Honors & Awards

  • The Merit Award, International Society for Stem Cell Research (ISSCR) Annual Meeting 2018, Melbourne, (June 2018)
  • Travel Grant ($1550), International Society for Stem Cell Research (ISSCR) Annual Meeting 2018, Melbourne, (June 2018)
  • The Transplant and Tissue Engineering Center of Excellence Fellowship ($40,820), Stanford University (July 2018-June 2019)
  • The National Endowment for Plastic Surgery grant ($50,000), The Plastic Surgery Foundation (PSF) (July 2018 – August 2019)
  • Investigator Initiated Research Grant award ($10,000), The Plastic Surgery Foundation (July 2019 – August 2020)

Professional Education

  • Master of Science, University College London (2012)
  • Bachelor of Science, University of Bristol (2011)
  • B of Medicine and B of Surgery, King's College School (2017)

All Publications

  • Acellular Dermal Matrix Reduces Myofibroblast Presence in the Breast Capsule. Plastic and reconstructive surgery. Global open Tevlin, R., Borrelli, M. R., Irizarry, D., Nguyen, D., Wan, D. C., Momeni, A. 2019; 7 (5): e2213


    Background: Capsular contracture remains a common complication after implant-based breast reconstruction. Previous work has suggested that the use of acellular dermal matrix (ADM) reduces the rate of capsular contracture, though little is understood about the underlying mechanism. As myofibroblasts are believed to be the key cells implicated in contracture formation, we hypothesized that ADM would result in a reduction in periprosthetic myofibroblast concentration.Methods: Five patients who underwent immediate prepectoral tissue expander placement with anterior ADM coverage and an inferior cuff were included. At the second stage, tissue samples were obtained of both ADM and capsule from each reconstructed breast. Samples were then prepared for hematoxylin and eosin staining and immunohistochemistry for myofibroblast identification (alpha smooth muscle actin and vimentin positive and desmin negative) and analysis. Experimental values are presented as mean ± SD unless otherwise stated. Statistical significance was determined using unpaired t test.Results: Successful incorporation of ADM was noted in all cases. A significant reduction in myofibroblast concentration was noted in the ADM versus the capsule (P = 0.0018). This was paralleled by significantly thicker periprosthetic capsule formation overlying the formerly raw pectoralis major muscle, that is, not covered by ADM (P < 0.0001).Conclusions: In the presence of ADM, there are significantly fewer myofibroblasts in breast capsules and thinner capsules on histology. Given the central role of myofibroblasts in the development of clinically significant capsular contracture, this study unmasks a possible mechanism for the protective effect of ADM with respect to capsular contracture development.

    View details for DOI 10.1097/GOX.0000000000002213

    View details for PubMedID 31333946

  • Pro-Fibrotic CD26-Positive Fibroblasts are Present in Greater Abundance in Breast Capsule Tissue of Irradiated Breasts. Aesthetic surgery journal Borrelli, M. R., Irizzary, D., Patel, R. A., Nguyen, D., Momeni, A., Longaker, M. T., Wan, D. C. 2019


    BACKGROUND: Breast capsular contracture is a major problem following implant-based breast reconstruction, particularly in the setting of radiation therapy. Recent work has identified a fibrogenic fibroblast subpopulation characterized by CD26 surface marker expression.OBJECTIVE: This work aimed to investigate the role of CD26-positive fibroblasts in the formation of breast implant capsules following radiation therapy.METHODS: Breast capsule specimens were obtained from irradiated and non-irradiated breasts of 10 patients following bilateral mastectomy and unilateral irradiation at the time of expander-implant exchange, under institutional review board approval. Specimens were processed for Hematoxylin and Eosin staining, as well as for immunohistochemistry and fluorescence activated cell sorting (FACS) for CD26-positive fibroblasts. Expression of fibrotic genes and production of collagen was compared between CD26-positive, CD26-negative, and unsorted fibroblasts.RESULTS: Capsule specimens from irradiated breast tissue were thicker and had greater CD26-postive cells on immunofluorescence imaging and on FACS analysis, than did capsule specimens from the non-irradiated breast. Compared to CD26-negative fibroblasts, CD26-positive fibroblasts produced more collagen and had increased expression of the profibrotic genes IL8, TGF-beta1, COL1A1, and TIMP4.CONCLUSIONS: CD26-positive fibroblasts were found in a significantly greater abundance in capsules of irradiated compared to non-irradiated breasts and demonstrated greater fibrotic potential. This fibrogenic fibroblast subpopulation may play an important role in the development of capsular contracture following irradiation, and its targeted depletion or moderation may represent a potential therapeutic option.

