects of immunomodulation by macrophage subsets on osteogenesis in vitro. Stem cell research & therapy Loi, F., Córdova, L. A., Zhang, R., Pajarinen, J., Lin, T., Goodman, S. B., Yao, Z. 2016; 7 (1): 15-?

  Abstract

  Bone formation and remodeling are influenced by the inflammatory state of the local microenvironment. In this regard, macrophages are postulated to play a crucial role in modulating osteogenesis. However, the differential effects of macrophage subsets and their plasticity on bone formation are currently unknown.Polarized primary murine macrophages and preosteoblastic MC3T3 cells were co-cultured to investigate the effect of non-activated M0, pro-inflammatory M1, and tissue-regenerative M2 macrophages on the osteogenic ability of MC3T3-E1 cells in vitro. Furthermore, to model the physiological transition from inflammation to tissue regeneration, M1-MC3T3 co-cultures were treated with interleukin-4 (IL-4) at different time points to modulate the M1 phenotype towards M2. Macrophage phenotypic markers were assessed by flow cytometry and enzyme-linked immunosorbent assay. A time course study of osteogenic markers at different time points was conducted: alkaline phosphatase (ALP) mRNA levels were evaluated at week 1, ALP activity and osteocalcin and osteopontin mRNA levels at week 2, and matrix mineralization and osteocalcin and osteopontin protein concentrations at week 3. Supernatant collected 72 hours after seeding or IL-4 treatment, whichever was later, was analyzed for oncostatin M, a cytokine released by macrophages that has been recognized to enhance osteogenesis. Unpaired t test or one-way ANOVA with Tukey's or Dunnett's post hoc tests were used for statistical comparison of the groups.Co-culture with any of the macrophage subtypes increased the osteogenic ability of MC3T3 cells as indicated by increases in ALP activity and matrix mineralization. Increased ALP activity, osteocalcin concentration, and matrix mineralization demonstrated that osteogenesis by M1-MC3T3 co-cultures was further enhanced by macrophage phenotype modulation to M2 via IL-4 treatment 72 hours after seeding. Increased oncostatin M protein concentration in untreated M1-MC3T3 co-cultures and M1-MC3T3 co-cultures treated with IL-4 at 72 hours correlated with greater ALP activity and matrix mineralization.These results suggest that a transient inflammatory phase is crucial for enhanced bone formation. Macrophage plasticity may offer new strategies for modulating the local inflammatory microenvironment with the aim of potentially enhancing bone repair.

  View details for DOI 10.1186/s13287-016-0276-5

  View details for PubMedID 26801095

• Local delivery of mutant CCL2 protein-reduced orthopaedic implant wear particle-induced osteolysis and inflammation in vivo. Journal of orthopaedic research Jiang, X., Sato, T., Yao, Z., Keeney, M., Pajarinen, J., Lin, T., Loi, F., Egashira, K., Goodman, S., Yang, F. 2016; 34 (1): 58-64

  Abstract

  Total joint replacement (TJR) has been widely used as a standard treatment for late-stage arthritis. One challenge for long-term efficacy of TJR is the generation of ultra-high molecular weight polyethylene wear particles from the implant surface that activates an inflammatory cascade that may lead to bone loss, prosthetic loosening and eventual failure of the procedure. Here we investigate the efficacy of local administration of mutant CCL2 proteins, such as 7ND, on reducing wear particle-induced inflammation and osteolysis in vivo using a mouse calvarial model. Mice were treated with local injection of 7ND or phosphate buffered saline (PBS) every other day for up to 14 days. Wear particle-induced osteolysis and the effects of 7ND treatment were evaluated using micro-CT, histology and immunofluorescence staining. Compared with the PBS control, 7ND treatment significantly decreased wear particle-induced osteolysis, which led to a higher bone volume fraction and bone mineral density. Furthermore, immunofluorescence staining showed 7ND treatment decreased the number of recruited inflammatory cells and osteoclasts. Together, our results support the feasibility of local delivery of 7ND for mitigating wear particle-induced inflammation and osteolysis, which may offer a promising strategy for extending the life time of TJRs. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jor.22977

  View details for PubMedID 26174978

• Pain Duration and Resolution following Surgery: An Inception Cohort Study PAIN MEDICINE Carroll, I. R., Hah, J. M., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Mackey, S. C. 2015; 16 (12): 2386-2396

  Abstract

  Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

  View details for DOI 10.1111/pme.12842

  View details for Web of Science ID 000368297000020

  View details for PubMedCentralID PMC4706803

• Immune modulation as a therapeutic strategy in bone regeneration. Journal of experimental orthopaedics Schlundt, C., Schell, H., Goodman, S. B., Vunjak-Novakovic, G., Duda, G. N., Schmidt-Bleek, K. 2015; 2 (1): 1

  Abstract

  We summarize research approaches and findings on bone healing and regeneration that were presented at a workshop at the 60th annual meeting of the Orthopedic Research Society (ORS) in New Orleans in 2014. The workshop was designed to discuss the role of inflammation in bone regeneration in the context of fundamental biology, and to develop therapeutic strategies that involve immune modulation. Delayed or non-healing of bone is a major clinical problem, with around 10% of fracture patients suffering from unsatisfying healing outcomes. Inflammation is traditionally seen as a defense mechanism, but was recently found essential in supporting and modulating regenerative cascades. In bone healing, macrophages and T- and B-cells interact with progenitor cells, bone forming osteoblasts and remodeling osteoclasts. Among the cells of the innate immunity, macrophages are promising candidates for targets in immune-modulatory interventions that would overcome complications in bone healing and bone-related diseases. Among the cells of the adaptive immune system, CD8+ T cells have been shown to have a negative impact on bone fracture healing outcome, whereas regulatory T cells could be promising candidates that have a positive, modulating effect on bone fracture healing. This workshop addressed recent advances and key challenges in this exciting interdisciplinary research field.

  View details for PubMedID 26914869

• NF-B decoy oligodeoxynucleotide inhibits wear particle-induced inflammation in a murine calvarial model JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Sato, T., Pajarinen, J., Lin, T., Tamaki, Y., Loi, F., Egashira, K., Yao, Z., Goodman, S. B. 2015; 103 (12): 3872-3878

  Abstract

  Wear particles induce periprosthetic inflammation and osteolysis through activation of Nuclear Factor kappa B (NF-κB) in macrophages, which up-regulates the downstream target gene expression for pro-inflammatory cytokines. It is hypothesized that direct suppression of NF-κB activity in the early phases of this disorder is a therapeutic strategy for mitigating the inflammatory response to wear particles, potentially mitigating osteolysis. NF-κB activity can be suppressed via competitive binding with double stranded NF-κB decoy oligodeoxynucleotides (ODNs) that block this transcription factor from binding to the promoter regions of targeted genes. In this murine calvarial study, clinically relevant polyethylene particles (PEs) with/without ODN were subcutaneously injected over the calvarial bone. In the presence of PE particles, macrophages migrated to the inflammatory site and induced tumor necrosis factor alpha (TNF-α) and Receptor Activator of Nuclear Factor kappa-B Ligand (RANKL) expression, resulting in an increase in the number of osteoclasts. Local injections of ODN mitigated the expression of TNF-α, RANKL, and induced the expression of two anti-inflammatory, anti-resorptive cytokines: Interleukin-1 receptor antagonist (IL-1ra) and Osteoprotegerin (OPG). Local intervention with NF-κB decoy ODN in early cases of particle-induced inflammation in which the prosthesis is still salvageable may potentially preserve periprosthetic bone stock. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbm.a.35532

  View details for PubMedID 26123702

• Pain Duration and Resolution following Surgery: An Inception Cohort Study. Pain medicine Carroll, I. R., Hah, J. M., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Mackey, S. C. 2015; 16 (12): 2386-2396

  Abstract

  Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

  View details for DOI 10.1111/pme.12842

  View details for PubMedID 26179223

• Establishment of Green Fluorescent Protein and Firefly Luciferase Expressing Mouse Primary Macrophages for In Vivo Bioluminescence Imaging PLOS ONE Pajarinen, J., Lin, T., Sato, T., Loi, F., Yao, Z., Konttinen, Y. T., Goodman, S. B. 2015; 10 (11)

  Abstract

  Macrophages play a key role in tissue homeostasis as well as in a range of pathological conditions including atherosclerosis, cancer, and autoimmunity. Many aspects of their in vivo behavior are, however, poorly understood. Bioluminescence imaging (BLI) with green fluorescent protein (GFP) and firefly luciferase (FLUC) labelled autologous reporter macrophages could potentially offer a powerful tool to study macrophage biology, but this approach has been hindered by the relative difficulty of efficient gene transfer into primary macrophages. Here we describe a straightforward method for producing large numbers of GFP/FLUC expressing mouse primary macrophages utilizing lentivirus vector, cyclosporine, and a double infection strategy. Using this method we achieved up to 60% of macrophages to express GFP with correspondingly high FLUC signal. When injected into the circulation using a mouse model of local biomaterial induced inflammation and osteolysis, macrophages were initially detectable within the lungs, followed by systemic homing to the local area of chronic inflammation in the distal femur. In addition, transduced macrophages maintained their ability to assume M1 and M2 phenotypes although the GFP/FLUC expression was altered by the polarizing signals. These reporter macrophages could prove to be valuable tools to study the role of macrophages in health and disease.

  View details for DOI 10.1371/journal.pone.0142736

  View details for Web of Science ID 000364430700164

  View details for PubMedID 26555613

• Nanocoating for biomolecule delivery using layer-by-layer self-assembly. Journal of materials chemistry. B Keeney, M., Jiang, X. Y., Yamane, M., Lee, M., Goodman, S., Yang, F. 2015; 3 (45): 8757-8770

  Abstract

  Since its introduction in the early 1990s, layer-by-layer (LbL) self-assembly of films has been widely used in the fields of nanoelectronics, optics, sensors, surface coatings, and controlled drug delivery. The growth of this industry is propelled by the ease of film manufacture, low cost, mild assembly conditions, precise control of coating thickness, and versatility of coating materials. Despite the wealth of research on LbL for biomolecule delivery, clinical translation has been limited and slow. This review provides an overview of methods and mechanisms of loading biomolecules within LbL films and achieving controlled release. In particular, this review highlights recent advances in the development of LbL coatings for the delivery of different types of biomolecules including proteins, polypeptides, DNA, particles and viruses. To address the need for co-delivery of multiple types of biomolecules at different timing, we also review recent advances in incorporating compartmentalization into LbL assembly. Existing obstacles to clinical translation of LbL technologies and enabling technologies for future directions are also discussed.

  View details for DOI 10.1039/c5tb00450k

  View details for PubMedID 27099754

  View details for PubMedCentralID PMC4835036

• Treatment of Secondary Osteonecrosis of the Knee With Local Debridement and Osteoprogenitor Cell Grafting JOURNAL OF ARTHROPLASTY Goodman, S. B., Hwang, K. L. 2015; 30 (11): 1892-1896

  Abstract

  Secondary osteonecrosis of the knee (SOK) affects young individuals with chronic diseases and corticosteroid use. We report a series of young patients in whom the osteonecrotic lesion was openly debrided, and concentrated bone marrow osteoprogenitor cells (OPCs) harvested from the iliac crest were placed in the defect. Twelve patients (fourteen knees) have undergone debridement and grafting of distal femoral osteonecrotic lesions. Age at surgery averaged 23 years. Follow-up averaged 5 years. None of the patients have undergone further surgery, or were taking medications for ipsilateral knee pain. Knee Society Score and Knee Function Score averaged 87 and 85 respectively. The technique of open debridement and osteoprogenitor cell grafting for SOK is relatively simple, efficacious, has low morbidity, and does not preclude future interventions.

  View details for DOI 10.1016/j.arth.2015.05.013

  View details for PubMedID 26067706

• Musculoskeletal regeneration research network: A global initiative JOURNAL OF ORTHOPAEDIC TRANSLATION Chan, K., Rolf, C. G., Qin, L., Fellaender-Tsai, L., Castelein, R. M., Saris, D. F., Malda, J., Richards, G., Goodman, S. B., Tuan, R. S., Maloney, W., Lidgren, L., Hopkins, C., Fu, S., Li, G., Ding, M., Tang, T., Zhang, X., Wei, L., Sun, H. B., Ouyang, H. 2015; 3 (4): 160–65

  View details for PubMedID 30035054

• Modulation of mouse macrophage polarization in vitro using IL-4 delivery by osmotic pumps. Journal of biomedical materials research. Part A Pajarinen, J., Tamaki, Y., Antonios, J. K., Lin, T., Sato, T., Yao, Z., Takagi, M., Konttinen, Y. T., Goodman, S. B. 2015; 103 (4): 1339-1345

  Abstract

  Modulation of macrophage polarization is emerging as promising means to mitigate wear particle-induced inflammation and periprosthetic osteolysis. As a model for continuous local drug delivery, we used miniature osmotic pumps to deliver IL-4 in order to modulate macrophage polarization in vitro from nonactivated M0 and inflammatory M1 phenotypes towards a tissue regenerative M2 phenotype. Pumps delivered IL-4 into vials containing mouse bone marrow macrophage (mBMM) media. This conditioned media (CM) was collected at seven day intervals up to four weeks (week 1 to week 4 samples). IL-4 concentration in the CM was determined by ELISA and its biological activity was assayed by exposing M0 and M1 mBMMs to week 1 or week 4 CM. The IL-4 concentration in the CM approximated the mathematically calculated amount, and its biological activity was well retained, as both M0 and M1 macrophages exposed to either the week 1 or week 4 CM assumed M2-like phenotype as determined by qRT-PCR, ELISA, and immunocytochemistry. The results show that IL-4 can be delivered using osmotic pumps and that IL-4 delivered can modulate macrophage phenotype. Results build a foundation for in vivo studies using our previously validated animal models and provide possible strategies to locally mitigate wear particle-induced macrophage activation and periprosthetic osteolysis. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2014.

  View details for DOI 10.1002/jbm.a.35278

  View details for PubMedID 25044942

• Yrjö tapio konttinen 1952-2014. Acta orthopaedica Pajarinen, J., Nordström, D., Nordström, D., Petterson, T., Ainola, M., Gómez-Barrena, E., Takagi, M., Goodman, S. B. 2015; 86 (2): 145-146

  View details for DOI 10.3109/17453674.2015.1022103

  View details for PubMedID 25708854

  View details for PubMedCentralID PMC4404763

• Interaction Between Osteoarthritic Chondrocytes and Adipose-Derived Stem Cells Is Dependent on Cell Distribution in Three-Dimension and Transforming Growth Factor-ß3 Induction. Tissue engineering. Part A Lai, J. H., Rogan, H., Kajiyama, G., Goodman, S. B., Smith, R. L., Maloney, W., Yang, F. 2015; 21 (5-6): 992-1002

  Abstract

  Stem cells hold great promise for treating cartilage degenerative diseases such as osteoarthritis (OA). The efficacy of stem cell-based therapy for cartilage repair is highly dependent on their interactions with local cells in the joint. This study aims at evaluating the interactions between osteoarthritic chondrocytes (OACs) and adipose-derived stem cells (ADSCs) using three dimensional (3D) biomimetic hydrogels. To examine the effects of cell distribution on such interactions, ADSCs and OACs were co-cultured in 3D using three co-culture models: conditioned medium (CM), bi-layered, and mixed co-culture with varying cell ratios. Furthermore, the effect of transforming growth factor (TGF)-β3 supplementation on ADSC-OAC interactions and the resulting cartilage formation was examined. Outcomes were analyzed using quantitative gene expression, cell proliferation, cartilage matrix production, and histology. TGF-β3 supplementation led to a substantial increase in cartilage matrix depositions in all groups, but had differential effects on OAC-ADSC interactions in different co-culture models. In the absence of TGF-β3, CM or bi-layered co-culture had negligible effects on gene expression or cartilage formation. With TGF-β3 supplementation, CM and bi-layered co-culture inhibited cartilage formation by both ADSCs and OACs. In contrast, a mixed co-culture with moderate OAC ratios (25% and 50%) resulted in synergistic interactions with enhanced cartilage matrix deposition and reduced catabolic marker expression. Our results suggested that the interaction between OACs and ADSCs is highly dependent on cell distribution in 3D and soluble factors, which should be taken into consideration when designing stem cell-based therapy for treating OA patients.

  View details for DOI 10.1089/ten.TEA.2014.0244

  View details for PubMedID 25315023

• A Rare Case of Pseudotumor Formation following Total Knee Arthroplasty MALAYSIAN ORTHOPAEDIC JOURNAL Suresh, S., Pirapat, R., Goodman, S. B. 2015; 9 (1): 44–46

  View details for DOI 10.5704/MOJ.1503.014

  View details for Web of Science ID 000450590100013

• A Rare Case of Pseudotumor Formation following Total Knee Arthroplasty. Malaysian orthopaedic journal Sivananthan, S., Pirapat, R., Goodman, S. B. 2015; 9 (1): 44-46

  Abstract

  A 59 year old man who had undergone left total knee arthroplasty in 2008 presented with a 5 month history of left knee pain and persistent swelling. Workup for infection was negative and the patient was suspected to be suffering from particle disease and chronic synovitis. Imaging revealed an internally rotated tibial component. Intraoperative findings revealed extensive polyethylene wear with resultant metalon- metal articulation, soft tissue metallosis and a pseudotumor like mass at the posterolateral aspect of the popliteal fossa. This was extensively debrided and revision knee arthroplasty was performed. Suboptimal component alignment can lead to localized high loading, wear and metallosis, which in this case resulted in the formation of a pseudotumor.

  View details for DOI 10.5704/MOJ.1503.014

  View details for PubMedID 28435598

• Implant Survival and Patient-Reported Outcomes After Total Hip Arthroplasty in Young Patients With Juvenile Idiopathic Arthritis JOURNAL OF ARTHROPLASTY Swarup, I., Lee, Y., Christoph, E. I., Mandl, L. A., Goodman, S. M., Figgie, M. P. 2015; 30 (3): 398-402

  Abstract

  Juvenile Idiopathic Arthritis (JIA) is a common rheumatologic disease that frequently involves the hip joint and requires treatment with total hip arthroplasty (THA). A retrospective study with prospective follow-up was conducted to determine implant survival and patient-reported outcomes in JIA patients aged 35 or younger treated with THA. This study included 56 patients, and the mean time to follow-up was 12 years. The 10-year implant survival was 85%, and implant survival was significantly longer in older patients (P value=0.04). Hip disability and osteoarthritis outcome (HOOS) scores were favorable at follow-up, but significantly worse in women and patients with custom implants or history of revision THA. Overall, patient factors and implant characteristics predict implant survival and outcomes after THA in young patients with JIA.

  View details for DOI 10.1016/j.arth.2014.09.018

  View details for Web of Science ID 000353503500016

  View details for PubMedID 25449584

• NF-?B Decoy Oligodeoxynucleotide Enhanced Osteogenesis in Mesenchymal Stem Cells Exposed to Polyethylene Particle. Tissue engineering. Part A Lin, T., Sato, T., Barcay, K. R., Waters, H., Loi, F., Zhang, R., Pajarinen, J., Egashira, K., Yao, Z., Goodman, S. B. 2015; 21 (5-6): 875-883

  Abstract

  Excessive generation of wear particles after total joint replacement may lead to local inflammation and periprosthetic osteolysis. Modulation of the key transcription factor NF-κB in immune cells could potentially mitigate the osteolytic process. We previously showed that local delivery of ultra-high molecular weight polyethylene (UHMWPE) particles recruited osteoprogenitor cells and reduced osteolysis. However, the biological effects of modulating the NF-κB signaling pathway on osteoprogenitor/mesenchymal stem cells (MSCs) remain unclear. Here we showed that decoy oligodeoxynucleotide (ODN) increased cell viability when primary murine MSCs were exposed to UHMWPE particles, but had no effects on cellular apoptosis. Decoy ODN increased TGF-β1 and osteoprotegerin in MSCs exposed to UHMWPE particles. Mechanistic studies showed that decoy ODN up-regulated osteoprotegerin expression through a TGF-β1 dependent pathway. By measuring alkaline phosphatase activity, osteocalcin levels, Runx2 and osteopontin expression, and performing a bone mineralization assay, we found that decoy ODN increased MSC osteogenic ability when the cells were exposed to UHMWPE particles. Furthermore, the cellular response to decoy ODN and UHMWPE particles with regards to cell phenotype, cell viability and osteogenic ability were confirmed using primary human MSCs. Our results suggest that modulation of wear particle induced inflammation by NF-κB decoy ODN had no adverse effects on MSCs, and may potentially further mitigate peri-prosthetic osteolysis by protecting MSC viability and osteogenic ability.

  View details for DOI 10.1089/ten.TEA.2014.0144

  View details for PubMedID 25518013

• Collagen VI Enhances Cartilage Tissue Generation by Stimulating Chondrocyte Proliferation. Tissue engineering. Part A Smeriglio, P., Dhulipala, L., Lai, J. H., Goodman, S. B., Dragoo, J. L., Smith, R. L., Maloney, W. J., Yang, F., Bhutani, N. 2015; 21 (3-4): 840-849

  Abstract

  Regeneration of human cartilage is inherently inefficient. Current cell-based approaches for cartilage repair, including autologous chondrocytes, are limited by the paucity of cells, associated donor site morbidity, and generation of functionally inferior fibrocartilage rather than articular cartilage. Upon investigating the role of collagen VI (Col VI), a major component of the chondrocyte pericellular matrix (PCM), we observe that soluble Col VI stimulates chondrocyte proliferation. Interestingly, both adult and osteoarthritis chondrocytes respond to soluble Col VI in a similar manner. The proliferative effect is, however, strictly due to the soluble Col VI as no proliferation is observed upon exposure of chondrocytes to immobilized Col VI. Upon short Col VI treatment in 2D monolayer culture, chondrocytes maintain high expression of characteristic chondrocyte markers like Col2a1, agc, and Sox9 whereas the expression of the fibrocartilage marker Collagen I (Col I) and of the hypertrophy marker Collagen X (Col X) is minimal. Additionally, Col VI-expanded chondrocytes show a similar potential to untreated chondrocytes in engineering cartilage in 3D biomimetic hydrogel constructs. Our study has, therefore, identified soluble Col VI as a biologic that can be useful for the expansion and utilization of scarce sources of chondrocytes, potentially for autologous chondrocyte implantation. Additionally, our results underscore the importance of further investigating the changes in chondrocyte PCM with age and disease and the subsequent effects on chondrocyte growth and function.

