Regenerative wound healing enabled by recombinant humanized collagen III releasing composite hydrogel.
High-quality repair of full-thickness skin defects necessitates not only epithelial tissue healing but the facilitation of orderly microstructural reconstruction. This includes aligned collagen deposition, regeneration of skin appendages such as hair follicles, and suppression of scar formation. To address these requirements, this study developed an injectable multifunctional composite hydrogel based on caffeic acid and quaternary ammonium-modified chitosan (qCSc), incorporated with recombinant humanized type III collagen (rhCol III) and laponite (LAP). This organic/inorganic hybrid hydrogel forms a stable three-dimensional network through dual crosslinking: enzymatic covalent bonding and LAP-mediated physical interactions, supported by chemical, electrostatic, and hydrogen bonding, which enables sustained release of rhCol III. In vitro, the hydrogel showed good biocompatibility, anti-inflammatory and antioxidative effects, attenuated M1-like macrophage activation, and enhanced fibroblast migration and angiogenesis. In full-thickness skin defect models, the hydrogel significantly accelerated wound closure, promoted early vascularization, facilitated well-organized collagen remodeling, and supported hair follicle-associated regenerative features, while effectively attenuating scar-prone remodeling. Taken together, this organic/inorganic composite hydrogel dressing, which enables sustained release of rhCol III, represents a promising and innovative strategy for management of full-thickness skin injuries. STATEMENT OF SIGNIFICANCE: Current wound dressings facilitate closure but offer limited support for high-quality repair. Here, we present a bioactive composite hydrogel with a distinct dual-crosslinked architecture comprising caffeic acid and quaternary ammonium-modified chitosan (qCSc) and Laponite (Lap), designed for the sustained delivery of recombinant humanized collagen III (rhCol III). This platform uniquely integrates multiple regeneration-relevant bioactivities, synergistically reducing inflammation and oxidative stress while promoting angiogenesis and cell migration in vitro. In full-thickness skin defect models, it not only accelerated wound closure but also achieved key regenerative outcomes with enhanced hair follicle-associated regeneration and reduced scar-prone remodeling. This work establishes a sustained-delivery strategy that couples matrix cues with microenvironment regulation for high-quality wound repair.