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All Publications


  • Wound healing, fibroblast heterogeneity, and fibrosis. Cell stem cell Talbott, H. E., Mascharak, S., Griffin, M., Wan, D. C., Longaker, M. T. 2022; 29 (8): 1161-1180

    Abstract

    Fibroblasts are highly dynamic cells that play a central role in tissue repair and fibrosis. However, the mechanisms by which they contribute to both physiologic and pathologic states of extracellular matrix deposition and remodeling are just starting to be understood. In this review article, we discuss the current state of knowledge in fibroblast biology and heterogeneity, with a primary focus on the role of fibroblasts in skin wound repair. We also consider emerging techniques in the field, which enable an increasingly nuanced and contextualized understanding of these complex systems, and evaluate limitations of existing methodologies and knowledge. Collectively, this review spotlights a diverse body of research examining an often-overlooked cell type-the fibroblast-and its critical functions in wound repair and beyond.

    View details for DOI 10.1016/j.stem.2022.07.006

    View details for PubMedID 35931028

  • Exploring the Overlooked Roles and Mechanisms of Fibroblasts in the Foreign Body Response. Advances in wound care Parker, J., Griffin, M., Spielman, A. F., Wan, D. C., Longaker, M. T. 2022

    Abstract

    Significance Foreign body response (FBR), wherein a fibrotic capsule forms around an implanted structure, is a common surgical complication that often leads to pain, discomfort, and eventual revision surgeries. Though believed to have some mechanistic overlap with normal wound healing, much remains to be discovered about the specific mechanism by which this occurs. Recent Advances Current understanding of FBR has focused on the roles of the immune system and the biomaterial, both major contributors to FBR. However, another key player, the fibroblast, is often overlooked. This review summarizes key contributors of FBR, focusing on the roles of fibroblasts. As much remains to be discovered about fibroblasts' specific roles in FBR, we draw on current knowledge of fibroblast subpopulations and functions during wound healing. We also provide an overview on candidate biomaterials and signalling pathways involved in FBR. Critical Issues and Future Directions While the global implantable medical devices market is considerable and continues to appreciate in value, FBR remains one of the most common surgical implant complications. In parallel with the continued development of candidate biomaterials, further exploration of potential fibroblast subpopulations at a transcriptional level would provide key insights into further understanding the underlying mechanisms by which fibrous encapsulation occurs, and unveil novel directions for anti-fibrotic and regenerative therapies in the future.

    View details for DOI 10.1089/wound.2022.0066

    View details for PubMedID 35819293

  • Transdermal deferoxamine administration improves excisional wound healing in chronically irradiated murine skin. Journal of translational medicine Lintel, H., Abbas, D. B., Lavin, C. V., Griffin, M., Guo, J. L., Guardino, N., Churukian, A., Gurtner, G. C., Momeni, A., Longaker, M. T., Wan, D. C. 2022; 20 (1): 274

    Abstract

    BACKGROUND: Radiation-induced skin injury is a well-known risk factor for impaired wound healing. Over time, the deleterious effects of radiation on skin produce a fibrotic, hypovascular dermis poorly suited to wound healing. Despite increasing understanding of the underlying pathophysiology, therapeutic options remain elusive. Deferoxamine (DFO), an iron-chelating drug, has been shown in prior murine studies to ameliorate radiation-induced skin injury as well as improve wound healing outcomes in various pathologic conditions when administered transdermally. In this preclinical study, we evaluated the effects of deferoxamine on wound healing outcomes in chronically irradiated murine skin.METHODS: Wild-type mice received 30Gy of irradiation to their dorsal skin and were left to develop chronic fibrosis. Stented excisional wounds were created on their dorsal skin. Wound healing outcomes were compared across 4 experimental conditions: DFO patch treatment, vehicle-only patch treatment, untreated irradiated wound, and untreated nonirradiated wounds. Gross closure rate, wound perfusion, scar elasticity, histology, and nitric oxide assays were compared across the conditions.RESULTS: Relative to vehicle and untreated irradiated wounds, DFO accelerated wound closure and reduced the frequency of healing failure in irradiated wounds. DFO augmented wound perfusion throughout healing and upregulated angiogenesis to levels observed in nonirradiated wounds. Histology revealed DFO increased wound thickness, collagen density, and improved collagen fiber organization to more closely resemble nonirradiated wounds, likely contributing to the observed improved scar elasticity. Lastly, DFO upregulated inducible nitric oxide synthase and increased nitric oxide production in early healing wounds.CONCLUSION: Deferoxamine treatment presents a potential therapeutic avenue through which to target impaired wound healing in patients following radiotherapy.

    View details for DOI 10.1186/s12967-022-03479-4

    View details for PubMedID 35715816

  • Profibrotic Signaling Pathways and Surface Markers Are Upregulated in Fibroblasts of Human Striae Distensae and in a Mouse Model System. Plastic and reconstructive surgery Borrelli, M. R., Griffin, M., Chen, K., Diaz, N. M., Adem, S., Mascharak, S., Shen, A. H., Ngaage, L. M., Lewis, N., Longaker, M. T., Gurtner, G., Wan, D. C., Lorenz, H. P. 2022

    Abstract

    INTRODUCTION: Striae distensae (SD) are common disfiguring cutaneous lesions but lack effective treatments due to an incomplete understanding of their pathophysiology. Dermal fibroblasts likely play an important role. We investigate the cellular-molecular features distinguishing fibroblasts from human SD and normal skin (NS). We also develop a mouse model of SD.METHODS: Human SD and NS samples were compared for tensile strength and histological structure. Fibroblasts from SD and NS were isolated by fluorescence-activated cell sorting (FACS) for gene expression analysis. Immunofluorescence staining and FACS were used to confirm gene expression data at the protein level. A mouse model of SD formation was created by administering corticosteroids and mechanically loading the dorsal skin.RESULTS: Human SD exhibited reduced tensile strength, more disordered collagen fibers, and epidermal atrophy compared to human NS. There were 296 upregulated genes in SD fibroblasts, including the profibrotic lineage and surface marker CD26. Upregulated genes were involved in profibrotic and mechanoresponsive signaling pathways (TGFbeta and FAK-PI3-AKT-signaling). In contrast, 571 genes were downregulated, including CD74 and genes of the AMPK pathway. Increased CD26 and decreased CD74 expression was confirmed by FACS and immunofluorescence. Similar cutaneous histological and gene expression changes were induced in hypercortisolemic mice by mechanically loading the dorsal skin.CONCLUSIONS: Fibroblasts from human SD exhibit increased profibrotic and decreased antifibrotic signaling. CD26 and CD74 are promising surface markers that may be targeted therapeutically. Our mouse model of SD can be used as a platform to test the efficacy of potential therapeutic agents.

    View details for DOI 10.1097/PRS.0000000000009363

    View details for PubMedID 35666152

  • Beyond the Scar: A Basic Science Review of Wound Remodeling. Advances in wound care Spielman, A. F., Griffin, M., Parker, J., Cotterell, A. C., Wan, D. C., Longaker, M. T. 2022

    Abstract

    SIGNIFICANCE: Increasing development of experimental animal models has allowed for the study of scar formation. However, many pathophysiological unknowns remain in the longest stage of healing, the remodeling stage, which may continue for a year or more. The wound healing process results in different types of scarring classified as normal or pathological depending on failures at each stage. Failures can also occur during wound remodeling, but the molecular mechanisms driving the wound remodeling process have yet to be investigated.RECENT ADVANCES: While current understanding of wound repair is based on investigations of acute healing, these experimental models have informed knowledge of key components of remodeling. This review examines the components that contribute to collagen organization and the final scar, including cell types, their regulation, and signaling pathways. Dysregulation in any one of these components causes pathologic healing.CRITICAL ISSUES AND FUTURE DIRECTIONS: As wounds continue to remodel months to years after re-epithelization, new models to better understand long-term remodeling will be critical for improving healing outcomes. Further investigation of the contributions of fibroblasts and cell signaling pathways involved during remodeling as well as their potential failures may inform new approaches in promoting regenerative healing beyond re-epithelization.