  View details for DOI 10.1089/ten.TEA.2014.0375

  View details for PubMedID 25257043

• Editorial Comment: 2014 Hip Society Proceedings CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B. 2015; 473 (2): 430–31

  View details for PubMedID 25256622

• Comparative potential of juvenile and adult human articular chondrocytes for cartilage tissue formation in three-dimensional biomimetic hydrogels. Tissue engineering. Part A Smeriglio, P., Lai, J. H., Dhulipala, L., Behn, A. W., Goodman, S. B., Smith, R. L., Maloney, W. J., Yang, F., Bhutani, N. 2015; 21 (1-2): 147-155

  Abstract

  Regeneration of human articular cartilage is inherently limited and extensive efforts have focused on engineering the cartilage tissue. Various cellular sources have been studied for cartilage tissue engineering including adult chondrocytes, as well as embryonic or adult stem cells. Juvenile chondrocytes (from donors below 13 years of age) have recently been reported to be a promising cell source for cartilage regeneration. Previous studies have compared the potential of adult and juvenile chondrocytes or adult and osteoarthritic (OA) chondrocytes. To comprehensively characterize the comparative potential of young, old and diseased chondrocytes, here we examined cartilage formation by juvenile, adult and OA chondrocytes in 3D biomimetic hydrogels composed of poly(ethylene glycol) and chondroitin sulfate. All three human articular chondrocytes were encapsulated in the 3D biomimetic hydrogels and cultured for 3 or 6 weeks to allow maturation and extracellular matrix formation. Outcomes were analyzed using quantitative gene expression, immunofluorescence staining, biochemical assays, and mechanical testing. After 3 and 6 weeks, juvenile chondrocytes showed a greater upregulation of chondrogenic gene expression than adult chondrocytes, while OA chondrocytes showed a downregulation. Aggrecan and type II collagen deposition and GAG accumulation were high for juvenile and adult chondrocytes but not for OA chondrocytes. Similar trend was observed in the compressive moduli of the cartilage constructs generated by the three different chondrocytes. In conclusion, the juvenile, adult and OA chondrocytes showed differential responses in the 3D biomimetic hydrogels. The 3D culture model described here may also provide a useful tool to further study the molecular differences among chondrocytes from different stages, which can help elucidate the mechanisms for age-related decline in the intrinsic capacity for cartilage repair.

  View details for DOI 10.1089/ten.TEA.2014.0070

  View details for PubMedID 25054343

• Biomaterial Hypersensitivity: Is It Real? Supportive Evidence and Approach Considerations for Metal Allergic Patients following Total Knee Arthroplasty BIOMED RESEARCH INTERNATIONAL Mitchelson, A. J., Wilson, C. J., Mihalko, W. M., Grupp, T. M., Manning, B. T., Dennis, D. A., Goodman, S. B., Tzeng, T. H., Vasdev, S., Saleh, K. J. 2015: 137287

  Abstract

  The prospect of biomaterial hypersensitivity developing in response to joint implant materials was first presented more than 30 years ago. Many studies have established probable causation between first-generation metal-on-metal hip implants and hypersensitivity reactions. In a limited patient population, implant failure may ultimately be related to metal hypersensitivity. The examination of hypersensitivity reactions in current-generation metal-on-metal knee implants is comparatively limited. The purpose of this study is to summarize all available literature regarding biomaterial hypersensitivity after total knee arthroplasty, elucidate overall trends about this topic in the current literature, and provide a foundation for clinical approach considerations when biomaterial hypersensitivity is suspected.

  View details for PubMedID 25883940

• The Use of Porous Tantalum for Reconstructing Bone Loss in Orthopedic Surgery ADVANCES IN METALLIC BIOMATERIALS: TISSUES, MATERIALS AND BIOLOGICAL REACTIONS Patil, N., Goodman, S. B., Niinomi, M., Narushima, T., Nakai, M. 2015; 3: 223–43

  View details for DOI 10.1007/978-3-662-46836-4_10

  View details for Web of Science ID 000368067000011

• Identification of periprosthetic joint infection after total hip arthroplasty JOURNAL OF ORTHOPAEDIC TRANSLATION Lee, K., Goodman, S. B. 2015; 3 (1): 21–25

  Abstract

  Although total hip arthroplasty (THA) is accepted as one of the most successful surgical procedures in orthopaedic surgery, periprosthetic joint infection after THA continues to be one of the most devastating complications. However, accurate preoperative identification of periprosthetic joint infection in patients presenting with joint pain or radiographic periprosthetic lucencies is often difficult, even after a comprehensive work-up. The purpose of this article is to review the diagnostic options available to improve the management and results of this potentially catastrophic complication.

  View details for PubMedID 30035036

• Factors Associated with Opioid Use in a Cohort of Patients Presenting for Surgery. Pain research and treatment Hah, J. M., Sharifzadeh, Y., Wang, B. M., Gillespie, M. J., Goodman, S. B., Mackey, S. C., Carroll, I. R. 2015; 2015: 829696-?

  Abstract

  Objectives. Patients taking opioids prior to surgery experience prolonged postoperative opioid use, worse clinical outcomes, increased pain, and more postoperative complications. We aimed to compare preoperative opioid users to their opioid naïve counterparts to identify differences in baseline characteristics. Methods. 107 patients presenting for thoracotomy, total knee replacement, total hip replacement, radical mastectomy, and lumpectomy were investigated in a cross-sectional study to characterize the associations between measures of pain, substance use, abuse, addiction, sleep, and psychological measures (depressive symptoms, Posttraumatic Stress Disorder symptoms, somatic fear and anxiety, and fear of pain) with opioid use. Results. Every 9-point increase in the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) score was associated with 2.37 (95% CI 1.29-4.32) increased odds of preoperative opioid use (p = 0.0005). The SOAPP-R score was also associated with 3.02 (95% CI 1.36-6.70) increased odds of illicit preoperative opioid use (p = 0.007). Also, every 4-point increase in baseline pain at the future surgical site was associated with 2.85 (95% CI 1.12-7.27) increased odds of legitimate preoperative opioid use (p = 0.03). Discussion. Patients presenting with preoperative opioid use have higher SOAPP-R scores potentially indicating an increased risk for opioid misuse after surgery. In addition, legitimate preoperative opioid use is associated with preexisting pain.

  View details for DOI 10.1155/2015/829696

  View details for PubMedID 26881072

• Nanocoating for biomolecule delivery using layer-by-layer self-assembly JOURNAL OF MATERIALS CHEMISTRY B Keeney, M., Jiang, X. Y., Yamane, M., Lee, M., Goodman, S., Yang, F. 2015; 3 (45): 8757-8770

  Abstract

  Since its introduction in the early 1990s, layer-by-layer (LbL) self-assembly of films has been widely used in the fields of nanoelectronics, optics, sensors, surface coatings, and controlled drug delivery. The growth of this industry is propelled by the ease of film manufacture, low cost, mild assembly conditions, precise control of coating thickness, and versatility of coating materials. Despite the wealth of research on LbL for biomolecule delivery, clinical translation has been limited and slow. This review provides an overview of methods and mechanisms of loading biomolecules within LbL films and achieving controlled release. In particular, this review highlights recent advances in the development of LbL coatings for the delivery of different types of biomolecules including proteins, polypeptides, DNA, particles and viruses. To address the need for co-delivery of multiple types of biomolecules at different timing, we also review recent advances in incorporating compartmentalization into LbL assembly. Existing obstacles to clinical translation of LbL technologies and enabling technologies for future directions are also discussed.

  View details for DOI 10.1039/c5tb00450k

  View details for Web of Science ID 000365012700001

  View details for PubMedCentralID PMC4835036

• Establishment of Green Fluorescent Protein and Firefly Luciferase Expressing Mouse Primary Macrophages for In Vivo Bioluminescence Imaging. PloS one Pajarinen, J., Lin, T., Sato, T., Loi, F., Yao, Z., Konttinen, Y. T., Goodman, S. B. 2015; 10 (11)

  Abstract

  Macrophages play a key role in tissue homeostasis as well as in a range of pathological conditions including atherosclerosis, cancer, and autoimmunity. Many aspects of their in vivo behavior are, however, poorly understood. Bioluminescence imaging (BLI) with green fluorescent protein (GFP) and firefly luciferase (FLUC) labelled autologous reporter macrophages could potentially offer a powerful tool to study macrophage biology, but this approach has been hindered by the relative difficulty of efficient gene transfer into primary macrophages. Here we describe a straightforward method for producing large numbers of GFP/FLUC expressing mouse primary macrophages utilizing lentivirus vector, cyclosporine, and a double infection strategy. Using this method we achieved up to 60% of macrophages to express GFP with correspondingly high FLUC signal. When injected into the circulation using a mouse model of local biomaterial induced inflammation and osteolysis, macrophages were initially detectable within the lungs, followed by systemic homing to the local area of chronic inflammation in the distal femur. In addition, transduced macrophages maintained their ability to assume M1 and M2 phenotypes although the GFP/FLUC expression was altered by the polarizing signals. These reporter macrophages could prove to be valuable tools to study the role of macrophages in health and disease.

  View details for DOI 10.1371/journal.pone.0142736

  View details for PubMedID 26555613

• Exposure of polyethylene particles induces interferon-? expression in a natural killer T lymphocyte and dendritic cell coculture system in vitro: a preliminary study. Journal of biomedical materials research. Part A Lin, T., Kao, S., Sato, T., Pajarinen, J., Zhang, R., Loi, F., Goodman, S. B., Yao, Z. 2015; 103 (1): 71-75

  Abstract

  Two major issues in total joint arthroplasty are loosening of implants and osteolysis caused by wear particle-induced inflammation. Wear particles stimulate the release of pro-inflammatory cytokines, chemokines and other inflammatory mediators from macrophages and other cells. Although the biological response of macrophages to wear debris is well established, the role of other cell types such as natural killer T lymphocytes (NKT) and dendritic cells (DCs) is limited. Here we show that ultra-high molecular weight polyethylene (UHMWPE) particles stimulate NKT cells to secrete Interferon-γ (IFN-γ); co-culture with DCs further enhanced IFN-γ secretion. Furthermore, UHMWPE particles did not stimulate NKT cells to secrete IL-4, while the NKT cell natural ligand α -Galactosylceramide (α-GalCer) treatment in the co-culture system significantly enhanced both IFN-γ and IL-4 expression by NKT cells. Comparatively, NKT cells and/or DCs exposed to polymethylmethacrylate particles did not stimulate Interferon-γ or IL-4 expression. Mouse bone marrow derived macrophage polarization by lipopolysaccharide and conditioned medium from NKT cells and/or DCs exposed to UHMWPE particles increased TNF-α, but reduced arginase-1 expression in macrophages. The current findings indicate that UHMWPE particles stimulate NKT cells/DCs to produce pro-inflammatory cytokines; this pathway is a novel therapeutic target to mitigate wear particle induced peri-prosthetic osteolysis.

  View details for DOI 10.1002/jbm.a.35159

  View details for PubMedID 24616165

• Exposure of polyethylene particles induces interferon-gamma expression in a natural killer T lymphocyte and dendritic cell coculture system in vitro: A preliminary study JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Lin, T., Kao, S., Sato, T., Pajarinen, J., Zhang, R., Loi, F., Goodman, S. B., Yao, Z. 2015; 103 (1): 71-75

  Abstract

  Two major issues in total joint arthroplasty are loosening of implants and osteolysis caused by wear particle-induced inflammation. Wear particles stimulate the release of pro-inflammatory cytokines, chemokines and other inflammatory mediators from macrophages and other cells. Although the biological response of macrophages to wear debris is well established, the role of other cell types such as natural killer T lymphocytes (NKT) and dendritic cells (DCs) is limited. Here we show that ultra-high molecular weight polyethylene (UHMWPE) particles stimulate NKT cells to secrete Interferon-γ (IFN-γ); co-culture with DCs further enhanced IFN-γ secretion. Furthermore, UHMWPE particles did not stimulate NKT cells to secrete IL-4, while the NKT cell natural ligand α -Galactosylceramide (α-GalCer) treatment in the co-culture system significantly enhanced both IFN-γ and IL-4 expression by NKT cells. Comparatively, NKT cells and/or DCs exposed to polymethylmethacrylate particles did not stimulate Interferon-γ or IL-4 expression. Mouse bone marrow derived macrophage polarization by lipopolysaccharide and conditioned medium from NKT cells and/or DCs exposed to UHMWPE particles increased TNF-α, but reduced arginase-1 expression in macrophages. The current findings indicate that UHMWPE particles stimulate NKT cells/DCs to produce pro-inflammatory cytokines; this pathway is a novel therapeutic target to mitigate wear particle induced peri-prosthetic osteolysis.

  View details for DOI 10.1002/jbm.a.35159

  View details for Web of Science ID 000345572100009

• What is the Trouble With Trunnions? CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Esposito, C. I., Wright, T. M., Goodman, S. B., Berry, D. J. 2014; 472 (12): 3652-3658

  Abstract

  Recent studies have attributed adverse local tissue reactions (ALTRs) in patients with total hip arthroplasties (THAs) to tribocorrosion debris generated by modular femoral stems. The presentations of ALTR are diverse, as are the causes of it, and the biological responses can be important reasons for failure after THA.(1) What clinical problems have been reported in patients with modular stems since 1988? (2) What THA design features are associated with tribocorrosion in taper junctions? (3) What are the microscopic and tribological characteristics of the debris produced at the taper junctions? (4) What are the cellular and immunological traits of the biological response to taper tribocorrosion debris?We conducted a systematic review using MEDLINE and EMBASE-cited articles to summarize failure modes associated with modular femoral stems. One hundred sixty-two of 1043 articles reported on the clinical performances or failure modes attributed to modular femoral stems. There were 10 laboratory studies, 26 case reports, 13 Level IV, 94 Level III, 18 Level II, and one Level I of Evidence papers. To address the remaining questions, we did a second review of 524 articles. One hundred twenty-seven articles met the eligibility criteria, including 81 articles on design features related to tribocorrosion, 15 articles on corrosion debris characteristics, and 31 articles on the biological response to tribocorrosion debris.Sixty-eight of 162 studies reported failure attributed to modular femoral stems for one of these four modularity-related failure modes: tribocorrosion-associated ALTR, dissociation of a taper junction, stem fracture, and mismatch of a femoral head taper attached to a stem with a different trunnion size. The remaining 94 studies found no clinical consequences related to the presence of a taper junction. THA component features associated with tribocorrosion included trunnion geometry and large-diameter femoral heads. Solid tribocorrosion debris is primarily chromium-orthophosphate material of variable size and may be more biologically reactive than wear debris.There has been an increase in publications describing ALTR around modular hip prostheses in the last 3 years. Implant design changes, including larger femoral heads and smaller trunnions, have been implicated, but there may also be more recognition of the problem by the orthopaedic community. Analyzing retrieved implants to understand the history of taper-related problems, designing clinically relevant in vitro corrosion tests to test modular junctions, and identifying biomarkers to recognize patients at risk of ALTR should be the focus of ongoing research to help surgeons avoid and detect tribocorrosion-related problems in joint replacements.

  View details for DOI 10.1007/s11999-014-3746-z

  View details for Web of Science ID 000344647200010

  View details for PubMedID 24980639

  View details for PubMedCentralID PMC4397760

• Editorial Comment: ABJS Carl T. Brighton Workshop on Implant Wear and Tribocorrosion of Total Joint Replacements CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B., Wright, T. M. 2014; 472 (12): 3650–51

  View details for PubMedID 25267269

• Total knee arthroplasty in patients with ipsilateral fused hip: a technical note. Clinics in orthopedic surgery Goodman, S. B., Huddleston, J. I., Hur, D., Song, S. J. 2014; 6 (4): 476-479

  Abstract

  We report the surgical technique used to perform posterior-stabilized total knee arthroplasty (TKA) in two patients with a well positioned and functional hip arthrodesis. Intraoperatively, the operating table was placed in an increased Trendelenburg position. Episodically, we flexed the foot of the table by 90° to allow maximal knee flexion to facilitate exposure and bone cuts. We opted to resect the patella and tibia first to enable exposure, given the stiffness of the arthritic knee. One patient's medical condition prohibited complex conversion total hip arthroplasty (THA) prior to the TKA. The other patient's scarred soft tissues around the hip, due to chronic infection and multiple operations, made THA risky. The final outcome provided satisfactory results at a minimum of 2 years postoperatively. TKA can be successfully performed with adjustments of table position and modification of the sequence of surgical steps in patients with ipsilateral hip fusion.

  View details for DOI 10.4055/cios.2014.6.4.476

  View details for PubMedID 25436074

• Interaction of Materials and Biology in Total Joint Replacement - Successes, Challenges and Future Directions. Journal of materials chemistry. B, Materials for biology and medicine Pajarinen, J., Lin, T., Sato, T., Yao, Z., Goodman, S. 2014; 2 (41): 7094-7108

  Abstract

  Total joint replacement (TJR) has revolutionized the treatment of end-stage arthritic disorders. This success is due, in large part, to a clear understanding of the important interaction between the artificial implant and the biology of the host. All surgical procedures in which implants are placed in the body evoke an initial inflammatory reaction, which generally subsides over several weeks. Thereafter, a series of homeostatic events occur leading to progressive integration of the implant within bone and the surrounding musculoskeletal tissues. The eventual outcome of the operation is dependent on the characteristics of the implant, the precision of the surgical technique and operative environment, and the biological milieu of the host. If these factors and events are not optimal, adverse events can occur such as the development of chronic inflammation, progressive bone loss due to increased production of degradation products from the implant (periprosthetic osteolysis), implant loosening or infection. These complications can lead to chronic pain and poor function of the joint reconstruction, and may necessitate revision surgery or removal of the prosthesis entirely. Recent advances in engineering, materials science, and the immunological aspects associated with orthopaedic implants have fostered intense research with the hope that joint replacements will last a lifetime, and facilitate pain-free, normal function.

  View details for DOI 10.1039/C4TB01005A

  View details for PubMedID 25541591

  View details for PubMedCentralID PMC4273175

• Clinical recovery from surgery correlates with single-cell immune signatures SCIENCE TRANSLATIONAL MEDICINE Gaudilliere, B., Fragiadakis, G. K., Bruggner, R. V., Nicolau, M., Finck, R., Tingle, M., Silva, J., Ganio, E. A., Yeh, C. G., Maloney, W. J., Huddleston, J. I., Goodman, S. B., Davis, M. M., Bendall, S. C., Fantl, W. J., Angst, M. S., Nolan, G. P. 2014; 6 (255)

  Abstract

  Delayed recovery from surgery causes personal suffering and substantial societal and economic costs. Whether immune mechanisms determine recovery after surgical trauma remains ill-defined. Single-cell mass cytometry was applied to serial whole-blood samples from 32 patients undergoing hip replacement to comprehensively characterize the phenotypic and functional immune response to surgical trauma. The simultaneous analysis of 14,000 phosphorylation events in precisely phenotyped immune cell subsets revealed uniform signaling responses among patients, demarcating a surgical immune signature. When regressed against clinical parameters of surgical recovery, including functional impairment and pain, strong correlations were found with STAT3 (signal transducer and activator of transcription), CREB (adenosine 3',5'-monophosphate response element-binding protein), and NF-κB (nuclear factor κB) signaling responses in subsets of CD14(+) monocytes (R = 0.7 to 0.8, false discovery rate <0.01). These sentinel results demonstrate the capacity of mass cytometry to survey the human immune system in a relevant clinical context. The mechanistically derived immune correlates point to diagnostic signatures, and potential therapeutic targets, that could postoperatively improve patient recovery.

  View details for DOI 10.1126/scitranslmed.3009701

  View details for Web of Science ID 000343316800006

• Clinical recovery from surgery correlates with single-cell immune signatures. Science translational medicine Gaudillière, B., Fragiadakis, G. K., Bruggner, R. V., Nicolau, M., Finck, R., Tingle, M., Silva, J., Ganio, E. A., Yeh, C. G., Maloney, W. J., Huddleston, J. I., Goodman, S. B., Davis, M. M., Bendall, S. C., Fantl, W. J., Angst, M. S., Nolan, G. P. 2014; 6 (255): 255ra131-?

  Abstract

  Delayed recovery from surgery causes personal suffering and substantial societal and economic costs. Whether immune mechanisms determine recovery after surgical trauma remains ill-defined. Single-cell mass cytometry was applied to serial whole-blood samples from 32 patients undergoing hip replacement to comprehensively characterize the phenotypic and functional immune response to surgical trauma. The simultaneous analysis of 14,000 phosphorylation events in precisely phenotyped immune cell subsets revealed uniform signaling responses among patients, demarcating a surgical immune signature. When regressed against clinical parameters of surgical recovery, including functional impairment and pain, strong correlations were found with STAT3 (signal transducer and activator of transcription), CREB (adenosine 3',5'-monophosphate response element-binding protein), and NF-κB (nuclear factor κB) signaling responses in subsets of CD14(+) monocytes (R = 0.7 to 0.8, false discovery rate <0.01). These sentinel results demonstrate the capacity of mass cytometry to survey the human immune system in a relevant clinical context. The mechanistically derived immune correlates point to diagnostic signatures, and potential therapeutic targets, that could postoperatively improve patient recovery.

  View details for DOI 10.1126/scitranslmed.3009701

  View details for PubMedID 25253674

• Mutant monocyte chemoattractant protein 1 protein attenuates migration of and inflammatory cytokine release by macrophages exposed to orthopedic implant wear particles. Journal of biomedical materials research. Part A Yao, Z., Keeney, M., Lin, T., Pajarinen, J., Barcay, K., Waters, H., Egashira, K., Yang, F., Goodman, S. 2014; 102 (9): 3291-3297

  Abstract

  Wear particles generated from total joint replacements can stimulate macrophages to release chemokines, such as monocyte chemoattractant protein 1 (MCP-1), which is the most important chemokine regulating systemic and local cell trafficking and infiltration of monocyte/macrophages in chronic inflammation. One possible strategy to curtail the adverse events associated with wear particles is to mitigate migration and activation of monocyte/macrophages. The purpose of this study is to modulate the adverse effects of particulate biomaterials and inflammatory stimuli such as endotoxin by interfering with the biological effects of the chemokine MCP-1. In the current study, the function of MCP-1 was inhibited by the mutant MCP-1 protein called 7ND, which blocks its receptor, the C-C chemokine receptor type 2 (CCR2) on macrophages. Addition of 7ND decreased MCP-1-induced migration of THP-1 cells in cell migration experiments in a dose-dependent manner. Conditioned media from murine macrophages exposed to clinically relevant polymethylmethacrylate (PMMA) particles with/without endotoxin [lipopolysaccharide (LPS)] had a chemotactic effect on human macrophages, which was decreased dramatically by 7ND. 7ND demonstrated no adverse effects on the viability of macrophages, and the capability of mesenchymal stem cells (MSCs) to form bone at the doses tested. Finally, proinflammatory cytokine production was mitigated when macrophages were exposed to PMMA particles with/without LPS in the presence of 7ND. Our studies confirm that the MCP-1 mutant protein 7ND can decrease macrophage migration and inflammatory cytokine release without adverse effects at the doses tested. Local delivery of 7ND at the implant site may provide a therapeutic strategy to diminish particle-associated periprosthetic inflammation and osteolysis. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

  View details for DOI 10.1002/jbm.a.34981

  View details for PubMedID 24123855

• Characterization of macrophage polarizing cytokines in the aseptic loosening of total hip replacements. Journal of orthopaedic research Jämsen, E., Kouri, V., Olkkonen, J., Cör, A., Goodman, S. B., Konttinen, Y. T., Pajarinen, J. 2014; 32 (9): 1241-1246

  Abstract

  Aseptic loosening of hip replacements is driven by the macrophage reaction to wear particles. The extent of particle-induced macrophage activation is dependent on the state of macrophage polarization, which is dictated by the local cytokine microenvironment. The aim of the study was to characterize cytokine microenvironment surrounding failed, loose hip replacements with an emphasis on identification of cytokines that regulate macrophage polarization. Using qRT-PCR, the expression of interferon gamma (IFN-γ), interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-13, and IL-17A was low and similar to the expression in control synovial tissues of patients undergoing primary hip replacement. Using immunostaining, no definite source of IFN-γ or IL-4 could be identified. IL-17A positive cells, identified as mast cells by double staining, were detected but their number was significantly reduced in interface tissues compared to the controls. Significant up-regulation of IL-10, M-CSF, IL-8, CCL2-4, CXCL9-10, CCL22, TRAP, cathepsin K, and down regulation of OPG was seen in the interface tissues, while expression of TNF-α, IL-1β, and CD206 were similar between the conditions. It is concluded that at the time of the revision surgery the peri-implant macrophage phenotype has both M1 and M2 characteristics and that the phenotype is regulated by other local and systemic factors than traditional macrophage polarizing cytokines. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

  View details for DOI 10.1002/jor.22658

  View details for PubMedID 24897980

• Toll-like receptors-2 and 4 are overexpressed in an experimental model of particle-induced osteolysis JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Valladares, R. D., Nich, C., Zwingenberger, S., Li, C., Swank, K. R., Gibon, E., Rao, A. J., Yao, Z., Goodman, S. B. 2014; 102 (9): 3004-3011

  Abstract

  Aseptic loosening secondary to particle-associated periprosthetic osteolysis remains a major cause of failure of total joint replacements (TJR) in the mid- and long term. As sentinels of the innate immune system, macrophages are central to the recognition and initiation of the inflammatory cascade, which results in the activation of bone resorbing osteoclasts. Toll-like receptors (TLRs) are involved in the recognition of pathogen-associated molecular patterns and danger-associated molecular patterns. Experimentally, polymethylmethacrylate and polyethylene (PE) particles have been shown to activate macrophages via the TLR pathway. The specific TLRs involved in PE particle-induced osteolysis remain largely unknown. We hypothesized that TLR-2, -4, and -9 mediated responses play a critical role in the development of PE wear particle-induced osteolysis in the murine calvarium model. To test this hypothesis, we first demonstrated that PE particles caused observable osteolysis, visible by microCT and bone histomorphometry when the particles were applied to the calvarium of C57BL/6 mice. The number of TRAP positive osteoclasts was significantly greater in the PE-treated group when compared to the control group without particles. Finally, using immunohistochemistry, TLR-2 and TLR-4 were highly expressed in PE particle-induced osteolytic lesions, whereas TLR-9 was downregulated. TLR-2 and -4 may represent novel therapeutic targets for prevention of wear particle-induced osteolysis and accompanying TJR failure.

