Dynamically responsive hydrogel with mechanical stimulation enhances diabetic wound healing via activation of Piezo1-mediated efferocytosis.

Abstract

Correcting the disordered metabolism and achieving dynamic, comprehensive management of chronic diabetic wounds remains a significant challenge. This study presents a double-network dynamic hydrogel exhibiting long-term anti-inflammatory, antioxidant properties, and tunable mechanical strength. The hydrogel is primarily composed of modified chitosan, hyaluronic acid, sodium alginate, and ZnO₂/Fe³⁺ nanoparticles. The incorporated ZnO₂/Fe³⁺ nanoparticles enable microenvironmental regulation by responding to H⁺ or reactive oxygen species (ROS), while the released Fe³⁺ ions drive hydrogel network reconstruction, thereby enhancing mechanical properties. In vitro studies demonstrate the hydrogel's efficacy in efficiently scavenging ROS and enhancing Piezo1-mediated macrophage efferocytosis through cell-matrix interactions, accelerating macrophage polarization towards the M2 phenotype and resolving inflammation. In vivo experiments further confirm that the CHS@ZnO₂/Fe³⁺ hydrogel significantly promotes re-epithelialization. Mechanical stimulation provided by the hydrogel recruited abundant fibroblasts and endothelial cells to the wound site, facilitating collagen deposition and angiogenesis. This novel hydrogel dressing, combining mechanical and biochemical dual-regulation, provides an advanced therapeutic strategy for the efficient repair of diabetic chronic wounds.