    View details for DOI 10.1089/wound.2022.0049

    View details for PubMedID 35658581

  • Disrupting mechanotransduction decreases fibrosis and contracture in split-thickness skin grafting. Science translational medicine Chen, K., Henn, D., Januszyk, M., Barrera, J. A., Noishiki, C., Bonham, C. A., Griffin, M., Tevlin, R., Carlomagno, T., Shannon, T., Fehlmann, T., Trotsyuk, A. A., Padmanabhan, J., Sivaraj, D., Perrault, D. P., Zamaleeva, A. I., Mays, C. J., Greco, A. H., Kwon, S. H., Leeolou, M. C., Huskins, S. L., Steele, S. R., Fischer, K. S., Kussie, H. C., Mittal, S., Mermin-Bunnell, A. M., Diaz Deleon, N. M., Lavin, C., Keller, A., Longaker, M. T., Gurtner, G. C. 2022; 14 (645): eabj9152

    Abstract

    Burns and other traumatic injuries represent a substantial biomedical burden. The current standard of care for deep injuries is autologous split-thickness skin grafting (STSG), which frequently results in contractures, abnormal pigmentation, and loss of biomechanical function. Currently, there are no effective therapies that can prevent fibrosis and contracture after STSG. Here, we have developed a clinically relevant porcine model of STSG and comprehensively characterized porcine cell populations involved in healing with single-cell resolution. We identified an up-regulation of proinflammatory and mechanotransduction signaling pathways in standard STSGs. Blocking mechanotransduction with a small-molecule focal adhesion kinase (FAK) inhibitor promoted healing, reduced contracture, mitigated scar formation, restored collagen architecture, and ultimately improved graft biomechanical properties. Acute mechanotransduction blockade up-regulated myeloid CXCL10-mediated anti-inflammation with decreased CXCL14-mediated myeloid and fibroblast recruitment. At later time points, mechanical signaling shifted fibroblasts toward profibrotic differentiation fates, and disruption of mechanotransduction modulated mesenchymal fibroblast differentiation states to block those responses, instead driving fibroblasts toward proregenerative, adipogenic states similar to unwounded skin. We then confirmed these two diverging fibroblast transcriptional trajectories in human skin, human scar, and a three-dimensional organotypic model of human skin. Together, pharmacological blockade of mechanotransduction markedly improved large animal healing after STSG by promoting both early, anti-inflammatory and late, regenerative transcriptional programs, resulting in healed tissue similar to unwounded skin. FAK inhibition could therefore supplement the current standard of care for traumatic and burn injuries.

    View details for DOI 10.1126/scitranslmed.abj9152

    View details for PubMedID 35584231

  • Fat Grafts Augmented With Vitamin E Improve Volume Retention and Radiation-Induced Fibrosis. Aesthetic surgery journal Abbas, D. B., Lavin, C. V., Fahy, E. J., Griffin, M., Guardino, N. J., Nazerali, R. S., Nguyen, D. H., Momeni, A., Longaker, M. T., Wan, D. C. 2022

    Abstract

    Treatments for radiation-induced fibrosis range from vitamin E and pentoxifylline systemically to deferoxamine and fat grafting locally. Regarding fat grafting, volume retention hinders its long-term functionality and is affected by two factors: inflammation and necrosis secondary to hypovascularity.We aimed to simultaneously improve fat graft retention and radiation-induced fibrosis by integrating vitamin E and pentoxifylline into fat grafts locally.Forty adult CD-1 nude male mice at 6 weeks of age underwent scalp irradiation and recovered for four weeks to allow for the development of fibrosis. Mice received 200μL of donor human fat graft to the scalp. Mice were separated into 4 conditions: no grafting, fat graft without treatment, graft treated with pentoxifylline, and graft treated with vitamin E. Fat graft volume retention was monitored in-vivo using microCT scans at weeks 0, 1, 2, 4, 6, and 8 after grafting. Histological and cytokine analysis of the scalp skin and fat grafts were also performed.Vitamin E (VE) treated grafts had significant improvement in dermal thickness and collagen density of overlying skin compared to all other groups. VE decreased 8-isoprostane and increased CD31 + staining compared to the other grafted groups. Cytokine analysis revealed decreased inflammatory and increased angiogenic markers in both the fat graft and overlying skin of the vitamin E group. Fat graft volume retention was significantly improved in the vitamin E group starting at 1 week post grafting.Radiation-induced fibrosis and fat graft volume retention are both simultaneously improved with local administration of vitamin E.

    View details for DOI 10.1093/asj/sjac066

    View details for PubMedID 35350074

  • Characterization of Mechanoresponsive Inflammatory Cells during Wound Healing Chen, K., Griffin, M., Henn, D., Bonham, C. A., Fischer, K., Padmanabhan, J., Trotsyuk, A. A., Sivaraj, D., Leeolou, M. C., Kussie, H. C., Huskins, S. L., Steele, S., Perrault, D., Longaker, M. T., Gurtner, G. C. WILEY. 2022: A5
  • Overcoming Radiation Induced Oral Fibrosis Through The Down Regulation Of WNT Signaling Using BMP-7 Inhibitors Guardino, N., Griffin, M., Spielman, A. F., Abbas, D. B., King, M., Parker, J., Wan, D., Longaker, M. T. WILEY. 2022: A5
  • Adipocytes Transition To Pro-Fibrotic Fibroblasts And Contribute To Muscle Fibrosis Following Nerve Injury Spielman, A. F., Griffin, M., Guardino, N., desJardins-Park, H. E., Bauer-Rowe, K. E., Guo, J. L., Parker, J., Abbas, D. B., Wan, D., Longaker, M. T. WILEY. 2022: A3-A4
  • Vitamin E Treated Fat Grafts Demonstrate Improved Volume Retention And Decreased Radiation-Induced Fibrosis Abbas, D. B., Lavin, C. V., Fahy, E. J., Lintel, H., Griffin, M., Nazerali, R., Dung Nguyen, Momeni, A., Longaker, M. T., Wan, D. WILEY. 2022: A16
  • Mechanical Stimulation Reverses Pro-Fibrotic Transcriptional States in Senescent Fibroblasts Guo, J. L., Griffin, M., Guardino, N., Chen, K., Gurtner, G. C., Longaker, M. T. WILEY. 2022: A14-A16
  • Interactions Of Fibroblasts Versus Macrophages In An In Vitro Model Of Scar Formation And Wound Healing Huskins, S. L., Griffin, M., Steele, S., Thomas, B., Kussie, H. C., Sivaraj, D., Leeolou, M. C., Trotsyuk, A. A., Padmanabhan, J., Longaker, M. T., Gurtner, G. C., Chen, K. WILEY. 2022: A53-A54
  • The Oral Mucosa Hosts Distinct Fibroblast Subpopulations to Facilitate Regenerative Wound Repair Griffin, M., Cook, J., Bofelli, D., Guardino, N., Spielman, A. F., Januszyk, M., Chen, K., Abbas, D. B., Zwick, R., Klein, O., Longaker, M. T. WILEY. 2022: A12-A13
  • Transdermal Deferoxamine Enhances Wound Healing In Chronically Irradiated Skin In Mice Lintel, H., Abbas, D. B., Lavin, C. V., Griffin, M., Guardino, N., Guo, J. L., Spielman, A. F., Gurtner, G. C., Longaker, M. T., Wan, D. WILEY. 2022: A29-A30
  • Characterization of Mechanoresponsive Inflammatory Cells during Wound Healing Chen, K., Griffin, M., Henn, D., Bonham, C. A., Fischer, K., Padmanabhan, J., Trotsyuk, A. A., Sivaraj, D., Leeolou, M. C., Kussie, H. C., Huskins, S. L., Steele, S., Perrault, D., Longaker, M. T., Gurtner, G. C. WILEY. 2022: A31-A32
  • Tension offloading improves cutaneous scar formation in Achilles tendon repair. Journal of surgical case reports Abbas, D. B., Lintel, H., Griffin, M., Guardino, N. J., Guo, J. L., Spielman, A. F., Cotterell, A. C., Parker, J. B., Januszyk, M., Wan, D. C. 2022; 2022 (3): rjac066

    Abstract

    Hypertrophic scar formation and non-healing wounds following Achilles tendon repair arise from poor vascularity to the incisional site or from excess mechanical stress/strain to the incision during the healing process. The embrace scar therapy dressing is a tension offloading device for incisional scars. This study explored the effects of tension offloading during Achilles scar formation. A healthy 30-year-old male without any medical co-morbidities developed an acute rupture of his left Achilles tendon. The patient underwent open repair 1 week after injury. At post-operative day (POD) 14, the patient started daily tension offloading treatment on the inferior portion of the incision through POD 120. By POD 120, the untreated portion of the Achilles incision appeared hypertrophic and hyperpigmented, while the treated portion of the scar appeared flat with minimal pigmentation changes. The 12-week treatment of tension offloading on an Achilles tendon repair incision significantly improved cosmesis compared to untreated incision.

