An injectable hydrogel of Enteromorpha polysaccharide/gelatin–derivatives inspired by siderophores and biocatalysis for addressing all phases of chronic diabetic wound healing

Given that chronic diabetic wounds are difficult to cure because of disruptions in the four healing phases (hemostasis, immune regulation, cell proliferation, and tissue regeneration), wound dressings promoting all of these phases and thus accelerating diabetic wound healing are highly desirable. To address this need, inspired by siderophore-Fe3+ chelation and horseradish peroxidase (HRP) catalysis, we synthesized a tyramine-modified Enteromorpha prolifera polysaccharide and dopamine-modified gelatin and used them to fabricate an injectable hydrogel (PG-Fe) featuring interpenetrating polymer networks facilitated by catecholate/carboxylate-Fe3+ coordination bonding and HRP-mediated covalent bonding between phenolic groups. PG-Fe exhibited good injectability, rapid gelation (11.5 s), suitable mechanical properties, enhanced tissue adhesiveness (50.5 kPa), and rapid self-healing (60 s) because of its intrinsic moieties and introduced modifications. Furthermore, it exhibited enhanced antioxidant, anti-inflammatory, cell adhesion, and migration effects. Consequently, PG-Fe simultaneously addressed all four wound healing phases, thereby shortening the closure time of normal and chronic diabetic wounds to 21 days. Following application, PG-Fe could be decomposed using a desferrioxamine solution and easily removed. Taken together, our study provides a novel strategy for fabricating injectable hydrogels that exhibit desirable physicochemical properties and enhanced biological functions to accelerate all phases of chronic diabetic wound healing.