Self-regulating hydrogel for diabetic wound healing: From animal models to a pilot clinical study

Chronic diabetic wounds affect millions and often fail to heal due to infection, inflammation, and poor angiogenesis, leading to high rates of amputation. Current treatments offer limited control over the wound microenvironment. Here, this work develops GPP@ZnBG hydrogels that can respond to elevated glucose and oxidative stress in diabetic wounds to release therapeutic ions in a self-pH-regulated and sequential manner. At an early stage, this hydrogel initiates a release of zinc ions under alkaline conditions, providing antibacterial activity while avoiding toxicity from excessive dosing. During the late stage, the hydrogel degrades, and it steadily releases zinc, calcium, and silicate ions that support angiogenesis, reduce inflammation, and promote tissue repair. In diabetic mice, GPP@ZnBG hydrogels improve neovascularization and enhance collagen deposition, leading to enhanced wound closure. Single-cell RNA sequencing results indicate that the hydrogel modulates fibroblast behavior, specifically fine-tuning NF-κB signaling to reduce detrimental inflammation and promote wound repair. A pilot clinical study demonstrates that topical GPP@ZnBG application showed a 94.57% relative reduction in a wound surface area within 4 weeks, with no adverse events reported. These findings establish a self-pH-driven ion delivery strategy that targets both infection and tissue regeneration, offering a promising therapeutic platform for chronic diabetic wound care.