    View details for DOI 10.1093/jscr/rjac066

    View details for PubMedID 35280050

  • Mechanical Stimulation Reverses Pro-Fibrotic Transcriptional States in Senescent Fibroblasts Guo, J. L., Griffin, M., Guardino, N., Chen, K., Gurtner, G. C., Longaker, M. T. WILEY. 2022: A33-A34
  • Impact of Incision Placement on Ischemic Complications in Microsurgical Breast Reconstruction. Plastic and reconstructive surgery Tevlin, R., Griffin, M., Karin, M., Wapnir, I., Momeni, A. 1800; 149 (2): 316-322

    Abstract

    BACKGROUND: Nipple-sparing mastectomy is associated with greater patient satisfaction than non-nipple-sparing approaches. Although various nipple-sparing mastectomy incisions have been described, the authors hypothesized that incision location would impact the rate and location of ischemic complications to the mastectomy skin flap.METHODS: A prospectively maintained database was queried to identify patients who underwent nipple-sparing mastectomy with immediate microsurgical reconstruction with a minimum postoperative follow-up of 12 months. The impact of incision location on postoperative ischemic complications was investigated. Major complications were defined as those that required reexploration in the operating room or inpatient management; minor complications were amenable to outpatient management. Multivariable logistic and linear regression were performed to investigate risk factors for postoperative complications following breast reconstruction.RESULTS: Eighty-seven patients met inclusion criteria. The following nipple-sparing mastectomy incisions were used: radial with a periareolar extension (39 percent), inframammary fold (31 percent), vertical with a periareolar extension (22 percent), vertical (6 percent), and radial (2 percent). Seven patients (8 percent) had major complications, whereas twenty-six patients (29.9 percent) developed minor postoperative complications. Inframammary fold incisions were associated with significantly greater rates of mastectomy skin flap necrosis (p = 0.002), whereas periareolar incisions were associated with significantly greater rates of postoperative nipple-areola complex necrosis (p = 0.04).CONCLUSIONS: The authors report a significant association between incision location and ischemic complications to the breast skin envelope in microsurgical breast reconstruction. The authors observed a significant association of inframammary fold and periareolar incisions with mastectomy skin flap and nipple-areola complex necrosis, respectively.CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

    View details for DOI 10.1097/PRS.0000000000008770

    View details for PubMedID 35077404

  • Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing. Cell stem cell Mascharak, S., Talbott, H. E., Januszyk, M., Griffin, M., Chen, K., Davitt, M. F., Demeter, J., Henn, D., Bonham, C. A., Foster, D. S., Mooney, N., Cheng, R., Jackson, P. K., Wan, D. C., Gurtner, G. C., Longaker, M. T. 1800

    Abstract

    Regeneration is the holy grail of tissue repair, but skin injury typically yields fibrotic, non-functional scars. Developing pro-regenerative therapies requires rigorous understanding of the molecular progression from injury to fibrosis or regeneration. Here, we report the divergent molecular events driving skin wound cells toward scarring or regenerative fates. We profile scarring versus YAP-inhibition-induced wound regeneration at the transcriptional (single-cell RNA sequencing), protein (timsTOF proteomics), and tissue (extracellular matrix ultrastructural analysis) levels. Using cell-surface barcoding, we integrate these data to reveal fibrotic and regenerative "molecular trajectories" of healing. We show that disrupting YAP mechanotransduction yields regenerative repair by fibroblasts with activated Trps1 and Wnt signaling. Finally, via invivo gene knockdown and overexpression in wounds, we identify Trps1 as a key regulatory gene that is necessary and partially sufficient for wound regeneration. Our findings serve as a multi-omic map of wound regeneration and could have therapeutic implications for pathologic fibroses.

    View details for DOI 10.1016/j.stem.2021.12.011

    View details for PubMedID 35077667

  • Harnessing a Feasible and Versatile ex vivo Calvarial Suture 2-D Culture System to Study Suture Biology. Frontiers in physiology Quarto, N., Menon, S., Griffin, M., Huber, J., Longaker, M. T. 2022; 13: 823661

    Abstract

    As a basic science, craniofacial research embraces multiple facets spanning from molecular regulation of craniofacial development, cell biology/signaling and ultimately translational craniofacial biology. Calvarial sutures coordinate development of the skull, and the premature fusion of one or more, leads to craniosynostosis. Animal models provide significant contributions toward craniofacial biology and clinical/surgical treatments of patients with craniofacial disorders. Studies employing mouse models are costly and time consuming for housing/breeding. Herein, we present the establishment of a calvarial suture explant 2-D culture method that has been proven to be a reliable system showing fidelity with the in vivo harvesting procedure to isolate high yields of skeletal stem/progenitor cells from small number of mice. Moreover, this method allows the opportunity to phenocopying models of craniosynostosis and in vitro tamoxifen-induction of ActincreERT2;R26Rainbow suture explants to trace clonal expansion. This versatile method tackles needs of large number of mice to perform calvarial suture research.

