Publications

All Publications


  • Inhibiting mechanotransduction signaling changes fibroblast heterogeneity and promotes tissue regeneration in healing wounds Chen, K., Kwon, S., Henn, D., Kuehlmann, B. A., Bonham, C. A., Padmanabhan, J., Noishiki, C., Barrera, J., Longaker, M. T., Januszyk, M., Gurtner, G. C. WILEY. 2020: S12?S13
  • Flexible smart bandage for wireless wound healing Trotsyuk, A. A., Jiang, Y., Niu, S., Larson, M., Beard, E., Saberi, A., Henn, D., Kwon, S., Bonham, C., Chen, K., Januszyk, M., Maan, Z., Barrera, J., Padmanabhan, J., Fischer, K. S., Bao, Z., Gurtner, G. C. WILEY. 2020: S24
  • Digit tip regeneration relies on germ layer restricted Wnt and Hedgehog signaling Barrera, J., Maan, Z., Rinkevich, Y., Henn, D., Chen, K., Bonham, C. A., Padmanabhan, J., Januszyk, M., Weissman, I. L., Gurtner, G. C. WILEY. 2020: S5
  • Human cryopreserved skingrafts recruit M2-macrophages and induce angiogenesis in a murine xenograft model Henn, D., Chen, K., Maan, Z. N., Illouz, S., Bonham, C. A., Fischer, K. S., Padmanabhan, J., Barrera, J. A., Wan, D. C., Januszyk, M., Gurtner, G. C. WILEY. 2020: S62?S63
  • Inhibiting mechanotransduction signaling changes fibroblast heterogeneity and promotes tissue regeneration in healing wounds Chen, K., Kwon, S., Henn, D., Kuehlmann, B. A., Bonham, C. A., Padmanabhan, J., Noishiki, C., Barrera, J., Longaker, M. T., Januszyk, M., Gurtner, G. C. WILEY. 2020: S13?S14
  • Conformable hyaluronic acid hydrogel delivers adipose-derived stem cells and promotes regeneration of burn injury. Acta biomaterialia Dong, Y., Cui, M., Qu, J., Wang, X., Kwon, S. H., Barrera, J., Elvassore, N., Gurtner, G. C. 2020

    Abstract

    Injury to the skin from severe burns can cause debilitating physical and psychosocial distress to the patients. Upon healing, deep dermal burns often result in devastating hypertrophic scar formation. For many decades, stem cell-based therapies have shown significant potential in improving wound healing. However, current cell delivery methods are often insufficient to maintain cell viability in a harmful burn wound environment to promote skin regeneration. In this study, we developed an enhanced approach to deliver adipose-derived stem cells (ASCs) for the treatment of burn wounds, using an in-situ-formed hydrogel system comprised of a multifunctional hyperbranched poly(ethylene glycol) diacrylate (HB-PEGDA) polymer, a commercially available thiol-functionalized hyaluronic acid (HA-SH) and a short RGD peptide. Stable hydrogels with tunable swelling and mechanical properties form within five minutes under physiological conditions via the Michael-type addition reaction. Combining with RGD peptide, as a cell adhesion motif, significantly alters the cellular morphology, enhances cell proliferation, and increases the paracrine activity of angiogenesis and tissue remodeling cytokines. Bioluminescence imaging of luciferase+ ASCs indicated that the hydrogel protected the implanted cells from the harmful wound environment in burns. Hydrogel-ASC treatment significantly enhanced neovascularization, accelerated wound closure and reduced the scar formation. Our findings suggest that PEG-HA-RGD-based hydrogel provides an effective niche capable of augmenting the regenerative potential of ASCs and promoting burn wound healing. Statement of Significance Burn injury is one of the most devastating injures, and patients suffer from many complications and post-burn scar formation despite modern therapies. Here, we designed a conformable hydrogel-based stem cell delivery platform that allows rapid in-situ gelation upon contact with wounds. Adipose-derived stem cells were encapsulated into a PEG-HA-RGD hydrogels. Introducing of RGD motif significantly improved the cellular morphology, proliferation, and secretion of angiogenesis and remodeling cytokines. A deep second-degree burn murine model was utilized to evaluate in-vivo cell retention and therapeutic effect of the hydrogel-ASC-based therapy on burn wound healing. Our hydrogel remarkably improved ASCs viability in burn wounds and the hydrogel-ASC treatment enhanced the neovascularization, promoted wound closure, and reduced scar formation.