  View details for DOI 10.1002/jbm.a.34972

  View details for PubMedID 24115330

• Characterization of Macrophage Polarizing Cytokines in the Aseptic Loosening of Total Hip Replacements JOURNAL OF ORTHOPAEDIC RESEARCH Jamsen, E., Kouri, V., Olkkonen, J., Coer, A., Goodman, S. B., Konttinen, Y. T., Pajarinen, J. 2014; 32 (9): 1241-1246

  Abstract

  Aseptic loosening of hip replacements is driven by the macrophage reaction to wear particles. The extent of particle-induced macrophage activation is dependent on the state of macrophage polarization, which is dictated by the local cytokine microenvironment. The aim of the study was to characterize cytokine microenvironment surrounding failed, loose hip replacements with an emphasis on identification of cytokines that regulate macrophage polarization. Using qRT-PCR, the expression of interferon gamma (IFN-γ), interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-13, and IL-17A was low and similar to the expression in control synovial tissues of patients undergoing primary hip replacement. Using immunostaining, no definite source of IFN-γ or IL-4 could be identified. IL-17A positive cells, identified as mast cells by double staining, were detected but their number was significantly reduced in interface tissues compared to the controls. Significant up-regulation of IL-10, M-CSF, IL-8, CCL2-4, CXCL9-10, CCL22, TRAP, cathepsin K, and down regulation of OPG was seen in the interface tissues, while expression of TNF-α, IL-1β, and CD206 were similar between the conditions. It is concluded that at the time of the revision surgery the peri-implant macrophage phenotype has both M1 and M2 characteristics and that the phenotype is regulated by other local and systemic factors than traditional macrophage polarizing cytokines. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

  View details for DOI 10.1002/jor.22658

  View details for Web of Science ID 000340587200021

• Suppression of wear-particle-induced pro-inflammatory cytokine and chemokine production in macrophages via NF-?B decoy oligodeoxynucleotide: A preliminary report. Acta biomaterialia Lin, T., Yao, Z., Sato, T., Keeney, M., Li, C., Pajarinen, J., Yang, F., Egashira, K., Goodman, S. B. 2014; 10 (8): 3747-3755

  Abstract

  Total joint replacement (TJR) is a very cost-effective surgery for end-stage arthritis. One important goal is to decrease the revision rate especially because TJR has been extended to younger patients. Continuous production of ultra-high molecular weight polyethylene (UHMWPE) wear particles induces macrophage infiltration and chronic inflammation, which can lead to peri-prosthetic osteolysis. Targeting individual pro-inflammatory cytokines directly has not reversed the osteolytic process in clinical trials, due to compensatory upregulation of other pro-inflammatory factors. We hypothesized that targeting the important transcription factor NF-κB could mitigate the inflammatory response to wear particles, potentially diminishing osteolysis. In the current study, we suppressed NF-κB activity in mouse RAW264.7 and human THP1 macrophage cell lines, as well as primary mouse and human macrophages, via competitive binding with double strand decoy oligodeoxynucleotide (ODN) containing an NF-κB binding element. We found that macrophage exposure to UHMWPE particles induced multiple pro-inflammatory cytokine and chemokine expression including TNF-α, MCP1, MIP1α and others. Importantly, the decoy ODN significantly suppressed the induced cytokine and chemokine expression in both murine and human macrophages, and resulted in suppression of macrophage recruitment. The strategic use of decoy NF-κB ODN, delivered locally, could potentially diminish particle-induced peri-prosthetic osteolysis.

  View details for DOI 10.1016/j.actbio.2014.04.034

  View details for PubMedID 24814879

• Current Modes of Failure in TKA: Infection, Instability, and Stiffness Predominate. Clinical orthopaedics and related research Le, D. H., Goodman, S. B., Maloney, W. J., Huddleston, J. I. 2014; 472 (7): 2197-2200

  Abstract

  Historically, polyethylene wear and its sequelae (osteolysis, late instability, aseptic loosening) were common causes for revision total knee arthroplasty (TKA). Recently, polyethylene manufacturing has become more consistent; furthermore, a clearer understanding of the importance of oxidation on polyethylene performance led to packaging of the polyethylene bearings in an inert environment. This improved the quality and consistency of polyethylene used in TKA, raising the question of whether different failure modes now predominate after TKA.The purpose of this study was to determine the current reasons for (1) early and (2) late failures after TKA at one high-volume arthroplasty center.We reviewed all first-time revision TKAs performed between 2001 and 2011 at one institution, yielding a group of 253 revision TKAs in 251 patients. Mean age at the time of revision was 64 years (SD 10 years). Mean time to revision was 35 months (SD 23 months). Preoperative evaluations, laboratory data, radiographs, and intraoperative findings were used to determine causes for revision. Early failure was defined as revision within 2 years of the index procedure. The primary failure mechanism was determined by the operating surgeon.Early failure accounted for 46% (116 of 253) of all revisions with infection (28 of 116 [24%]), instability (30 of 116 [26%]), and stiffness (21 of 116 [18%]) being the leading causes. Late failure accounted for 54% (137 of 253) of all revisions with the most common causes including infection (34 of 137 [25%]), instability (24 of 137 [18%]), and stiffness (19 of 253 [14%]). Polyethylene wear was implicated as the failure mechanism in 2% of early cases (two of 116) and 9% of late cases (13 of 137).In contrast to previous studies, wear-related implant failure in TKA was relatively uncommon in this series. Changes in polyethylene manufacturing, sterilization, and storage may have accounted for some of this difference; however, longer-term followup will be required to verify this finding. Infection, instability, and stiffness represent the most common causes of early and late failure. Strategies to improve outcomes in TKA should be aimed at infection prophylaxis and treatment, surgical technique, and patient selection.Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

  View details for DOI 10.1007/s11999-014-3540-y

  View details for PubMedID 24615421

• Polyethylene wear and osteolysis is associated with high revision rate of a small sized porous coated THA in patients with hip dysplasia. journal of arthroplasty Murray, P. J., Hwang, K. L., Imrie, S. N., Huddleston, J. I., Goodman, S. B. 2014; 29 (7): 1373-1377

  Abstract

  The outcome of 25 primary THAs in patients with hip dysplasia using the AML Bantam femoral stem (DePuy) is reported. Age at operation averaged 43 ± 10 years. Twenty-two of 25 stems were cementless. All cementless acetabular components had conventional or cross-linked polyethylene and screws. Follow-up averaged 11 ± 5 years (range 4-18). Four cementless stems were revised after 3, 4, 8, and 9 years; 2/3 cemented stems were revised at 8 and 18 years. Femoral revisions demonstrated extensive conventional polyethylene wear, periprosthetic osteolysis and loosening. Five entire cups were revised for wear and loosening; four liners were replaced. Harris Hip Scores for patients with retained stems went from 43 ± 12 to 85 ± 13. High revision rates with the proximally porous coated Bantam stem are due to loss of fixation, often associated with polyethylene wear and osteolysis.

  View details for DOI 10.1016/j.arth.2014.02.027

  View details for PubMedID 24698818

• Self-Loathing Aspects of Depression Reduce Postoperative Opioid Cessation Rate PAIN MEDICINE Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

  Abstract

  We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

  View details for DOI 10.1111/pme.12439

  View details for Web of Science ID 000338025900009

  View details for PubMedCentralID PMC4083472

• Outcome of porous tantalum acetabular components for paprosky type 3 and 4 acetabular defects. The Journal of arthroplasty Batuyong, E. D., Brock, H. S., Thiruvengadam, N., Maloney, W. J., Goodman, S. B., Huddleston, J. I. 2014; 29 (6): 1318-22

  Abstract

  Porous tantalum acetabular implants provide a potential solution for dealing with significant acetabular bone loss. This study reviews 24 acetabular revisions using tantalum implants for Paprosky type 3 and 4 defects. The mean Harris Hip Score improved from 35±19 (range, 4-71) to 88±14 (range, 41-100), p<0.0001. Postoperative radiographs showed radiolucent lines in 14 hips with a mean width of 1.3±1.0mm (range, 0.27-4.37mm). No gaps enlarged and 71% of them disappeared at a mean of 13±10months (range, 3-29months). At a mean follow-up of 37±14months (range, 24-66months), 22 reconstructions showed radiograpic evidence of osseointegration (92%). The two failures were secondary to septic loosening. When dealing with severe acetabular bone loss, porous tantalum acetabular components show promising short-term results.

  View details for DOI 10.1016/j.arth.2013.12.002

  View details for PubMedID 24405625

• Contributions of human tissue analysis to understanding the mechanisms of loosening and osteolysis in total hip replacement ACTA BIOMATERIALIA Gallo, J., Vaculova, J., Goodman, S. B., Konttinen, Y. T., Thyssen, J. P. 2014; 10 (6): 2354-2366

  Abstract

  Aseptic loosening and osteolysis are the most frequent late complications of total hip arthroplasty (THA) leading to revision of the prosthesis. This review aims to demonstrate how histopathological studies contribute to our understanding of the mechanisms of aseptic loosening/osteolysis development. Only studies analysing periprosthetic tissues retrieved from failed implants in humans were included. Data from 101 studies (5532 patients with failure of THA implants) published in English or German between 1974 and 2013 were included. "Control" samples were reported in 45 of the 101 studies. The most frequently examined tissues were the bone-implant interface membrane and pseudosynovial tissues. Histopathological studies contribute importantly to determination of key cell populations underlying the biological mechanisms of aseptic loosening and osteolysis. The studies demonstrated the key molecules of the host response at the protein level (chemokines, cytokines, nitric oxide metabolites, metalloproteinases). However, these studies also have important limitations. Tissues harvested at revision surgery reflect specifically end-stage failure and may not adequately reveal the evolution of pathophysiological events that lead to prosthetic loosening and osteolysis. One possible solution is to examine tissues harvested from stable total hip arthroplasties that have been revised at various time periods due to dislocation or periprosthetic fracture in multicenter studies.

  View details for DOI 10.1016/j.actbio.2014.02.003

  View details for PubMedID 24525037

• Outcome of Porous Tantalum Acetabular Components for Paprosky Type 3 and 4 Acetabular Defects JOURNAL OF ARTHROPLASTY Batuyong, E. D., Brock, H. S., Thiruvengadam, N., Maloney, W. J., Goodman, S. B., Huddleston, J. I. 2014; 29 (6): 1318-1322

  Abstract

  Porous tantalum acetabular implants provide a potential solution for dealing with significant acetabular bone loss. This study reviews 24 acetabular revisions using tantalum implants for Paprosky type 3 and 4 defects. The mean Harris Hip Score improved from 35±19 (range, 4-71) to 88±14 (range, 41-100), p<0.0001. Postoperative radiographs showed radiolucent lines in 14 hips with a mean width of 1.3±1.0mm (range, 0.27-4.37mm). No gaps enlarged and 71% of them disappeared at a mean of 13±10months (range, 3-29months). At a mean follow-up of 37±14months (range, 24-66months), 22 reconstructions showed radiograpic evidence of osseointegration (92%). The two failures were secondary to septic loosening. When dealing with severe acetabular bone loss, porous tantalum acetabular components show promising short-term results.

  View details for DOI 10.1016/j.arth.2013.12.002

  View details for Web of Science ID 000338115400048

• Self-loathing aspects of depression reduce postoperative opioid cessation rate. Pain medicine Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

  Abstract

  We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

  View details for DOI 10.1111/pme.12439

  View details for PubMedID 24964916

• Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement. Journal of the Royal Society, Interface / the Royal Society Goodman, S. B., Gibon, E., Pajarinen, J., Lin, T., Keeney, M., Ren, P., Nich, C., Yao, Z., Egashira, K., Yang, F., KONTTINEN, Y. T. 2014; 11 (93): 20130962-?

  Abstract

  Wear particles and by-products from joint replacements and other orthopaedic implants may result in a local chronic inflammatory and foreign body reaction. This may lead to persistent synovitis resulting in joint pain and swelling, periprosthetic osteolysis, implant loosening and pathologic fracture. Strategies to modulate the adverse effects of wear debris may improve the function and longevity of joint replacements and other orthopaedic implants, potentially delaying or avoiding complex revision surgical procedures. Three novel biological strategies to mitigate the chronic inflammatory reaction to orthopaedic wear particles are reported. These include (i) interference with systemic macrophage trafficking to the local implant site, (ii) modulation of macrophages from an M1 (pro-inflammatory) to an M2 (anti-inflammatory, pro-tissue healing) phenotype in the periprosthetic tissues, and (iii) local inhibition of the transcription factor nuclear factor kappa B (NF-κB) by delivery of an NF-κB decoy oligodeoxynucleotide, thereby interfering with the production of pro-inflammatory mediators. These three approaches have been shown to be viable strategies for mitigating the undesirable effects of wear particles in preclinical studies. Targeted local delivery of specific biologics may potentially extend the lifetime of orthopaedic implants.

  View details for DOI 10.1098/rsif.2013.0962

  View details for PubMedID 24478281

• Fibronectin-aggrecan complex as a marker for cartilage degradation in non-arthritic hips. Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA Abrams, G. D., Safran, M. R., Shapiro, L. M., Maloney, W. J., Goodman, S. B., Huddleston, J. I., Bellino, M. J., Scuderi, G. J. 2014; 22 (4): 768-773

  Abstract

  To report hip synovial fluid cytokine concentrations in hips with and without radiographic arthritis.Patients with no arthritis (Tonnis grade 0) and patients with Tonnis grade 2 or greater hip osteoarthritis (OA) were identified from patients undergoing either hip arthroscopy or arthroplasty. Synovial fluid was collected at the time of portal establishment for those undergoing hip arthroscopy and prior to arthrotomy for the arthroplasty group. Analytes included fibronectin-aggrecan complex (FAC) as well as a standard 12 cytokine array. Variables recorded were Tonnis grade, centre-edge angle of Wiberg, as well as labrum and cartilage pathology for the hip arthroscopy cohort. A priori power analysis was conducted, and a Mann-Whitney U test and regression analyses were used with an alpha value of 0.05 set as significant.Thirty-four patients were included (17 arthroplasty, 17 arthroscopy). FAC was the only analyte to show a significant difference between those with and without OA (p < 0.001). FAC had significantly higher concentration in those without radiographic evidence of OA undergoing microfracture versus those not receiving microfracture (p < 0.05).There was a significantly higher FAC concentration in patients without radiographic OA. Additionally, those undergoing microfracture had increased levels of FAC. As FAC is a cartilage breakdown product, no significant amounts may be present in those with OA. In contrast, those undergoing microfracture have focal area(s) of cartilage breakdown. These data suggest that FAC may be useful in predicting cartilage pathology in those patients with hip pain but without radiographic evidence of arthritis.Diagnostic, Level III.

  View details for DOI 10.1007/s00167-014-2863-2

  View details for PubMedID 24477496

• Enhancement of BMP-2 Induced Bone Regeneration by SDF-1a Mediated Stem Cell Recruitment. Tissue engineering. Part A Zwingenberger, S., Yao, Z., Jacobi, A., Vater, C., Valladares, R. D., Li, C., Nich, C., Rao, A. J., Christman, J. E., Antonios, J. K., Gibon, E., Schambach, A., Maetzig, T., Goodman, S. B., Stiehler, M. 2014; 20 (3-4): 810-818

  Abstract

  Treatment of critical size bone defects is challenging. Recent studies showed that the cytokine stromal cell-derived factor 1 alpha (SDF-1α) has potential to improve the bone regenerative effect of low bone morphogenetic protein 2 (BMP-2) concentrations. The goal of this study was to demonstrate the combined effect of SDF-1α and BMP-2 on bone regeneration and stem cell recruitment using a critical size femoral bone defect model. A total of 72 mice were randomized to six groups. External fixators were implanted onto the right femur of each mouse and 3 mm defects were created. Depending on the group affiliation, adenovirally activated fat tissue grafts expressing SDF-1α or/and BMP-2 were implanted at the defect site. One day after operation, 1×10(6) murine mesenchymal stromal cells (MSCs), lentivirally transduced to express the gene enhanced green fluorescent protein (eGFP), firefly luciferase, and CXCR4 were injected systemically in selected groups. Migration of the injected MSCs was observed by bioluminescence imaging on days 0, 2, 4, 6, 8, 10, 12, 14, 21, 28, and 42. After 6 weeks, animals were euthanized and 80 μm CT-scans were performed. For histological investigations, hematoxylin and eosin-, tartrate-resistant acid phosphatase-, alkaline phosphatase-, and anti-eGFP-stained sections were prepared. BMP-2 and SDF-1α combined at the defect site increased bone volume (BV) (2.72 mm(3); 95% CI 1.95-3.49 mm(3)) compared with the negative control group (1.80 mm(3); 95% CI 1.56-2.04 mm(3); p<0.05). In addition, histological analysis confirmed a higher degree of bone healing in the BMP-2 and SDF-1α combined group compared with the negative control group. Bioluminescence imaging demonstrated higher numbers of migrated MSCs toward the defect site in the presence of both BMP-2 and SDF-1α at the defect site. Furthermore, eGFP-labeled migrated MSCs were found in all defect areas, when cells were injected. The ratio of osteoblasts to osteoclasts, assessed by immunohistological staining, was higher and thus showed a trend toward more bone formation for the combined use of BMP-2 and SDF-1α compared with all other groups. This study demonstrated that SDF-1α enhanced BMP-2 mediated bone healing in a critical size segmental bone defect model. Notably, both proteins alone also provided a cumulative effect on MSC attraction toward the site of injury.

  View details for DOI 10.1089/ten.TEA.2013.0222

  View details for PubMedID 24090366

• Editorial Comment: Symposium: 2013 Hip Society Proceedings CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B. 2014; 472 (2): 415–16

  View details for PubMedID 24326592

• Causes of instability after total knee arthroplasty. journal of arthroplasty Song, S. J., Detch, R. C., Maloney, W. J., Goodman, S. B., Huddleston, J. I. 2014; 29 (2): 360-364

  Abstract

  The purpose of the present study was to characterize the underlying causes that lead to instability after total knee arthroplasty (TKA). We reviewed 83 revision TKAs (79 patients) performed for instability. After detailed analysis of patient's history, physical examination, operative report and radiographs, we identified six categories: flexion/extension gap mismatch, component malposition, isolated ligament insufficiency, extensor mechanism insufficiency, component loosening, and global instability. Twenty-five knees presented with multi-factorial instability. When these knees were classified according to the most fundamental category, each category above included 24, 12, 11, 10, 10 and 16 knees respectively. The unstable TKA may result from a variety of distinct etiologies which must be identified and treated at the time of revision. The revision TKA could be tailored to the specific causes.

  View details for DOI 10.1016/j.arth.2013.06.023

  View details for PubMedID 23896358

• High Complication Rate in Revision Total Hip Arthroplasty in Juvenile Idiopathic Arthritis Open Scientific Meeting of the Hip-Society in Conjunction with the Annual Meeting of the American-Academy-of-Orthopaedic-Surgeons (AAOS) Goodman, S. B., Hwang, K., Imrie, S. SPRINGER. 2014: 637–44

  Abstract

  Revision total hip arthroplasty (THA) in patients with juvenile idiopathic arthritis (JIA) is challenging as a result of the patient's young age, systemic disease, multiple affected joints, small proportions, and bone loss. The intermediate- to long-term results of these surgeries remain unknown.The purpose of this study is to determine the (1) functional outcomes; (2) surgical complications; and (3) frequency of reoperation or revision after revision THA for JIA.We reviewed the records of all patients from one center who underwent revision THA for JIA who had a minimum of 5 years of followup (mean, 9 years; range, 5-19 years). This resulted in a series of 24 revision THAs in 15 patients. All patients were Charnley Class C. Age at revision averaged 35 years (range, 21-53 years). The 20 acetabular and 12 femoral revision components included 15 cementless cups, five reconstruction/roof rings with a cemented cup, and four cemented and eight cementless femoral stems.The Harris hip scores improved from 54 (range, 34-85) to 77 (range, 37-100) (p < 0.001). Complications included two proximal femoral fractures associated with severe osteolysis and one sciatic nerve palsy in a patient with severe acetabular deficiency. A total of seven hips (29%) required reoperation or revision surgery, including three for infection (one early and two late) and four for mechanical loosening.Revision THA in JIA is very challenging owing to patients' small proportions and compromised bone stock. The intraoperative and early complication rates are relatively high. Prognosis for long-term survivorship is guarded; limiting factors include periprosthetic osteolysis associated with older implants that used conventional polyethylene and cemented stems.