    View details for DOI 10.3389/fphys.2022.823661

    View details for PubMedID 35222087

  • Where There Is Fat There Is Fibrosis: Elucidating the Mechanisms of Creeping Fat-Driven Stricture Formation Bauer-Rowe, K. E., Griffin, M., Foster, D., desJardins-Park, H. E., Mascharak, S., Norton, J. A., Hyun, J. S., Longaker, M. T. ELSEVIER SCIENCE INC. 2021: S65
  • The Impact of Reconstructive Modality on the Severity of Postoperative Complications in Breast Reconstruction Pedreira, R., Tevlin, R., Griffin, M., Wan, D., Momeni, A. ELSEVIER SCIENCE INC. 2021: S211-S212
  • Analysis of Online Educational Materials Relating to Craniosynostosis Lavin, C. V., Fahy, E. J., Abbas, D. B., Deleon, N., Lee, D. K., Griffin, M., King, M. W., Guardino, N., Wan, D. C. ELSEVIER SCIENCE INC. 2021: S203-S204
  • Transdermal Deferoxamine in a Porcine Model Is a Safe Treatment to Improve Elasticity Secondary to Radiation-induced Fibrosis Abbas, D. B., Fahy, E. J., Lavin, C. V., Griffin, M., Deleon, N., King, M. E., Gurtner, G. C., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: E164
  • CD34+CD146+Adipose-derived Stromal Cells (ASCs) Enrichment of Fat Grafts Enhance Regeneration of Irradiated Skin and Graft Retention Deleon, N., Abbas, D. B., Borrelli, M. R., Adem, S., Lavin, C. V., Griffin, M., King, M. E., Lee, D., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: E198
  • Dermal Iron Chelation Reduces Indirect Radiation Injury Lavin, C. V., Fahy, E. J., Abbas, D. B., Griffin, M., Lee, D. K., Deleon, N., Guardino, N., Gurtner, G. C., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: E155
  • Dorsal Skin Fibrosis Secondary to Radiation Is Mitigated by Fat Grafting in Engrailed-1 Mice Abbas, D. B., Fahy, E. J., Griffin, M., Lavin, C. V., Deleon, N., King, M. E., Lee, D., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: E159-E160
  • Suprazygomatic Maxillary Nerve Blocking Reduces Postoperative Pain and Opioid Use Following Bimaxillary Osteotomy Lavin, C. V., Lee, D. K., Fahy, E. J., Abbas, D. B., Griffin, M., King, M. E., Momeni, A., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: E157
  • Optimizing Cutometer Mpa 580 Calculated Parameters to Determine In-vivo Elasticity of Human Skin Abbas, D. B., Lavin, C. V., Fahy, E., Griffin, M., Guardino, N., Lee, D., Gurtner, G. C., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: E162
  • Temperature Influence on Scanning Laser Doppler Flowmetry in Anesthetized Mice Fahy, E. J., Lavin, C. V., Abbas, D., Griffin, M., King, M. E., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: E157
  • Acellular Dermal Matrix Grafts Decrease Radiation-Induced Contracture and Dermal Thickening Deleon, N., Lavin, C. D., Abbas, D., Griffin, M., King, M. E., Fahy, E. J., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: E197
  • Adipose-Derived Stromal Cell (ASC) Subpopulation with Adipogenic Capabilities Increase Fat Graft Quality in Irradiated Tissue Deleon, N., Adem, S., Borrelli, M. R., Abbas, D. B., Lavin, C. V., Griffin, M., King, M. E., Lee, D., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: E197-E198
  • Acellular Dermal Matrix Modulation of the Peri-Prosthetic Breast Microenvironment During Breast Reconstruction Tevlin, R., Januszyk, M., Griffin, M., Shefren, K., Chan, C. F., Momeni, A., Wan, D. C., Longaker, M. T. ELSEVIER SCIENCE INC. 2021: S195-S196
  • Fibroblast Sub-Populations Dynamically Change Composition to Heal Dorsal Skin Radiation Wounds in Wild-Type Mice Abbas, D. B., Griffin, M., Fahy, E. J., Lavin, C., Lee, D., Mascharak, S., King, M., Januszyk, M., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: S207-S208
  • Adipose Precursor Cell-Embedded Collagen Gels Attenuate Inflammation and Improve Tissue Perfusion in Cutaneous Wounds Fahy, E. J., Griffin, M., Abbas, D., Lavin, C. V., King, M. E., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: S196
  • Denervation During Mandibular Distraction Osteogenesis Results in Impaired Osteogenesis Tevlin, R., Januszyk, M., Griffin, M., Salhotra, A., Wan, D. C., Chan, C. F., Longaker, M. T. ELSEVIER SCIENCE INC. 2021: S196-S197
  • Topical Deferoxamine Patch Is Superior to Direct Injection for the Treatment of Radiation-Induced Skin Fibrosis Lavin, C. V., Abbas, D. B., Fahy, E. J., Lee, D. K., Griffin, M., Deleon, N., Mascharak, S., Gurtner, G. C., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: S202-S203
  • Effects of beta(3) Adrenergic Receptor Agonist Treatment in Murine Full Thickness Dorsal Cutaneous Wounds Fahy, E. J., Griffin, M., Abbas, D., Lavin, C. V., King, M. E., Lee, D., Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: S197-S198
  • Single-Cell RNA Sequencing Reveals Fibroblast Heterogeneity Across Mouse and Human Embryonic Origins Griffin, M., King, M. W., Guardino, N., Tevlin, R., Fahy, E. J., Mascharak, S., Abbas, D., Lavin, C. V., Wan, D., Longaker, M. ELSEVIER SCIENCE INC. 2021: S201-S202
  • Local Vitamin E Administration Improves Fat Graft Retention and Radiation-Induced Fibrosis in a Mouse Model Abbas, D. B., Lavin, C. V., Fahy, E. J., Griffin, M., King, M. E., Lee, D., Dung Nguyen, Longaker, M. T., Wan, D. C. ELSEVIER SCIENCE INC. 2021: S199
  • A comparative analysis of deferoxamine treatment modalities for dermal radiation-induced fibrosis. Journal of cellular and molecular medicine Lavin, C. V., Abbas, D. B., Fahy, E. J., Lee, D. K., Griffin, M., Diaz Deleon, N. M., Mascharak, S., Chen, K., Momeni, A., Gurtner, G. C., Longaker, M. T., Wan, D. C. 2021

    Abstract

    The iron chelator, deferoxamine (DFO), has been shown to potentially improve dermal radiation-induced fibrosis (RIF) in mice through increased angiogenesis and reduced oxidative damage. This preclinical study evaluated the efficacy of two DFO administration modalities, transdermal delivery and direct injection, as well as temporal treatment strategies in relation to radiation therapy to address collateral soft tissue fibrosis. The dorsum of CD-1 nude mice received 30Gy radiation, and DFO (3mg) was administered daily via patch or injection. Treatment regimens were prophylactic, during acute recovery, post-recovery, or continuously throughout the experiment (n=5 per condition). Measures included ROS-detection, histology, biomechanics and vascularity changes. Compared with irradiated control skin, DFO treatment decreased oxidative damage, dermal thickness and collagen content, and increased skin elasticity and vascularity. Metrics of improvement in irradiated skin were most pronounced with continuous transdermal delivery of DFO. In summary, DFO administration reduces dermal fibrosis induced by radiation. Although both treatment modalities were efficacious, the transdermal delivery showed greater effect than injection for each temporal treatment strategy. Interestingly, the continuous patch group was more similar to normal skin than to irradiated control skin by most measures, highlighting a promising approach to address detrimental collateral soft tissue injury following radiation therapy.

    View details for DOI 10.1111/jcmm.16913

    View details for PubMedID 34612609

  • A Novel Xenograft Model Demonstrates Human Fibroblast Behavior During Skin Wound Repair and Fibrosis. Advances in wound care Borrelli, M., Shen, A. H., Griffin, M., Mascharak, S., Adem, S., Diaz Deleon, N. M., Ngaage, L. M., Longaker, M. T., Wan, D. C., Lorenz, H. P. 2021

    Abstract

    OBJECTIVE: Xenografts of human skin on immunodeficient mice provide a means of assessing human skin physiology and its response to wounding.APPROACH: We describe a novel xenograft model using full-thickness human neonatal foreskin to examine human skin wound repair and fibroblast heterogeneity. Full-thickness 8-mm human neonatal foreskin biopsies were sutured into the dorsum of NSG (NOD.Cg-Prkdc scidIl2rgtm1Wjl/SzJ) pups as subcutaneous grafts and exposed to cutaneous grafts at the time of weaning (postnatal day 21). To model fibrosis, xenografts were wounded with 5-mm linear incisions and monitored until post-wound day (PWD) 14. To explore whether our model can be used to test the efficacy of topical therapies, wounded xenografts were injected with fibroblast growth factor-2 (FGF2) for the first four consecutive PWDs. Xenografts were harvested for analysis by histology and fluorescence-activated cell sorting (FACS).RESULTS: Xenografts successfully engrafted with evidence of mouse-human anastomoses and resembled native neonatal foreskin at the gross and microscopic level. Wounded xenografted skin scarred with human collagen and an expansion of CD26-positive human fibroblasts. Collagen scar was quantitated by neural network analysis, which revealed distinct clustering of collagen fiber networks from unwounded skin and wounded skin at PWD7 and PWD14. Collagen fiber networks within FGF2-treated wounds at PWD14 resembled those in untreated wounded xenografts at PWD7, suggesting that FGF2 treatment at time of wounding can reduce fibrosis. Innovation and Conclusion: This novel xenograft model can be used to investigate acute fibrosis, fibroblast heterogeneity, and the efficacy of antifibrotic agents during wound repair in human skin.

    View details for DOI 10.1089/wound.2020.1392

    View details for PubMedID 34521222

  • Understanding Scarring in the Oral Mucosa. Advances in wound care Griffin, M., Fahy, E., King, M., Guardino, N., Chen, K., Abbas, D. B., Lavin, C., Diaz Deleon, N. M., Lorenz, H. P., Longaker, M. T., Wan, D. C. 2021

    Abstract

    SIGNIFICANCE: Skin inevitably heals with the formation of a fibrotic scar. Patients affected by skin fibrosis suffer from long-term psychological and physical burdens. Recent Advances: Since the discovery of fetal scarless skin-wound healing, research has hoped to identify and mimic scarless healing for adult skin. Oral mucosa healing in adults provides the closest example to fetal scarless healing. Injuries to the oral mucosa heal with very minimal scarring. Understanding the mechanisms through which this process occurs may bring us closer to achieving scarless healing in adults.CRITICAL ISSUES: In this review, we summarize the current evidence that illustrates distinct mechanisms involved in oral mucosal healing. We discuss the role of the oral niche in contributing to wound repair. The intrinsic properties of immune cells, fibroblasts, and keratinocytes within the oral mucosa that support regenerative repair are provided. We highlight the contribution of cytokines, growth factors, and chemokine secretion in permitting a scarless mucosal environment. Furthermore, we discuss the role of stem cell-like progenitor populations in the mucosa that may contribute to wound healing. We also provide suggestions for future studies that are needed to achieve scarless healing in adults.FUTURE DIRECTIONS: Many characteristics of the oral mucosa have been shown to contribute to decreased scarring, but the specific mechanism(s) is unclear. Advancing our understanding of oral healing may yield therapeutic therapies that can be used to overcome dermal fibrosis and scarring.