    View details for DOI 10.1016/j.actbio.2020.03.040

    View details for PubMedID 32251786

  • Tissue Engineering of Axially Vascularized Soft-Tissue Flaps with a Poly-(e-Caprolactone) Nanofiber-Hydrogel Composite ADVANCES IN WOUND CARE Henn, D., Chen, K., Fischer, K., Rauh, A., Barrera, J. A., Kim, Y., Martin, R., Hannig, M., Niedoba, P., Reddy, S., Mao, H., Kneser, U., Gurtner, G., Sacks, J. M., Schmidt, V. J. 2020
  • Tissue Engineering of Axially Vascularized Soft-Tissue Flaps with a Poly-(?-Caprolactone) Nanofiber-Hydrogel Composite. Advances in wound care Henn, D., Chen, K., Fischer, K., Rauh, A., Barrera, J. A., Kim, Y. J., Martin, R. A., Hannig, M., Niedoba, P., Reddy, S. K., Mao, H. Q., Kneser, U., Gurtner, G. C., Sacks, J. M., Schmidt, V. J. 2020; 9 (7): 365?77

    Abstract

    Objective: To develop a novel approach for tissue engineering of soft-tissue flaps suitable for free microsurgical transfer, using an injectable nanofiber hydrogel composite (NHC) vascularized by an arteriovenous (AV) loop. Approach: A rat AV loop model was used for tissue engineering of vascularized soft-tissue flaps. NHC or collagen-elastin (CE) scaffolds were implanted into isolation chambers together with an AV loop and explanted after 15 days. Saphenous veins were implanted into the scaffolds as controls. Neoangiogenesis, ultrastructure, and protein expression of SYNJ2BP, EPHA2, and FOXC1 were analyzed by immunohistochemistry and compared between the groups. Rheological properties were compared between the two scaffolds and native human adipose tissue. Results: A functional neovascularization was evident in NHC flaps with its amount being comparable with CE flaps. Scanning electron microscopy revealed a strong mononuclear cell infiltration along the nanofibers in NHC flaps and a trend toward higher fiber alignment compared with CE flaps. SYNJ2BP and EPHA2 expression in endothelial cells (ECs) was lower in NHC flaps compared with CE flaps, whereas FOXC1 expression was increased in NHC flaps. Compared with the stiffer CE flaps, the NHC flaps showed similar rheological properties to native human adipose tissue. Innovation: This is the first study to demonstrate the feasibility of tissue engineering of soft-tissue flaps with similar rheological properties as human fat, suitable for microsurgical transfer using an injectable nanofiber hydrogel composite. Conclusions: The injectable NHC scaffold is suitable for tissue engineering of axially vascularized soft-tissue flaps with a solid neovascularization, strong cellular infiltration, and biomechanical properties similar to human fat. Our data indicate that SYNJ2BP, EPHA2, and FOXC1 are involved in AV loop-associated angiogenesis and that the scaffold material has an impact on protein expression in ECs.

    View details for DOI 10.1089/wound.2019.0975

    View details for PubMedID 32587789

    View details for PubMedCentralID PMC7307685

  • Current and Emerging Topical Scar Mitigation Therapies for Craniofacial Burn Wound Healing. Frontiers in physiology Kwon, S. H., Barrera, J. A., Noishiki, C., Chen, K., Henn, D., Sheckter, C. C., Gurtner, G. C. 2020; 11: 916

    Abstract

    Burn injury in the craniofacial region causes significant health and psychosocial consequences and presents unique reconstructive challenges. Healing of severely burned skin and underlying soft tissue is a dynamic process involving many pathophysiological factors, often leading to devastating outcomes such as the formation of hypertrophic scars and debilitating contractures. There are limited treatment options currently used for post-burn scar mitigation but recent advances in our knowledge of the cellular and molecular wound and scar pathophysiology have allowed for development of new treatment concepts. Clinical effectiveness of these experimental therapies is currently being evaluated. In this review, we discuss current topical therapies for craniofacial burn injuries and emerging new therapeutic concepts that are highly translational.

