Responsive hydrogel modulator with self-regulated polyphenol release for accelerating diabetic wound healing via precise immunoregulation

Abstract

Nonhealing chronic wounds are intractable clinical complications of diabetes and are characterized by high protease activity, severe oxidative stress and sustained inflammatory response. In this case, the development of functional hydrogel dressings to modulate the immune microenvironment is a well-known strategy, where the precise stimuli-responsive and spatiotemporally controlled release of bioactive molecules remains a huge challenge. Herein, we developed responsive hydrogels with self-regulated bioactive molecule release based on the protease activity in diabetic wound sites, to serve as a smart immune microenvironment modulator for accelerating wound healing. The hydrogels were fabricated by grafting oxidized hyaluronic acid with epigallocatechin-3-gallate (EGCG) and gelatin methacryloyl (GelMA) under UV irradiation. Resveratrol nanoparticles were further loaded into the hydrogels before gelation to construct a polyphenol delivery system. The prepared hydrogels could achieve the on-demand release of polyphenol upon degradation by protease, as confirmed via degradation and polyphenol release experiments. The released polyphenol was demonstrated to have the capacity to effectively scavenge excessive free radicals, promote macrophage polarization, reduce proinflammatory factor (TNF-α) expression and augment anti-inflammatory factor (IL-10) expression in vitro. Additionally, in vivo rat wound healing model experiment results confirmed that these hydrogels promoted collagen deposition and granulation tissue regeneration, accelerating diabetic wound healing. Based on the protease-responsive degradation characteristic of the hydrogels and high protease activity in the diabetic wound microenvironment, hydrogels with exquisite polyphenol release controllability are promising candidates as dressings for diabetic wound management.