    View details for DOI 10.1089/wound.2021.0038

    View details for PubMedID 34470520

  • Standardizing dimensionless cutometer parameters to determine in-vivo elasticity of human skin. Advances in wound care Abbas, D. B., Lavin, C., Fahy, E., Griffin, M., Guardino, N., King, M., Chen, K., Lorenz, H. P., Gurtner, G. C., Longaker, M. T., Momeni, A., Wan, D. C. 2021

    Abstract

    OBJECTIVE: Skin fibrosis places an enormous burden on patients and society, but disagreement exists over methods to quantify severity of skin scarring. A suction cutometer measures skin elasticity in-vivo, but it has not been widely adopted due to inconsistency in data produced. We investigated variability of several dimensionless parameters generated by the cutometer to improve their precision and accuracy.APPROACH: Twenty adult human subjects underwent suction cutometer measurement of normal skin and fibrotic scars. Using Mode 1, each subject underwent 5 trials with each trial containing 4 curves. R0/2/5/6/7 and Q1/2/3 data were collected. Analyses were performed on these calculated parameters.RESULTS: R0/2/5/6/7 and Q1/2 parameters from curves 1-4 demonstrated significant differences, while these same parameters were not significantly different when only using curves 2-4. Individual analysis of all parameters between curve 1 and every subsequent curve was statistically significant for R0, R2, R5, R6, R7, Q1, and Q2. No differences were appreciated for parameter Q3. Comparison between normal skin and fibrotic scars were significantly different for parameters R5, Q1, and Q3.INNOVATION: Our study is the first demonstration of accurate comparison between normal skin and fibrotic scars using the dimensionless parameters of a suction cutometer.CONCLUSION: Measured parameters from the first curve of each trial were significantly different from subsequent curves for both normal skin and fibrotic scars. Precision and reproducibility of data from dimensionless parameters can therefore be improved by removing the first curve. R5, Q1, and Q3 parameters differentiated normal skin as more elastic than fibrotic scars.

    View details for DOI 10.1089/wound.2021.0082

    View details for PubMedID 34470542

  • JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models. Science translational medicine Griffin, M. F., Borrelli, M. R., Garcia, J. T., Januszyk, M., King, M., Lerbs, T., Cui, L., Moore, A. L., Shen, A. H., Mascharak, S., Diaz Deleon, N. M., Adem, S., Taylor, W. L., desJardins-Park, H. E., Gastou, M., Patel, R. A., Duoto, B. A., Sokol, J., Wei, Y., Foster, D., Chen, K., Wan, D. C., Gurtner, G. C., Lorenz, H. P., Chang, H. Y., Wernig, G., Longaker, M. T. 2021; 13 (609): eabb3312

    Abstract

    [Figure: see text].

    View details for DOI 10.1126/scitranslmed.abb3312

    View details for PubMedID 34516825

  • The role of Wnt signaling in skin fibrosis. Medicinal research reviews Griffin, M. F., Huber, J., Evan, F. J., Quarto, N., Longaker, M. T. 2021

    Abstract

    Skin fibrosis is the excessive deposition of extracellular matrix in the dermis. Cutaneous fibrosis can occur following tissue injury, including burns, trauma, and surgery, resulting in scars that are disfiguring, limit movement and cause significant psychological distress for patients. Many molecular pathways have been implicated in the development of skin fibrosis, yet effective treatments to prevent or reverse scarring are unknown. The Wnt signaling pathways are known to play an important role in skin homeostasis, skin injury, and in the development of fibrotic skin diseases. This review provides a detailed overview of the role of the canonical Wnt signaling pathways in regulating skin scarring. We also discuss how Wnt signaling interacts with other known fibrotic molecular pathways to cause skin fibrosis. We further provide a summary of the different Wnt inhibitor types available for treating skin scarring. Understanding the role of the Wnt pathway in cutaneous fibrosis will accelerate the development of effective Wnt modulators for the treatment of skin fibrosis.

    View details for DOI 10.1002/med.21853

    View details for PubMedID 34431110

  • Decellularized Adipose Matrices can Alleviate Radiation-induced Skin Fibrosis. Advances in wound care Adem, S., Abbas, D. B., Lavin, C., Fahy, E., Griffin, M., Diaz Deleon, N. M., Borrelli, M. R., Mascharak, S., Shen, A. H., Patel, R. A., Longaker, M. T., Nazerali, R. S., Wan, D. C. 2021

    Abstract

    OBJECTIVE: Radiation therapy is commonplace for cancer treatment but often results in fibrosis and atrophy of surrounding soft tissue. Decellularized adipose matrices (DAMs) have been reported to improve these soft tissue defects through the promotion of adipogenesis. These matrices are decellularized by a combination of physical, chemical, and enzymatic methods to minimize their immunologic effects while promoting their regenerative effects. In this study, we aimed to explore the regenerative ability of a DAM (Renuva, MTF Biologics, New Jersey, USA) in radiation-induced soft tissue injury.APPROACH: Fresh human lipoaspirate or DAM was injected into the irradiated scalp of CD-1 nude mice, and volume retention was monitored radiographically over 8 weeks. Explanted grafts were histologically assessed, and overlying skin was examined histologically and biomechanically. Irradiated human skin was also evaluated from patients following fat grafting or DAM injection. However, integrating data between murine and human skin in all cohorts is limited given the genetic variability between the two species.RESULTS: Volume retention was found to be greater with fat grafts, though DAM retention was nonetheless appreciated at irradiated sites. Improvement in both mouse and human irradiated skin overlying fat and DAM grafts was observed in terms of biomechanical stiffness, dermal thickness, collagen density, collagen fiber networks, and skin vascularity.INNOVATION: This is the first demonstration of the use of DAMs for augmenting the regenerative potential of irradiated mouse and human skin.CONCLUSIONS: These findings support use of DAMs to address soft tissue atrophy following radiation therapy. Morphological characteristics of the irradiated skin can also be improved with DAM grafting.

    View details for DOI 10.1089/wound.2021.0008

    View details for PubMedID 34346243

  • Mechanical Strain Drives Myeloid Cell Differentiation Toward Pro-Inflammatory Subpopulations. Advances in wound care Chen, K., Henn, D., Sivaraj, D., Bonham, C. A., Griffin, M., Choi Kussie, H., Padmanabhan, J., Trotsyuk, A. A., Wan, D. C., Januszyk, M., Longaker, M. T., Gurtner, G. C. 2021

    Abstract

    OBJECTIVE: After injury, humans and other mammals heal by forming fibrotic scar tissue with diminished function, and this healing process involves the dynamic interplay between resident cells within the skin and cells recruited from the circulation. Recent studies have provided mounting evidence that external mechanical forces stimulate intracellular signaling pathways to drive fibrotic processes.INNOVATION: While most studies have focused on studying mechanotransduction in fibroblasts, recent data suggest that mechanical stimulation may also shape the behavior of immune cells, referred to as "mechano-immunomodulation". However, the effect of mechanical strain on myeloid cell recruitment and differentiation remains poorly understood and has never been investigated at the single cell level.APPROACH: In this study, we utilized a three-dimensional (3D) in vitro culture system that permits the precise manipulation of mechanical strain applied to cells. We cultured myeloid cells and used single cell RNA-sequencing to interrogate the effects of strain on myeloid differentiation and transcriptional programming.RESULTS: Our data indicate that myeloid cells are indeed mechanoresponsive, with mechanical stress influencing myeloid differentiation. Mechanical strain also upregulated a cascade of inflammatory chemokines, most notably from the Ccl family.CONCLUSION: Further understanding of how mechanical stress affects myeloid cells in conjunction with other cell types in the complicated, multicellular milieu of wound healing may lead to novel insights and therapies for the treatment of fibrosis.