    View details for DOI 10.3389/fphys.2020.00916

    View details for PubMedID 32848859

    View details for PubMedCentralID PMC7403506

  • Cryopreserved human skin allografts promote angiogenesis and dermal regeneration in a murine model. International wound journal Henn, D., Chen, K., Maan, Z. N., Greco, A. H., Moortgat Illouz, S. E., Bonham, C. A., Barrera, J. A., Trotsyuk, A. A., Padmanabhan, J., Momeni, A., Wan, D. C., Nguyen, D., Januszyk, M., Gurtner, G. C. 2020

    Abstract

    Cryopreserved human skin allografts (CHSAs) are used for the coverage of major burns when donor sites for autografts are insufficiently available and have clinically shown beneficial effects on chronic non-healing wounds. However, the biologic mechanisms behind the regenerative properties of CHSA remain elusive. Furthermore, the impact of cryopreservation on the immunogenicity of CHSA has not been thoroughly investigated and raised concerns with regard to their clinical application. To investigate the importance and fate of living cells, we compared cryopreserved CHSA with human acellular dermal matrix (ADM) grafts in which living cells had been removed by chemical processing. Both grafts were subcutaneously implanted into C57BL/6 mice and explanted after 1, 3, 7, and 28?days (n = 5 per group). A sham surgery where no graft was implanted served as a control. Transmission electron microscopy (TEM) and flow cytometry were used to characterise the ultrastructure and cells within CHSA before implantation. Immunofluorescent staining of tissue sections was used to determine the immune reaction against the implanted grafts, the rate of apoptotic cells, and vascularisation as well as collagen content of the overlaying murine dermis. Digital quantification of collagen fibre alignment on tissue sections was used to quantify the degree of fibrosis within the murine dermis. A substantial population of live human cells with intact organelles was identified in CHSA prior to implantation. Subcutaneous pockets with implanted xenografts or ADMs healed without clinically apparent rejection and with a similar cellular immune response. CHSA implantation largely preserved the cellularity of the overlying murine dermis, whereas ADM was associated with a significantly higher rate of cellular apoptosis, identified by cleaved caspase-3 staining, and a stronger dendritic cell infiltration of the murine dermis. CHSA was found to induce a local angiogenic response, leading to significantly more vascularisation of the murine dermis compared with ADM and sham surgery on day 7. By day 28, aggregate collagen-1 content within the murine dermis was greater following CHSA implantation compared with ADM. Collagen fibre alignment of the murine dermis, correlating with the degree of fibrosis, was significantly greater in the ADM group, whereas CHSA maintained the characteristic basket weave pattern of the native murine dermis. Our data indicate that CHSAs promote angiogenesis and collagen-1 production without eliciting a significant fibrotic response in a xenograft model. These findings may provide insight into the beneficial effects clinically observed after treatment of chronic wounds and burns with CHSA.

    View details for DOI 10.1111/iwj.13349

    View details for PubMedID 32227459

  • Small molecule inhibition of dipeptidyl peptidase-4 enhances bone marrow progenitor cell function and angiogenesis in diabetic wounds TRANSLATIONAL RESEARCH Whittam, A. J., Maan, Z. N., Duscher, D., Barrera, J. A., Hu, M. S., Fischer, L. H., Khong, S., Kwon, S., Wong, V. W., Walmsley, G. G., Giacco, F., Januszyk, M., Brownlee, M., Longaker, M. T., Gurtner, G. C. 2019; 205: 51?63
  • Bony Incarceration of the Extensor Pollicis Longus Tendon Mimicking Rupture. Journal of wrist surgery Barrera, J., Ryu, J., Yao, J. 2019; 8 (3): 245?49

    Abstract

    Background ?Distal radius fractures are a relatively common injury, and rupture of the extensor pollicis longus (EPL) has been known to occur in a small number of nondisplaced distal radius fractures. In contrast, bony incarceration of the EPL tendon is an exceedingly rare occurrence and warrants special attention. Case Description ?Here we present a case of bony incarceration of the EPL tendon following distal radius fracture that mimicked tendon rupture. Following EPL release, the patient had improved function and pain in the wrist. Literature Review ?We identified three case reports of EPL tendon entrapment following distal radius fracture, and compared and contrasted the clinical features of tendon rupture versus bony entrapment. Clinical Relevance ?Our results suggest that both the type of fracture (displaced vs. nondisplaced) and the chronicity of symptoms may provide important diagnostic clues for the hand surgeon managing distal radius fracture patients presenting with EPL dysfunction.