    View details for PubMedID 30972420

  • Compliance of Randomized Controlled Trials Published in General Surgical Journals With the CONSORT 2010 Statement ANNALS OF SURGERY Limb, C., White, A., Fielding, A., Lunt, A., Borrelli, M. R., Alsafi, Z., Schembri, M., Fowler, A. J., Agha, R. A. 2019; 269 (3): E25–E27
  • Compliance of Randomized Controlled Trials Published in General Surgical Journals With the CONSORT 2010 Statement. Annals of surgery Limb, C., White, A., Fielding, A., Lunt, A., Borrelli, M. R., Alsafi, Z., Schembri, M., Fowler, A. J., Agha, R. A. 2019; 269 (3): e25–e27

    View details for PubMedID 29266005

  • Wounds Inhibit Tumor Growth In Vivo. Annals of surgery Hu, M. S., Maan, Z. N., Leavitt, T., Hong, W. X., Rennert, R. C., Marshall, C. D., Borrelli, M. R., Zhu, T. N., Esquivel, M., Zimmermann, A., McArdle, A., Chung, M. T., Foster, D. S., Jones, R. E., Gurtner, G. C., Giaccia, A. J., Lorenz, H. P., Weissman, I. L., Longaker, M. T. 2019


    OBJECTIVE: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo.SUMMARY OF BACKGROUND DATA: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo.METHODS: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells.RESULTS: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds.CONCLUSION: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.

    View details for PubMedID 30829705

  • Fat Chance: The Rejuvenation of Irradiated Skin PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN Borrelli, M. R., Patel, R. A., Sokol, J., Dung Nguyen, Momeni, A., Longaker, M. T., Wan, D. C. 2019; 7 (2): e2092


    Radiotherapy (RT) helps cure and palliate thousands of patients with a range of malignant diseases. A major drawback, however, is the collateral damage done to tissues surrounding the tumor in the radiation field. The skin and subcutaneous tissue are among the most severely affected regions. Immediately following RT, the skin may be inflamed, hyperemic, and can form ulcers. With time, the dermis becomes progressively indurated. These acute and chronic changes cause substantial patient morbidity, yet there are few effective treatment modalities able to reduce radiodermatitis. Fat grafting is increasingly recognized as a tool able to reverse the fibrotic skin changes and rejuvenate the irradiated skin. This review outlines the current progress toward describing and understanding the cellular and molecular effects of fat grafting in irradiated skin. Identification of the key factors involved in the pathophysiology of fibrosis following RT will inform therapeutic interventions to enhance its beneficial effects.

    View details for PubMedID 30881833

  • Wnt Pathway in Bone Repair and Regeneration - What Do We Know So Far FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY Houschyar, K. S., Tapking, C., Borrelli, M. R., Popp, D., Duscher, D., Maan, Z. N., Chelliah, M. P., Li, J., Harati, K., Wallner, C., Rein, S., Pfoerringer, D., Reumuth, G., Grieb, G., Mouraret, S., Dadras, M., Wagner, J. M., Cha, J. Y., Siemers, F., Lehnhardt, M., Behr, B. 2019; 6: 170


    Wnt signaling plays a central regulatory role across a remarkably diverse range of functions during embryonic development, including those involved in the formation of bone and cartilage. Wnt signaling continues to play a critical role in adult osteogenic differentiation of mesenchymal stem cells. Disruptions in this highly-conserved and complex system leads to various pathological conditions, including impaired bone healing, autoimmune diseases and malignant degeneration. For reconstructive surgeons, critically sized skeletal defects represent a major challenge. These are frequently associated with significant morbidity in both the recipient and donor sites. The Wnt pathway is an attractive therapeutic target with the potential to directly modulate stem cells responsible for skeletal tissue regeneration and promote bone growth, suggesting that Wnt factors could be used to promote bone healing after trauma. This review summarizes our current understanding of the essential role of the Wnt pathway in bone regeneration and repair.

