All Publications

  • Understanding Tendon Fibroblast Biology and Heterogeneity. Biomedicines DiIorio, S. E., Young, B., Parker, J. B., Griffin, M. F., Longaker, M. T. 2024; 12 (4)


    Tendon regeneration has emerged as an area of interest due to the challenging healing process of avascular tendon tissue. During tendon healing after injury, the formation of a fibrous scar can limit tendon strength and lead to subsequent complications. The specific biological mechanisms that cause fibrosis across different cellular subtypes within the tendon and across different tendons in the body continue to remain unknown. Herein, we review the current understanding of tendon healing, fibrosis mechanisms, and future directions for treatments. We summarize recent research on the role of fibroblasts throughout tendon healing and describe the functional and cellular heterogeneity of fibroblasts and tendons. The review notes gaps in tendon fibrosis research, with a focus on characterizing distinct fibroblast subpopulations in the tendon. We highlight new techniques in the field that can be used to enhance our understanding of complex tendon pathologies such as fibrosis. Finally, we explore bioengineering tools for tendon regeneration and discuss future areas for innovation. Exploring the heterogeneity of tendon fibroblasts on the cellular level can inform therapeutic strategies for addressing tendon fibrosis and ultimately reduce its clinical burden.

    View details for DOI 10.3390/biomedicines12040859

    View details for PubMedID 38672213

    View details for PubMedCentralID PMC11048404

  • Deferoxamine topical cream superior to patch in rescuing radiation-induced fibrosis of unwounded and wounded skin. Journal of cellular and molecular medicine Berry, C. E., Abbas, D. B., Griffin, M., Lintel, H., Guo, J., Kameni, L., Churukian, A. A., Fazilat, A. Z., Chen, K., Gurtner, G. C., Longaker, M. T., Momeni, A., Wan, D. C. 2024; 28 (8): e18306


    Topical patch delivery of deferoxamine (DFO) has been studied as a treatment for this fibrotic transformation in irradiated tissue. Efficacy of a novel cream formulation of DFO was studied as a RIF therapeutic in unwounded and excisionally wounded irradiated skin. C57BL/6J mice underwent 30 Gy of radiation to the dorsum followed by 4 weeks of recovery. In a first experiment, mice were separated into six conditions: DFO 50 mg cream (D50), DFO 100 mg cream (D100), soluble DFO injections (DI), DFO 1 mg patch (DP), control cream (Vehicle), and irradiated untreated skin (IR). In a second experiment, excisional wounds were created on the irradiated dorsum of mice and then divided into four treatment groups: DFO 100 mg Cream (W-D100), DFO 1 mg patch (W-DP), control cream (W-Vehicle), and irradiated untreated wounds (W-IR). Laser Doppler perfusion scans, biomechanical testing, and histological analysis were performed. In irradiated skin, D100 improved perfusion compared to D50 or DP. Both D100 and DP enhanced dermal characteristics, including thickness, collagen density and 8-isoprostane staining compared to untreated irradiated skin. D100 outperformed DP in CD31 staining, indicating higher vascular density. Extracellular matrix features of D100 and DP resembled normal skin more closely than DI or control. In radiated excisional wounds, D100 facilitated faster wound healing and increased perfusion compared to DP. The 100 mg DFO cream formulation rescued RIF of unwounded irradiated skin and improved excisional wound healing in murine skin relative to patch delivery of DFO.

    View details for DOI 10.1111/jcmm.18306

    View details for PubMedID 38613357

  • Understanding wound healing in obesity. World journal of experimental medicine Cotterell, A., Griffin, M., Downer, M. A., Parker, J. B., Wan, D., Longaker, M. T. 2024; 14 (1): 86898


    Obesity has become more prevalent in the global population. It is associated with the development of several diseases including diabetes mellitus, coronary heart disease, and metabolic syndrome. There are a multitude of factors impacted by obesity that may contribute to poor wound healing outcomes. With millions worldwide classified as obese, it is imperative to understand wound healing in these patients. Despite advances in the understanding of wound healing in both healthy and diabetic populations, much is unknown about wound healing in obese patients. This review examines the impact of obesity on wound healing and several animal models that may be used to broaden our understanding in this area. As a growing portion of the population identifies as obese, understanding the underlying mechanisms and how to overcome poor wound healing is of the utmost importance.

    View details for DOI 10.5493/wjem.v14.i1.86898

    View details for PubMedID 38590299

    View details for PubMedCentralID PMC10999071

  • Natural Compounds and Biomimetic Engineering to Influence Fibroblast Behavior in Wound Healing. International journal of molecular sciences Berry, C. E., Brenac, C., Gonzalez, C. E., Kendig, C. B., Le, T., An, N., Griffin, M. F. 2024; 25 (6)


    Throughout history, natural products have played a significant role in wound healing. Fibroblasts, acting as primary cellular mediators in skin wound healing, exhibit behavioral responses to natural compounds that can enhance the wound healing process. Identifying bioactive natural compounds and understanding their impact on fibroblast behavior offers crucial translational opportunities in the realm of wound healing. Modern scientific techniques have enabled a detailed understanding of how naturally derived compounds modulate wound healing by influencing fibroblast behavior. Specific compounds known for their wound healing properties have been identified. Engineered biomimetic compounds replicating the natural wound microenvironment are designed to facilitate normal healing. Advanced delivery methods operating at micro- and nano-scales have been developed to effectively deliver these novel compounds through the stratum corneum. This review provides a comprehensive summary of the efficacy of natural compounds in influencing fibroblast behavior for promoting wound regeneration and repair. Additionally, it explores biomimetic engineering, where researchers draw inspiration from nature to create materials and devices mimicking physiological cues crucial for effective wound healing. The review concludes by describing novel delivery mechanisms aimed at enhancing the bioavailability of natural compounds. Innovative future strategies involve exploring fibroblast-influencing pathways, responsive biomaterials, smart dressings with real-time monitoring, and applications of stem cells. However, translating these findings to clinical settings faces challenges such as the limited validation of biomaterials in large animal models and logistical obstacles in industrial production. The integration of ancient remedies with modern approaches holds promise for achieving effective and scar-free wound healing.

    View details for DOI 10.3390/ijms25063274

    View details for PubMedID 38542247

  • A tension offloading patch mitigates dermal fibrosis induced by pro-fibrotic skin injections. Research square Talbott, H. E., Griffin, M. F., Mascharak, S., Parker, J. B., Kuhnert, M. M., Guo, J. L., Diaz Deleon, N. M., Lavin, C., Abbas, D., Guardino, N., Morgan, A., Valencia, C., Cotterell, A., Longaker, M. T., Wan, D. C. 2024


    Skin fibrosis is a clinical problem with devastating impacts but limited treatment options. In the setting of diabetes, insulin administration often causes local dermal fibrosis, leading to a range of clinical sequelae including impeded insulin absorption. Mechanical forces are important drivers of fibrosis and, clinically, physical tension offloading at the skin level using an elastomeric patch significantly reduces wound scarring. However, it is not known whether tension offloading could similarly prevent skin fibrosis in the setting of pro-fibrotic injections. Here, we develop a porcine model using repeated local injections of bleomycin to recapitulate key features of insulin-induced skin fibrosis. Using histologic, tissue ultrastructural, and biomechanical analyses, we show that application of a tension-offloading patch both prevents and rescues existing skin fibrosis from bleomycin injections. By applying single-cell transcriptomic analysis, we find that the fibrotic response to bleomycin involves shifts in myeloid cell dynamics from favoring putatively pro-regenerative to pro-fibrotic myeloid subtypes; in a mechanomodulatory in vitro platform, we show that these shifts are mechanically driven and reversed by exogenous IL4. Finally, using a human foreskin xenograft model, we show that IL4 treatment mitigates bleomycin-induced dermal fibrosis. Overall, this study highlights that skin tension offloading, using an FDA cleared, commercially available patch, could have significant potential clinical benefit for the millions of patients dependent on insulin.

