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.info:eu-repo/semantics/publishedVersio