  View details for DOI 10.1007/s11999-013-3326-7

  View details for PubMedID 24136805

• Innate immunity sensors participating in pathophysiology of joint diseases: a brief overview. Journal of long-term effects of medical implants Gallo, J., Raska, M., Konttinen, Y. T., Nich, C., Goodman, S. B. 2014; 24 (4): 297-317

  Abstract

  The innate immune system consists of functionally specialized "modules" that are activated in response to a particular set of stimuli via sensors located on the surface or inside the tissue cells. These cells screen tissues for a wide range of exogenous and endogenous danger/damage-induced signals with the aim to reject or tolerate them and maintain tissue integrity. In this line of thinking, inflammation evolved as an adaptive tool for restoring tissue homeostasis. A number of diseases are mediated by a maladaptation of the innate immune response, perpetuating chronic inflammation and tissue damage. Here, we review recent evidence on the cross talk between innate immune sensors and development of rheumatoid arthritis, osteoarthritis, and aseptic loosening of total joint replacements. In relation to the latter topic, there is a growing body of evidence that aseptic loosening and periprosthetic osteolysis results from long-term maladaptation of periprosthetic tissues to the presence of by-products continuously released from an artificial joint.

  View details for PubMedID 25747032

• Suppression of NF-?B signaling mitigates polyethylene wear particle-induced inflammatory response. Inflammation and cell signaling Lin, T., Goodman, S. B. 2014; 1 (4)

  Abstract

  In end-stage arthritis patients, total joint replacement is a very effective surgical procedure. Nevertheless, the high revision rate after surgery remains a major concern. The wear particles generated from biomaterial-induced tissue responses may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Several important signaling pathways are involved in wear particles induced inflammatory reactions, including the transcription factor NF-κB. We recently reported that RAW264.7 macrophage cell exposure to ultra-high molecular weight polyethylene (UHMWPE) particles significantly increased the NF-κB activity in a generated NF-κB responsive luciferase reporter cell clone. The NF-κB activity induced by UHMWPE particles in a mouse RAW264.7 macrophage cell line, bone marrow derived macrophages, and human THP1 macrophage cell line, were suppressed by double strand decoy oligodeoxynucleotide (ODN) containing an NF-κB binding element. Macrophages exposure to UHMWPE particles with or without endotoxin induced pro-inflammatory cytokine and chemokine expression including TNF-α, MCP1, MIP1α, and others. Finally, the decoy ODN significantly suppressed the induced cytokine and chemokine expression in both murine and human macrophages, consequently reducing macrophage recruitment by cellular conditioned medium exposed to wear particles. These findings suggest that local suppression of inflammatory cytokine production via inhibition of NF-κB activity with decoy ODN in total joint replacement patients could potentially be an effective strategy to alleviate wear particle-induced chronic inflammation.

  View details for PubMedID 26052541

• Case report: Pseudotumor associated with corrosion of a femoral component with a modular neck and a ceramic-on-polyethylene bearing. Journal of long-term effects of medical implants Messana, J., Adelani, M., Goodman, S. B. 2014; 24 (1): 1-5

  Abstract

  Pseudotumor is a rare complication that can occur following hip arthroplasty. This complication may present with pain, swelling, and decreased function and may lead to bone and soft-tissue destruction. We report a case of pseudotumor formation resulting from corrosion of a modular neck in a hip replacement with a ceramic-on-polyethylene bearing. The patient underwent successful revision surgery using an extended trochanteric osteotomy, removal of the entire stem, and implantation of a new femoral stem and ceramic-polyethylene bearing without a modular neck.

  View details for PubMedID 24941400

• Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-?B as a therapeutic target. Acta biomaterialia Lin, T., Tamaki, Y., Pajarinen, J., Waters, H. A., Woo, D. K., Yao, Z., Goodman, S. B. 2014; 10 (1): 1-10

  Abstract

  Biomaterial-induced tissue responses in patients with total joint replacement are associated with the generation of wear particles, which may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Inflammatory reactions associated with wear particles are mediated by several important signaling pathways, the most important of which involves the transcription factor NF-κB. NF-κB activation is essential for macrophage recruitment and maturation, as well as the production of pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6 and MCP1. In addition, NF-κB activation contributes to osteoclast differentiation and maturation via RANK/RANKL signaling, which increases bone destruction and reduces bone formation. Targeting individual downstream cytokines directly (such as TNF-α or IL-1β) may not effectively prevent wear particle induced osteolysis. A more logical upstream therapeutic approach may be provided by direct modulation of the core IκB/IKKα/β/NF-κB signaling pathway in the local environment. However, the timing, dose and strategy for administration should be considered. Suppression of chronic inflammation via inhibition of NF-κB activity in patients with malfunctioning joint replacements may be an effective strategy to mitigate wear particle induced periprosthetic osteolysis.

  View details for DOI 10.1016/j.actbio.2013.09.034

  View details for PubMedID 24090989

• Joint replacement surgery and the innate immune system. Journal of long-term effects of medical implants Goodman, S. B., Konttinen, Y. T., Takagi, M. 2014; 24 (4): 253-257

  Abstract

  Total joint replacement is a highly successful, cost-effective surgical procedure that relieves pain and improves function for patients with end-stage arthritis. The most commonly used materials for modern joint replacements include metal alloys such as cobalt chrome and titanium alloys, polymers including polymethylmethacrylate and polyethylene, and ceramics. Implantation of a joint prosthesis incites an acute inflammatory reaction that is regulated by the innate immune system, a preprogrammed non-antigen specific biological response composed of cells, proteins, and other factors. This "frontline" immune mechanism was originally designed to combat invading microorganisms, but now responds to both pathogen-associated molecular patterns or PAMPS (by-products from microorganisms), and damage associated molecular patterns or DAMPS (molecular by-products from cells), via pattern recognition receptors (PRRs). In this way, potentially injurious stimuli that might disrupt the normal homeostatic regulatory mechanisms of the organism are efficiently dealt with, ensuring the survival of the host. Initial surgical implantation of the joint replacement, as well as ongoing generation of wear debris and byproducts during usage of the joint, activates the innate immune system. Understanding and potentially modulating these events may lead to improved function and increased longevity of joint replacements in the future.

  View details for PubMedID 25747028

• Interaction of materials and biology in total joint replacement - successes, challenges and future directions JOURNAL OF MATERIALS CHEMISTRY B Pajarinen, J., Lin, T., Sato, T., Yao, Z., Goodman, S. B. 2014; 2 (41): 7094-7108

  Abstract

  Total joint replacement (TJR) has revolutionized the treatment of end-stage arthritic disorders. This success is due, in large part, to a clear understanding of the important interaction between the artificial implant and the biology of the host. All surgical procedures in which implants are placed in the body evoke an initial inflammatory reaction, which generally subsides over several weeks. Thereafter, a series of homeostatic events occur leading to progressive integration of the implant within bone and the surrounding musculoskeletal tissues. The eventual outcome of the operation is dependent on the characteristics of the implant, the precision of the surgical technique and operative environment, and the biological milieu of the host. If these factors and events are not optimal, adverse events can occur such as the development of chronic inflammation, progressive bone loss due to increased production of degradation products from the implant (periprosthetic osteolysis), implant loosening or infection. These complications can lead to chronic pain and poor function of the joint reconstruction, and may necessitate revision surgery or removal of the prosthesis entirely. Recent advances in engineering, materials science, and the immunological aspects associated with orthopaedic implants have fostered intense research with the hope that joint replacements will last a lifetime, and facilitate pain-free, normal function.

  View details for DOI 10.1039/c4tb01005a

  View details for Web of Science ID 000342763700001

  View details for PubMedCentralID PMC4273175

• Chronic inflammation in biomaterial-induced periprosthetic osteolysis: NF-?B as a therapeutic target. Acta biomaterialia Lin, T., Tamaki, Y., Pajarinen, J., Waters, H. A., Woo, D. K., Yao, Z., Goodman, S. B. 2014; 10 (1): 1-10

  Abstract

  Biomaterial-induced tissue responses in patients with total joint replacement are associated with the generation of wear particles, which may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Inflammatory reactions associated with wear particles are mediated by several important signaling pathways, the most important of which involves the transcription factor NF-κB. NF-κB activation is essential for macrophage recruitment and maturation, as well as the production of pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6 and MCP1. In addition, NF-κB activation contributes to osteoclast differentiation and maturation via RANK/RANKL signaling, which increases bone destruction and reduces bone formation. Targeting individual downstream cytokines directly (such as TNF-α or IL-1β) may not effectively prevent wear particle induced osteolysis. A more logical upstream therapeutic approach may be provided by direct modulation of the core IκB/IKKα/β/NF-κB signaling pathway in the local environment. However, the timing, dose and strategy for administration should be considered. Suppression of chronic inflammation via inhibition of NF-κB activity in patients with malfunctioning joint replacements may be an effective strategy to mitigate wear particle induced periprosthetic osteolysis.

  View details for DOI 10.1016/j.actbio.2013.09.034

  View details for PubMedID 24090989

• Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement. Journal of the Royal Society, Interface / the Royal Society Goodman, S. B., Gibon, E., Pajarinen, J., Lin, T., Keeney, M., Ren, P., Nich, C., Yao, Z., Egashira, K., Yang, F., KONTTINEN, Y. T. 2014; 11 (93): 20130962-?

  Abstract

  Wear particles and by-products from joint replacements and other orthopaedic implants may result in a local chronic inflammatory and foreign body reaction. This may lead to persistent synovitis resulting in joint pain and swelling, periprosthetic osteolysis, implant loosening and pathologic fracture. Strategies to modulate the adverse effects of wear debris may improve the function and longevity of joint replacements and other orthopaedic implants, potentially delaying or avoiding complex revision surgical procedures. Three novel biological strategies to mitigate the chronic inflammatory reaction to orthopaedic wear particles are reported. These include (i) interference with systemic macrophage trafficking to the local implant site, (ii) modulation of macrophages from an M1 (pro-inflammatory) to an M2 (anti-inflammatory, pro-tissue healing) phenotype in the periprosthetic tissues, and (iii) local inhibition of the transcription factor nuclear factor kappa B (NF-κB) by delivery of an NF-κB decoy oligodeoxynucleotide, thereby interfering with the production of pro-inflammatory mediators. These three approaches have been shown to be viable strategies for mitigating the undesirable effects of wear particles in preclinical studies. Targeted local delivery of specific biologics may potentially extend the lifetime of orthopaedic implants.

  View details for DOI 10.1098/rsif.2013.0962

  View details for PubMedID 24478281

• Total Knee Arthroplasty in Patients With Juvenile Idiopathic Arthritis CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Heyse, T. J., Ries, M. D., Bellemans, J., Goodman, S. B., Scott, R. D., Wright, T. M., Lipman, J. D., Schwarzkopf, R., Figgie, M. P. 2014; 472 (1): 147-154

  Abstract

  Total knee arthroplasty (TKA) for juvenile idiopathic arthritis is rare but is nonetheless indicated for many patients with this disease. Few reports exist on the results of TKA in patients with juvenile idiopathic arthritis.It was sought to determine (1) survivorship and (2) functional outcomes of TKAs in patients with juvenile idiopathic arthritis.Results were combined from patients treated by experienced surgeons at five hospitals between 1979 and 2011. Two hundred nineteen patients (349 TKAs) were identified and contacted to survey their outcomes at a minimum followup of 2 years (mean, 12 ± 8 years; range, 2-33 years). The average age at surgery was 28.9 ± 9.7 years (range, 11-58 years). Data on revision surgery and ability to perform daily activities were collected.The 10-year survivorship was 95%, decreasing to 82% by 20 years. At latest followup, 31 of 349 TKAs (8.9%) had been revised for either polyethylene failure or loosening (18 TKAs), infection (four), stiffness (three), periprosthetic fractures (two), bilateral amputation for vascular reasons (two), patellar resurfacing (one), and instability (one). Walking tolerance was unlimited in 49%, five to 10 blocks in 23%, and less than five blocks in 28%. Eleven percent could not manage stairs, and another 59% depended on railings. A cane was used by 12% and crutches by 7%; 12% were wheelchair-dependent.TKA survivorship in patients with juvenile idiopathic arthritis was inferior to that typically seen in younger patients with osteoarthritis or even rheumatoid arthritis confirming results of earlier studies with smaller patient numbers. This is especially disconcerting because younger patients require better durability of their TKAs.

  View details for DOI 10.1007/s11999-013-3095-3

  View details for Web of Science ID 000328824400024

  View details for PubMedID 23761173

  View details for PubMedCentralID PMC3889456

• Innate Immune Reactions in Septic and Aseptic Osteolysis around Hip Implants. Journal of long-term effects of medical implants Pajarinen, J., Jamsen, E., Konttinen, Y. T., Goodman, S. B. 2014; 24 (4): 283-296

  Abstract

  According to the long-standing definition, septic and aseptic total joint replacement loosening are two distinct conditions with little in common. Septic joint replacement loosening is driven by bacterial infection whereas aseptic loosening is caused by biomaterial wear debris released from the bearing surfaces. However, recently it has been recognized that the mechanisms that drive macrophage activation in septic and aseptic total joint replacement loosening resemble each other. In particular, accumulating evidence indicates that in addition to mediating bacterial recognition and the subsequent inflammatory reaction, toll-like receptors (TLRs) and their ligands, pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS), play a key role in wear debris-induced inflammation and macrophage activation. In addition, subclinical bacterial biofilms have been identified from some cases of seemingly aseptic implant loosening. Furthermore, metal ions released from some total joint replacements can activate TLR signaling similar to bacterial derived PAMPs. Likewise, metal ions can function as haptens activating the adaptive immune system similar to bacterial derived antigens. Thus, it appears that aseptic and septic joint replacement loosening share similar underlying pathomechanisms and that this strict dichotomy to sterile aseptic and bacterial-caused septic implant loosening is somewhat questionable. Indeed, rather than being two, well-defined clinical entities, peri-implant osteolysis is, in fact, a spectrum of conditions in which the specific clinical picture is determined by complex interactions of multiple local and systemic factors.

  View details for PubMedID 25747031

• Role of macrophages in the biological reaction to wear debris from joint replacements. Journal of long-term effects of medical implants Nich, C., Goodman, S. B. 2014; 24 (4): 259-265

  Abstract

  Normal usage of total joint replacements results in the production of wear debris and other byproducts. In particular, polyethylene particles are heavily involved in the stimulation of local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone resorption (osteolysis), and, eventually, implant loosening. As sentinels of the innate immune system, cells of the monocyte/macrophage lineage initiate the inflammatory cascade that leads to osteolysis. The biological processes involved are complex, based on the unique properties of the monocytes/macrophages, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The interaction with wear debris triggers the release of pro-inflammatory factors, such as TNF-α, IL-1, and others, pro-osteoclastic factors such as RANKL, and chemokines, such as MCP-1 and MIP-1, all being crucial to the recruitment, migration, differentiation, and ultimately activation of bone resorbing osteoclasts. In parallel, other distinct macrophage populations inhibit inflammation and mitigate its consequences on the bone-implant interface. Here, the role of the monocyte/macrophage cell lineage in the initiation and maintenance of the host inflammatory response to wear debris and subsequent periprosthetic osteolysis is presented.

  View details for PubMedID 25747029

• Macrophage polarization and activation in response to implant debris: influence by "particle disease" and "ion disease". Journal of long-term effects of medical implants Konttinen, Y. T., Pajarinen, J., Takakubo, Y., Gallo, J., Nich, C., Takagi, M., Goodman, S. B. 2014; 24 (4): 267-281

  Abstract

  Macrophages derive from human embryonic and fetal stem cells and from human bone marrow-derived blood monocytes. They play a major homeostatic role in tissue remodeling and maintenance facilitated by apoptotic "eat me" opsonins like CRP, serum amyloid P, C1q, C3b, IgM, ficolin, and surfactant proteins. Three subsets of monocytes, classic, intermediate, and nonclassic, are mobilized and transmigrate to tissues. Implant-derived wear particles opsonized by danger signals regulate macrophage priming, polarization (M1, M2, M17, and Mreg), and activation. CD14+ monocytes in healthy controls and CD16+ monocytes in inflammation differentiate/polarize to foreign body giant cells/osteoclasts or inflammatory dendritic cells (infDC). These danger signal opsonins can be pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs), but in aseptic loosening, usually are damage-associated molecular patterns (DAMPs). Danger signal-opsonized particles elicit "particle disease" and aseptic loosening. They provide soluble and cell membrane-bound co-stimulatory signals that can lead to cell-mediated immune reactions to metal ions. Metal-on-metal implant failure has disclosed that quite like Ni2+, its neighbor in the periodic table Co2+ can directly activate toll-like receptor 4 (TLR4) as a lipopolysaccharide-mimic. "Ion disease" concept needs to be incorporated into the "particle disease" concept, due to the toxic, immune, and inflammatory potential of metal ions.

  View details for PubMedID 25747030

• Mutant MCP-1 protein delivery from layer-by-layer coatings on orthopedic implants to modulate inflammatory response. Biomaterials Keeney, M., Waters, H., Barcay, K., Jiang, X., Yao, Z., Pajarinen, J., Egashira, K., Goodman, S. B., Yang, F. 2013; 34 (38): 10287-10295

  Abstract

  Total joint replacement (TJR) is a common and effective surgical procedure for hip or knee joint reconstruction. However, the production of wear particles is inevitable for all TJRs, which activates macrophages and initiates an inflammatory cascade often resulting in bone loss, prosthetic loosening and eventual TJR failure. Macrophage Chemoattractant Protein-1 (MCP-1) is one of the most potent cytokines responsible for macrophage cell recruitment, and previous studies suggest that mutant MCP-1 proteins such as 7ND may be used as a decoy drug to block the receptor and reduce inflammatory cell recruitment. Here we report the development of a biodegradable, layer-by-layer (LBL) coating platform that allows efficient loading and controlled release of 7ND proteins from the surface of orthopedic implants using as few as 14 layers. Scanning electron microscopy and fluorescence imaging confirmed effective coating using the LBL procedure on titanium rods. 7ND protein loading concentration and release kinetics can be modulated by varying the polyelectrolytes of choice, the polymer chemistry, the pH of the polyelectrolyte solution, and the degradation rate of the LBL assembly. The released 7ND from LBL coating retained its bioactivity and effectively reduced macrophage migration towards MCP-1. Finally, the LBL coating remained intact following a femoral rod implantation procedure as determined by immunostaining of the 7ND coating. The LBL platform reported herein may be applied for in situ controlled release of 7ND protein from orthopedic implants, to reduce wear particle-induced inflammatory responses in an effort to prolong the lifetime of implants.

  View details for DOI 10.1016/j.biomaterials.2013.09.028

  View details for PubMedID 24075408

• Macrophage polarization in response to wear particles in vitro CELLULAR & MOLECULAR IMMUNOLOGY Antonios, J. K., Yao, Z., Li, C., Rao, A. J., Goodman, S. B. 2013; 10 (6): 471-482

  Abstract

  Total joint replacement is a highly successful surgical procedure for treatment of patients with disabling arthritis and joint dysfunction. However, over time, with high levels of activity and usage of the joint, implant wear particles are generated from the articulating surfaces. These wear particles can lead to activation of an inflammatory reaction, and subsequent bone resorption around the implant (periprosthetic osteolysis). Cells of the monocyte/macrophage lineage orchestrate this chronic inflammatory response, which is dominated by a pro-inflammatory (M1) macrophage phenotype rather than an anti-inflammatory pro-tissue healing (M2) macrophage phenotype. While it has been shown that interleukin-4 (IL-4) selectively polarizes macrophages towards an M2 anti-inflammatory phenotype which promotes bone healing, rather than inflammation, little is known about the time course in which this occurs or conditions in which repolarization through IL-4 is most effective. The goal of this work was to study the time course of murine macrophage polarization and cytokine release in response to challenge with combinations of polymethyl methacrylate (PMMA) particles, lipopolysaccharide (LPS) and IL-4 in vitro. Treatment of particle-challenged monocyte/macrophages with IL-4 led to an initial suppression of pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) production and subsequent polarization into an M2 anti-inflammatory phenotype. This result was optimized when IL-4 was delivered before PMMA particle challenge, to an M1 phenotype rather than to uncommitted (M0) macrophages. The effects of this polarization were sustained over a 5-day time course. Polarization of M1 macrophages into an M2 phenotype may be a strategy to mitigate wear particle associated periprosthetic osteolysis.

  View details for DOI 10.1038/cmi.2013.39

  View details for Web of Science ID 000326688400005

  View details for PubMedID 24013843

  View details for PubMedCentralID PMC3818297

• Macrophages-Key cells in the response to wear debris from joint replacements JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Nich, C., Takakubo, Y., Pajarinen, J., Ainola, M., Salem, A., Sillat, T., Rao, A. J., Raska, M., Tamaki, Y., Takagi, M., Konttinen, Y. T., Goodman, S. B., Gallo, J. 2013; 101 (10): 3033-3045

  Abstract

  The generation of wear debris is an inevitable result of normal usage of joint replacements. Wear debris particles stimulate local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone destruction, and eventually, implant loosening, and revision surgery. The latter may be indicated in up to 15% patients in the decade following the arthroplasty using conventional polyethylene. Macrophages play multiple roles in both inflammation and in maintaining tissue homeostasis. As sentinels of the innate immune system, they are central to the initiation of this inflammatory cascade, characterized by the release of proinflammatory and pro-osteoclastic factors. Similar to the response to pathogens, wear particles elicit a macrophage response, based on the unique properties of the cells belonging to this lineage, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The biological processes involved are complex, redundant, both local and systemic, and highly adaptive. Cells of the monocyte/macrophage lineage are implicated in this phenomenon, ultimately resulting in differentiation and activation of bone resorbing osteoclasts. Simultaneously, other distinct macrophage populations inhibit inflammation and protect the bone-implant interface from osteolysis. Here, the current knowledge about the physiology of monocyte/macrophage lineage cells is reviewed. In addition, the pattern and consequences of their interaction with wear debris and the recent developments in this field are presented. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

  View details for DOI 10.1002/jbm.a.34599

  View details for Web of Science ID 000323648300028

• Macrophages-Key cells in the response to wear debris from joint replacements. Journal of biomedical materials research. Part A Nich, C., Takakubo, Y., Pajarinen, J., Ainola, M., Salem, A., Sillat, T., Rao, A. J., Raska, M., Tamaki, Y., Takagi, M., Konttinen, Y. T., Goodman, S. B., Gallo, J. 2013; 101 (10): 3033-3045

  Abstract

  The generation of wear debris is an inevitable result of normal usage of joint replacements. Wear debris particles stimulate local and systemic biological reactions resulting in chronic inflammation, periprosthetic bone destruction, and eventually, implant loosening, and revision surgery. The latter may be indicated in up to 15% patients in the decade following the arthroplasty using conventional polyethylene. Macrophages play multiple roles in both inflammation and in maintaining tissue homeostasis. As sentinels of the innate immune system, they are central to the initiation of this inflammatory cascade, characterized by the release of proinflammatory and pro-osteoclastic factors. Similar to the response to pathogens, wear particles elicit a macrophage response, based on the unique properties of the cells belonging to this lineage, including sensing, chemotaxis, phagocytosis, and adaptive stimulation. The biological processes involved are complex, redundant, both local and systemic, and highly adaptive. Cells of the monocyte/macrophage lineage are implicated in this phenomenon, ultimately resulting in differentiation and activation of bone resorbing osteoclasts. Simultaneously, other distinct macrophage populations inhibit inflammation and protect the bone-implant interface from osteolysis. Here, the current knowledge about the physiology of monocyte/macrophage lineage cells is reviewed. In addition, the pattern and consequences of their interaction with wear debris and the recent developments in this field are presented. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

  View details for DOI 10.1002/jbm.a.34599

  View details for PubMedID 23568608

• Cause for concern: pseudotumors in patients with hip resurfacing: commentary on an article by R. Bisschop, MD et al.: "High prevalence of pseudotumors in patients with a Birmingham Hip Resurfacing prosthesis: a prospective cohort study of one hundred and twenty-nine patients". The Journal of bone and joint surgery. American volume Goodman, S. B. 2013; 95 (17): e1271–2

  View details for PubMedID 24005211

• Osteolysis around total knee arthroplasty: A review of pathogenetic mechanisms ACTA BIOMATERIALIA Gallo, J., Goodman, S. B., KONTTINEN, Y. T., Wimmer, M. A., Holinka, M. 2013; 9 (9): 8046-8058

  Abstract

  Aseptic loosening and other wear-related complications are some of the most frequent late reasons for revision of total knee arthroplasty (TKA). Periprosthetic osteolysis (PPOL) pre-dates aseptic loosening in many cases, indicating the clinical significance of this pathogenic mechanism. A variety of implant-, surgery- and host-related factors have been delineated to explain the development of PPOL. These factors influence the development of PPOL because of changes in mechanical stresses within the vicinity of the prosthetic device, excessive wear of the polyethylene liner, and joint fluid pressure and flow acting on the peri-implant bone. The process of aseptic loosening is initially governed by factors such as implant/limb alignment, device fixation quality and muscle coordination/strength. Later, large numbers of wear particles detached from TKA trigger and perpetuate particle disease, as highlighted by progressive growth of inflammatory/granulomatous tissue around the joint cavity. An increased accumulation of osteoclasts at the bone-implant interface, impairment of osteoblast function, mechanical stresses and increased production of joint fluid contribute to bone resorption and subsequent loosening of the implant. In addition, hypersensitivity and adverse reactions to metal debris may contribute to aseptic TKA failure, but should be determined more precisely. Patient activity level appears to be the most important factor when the long-term development of PPOL is considered. Surgical technique, implant design and material factors are the most important preventative factors, because they influence both the generation of wear debris and excessive mechanical stresses. New generations of bearing surfaces and designs for TKA should carefully address these important issues in extensive preclinical studies. Currently, there is little evidence that PPOL can be prevented by pharmacological intervention.