    View details for DOI 10.21203/

    View details for PubMedID 38464040

  • The Urgent Need to Define HbA1C Cutoffs in Hand Surgery. Hand (New York, N.Y.) Griffin, M. F., Curtin, C. 2024: 15589447241233358

    View details for DOI 10.1177/15589447241233358

    View details for PubMedID 38388391

  • Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Aggarwal, N. R., Nordwall, J., Braun, D. L., Chung, L., Coslet, J., Der, T., Eriobu, N., Ginde, A. A., Hayanga, A. J., Highbarger, H., Holodniy, M., Horcajada, J. P., Jain, M. K., Kim, K., Laverdure, S., Lundgren, J., Natarajan, V., Nguyen, H. H., Pett, S. L., Phillips, A., Poulakou, G., Price, D. A., Robinson, P., Rogers, A. J., Sandkovsky, U., Shaw-Saliba, K., Sturek, J. M., Trautner, B. W., Waters, M., Reilly, C. 2024


    Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials.A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models.Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time.Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

    View details for DOI 10.1093/cid/ciad780

    View details for PubMedID 38376212

  • Pharmacological and cell-based treatments to increase local skin flap viability in animal models. Journal of translational medicine Berry, C. E., Le, T., An, N., Griffin, M., Januszyk, M., Kendig, C. B., Fazilat, A. Z., Churukian, A. A., Pan, P. M., Wan, D. C. 2024; 22 (1): 68


    Local skin flaps are frequently employed for wound closure to address surgical, traumatic, congenital, or oncologic defects. (1) Despite their clinical utility, skin flaps may fail due to inadequate perfusion, ischemia/reperfusion injury (IRI), excessive cell death, and associated inflammatory response. (2) All of these factors contribute to skin flap necrosis in 10-15% of cases and represent a significant surgical challenge. (3, 4) Once flap necrosis occurs, it may require additional surgeries to remove the entire flap or repair the damage and secondary treatments for infection and disfiguration, which can be costly and painful. (5) In addition to employing appropriate surgical techniques and identifying healthy, well-vascularized tissue to mitigate the occurrence of these complications, there is growing interest in exploring cell-based and pharmacologic augmentation options. (6) These agents typically focus on preventing thrombosis and increasing vasodilation and angiogenesis while reducing inflammation and oxidative stress. Agents that modulate cell death pathways such as apoptosis and autophagy have also been investigated. (7) Implementation of drugs and cell lines with potentially beneficial properties have been proposed through various delivery techniques including systemic treatment, direct wound bed or flap injection, and topical application. This review summarizes pharmacologic- and cell-based interventions to augment skin flap viability in animal models, and discusses both translatability challenges facing these therapies and future directions in the field of skin flap augmentation.

    View details for DOI 10.1186/s12967-024-04882-9

    View details for PubMedID 38233920

    View details for PubMedCentralID 7791712

  • Investigating Immunomodulatory Biomaterials for Preventing the Foreign Body Response. Bioengineering (Basel, Switzerland) Kim, A., Downer, M. A., Berry, C. E., Valencia, C., Fazilat, A. Z., Griffin, M. 2023; 10 (12)


    Implantable biomaterials represent the forefront of regenerative medicine, providing platforms and vessels for delivering a creative range of therapeutic benefits in diverse disease contexts. However, the chronic damage resulting from implant rejection tends to outweigh the intended healing benefits, presenting a considerable challenge when implementing treatment-based biomaterials. In response to implant rejection, proinflammatory macrophages and activated fibroblasts contribute to a synergistically destructive process of uncontrolled inflammation and excessive fibrosis. Understanding the complex biomaterial-host cell interactions that occur within the tissue microenvironment is crucial for the development of therapeutic biomaterials that promote tissue integration and minimize the foreign body response. Recent modifications of specific material properties enhance the immunomodulatory capabilities of the biomaterial and actively aid in taming the immune response by tuning interactions with the surrounding microenvironment either directly or indirectly. By incorporating modifications that amplify anti-inflammatory and pro-regenerative mechanisms, biomaterials can be optimized to maximize their healing benefits in harmony with the host immune system.

    View details for DOI 10.3390/bioengineering10121411

    View details for PubMedID 38136002

  • Current Biomaterials for Wound Healing. Bioengineering (Basel, Switzerland) Downer, M., Berry, C. E., Parker, J. B., Kameni, L., Griffin, M. 2023; 10 (12)


    Wound healing is the body's process of injury recovery. Skin healing is divided into four distinct overlapping phases: hemostasis, inflammation, proliferation, and remodeling. Cell-to-cell interactions mediated by both cytokines and chemokines are imperative for the transition between these phases. Patients can face difficulties in the healing process due to the wound being too large, decreased vascularization, infection, or additional burdens of a systemic illness. The field of tissue engineering has been investigating biomaterials as an alternative for skin regeneration. Biomaterials used for wound healing may be natural, synthetic, or a combination of both. Once a specific biomaterial is selected, it acts as a scaffold for skin regeneration. When the scaffold is applied to a wound, it allows for the upregulation of distinct molecular signaling pathways important for skin repair. Although tissue engineering has made great progress, more research is needed in order to support the use of biomaterials for wound healing for clinical translation.

    View details for DOI 10.3390/bioengineering10121378

    View details for PubMedID 38135969

  • Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19. The Journal of infectious diseases Jensen, T. O., Grandits, G. A., Jain, M. K., Murray, T. A., Grund, B., Shaw-Saliba, K., Matthay, M. A., Abassi, M., Ardelt, M., Baker, J. V., Chen, P., Dewar, R. L., Goodman, A. L., Hatlen, T. J., Highbarger, H. C., Holodniy, M., Lallemand, P., Laverdure, S., Leshnower, B. G., Looney, D., Moschopoulos, C. D., Mugerwa, H., Murray, D. D., Mylonakis, E., Nagy-Agren, S., Rehman, M. T., Rupert, A., Stevens, R. A., Turville, S., Weintrob, A., Wick, K., Lundgren, J., Ko, E. R. 2023


    Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood.Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and d-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models.Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P < .001), and a steeper rate of decline through the first 5 days (P < .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale.Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed.NCT04501978.