    View details for PubMedID 30666305

  • Tissue Engineering and Regenerative Medicine in Craniofacial Reconstruction and Facial Aesthetics. The Journal of craniofacial surgery Borrelli, M. R., Hu, M. S., Longaker, M. T., Lorenz, H. P. 2019


    The craniofacial region is anatomically complex and is of critical functional and cosmetic importance, making reconstruction challenging. The limitations of current surgical options highlight the importance of developing new strategies to restore the form, function, and esthetics of missing or damaged soft tissue and skeletal tissue in the face and cranium. Regenerative medicine (RM) is an expanding field which combines the principles of tissue engineering (TE) and self-healing in the regeneration of cells, tissues, and organs, to restore their impaired function. RM offers many advantages over current treatments as tissue can be engineered for specific defects, using an unlimited supply of bioengineered resources, and does not require immunosuppression. In the craniofacial region, TE and RM are being increasingly used in preclinical and clinical studies to reconstruct bone, cartilage, soft tissue, nerves, and blood vessels. This review outlines the current progress that has been made toward the engineering of these tissues for craniofacial reconstruction and facial esthetics.

    View details for DOI 10.1097/SCS.0000000000005840

    View details for PubMedID 31369496

  • A systematic review and meta-analysis of antibiotic prophylaxis in skin graft surgery: A protocol INTERNATIONAL JOURNAL OF SURGERY PROTOCOLS Borrelli, M. R., Sinha, V., Landin, M. L., Chicco, M., Echlin, K., Agha, R. A., Ross, A. 2019; 14: 14–18
  • Assessing the Compliance of Randomized Controlled Trials Published in Craniofacial Surgery Journals With the CONSORT Statement Borrelli, M. R., Farwana, R., Andrew, T. W., Chicco, M., Abukhder, M., Mobarak, D., Thavayogan, R., Agha, R., Pidgeon, T. E. LIPPINCOTT WILLIAMS & WILKINS. 2019: 96–104
  • Radiation-Induced Skin Fibrosis: Pathogenesis, Current Treatment Options, and Emerging Therapeutics. Annals of plastic surgery Borrelli, M. R., Shen, A. H., Lee, G. K., Momeni, A., Longaker, M. T., Wan, D. C. 2019; 83 (4S Suppl 1): S59–S64


    Radiotherapy (RT) has become an indispensable part of oncologic treatment protocols for a range of malignancies. However, a serious adverse effect of RT is radiodermatitis; almost 95% of patients develop moderate to severe skin reactions following radiation treatment. In the acute setting, these can be erythema, desquamation, ulceration, and pain. Chronically, soft tissue atrophy, alopecia, and stiffness can be noted. Radiodermatitis can delay oncologic treatment protocols and significantly impair quality of life. There is currently a paucity of effective treatment options and prevention strategies for radiodermatitis. Importantly, recent preclinical and clinical studies have suggested that fat grafting may be of therapeutic benefit, reversing detrimental changes to soft tissue following RT. This review outlines the damaging effects of RT on the skin and soft tissue as well as discusses available treatment options for radiodermatitis. Emerging strategies to mitigate detrimental, chronic radiation-induced changes are also presented.

    View details for DOI 10.1097/SAP.0000000000002098

    View details for PubMedID 31513068

  • Discussion: Adipose-Derived Stem Cells and Ceiling Culture-Derived Preadipocytes Cultured from Subcutaneous Fat Tissue Differ in Their Epigenetic Characteristics and Osteogenic Potential. Plastic and reconstructive surgery Borrelli, M. R., Longaker, M. T., Wan, D. C. 2019; 144 (3): 656–57

    View details for DOI 10.1097/PRS.0000000000005914

    View details for PubMedID 31461021

  • Composite grafts for fingertip amputations: A systematic review protocol INTERNATIONAL JOURNAL OF SURGERY PROTOCOLS Borrelli, M. R., Landin, M. L., Agha, R., Greig, A. 2019; 16: 1–4
  • Preoperative Computed Tomography Angiography in Autologous Breast Reconstruction-Incidence and Impact of Incidentalomas PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN Tevlin, R., Borrelli, M. R., Dung Nguyen, Momeni, A. 2018; 6 (12): e2019