  View details for DOI 10.1016/j.actbio.2013.05.005

  View details for Web of Science ID 000323402600002

  View details for PubMedID 23669623

  View details for PubMedCentralID PMC4003873

• Development of Poly(ß-amino ester)-Based Biodegradable Nanoparticles for Nonviral Delivery of Minicircle DNA. ACS nano Keeney, M., Ong, S., Padilla, A., Yao, Z., Goodman, S., Wu, J. C., Yang, F. 2013; 7 (8): 7241-7250

  Abstract

  Gene therapy provides a powerful tool for regulating cellular processes and tissue repair. Minicircle (MC) DNA are supercoiled DNA molecules free of bacterial plasmid backbone elements and have been reported to enhance prolonged gene expression compared to conventional plasmids. Despite the great promise of MC DNA for gene therapy, methods for safe and efficient MC DNA delivery remain lacking. To overcome this bottleneck, here we report the development of a poly(β-amino ester) (PBAE)-based, biodegradable nanoparticulate platform for efficient delivery of MC DNA driven by a Ubc promoter in vitro and in vivo. By synthesizing and screening a small library of 18 PBAE polymers with different backbone and end-group chemistry, we identified lead cationic PBAE structures that can complex with minicircle DNA to form nanoparticles, and delivery efficiency can be further modulated by tuning PBAE chemistry. Using human embryonic kidney 293 cells and mouse embryonic fibroblasts as model cell types, we identified a few PBAE polymers that allow efficient MC delivery at levels that are comparable or even surpassing Lipofectamine 2000. The biodegradable nature of PBAE-based nanoparticles facilitates in vivo applications and clinical translation. When injected via intraperitoneal route in vivo, MC alone resulted in high transgene expression, and a lead PBAE/MC nanoparticle formulation achieved a further 2-fold increase in protein expression compared to MC alone. Together, our results highlight the promise of PBAE-based nanoparticles as promising nonviral gene carriers for MC delivery, which may provide a valuable tool for broad applications of MC DNA-based gene therapy.

  View details for DOI 10.1021/nn402657d

  View details for PubMedID 23837668

• Local effect of IL-4 delivery on polyethylene particle induced osteolysis in the murine calvarium. Journal of biomedical materials research. Part A Rao, A. J., Nich, C., Dhulipala, L. S., Gibon, E., Valladares, R., Zwingenberger, S., Smith, R. L., Goodman, S. B. 2013; 101 (7): 1926-1934

  Abstract

  Wear particles generated with use of total joint replacements incite a chronic macrophage-mediated inflammatory reaction, which leads to implant failure. Macrophage activation may be polarized into two states, with an M1 proinflammatory state dominating an alternatively activated M2 anti-inflammatory state. We hypothesized that IL-4, an activator of M2 macrophages, could modulate polyethylene (PE) particle-induced osteolysis in an experimental murine model. Four animal groups included (a) calvarial saline injection with harvest at 14 days (b) single calvarial injection of PE particles subcutaneously (SC) without IL-4 (c) PE particles placed as in (b), then IL-4 given SC for 14 consecutive days and (d) PE particles as in (b) then IL-4 beginning 7 days after particle injection for 7 days. The calvarial bone volume to total tissue volume was measured using microCT and histomorphometry. Calvaria were cultured for 24 h to assess release of RANKL, OPG, TNF-α, and IL-1ra and isolation and identification of M1 and M2 specific proteins. MicroCT and histomorphometric analysis showed that bone loss was significantly decreased following IL-4 administration to PE treated calvaria for both 7 and 14 days. Western blot analysis showed an increased M1/M2 ratio in the PE treated calvaria, which decreased with addition of IL-4. Cytokine analysis showed that the RANKL/OPG ratio and TNF-α/IL-1ra ratio decreased in PE-treated calvaria following IL-4 addition for 14 days. IL-4 delivery mitigated PE particle-induced osteolysis through macrophage polarization. Modulation of macrophage polarization is a potential treatment strategy for wear particle induced periprosthetic osteolysis. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

  View details for DOI 10.1002/jbm.a.34486

  View details for PubMedID 23225668

• Stem cell attraction via SDF-1 expressing fat tissue grafts JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Zwingenberger, S., Yao, Z., Jacobi, A., Vater, C., Valladares, R. D., Li, C., Nich, C., Rao, A. J., Christman, J. E., Antonios, J. K., Gibon, E., Schambach, A., Maetzig, T., Guenther, K., Goodman, S. B., Stiehler, M. 2013; 101A (7): 2067-2074

  Abstract

  Mesenchymal stromal cell (MSCs) are key cellular components for site-specific tissue regeneration. The chemokine stromal derived factor 1 alpha (SDF-1α) is known to attract stem cells via the C-X-C chemokine receptor-4 (CXCR4) receptor. The aim of the study was to develop a model for stem cell attraction using SDF-1α overexpressing fat tissue grafts. Murine MSCs were lentiviral transduced to express the genes for enhanced green fluorescent protein, firefly luciferace, and human CXCR4 (hCXCR4). Murine fat tissue was adenoviral transduced to express SDF-1α and red fluorescent protein transgenes. MSCs were cultured on transwells with SDF-1α containing supernatants from transduced fat tissue. The numbers of migrated MSCs in four groups (with hCXCR4 positive (+) or hCXCR4 negative (-) MSCs with or without SDF-1α containing supernatant) were investigated. After 36 h of culture, 9025 ± 925 cells migrated through the membrane of the transwells in group 1 (CXCR4+/SDF-1α+), 4817 ± 940 cells in group 2 (CXCR4-/SDF-1α+), 2050 ± 766 cells in group 3 (CXCR4+/SDF-1α-), and 2108 ± 426 cells in group 4 (CXCR4-/SDF-1α-). Both, the presence of SDF-1α and the expression of hCXCR4 significantly increased the migration rates (p < 0.0001). MSCs overexpressing the CXCR4 receptor by lentiviral transduction are highly attracted by medium from SDF-1α expressing fat tissue in vitro. Thus, SDF-1α activated tissue grafts may be a strategy to enhance site-specific musculoskeletal tissue regeneration. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

  View details for DOI 10.1002/jbm.a.34512

  View details for Web of Science ID 000319424100025

• Direct subcutaneous injection of polyethylene particles over the murine calvaria results in dramatic osteolysis INTERNATIONAL ORTHOPAEDICS Rao, A. J., Zwingenberger, S., Valladares, R., Li, C., Smith, R. L., Goodman, S. B., Nich, C. 2013; 37 (7): 1393-1398

  Abstract

  PURPOSE: The murine calvarial model has been widely employed for the in vivo study of particle-induced osteolysis, the most frequent cause of aseptic loosening of total joint replacements. Classically, this model uses an open surgical technique in which polyethylene (PE) particles are directly spread over the calvarium for the induction of osteolysis. We evaluated a minimally invasive modification of the calvarial model by using a direct subcutaneous injection of PE particles. METHODS: Polyethylene (PE) particles were injected subcutaneously over the calvaria of C57BL6J ten-week-old mice ("injection" group) or were implanted after surgical exposure of the calvaria ("open" group) (n = 5/group). For each group, five additional mice received no particles and served as controls. Particle-induced osteolysis was evaluated two weeks after the procedure using high-definition microCT imaging. RESULTS: Polyethylene particle injection over the calvaria resulted in a 40 % ± 1.8 % decrease in the bone volume fraction (BVF), compared to controls. Using the "open surgical technique", the BVF decreased by 16 % ± 3.8 % as compared to controls (p < 0.0001). CONCLUSIONS: Direct subcutaneous injection of PE particles over the murine calvaria produced more profound resorption of bone. Polyethylene particle implantation by injection is less invasive and reliably induces osteolysis to a greater degree than the open technique. This subcutaneous injection method will prove useful for repetitive injections of particles, and the assessment of potential local or systemic therapies.

  View details for DOI 10.1007/s00264-013-1887-4

  View details for Web of Science ID 000320660500028

• Stem cell attraction via SDF-1a expressing fat tissue grafts. Journal of biomedical materials research. Part A Zwingenberger, S., Yao, Z., Jacobi, A., Vater, C., D Valladares, R., Li, C., Nich, C., Rao, A. J., Christman, J. E., Antonios, J. K., Gibon, E., Schambach, A., Mätzig, T., Günther, K., Goodman, S. B., Stiehler, M. 2013; 101 (7): 2067-2074

  Abstract

  Mesenchymal stromal cell (MSCs) are key cellular components for site-specific tissue regeneration. The chemokine stromal derived factor 1 alpha (SDF-1α) is known to attract stem cells via the C-X-C chemokine receptor-4 (CXCR4) receptor. The aim of the study was to develop a model for stem cell attraction using SDF-1α overexpressing fat tissue grafts. Murine MSCs were lentiviral transduced to express the genes for enhanced green fluorescent protein, firefly luciferace, and human CXCR4 (hCXCR4). Murine fat tissue was adenoviral transduced to express SDF-1α and red fluorescent protein transgenes. MSCs were cultured on transwells with SDF-1α containing supernatants from transduced fat tissue. The numbers of migrated MSCs in four groups (with hCXCR4 positive (+) or hCXCR4 negative (-) MSCs with or without SDF-1α containing supernatant) were investigated. After 36 h of culture, 9025 ± 925 cells migrated through the membrane of the transwells in group 1 (CXCR4+/SDF-1α+), 4817 ± 940 cells in group 2 (CXCR4-/SDF-1α+), 2050 ± 766 cells in group 3 (CXCR4+/SDF-1α-), and 2108 ± 426 cells in group 4 (CXCR4-/SDF-1α-). Both, the presence of SDF-1α and the expression of hCXCR4 significantly increased the migration rates (p < 0.0001). MSCs overexpressing the CXCR4 receptor by lentiviral transduction are highly attracted by medium from SDF-1α expressing fat tissue in vitro. Thus, SDF-1α activated tissue grafts may be a strategy to enhance site-specific musculoskeletal tissue regeneration. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

  View details for DOI 10.1002/jbm.a.34512

  View details for PubMedID 23281045

• Local effect of IL-4 delivery on polyethylene particle induced osteolysis in the murine calvarium JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Rao, A. J., Nich, C., Dhulipala, L. S., Gibon, E., Valladares, R., Zwingenberger, S., Smith, R. L., Goodman, S. B. 2013; 101A (7): 1925-1934

  Abstract

  Wear particles generated with use of total joint replacements incite a chronic macrophage-mediated inflammatory reaction, which leads to implant failure. Macrophage activation may be polarized into two states, with an M1 proinflammatory state dominating an alternatively activated M2 anti-inflammatory state. We hypothesized that IL-4, an activator of M2 macrophages, could modulate polyethylene (PE) particle-induced osteolysis in an experimental murine model. Four animal groups included (a) calvarial saline injection with harvest at 14 days (b) single calvarial injection of PE particles subcutaneously (SC) without IL-4 (c) PE particles placed as in (b), then IL-4 given SC for 14 consecutive days and (d) PE particles as in (b) then IL-4 beginning 7 days after particle injection for 7 days. The calvarial bone volume to total tissue volume was measured using microCT and histomorphometry. Calvaria were cultured for 24 h to assess release of RANKL, OPG, TNF-α, and IL-1ra and isolation and identification of M1 and M2 specific proteins. MicroCT and histomorphometric analysis showed that bone loss was significantly decreased following IL-4 administration to PE treated calvaria for both 7 and 14 days. Western blot analysis showed an increased M1/M2 ratio in the PE treated calvaria, which decreased with addition of IL-4. Cytokine analysis showed that the RANKL/OPG ratio and TNF-α/IL-1ra ratio decreased in PE-treated calvaria following IL-4 addition for 14 days. IL-4 delivery mitigated PE particle-induced osteolysis through macrophage polarization. Modulation of macrophage polarization is a potential treatment strategy for wear particle induced periprosthetic osteolysis. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2013.

  View details for DOI 10.1002/jbm.a.34486

  View details for Web of Science ID 000319424100010

• Direct subcutaneous injection of polyethylene particles over the murine calvaria results in dramatic osteolysis. International orthopaedics Rao, A. J., Zwingenberger, S., Valladares, R., Li, C., Lane Smith, R., Goodman, S. B., Nich, C. 2013; 37 (7): 1393-1398

  Abstract

  PURPOSE: The murine calvarial model has been widely employed for the in vivo study of particle-induced osteolysis, the most frequent cause of aseptic loosening of total joint replacements. Classically, this model uses an open surgical technique in which polyethylene (PE) particles are directly spread over the calvarium for the induction of osteolysis. We evaluated a minimally invasive modification of the calvarial model by using a direct subcutaneous injection of PE particles. METHODS: Polyethylene (PE) particles were injected subcutaneously over the calvaria of C57BL6J ten-week-old mice ("injection" group) or were implanted after surgical exposure of the calvaria ("open" group) (n = 5/group). For each group, five additional mice received no particles and served as controls. Particle-induced osteolysis was evaluated two weeks after the procedure using high-definition microCT imaging. RESULTS: Polyethylene particle injection over the calvaria resulted in a 40 % ± 1.8 % decrease in the bone volume fraction (BVF), compared to controls. Using the "open surgical technique", the BVF decreased by 16 % ± 3.8 % as compared to controls (p < 0.0001). CONCLUSIONS: Direct subcutaneous injection of PE particles over the murine calvaria produced more profound resorption of bone. Polyethylene particle implantation by injection is less invasive and reliably induces osteolysis to a greater degree than the open technique. This subcutaneous injection method will prove useful for repetitive injections of particles, and the assessment of potential local or systemic therapies.

  View details for DOI 10.1007/s00264-013-1887-4

  View details for PubMedID 23604215

• Regional variation in T1? and T2 times in osteoarthritic human menisci: correlation with mechanical properties and matrix composition. Osteoarthritis and cartilage Son, M., Goodman, S. B., Chen, W., Hargreaves, B. A., Gold, G. E., Levenston, M. E. 2013; 21 (6): 796-805

  Abstract

  Changes in T1ρ and T2 magnetic resonance relaxation times have been associated with articular cartilage degeneration, but similar relationships for meniscal tissue have not been extensively investigated. This work examined relationships between T1ρ and T2 measurements and biochemical and mechanical properties across regions of degenerate human menisci.Average T1ρ and T2 relaxation times were determined for nine regions each of seven medial and 13 lateral menisci from 14 total knee replacement patients. Sulfated glycosaminoglycan (sGAG), collagen and water contents were measured for each region. Biomechanical measurements of equilibrium compressive, dynamic compressive and dynamic shear moduli were made for anterior, central and posterior regions.T1ρ and T2 times showed similar regional patterns, with longer relaxation times in the (radially) middle region compared to the inner and outer regions. Pooled over all regions, T1ρ and T2 times showed strong correlations both with one another and with water content. Correlations with biochemical content varied depending on normalization to wet or dry mass, and both imaging parameters showed stronger correlations with collagen compared to sGAG content. Mechanical properties displayed moderate inverse correlations with increasing T1ρ and T2 times and water content.Both T1ρ and T2 relaxation times correlated strongly with water content and moderately with mechanical properties in osteoarthritic menisci, but not as strongly with sGAG or collagen contents alone. While the ability of magnetic resonance imaging (MRI) to detect early osteoarthritic changes remains the subject of investigation, these results suggest that T1ρ and T2 relaxation times have limited ability to detect compositional variations in degenerate menisci.

  View details for DOI 10.1016/j.joca.2013.03.002

  View details for PubMedID 23499673

• Lower Extremity Arthroplasty in Patients With Inflammatory Arthritis: Preoperative and Perioperative Management JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS Goodman, S. M., Figgie, M. 2013; 21 (6): 355-363

  Abstract

  Spondylarthritis, which includes conditions such as ankylosing spondylitis and psoriatic arthritis, and rheumatoid arthritis are the most common forms of inflammatory arthritis. Joint inflammation and damage may result in the need for arthroplasty, and the surgeon must be aware of the perioperative challenges associated with these systemic diseases. In patients with inflammatory arthritis who have polyarticular disease and spinal involvement at the time of presentation for lower extremity arthroplasty, preoperative evaluation must include careful evaluation of all joints, including the cervical spine. Preoperative assessment and perioperative management must be appropriate to minimize cardiac and pulmonary complications. Finally, the perioperative management of medications used to manage inflammatory arthritis is critical because these medications may increase the risk of infection and compromise wound healing.

  View details for DOI 10.5435/JAAOS-21-06-355

  View details for Web of Science ID 000209280800006

• Establishment of a femoral critical-size bone defect model in immunodeficient mice JOURNAL OF SURGICAL RESEARCH Zwingenberger, S., Niederlohmann, E., Vater, C., Rammelt, S., Matthys, R., Bernhardt, R., Valladares, R. D., Goodman, S. B., Stiehler, M. 2013; 181 (1): E7-E14

  Abstract

  The development of innovative therapies for bone regeneration requires the use of advanced site-specific bone defect small-animal models. The achievement of proper fixation with a murine model is challenging due to the small dimensions of the murine femur. The aim of this investigation was to find the optimal defect size for a murine critical-size bone defect model using external fixation method.An external fixation device was attached to the right femur of 30 mice. Femoral bone defects of 1 mm (n = 10), 2 mm (n = 10), and 3 mm (n = 10) were created. Wounds were closed without any additional treatment. To investigate bone healing during the 12-wk observation period, x-ray analysis, histomorphology, immunohistochemistry, and μCT scans were performed.MicroCT analyses after 12 wk showed that 3/8 1-mm defects, 5/8 2-mm defects, and 8/8 3-mm defects remained as nonunions. The defect volumes were 0.36 ± 0.42 mm³ (1-mm group), 1.40 ± 0.88 mm³ (2-mm group), and 2.88 ± 0.28 mm³ (3-mm group; P < 0.001, between all groups).Using external fixation, a defect size of 3 mm is necessary to reliably create a persisting femoral bone defect in nude mice.

  View details for DOI 10.1016/j.jss.2012.06.039

  View details for PubMedID 22765996

• The future of biologic coatings for orthopaedic implants BIOMATERIALS Goodman, S. B., Yao, Z., Keeney, M., Yang, F. 2013; 34 (13): 3174-3183

  Abstract

  Implants are widely used for orthopaedic applications such as fixing fractures, repairing non-unions, obtaining a joint arthrodesis, total joint arthroplasty, spinal reconstruction, and soft tissue anchorage. Previously, orthopaedic implants were designed simply as mechanical devices; the biological aspects of the implant were a byproduct of stable internal/external fixation of the device to the surrounding bone or soft tissue. More recently, biologic coatings have been incorporated into orthopaedic implants in order to modulate the surrounding biological environment. This opinion article reviews current and potential future use of biologic coatings for orthopaedic implants to facilitate osseointegration and mitigate possible adverse tissue responses including the foreign body reaction and implant infection. While many of these coatings are still in the preclinical testing stage, bioengineers, material scientists and surgeons continue to explore surface coatings as a means of improving clinical outcome of patients undergoing orthopaedic surgery.

  View details for DOI 10.1016/j.biomaterials.2013.01.074

  View details for PubMedID 23391496

• Cell-based therapies for regenerating bone. Minerva ortopedica e traumatologica : organo ufficiale della Societa piemontese-ligure-lombarda di ortopedia e traumatologia Goodman, S. B. 2013; 64 (2): 107-113

  Abstract

  Cellular therapies to replenish bone lost due to acquired conditions such as trauma, infection, tumor, periprosthetic osteolysis and other etiologies have become widespread. Traditional, open, surgical bone grafting techniques have given way to newer cellular therapies that are potentially less invasive and have a lower complication rate and faster recovery time. These new technologies include bone marrow harvesting with concentration of osteoprogenitor cells with/without cell culture, scaffolds which are both osteoconductive and osteoinductive, attempts to facilitate mesenchymal stem cell and osteoprogenitor cell homing both locally and systemically, genetic engineering of specialized stem cells, and the use of potentially immune-privileged fetal and other types of stem cells. Some of these techniques have already been introduced into the orthopaedic clinic, whereas others are still in the pre-clinical testing phase. Given the limited supply of autologous graft, these new techniques will have a dramatic impact on bone regeneration in the future.

