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Skin substitute-assisted repair shows reduced dermal fibrosis in acute ... Bioengineering Group, School of Materials, University of Manchester, and. 5. Department of ..... was no different from baseline in controls, CG, and auto- grafts (p5 0.440 ...

Skin substitute-assisted repair shows reduced dermal fibrosis in acute human wounds validated simultaneously by histology and optical coherence tomography Nicholas S. Greaves, MBChB1,3,4; Syed A. Iqbal, PhD1; Tom Hodgkinson, PhD1; Julie Morris, MSc2; Brian Benatar, FRCPath5; Teresa Alonso-Rasgado, PhD4; Mohamed Baguneid, MD3; Ardeshir Bayat, MBBS, PhD1,4 1. 2. 3. 4. 5.

Plastic and Reconstructive Surgery Research, Institute of Inflammation and Repair, The University of Manchester, Department of Medical Statistics, University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Department of Vascular Surgery, University Hospital of South Manchester NHS Foundation Trust, Wythenshawe Hospital, Manchester, Bioengineering Group, School of Materials, University of Manchester, and Department of Histopathology, The Pennine Acute Hospitals NHS Trust, The Royal Oldham Hospital, Oldham, United Kingdom

Reprint requests: Dr. Ardeshir Bayat, Plastic and Reconstructive Surgery Research, Manchester Institute of Biotechnology (MIB), 131 Princess Road, Manchester M1 7ND, United Kingdom. Tel/Fax: 10044 161 306 5177; Email: [email protected] Manuscript received: March 17, 2015 Accepted in final form: April 21, 2015 DOI:10.1111/wrr.12308 Related presentations: This paper was shortlisted in the Young Investigator award section of the European Tissue Repair Society (ETRS) annual meeting in October 2014 (Edinburgh, UK) and given as an oral podium presentation.

aSMA CG CTGF d DCD dSS ECM IL LOX

ABSTRACT Skin substitutes are heterogeneous biomaterials designed to accelerate wound healing through provision of replacement extracellular matrix. Despite growing evidence for their use in chronic wounds, the role of skin substitutes in acute wound management and their influence on fibrogenesis remains unclear. Skin substitute characteristics including biocompatibility, porosity, and elasticity strongly influence cellular behavior during wound healing. Thus, we hypothesize that structural and biomechanical variation between biomaterials may induce differential scar formation after cutaneous injury. The following human prospective cohort study was designed to investigate this premise. Four 5-mm full thickness punch biopsies were harvested from 50 volunteers. In all cases, site 1 healed by secondary intention, site 2 was treated with collagen-GAG scaffold (CG), and decellularised dermis (DCD) was applied to site 3 while tissue extracted from site 4 was replaced (autograft). Healing tissue was assessed weekly with optical coherence tomography (OCT), before being excised on days 7, 14, 21, or 28 depending on study group allocation for later histological and immunohistochemical evaluation. Extracted RNA was used in microarray analysis and polymerase chain reaction of highlighted genes. Autograft treatment resulted in minimal fibrosis confirmed immunohistochemically and with OCT through significantly lower collagen I levels (p 5 0.047 and 0.03) and reduced mean grayscale values (p 5 0.038 and 0.015), respectively. DCD developed intermediate scar formation with partial rete ridge reformation and reduced fasiculonodular fibrosis. It was uniquely associated with late up-regulation of matrix metalloproteinases 1 and 3, oncostatin M, and interleukin-10 (p 5 0.007, 0.04, 0.019, 0.019). Regenerated dermis was significantly thicker in DCD and autografts 28 days post-injury compared with control and CG samples (p 5 0.003 and

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