    Incidentalomas are lesions found coincidentally during examination, imaging, or surgical procedures. Preoperative computed tomography angiography (CTA) before abdominal flap harvest for breast reconstruction can lead to identification of incidentalomas leading to the need for further investigations. The aim of this study was to examine the prevalence of incidental findings on preoperative CTA and to determine their impact on management.A retrospective chart review was performed at a single tertiary institution. CTA reports were analyzed for the presence of incidental findings and details of follow-up were studied. Logistic regression was used to identify factors associated with incidental findings.One hundred eighteen patients with a mean age of 49 years were included in the study. The majority of patients underwent bilateral reconstruction (65%, n = 77) in the immediate setting (70%, n = 83). Fifty-six percentage had an incidental finding on CTA, with hepatic (20%), renal (14%), and osseous (11%) abnormalities being most common. Additional imaging including ultrasound, CT, and magnetic resonance imaging were recommended in 19 cases (16%). Additional consultations were sought for 3 patients before reconstruction (with suspicion of bone metastases, an intraabdominal mass, and suspicion of colonic malignancy, respectively). No significant surgical delay secondary to CT findings was noted.Incidentalomas following preoperative CTA of the abdomen/pelvis are common (56%). However, unlike previous reports, we did not observe a change in reconstructive plan following incidentaloma discovery. We recommend that all patients are counseled pre-CTA regarding the possibilities of incidentaloma detection and need for additional imaging.

    View details for PubMedID 30656111

  • Assessing the Compliance of Randomized Controlled Trials Published in Craniofacial Surgery Journals With the CONSORT Statement. The Journal of craniofacial surgery Borrelli, M. R., Farwana, R., Andrew, T. W., Chicco, M., Abukhder, M., Mobarak, D., Thavayogan, R., Agha, R., Pidgeon, T. E. 2018


    BACKGROUND: Randomized controlled trials (RCTs) are gold standard assessments for healthcare interventions. The Consolidated Standards of Reporting Trials (CONSORT) statement was published to maximize RCT reporting transparency. The authors conducted a systematic review to assess current compliance of RCTs published within craniofacial surgery with the CONSORT statement.METHODS: The Thomson Reuters Impact Factor Report 2016 was consulted to identify craniofacial surgery journals. PubMed was used to search for recent RCTs published within the 5 journals identified. Two independent researchers assessed each study for inclusion and performed data extraction. The primary outcome was compliance of each RCT with the CONSORT statement. Secondary outcomes were the pathology and interventions examined, impact factor, multi-versus-single center, number of authors, and publication date.RESULTS: Eighty-six studies met the inclusion criteria, across which a median of 56% (range 33%-94%) applicable CONSORT items were reported. The 5 least reported items were: trial design (3a); registration number and name of trial registry (23); who generated random allocation sequences, enrolled participants, and assigned participants to interventions (10); sample size determination (7a); mentioning "randomized trial" in the title (1a).CONCLUSION: The compliance of craniofacial surgery RCTs with the CONSORT statement requires improvement. Areas in need are identified, and methods to improve reporting transparency, are discussed.

    View details for PubMedID 30444780

  • The PROCESS 2018 Statement: Updating Consensus Preferred Reporting Of CasE Series in Surgery (PROCESS) Guidelines. International journal of surgery (London, England) Agha, R. A., Borrelli, M. R., Farwana, R., Koshy, K., Fowler, A., Orgill, D. P., SCARE Group 2018


    INTRODUCTION: The PROCESS guidelines were published in 2016 to provide a structure for reporting surgical case series. The PROCESS guidelines have since been widely endorsed by a number of journals. The requirement to report compliance with each item outlined in the PROCESS statement has improved the reporting transparency of case series across a number of surgical specialties. Here, we undertook a new Delphi consensus exercise to update the PROCESS guidelines.METHODS: All members of the previous Delphi group were invited to participate. In addition, researchers, editors, and reviewers who have previously published or reviewed case series with the International Journal of Surgery were invited to collaborate. An online questionnaire was sent to participants asking them to rate their agreement with amendments to each of the 29 items.RESULTS: 140 experts were invited to participate, 56 people agreed to participate, and 45 (80%) recipients completed the survey. There was a high level of agreement amongst the expert group, and unanimous consensus was reached in the first round. All except three proposed items were accepted, and the original guidelines were modified accordingly.CONCLUSION: A modified and improved PROCESS checklist is presented, after a Delphi consensus exercise was completed.