  View details for PubMedID 24436510

  View details for PubMedCentralID PMC3891509

• Cell-based therapies for regenerating bone MINERVA ORTOPEDICA E TRAUMATOLOGICA Goodman, S. B. 2013; 64 (2): 107-113

  Abstract

  Cellular therapies to replenish bone lost due to acquired conditions such as trauma, infection, tumor, periprosthetic osteolysis and other etiologies have become widespread. Traditional, open, surgical bone grafting techniques have given way to newer cellular therapies that are potentially less invasive and have a lower complication rate and faster recovery time. These new technologies include bone marrow harvesting with concentration of osteoprogenitor cells with/without cell culture, scaffolds which are both osteoconductive and osteoinductive, attempts to facilitate mesenchymal stem cell and osteoprogenitor cell homing both locally and systemically, genetic engineering of specialized stem cells, and the use of potentially immune-privileged fetal and other types of stem cells. Some of these techniques have already been introduced into the orthopaedic clinic, whereas others are still in the pre-clinical testing phase. Given the limited supply of autologous graft, these new techniques will have a dramatic impact on bone regeneration in the future.

  View details for Web of Science ID 000320747000002

  View details for PubMedCentralID PMC3891509

• Particle disease: Biologic mechanisms of periprosthetic osteolysis in total hip arthroplasty INNATE IMMUNITY Gallo, J., Goodman, S. B., Konttinen, Y. T., Raska, M. 2013; 19 (2): 213-224

  Abstract

  Numerous studies provide detailed insight into the triggering and amplification mechanisms of the inflammatory response associated with prosthetic wear particles, promoting final dominance of bone resorption over bone formation in multiple bone multicellular units around an implant. In fact, inflammation is a highly regulated process tightly linked to simultaneous stimulation of tissue protective and regenerative mechanisms in order to prevent collateral damage of periprosthetic tissues. A variety of cytokines, chemokines, hormones and specific cell populations, including macrophages, dendritic and stem cells, attempt to balance tissue architecture and minimize inflammation. Based on this fact, we postulate that the local tissue homeostatic mechanisms more effectively regulate the pro-inflammatory/pro-osteolytic cells/pathways in patients with none/mild periprosthetic osteolysis (PPOL) than in patients with severe PPOL. In this line of thinking, 'particle disease theory' can be understood, at least partially, in terms of the failure of local tissue homeostatic mechanisms. As a result, we envision focusing current research on homeostatic mechanisms in addition to traditional efforts to elucidate details of pro-inflammatory/pro-osteolytic pathways. We believe this approach could open new avenues for research and potential therapeutic strategies.

  View details for DOI 10.1177/1753425912451779

  View details for Web of Science ID 000317721600011

  View details for PubMedID 22751380

  View details for PubMedCentralID PMC3712274

• Papers Presented at the Annual Meetings of The Hip Society 2012: Editorial Comment CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B. 2013; 471 (2): 375-376

  View details for DOI 10.1007/s11999-012-2648-1

  View details for Web of Science ID 000313798500007

  View details for PubMedID 23070663

  View details for PubMedCentralID PMC3549189

• Effects of sclerostin antibody on healing of a non-critical size femoral bone defect JOURNAL OF ORTHOPAEDIC RESEARCH Jawad, M. U., Fritton, K. E., Ma, T., Ren, P., Goodman, S. B., Ke, H. Z., Babij, P., Genovese, M. C. 2013; 31 (1): 155-163

  Abstract

  Sclerostin is a glycoprotein secreted by osteocytes and inhibits osteoblastogenesis via inhibition of Wnt signaling. We hypothesized that sclerostin antibody (Scl-AbIII) would accelerate the healing of a murine femoral non-critical size bone defect model. A unilateral and unicortical 0.8 mm-sized drill hole was made in the proximal femoral shaft of adult female nude mice. One group of mice received subcutaneous injections of Scl-AbIII and a second group received vehicle only. Reporter MC3T3 osteoprogenitor cells were injected via the tail vein 3 days after surgery to monitor systemic trafficking of exogenous osteoprogenitors. Bioluminescence imaging (BLI), microcomputed tomography (microCT), micropositron emission tomography (microPET) and histological analysis were used to compare the bone healing responses to Scl-AbIII treatment. Bone mineral density (BMD) significantly increased at the defect site after week 1, and was significantly higher in the treatment compared with the control group at all time points. This finding was also confirmed on histological analysis by increased deposition of new woven bone. MicroPET scanning showed a trend for greater activity in the control group at day 21 compared with the Scl-AbIII group, indicating early bone maturation following treatment with Scl-AbIII. Whereas the BLI signals derived from the injected osteoprogenitor cells showed no differences between vehicle and Scl-AbIII treated groups, systemic migration of MC3T3 cells to the bone defect was clearly identified in both groups using immunohistochemistry. Systemic administration of Scl-AbIII resulted in earlier healing and maturation of a non-critical size bone defect. These findings underscore the potential use of Scl-AbIII for treatment of complicated fractures, non-unions, and other clinical scenarios.

  View details for DOI 10.1002/jor.22186

  View details for PubMedID 22887736

• The Cycle of Comorbidities Potential Risks With Delayed Joint Replacement ORTHOPAEDIC NURSING Camillo, P., Thompson, P., Goodman, S. B., Jiang, Y. 2013; 32 (1): 6-13

  Abstract

  Joint replacement is an option that has demonstrated significant improvement in the quality of life for individuals with severe arthritis. However, it is often delayed either in an attempt to avoid future revision surgeries or for other personal reasons. Increasing disability leads to inactivity, chronic pain, and sleep disruption, each of which cycles into significant comorbid risks, many of which are life-threatening. A beginning conceptual framework identified as the cycle of comorbidities is presented to identify these risks and help guide both the patient and the provider in the decision-making process associated with joint replacement surgery.

  View details for DOI 10.1097/NOR.0b013e31827d96be

  View details for PubMedID 23344483

• The basic science of periprosthetic osteolysis. Instructional course lectures Goodman, S. B., Gibon, E., Yao, Z. 2013; 62: 201-206

  Abstract

  Total joint arthroplasty has revolutionized the treatment of arthritic and degenerative conditions for many joints in the body; however, wear debris is continuously generated with day-to-day use of an artificial joint. Excessive production of wear by-products induces a foreign body and chronic inflammatory reaction that accelerates periprosthetic bone destruction and inhibits bone formation. The specific biologic reaction is dependent on the type, amount, and characteristics of the by-products of wear, along with individual genetic variations. For polymeric and ceramic particles, the inflammatory reaction is generally nonspecific and nonimmune; however, with metallic by-products, a type IV, T lymphocyte-mediated, antigen-dependent immune reaction can occur in some patients. The production of proinflammatory cytokines, chemokines, reactive oxygen species, and other mediators is upregulated by wear particles. Animal models have shown that the biologic reaction to wear particles is systemic in nature, not a localized event. Mechanical stimuli and the presence of endotoxin also appear to be important. Efficacious biologic treatments of periprosthetic osteolysis are not yet available. Research continues with the hope that viable strategies for preventing and treating particle-induced osteolysis will be introduced in the future, thus mitigating the need for revision surgery.

  View details for PubMedID 23395025

• CORR Insights: Do Patients Lose Weight After Joint Arthroplasty Surgery? A Systematic Review CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B. 2013; 471 (1): 299-300

  Abstract

  This CORR Insights™ is a commentary on the article "Do Patients Lose Weight After Joint Arthroplasty Surgery? A Systematic Review" by Inacio and colleagues available at DOI 10.1007/s11999-012-2537-7 .

  View details for DOI 10.1007/s11999-012-2538-6

  View details for PubMedID 22956234

• Role of direct estrogen receptor signaling in wear particle-induced osteolysis BIOMATERIALS Nich, C., Rao, A. J., Valladares, R. D., Li, C., Christman, J. E., Antonios, J. K., Yao, Z., Zwingenberger, S., Petite, H., Hamadouche, M., Goodman, S. B. 2013; 34 (3): 641-650

  Abstract

  Estrogen withdrawal following surgical ovariectomy was recently shown to mitigate particle-induced osteolysis in the murine calvarial model. Currently, we hypothesize that estrogen receptors (ERs) were involved in this paradoxical phenomenon. To test this hypothesis, we first evaluated polyethylene (PE) particle-induced osteolysis in the murine calvarial model, using wild type (WT) C57BL6J female mice, ERα deficient (ERαKO) mice, and WT mice either treated with 17β-estradiol (E2) or with the ER pan-antagonist ICI 182,780. According to micro-CT and histomorphometry, we showed that bone resorption was consistently altered in both ERαKO and ICI 182,780 treated mice as compared to WT and E2 groups. Then, we demonstrated that ER disruption consistently decreased both PE and polymethylmethacrylate (PMMA) particle-induced production of TNF-α by murine macrophages in vitro. Similar results were obtained following ER blockade using ICI 182,780 in RAW 264.7 and WT macrophages. ER disruption and pre treatment with ICI 182,780 resulted in a consistent down-regulation of particle-induced TNF-α mRNA expression relative to WT macrophages or untreated RAW cells. These results indicate that the response to wear particles involves estrogen receptors in female mice, as part of macrophage activation. Estrogen receptors may be considered as a future therapeutic target for particle-induced osteolysis.

  View details for DOI 10.1016/j.biomaterials.2012.10.030

  View details for PubMedID 23113918

• Exogenous MC3T3 Preosteoblasts Migrate Systemically and Mitigate the Adverse Effects of Wear Particles TISSUE ENGINEERING PART A Fritton, K., Ren, P., Gibon, E., Rao, A. J., Ma, T., Biswal, S., Gambhir, S. S., Goodman, S. B. 2012; 18 (23-24): 2559-2567

  Abstract

  Understanding how relevant cell types respond to wear particles will reveal new avenues for treating osteolysis following joint replacements. In this study, we investigate the effects of ultrahigh molecular weight polyethylene (UHMWPE) particles on preosteoblast migration and function. We infused UHMWPE particles or saline into the left femur of mice and injected luciferase-expressing preosteoblasts (MC3T3 cells) into each left ventricle. Bioluminescence imaging (BLI) confirmed systemic administration of MC3T3 cells. BLI throughout the 28-day experiment showed greater MC3T3 migration to the site of particle infusion than to the site of saline infusion, with significant differences on days 0, 4, and 6 (p≤0.055). Immunostaining revealed a greater number of osteoblasts and osteoclasts in the particle-infused femora, indicating greater bone turnover. The bone mineralization of the particle-infused femora increased significantly when compared to saline-infused femora (an increase of 146.4±27.9 vs. 12.8±8.7 mg/mL, p=0.008). These results show that infused preosteoblasts can migrate to the site of wear particles. Additionally, as the migrated cells were associated with increased bone mineralization in spite of the presence of particles, increasing osteoblast recruitment is a potential strategy for combating bone loss due to increased osteoclast/macrophage number and decreased osteoblast function.

  View details for DOI 10.1089/ten.tea.2012.0086

  View details for PubMedID 22741555

• MI TKA: a risk factor for early revision surgery. The journal of knee surgery Mayle, R. E., Graw, B. P., Huddleston, H. G., Woolson, S. T., Goodman, S. B., Huddleston, J. I. 2012; 25 (5): 423-427

  Abstract

  Minimal incision total knee arthroplasty (MI TKA) was developed with the potential to decrease surgical trauma, pain, and recovery time. While this procedure has increased in popularity, some surgeons have questioned its safety and long-term efficacy. In this study 58 consecutive revision total knee arthroplasties (TKAs) (57 patients) performed at one academic medical center from 2006 to 2008 are reviewed. Prospectively collected clinical and radiographic data included: incision length, gender, age, time to revision surgery, and primary diagnosis at time of revision. Of these, 34 knees involving infection and rerevision were excluded. Of the remaining 24 knees, 11 knees that met inclusion criteria had undergone MI TKA. There were no differences between the groups with regard to age, diagnosis, body mass index, and gender. Average time to revision was shorter for the MI TKA patients (29 vs. 65 months, p < 0.032, odds ratio 14.7). Reasons for revision were aseptic loosening (55%), pain/stiffness (27%), malrotation (9%), and instability (9%) in the MI TKA group and aseptic loosening (53%), instability (15%), pain/stiffness (8%), malrotation (8%), combined malrotation and instability (8%), and polyethylene wear/osteolysis (8%) in the traditional TKA group. These data suggest that MI TKA may be a risk factor for early revision.

  View details for DOI 10.1055/s-0032-1313757

  View details for PubMedID 23150354

• MI TKA: A Risk Factor for Early Revision Surgery JOURNAL OF KNEE SURGERY Mayle, R. E., Graw, B. P., Huddleston, H. G., Woolson, S. T., Goodman, S. B., Huddleston, J. I. 2012; 25 (5): 423-427

  Abstract

  Minimal incision total knee arthroplasty (MI TKA) was developed with the potential to decrease surgical trauma, pain, and recovery time. While this procedure has increased in popularity, some surgeons have questioned its safety and long-term efficacy. In this study 58 consecutive revision total knee arthroplasties (TKAs) (57 patients) performed at one academic medical center from 2006 to 2008 are reviewed. Prospectively collected clinical and radiographic data included: incision length, gender, age, time to revision surgery, and primary diagnosis at time of revision. Of these, 34 knees involving infection and rerevision were excluded. Of the remaining 24 knees, 11 knees that met inclusion criteria had undergone MI TKA. There were no differences between the groups with regard to age, diagnosis, body mass index, and gender. Average time to revision was shorter for the MI TKA patients (29 vs. 65 months, p < 0.032, odds ratio 14.7). Reasons for revision were aseptic loosening (55%), pain/stiffness (27%), malrotation (9%), and instability (9%) in the MI TKA group and aseptic loosening (53%), instability (15%), pain/stiffness (8%), malrotation (8%), combined malrotation and instability (8%), and polyethylene wear/osteolysis (8%) in the traditional TKA group. These data suggest that MI TKA may be a risk factor for early revision.

  View details for DOI 10.1055/s-0032-1313757

  View details for Web of Science ID 000209168300012

• A Pilot Cohort Study of the Determinants of Longitudinal Opioid Use After Surgery ANESTHESIA AND ANALGESIA Carroll, I., Barelka, P., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F., Whyte, R. I., Donington, J. S., Cannon, W. B., Mackey, S. C. 2012; 115 (3): 694-702

  Abstract

  Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery.Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done.Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self-perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%-87%) reduction in the rate of opioid cessation after surgery (P = 0.0009). Additionally, each 1-point increase (on a 4-point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%-71%) reduction in the rate of opioid cessation (P = 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%-58%) reduction in the rate of opioid cessation (P = 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity.Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity.

  View details for DOI 10.1213/ANE.0b013e31825c049f

  View details for PubMedID 22729963

• Advanced Age and Comorbidity Increase the Risk for Adverse Events After Revision Total Hip Arthroplasty JOURNAL OF ARTHROPLASTY Koenig, K., Huddleston, J. I., Huddleston, H., Maloney, W. J., Goodman, S. B. 2012; 27 (7): 1402-1407

  Abstract

  With the institution of quality-assurance parameters in health care, physicians must accurately measure and report the true baseline rates of adverse events (AEs) after complex surgical interventions. To better quantify the risk of AEs for revision total hip arthroplasty (THA), we divided a cohort of 306 patients (322 procedures) into age groups: group I (<65 years, n = 138), group II (65-79 years, n = 119), and group III (≥80 years, n = 65). Ninety-day rates of major AE were 9%, 19%, and 34% in the groups, respectively. Group III had an increased chance of experiencing major AE compared with groups I and II. Age and Charlson Comorbidity Index independently predicted major complications, whereas body mass index, sex, and type of revision did not.

  View details for DOI 10.1016/j.arth.2011.11.013

  View details for PubMedID 22245123

• Revision joint replacement, wear particles, and macrophage polarization ACTA BIOMATERIALIA Rao, A. J., Gibon, E., Ma, T., Yao, Z., Smith, R. L., Goodman, S. B. 2012; 8 (7): 2815-2823

  Abstract

  Currently, younger, more active patients are being offered total joint replacement (TJR) for end-stage arthritic disorders. Despite improved durability of TJRs, particle-associated wear of the bearing surfaces continues to be associated with particulate debris, which can activate monocyte/macrophages. Activated macrophages then produce pro-inflammatory factors and cytokines that induce an inflammatory reaction that activates osteoclasts leading to bone breakdown and aseptic loosening. We hypothesized that activated macrophages in tissues harvested from revised joint replacements predominantly express an M1 pro-inflammatory phenotype due to wear-particle-associated cell activation, rather than an M2 anti-inflammatory phenotype. We further questioned whether it is possible to convert uncommitted monocyte/macrophages to an M2 phenotype by the addition of interleukin-4 (IL-4), or whether it is necessary to first pass through an M1 intermediate stage. Retrieved periprosthetic tissues demonstrated increased M1/M2 macrophage ratios compared to non-operated osteoarthritic synovial tissues, using immunohistochemical staining and Western blotting. Uncommitted monocyte/macrophages with/without polymethyl-methacrylate particles were transformed to an M2 phenotype by IL-4 more efficiently when the cells were first passed through an M1 phenotype by exposure to endotoxin. Wear particles induce a pro-inflammatory microenvironment that facilitates osteolysis; these events may potentially be modulated favorably by exposure to IL-4.

  View details for DOI 10.1016/j.actbio.2012.03.042

  View details for PubMedID 22484696

• Effect of a CCR1 receptor antagonist on systemic trafficking of MSCs and polyethylene particle-associated bone loss BIOMATERIALS Gibon, E., Yao, Z., Rao, A. J., Zwingenberger, S., Batke, B., Valladares, R., Smith, R. L., Biswal, S., Gambhir, S. S., Goodman, S. B. 2012; 33 (14): 3632-3638

  Abstract

  Particle-associated periprosthetic osteolysis remains a major issue in joint replacement. Ongoing bone loss resulting from wear particle-induced inflammation is accompanied by continued attempts at bone repair. Previously we showed that mesenchymal stem cells (MSCs) are recruited systemically to bone exposed to continuous infusion of ultra high molecular weight polyethylene (UHMWPE) particles. The chemokine-receptor axis that mediates this process is unknown. We tested two hypotheses: (1) the CCR1 receptor mediates the systemic recruitment of MSCs to UHMWPE particles and (2) recruited MSCs are able to differentiate into functional mature osteoblasts and decrease particle-associated bone loss. Nude mice were allocated randomly to four groups. UHMWPE particles were continuously infused into the femoral shaft using a micro-pump. Genetically modified murine wild type reporter MSCs were injected systemically via the left ventricle. Non-invasive imaging was used to assay MSC migration and bone mineral density. Bioluminescence and immunohistochemistry confirmed the chemotaxis of reporter cells and their differentiation into mature osteoblasts in the presence of infused particles. Injection of a CCR1 antagonist decreased reporter cell recruitment to the UHMWPE particle infusion site and increased osteolysis. CCR1 appears to be a critical receptor for chemotaxis of MSCs in the presence of UHMWPE particles. Interference with CCR1 exacerbates particle-induced bone loss.

  View details for DOI 10.1016/j.biomaterials.2012.02.003

  View details for PubMedID 22364730

• Macrophage polarization: An opportunity for improved outcomes in and regenerative medicine BIOMATERIALS Brown, B. N., Ratner, B. D., Goodman, S. B., Amar, S., Badylak, S. F. 2012; 33 (15): 3792-3802

  Abstract

  The host response to biomaterials has been studied for decades. Largely, the interaction of host immune cells, macrophages in particular, with implanted materials has been considered to be a precursor to granulation tissue formation, the classic foreign body reaction, and eventual encapsulation with associated negative impacts upon device functionality. However, more recently, it has been shown that macrophages, depending upon context dependent polarization profiles, are capable of affecting both detrimental and beneficial outcomes in a number of disease processes and in tissue remodeling following injury. Herein, the diverse roles played by macrophages in these processes are discussed in addition to the potential manipulation of macrophage effector mechanisms as a strategy for promoting site-appropriate and constructive tissue remodeling as opposed to deleterious persistent inflammation and scar tissue formation.

  View details for DOI 10.1016/j.biomaterials.2012.02.034

  View details for Web of Science ID 000303273200002

  View details for PubMedID 22386919

• MC3T3-E1 Osteoprogenitor Cells Systemically Migrate to a Bone Defect and Enhance Bone Healing TISSUE ENGINEERING PART A Gibon, E., Batke, B., Jawad, M. U., Fritton, K., Rao, A., Yao, Z., Biswal, S., Gambhir, S. S., Goodman, S. B. 2012; 18 (9-10): 968-973

  Abstract

  Although iliac crest autologous bone graft remains the gold standard for treatment of bone defects, delayed- and nonunions, and arthrodeses, several alternative strategies have been attempted, including the use of mesenchymal stem cells. Whether cells from the osteoblast lineage demonstrate systemic recruitment to an acute bone defect or fracture, and whether these cells directly participate in bone healing is controversial. This study tests two hypotheses: (1) that exogenous murine MC3T3-E1 osteoprogenitor cells with a high propensity for osteoblast differentiation are able to systemically migrate to a bone defect and (2) that the migrated MC3T3-E1 cells enhance bone healing. Two groups of nude mice were used; a bone defect was drilled in the left femoral shaft in both groups. MC3T3-E1 were used as reporter cells and injected in the left ventricle of the heart, to avoid sequestration in the lungs. Injection of saline served as a control. We used bioluminescence and microCT to assay cell recruitment and bone mineral density (BMD). Immunohistochemical staining was used to confirm the migration of reporter cells. MC3T3-E1 cells were found to systemically migrate to the bone defect. Further, BMD at the defect was significantly increased when cells were injected. Systemic cell therapy using osteoprogenitor cells may be a potential strategy to enhance bone healing.

  View details for DOI 10.1089/ten.tea.2011.0545

  View details for PubMedID 22129134

• American Academy of Orthopaedic Surgeons clinical practice guideline on: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. journal of bone and joint surgery. American volume Jacobs, J. J., Mont, M. A., Bozic, K. J., Della Valle, C. J., Goodman, S. B., Lewis, C. G., Yates, A. C., Boggio, L. N., Watters, W. C., Turkelson, C. M., Wies, J. L., Sluka, P., Hitchcock, K. 2012; 94 (8): 746-747

  View details for DOI 10.2106/JBJS.9408.ebo746

  View details for PubMedID 22517391

  View details for PubMedCentralID PMC3326685

• Selective inhibition of the MCP-1-CCR2 ligand-receptor axis decreases systemic trafficking of macrophages in the presence of UHMWPE particles JOURNAL OF ORTHOPAEDIC RESEARCH Gibon, E., Ma, T., Ren, P., Fritton, K., Biswal, S., Yao, Z., Smith, L., Goodman, S. B. 2012; 30 (4): 547-553

  Abstract

  The biological mechanisms leading to periprosthetic osteolysis involve both chemokines and the monocyte/macrophage cell lineage. Whether MCP-1 plays a major role in macrophage recruitment in the presence of wear particles is unknown. We tested two hypotheses: (1) that exogenous local delivery of MCP-1 induces systematic macrophage recruitment and (2) that blockade of the MCP-1 ligand-receptor axis decreases macrophage recruitment and osteolysis in the presence of ultra high molecular weight polyethylene (UHMWPE) particles. Six groups of nude mice were used. We used non-invasive imaging to assay macrophage recruitment and osteolysis. A murine macrophage cell line and primary wild type and CCR2 knockout murine macrophages were used as the reporter cells. Particles were infused into the femoral canal. Bioluminescence and immunohistochemical staining were used to confirm the migration of reporter cells. Locally infused MCP-1 induced systemic macrophage trafficking to bone. Injection of MCP-1 receptor antagonist significantly decreased reporter cell recruitment to bone infused with UHMWPE particles and decreased osteolysis. Systemic migration of reporter cells to infused particles was decreased when the reporter cells were deficient in the CCR2 receptor. Interruption of the MCP-1 ligand-receptor axis appears to be a viable strategy to mitigate trafficking of macrophages and osteolysis due to UHMWPE particles.