    View details for DOI 10.1089/wound.2021.0036

    View details for PubMedID 34278820

  • Readability of Online Patient Information Relating to Cleft Palate Surgery. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association Lavin, C. V., Fahy, E. J., Abbas, D. B., Griffin, M., Deleon, N. M., Lee, D. K., Khosla, R. K., Bruckman, K., Lorenz, H. P., Wan, D. C. 2021: 10556656211013177

    Abstract

    OBJECTIVE: It is important for health care education materials to be easily understood by caretakers of children requiring craniofacial surgery. This study aimed to analyze the readability of Google search results as they pertain to "Cleft Palate Surgery" and "Palatoplasty." Additionally, the study included a search from several locations globally to identify possible geographic differences.DESIGN: Google searches of the terms "Cleft Palate Surgery" and "Palatoplasty" were performed. Additionally, searches of only "Cleft Palate Surgery" were run from several internet protocol addresses globally.MAIN OUTCOME MEASURES: Flesch-Kincaid Grade Level and Readability Ease, Gunning Fog Index, Simple Measure of Gobbledygook (SMOG) index, and Coleman-Liau Index.RESULTS: Search results for "Cleft Palate Surgery" were easier to read and comprehend compared to search results for "Palatoplasty." Mean Flesch-Kincaid Grade Level scores were 7.0 and 10.11, respectively (P = .0018). Mean Flesch-Kincaid Reading Ease scores were 61.29 and 40.71, respectively (P = .0003). Mean Gunning Fog Index scores were 8.370 and 10.34, respectively (P = .0458). Mean SMOG Index scores were 6.84 and 8.47, respectively (P = .0260). Mean Coleman-Liau Index scores were 12.95 and 15.33, respectively (P = .0281). No significant differences were found in any of the readability measures based on global location.CONCLUSIONS: Although some improvement can be made, craniofacial surgeons can be confident in the online information pertaining to cleft palate repair, regardless of where the search is performed from. The average readability of the top search results for "Cleft Palate Surgery" is around the seventh-grade reading level (US educational system) and compares favorably to other health care readability analyses.

    View details for DOI 10.1177/10556656211013177

    View details for PubMedID 33960204

  • Wnt-active Engrailed-1 Lineage-negative Fibroblasts Mediate Postnatal Skin Regeneration Mascharak, S., desJardins-Park, H. E., Januszyk, M., Chen, K., Davitt, M. F., Demeter, J., Henn, D., Griffin, M., Bonham, C. A., Mooney, N., Cheng, R., Jackson, P. K., Wan, D. C., Gurtner, G. C., Longaker, M. T. WILEY. 2021: A30
  • Single Cell RNA Sequencing Reveals Fibroblast Heterogeneity Across Embryonic Origins Of Skin Griffin, M., King, M., Chen, K., desJardins-Park, H., Mascharak, S., Fahy, E., Guardino, N., Lavin, C., Abbas, D., Januszyk, M., Wan, D., Longaker, M. WILEY. 2021: A11-A12
  • Novel Genetic Analysis Of MRL Mice Reveals That Complement Inhibition By Factor H Reduces Scarring desJardins-Park, H. E., Mack, K. L., Guardino, N., Griffin, M., Davitt, M. F., Mascharak, S., Wan, D. C., Fraser, H. B., Longaker, M. T. WILEY. 2021: A13
  • Adipocytes In Dermal Wounds Undergo Conversion To Pro-fibrotic Fibroblasts That Contribute To Scar Formation Guardino, N., desJardins-Park, H. E., Griffin, M., Bauer-Rowe, K. E., King, M. E., King, M. E., Mascharak, S., Longaker, M. T. WILEY. 2021: A31
  • Transgenic Inhibition Of Engrailed-1 Results In Endogenous Postnatal Skin Regeneration Mascharak, S., desJardins-Park, H. E., Davitt, M. F., Chen, K., Griffin, M., Guardino, N., Lorenz, H., Wan, D. C., Gurtner, G. C., Longaker, M. T. WILEY. 2021: A14-A15
  • Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science (New York, N.Y.) Mascharak, S., desJardins-Park, H. E., Davitt, M. F., Griffin, M., Borrelli, M. R., Moore, A. L., Chen, K., Duoto, B., Chinta, M., Foster, D. S., Shen, A. H., Januszyk, M., Kwon, S. H., Wernig, G., Wan, D. C., Lorenz, H. P., Gurtner, G. C., Longaker, M. T. 2021; 372 (6540)

    Abstract

    Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. Engrailed-1 lineage-positive fibroblasts (EPFs) are known to function in scarring, but Engrailed-1 lineage-negative fibroblasts (ENFs) remain poorly characterized. Using cell transplantation and transgenic mouse models, we identified a dermal ENF subpopulation that gives rise to postnatally derived EPFs by activating Engrailed-1 expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives Engrailed-1 activation via canonical mechanotransduction signaling. Finally, we showed that blocking mechanotransduction signaling with either verteporfin, an inhibitor of Yes-associated protein (YAP), or fibroblast-specific transgenic YAP knockout prevents Engrailed-1 activation and promotes wound regeneration by ENFs, with recovery of skin appendages, ultrastructure, and mechanical strength. This finding suggests that there are two possible outcomes to postnatal wound healing: a fibrotic response (EPF-mediated) and a regenerative response (ENF-mediated).

    View details for DOI 10.1126/science.aba2374

    View details for PubMedID 33888614

  • PRISMA 2020 statement: What's new and the importance of reporting guidelines. International journal of surgery (London, England) Sohrabi, C., Franchi, T., Mathew, G., Kerwan, A., Nicola, M., Griffin, M., Agha, M., Agha, R. 2021: 105918

    Abstract

    The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement, first published in 2009 [1], was developed in an attempt to increase the clarity, transparency, quality and value of these reports [2]. The 27-item checklist and four-phase flow diagram have become the hallmark of academic rigour in the publication of systematic reviews and meta-analyses, having been cited by over 60,000 papers [3]. These are frequently endorsed by journals in their 'Instructions to Authors' [4]. Developments in the methodology and terminology used when conducting systematic reviews [5], alongside the identification of limitations responsible for poor adherence, such as the use of ambiguous wording [6], have warranted an update to the PRISMA statement. The PRISMA 2020 statement, therefore, is intended to reflect this recent evolution in the identification, selection, appraisal and synthesis of research [7]. Here, we present an interpretive analysis of the updated statement, with a view towards encouraging its adoption by both journals and authors in the pursuit of advancing evidence-based medicine.

    View details for DOI 10.1016/j.ijsu.2021.105918

    View details for PubMedID 33789825

  • Impact of the coronavirus (COVID-19) pandemic on scientific research and implications for clinical academic training - a review. International journal of surgery (London, England) Sohrabi, C. n., Mathew, G. n., Franchi, T. n., Kerwan, A. n., Griffin, M. n., Soleil C Del Mundo, J. n., Ali, S. A., Agha, M. n., Agha, R. n. 2021

    Abstract

    A pneumonia outbreak of unknown aetiology emerged in Wuhan, China in December 2019. The causative organism was identified on the 7th of January 2020 as a novel coronavirus (nCoV or 2019-nCoV), later renamed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The resulting coronavirus (COVID-19) disease has infected over 37 57.8 million individuals, resulted in over 1 1.3 million deaths, and has led to an unprecedented impact on research activities worldwide. Extraordinary challenges have also been imposed upon medical and surgical trainees following re-deployment to full-time clinical duties. Moreover, the introduction of travel restrictions and strict lockdown measures have forced the closure of many institutions and laboratories working on research unrelated to the pandemic. The lockdown has similarly stifled supply chains and slowed research and development endeavours, whilst research charities have endured significant financial strains that have since reshaped the allocation and availability of funds. Worldwide scientific adaptation to the COVID-19 pandemic has also been observed through unprecedented levels of international collaboration as well as the uprise of remote telecommunication platforms. Although the long-term consequence of the COVID-19 pandemic on research and academic training is difficult to ascertain, the current crises will inevitably shape working and teaching patterns for years to come. To this end, we provide a comprehensive and critical evaluation of the impact of COVID-19 on scientific research and funding, as well as academic medical and surgical training.

