“Delivery of External Volume Expansion (EVE) through Micro-deformational Interfaces Safely Induces Angiogenesis in a Murine Model of Intact Diabetic Skin with Endothelial Cell Dysfunction (ECD)”

Introduction: External Volume Expansion (EVE) promotes angiogenesis in tissues by inducing a sub-critical hypoxia, mechanically stimulating endothelia, and creating mild inflammation. Application of EVE to less-vascularized tissues with endothelial cell dysfunction (ECD) (e.g., diabetic skin) poses a risk for ineffectiveness or ischemic damage. We investigated the effects of EVE on a murine model of diabetes type-2 and tested whether the adoption of micro-deformational interfaces of EVE optimizes its angiogenic properties while limiting complications to tissues. Materials and Methods: Adult diabetic mice (Db/Db) received stimulation with EVE on their dorsal skin using a standard Cup-shaped silicone interface (C-EVE), a polyurethane Foam-shaped interface (F-EVE), or a silicone Micro-array chamber interface (M-EVE); controls received no treatment. Skin damage was visually assessed on the last day of stimulation and five days later. At a five-day follow-up, skin specimens (n = 5 /group) were procured and analyzed by histology to assess angiogenesis, adipose tissue and skin remodeling, and inflammation. Results: All treatments significantly increased the density of blood vessels in skin compared to controls; F-EVE showed the most robust effect (+80 %). No relevant complications were observed using F-EVE or M-EVE but C-EVE lead to substantial skin damage and caused intense inflammation, fibrosis of the subcutaneous tissue, and dermal remodeling (increased thickness/collagen deposition). No effect on adipose tissue was observed in any of the groups. Conclusions: The adoption of EVE with micro-deformational interfaces allows the effective and safe preconditioning of tissues with ECD and could improve outcomes in diabetic patients at high-risk for surgical complications. Acknowledgments, conflict of interest and role of funding sources disclosure statement: Authors are thankful to the BioMEMS Resource Center (Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA) and Harrison Prentice-Mott for fabricating and providing the M-EVE interface. Authors are also thankful to KCI, Inc. for providing the pumps and the foam-shaped interface used in this study. All authors declare no actual or potential conflict of interests: in addition, they disclose any commercial or financial associations, personal or other relationships with other people or organizations that could inappropriately influence the reported manuscript or create a conflict of interest with the information presented. This study was funded by a research grant from the Gillian Reny Stepping Strong Foundation to Brigham and Women's Hospital. Authorship: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors have seen and agreed to the submitted version of the manuscript and bear responsibility for it. Ethics: The displayed study was carried out with respect to high ethical standards. All the studies have been approved, when required, by the appropriate ethics committee and have, therefore, been performed in accordance and in conformity to the World Medical Association Declaration of Helsinki (June 1964) and subsequent amendments. Meetings at which the paper has been presented: None. Corresponding author: Giorgio Giatsidis (* corresponding author), Tissue Engineering and Wound Healing Laboratory,Department of Surgery, Division of Plastic Surgery, Brigham and Women's Hospital - Harvard Medical School, 75 Francis St., Boston MA 02115, T: 617-525-7837F: 617-730-2855 E: ggiatsidis@bwh.harvard.edu ©2018American Society of Plastic Surgeons

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