    View details for DOI 10.1093/infdis/jiad446

    View details for PubMedID 37948759

  • IL-1RA and IL-12 Decrease Pancreatic Ductal Adenocarcinoma Tumor Mass and Prolong Survival by Inhibiting Mechanoresponsive Cafs Morgan, A., Griffin, M., Downer, M., Lindsay, H., Parker, J. B., Guo, J. L., Longaker, M. T., Norton, J. A. LIPPINCOTT WILLIAMS & WILKINS. 2023: S455-S456
  • Single-Cell RNA-Seq Analysis Reveals Similar Fibroblasts in Irradiated Skin of Humans, Mice, and Pigs Kameni, L., Berry, C., Griffin, M., Januszyk, M., Downer, M., Huber, J. L., Parker, J., Momeni, A., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2023: S389
  • Single-Cell RNA-Sequencing Identifies Modulator of Foreign Body Response with Use of Acellular Dermal Matrix in Breast Reconstruction Liang, N., Tevlin, R., Griffin, M., Parker, J. B., Henn, D., Navarro, R. S., Dung Nguyen, Momeni, A., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2023: S389-S390
  • Tissue Microenvironment a Key Driver in Fibrotic Capsules Formed During Foreign Body Response Parker, J. B., Griffin, M., Downer, M., Morgan, A., Guo, J. L., Liang, N., Berry, C., Diiorio, S., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2023: S393
  • Fat Grafting Treatment for Radiation-Induced Fibrosis Results in Downregulation of Inflammatory and Fibrotic Signaling Pathways Berry, C., Abbas, D., Kameni, L., Griffin, M., Downer, M., Parker, J. B., Guo, J. L., Januszyk, M., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2023: S381-S382
  • Investigating Dysmotility and the Expansion of Glial Cells and Interstitial Cells of Cajal in Crohn's Disease Strictures Using a Novel Surgical Mouse Model Kim, A., Bauer-rowe, K. E., Griffin, M., Foster, D., Longaker, M. T., Hyun, J. S. LIPPINCOTT WILLIAMS & WILKINS. 2023: S355
  • Analysis of Collagen Extracellular Matrix Ultrastructure in Mouse Long Bone Distraction Osteogenesis Diiorio, S., Guo, J. L., Griffin, M., Huber, J. L., Downer, M., Berry, C., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2023: S378-S379
  • Grafting of Human Foreskin onto Murine Dorsum Provides a Novel Model of Chronic Radiation-Induced Fibrosis Berry, C., Abbas, D., Griffin, M., Kameni, L., Downer, M., Parker, J. B., Liang, N., Dilorio, S., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2023: S398
  • Meta-Analysis of Single-Cell Transcriptomics Data of Cardiac Fibroblasts Reveals Temporal Heterogeneity of Cardiac Fibroblast Response after MI Lu, J., Januszyk, M., Griffin, M., Guo, J. L., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2023: S68
  • Novel Deferoxamine Cream Formulation Improves Perfusion, Elasticity, and Tissue Architecture in Chronically Irradiated Murine Skin Compared to Transdermal Patch Berry, C., Abbas, D., Kameni, L., Griffin, M., Downer, M., Parker, J. B., Liang, N., Guo, J. L., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2023: S386
  • Pioglitazone Decreases Adipogenisis Leading to Melanoma Skin Tumor Suppression Downer, M., Griffin, M., Morgan, A., Parker, J. B., Berry, C., Li, D. J., Liang, N., Kameni, L., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2023: S387-S388
  • Ferropotosis Levels Decrease in Response to Deferoxamine Treatment in Irradiated Murine Skin Berry, C., Kameni, L., Griffin, M., Downer, M., Parker, J. B., Guo, J. L., Liang, N., Januszyk, M., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2023: S382
  • Healing of Chronically Irradiated Excisional Wounds Improved by Topical Deferoxamine Treatment Berry, C., Griffin, M., Kameni, L., Abbas, D., Downer, M., Parker, J. B., Liang, N., Januszyk, M., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2023: S382-S383
  • Where There Is Fat, There Is Fibrosis: Elucidating the Mechanisms of Creeping Fat-Driven Stricture Formation Bauer-Rowe, K. E., Kim, A., Griffin, M., Liang, N., Foster, D., Guo, J. L., Norton, J. A., Longaker, M. T., Hyun, J. S. LIPPINCOTT WILLIAMS & WILKINS. 2023: S365-S366
  • A Review of Radiation-Induced Vascular Injury and Clinical Impact. Annals of plastic surgery Kameni, L. E., Januszyk, M., Berry, C. E., Downer, M. A., Parker, J. B., Morgan, A. G., Valencia, C., Griffin, M., Li, D. J., Liang, N. E., Momeni, A., Longaker, M. T., Wan, D. C. 2023


    ABSTRACT: The number of cancer survivors continues to increase because of advances in therapeutic modalities. Along with surgery and chemotherapy, radiotherapy is a commonly used treatment modality in roughly half of all cancer patients. It is particularly helpful in the oncologic treatment of patients with breast, head and neck, and prostate malignancies. Unfortunately, among patients receiving radiation therapy, long-term sequalae are often unavoidable, and there is accumulating clinical evidence suggesting significant radiation-related damage to the vascular endothelium. Ionizing radiation has been known to cause obliterative fibrosis and increased wall thickness in irradiated blood vessels. Clinically, these vascular changes induced by ionizing radiation can pose unique surgical challenges when operating in radiated fields. Here, we review the relevant literature on radiation-induced vascular damage focusing on mechanisms and signaling pathways involved and highlight microsurgical anastomotic outcomes after radiotherapy. In addition, we briefly comment on potential therapeutic strategies, which may have the ability to mitigate radiation injury to the vascular endothelium.

    View details for DOI 10.1097/SAP.0000000000003723

    View details for PubMedID 37962260

  • Optimized Nuclei Isolation from Fresh and Frozen Solid Tumor Specimens for Multiome Sequencing. Journal of visualized experiments : JoVE Foster, D. S., Griffin, M., Januszyk, M., Delitto, D., Norton, J. A., Longaker, M. T. 2023


    Multiome sequencing, which provides same-cell/paired single-cell RNA- and the assay for transposase-accessible chromatin with sequencing (ATAC-sequencing) data, represents a breakthrough in our ability to discern tumor cell heterogeneity-a primary focus of translational cancer research at this time. However, the quality of sequencing data acquired using this advanced modality is highly dependent on the quality of the input material. Digestion conditions need to be optimized to maximize cell yield without sacrificing quality. This is particularly challenging in the context of solid tumors with dense desmoplastic matrices that must be gently broken down for cell release. Freshly isolated cells from solid tumor tissue are more fragile than those isolated from cell lines. Additionally, as the cell types isolated are heterogeneous, conditions should be selected to support the total cell population. Finally, nuclear isolation conditions must be optimized based on these qualities in terms of lysis times and reagent types/ratios. In this article, we describe our experience with nuclear isolation for the 10x Genomics multiome sequencing platform from solid tumor specimens. We provide recommendations for tissue digestion, storage of single-cell suspensions (if desired), and nuclear isolation and assessment.

    View details for DOI 10.3791/65831

    View details for PubMedID 37902368

  • Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma. Cell reports. Medicine Mascharak, S., Guo, J. L., Foster, D. S., Khan, A., Davitt, M. F., Nguyen, A. T., Burcham, A. R., Chinta, M. S., Guardino, N. J., Griffin, M., Lopez, D. M., Miller, E., Januszyk, M., Raghavan, S. S., Longacre, T. A., Delitto, D. J., Norton, J. A., Longaker, M. T. 2023: 101248


    Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death. Hallmarks include desmoplasia with variable extracellular matrix (ECM) architecture and a complex microenvironment with spatially defined tumor, stromal, and immune populations. Nevertheless, the role of desmoplastic spatial organization in patient/tumor variability remains underexplored, which we elucidate using two technologies. First, we quantify ECM patterning in 437 patients, revealing architectures associated with disease-free and overall survival. Second, we spatially profile the cellular milieu of 78 specimens using codetection by indexing, identifying an axis of pro-inflammatory cell interactions predictive of poorer outcomes. We discover that clinical characteristics, including neoadjuvant chemotherapy status, tumor stage, and ECM architecture, correlate with differential stromal-immune organization, including fibroblast subtypes with distinct niches. Lastly, we define unified signatures that predict survival with areas under the receiver operating characteristic curve (AUCs) of 0.872-0.903, differentiating survivorship by 655 days. Overall, our findings establish matrix ultrastructural and cellular organizations of fibrosis linked to poorer outcomes.