    View details for PubMedID 30359781

  • The SCARE 2018 Statement: Updating Consensus Surgical CAse REport (SCARE) Guidelines. International journal of surgery (London, England) Agha, R. A., Borrelli, M. R., Farwana, R., Koshy, K., Fowler, A., Orgill, D. P., SCARE Group, Zhu, H., Alsawadi, A., Noureldin, A., Rao, A., Enam, A., Thoma, A., Bashashati, M., Vasudevan, B., Beamish, A., Challacombe, B., De Wilde, R. L., Machado-Aranda, D., Laskin, D., Muzumdar, D., D'cruz, A., Manning, T., Healy, D., Pagano, D., Goel, P., Ranganathan, P., Pai, P. S., Raja, S., Ather, M. H., Kadioazlu, H., Nixon, I., Mukherjee, I., Gomez Rivas, J., Raveendran, K., Derbyshire, L., Valmasoni, M., Chalkoo, M., Raison, N., Muensterer, O., Bradley, P., Roberto, C., Afifi, R., Rosin, D., Klappenbach, R., Wynn, R., Giordano, S., Basu, S., Surani, S., Suman, P., Thorat, M., Kasi, V. 2018


    INTRODUCTION: The SCARE Guidelines were published in 2016 to provide a structure for reporting surgical case reports. Since their publication, SCARE guidelines have been widely endorsed by authors, journal editors, and reviewers, and have helped to improve reporting transparency of case reports across a range of surgical specialties. In order to encourage further progress in reporting quality, the SCARE guidelines must themselves be kept up to date. We completed a Delphi consensus exercise to update the SCARE guidelines.METHODS: A Delphi consensus exercise was undertaken. All members of the previous Delphi group were invited to participate, in addition to researchers who have previously studied case reports, and editors from the International Journal of Surgery Case Reports. The expert group was sent an online questionnaire where they were asked to rate their agreement with proposed changes to each of the 24 items.RESULTS: 56 people agreed to participate and 45 (80%) invitees completed the survey which put forward modifications to the original guideline. The collated responses resulted in modifications. There was high agreement amongst the expert group.CONCLUSION: A modified and improved SCARE checklist is presented, after a Delphi consensus exercise was completed. The SCARE 2018 Statement: Updating Consensus Surgical CAse REport (SCARE) Guidelines.

    View details for PubMedID 30342279

  • Method of Isolating and Transplanting the Hematopoietic Stem Cell with Its Microenvironment Which Improves Functional Hematopoietic Engraftment Borrelli, M. R., Lopez, M., Gulati, G., Murphy, M. P., Sinha, R., Longaker, M. T., Weissman, I. L., Newman, A. M., Chan, C. K., Sokol, J. ELSEVIER SCIENCE INC. 2018: E224
  • Translational Approach Using Trimodal Manipulation of Resident Skeletal Stem Cells for Articular Cartilage Repair Murphy, M. P., Koepke, L. S., Lopez, M., Ransom, R. C., Brewer, R. E., Borrelli, M. R., Marecic, O., Chan, C. F., Longaker, M. T. ELSEVIER SCIENCE INC. 2018: S213–S214
  • Identification of the Human Skeletal Stem Cell. Cell Chan, C. K., Gulati, G. S., Sinha, R., Tompkins, J. V., Lopez, M., Carter, A. C., Ransom, R. C., Reinisch, A., Wearda, T., Murphy, M., Brewer, R. E., Koepke, L. S., Marecic, O., Manjunath, A., Seo, E. Y., Leavitt, T., Lu, W., Nguyen, A., Conley, S. D., Salhotra, A., Ambrosi, T. H., Borrelli, M. R., Siebel, T., Chan, K., Schallmoser, K., Seita, J., Sahoo, D., Goodnough, H., Bishop, J., Gardner, M., Majeti, R., Wan, D. C., Goodman, S., Weissman, I. L., Chang, H. Y., Longaker, M. T. 2018; 175 (1): 43