    View details for DOI 10.1016/j.ijsu.2020.12.008

    View details for PubMedID 33444873

  • Striae Distensae: Scars without Wounds. Plastic and reconstructive surgery Borrelli, M. R., Griffin, M., Ngaage, L. M., Longaker, M. T., Lorenz, H. P. 2021; 148 (1): 77-87

    Abstract

    Striae distensae, or stretch marks, are common linear lesions of atrophic skin characterized histologically by epidermal atrophy, absent rete ridges, and alterations in connective tissue architecture. Hormonal excess, mechanical stress, and genetic predisposition are all associated with striae distensae, but their exact pathogenesis remains unknown. Despite a multitude of options, no single treatment has yet proven effective. In this article, the authors describe an up-to-date overview of striae distensae in terms of their etiology, pathophysiology, and therapeutic options. Further research is required to better elucidate their pathophysiology and to develop targeted effective treatments.

    View details for DOI 10.1097/PRS.0000000000008065

    View details for PubMedID 34181606

  • Disrupting biological sensors of force promotes tissue regeneration in large organisms. Nature communications Chen, K., Kwon, S. H., Henn, D., Kuehlmann, B. A., Tevlin, R., Bonham, C. A., Griffin, M., Trotsyuk, A. A., Borrelli, M. R., Noishiki, C., Padmanabhan, J., Barrera, J. A., Maan, Z. N., Dohi, T., Mays, C. J., Greco, A. H., Sivaraj, D., Lin, J. Q., Fehlmann, T., Mermin-Bunnell, A. M., Mittal, S., Hu, M. S., Zamaleeva, A. I., Keller, A., Rajadas, J., Longaker, M. T., Januszyk, M., Gurtner, G. C. 2021; 12 (1): 5256

    Abstract

    Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.

    View details for DOI 10.1038/s41467-021-25410-z

    View details for PubMedID 34489407

  • Angiogenic CD34+CD146+ adipose-derived stromal cells augment recovery of soft tissue after radiotherapy. Journal of tissue engineering and regenerative medicine Diaz Deleon, N. M., Adem, S., Lavin, C. V., Abbas, D. B., Griffin, M., King, M. E., Borrelli, M. R., Patel, R. A., Fahy, E. J., Lee, D., Shen, A. H., Momeni, A., Longaker, M. T., Wan, D. C. 2021

    Abstract

    Radiation therapy is effective for cancer treatment but may also result in collateral soft tissue contracture, contour deformities, and non-healing wounds. Autologous fat transfer has been described to improve tissue architecture and function of radiation-induced fibrosis and these effects may be augmented by enrichment with specific adipose-derived stromal cells (ASCs) with enhanced angiogenic potential. CD34+CD146+, CD34+CD146-, or CD34+ unfractionated (UF) human ASCs were isolated by flow cytometry and used to supplement human lipoaspirate placed beneath the scalp of irradiated mice. Volume retention was followed radiographically and fat grafts as well as overlying soft tissue were harvested after eight weeks for histologic and biomechanical analyses. Radiographic evaluation revealed the highest volume retention in fat grafts supplemented with CD34+CD146+ ASCs, and these grafts were also found to have greater histologic integrity than other groups. Irradiated skin overlying CD34+CD146+ ASC-enriched grafts was significantly more vascularized than other treatment groups, had significantly less dermal thickness and collagen deposition, and the greatest improvement in fibrillin staining and return of elasticity. Radiation therapy obliterates vascularity and contributes to scarring and loss of tissue function. ASC-enrichment of fat grafts with CD34+CD146+ ASCs not only enhances fat graft vascularization and retention, but also significantly promotes improvement in overlying radiation-injured soft tissue. This regenerative effect on skin is highly promising for patients with impaired wound healing and deformities following radiotherapy. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/term.3253

    View details for PubMedID 34582109

  • The Adrenergic System in Plastic and Reconstructive Surgery: Physiology and Clinical Considerations. Annals of plastic surgery Fahy, E. J., Griffin, M. n., Lavin, C. n., Abbas, D. n., Longaker, M. T., Wan, D. n. 2021

    Abstract

    The primary organ systems and tissues concerning plastic and reconstructive surgery include the integument, vasculature, subcutis, and peripheral nerves, because these may individually or collectively be injured requiring reconstruction, or indeed be used in reconstruction themselves through grafts, flaps, or anastomoses. Adrenergic receptors are present throughout these anatomic components on the vasculature, adipose, platelets, immune cells, keratinocytes, melanocytes, fibroblasts, peripheral nerves, and tendons. Herein, the influence of adrenergic signaling on the physiology of anatomic components related to plastic surgery is discussed, along with clinical considerations of this systems involvement in procedures, such as free flap reconstruction, skin grafting, fat grafting, and other areas relevant to plastic and reconstructive surgery. Current evidence as well as potential for further investigation is discussed.

    View details for DOI 10.1097/SAP.0000000000002706

    View details for PubMedID 33833152

  • Preparing for COVID-19 exit strategies. Annals of medicine and surgery (2012) Griffin, M., Sohrabi, C., Alsafi, Z., Nicola, M., Kerwan, A., Mathew, G., Agha, R. 2021; 61: 88–92

    Abstract

    The COVID-19 pandemic has affected 20 million people worldwide with over 732,000 deaths and trillions of dollars of lost economic productivity. It has put many countries into lockdown to contain the virus and save lives. As COVID-19 cases in some countries start to plateau and societies work hard to 'flatten the curve', leaders are being asked to formulate plans for safe and staged 'exit strategies' to reopen society. Each country will decide on their own exit strategy but many plans are considering similar vital healthcare principles including the maintenance of social distancing to prevent ongoing community transmission, testing capacity, protection of the healthcare systems and the health of their care workers. This review aims to provide an overview of essential factors that plans for exit strategy should consider and their effect on the societies' social and healthcare life.

    View details for DOI 10.1016/j.amsu.2020.12.012

    View details for PubMedID 33391762

  • Exosomes - a tool for bone tissue engineering. Tissue engineering. Part B, Reviews Huber, J. L., Griffin, M., Longaker, M. T., Quarto, N. 2020

    Abstract

    Mesenchymal stem cells (MSC) have been repeatedly shown to be a valuable source for cell-based therapy in regenerative medicine, including bony tissue repair. However, engraftment at the injury site is poor. Recently, it has been suggested that MSCs and other cells act via a paracrine signaling mechanism. Exosomes are nanostructures that have been implicated in this process. They carry DNA, RNA, proteins and lipids and play an important role in cell-to-cell communication directly modulating their target cell at a transcriptional level. In a bone microenvironment, they have been shown to increase osteogenesis and osteogenic differentiation in vivo and in vitro. In the following review, we will discuss the most advanced and significant knowledge of biological functions of exosomes in bone regeneration and their clinical applications in osseous diseases.

    View details for DOI 10.1089/ten.TEB.2020.0246

    View details for PubMedID 33297857

  • Prrx1 Fibroblasts Represent a Pro-fibrotic Lineage in the Mouse Ventral Dermis. Cell reports Leavitt, T., Hu, M. S., Borrelli, M. R., Januszyk, M., Garcia, J. T., Ransom, R. C., Mascharak, S., desJardins-Park, H. E., Litzenburger, U. M., Walmsley, G. G., Marshall, C. D., Moore, A. L., Duoto, B., Adem, S., Foster, D. S., Salhotra, A., Shen, A. H., Griffin, M., Shen, E. Z., Barnes, L. A., Zielins, E. R., Maan, Z. N., Wei, Y., Chan, C. K., Wan, D. C., Lorenz, H. P., Chang, H. Y., Gurtner, G. C., Longaker, M. T. 2020; 33 (6): 108356

    Abstract

    Fibroblast heterogeneity has been shown within the unwounded mouse dorsal dermis, with fibroblast subpopulations being identified according to anatomical location and embryonic lineage. Using lineage tracing, we demonstrate that paired related homeobox 1 (Prrx1)-expressing fibroblasts are responsible for acute and chronic fibroses in the ventral dermis. Single-cell transcriptomics further corroborated the inherent fibrotic characteristics of Prrx1 fibroblasts during wound repair. In summary, we identify and characterize a fibroblast subpopulation in the mouse ventral dermis with intrinsic scar-forming potential.

