A Dual-Enzymatic Cross-linked Adhesive and Self-Contraction Hyaluronic Acid Hydrogel Laden with Adipose-Derived Stem Cells to Enhance Regeneration of Full-Thickness Wound Defect

GOx/HRP crosslinked HAA-Tyr hydrogel system which with robust temperature-independent anti-swelling and self-contracting capability was developed. • Accompany with excellent self-contracting property, HAA-Tyr hydrogel showed excellent cytocompatibility that enables stem cell encapsulation and delivery. • Through integrating mechanical-biological clues of HAA-Tyr and ADSCs, ADSC@HAA-Tyr wound dressing showed enhanced performance in guiding full-thickness skin regeneration. Wound dressing combining mechanical cues and the biological activity of stem cells is a promising candidate for chronic wound healing. Here, we developed an adipose-derived mesenchymal stem cells (ADSCs) loaded self-contractile and tissue-adhesive hydrogel patch cross-linked via the peroxidase (HRP) and glucose oxidase (GOx) mediated cascade enzymatic crosslinking of aldehyde tyramine-dual modified hyaluronic acid (HAA-Tyr). Apart from the great cell encapsulation ability, aldehyde modified hyaluronic acid (HAA) hydrogel exhibited excellent self-contraction and tissue adhesion properties, which are beneficial for wound closure. Moreover, the ADSCs-loaden HAA-Tyr hydrogel showed improved bioactivity in promoting cell migration and neovascularization. The in vivo full-thickness skin defect model showed that the hydrogel dressing significantly promoted the wound healing process through enhancing angiogenesis and reducing early inflammatory response. In conclusion, wound dressings developed by integrating autonomously contractile, tissue-adhesive hydrogel systems with stem cell paracrine functionality hold considerable promise for chronic wound management.