    View details for DOI 10.1016/j.xcrm.2023.101248

    View details for PubMedID 37865092

  • Quality Assessment of Online Resources for Gender-affirming Surgery. Plastic and reconstructive surgery. Global open Berry, C. E., Fazilat, A. Z., Churukian, A. A., Abbas, D. B., Griffin, M., Downer, M., Januszyk, M., Momeni, A., Morrison, S. D., Wan, D. C. 2023; 11 (10): e5306


    Background: As visibility of the transgender patient population and utilization of online resources increases, it is imperative that web-based gender-affirming surgery (GAS) materials for patients are readable, accessible, and of high quality.Methods: A search trends analysis was performed to determine frequency of GAS-related searches over time. The top 100 most common results for GAS-related terms were analyzed using six readability formulas. Accessibility of patient-facing GAS sources was determined by categorizing types of search results. Frequency of article types was compared in low- and high-population dense areas. Quality was assigned to GAS web-based sources using the DISCERN score.Results: Search engine trend data demonstrates increasing occurrence of searches related to GAS. Readability scores of the top 100 online sources for GAS were discovered to exceed recommended levels for patient proficiency. Availability of patient-facing online information related to GAS was found to be 60%, followed by information provided by insurance companies (17%). Differences in availability of online resources in varying dense cities were found to be minimal. The average quality of sources determined by the DISCERN score was found to be 3, indicating "potential important shortcomings."Conclusions: Despite increasing demand for web-based GAS information, the readability of online resources related to GAS was found to be significantly greater than the grade level of proficiency recommended for patients. A high number of nonpatient-facing search results appear in response to GAS search terms. Quality sources are still difficult for patients to find, as search results have a high incidence of low-quality resources.

    View details for DOI 10.1097/GOX.0000000000005306

    View details for PubMedID 37817924

  • Allele-specific expression reveals genetic drivers of tissue regeneration in mice. Cell stem cell Mack, K. L., Talbott, H. E., Griffin, M. F., Parker, J. B., Guardino, N. J., Spielman, A. F., Davitt, M. F., Mascharak, S., Downer, M., Morgan, A., Valencia, C., Akras, D., Berger, M. J., Wan, D. C., Fraser, H. B., Longaker, M. T. 2023


    In adult mammals, skin wounds typically heal by scarring rather than through regeneration. In contrast, "super-healer" Murphy Roths Large (MRL) mice have the unusual ability to regenerate ear punch wounds; however, the molecular basis for this regeneration remains elusive. Here, in hybrid crosses between MRL and non-regenerating mice, we used allele-specific gene expression to identify cis-regulatory variation associated with ear regeneration. Analyzing three major cell populations (immune, fibroblast, and endothelial), we found that genes with cis-regulatory differences specifically in fibroblasts were associated with wound-healing pathways and also co-localized with quantitative trait loci for ear wound-healing. Ectopic treatment with one of these proteins, complement factor H (CFH), accelerated wound repair and induced regeneration in typically fibrotic wounds. Through single-cell RNA sequencing (RNA-seq), we observed that CFH treatment dramatically reduced immune cell recruitment to wounds, suggesting a potential mechanism for CFH's effect. Overall, our results provide insights into the molecular drivers of regeneration with potential clinical implications.

    View details for DOI 10.1016/j.stem.2023.08.010

    View details for PubMedID 37714154

  • Technical Tips to Reduce Implant Rippling in Staged Pre-pectoral Breast Reconstruction. Aesthetic plastic surgery Tevlin, R., Sharma, A. D., Griffin, M., Wan, D., Momeni, A. 2023


    INTRODUCTION: Pre-pectoral implant-based breast reconstruction (IBR) is becoming increasingly popular, permitting optimal implant positioning on the chest wall, prevention of animation deformity, and reduced patient discomfort. There are, however, concerns related to increased rates of breast implant rippling in pre-pectoral (versus submuscular) IBR, which can prompt a patient to seek revisionary surgery. The aim of this study is to identify factors that can be implemented to reduce implant rippling in the setting of pre-pectoral IBR.METHODS: A literature review was conducted using the PubMed database to determine the rate of rippling in pre-pectoral IBR. Clinical studies in English were included. Further review was then performed to explore technical strategies associated with reduced rates of rippling in pre-pectoral two-stage breast reconstruction.RESULTS: Implant rippling has been reported with a rate varying from 0 to 53.8% in 25 studies of pre-pectoral IBR (including both direct-to-implant and two-stage IBR). The majority of studies reviewed did not demonstrate a significant association between BMI and rippling, suggesting that other factors, likely technical and device-related, contribute to the manifestation of implant rippling. Hence, we explored whether specific technical modifications could be implemented that would reduce the risk of rippling in patients undergoing pre-pectoral IBR. Specifically, we highlight the need for close attention to expansion protocol and pocket dimension, expander fill medium and implant characteristics, and the rationale behind adjunctive procedures to reduce implant rippling.CONCLUSION: Surgical modifications may reduce the incidence of rippling in pre-pectoral breast reconstruction.LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors .

    View details for DOI 10.1007/s00266-023-03616-4

    View details for PubMedID 37704858

  • Understanding Fibroblast Heterogeneity in Form and Function. Biomedicines Parker, J. B., Valencia, C., Akras, D., DiIorio, S. E., Griffin, M. F., Longaker, M. T., Wan, D. C. 2023; 11 (8)


    Historically believed to be a homogeneous cell type that is often overlooked, fibroblasts are more and more understood to be heterogeneous in nature. Though the mechanisms behind how fibroblasts participate in homeostasis and pathology are just beginning to be understood, these cells are believed to be highly dynamic and play key roles in fibrosis and remodeling. Focusing primarily on fibroblasts within the skin and during wound healing, we describe the field's current understanding of fibroblast heterogeneity in form and function. From differences due to embryonic origins to anatomical variations, we explore the diverse contributions that fibroblasts have in fibrosis and plasticity. Following this, we describe molecular techniques used in the field to provide deeper insights into subpopulations of fibroblasts and their varied roles in complex processes such as wound healing. Limitations to current work are also discussed, with a focus on future directions that investigators are recommended to take in order to gain a deeper understanding of fibroblast biology and to develop potential targets for translational applications in a clinical setting.

    View details for DOI 10.3390/biomedicines11082264

    View details for PubMedID 37626760

  • Understanding the Role of Adipocytes and Fibroblasts in Cancer. Annals of plastic surgery Downer, M. A., Griffin, M. F., Morgan, A. G., Parker, J. B., Li, D. J., Berry, C. E., Liang, N. E., Kameni, L., Cotterell, A. C., Akras, D., Valencia, C., Longaker, M. T., Wan, D. C. 2023


    Cancer is currently the second leading cause of death in the United States. There is increasing evidence that the tumor microenvironment (TME) is pivotal for tumorigenesis and metastasis. Recently, adipocytes and cancer-associated fibroblasts (CAFs) in the TME have been shown to play a major role in tumorigenesis of different cancers, specifically melanoma. Animal studies have shown that CAFs and adipocytes within the TME help tumors evade the immune system, for example, by releasing chemokines to blunt the effectiveness of the host defense. Although studies have identified that adipocytes and CAFs play a role in tumorigenesis, adipocyte transition to fibroblast within the TME is fairly unknown. This review intends to elucidate the potential that adipocytes may have to transition to fibroblasts and, as part of the TME, a critical role that CAFs may play in affecting the growth and invasion of tumor cells. Future studies that illuminate the function of adipocytes and CAFs in the TME may pave way for new antitumor therapies.