    View details for DOI 10.1055/s-0038-1675562

    View details for PubMedID 31192048

    View details for PubMedCentralID PMC6546488

  • Optimization of transdermal deferoxamine leads to enhanced efficacy in healing skin wounds. Journal of controlled release : official journal of the Controlled Release Society Duscher, D., Trotsyuk, A. A., Maan, Z. N., Kwon, S. H., Rodrigues, M., Engel, K., Stern-Buchbinder, Z. A., Bonham, C. A., Whittam, A. J., Barrera, J., Hu, M. S., Inayathullah, M., Rajadas, J., Gurtner, G. C. 2019

    Abstract

    Chronic wounds remain a significant burden to both the healthcare system and individual patients, indicating an urgent need for new interventions. Deferoxamine (DFO), an iron-chelating agent clinically used to treat iron toxicity, has been shown to reduce oxidative stress and increase hypoxia-inducible factor-1 alpha (HIF-1?) activation, thereby promoting neovascularization and enhancing regeneration in chronic wounds. However due to its short half-life and adverse side effects associated with systemic absorption, there is a pressing need for targeted DFO delivery. We recently published a preclinical proof of concept drug delivery system (TDDS) which showed that transdermally applied DFO is effective in improving chronic wound healing. Here we present an enhanced TDDS (eTDDS) comprised exclusively of FDA-compliant constituents to optimize drug release and expedite clinical translation. We evaluate the eTDDS to the original TDDS and compare this with other commonly used delivery methods including DFO drip-on and polymer spray applications. The eTDDS displayed excellent physicochemical characteristics and markedly improved DFO delivery into human skin when compared to other topical application techniques. We demonstrate an accelerated wound healing response with the eTDDS treatment resulting in significantly increased wound vascularity, dermal thickness, collagen deposition and tensile strength. Together, these findings highlight the immediate clinical potential of DFO eTDDS to treating diabetic wounds. Further, the topical drug delivery platform has important implications for targeted pharmacologic therapy of a wide range of cutaneous diseases.

    View details for DOI 10.1016/j.jconrel.2019.07.009

    View details for PubMedID 31299261

  • Small molecule inhibition of dipeptidyl peptidase-4 enhances bone marrow progenitor cell function and angiogenesis in diabetic wounds. Translational research : the journal of laboratory and clinical medicine Whittam, A. J., Maan, Z. N., Duscher, D., Barrera, J. A., Hu, M. S., Fischer, L. H., Khong, S., Kwon, S. H., Wong, V. W., Walmsley, G. G., Giacco, F., Januszyk, M., Brownlee, M., Longaker, M. T., Gurtner, G. C. 2018

    Abstract

    In diabetes, stromal cell-derived factor-1 (SDF-1) expression and progenitor cell recruitment are reduced. Dipeptidyl peptidase-4 (DPP-4) inhibits SDF-1 expression and progenitor cell recruitment. Here we examined the impact of the DPP-4 inhibitor, MK0626, on progenitor cell kinetics in the context of wound healing. Wildtype (WT) murine fibroblasts cultured under high-glucose to reproduce a diabetic microenvironment were exposed to MK0626, glipizide, or no treatment, and SDF-1 expression was measured with ELISA. Diabetic mice received MK0626, glipizide, or no treatment for 6 weeks and then were wounded. Immunohistochemistry was used to quantify neovascularization and SDF-1 expression. Gene expression was measured at the RNA and protein level using quantitative polymerase chain reaction and ELISA, respectively. Flow cytometry was used to characterize bone marrow-derived mesenchymal progenitor cell (BM-MPC) population recruitment to wounds. BM-MPC gene expression was assayed using microfluidic single cell analysis. WT murine fibroblasts exposed to MK0626 demonstrated increased SDF-1 expression. MK0626 treatment significantly accelerated wound healing and increased wound vascularity, SDF-1 expression, and dermal thickness in diabetic wounds. MK0626 treatment increased the number of BM-MPCs present in bone marrow and in diabetic wounds. MK0626 had no effect on BM-MPC population dynamics. BM-MPCs harvested from MK0626-treated mice exhibited increased chemotaxis in response to SDF-1 when compared to diabetic controls. Treatment with a DPP-4 inhibitor significantly improved wound healing, angiogenesis, and endogenous progenitor cell recruitment in the setting of diabetes.

