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.