Dual-network gallic acid-functionalized chitosan methacryloyl/FGelMA hydrogel for diabetic wound healing via enhanced angiogenesis and inflammation modulation.

Abstract

Excessive oxidative stress, persistent chronic inflammation, impaired angiogenesis, and delayed extracellular matrix (ECM) remodeling contribute to the chronic non-healing of diabetic wounds, which is a major clinical challenge worldwide that decreases patients' quality of life. Herein, a novel photocrosslinked hydrogel based on gallic acid functionalized chitosan methacryloyl (GA-CSMA) and fish gelatin methacryloyl (FGelMA) was developed for diabetic chronic wound treatment without exogenous therapeutic agents to provide structural stability and intrinsic bioactivity. Quantitative pore-size analysis and bulk mechanical testing confirmed that incorporation of GA-CSMA generated a denser porous architecture and improved the compressive and tensile mechanical performance of the FGelMA-based hydrogel. In addition, the optimized hydrogel formulation showed cytoprotective effects against oxidative stress by reducing intracellular reactive oxygen species (ROS) and exhibited macrophage-associated immunomodulatory activity, as evidenced by reduced pro-inflammatory mediators and enhanced pro-healing marker expression. Furthermore, GM/G-CMIII significantly promotes the proliferation, migration and in vitro angiogenesis. In vivo experiments further reveal that the hydrogel significantly accelerated wound closure via improved re-epithelialization, collagen production, and neovascularization and modulated macrophage polarization toward M2 phenotype in full-thickness wound model in streptozotocin (STZ)-induced diabetic mice. Therefore, this photocrosslinked hydrogel system can serve as a promising wound dressing for hard-to-heal chronic wounds.