  View details for DOI 10.1002/jor.21548

  View details for PubMedID 21913218

• Cancellous Impaction Bone Grafting of Acetabular Defects in Complex Primary and Revision Total Hip Arthroplasty ORTHOPEDICS Patil, N., Hwang, K., Goodman, S. B. 2012; 35 (3): E306-E312

  Abstract

  The reconstruction of major acetabular bone defects during revision, conversion, and primary total hip arthroplasties (THAs) is challenging. We reviewed a consecutive series of 168 THAs (108 revisions, 8 conversions, and 52 primary THAs) performed by 1 surgeon (S.B.G.) between 1997 and 2008 using impaction bone grafting for acetabular reconstruction. Autograft, cancellous allograft croutons, and demineralized bone matrix were used to fill bone defects as needed. The acetabular bone deficiency was classified according to the American Academy of Orthopaedic Surgeons: type I, segmental deficiency with significant rim defect; type II, cavitary defects medially or posteriorly; type III, combined cavitary and segmental deficiency; type IV, pelvic discontinuity; and type V, arthrodesis. According to this method, 56 hips had type I, 31 hips had type II, 48 hips had type III, and 27 hips had type IV deficiencies. Of the 168 patients, 19 subsequently died of causes unrelated to the THA, and 11 were lost to follow-up. All patients had at least 2 years of follow-up. Average Harris Hip Score improved from 45.5±17.9 preoperatively to 81.1±16.5 postoperatively (P<.05) for revision THAs, from 40.0±11.3 preoperatively to 85.0±12.8 postoperatively (P<.05) for conversion THAs, and from 42.3±14.9 preoperatively to 85.0±12.0 postoperatively (P<.05) for primary THAs. All impaction grafted bone (allograft, autograft, or a combination) incorporated radiographically, thus restoring bone stock. Complications included 1 early infection, which was managed successfully with debridement and liner exchange, and 2 late infections that were managed successfully with staged revision. Two revisions required subsequent re-revision for late loosening. Two hip dislocations occurred, 1 of which required surgical treatment to place a constrained liner.

  View details for DOI 10.3928/01477447-20120222-24

  View details for Web of Science ID 000301501500002

  View details for PubMedID 22385438

• Context and Consequences of Delaying Hip Replacement Surgery: A Case Study JNP-JOURNAL FOR NURSE PRACTITIONERS Camillo, P., Goodman, S. B., Thompson, P., Imrie, S. N. 2012; 8 (3): 212-?

  View details for DOI 10.1016/j.nurpra.2011.07.029

  View details for Web of Science ID 000209401900008

• Papers Presented at the Annual Meetings of the Hip Society 2011 CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B. 2012; 470 (2): 327-328

  View details for DOI 10.1007/s11999-011-2122-5

  View details for Web of Science ID 000299056000001

  View details for PubMedID 22002825

  View details for PubMedCentralID PMC3254752

• Unexpected failure of highly cross-linked polyethylene acetabular liner. journal of arthroplasty Waewsawangwong, W., Goodman, S. B. 2012; 27 (2): 323 e1-4

  Abstract

  Highly cross-linked polyethylene (HXPE) in total hip arthroplasty has been shown to decrease wear rate compared with conventional liner. However, it has some disadvantages in that the mechanical properties cause early failure of the implant. This case report presents an unexpected failure of total hip arthroplasty in a 72-year-old woman that occurred at 20 months postsurgery. Operative findings revealed fracture of superior rim at locking groove of liner. We concluded that the failure was caused by decreased mechanical properties of highly cross-linked polyethylene, less thickness of polyethylene, more vertical cup, and use of large femoral head.

  View details for DOI 10.1016/j.arth.2011.04.010

  View details for PubMedID 21601415

• Recommendations and Considerations for the Use of Biologics in Orthopedic Surgery BIODRUGS Zwingenberger, S., Nich, C., Valladares, R. D., Yao, Z., Stiehler, M., Goodman, S. B. 2012; 26 (4): 245-256

  Abstract

  Reconstruction of extensive bone defects remains technically challenging and has considerable medical and financial impact on our society. Surgical procedures often require a bone/substitute graft to enhance and accelerate bone repair. Bone autografts are associated with morbidity related to bone harvesting and are limited in quantity. Alternatively, bone allografts expose the patient to the risk of transmission of infectious disease. Synthetic bone graft substitutes, such as calcium sulfates, hydroxyapatite, tricalcium phosphate, and combinations, circumvent some of the disadvantages of auto- and allografts, but have limited indications. Biomedical research has made possible the stimulation of the body's own healing mechanisms, either by delivering exogenous growth factors locally, or by stimulating their local production by gene transfer. Among all known factors having osteoinductive properties, only two bone morphogenetic proteins (for specific indications) and demineralized bone matrix have been approved for clinical use. In addition, ongoing research is exploring the efficacy of cell therapy and tissue engineering. The present report examines the composition, biological properties, indications, clinical experience and regulations of several of the biotherapeutics employed for bone reconstruction.

  View details for PubMedID 22671767

• Advantages and disadvantages of ceramic on ceramic total hip arthroplasty: A review BIOMEDICAL PAPERS-OLOMOUC Gallo, J., Goodman, S. B., Lostak, J., Janout, M. 2012; 156 (3): 204-212

  Abstract

  Ceramic on ceramic (COC) total hip arthroplasty (THA) was developed to reduce wear debris and accordingly, the occurrence of osteolysis and aseptic loosening especially in younger patients. Based on the excellent tribological behavior of current COC bearings and the relatively low biological activity of ceramic particles, significant improvement in survivorship of these implants is expected.We used manual search to identify all relevant studies reporting clinical data on COC THAs in PubMed. The objective was to determine whether current COC THA offers a better clinical outcome and survivorship than non-COC THA.Studies with early generation ceramic bearings yielded 68% to 84% mean survivorship at 20 years follow-up which is comparable with the survivorship of non-COC THAs. Studies on current ceramic bearings report a 10-year revision-free interval of 92% to 99%. These outcomes are comparable to the survivorship of the best non-COC THAs. However, there are still concerns regarding fracture of sandwich ceramic liners, squeaking, and impingement of the femoral neck on the rim of the ceramic liner leading to chipping, especially in younger and physically active patients.Current COC THA leads to equivalent but not improved survivorship at 10 years follow-up in comparison to the best non-COC THA. Based on this review, we recommend that surgeons weigh the potential advantages and disadvantages of current COC THA in comparison to other bearing surfaces when considering young very active patients who are candidates for THA.

  View details for DOI 10.5507/bp.2012.063

  View details for Web of Science ID 000310725900003

  View details for PubMedID 23069885

• Successful closed reduction of a dislocated constrained total hip arthroplasty: a case report and literature review. The open orthopaedics journal Sonohata, M., Waewsawangwong, W., Goodman, S. B. 2012; 6: 211-214

  Abstract

  Many surgeons use acetabular components with constrained polyethylene liners to improve stability after total hip arthroplasty in patients with a history of hip dislocation. Surgical treatment is generally thought to be the only available option for the dislocated constrained liner. The success rate and clinical results of closed reduction for such patients is unclear. This report presents a case of a successful closed reduction of a dislocated constrained liner. Few papers have so far addressed closed reduction of a dislocated constrained liner. Furthermore, previous studies reported a variety of components. Publication of additional successful and unsuccessful case reports is therefore needed to help establish the optimal treatment protocol for a dislocated constrained liner.

  View details for DOI 10.2174/1874325001206010211

  View details for PubMedID 22675412

• Identification of a central role for complement in osteoarthritis NATURE MEDICINE Wang, Q., Rozelle, A. L., Lepus, C. M., Scanzello, C. R., Song, J. J., Larsen, D. M., Crish, J. F., Bebek, G., Ritter, S. Y., Lindstrom, T. M., Hwang, I., Wong, H. H., Punzi, L., Encarnacion, A., Shamloo, M., Goodman, S. B., Wyss-Coray, T., Goldring, S. R., Banda, N. K., Thurman, J. M., Gobezie, R., Crow, M. K., Holers, V. M., Lee, D. M., Robinson, W. H. 2011; 17 (12): 1674-U196

  Abstract

  Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.

  View details for DOI 10.1038/nm.2543

  View details for Web of Science ID 000297978000042

  View details for PubMedID 22057346

  View details for PubMedCentralID PMC3257059

• Outcome of Primary Total Hip Arthroplasty in Charnley Class C Patients with Juvenile Idiopathic Arthritis A Case Series JOURNAL OF ARTHROPLASTY De Ranieri, A., Wagner, N., Imrie, S. N., Hwang, K. L., Goodman, S. B. 2011; 26 (8): 1182-1188

  Abstract

  The outcome and complications of 37 primary total hip arthroplasties by one surgeon in 24 patients with Charnley Class C juvenile idiopathic arthritis with up to 19.6 years follow-up are reported. Twenty-six femoral components were cementless; all acetabular components were cementless with screws. Age at operation averaged 22.6 years. Two patients (3 hips) have died. Twelve hips in 9 patients have failed. Six cementless acetabular components with conventional polyethylene were revised because of osteolysis after 5.5 to 14.5 years. All 3 cementless C2 femoral stems with minimal porous coating failed. One of eight cemented AML Bantam stems loosened at 3.5 years; 2 of 23 cementless AML Bantam stems loosened at 9.5 and 19.6 years. Pain relief and functional improvement are dramatic after total hip arthroplasty in juvenile idiopathic arthritis; however, the long-term outcome is guarded.

  View details for DOI 10.1016/j.arth.2010.10.003

  View details for PubMedID 21167675

• Preventing Venous Thromboembolic Disease in Patients Undergoing Elective Hip and Knee Arthroplasty JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS Mont, M. A., Jacobs, J. J., Boggio, L. N., Bozic, K. J., Della Valle, C. J., Goodman, S. B., Lewis, C. G., Yates, A. J., Watters, W. C., Turkelson, C. M., Wies, J. L., Donnelly, P., Patel, N., Sluka, P. 2011; 19 (12): 768-776

  Abstract

  This guideline supersedes a prior one from 2007 on a similar topic. The work group evaluated the available literature concerning various aspects of patient screening, risk factor assessment, and prophylactic treatment against venous thromboembolic disease (VTED), as well as the use of postoperative mobilization, neuraxial agents, and vena cava filters. The group recommended further assessment of patients who have had a previous venous thromboembolism but not for other potential risk factors. Patients should be assessed for known bleeding disorders, such as hemophilia, and for the presence of active liver disease. Patients who are not at elevated risk of VTED or for bleeding should receive pharmacologic prophylaxis and mechanical compressive devices for the prevention of VTED. The group did not recommend specific pharmacologic agents and/or mechanical devices. The work group recommends, by consensus opinion, early mobilization for patients following elective hip and knee arthroplasty. The use of neuraxial anesthesia can help limit blood loss but was not found to affect the occurrence of VTED. No clear evidence was established regarding whether inferior vena cava filters can prevent pulmonary embolism in patients who have a contraindication to chemoprophylaxis and/or known VTED.

  View details for Web of Science ID 000297563900007

  View details for PubMedID 22134209

• Prospective, Randomized Study Between Insall-Burstein II and NexGen Legacy with a Minimum 9-Year Follow-Up JOURNAL OF ARTHROPLASTY Oh, K., Goodman, S. B., Yang, J. 2011; 26 (8): 1232-1238

  Abstract

  A randomized, prospective, comparative study was performed in 2 related, adjacent generation posterior stabilized total knee prostheses, to evaluate whether the newer design improved the clinical and radiographic outcome for treatment of advanced osteoarthritis of the knee. Ninety one total knee arthroplasties in 84 patients (45 Insall-Burstein II and 46 NexGen Legacy posterior stabilized [both from Zimmer, Warsaw, Ind] prostheses) with an average of 10.3 years of follow-up (range, 9-11.8 years) were included. The preoperative diagnoses were primary osteoarthritis in all patients. At the latest evaluation, there were no significant differences detected in the mean clinical and functional knee scores, average postoperative active range of motion, and anterior knee pain between the Insall-Burstein II and the NexGen Legacy groups postoperatively.

  View details for DOI 10.1016/j.arth.2010.12.018

  View details for Web of Science ID 000297389100020

  View details for PubMedID 21295941

• Molecular profile of osteoprogenitor cells seeded on allograft bone JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE Smith, K. E., Huang, Z., Ma, T., Irani, A., Smith, R. L., Goodman, S. B. 2011; 5 (9): 704-711

  Abstract

  In order to optimize and modulate bone formation it is essential to understand the expression patterns of key bone-specific growth factors, as osteoprogenitor cells undergo the processes of proliferation, differentiation and maturation. This study reports the sequential expression of bone-related growth and transcription factors when bone marrow-derived osteoprogenitor cells from C57BL mice were cultured on allograft bone discs. Mineralization and osteocalcin protein levels were used to track osteogenic differentiation and maturation. Bone-related growth factors, such as Bmp-2, Bmp-7, Ctnnb-1, Fgf-2, Igf-1, Vegf-a and Tgf-β1, and transcription factors, such as Runx-2 and osteocalcin, were examined by enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR). Total density of mineralized bone was significantly increased 7.6 ± 0.7% in allografts cultured with cells, compared with a 0.5 ± 2.0% increase in the controls without cells (p < 0.01). Osteocalcin protein levels peaked at day 4. Protein expression showed peaks of BMP-2 and TGF-β1 on day 2, with VEGF peaking on day 8, and IGF-1 decreasing on day 2. mRNA for Pdgf-a peaked on day 2; Bmp-2 on days 4 and 16; Ctnnb-1 on days 8 and 20; Vegf-a, Fgf-2, Runx-2 and Igf-1 on day 12; Tgf-β1 on day 16; and Pdgf-b on day 20. Osteogenic growth factors correlated with Runx-2 and Ctnnb-1, whereas a predominant vascular growth factor, Vegf-a, did not follow this pattern. Specific bone-related genes and proteins were expressed in a time-dependent manner when osteoprogenitor cells were cultured on cortico-cancellous bone discs in vitro.

  View details for DOI 10.1002/term.367

  View details for PubMedID 21953868

• Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis JOURNAL OF CLINICAL INVESTIGATION Song, J. J., Hwang, I., Cho, K. H., Garcia, M. A., Kim, A. J., Wang, T. H., Lindstrom, T. M., Lee, A. T., Nishimura, T., Zhao, L., Morser, J., Nesheim, M., Goodman, S. B., Lee, D. M., Bridges, S. L., Gregersen, P. K., Leung, L. L., Robinson, W. H. 2011; 121 (9): 3517-3527

  Abstract

  The immune and coagulation systems are both implicated in the pathogenesis of rheumatoid arthritis (RA). Plasma carboxypeptidase B (CPB), which is activated by the thrombin/thrombomodulin complex, plays a procoagulant role during fibrin clot formation. However, an antiinflammatory role for CPB is suggested by the recent observation that CPB can cleave proinflammatory mediators, such as C5a, bradykinin, and osteopontin. Here, we show that CPB plays a central role in downregulating C5a-mediated inflammatory responses in autoimmune arthritis. CPB deficiency exacerbated inflammatory arthritis in a mouse model of RA, and cleavage of C5a by CPB suppressed the ability of C5a to recruit immune cells in vivo. In human patients with RA, genotyping of nonsynonymous SNPs in the CPB-encoding gene revealed that the allele encoding a CPB variant with longer half-life was associated with a lower risk of developing radiographically severe RA. Functionally, this CPB variant was more effective at abrogating the proinflammatory properties of C5a. Additionally, expression of both CPB and C5a in synovial fluid was higher in patients with RA than in those with osteoarthritis. These findings suggest that CPB plays a critical role in dampening local, C5a-mediated inflammation and represents a molecular link between inflammation and coagulation in autoimmune arthritis.

  View details for DOI 10.1172/JCI46387

  View details for PubMedID 21804193

• Role of the Toll-like receptor pathway in the recognition of orthopedic implant wear-debris particles BIOMATERIALS Pearl, J. I., Ma, T., Irani, A. R., Huang, Z., Robinson, W. H., Smith, R. L., Goodman, S. B. 2011; 32 (24): 5535-5542

  Abstract

  The inflammatory response to prosthetic implant-derived wear particles is the primary cause of bone loss and aseptic loosening of implants, but the mechanisms by which macrophages recognize and respond to particles remain unknown. Studies of innate immunity demonstrate that Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS). All TLRs signal through myeloid differentiation factor 88 (MyD88), except TLR3 which signals through TIR domain containing adapter inducing interferon-beta (TRIF), and TLR4 which signals through both MyD88 and TRIF. We hypothesized that wear-debris particles may act as PAMPs/DAMPs and activate macrophages via TLRs. To test this hypothesis, we first demonstrated that inhibition of MyD88 decreases polymethylmethacrylate (PMMA) particle-induced production of TNF-α in RAW 264.7 macrophages. Next we compared particle-induced production of TNF-α among MyD88 knockout (MyD88(-/-)), TRIF knockout (TRIF(-/-)), and wild type (WT) murine macrophages. Relative to WT, disruption of MyD88 signaling diminished, and disruption of TRIF amplified the particle-induced production of TNF-α. Gene expression data indicated that this latter increase in TNF-α was due to a compensatory increase in expression of MyD88 associated components of the TLR pathway. Finally, using an in vivo model, MyD88(-/-) mice developed less particle-induced osteolysis than WT mice. These results indicate that the response to PMMA particles is partly dependent on MyD88, presumably as part of TLR signaling; MyD88 may represent a therapeutic target for prevention of wear debris-induced periprosthetic osteolysis.

  View details for DOI 10.1016/j.biomaterials.2011.04.046

  View details for PubMedID 21592562

• Toll-Like Receptors and Their Adaptors are Regulated in Macrophages after Phagocytosis of Lipopolysaccharide-Coated Titanium Particles JOURNAL OF ORTHOPAEDIC RESEARCH Hirayama, T., Tamaki, Y., Takakubo, Y., Iwazaki, K., Sasaki, K., Ogino, T., Goodman, S. B., Konttinen, Y. T., Takagi, M. 2011; 29 (7): 984-992

  Abstract

  Macrophages phagocytose metallic wear particles and produce mediators, which can induce cellular host response and aseptic implant loosening. Lipopolysaccharide (LPS) on the wear debris can stimulate macrophages via Toll-like receptor 4 (TLR4) and enhance the response. However, the precise functional role and interaction of TLRs and their adaptor molecules is still unclear. Rat bone marrow macrophages were stimulated with titanium particle (Ti) coated by LPS (Ti/LPS+) and LPS-free Ti (Ti/LPS-). mRNA levels of cytokines, TLRs and their adaptor molecules were measured using real time PCR. mRNA levels of TNF-α, IL-1β, and IL-6 increased in Ti/LPS+ than Ti/LPS-. In contrast, mRNA levels of TLR4, TLR5, and TLR9 decreased in Ti/LPS+ compared to Ti/LPS-. mRNA levels of MyD88, IRAK1, IRAK4 decreased gradually, and TRAF6 underwent an initial transient increase, followed by suppression in Ti/LPS+. However, mRNA levels of TLR2 and IRAK2 increased after phagocytosis of Ti/LPS+ than Ti/LPS-. The increased expressions of proinflammatory cytokines found in Ti/LPS+ indicated that their productions cytokines could be enhanced by phagocytosis of LPS-coated particles. Subsequent down-regulation of TLR4, TLR5, TLR9, MyD88, IRAK1, and IRAK4 suggests that self-protective mechanisms to regulate excessive host responses are activated in macrophages. Increase of TLR2 and IRAK2 and a transient increase of TRAF6 in Ti/LPS+ suggest that another possible pathway to modulate TLR-mediated cellular response to prolong inflammatory response in foreign body reaction of aseptic loosening. This down- and/or up-regulation of the potential TLR-mediated responses to LPS-coated particles reflects the proactive behavior of effector cells.

  View details for DOI 10.1002/jor.21369

  View details for Web of Science ID 000290632900003

  View details for PubMedID 21308757

• New MR Imaging Methods for Metallic Implants in the Knee: Artifact Correction and Clinical Impact JOURNAL OF MAGNETIC RESONANCE IMAGING Chen, C. A., Chen, W., Goodman, S. B., Hargreaves, B. A., Koch, K. M., Lu, W., Brau, A. C., Draper, C. E., Delp, S. L., Gold, G. E. 2011; 33 (5): 1121-1127

  Abstract

  To evaluate two magnetic resonance imaging (MRI) techniques, slice encoding for metal artifact correction (SEMAC) and multiacquisition variable-resonance image combination (MAVRIC), for their ability to correct for artifacts in postoperative knees with metal.A total of 25 knees were imaged in this study. Fourteen total knee replacements (TKRs) in volunteers were scanned with SEMAC, MAVRIC, and 2D fast spin-echo (FSE) to measure artifact extent and implant rotation. The ability of the sequences to measure implant rotation and dimensions was compared in a TKR knee model. Eleven patients with a variety of metallic hardware were imaged with SEMAC and FSE to compare artifact extent and subsequent patient management was recorded.SEMAC and MAVRIC significantly reduced artifact extent compared to FSE (P < 0.0001) and were similar to each other (P = 0.58), allowing accurate measurement of implant dimensions and rotation. The TKRs were properly aligned in the volunteers. Clinical imaging with SEMAC in symptomatic knees significantly reduced artifact (P < 0.05) and showed findings that were on the majority confirmed by subsequent noninvasive or invasive patient studies.SEMAC and MAVRIC correct for metal artifact, noninvasively providing high-resolution images with superb bone and soft tissue contrast.

  View details for DOI 10.1002/jmri.22534

  View details for PubMedID 21509870

• Anesthesia and Rheumatoid Arthritis REVISTA BRASILEIRA DE ANESTESIOLOGIA Vieira, E. M., Goodman, S., Tanaka, P. P. 2011; 61 (3): 367-375

  Abstract

  Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology. It is known that RA patients have a reduced life expectancy when compared with the general population. Rheumatic diseases are numerous and occur with high variability; some of them develop very rapidly while others occur chronically provoking disability throughout life. Anesthetic risks in osteoarticular disorders involve not only the mechanical deformations caused by the disease, but also the cardiovascular, respiratory, renal, and digestive systems.The purpose of this review was to stress the importance of stages in disease process that may affect anesthesia control before, during, and after surgery, highlighting the authors' experience in a retrospective review of patients with juvenile rheumatoid arthritis (JRA) undergoing placement of orthopedic prosthesis with emphasis on intubation techniques.Rheumatoid arthritis patients can present a number of complex problems for the anesthesiologist. This requires careful preoperative evaluation; anesthesia requires experience with the technique; and postoperative care should be judiciously chosen to meet the specific needs of the patient. The procedure requires effective communication among surgeon, rheumatologist and anesthesiologist so each member of the multidisciplinary team can contribute with his/her expertise in order to better benefit the patient.