    View details for DOI 10.1097/SAP.0000000000003658

    View details for PubMedID 37553786

  • Medical Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer. Biology Morgan, A., Griffin, M., Kameni, L., Wan, D. C., Longaker, M. T., Norton, J. A. 2023; 12 (8)


    Pancreatic cancer is one of the deadliest forms of cancer with one of the lowest 5-year survival rates of all cancer types. A defining characteristic of pancreatic cancer is the existence of dense desmoplastic stroma that, when exposed to stimuli such as cytokines, growth factors, and chemokines, generate a tumor-promoting environment. Cancer-associated fibroblasts (CAFs) are activated during the progression of pancreatic cancer and are a crucial component of the tumor microenvironment (TME). CAFs are primarily pro-tumorigenic in their activated state and function as promoters of cancer invasion, proliferation, metastasis, and immune modulation. Aided by many signaling pathways, cytokines, and chemokines in the tumor microenvironment, CAFs can originate from many cell types including resident fibroblasts, mesenchymal stem cells, pancreatic stellate cells, adipocytes, epithelial cells, endothelial cells, and other cell types. CAFs are a highly heterogeneous cell type expressing a variety of surface markers and performing a wide range of tumor promoting and inhibiting functions. Single-cell transcriptomic analyses have revealed a high degree of specialization among CAFs. Some examples of CAF subpopulations include myofibrotic CAFs (myCAFs), which exhibit a matrix-producing contractile phenotype; inflammatory CAFs (iCAF) that are classified by their immunomodulating, secretory phenotype; and antigen-presenting CAFs (apCAFs), which have antigen-presenting capabilities and express Major Histocompatibility Complex II (MHC II). Over the last several years, various attempts have been undertaken to describe the mechanisms of CAF-tumor cell interaction, as well as CAF-immune cell interaction, that contribute to tumor proliferation, invasion, and metastasis. Although our understanding of CAF biology in cancer has steadily increased, the extent of CAFs heterogeneity and their role in the pathobiology of pancreatic cancer remains elusive. In this regard, it becomes increasingly evident that further research on CAFs in pancreatic cancer is necessary.

    View details for DOI 10.3390/biology12081044

    View details for PubMedID 37626931

  • Reduction of Tendon Fibrosis Using Galectin-3 Inhibitors. Plastic and reconstructive surgery Spielman, A. F., Griffin, M. F., Titan, A. L., Guardino, N., Cotterell, A. C., Akras, D., Wan, D. C., Longaker, M. T. 2023


    BACKGROUND: Fibrosis is a complication of both tendon injuries and repairs. We aim to develop a mouse model to assess tendon fibrosis and to identify an antifibrotic agent capable of overcoming tendon fibrosis.METHODS: Adult C57Bl/6 mice underwent a skin incision to expose the Achilles tendon, followed by 50% tendon injury and abrasion with sandpaper. Sham surgeries were conducted on contralateral hindlimbs. Histology and immunofluorescent staining for fibrotic markers (Col1, alpha-SMA) were used to confirm that the model induced tendon fibrosis. A second experiment was conducted to further examine the role of alpha-SMA in adhesion formation using alpha-SMA.mTmG mice (6-8 weeks old) (n=3) with the same injury model. The control group (tendon injury) was compared to the sham group, using the contralateral limb with skin incision only. A second experiment was conducted to further examine the role of alpha-SMA in adhesion formation using alpha-SMA.mTmG mice (6-8 weeks old) (n=3) with the same injury model. The control group (tendon injury) was compared to the sham group, using the contralateral limb with skin incision only. Lastly, alpha-SMA.mTmG mice were randomized to either condition 1. Tendon injury (control group) or 2. Tendon injury with Galectin-3 inhibitor (Gal3i) treatment at time of injury (treatment group).RESULTS: Histological analyses confirmed tendon thickening and collagen deposition after tendon injury and abrasion compared to control. Immunofluorescence showed higher levels of Col1 and alpha-SMA protein expression after injury compared to sham (*p<0.05). RT-qPCR also demonstrated increased gene expression of Col1 and alpha-SMA after injury compared to sham (*p<0.05). Gal3 protein expression also increased after injury and co-localized with alpha-SMA positive fibroblasts surrounding the fibrotic tendon. Gal3i treatment decreased collagen deposition and scarring observed in the treatment group (*p<0.05). Flow cytometry analysis further showed reduced numbers of profibrotic fibroblasts (CD26+) in the treatment compared to the control group (*p<0.05).CONCLUSIONS: Our study provides a reproducible and reliable model to investigate tendon fibrosis. Findings suggest the potential of Gal3i to overcome fibrosis resulting from tendon injuries.

    View details for DOI 10.1097/PRS.0000000000010880

    View details for PubMedID 37344932

  • Attenuating Chronic Fibrosis: Decreasing Foreign Body Response with Acellular Dermal Matrix. Tissue engineering. Part B, Reviews Liang, N. E., Griffin, M., Berry, C. E., Parker, J. B., Downer, M. A., Wan, D. C., Longaker, M. T. 2023


    Surgical implants are increasingly used across multiple medical disciplines, with applications ranging from tissue reconstruction to improving compromised organ and limb function. Despite their significant potential for improving health and quality of life, biomaterial implant function is severely limited by the body's immune response to its presence: this is known as the foreign body response and is characterized by chronic inflammation and fibrotic capsule formation. This response can result in life-threatening sequelae such as implant malfunction, superimposed infection and associated vessel thrombosis, in addition to soft tissue disfigurement. Patients may require frequent medical visits, as well as repeated invasive procedures, increasing the burden on an already strained healthcare system. Currently, the foreign body response and the cells and molecular mechanisms that mediate it are poorly understood. With applications across a wide array of surgical specialties, acellular dermal matrix has emerged as a potential solution to the fibrotic reaction seen with FBR. Though the mechanisms by which acellular dermal matrix decreases chronic fibrosis remain to be clearly characterized, animal studies across diverse surgical models point to its biomimetic properties that facilitate decreased periprosthetic inflammation and improved host cell incorporation.

    View details for DOI 10.1089/ten.TEB.2023.0060

    View details for PubMedID 37212342

  • Overcoming Radiation Induced Oral Fibrosis through the Down Regulation of Wnt Signaling Using Bmp-7 Inhibitors Cotterell, A. C., Griffin, M., Spielman, A., Guardino, N., Lintel, H., Abbas, D., Guo, J. L., Parker, J., Wan, D., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2023: S90
  • Topical Vanadate Improves Excisional Wound Healing in Murine Model Lintel, H., Abbas, D., Mackay, D. D., Griffin, M., Spielman, A., Guardino, N., Churukian, A., Guo, J. L., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2023: S91
  • Lineage Tracing Reveals Adipocytes Are Responsible for Muscle Fibrosis Following Nerve Injury Spielman, A., Griffin, M., Cotterell, A. C., Erich, K., Guo, B. L., Abbas, D., Parker, J. L., Lintel, H., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2023: S92
  • Developing a Mouse Model to Evaluate Tibial Distraction Osteogenesis DiIorio, S., Tevlin, R., Shah, H. N., Salhotra, A., Griffin, M., Januszyk, M., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2023: S90
  • Radiation Injury Genetically Alters Fibroblast Subpopulations to Induce Fibrosis Abbas, D., Griffin, M., Guo, J. L., Lavin, C. V., Fahy, E. J., Guardino, N. J., Lintel, H., Januszyk, M., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2023: S94
  • Radiation Injury Therapy with Transdermal Deferoxamine Patch is Dose Dependent Abbas, D., Griffin, M., Lavin, C. V., Fahy, E. J., Lintel, H., Guardino, N. J., Guo, J. L., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2023: S91
  • Quantitative Analysis of the Collagen Matrix Ultrastructure in Mouse Hearts after Myocardial Infarction Lu, J., Griffin, M., Guo, J. L., Mascharak, S., Guardino, N. J., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2023: S13-S14
  • The effects of mechanical force on fibroblast behavior in cutaneous injury. Frontiers in surgery Berry, C. E., Downer, M., Morgan, A. G., Griffin, M., Liang, N. E., Kameni, L., Laufey Parker, J. B., Guo, J., Longaker, M. T., Wan, D. C. 2023; 10: 1167067