    View details for DOI 10.1016/j.celrep.2020.108356

    View details for PubMedID 33176144

  • Elucidating Molecular Drivers of Wound Regeneration in MRL Mice Via Novel Transcriptomic Analyses desJardins-Park, H. E., Mack, K. L., Davitt, M. F., Griffin, M., Mascharak, S., Fraser, H. B., Longaker, M. T. ELSEVIER SCIENCE INC. 2020: S225
  • A Surgical Model for Investigating the Role of Creeping Fat in Intestinal Fibrosis Bauer-Rowe, K. E., Foster, D., Titan, A., Chinta, M., desJardins-Park, H., Griffin, M., Longaker, M. T. ELSEVIER SCIENCE INC. 2020: S50–S51
  • Harnessing novel gene expression analyses to identify drivers of regenerative ear wound healing in MRL mice desJardins-Park, H. E., Mack, K. L., Davitt, M. F., Griffin, M., Fraser, H. B., Longaker, M. T. WILEY. 2020: S25
  • Impact of the Coronavirus (COVID-19) pandemic on surgical practice - Part 2 (surgical prioritisation) INTERNATIONAL JOURNAL OF SURGERY Al-Jabir, A., Kerwan, A., Nicola, M., Alsafi, Z., Khan, M., Sohrabi, C., O'Neill, N., Iosifidis, C., Griffin, M., Mathew, G., Agha, R. 2020; 79: 233–48
  • Stretch marks are abundant in CD26-positive human dermal fibroblasts and exhibit increased profibrotic mechanosensitive signaling Borrelli, M. R., Griffin, M., Ngaage, L. M., Mascharak, S., Lewis, N., Januszyk, M., Wan, D. C., Longaker, M. T., Lorenz, H. P. WILEY. 2020: S32
  • Health Policy and Leadership Models During the COVID-19 Pandemic- Review Article. International journal of surgery (London, England) Nicola, M. n., Sohrabi, C. n., Mathew, G. n., Kerwan, A. n., Al-Jabir, A. n., Griffin, M. n., Agha, M. n., Agha, R. n. 2020

    Abstract

    On 11th March 2020, the spread of the SARS-CoV-2 virus was declared a pandemic by the World Health Organisation (WHO). Approximately 5.6 million have now been infected and over 350,000 have died. This global public health crisis has since cascaded into a series of challenges for leaders around the world, threatening both the health and economy of populations. This paper attempts to compartmentalise leadership aspects, allowing a closer examination of reports and the analysis of outcomes. The authors are thus enabled to formulate a number of evidence-based recommendations on the de-escalation of restrictions.

    View details for DOI 10.1016/j.ijsu.2020.07.026

    View details for PubMedID 32687873

  • Understanding the impact of fibroblast heterogeneity on skin fibrosis. Disease models & mechanisms Griffin, M. F., desJardins-Park, H. E., Mascharak, S. n., Borrelli, M. R., Longaker, M. T. 2020; 13 (6)

    Abstract

    Tissue fibrosis is the deposition of excessive extracellular matrix and can occur as part of the body's natural wound healing process upon injury, or as a consequence of diseases such as systemic sclerosis. Skin fibrosis contributes to significant morbidity due to the prevalence of injuries resulting from trauma and burn. Fibroblasts, the principal cells of the dermis, synthesize extracellular matrix to maintain the skin during homeostasis and also play a pivotal role in all stages of wound healing. Although it was previously believed that fibroblasts are homogeneous and mostly quiescent cells, it has become increasingly recognized that numerous fibroblast subtypes with unique functions and morphologies exist. This Review provides an overview of fibroblast heterogeneity in the mammalian dermis. We explain how fibroblast identity relates to their developmental origin, anatomical site and precise location within the skin tissue architecture in both human and mouse dermis. We discuss current evidence for the varied functionality of fibroblasts within the dermis and the relationships between fibroblast subtypes, and explain the current understanding of how fibroblast subpopulations may be controlled through transcriptional regulatory networks and paracrine communications. We consider how fibroblast heterogeneity can influence wound healing and fibrosis, and how insight into fibroblast heterogeneity could lead to novel therapeutic developments and targets for skin fibrosis. Finally, we contemplate how future studies should be shaped to implement knowledge of fibroblast heterogeneity into clinical practice in order to lessen the burden of skin fibrosis.

    View details for DOI 10.1242/dmm.044164

    View details for PubMedID 32541065

  • Impact of the Coronavirus (COVID-19) pandemic on surgical practice - Part 1 (Review Article). International journal of surgery (London, England) Al-Jabir, A. n., Kerwan, A. n., Nicola, M. n., Alsafi, Z. n., Khan, M. n., Sohrabi, C. n., O'Neill, N. n., Iosifidis, C. n., Griffin, M. n., Mathew, G. n., Agha, R. n. 2020

    Abstract

    The Coronavirus (COVID-19) pandemic has resulted in over 2.3 million confirmed cases and over 160,000 deaths. The impact of COVID-19 on surgical practice is widespread ranging from workforce and staffing issues, procedural prioritisation, viral transmission risk intraoperatively, changes to perioperative practice and ways of working alongside the impact on surgical education and training. Whilst there has been a growing literature base describing the early clinical course of COVID-19 and on aspects of critical care related to treating these patients, there has been a dearth of evidence on how this pandemic will affect surgical practice. This paper seeks to review the current evidence and offers recommendations for changes to surgical practice to minimise the effect of the COVID-19 pandemic.

    View details for DOI 10.1016/j.ijsu.2020.05.022

    View details for PubMedID 32407799

    View details for PubMedCentralID PMC7214340

  • Impact of the coronavirus (COVID-19) pandemic on surgical practice - Part 2 (surgical prioritisation). International journal of surgery (London, England) Al-Jabir, A. n., Kerwan, A. n., Nicola, M. n., Alsafi, Z. n., Khan, M. n., Sohrabi, C. n., O'Neill, N. n., Iosifidis, C. n., Griffin, M. n., Mathew, G. n., Agha, R. n. 2020

    Abstract

    The Coronavirus (COVID-19) Pandemic represents a once in a century challenge to human healthcare with 2.4 million cases and 165,000 deaths thus far. Surgical practice has been significantly impacted with all specialties writing guidelines for how to manage during this crisis. All specialties have had to triage the urgency of their daily surgical procedures and consider non-surgical management options where possible. The Pandemic has had ramifications for ways of working, surgical techniques, open vs minimally invasive, theatre workflow, patient and staff safety, training and education. With guidelines specific to each specialty being implemented and followed, surgeons should be able to continue to provide safe and effective care to their patients during the COVID-19 pandemic. In this comprehensive and up to date review we assess changes to working practices through the lens of each surgical specialty.

    View details for DOI 10.1016/j.ijsu.2020.05.002

    View details for PubMedID 32413502

    View details for PubMedCentralID PMC7217115

  • The regenerative role of adipose-derived stem cells (ADSC) in plastic and reconstructive surgery INTERNATIONAL WOUND JOURNAL Naderi, N., Combellack, E. J., Griffin, M., Sedaghati, T., Javed, M., Findlay, M. W., Wallace, C. G., Mosahebi, A., Butler, P. E., Seifalian, A. M., Whitaker, I. S. 2017; 14 (1): 112-124

    Abstract

    The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs offers a paradigm shift in plastic and reconstructive surgery. The use of either embryonic stem cells (ESC) or induced pluripotent stem cells (iPSC) in clinical situations is limited because of regulations and ethical considerations even though these cells are theoretically highly beneficial. Adult mesenchymal stem cells appear to be an ideal stem cell population for practical regenerative medicine. Among these cells, adipose-derived stem cells (ADSC) have the potential to differentiate the mesenchymal, ectodermal and endodermal lineages and are easy to harvest. Additionally, adipose tissue yields a high number of ADSC per volume of tissue. Based on this background knowledge, the purpose of this review is to summarise and describe the proliferation and differentiation capacities of ADSC together with current preclinical data regarding the use of ADSC as regenerative tools in plastic and reconstructive surgery.

    View details for DOI 10.1111/iwj.12569

    View details for Web of Science ID 000392919100017

    View details for PubMedID 26833722