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

    View details for PubMedID 30241615

  • Utilizing Confocal Microscopy to Characterize Human and Mouse Adipose Tissue. Tissue engineering. Part C, Methods Blackshear, C., Borrelli, M. R., Shen, E. Z., Ransom, R. C., Chung, N. N., Vistnes, S., Irizarry, D., Nazerali, R., Momeni, A., Longaker, M. T., Wan, D. C. 2018


    Significant advances in our understanding of human obesity, endocrinology, and metabolism have been made possible by murine comparative models, in which anatomically analogous fat depots are utilized; however, current research has questioned how truly analogous these depots are. In this study, we assess the validity of the analogy from the perspective of cellular architecture. Whole tissue mounting, confocal microscopy, and image reconstruction software were employed to characterize the three-dimensional structure of the inguinal fat pad in mice, gluteofemoral fat in humans, and subcutaneous adipose tissue of the human abdominal wall. Abdominal and gluteofemoral adipose tissue specimens from 12 human patients and bilateral inguinal fat pads from 12 mice were stained for adipocytes, blood vessels, and a putative marker for adipose-derived multipotent progenitor cells, CD34. Samples were whole-mounted and imaged with laser scanning confocal microscopy. Expectedly, human adipocytes were larger and demonstrated greater size heterogeneity. Mouse fat displayed significantly higher vascular density compared to human fat when normalized to adipocyte count. There was no significant difference in the concentration of CD34+ stromal cells from either species. However, the mean distance between CD34+ stromal cells and blood vessels was significantly greater in human fat. Finally, mouse inguinal fat contained larger numbers of brown adipocytes than did human gluteofemoral or human abdominal fat. Overall, the basic architecture of human adipose tissue differs significantly from that of mice. Insofar as human gluteofemoral fat differs from human abdominal adipose tissue, it was closer to mouse inguinal fat, being its comparative developmental analogue. These differences likely confer variance in functional properties between the two sources, and thus must be considered when designing murine models of human disease.

    View details for PubMedID 30215305

  • Embryonic skin development and repair. Organogenesis Hu, M. S., Borrelli, M. R., Hong, W. X., Malhotra, S., Cheung, A. T., Ransom, R. C., Rennert, R. C., Morrison, S. D., Lorenz, H. P., Longaker, M. T. 2018: 1–18


    Fetal cutaneous wounds have the unique ability to completely regenerate wounded skin and heal without scarring. However, adult cutaneous wounds heal via a fibroproliferative response which results in the formation of a scar. Understanding the mechanism(s) of scarless wound healing leads to enormous clinical potential in facilitating an environment conducive to scarless healing in adult cutaneous wounds. This article reviews the embryonic development of the skin and outlines the structural and functional differences in adult and fetal wound healing phenotypes. A review of current developments made towards applying this clinical knowledge to promote scarless healing in adult wounds is addressed.

    View details for PubMedID 29420124

  • An Improved Humanized Mouse Model for Excisional Wound Healing Using Double Transgenic Mice ADVANCES IN WOUND CARE Hu, M. S., Cheng, J., Borrelli, M. R., Leavitt, T., Walmsley, G. G., Zielins, E. R., Hong, W., Cheung, A. M., Duscher, D., Maan, Z. N., Irizarry, D. M., Stephan, B., Parsa, F., Wan, D. C., Gurtner, G. C., Lorenz, H., Longaker, M. T. 2018; 7 (1): 11–17