    Wound healing results in the formation of scar tissue which can be associated with functional impairment, psychological stress, and significant socioeconomic cost which exceeds 20 billion dollars annually in the United States alone. Pathologic scarring is often associated with exaggerated action of fibroblasts and subsequent excessive accumulation of extracellular matrix proteins which results in fibrotic thickening of the dermis. In skin wounds, fibroblasts transition to myofibroblasts which contract the wound and contribute to remodeling of the extracellular matrix. Mechanical stress on wounds has long been clinically observed to result in increased pathologic scar formation, and studies over the past decade have begun to uncover the cellular mechanisms that underly this phenomenon. In this article, we will review the investigations which have identified proteins involved in mechano-sensing, such as focal adhesion kinase, as well as other important pathway components that relay the transcriptional effects of mechanical forces, such as RhoA/ROCK, the hippo pathway, YAP/TAZ, and Piezo1. Additionally, we will discuss findings in animal models which show the inhibition of these pathways to promote wound healing, reduce contracture, mitigate scar formation, and restore normal extracellular matrix architecture. Recent advances in single cell RNA sequencing and spatial transcriptomics and the resulting ability to further characterize mechanoresponsive fibroblast subpopulations and the genes that define them will be summarized. Given the importance of mechanical signaling in scar formation, several clinical treatments focused on reducing tension on the wound have been developed and are described here. Finally, we will look toward future research which may reveal novel cellular pathways and deepen our understanding of the pathogenesis of pathologic scarring. The past decade of scientific inquiry has drawn many lines connecting these cellular mechanisms that may lead to a map for the development of transitional treatments for patients on the path to scarless healing.

    View details for DOI 10.3389/fsurg.2023.1167067

    View details for PubMedID 37143767

    View details for PubMedCentralID PMC10151708

  • Establishing a xenograft model with CD-1 nude mice to study human skin wound repair. Plastic and reconstructive surgery Abbas, D. B., Griffin, M., Fahy, E. J., Spielman, A. F., Guardino, N. J., Pu, A., Lintel, H., Lorenz, H. P., Longaker, M. T., Wan, D. C. 2023


    A significant gap exists in the translatability of small animal models to human subjects. One important factor is poor laboratory models involving human tissue. Thus, we have created a viable postnatal human skin xenograft model using athymic mice.Discarded human foreskins were collected following circumcision. All subcutaneous tissue was removed from these samples sterilely. Host CD-1 nude mice were then anesthetized, and dorsal skin was sterilized. A 1.2cm diameter, full-thickness section of dorsal skin was excised. The foreskin sample was then placed into the full-thickness defect in the host mice and sutured into place. Xenografts underwent dermal wounding using a 4 mm punch biopsy after engraftment. Xenografts were monitored for 14 days after wounding and then harvested.At 14 days postoperatively, all mice survived the procedure. Grossly, the xenograft wounds showed formation of a human scar at POD-14. H&E and Masson Trichome staining confirmed scar formation in the wounded human skin. Using a novel Artificial Intelligence (AI) algorithm using Picrosirius-Red staining, scar formation was confirmed in human wounded skin compared to the unwounded skin. Histologically, CD31 + immunostaining confirmed vascularization of the xenograft. The xenograft exclusively showed human collagen I, CD26 +, and human nuclear antigen in the human scar without any staining of these human markers in the murine skin.The proposed model demonstrates wound healing to be a local response from tissue resident human fibroblasts and allows for reproducible evaluation of human skin wound repair in a preclinical model.

    View details for DOI 10.1097/PRS.0000000000010465

    View details for PubMedID 36988644

  • Mechanoresponsive Pancreatic Ductal Adenocarcinoma Cancer Associated Fibroblasts Shows an FAK-Dependent Subtype Divergent from Canonical Fibrotic TGFB-Pathway Dependence Foster, D., Delitto, D., Januszyk, M., Yost, K., Griffin, M., Guo, J., Guardino, N., Delitto, A., Chinta, M., Burcham, A., Nguyen, A., Bauer-, K., Berry, C., Kim, A., Nosrati, F., Wapnir, I., Chang, H., Norton, J. A., Longaker, M. SPRINGER. 2023: S30-S31
  • Denervation during mandibular distraction osteogenesis results in impaired bone formation. Scientific reports Tevlin, R., Griffin, M., Chen, K., Januszyk, M., Guardino, N., Spielman, A., Walters, S., Gold, G. E., Chan, C. K., Gurtner, G. C., Wan, D. C., Longaker, M. T. 2023; 13 (1): 2097


    Mandibular distraction osteogenesis (DO) is mediated by skeletal stem cells (SSCs) in mice, which enact bone regeneration via neural crest re-activation. As peripheral nerves are essential to progenitor function during development and in response to injury, we questioned if denervation impairs mandibular DO. C57Bl6 mice were divided into two groups: DO with a segmental defect in the inferior alveolar nerve (IAN) at the time of mandibular osteotomy ("DO Den") and DO with IAN intact ("DO Inn"). DO Den demonstrated significantly reduced histological and radiological osteogenesis relative to DO Inn. Denervation preceding DO results in reduced SSC amplification and osteogenic potential in mice. Single cell RNA sequencing analysis revealed that there was a predominance of innervated SSCs in clusters dominated by pathways related to bone formation. A rare human patient specimen was also analyzed and suggested that histological, radiological, and transcriptional alterations seen in mouse DO may be conserved in the setting of denervated human mandible distraction. Fibromodulin (FMOD) transcriptional and protein expression were reduced in denervated relative to innervated mouse and human mandible regenerate. Finally, when exogenous FMOD was added to DO-Den and DO-Inn SSCs undergoing in vitro osteogenic differentiation, the osteogenic potential of DO-Den SSCs was increased in comparison to control untreated DO-Den SSCs, modeling the superior osteogenic potential of DO-Inn SSCs.

