On-demand hydrogen sulfide-releasing hydrogel reprogramming the diabetic wound microenvironment to accelerate healing.

Abstract

Chronic diabetic wounds often progress to infection, amputation, and high mortality due to excessive reactive oxygen species (ROS), persistent inflammation, and impaired angiogenesis. Hydrogen sulfide (H₂S) can promote angiogenesis, enhance antioxidant defenses, and drive macrophages toward reparative M2 phenotypes, but its clinical use is limited by instability and toxicity. We developed a multifunctional hydrogel (CCT@HSD) composed of collagen, carboxymethyl chitosan, and tannic acid, incorporating a ROS-responsive H₂S donor (HSD) for on-demand release. This hydrogel integrated antibacterial, antioxidant, angiogenesis, and immunomodulatory functions, effectively reprogramming the wound microenvironment. It accelerated hemostasis, scavenged ROS, eradicated MRSA within 1 h, and promoted endothelial migration, while showing excellent hemocompatibility and biodegradability. Importantly, robust pro-healing performance was observed across multiple diabetic animal models, including the porcine diabetic wound model with skin architecture closer to human tissue, thereby providing stronger evidence of comparative advantage and translational potential. Metabolomic profiling further revealed various altered metabolites relative to purine, nitrogen, folate, and selenium metabolism, with key hubs such as pyruvate and folate correlating positively with angiogenesis and immunomodulation. Collectively, CCT@HSD hydrogel achieves high-quality wound repair through combined antimicrobial, antioxidant, and metabolic reprogramming, highlighting strong translational potential for refractory diabetic wounds.