Stem cell-containing hyaluronic acid-based spongy hydrogels for integrated diabetic wound healing

The detailed pathophysiology of diabetic foot ulcers is yet to be established and improved treatments are still required. We propose a strategy that directs inflammation, neovascularization, and neoinnervation of diabetic wounds. Aiming to potentiate a relevant secretome for nerve regeneration, stem cells were precultured in hyaluronic acid-based spongy hydrogels under neurogenic/standard media before transplantation into diabetic mice full-thickness wounds. Acellular spongy hydrogels and empty wounds were used as controls. Reepithelialization was attained 4 weeks after transplantation independently of the test groups, whereas a thicker and more differentiated epidermis was observed for the cellular spongy hydrogels. A switch from the inflammatory to the proliferative phase of wound healing was revealed for all the experimental groups 2 weeks after injury, but a significantly higher M2(CD163 þ )/M1(CD86 þ ) subtype ratio was observed in the neurogenic preconditioned group that also failed to promote neoinnervation. A higher number of intraepidermal nerve fibers were observed for the unconditioned group probably due to a more controlled transition from the inflammatory to the proliferative phase. Overall, stem cell-containing spongy hydrogels represent a promising approach to enhance diabetic wound healing by positively impacting re-epithelialization and by modulating the inflammatory response to promote a successful neoinnervation.The authors would like to acknowledge Gene2Skin Project (H2020-TWINN2015-692221) and Fundac¸a˜o para a Cieˆncia e Tecnologia for SFRH/BD/ 78025/2011 (LPdS), SFRH/BPD/96611/2013 (MTC), SFRH/BPD/101886/2014 (RPP), SFRH/BPD/101952/2014 (TCS) grants. Moreover, the authors would also like to acknowledge Teresa Oliveira for histology support, Andreia Carvalho for hASCs supply, Luca Gasperini for cell profiler analysis, and Manuela E. L. Lago and Carla M. Abreu for intraepidermal nerve fiber quantification.