    View details for DOI 10.1038/s41598-023-27921-9

    View details for PubMedID 36747028

  • An Inexpensive 3D Printed Mouse Model of Successful, Complication-free Long Bone Distraction Osteogenesis. Plastic and reconstructive surgery. Global open Tevlin, R., Shah, H. N., Salhotra, A., Di Iorio, S. E., Griffin, M., Januszyk, M., Wan, D. C., Longaker, M. T. 2023; 11 (2): e4674


    Distraction osteogenesis (DO) is used for skeletal defects; however, up to 50% of cases exhibit complications. Previous mouse models of long bone DO have been anecdotally hampered by postoperative complications, expense, and availability. To improve clinical techniques, cost-effective, reliable animal models are needed. Our focus was to develop a new mouse tibial distractor, hypothesized to result in successful, complication-free DO.A lightweight tibial distractor was developed using CAD and 3D printing. The device was fixed to the tibia of C57Bl/6J mice prior to osteotomy. Postoperatively, mice underwent 5 days latency, 10 days distraction (0.15 mm every 12 hours), and 28 days consolidation. Bone regeneration was examined on postoperative day 43 using micro-computed tomography (μCT) and Movat's modified pentachrome staining on histology (mineralized volume fraction and pixels, respectively). Costs were recorded. We compared cohorts of 11 mice undergoing sham, DO, or acute lengthening (distractor acutely lengthened 3.0 mm).The histological bone regenerate was significantly increased in DO (1,879,257 ± 155,415 pixels) compared to acute lengthening (32847 ± 1589 pixels) (P < 0.0001). The mineralized volume fraction (bone/total tissue volume) of the regenerate was significantly increased in DO (0.9 ± 0.1) compared to acute lengthening (0.7 ± 0.1) (P < 0.001). There was no significant difference in bone regenerate between DO and sham. The distractor was relatively low cost ($11), with no complications.Histology and µCT analysis confirmed that the proposed tibial DO model resulted in successful bone formation. Our model is cost-effective and reproducible, enabling implementation in genetically dissectible transgenic mice.

    View details for DOI 10.1097/GOX.0000000000004674

    View details for PubMedID 36798717

    View details for PubMedCentralID PMC9925097

  • Chelating the valley of death: Deferoxamine's path from bench to wound clinic. Frontiers in medicine Parker, J. B., Griffin, M. F., Downer, M. A., Akras, D., Berry, C. E., Cotterell, A. C., Gurtner, G. C., Longaker, M. T., Wan, D. C. 2023; 10: 1015711


    There is undisputable benefit in translating basic science research concretely into clinical practice, and yet, the vast majority of therapies and treatments fail to achieve approval. The rift between basic research and approved treatment continues to grow, and in cases where a drug is granted approval, the average time from initiation of human trials to regulatory marketing authorization spans almost a decade. Albeit with these hurdles, recent research with deferoxamine (DFO) bodes significant promise as a potential treatment for chronic, radiation-induced soft tissue injury. DFO was originally approved by the Food and Drug Administration (FDA) in 1968 for the treatment of iron overload. However, investigators more recently have posited that its angiogenic and antioxidant properties could be beneficial in treating the hypovascular and reactive-oxygen species-rich tissues seen in chronic wounds and radiation-induced fibrosis (RIF). Small animal experiments of various chronic wound and RIF models confirmed that treatment with DFO improved blood flow and collagen ultrastructure. With a well-established safety profile, and now a strong foundation of basic scientific research that supports its potential use in chronic wounds and RIF, we believe that the next steps required for DFO to achieve FDA marketing approval will include large animal studies and, if those prove successful, human clinical trials. Though these milestones remain, the extensive research thus far leaves hope for DFO to bridge the gap between bench and wound clinic in the near future.

    View details for DOI 10.3389/fmed.2023.1015711

    View details for PubMedID 36873870

  • Multiplexed evaluation of mouse wound tissue using oligonucleotide barcoding with single-cell RNA sequencing. STAR protocols Januszyk, M., Griffin, M., Mascharak, S., Talbott, H. E., Chen, K., Henn, D., Spielman, A. F., Parker, J. B., Liang, N. E., Cotterell, A., Guardino, N., Foster, D. S., Wagh, D., Coller, J., Gurtner, G. C., Wan, D. C., Longaker, M. T. 2022; 4 (1): 101946


    Despite its rapidly increased availability for the study of complex tissue, single-cell RNA sequencing remains prohibitively expensive for large studies. Here, we present a protocol using oligonucleotide barcoding for the tagging and pooling of multiple samples from healing wounds, which are among the most challenging tissue types for this application. We describe steps to generate skin wounds in mice, followed by tissue harvest and oligonucleotide barcoding. This protocol is also applicable to other species including rats, pigs, and humans. For complete details on the use and execution of this protocol, please refer to Stoeckius etal. (2018),1 Galiano etal. (2004),2 and Mascharak etal. (2022).3.

    View details for DOI 10.1016/j.xpro.2022.101946

    View details for PubMedID 36525348

  • Topical vanadate improves tensile strength and alters collagen organization of excisional wounds in a mouse model. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society Lintel, H., Abbas, D. B., Mackay, D. J., Griffin, M., Lavin, C. V., Berry, C. E., Guardino, N. J., Guo, J. L., Momeni, A., Mackay, D. R., Longaker, M. T., Wan, D. C. 2022


    Wound dehiscence, oftentimes a result of the poor tensile strength of early healing wounds, is a significant threat to the postoperative patient, potentially causing life-threatening complications. Vanadate, a protein tyrosine phosphatase inhibitor, has been shown to alter the organization of deposited collagen in healing wounds and significantly improve the tensile strength of incisional wounds in rats. In this study, we sought to explore the effects of locally administered vanadate on tensile strength and collagen organization in both the early and remodeling phases of excisional wound healing in a murine model. Wild-type mice underwent stented excisional wounding on their dorsal skin and were divided equally into three treatment conditions: vanadate injection, saline injection control, and an untreated control. Tensile strength testing, in vivo suction Cutometer analysis, gross wound measurements, and histologic analysis were performed during healing, immediately upon wound closure, and after four weeks of remodeling. We found that vanadate treatment significantly increased the tensile strength of wounds and their stiffness relative to control wounds, both immediately upon healing and into the remodeling phase. Histologic analysis revealed that these biomechanical changes were likely the result of increased collagen deposition and an altered collagen organization composed of thicker and distinctly organized collagen bundles. Given the risk that dehiscence poses to all operative patients, vanadate presents an interesting therapeutic avenue to improve the strength of post-operative wounds and unstable chronic wounds in order to reduce the risk of dehiscence.

    View details for DOI 10.1111/wrr.13062

    View details for PubMedID 36484112

  • Investigating the Severity of Complications following Nipple-sparing Mastectomy and Immediate Prepectoral Implant-based vs. Autologous Reconstruction - A Single-Surgeon Experience. Plastic and reconstructive surgery Pedreira, R., Tevlin, R., Griffin, M., Wan, D., Momeni, A. 2022


    Several clinical studies have reported autologous breast reconstruction (ABR) to be associated with a higher postoperative complication rate; however, few have investigated the impact of reconstructive modality on complication severity. This study examines the impact of reconstructive modality on complication severity in a matched cohort of patients who underwent ABR versus implant-based breast reconstruction (IBR).A retrospective study of patients who underwent nipple-sparing mastectomy with immediate reconstruction was performed. Propensity score matching (PSM) ensured adequate matching of patients who underwent ABR and staged prepectoral IBR, respectively. Patient demographics, breast measurements and postoperative outcomes, including the incidence and severity of complications were analyzed. Multivariable logistic regression analysis was performed. A P-value of <0.05 was considered significant.128 patients (214 breast reconstructions) were included for analysis (ABR n = 64; IBR n = 64). No difference in overall complication rate was noted (p = 0.61). However, a significant association of IBR with major complications was noted (p = 0.02). In contrast, minor complications were significantly more frequent following ABR (p = 0.04).While the reconstructive modality did not appear to have an effect on the overall complication rate, it did significantly affect the severity of postoperative complications with major and minor complications being associated with IBR and ABR, respectively. These findings are relevant to patient-centered decision-making as they provide further granularity regarding postoperative complications and address the issue of complication severity.

