An Antioxidative and Active Shrinkage Hydrogel Integratedly Promotes Re‐Epithelization and Skin Constriction for Enhancing Wound Closure

Abstract Delayed re‐epithelization and weakened skin contractions are the two primary factors that hinder wound closure in large‐scale acute or chronic wounds. However, effective strategies for targeting these two aspects concurrently are still lacking. Herein, an antioxidative active‐shrinkage hydrogel (AHF@AS Gel) is constructed that can integratedly promote re‐epithelization and skin constriction to accelerate large‐scale acute and diabetic chronic wound closure. The AHF@AS Gel is encapsulated by antioxidative amino‐ and hydroxyl‐modified C70 fullerene (AHF) and a thermosensitive active shrinkage hydrogel (AS Gel). Specifically, AHF relieves overactivated inflammation, prevents cellular apoptosis, and promotes fibroblast migration in vitro by reducing excessive reactive oxygen species (ROS). Notably, the AHF@AS Gel achieved ≈2.7‐fold and ≈1.7‐fold better re‐epithelization in acute wounds and chronic diabetic wounds, respectively, significantly contributing to the promotion of wound closure. Using proteomic profiling and mechanistic studies, it is identified that the AHF@AS Gel efficiently promoted the transition of the inflammatory and proliferative phases to the remodeling phase. Notably, it is demonstrated that AS Gel alone activates the mechanosensitive epidermal growth factor receptor/Akt (EGFR/Akt) pathway and promotes cell proliferation. The antioxidative active shrinkage hydrogel offers a comprehensive strategy for acute wound and diabetic chronic wound closure via biochemistry regulation integrating with mechanical forces stimulation.