    View details for PubMedID 30452888

  • Acceleration of Diabetic Wound Healing with PHD2- and miR-210-targeting Oligonucleotides. Tissue engineering. Part A Dallas, A., Trotsyuk, A., Ilves, H., Bonham, C. A., Rodrigues, M., Engel, K., Barrera, J. A., Kosaric, N., Stern-Buchbinder, Z. A., White, A., Mandell, K. J., Hammond, P., Mansbridge, J. N., Jayasena, S., Gurtner, G. C., Johnston, B. H. 2018

    Abstract

    [PLACEHOLDER].

    View details for PubMedID 29644938

  • Ultrasound-Assisted Liposuction Does Not Compromise the Regenerative Potential of Adipose-Derived Stem Cells. Stem cells translational medicine Duscher, D., Atashroo, D., Maan, Z. N., Luan, A., Brett, E. A., Barrera, J., Khong, S. M., Zielins, E. R., Whittam, A. J., Hu, M. S., Walmsley, G. G., Pollhammer, M. S., Schmidt, M., Schilling, A. F., Machens, H., Huemer, G. M., Wan, D. C., Longaker, M. T., Gurtner, G. C. 2016; 5 (2): 248-257

    Abstract

    Human mesenchymal stem cells (MSCs) have recently become a focus of regenerative medicine, both for their multilineage differentiation capacity and their excretion of proregenerative cytokines. Adipose-derived mesenchymal stem cells (ASCs) are of particular interest because of their abundance in fat tissue and the ease of harvest via liposuction. However, little is known about the impact of different liposuction methods on the functionality of ASCs. Here we evaluate the regenerative abilities of ASCs harvested via a third-generation ultrasound-assisted liposuction (UAL) device versus ASCs obtained via standard suction-assisted lipoaspiration (SAL). Lipoaspirates were sorted using fluorescent assisted cell sorting based on an established surface-marker profile (CD34+/CD31-/CD45-), to obtain viable ASCs. Yield and viability were compared and the differentiation capacities of the ASCs were assessed. Finally, the regenerative potential of ASCs was examined using an in vivo model of tissue regeneration. UAL- and SAL-derived samples demonstrated equivalent ASC yield and viability, and UAL ASCs were not impaired in their osteogenic, adipogenic, or chondrogenic differentiation capacity. Equally, quantitative real-time polymerase chain reaction showed comparable expression of most osteogenic, adipogenic, and key regenerative genes between both ASC groups. Cutaneous regeneration and neovascularization were significantly enhanced in mice treated with ASCs obtained by either UAL or SAL compared with controls, but there were no significant differences in healing between cell-therapy groups. We conclude that UAL is a successful method of obtaining fully functional ASCs for regenerative medicine purposes. Cells harvested with this alternative approach to liposuction are suitable for cell therapy and tissue engineering applications. Significance: Adipose-derived mesenchymal stem cells (ASCs) are an appealing source of therapeutic progenitor cells because of their multipotency, diverse cytokine profile, and ease of harvest via liposuction. Alternative approaches to classical suction-assisted liposuction are gaining popularity; however, little evidence exists regarding the impact of different liposuction methods on the regenerative functionality of ASCs. Human ASC characteristics and regenerative capacity were assessed when harvested via ultrasound-assisted (UAL) versus standard suction-assisted liposuction. ASCs obtained via UAL were of equal quality when directly compared with the current gold standard harvest method. UAL is an adjunctive source of fully functional mesenchymal stem cells for applications in basic research and clinical therapy.