    View details for DOI 10.1097/PRS.0000000000009827

    View details for PubMedID 36332003

  • Adipose-Derived Stromal Cell-based Therapies for Radiation-Induced Fibrosis. Advances in wound care Berry, C., Abbas, D. B., Lintel, H., Churukian, A., Griffin, M., Guo, J., Cotterell, A. C., Parker, J., Downer, M. A., Longaker, M. T., Wan, D. C. 2022


    SIGNIFICANCE: Half of all cancer patients receive radiation therapy as a component of their treatment regimen, and the most common resulting complication is radiation-induced fibrosis of the skin and soft tissue. This thickening of the dermis paired with decreased vascularity results in functional limitations, aesthetic concerns, and poses unique challenges when considering surgical exploration or reconstruction. Existing therapeutic options for radiation-induced fibrosis of the skin are limited both in scope and efficacy. Cell-based therapies have emerged as a promising means of utilizing regenerative cell populations to improve both functional and aesthetic outcomes, and even as prophylaxis for radiation-induced fibrosis.RECENT ADVANCES: As one of the leading areas of cell-based therapy research, adipose-derived stromal cells (ADSCs) demonstrate significant therapeutic potential in the treatment of radiation-induced fibrosis (RIF). The introduction of the ADSC-augmented fat graft has shown clinical utility. Recent research dedicated to characterizing specific ADSC subpopulations points toward further granularity in understanding of the mechanisms driving the well-established clinical outcomes seen with fat grafting therapy.CRITICAL ISSUES: Various animal models of radiation-induced fibrosis demonstrated improved clinical outcomes following treatment with cell-based therapies, but the cellular and molecular basis underlying these effects remains poorly understood.FUTURE DIRECTIONS: Recent literature has focused on improving the efficacy of cell-based therapies, most notably through 1) augmentation of fat grafts with platelet-rich plasma and 2) the modification of expressed RNA through epitranscriptomics. For the latter, new and promising gene targets continue to be identified which have the potential to reverse the effects of fibrosis by increasing angiogenesis, decreasing inflammation, and promoting adipogenesis.

    View details for DOI 10.1089/wound.2022.0103

    View details for PubMedID 36345216

  • Machine Learning-Based Desmoplastic Signatures Predict Patient Outcomes in Pancreatic Ductal Adenocarcinoma Guo, J. L., Mascharak, S., Foster, D. S., Guardino, N. J., Griffin, M., Miller, E., Raghavan, S., Longacre, T. A., Norton, J. A., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S53-S54
  • Inhibition of Yes-Associated Protein Promotes Skin Wound Regeneration in Large Animals Januszyk, M., Talbott, H. E., Griffin, M., Guardino, N., Spielman, A., Guo, J. L., Mascharak, S., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S196
  • Denervation During Mouse and Human Mandibular Distraction Osteogenesis Results in Impaired Osteogenesis Tevlin, R., Griffin, M., Chen, K., Januszyk, M., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S202
  • Adipocytes the Forgotten Culprit in Skin Fibrosis: Exploring the Mechanism of Fat Driven Skin Fibrosis Griffin, M., Guardino, N., Spielman, A. F., Mascharak, S., Parker, J. L., Guo, J. L., Abbas, D., Wan, D. C., Bauer-Rowe, K. E., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S199
  • Adipocyte Progenitor Cells Embedded in Collagen Gels Accelerate Bone Formation in a Murine Calvarial Critical Defect Model Cotterell, A. C., Griffin, M., Guardino, N., Spielman, A. F., Lintel, H., Abbas, D., Guo, J. L., Parker, J. L., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S198-S199
  • Transdermal Deferoxamine Improves Acute Wound Healing in Chronic Irradiated Skin in a Mouse Model Lintel, H., Abbas, D., Lavin, C., Griffin, M., Guo, J. L., Guardino, N., Churukian, A., Chen, K., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2022: S211-S212
  • Fibroblast Subpopulations Are Modified with Fat Grafting to Treat Radiation-Induced Fibrosis Abbas, D. B., Guo, J. L., Griffin, M., Lintel, H., Guardino, N. J., Berry, C. E., Pu, A., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2022: S202-S203
  • Semantics Matter: Cheiloschisis Web-Based Information Differs from Cleft Lip Abbas, D. B., Lintel, H., Guardino, N. J., Griffin, M., Guo, J. L., Cotterell, A. C., Spielman, A. F., Parker, J. L., Longaker, M. T., Wan, D. C. LIPPINCOTT WILLIAMS & WILKINS. 2022: S209
  • Where There Is Fat There Is Fibrosis: Elucidating the Mechanisms of Creeping Fat-Driven Stricture Formation Bauer-Rowe, K. E., Kim, A., Griffin, M., Foster, D., Guardino, N., Guo, J. L., Talbott, H. E., Norton, J. A., Hyun, J. S., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S59-S60
  • Multi-Modal Analysis of Cell Populations and Architectural States Mediating the Progression and Resolution of Pulmonary Fibrosis Guo, J. L., Griffin, M., Guardino, N. J., Abbas, D., Lu, J., Spielman, A., Lintel, H., Cotterell, A. C., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S82
  • Engrailed-Positive Fibroblasts: The Primary Cell Type Present in Fibrotic Capsules During Foreign Body Response Parker, J. B., Griffin, M., Mascharak, S., Spielman, A., Cotterell, A. C., Abbas, D., Lintel, H., Januszyk, M., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S68
  • Reversal of Senescence in Skin-derived Fibroblasts Using Exogenous Mechanical Stimulation Guo, J. L., Griffin, M., Guardino, N. J., Chen, K., Cotterell, A. C., Abbas, D., Spielman, A., Lintel, H., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S70
  • Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin. Cancer cell Foster, D. S., Januszyk, M., Delitto, D., Yost, K. E., Griffin, M., Guo, J., Guardino, N., Delitto, A. E., Chinta, M., Burcham, A. R., Nguyen, A. T., Bauer-Rowe, K. E., Titan, A. L., Salhotra, A., Jones, R. E., da Silva, O., Lindsay, H. G., Berry, C. E., Chen, K., Henn, D., Mascharak, S., Talbott, H. E., Kim, A., Nosrati, F., Sivaraj, D., Ransom, R. C., Matthews, M., Khan, A., Wagh, D., Coller, J., Gurtner, G. C., Wan, D. C., Wapnir, I. L., Chang, H. Y., Norton, J. A., Longaker, M. T. 2022


    Cancer-associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. CAFs were once thought to be a relatively uniform population of matrix-producing cells, but single-cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probed CAF heterogeneity with a comprehensive multiomics approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provided an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters: steady state-like (SSL), mechanoresponsive (MR), and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and affected tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating therapeutic targets in a species- and tumor-agnostic manner.

    View details for DOI 10.1016/j.ccell.2022.09.015

    View details for PubMedID 36270275

  • 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., Kussie, H. C., Huskins, S., Steele, S., Perrault, D., Longaker, M. T., Gurtner, G. C. WILEY. 2022: A22
  • 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


    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


    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


    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


    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


    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


    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


    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


    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


    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


    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


    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


    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


    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


    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


    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


    [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


    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


    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


    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


    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)


    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


    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


    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


    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


    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


    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


    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


    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


    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


    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


    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

  • 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


    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


    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

  • 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)


    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

  • 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


    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