    Objective: Splinting full-thickness cutaneous wounds in mice has allowed for a humanized model of wound healing. Delineating the epithelial edge and assessing time to closure of these healing wounds via macroscopic visualization have remained a challenge. Approach: Double transgenic mice were created by crossbreeding K14-Cre and ROSAmT/mG reporter mice. Full-thickness excisional wounds were created in K14-Cre/ROSAmT/mG mice (n = 5) and imaged using both normal and fluorescent light on the day of surgery, and every other postoperative day (POD) until wound healing was complete. Ten blinded observers analyzed a series of images from a single representative healing wound, taken using normal or fluorescent light, to decide the POD when healing was complete. K14-Cre/ROSAmT/mG mice (n = 4) were subsequently sacrificed at the four potential days of rated wound closure to accurately determine the histological point of wound closure using microscopic fluorescence imaging. Results: Average time to wound closure was rated significantly longer in the wound series images taken using normal light, compared with fluorescent light (mean POD 13.6 vs. 11.6, *p = 0.008). Fluorescence imaging of histological samples indicated that reepithelialization was complete at 12 days postwounding. Innovation: We describe a novel technique, using double transgenic mice K14-Cre/ROSAmT/mG and fluorescence imaging, to more accurately determine the healing time of wounds in mice upon macroscopic evaluation. Conclusion: The accuracy by which wound healing can be macroscopically determined in vivo in mouse models of wound healing is significantly enhanced using K14-Cre/ROSAmT/mG double transgenic mice and fluorescence imaging.

    View details for PubMedID 29344430

  • Pathway Analysis of Gene Expression of E14 Versus E18 Fetal Fibroblasts ADVANCES IN WOUND CARE Hu, M. S., Borrelli, M. R., Januszyk, M., Luan, A., Malhotra, S., Walmsley, G. G., Hong, W., Tevlin, R., Gurtner, G. C., Longaker, M. T., Lorenz, H. P. 2018; 7 (1): 1–10


    Objective: Fetuses early in gestation heal skin wounds without forming scars. The biological mechanisms behind this process are largely unknown. Fibroblasts, however, are cells known to be intimately involved in wound healing and scar formation. We examined fibroblasts in different stages of development to characterize differences in gene expression that may result in the switch from regenerative wound repair to repair with scarring. Approach: Fibroblasts were isolated and cultured from the back skin of BALB/c wild-type mouse fetuses at embryonic day (E)14 and E18 (n = 10). The fibroblast total RNA was extracted, and microarray analysis was conducted using chips containing 42,000 genes. Significance analysis of microarrays was performed to identify genes with greater than twofold expression difference and a false discovery rate of less than two. Identified genes subsequently underwent enrichment analysis to detect differentially expressed pathways. Results: Two hundred seventy-five genes were differentially expressed between E14 and E18 in fetal fibroblasts. Thirty genes were significantly downregulated and 245 genes were significantly upregulated at E18 compared with E14. Ingenuity pathway analysis identified the top 20 signaling pathways differentially activated in fetal fibroblasts between the E18 and E14 time points. Innovation: To our knowledge, this work represents the first instance where differentially expressed genes and signaling pathways between fetal fibroblasts at E14 and E18 have been studied. Conclusion: The genes and pathways identified here potentially underlie the mechanism behind the transition from fetal wound healing via regeneration to wound healing by repair, and may prove to be key targets for future therapeutics.

    View details for PubMedID 29344429

  • Mesenchymal Stromal Cells and Cutaneous Wound Healing: A Comprehensive Review of the Background, Role, and Therapeutic Potential STEM CELLS INTERNATIONAL Hu, M. S., Borrelli, M. R., Lorenz, H., Longaker, M. T., Wan, D. C. 2018: 6901983


    Cutaneous wound repair is a highly coordinated cascade of cellular responses to injury which restores the epidermal integrity and its barrier functions. Even under optimal healing conditions, normal wound repair of adult human skin is imperfect and delayed healing and scarring are frequent occurrences. Dysregulated wound healing is a major concern for global healthcare, and, given the rise in diabetic and aging populations, this medicoeconomic disease burden will continue to rise. Therapies to reliably improve nonhealing wounds and reduce scarring are currently unavailable. Mesenchymal stromal cells (MSCs) have emerged as a powerful technique to improve skin wound healing. Their differentiation potential, ease of harvest, low immunogenicity, and integral role in native wound healing physiology make MSCs an attractive therapeutic remedy. MSCs promote cell migration, angiogenesis, epithelialization, and granulation tissue formation, which result in accelerated wound closure. MSCs encourage a regenerative, rather than fibrotic, wound healing microenvironment. Recent translational research efforts using modern bioengineering approaches have made progress in creating novel techniques for stromal cell delivery into healing wounds. This paper discusses experimental applications of various stromal cells to promote wound healing and discusses the novel methods used to increase MSC delivery and efficacy.

    View details for PubMedID 29887893

    View details for PubMedCentralID PMC5985130