  View details for Web of Science ID 000290844000013

  View details for PubMedID 21596198

• Expression of Toll-like Receptors and Their Signaling Pathways in Rheumatoid Synovitis JOURNAL OF RHEUMATOLOGY Tamaki, Y., Takakubo, Y., Hirayama, T., Konttinen, Y. T., Goodman, S. B., Yamakawa, M., Takagi, M. 2011; 38 (5): 810-820

  Abstract

  Toll-like receptors (TLR) recognizing endogenous and exogenous danger signals could play a role in rheumatoid arthritis (RA). Our aim was to describe the presence, localization, and extent of expression of TLR and their adapters.TLR 1, 2, 3, 4, 5, 6, and 9 receptors, and myeloid differentiation primary response protein 88, Toll/interleukin receptor (TIR) domain-containing adapter protein MyD88 adapter-like, and TIR domain-containing adapter-inducing interferon/TIR-containing adapter molecule-1 adapters were analyzed in RA (n = 10) and osteoarthritis (OA; n = 5) samples using real-time polymerase chain reaction (PCR). Their colocalization with cellular markers CD68, CD15, CD3, CD4, CD8, CD20, dendritic cell lysosomal-associated membrane protein (DC-LAMP), CD123, and 5B5 was analyzed in double immunofluorescence staining.In RA, ß-actin standardized messenger RNA of TLR 2, 3, and 9 (p < 0.001) were particularly high. TLR 5 and 6 were also elevated (p < 0.05), but TLR 1 and 4 and adapters did not differ between RA and OA. In double-staining, TLR and adapters were strongly labeled in myeloid and plasmacytoid dendritic cells (DC), moderately in CD68+ type A lining cells/macrophages, and weakly to moderately in 5B5+ type B lining cells/fibroblasts. CD3+/CD4+ and CD3+/CD8+ T cells and CD20+ B cells in perivenular areas and in lymphoid follicles were moderately TLR- and weakly adapter-positive. In OA, TLR and adapters were weakly immunolabeled in vascular, lining, and inflammatory cells.RA synovium showed abundant expression of TLR. RA synovitis tissue seems to be responsive to TLR ligands. DC, type A cells/macrophages, and type B cells/fibroblasts are, in that order from highest to lowest, equipped with TLR, suggesting a hierarchical responsiveness. In RA, danger-associated molecular patterns to TLR interactions may particularly drive DC to autoinflammatory and autoimmune cascades/synovitis.

  View details for DOI 10.3899/jrheum.100732

  View details for Web of Science ID 000290780700006

  View details for PubMedID 21324962

• Effects of Intermittent Hydrostatic Pressure and BMP-2 on Osteoarthritic Human Chondrocyte Metabolism In Vitro JOURNAL OF ORTHOPAEDIC RESEARCH Smith, R. L., Lindsey, D. P., Dhulipala, L., Harris, A. H., Goodman, S. B., Maloney, W. J. 2011; 29 (3): 361-368

  Abstract

  This study examined effects of intermittent hydrostatic pressure (IHP) and a chondrogenic growth factor, bone morphogenetic protein-2 (BMP-2), on anabolic, catabolic, and other metabolic markers in human osteoarthritic (OA) chondrocytes in vitro.Articular chondrocytes, isolated from femoral OA cartilage and maintained in high-density monolayer culture, were examined for effects of BMP-2 and IHP on gene expression of matrix-associated proteins (aggrecan, type II collagen, and SOX9) and catabolic matrix metalloproteinases (MMP-2 and MMP-3) and culture medium levels of the metabolic markers MMP-2, nitric oxide (NO), and glycosaminoglycan (GAG). The results were analyzed using a mixed linear regression model to investigate the effects of load and growth factor concentration.IHP and BMP-2 modulated OA chondrocyte metabolism in accordance with growth factor concentration independently, without evidence of synergism or antagonism. Each type of stimulus acted independently on anabolic matrix gene expression. Type II collagen and SOX9 gene expression were stimulated by both IHP and BMP-2 whereas aggrecan was increased only by BMP-2. IHP exhibited a trend to decrease MMP-2 gene expression as a catabolic marker whereas BMP-2 did not. NO production was increased by addition of BMP-2 and IHP exhibited a trend for increased levels. GAG production was increased by BMP-2.This study confirmed the hypothesis that human OA chondrocytes respond to a specific type of mechanical load, IHP, through enhanced articular cartilage macromolecule gene expression and that IHP, in combination with a chondrogenic growth factor BMP-2, additively enhanced matrix gene expression without interactive effects.

  View details for DOI 10.1002/jor.21250

  View details for Web of Science ID 000287173500009

  View details for PubMedID 20882590

• Papers Presented at the Hip Society Meetings 2010 Editorial Comment CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B. 2011; 469 (2): 317-318

  View details for DOI 10.1007/s11999-010-1631-y

  View details for Web of Science ID 000286939300001

  View details for PubMedID 20963529

  View details for PubMedCentralID PMC3018188

• Noninvasive Monitoring of Placenta-Specific Transgene Expression by Bioluminescence Imaging PLOS ONE Fan, X., Ren, P., Dhal, S., Bejerano, G., Goodman, S. B., Druzin, M. L., Gambhir, S. S., Nayak, N. R. 2011; 6 (1)

  Abstract

  Placental dysfunction underlies numerous complications of pregnancy. A major obstacle to understanding the roles of potential mediators of placental pathology has been the absence of suitable methods for tissue-specific gene manipulation and sensitive assays for studying gene functions in the placentas of intact animals. We describe a sensitive and noninvasive method of repetitively tracking placenta-specific gene expression throughout pregnancy using lentivirus-mediated transduction of optical reporter genes in mouse blastocysts.Zona-free blastocysts were incubated with lentivirus expressing firefly luciferase (Fluc) and Tomato fluorescent fusion protein for trophectoderm-specific infection and transplanted into day 3 pseudopregnant recipients (GD3). Animals were examined for Fluc expression by live bioluminescence imaging (BLI) at different points during pregnancy, and the placentas were examined for tomato expression in different cell types on GD18. In another set of experiments, blastocysts with maximum photon fluxes in the range of 2.0E+4 to 6.0E+4 p/s/cm(2)/sr were transferred. Fluc expression was detectable in all surrogate dams by day 5 of pregnancy by live imaging, and the signal increased dramatically thereafter each day until GD12, reaching a peak at GD16 and maintaining that level through GD18. All of the placentas, but none of the fetuses, analyzed on GD18 by BLI showed different degrees of Fluc expression. However, only placentas of dams transferred with selected blastocysts showed uniform photon distribution with no significant variability of photon intensity among placentas of the same litter. Tomato expression in the placentas was limited to only trophoblast cell lineages.These results, for the first time, demonstrate the feasibility of selecting lentivirally-transduced blastocysts for uniform gene expression in all placentas of the same litter and early detection and quantitative analysis of gene expression throughout pregnancy by live BLI. This method may be useful for a wide range of applications involving trophoblast-specific gene manipulations in utero.

  View details for DOI 10.1371/journal.pone.0016348

  View details for PubMedID 21283713

• Continuous Infusion of UHMWPE Particles Induces Increased Bone Macrophages and Osteolysis Annual Scientific Meeting of the Knee-Society Ren, P., Irani, A., Huang, Z., Ma, T., Biswal, S., Goodman, S. B. SPRINGER. 2011: 113–22

  Abstract

  Aseptic loosening and periprosthetic osteolysis resulting from wear debris are major complications of total joint arthroplasty. Monocyte/macrophages are the key cells related to osteolysis at the bone-implant interface of joint arthroplasties. Whether the monocyte/macrophages found at the implant interface in the presence of polyethylene particles are locally or systemically derived is unknown.We therefore asked (1) whether macrophages associated with polyethylene particle-induced chronic inflammation are recruited locally or systemically and (2) whether the recruited macrophages are associated with enhanced osteolysis locally.Noninvasive in vivo imaging techniques (bioluminescence and microCT) were used to investigate initial macrophage migration systemically from a remote injection site to polyethylene wear particles continuously infused into the femoral canal. We used histologic and immunohistologic staining to confirm localization of migrated macrophages to the polyethylene particle-treated femoral canals and monitor cellular markers of bone remodeling.The values for bioluminescence were increased for animals receiving UHMWPE particles compared with the group in which the carrier saline was infused. At Day 8, the ratio of bioluminescence (operated femur divided by nonoperated contralateral femur of each animal) for the UHMWPE group was 13.95 ± 5.65, whereas the ratio for the saline group was 2.60 ± 1.14. Immunohistologic analysis demonstrated the presence of reporter macrophages in the UHMWPE particle-implanted femora only. MicroCT scans showed the bone mineral density for the group with both UHMWPE particles and macrophage was lower than the control groups.Infusion of clinically relevant polyethylene particles, similar to the human scenario, stimulated systemic migration of remotely injected macrophages and local net bone resorption.

  View details for DOI 10.1007/s11999-010-1645-5

  View details for PubMedID 21042895

• Stem cell homing in musculoskeletal injury BIOMATERIALS Fong, E. L., Chan, C. K., Goodman, S. B. 2011; 32 (2): 395-409

  Abstract

  The regenerative potential of injured adult tissue suggests the physiological existence of cells capable of participating in the reparative process. Recent studies indicate that stem-like cells residing in tissues contribute to tissue repair and are replenished by precursor bone marrow-derived cells. Mesenchymal stromal cells (MSC) are among the candidates for reparative cells. These cells can potentially be mobilized into the circulation in response to injury signals and exert their reparative effects at the site of injury. Current therapies for musculoskeletal injuries pose unavoidable risks which can impede full recovery. Trafficking of MSC to the injury site and their subsequent participation in the regenerative process is thought to be a natural healing response that can be imitated or augmented by enhancing the endogenous MSC pool with exogenously administered MSC. Therefore, a promising alternative to the existing strategies employed in the treatment of musculoskeletal injuries is to reinforce the inherent reparative capacity of the body by delivering MSC harvested from the patient's own tissues to the site of injury. The aim of this review is to inform the reader of studies that have evaluated the intrinsic homing and regenerative abilities of MSC, with particular emphasis on the repair of musculoskeletal injuries. Research that supports the direct use of MSC (without in vitro differentiation into tissue-specific cells) will also be reported. Based on accruing evidence that the natural healing mechanism involves the recruitment of MSC and their subsequent reparative actions at the site of injury, as well as documented therapeutic response after the exogenous administration of MSC, the feasibility of the emerging strategy of instant stem-cell therapy will be proposed.

  View details for DOI 10.1016/j.biomaterials.2010.08.101

  View details for Web of Science ID 000285401500008

  View details for PubMedID 20933277

  View details for PubMedCentralID PMC2991369

• Use and Cost-Effectiveness of Intraoperative Acid-Fast Bacilli and Fungal Cultures in Assessing Infection of Joint Arthroplasties JOURNAL OF ARTHROPLASTY Wadey, V. M., Huddleston, J. I., Goodman, S. B., Schurman, D. J., Maloney, W. J., Baron, E. J. 2010; 25 (8): 1231-1234

  Abstract

  The objective of this study is to determine a protocol for collecting acid-fast bacilli (AFB) and fungal intraoperative cultures during orthopedic procedures. An observational study was undertaken. Four hundred forty-six AFB cultures and 486 fungal cultures were processed over a 2-year period. The number of positive cultures was determined. A protocol specific to handling these types of specimens was developed. Cost analysis was completed to determine both the time and money saved if the new protocol was implemented. The infrequency of positive AFB and fungal cultures in this study suggests that it is only necessary to routinely request AFB and fungal cultures on 1 of 5 samples. Implementation of this protocol has potential to lead to substantial cost reduction and resource savings without diminishing patient outcomes.

  View details for DOI 10.1016/j.arth.2009.08.018

  View details for Web of Science ID 000284749500009

  View details for PubMedID 19879728

• Synovial Tissue-Infiltrating Natural Killer Cells in Osteoarthritis and Periprosthetic Inflammation ARTHRITIS AND RHEUMATISM Huss, R. S., Huddleston, J. I., Goodman, S. B., Butcher, E. C., Zabel, B. A. 2010; 62 (12): 3799-3805

  Abstract

  Infiltrating immune cells play a central role in degenerative joint disease associated with osteoarthritis (OA) and particle-mediated periprosthetic osteolysis. The goal of this study was to characterize a newly identified population of synovial tissue-infiltrating natural killer (NK) cells obtained from patients with OA or patients with periprosthetic joint inflammation.Synovial and interfacial tissue samples were collected from patients with OA who were undergoing primary or revision total joint replacement (TJR) surgery. The histologic features of OA synovium obtained from patients undergoing primary surgery and interfacial tissue obtained from patients undergoing revision surgery were determined by immunohistochemistry and immunofluorescence. Synovial tissue-infiltrating NK cells were evaluated for the expression of surface receptors, using flow cytometry. Chemoattractant and cytokine protein and RNA levels in synovial and interfacial tissue and fluid were assessed by Luminex assay and real-time quantitative polymerase chain reaction. Cytokine production and degranulation by stimulated synovial tissue versus normal blood NK cells were evaluated by intracellular cytokine staining.NK cells comprised nearly 30% of the CD45+ mononuclear cell infiltrate in synovial tissue obtained from patients undergoing primary TJR and from patients undergoing revision TJR. NK cells from both groups expressed CXCR3, CCR5, L-selectin, α4 integrins, and cutaneous lymphocyte antigen. Synovial fluid from patients undergoing revision surgery contained elevated concentrations of the NK cell attractants CCL4, CCL5, CXCL9, and CXCL10; all levels in synovial fluid obtained from patients undergoing revision surgery were higher than those in synovial fluid from patients undergoing primary surgery. Cytokine-stimulated interferon-γ production was significantly impaired in NK cells derived from primary and revision TJRs compared with blood NK cells.NK cells are a principal tissue-infiltrating lymphocyte subset in patients with OA and patients with periprosthetic inflammation and display a quiescent phenotype that is consistent with postactivation exhaustion.

  View details for DOI 10.1002/art.27751

  View details for PubMedID 20848566

• Bilateral knee arthrodesis in a patient with common variable immunodeficiency. journal of arthroplasty Irani, A. R., Graw, B. P., Goodman, S. B. 2010; 25 (7): 1169 e13-6

  Abstract

  Patients with common variable immunodeficiency can present with debilitating arthritis. We present the case of a 42-year-old man with bilateral knee arthritis who underwent a right total knee arthroplasty that subsequently became infected. Five months after resection arthroplasty, his right leg spontaneously fused in extension, but his left knee was limited to an arc of motion between 90° and 110°. At the patient's request, he underwent a noninstrumented arthrodesis of the left knee. The patient now has bilateral arthrodeses and ambulates with a cane. While arthroplasty may be attempted in such patients, the increased risk of infection may potentially result in arthrodesis, possibly without instrumentation.

  View details for DOI 10.1016/j.arth.2009.07.005

  View details for PubMedID 19729268

• Effects of orthopedic polymer particles on chemotaxis of macrophages and mesenchymal stem cells. Journal of biomedical materials research. Part A Huang, Z., Ma, T., Ren, P., Smith, R. L., Goodman, S. B. 2010; 94 (4): 1264-1269

  Abstract

  Wear particles generated from total joint arthroplasty (TJA) stimulate macrophages to release chemokines. The role of chemokines released from wear particle-stimulated macrophages on the migration of macrophages and osteoprogenitor cells in vitro has not been elucidated. In this study, we challenged murine macrophages (RAW 264.7) with clinically relevant polymethyl methacrylate (PMMA, 1-10 microm) and ultra high molecular weight polyethylene (UHMWPE, 2-3 microm) particles. The chemotactic effects of the conditioned media (CM) were tested in vitro using human macrophages (THP-1) and human mesenchymal stem cells (MSCs) as the migrating cells. CM collected from both particle types had a chemotactic effect on human macrophages, which could be eliminated by monocyte chemotactic protein-1 (MCP-1) neutralizing antibody. Blocking the CCR1 receptor eliminated the chemotactic effect, while CCR2 antibody only partially decreased THP-1 cell migration. CM from PMMA but not UHMWPE-exposed macrophages led to chemotaxis of MSCs; this effect could be eliminated by macrophage inflammatory protein-1 alpha (MIP-1alpha) neutralizing antibody. Neither CCR1 nor CCR2 blocking antibodies showed an effect on the migration of MSCs. Chemokines released by macrophages stimulated by wear particles can have an effect on the migration of macrophages and MSCs. This effect seems to be dependent on the particle type, and may be modulated by MCP-1 and MIP-1alpha, however, more than one chemokine may be necessary for chemotaxis.

  View details for DOI 10.1002/jbm.a.32803

  View details for PubMedID 20694994

• Effects of orthopedic polymer particles on chemotaxis of macrophages and mesenchymal stem cells JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Huang, Z., Ma, T., Ren, P., Smith, R. L., Goodman, S. B. 2010; 94A (4): 1264-1269

  Abstract

  Wear particles generated from total joint arthroplasty (TJA) stimulate macrophages to release chemokines. The role of chemokines released from wear particle-stimulated macrophages on the migration of macrophages and osteoprogenitor cells in vitro has not been elucidated. In this study, we challenged murine macrophages (RAW 264.7) with clinically relevant polymethyl methacrylate (PMMA, 1-10 microm) and ultra high molecular weight polyethylene (UHMWPE, 2-3 microm) particles. The chemotactic effects of the conditioned media (CM) were tested in vitro using human macrophages (THP-1) and human mesenchymal stem cells (MSCs) as the migrating cells. CM collected from both particle types had a chemotactic effect on human macrophages, which could be eliminated by monocyte chemotactic protein-1 (MCP-1) neutralizing antibody. Blocking the CCR1 receptor eliminated the chemotactic effect, while CCR2 antibody only partially decreased THP-1 cell migration. CM from PMMA but not UHMWPE-exposed macrophages led to chemotaxis of MSCs; this effect could be eliminated by macrophage inflammatory protein-1 alpha (MIP-1alpha) neutralizing antibody. Neither CCR1 nor CCR2 blocking antibodies showed an effect on the migration of MSCs. Chemokines released by macrophages stimulated by wear particles can have an effect on the migration of macrophages and MSCs. This effect seems to be dependent on the particle type, and may be modulated by MCP-1 and MIP-1alpha, however, more than one chemokine may be necessary for chemotaxis.

  View details for DOI 10.1002/jbm.a.32803

  View details for Web of Science ID 000280860000029

  View details for PubMedCentralID PMC2919831

• Surveillance of systemic trafficking of macrophages induced by UHMWPE particles in nude mice by noninvasive imaging. Journal of biomedical materials research. Part A Ren, P., Huang, Z., Ma, T., Biswal, S., Smith, R. L., Goodman, S. B. 2010; 94 (3): 706-711

  Abstract

  Macrophages constitute a major part of the cell response to wear particles produced at articulating and nonarticulating interfaces of joint replacements. This foreign body reaction can result in periprosthetic osteolysis and implant loosening. We demonstrate that ultra-high molecular weight polyethylene (UHMWPE) particles induce systemic trafficking of macrophages by noninvasive in vivo imaging and immunohistochemistry. The distal femora of nude mice were injected with 60 mg/mL UHMWPE suspension or saline alone. Reporter RAW264.7 macrophages that stably expressed the bioluminescent reporter gene and the fluorescence reporter gene were injected intravenously. Bioluminescence imaging was performed using an in vivo imaging system immediately after macrophage injection and at 2-day intervals. Compared with the nonoperated contralateral femora, at day 4, 6, and 8, the bioluminescent signal of femora containing UHMWPE suspension increased 1.30 +/- 0.09-, 2.36 +/- 0.92-, and 10.32 +/- 7.61-fold, respectively. The values at same time points for saline-injected control group were 1.08 +/- 0.07-, 1.14 +/- 0.27-, and 1.14 +/- 0.35-fold, respectively. The relative bioluminescence of the UHMWPE group was higher at all postinjection days and significantly greater than the saline group at day 8 (p < 0.05). Histological analysis confirmed the presence of reporter macrophages within the medullary canal of mice with implanted UHMWPE particles. The presence of UHMWPE particles induced enhanced bone remodeling activity. Clinically relevant UHMWPE particles stimulated the systemic recruitment of macrophages during an early time course using the murine femoral implant model. Interference with systemic macrophage trafficking may potentially mitigate UHMWPE particle-induced periprosthetic osteolysis.

  View details for DOI 10.1002/jbm.a.32744

  View details for PubMedID 20213815

• Surveillance of systemic trafficking of macrophages induced by UHMWPE particles in nude mice by noninvasive imaging JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Ren, P., Huang, Z., Ma, T., Biswal, S., Smith, R. L., Goodman, S. B. 2010; 94A (3): 706-711

  Abstract

  Macrophages constitute a major part of the cell response to wear particles produced at articulating and nonarticulating interfaces of joint replacements. This foreign body reaction can result in periprosthetic osteolysis and implant loosening. We demonstrate that ultra-high molecular weight polyethylene (UHMWPE) particles induce systemic trafficking of macrophages by noninvasive in vivo imaging and immunohistochemistry. The distal femora of nude mice were injected with 60 mg/mL UHMWPE suspension or saline alone. Reporter RAW264.7 macrophages that stably expressed the bioluminescent reporter gene and the fluorescence reporter gene were injected intravenously. Bioluminescence imaging was performed using an in vivo imaging system immediately after macrophage injection and at 2-day intervals. Compared with the nonoperated contralateral femora, at day 4, 6, and 8, the bioluminescent signal of femora containing UHMWPE suspension increased 1.30 +/- 0.09-, 2.36 +/- 0.92-, and 10.32 +/- 7.61-fold, respectively. The values at same time points for saline-injected control group were 1.08 +/- 0.07-, 1.14 +/- 0.27-, and 1.14 +/- 0.35-fold, respectively. The relative bioluminescence of the UHMWPE group was higher at all postinjection days and significantly greater than the saline group at day 8 (p < 0.05). Histological analysis confirmed the presence of reporter macrophages within the medullary canal of mice with implanted UHMWPE particles. The presence of UHMWPE particles induced enhanced bone remodeling activity. Clinically relevant UHMWPE particles stimulated the systemic recruitment of macrophages during an early time course using the murine femoral implant model. Interference with systemic macrophage trafficking may potentially mitigate UHMWPE particle-induced periprosthetic osteolysis.

  View details for DOI 10.1002/jbm.a.32744

  View details for Web of Science ID 000280536300006

  View details for PubMedCentralID PMC2936785

• Minimal Incision Surgery as a Risk Factor for Early Failure of Total Hip Arthroplasty CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Graw, B. P., Woolson, S. T., Huddleston, H. G., Goodman, S. B., Huddleston, J. I. 2010; 468 (9): 2372-2376

  Abstract

  Minimal incision total hip arthroplasty (MI THA) techniques were developed to decrease postoperative pain and recovery time. Although these techniques have increased in popularity, the long-term survivorship of these procedures is unknown.We therefore investigated whether the time to revision in our referral practice was shorter for patients who underwent primary MI THA compared to primary traditional THA.We retrospectively reviewed 46 revision THAs performed during a 3-year period. We excluded revisions performed for infection and rerevisions. Patients with incisions less than or equal to 10 cm were defined as having had MI THA. Fifteen of the 46 patients (33%) h