Multi-crosslinking 2,3-catechol-functionalized chitosan hydrogel: Oxidation-resistive and ROS-scavenging platform for granulation regeneration

Diabetic wound healing remains a major clinical challenge due to a pathological microenvironment characterized by excessive reactive oxygen species (ROS) and chronic inflammation. Excessive ROS through multiple distinct pathways hinders the regeneration of granulation tissue, which is the essential scaffold for wound repair. Although catechol attracted considerable interest for antioxidant applications in biomaterials, its inherent chemical instability under physiological conditions severely limits its therapeutic potential and clinical applications. To address these critical challenges, an antioxidant 2,3-HCat-CS/STPP hydrogel has been developed via the freeze-thaw method, composed of 2,3-dihydroxybenzoic acid modification of chitosan (2,3-HCat-CS) and sodium tripolyphosphate (STPP). As an antioxidant, 2,3-HCat-CS was demonstrated both theoretically and experimentally to possess superior oxidative stability and ROS-scavenging property compared to the conventional 3,4-isomer. Exploration of the gelation mechanism revealed that 2,3-HCat-CS/STPP hydrogel is formed from electrostatic interactions, crystalline regions and hydrogen bonds. Hydrogel exhibited excellent antioxidant property and biocompatibility in vitro. In a full-thickness wound model in db/db mice, treatment with 2,3-HCat-CS/STPP hydrogel effectively reduced local ROS levels, mitigated inflammation and increased the levels of key anti-inflammatory cytokines (TGF-β1 and IL-10). This intervention effectively disrupted the detrimental inflammatory cycle characteristic of diabetic wounds, thereby fostering the process of angiogenesis and granulation regeneration. This work combines the molecular design of catechol and the fabrication process of chitosan gelation to create 2,3-HCat-CS/STPP hydrogel that promotes granulation regeneration in diabetic wounds, which presents a potential therapeutic platform for chronic wounds management.