    View details for DOI 10.5966/sctm.2015-0064

    View details for PubMedID 26702129

    View details for PubMedCentralID PMC4729547

  • Challenges and Opportunities in Drug Delivery for Wound Healing. Advances in wound care Whittam, A. J., Maan, Z. N., Duscher, D., Wong, V. W., Barrera, J. A., Januszyk, M., Gurtner, G. C. 2016; 5 (2): 79-88

    Abstract

    Significance: Chronic wounds remain a significant public health problem. Alterations in normal physiological processes caused by aging or diabetes lead to impaired tissue repair and the development of chronic and nonhealing wounds. Understanding the unique features of the wound environment will be required to develop new therapeutics that impact these disabling conditions. New drug-delivery systems (DDSs) may enhance current and future therapies for this challenging clinical problem. Recent Advances: Historically, physical barriers and biological degradation limited the efficacy of DDSs in wound healing. In aiming at improving and optimizing drug delivery, recent data suggest that combinations of delivery mechanisms, such as hydrogels, small molecules, RNA interference (RNAi), as well as growth factor and stem cell-based therapies (biologics), could offer exciting new opportunities for improving tissue repair. Critical Issues: The lack of effective therapeutic approaches to combat the significant disability associated with chronic wounds has become an area of increasing clinical concern. However, the unique challenges of the wound environment have limited the development of effective therapeutic options for clinical use. Future Directions: New platforms presented in this review may provide clinicians and scientists with an improved understanding of the alternatives for drug delivery in wound care, which may facilitate the development of new therapeutic approaches for patients.

    View details for PubMedID 26862465

  • Adipose-Derived Stem Cell-Seeded Hydrogels Increase Endogenous Progenitor Cell Recruitment and Neovascularization in Wounds TISSUE ENGINEERING PART A Kosaraju, R., Rennert, R. C., Maan, Z. N., Duscher, D., Barrera, J., Whittam, A. J., Januszyk, M., Rajadas, J., Rodrigues, M., Gurtner, G. C. 2016; 22 (3-4): 295-305

    Abstract

    Adipose-derived mesenchymal stem cells (ASCs) are appealing for cell-based wound therapies because of their accessibility and ease of harvest, but their utility is limited by poor cell survival within the harsh wound microenvironment. In prior work, our laboratory has demonstrated that seeding ASCs within a soft pullulan-collagen hydrogel enhances ASC survival and improves wound healing. To more fully understand the mechanism of this therapy, we examined whether ASC-seeded hydrogels were able to modulate the recruitment and/or functionality of endogenous progenitor cells. Employing a parabiosis model and fluorescence-activated cell sorting analysis, we demonstrate that application of ASC-seeded hydrogels to wounds, when compared with injected ASCs or a noncell control, increased the recruitment of provascular circulating bone marrow-derived mesenchymal progenitor cells (BM-MPCs). BM-MPCs comprised 23.0% of recruited circulating progenitor cells in wounds treated with ASC-seeded hydrogels versus 8.4% and 2.1% in those treated with controls, p?

    View details for DOI 10.1089/ten.tea.2015.0277

    View details for Web of Science ID 000369987900012

    View details for PubMedID 26871860

    View details for PubMedCentralID PMC4779321

  • Stem Cells in Wound Healing: The Future of Regenerative Medicine? A Mini-Review. Gerontology Duscher, D., Barrera, J., Wong, V. W., Maan, Z. N., Whittam, A. J., Januszyk, M., Gurtner, G. C. 2016; 62 (2): 216-225

    Abstract

    The increased risk of disease and decreased capacity to respond to tissue insult in the setting of aging results from complex changes in homeostatic mechanisms, including the regulation of oxidative stress and cellular heterogeneity. In aged skin, the healing capacity is markedly diminished resulting in a high risk for chronic wounds. Stem cell-based therapies have the potential to enhance cutaneous regeneration, largely through trophic and paracrine activity. Candidate cell populations for therapeutic application include adult mesenchymal stem cells, embryonic stem cells and induced pluripotent stem cells. Autologous cell-based approaches are ideal to minimize immune rejection but may be limited by the declining cellular function associated with aging. One strategy to overcome age-related impairments in various stem cell populations is to identify and enrich with functionally superior stem cell subsets via single cell transcriptomics. Another approach is to optimize cell delivery to the harsh environment of aged wounds via scaffold-based cell applications to enhance engraftment and paracrine activity of therapeutic stem cells. In this review, we shed light on challenges and recent advances surrounding stem cell therapies for wound healing and discuss limitations for their clinical adoption.

    View details for DOI 10.1159/000381877

    View details for PubMedID 26045256

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