Zero-valent copper nanozymes hydrogels promote diabetic wound healing

Persistent oxidative stress, inflammation, and impaired angiogenesis delay diabetic wound repair. Copper-containing materials can influence these processes through both redox chemistry and copper delivery. Here, zero-valent copper (Cu 0 ) nanozymes were incorporated into an alginate hydrogel (Cu 0 @Alg) to combine antioxidant activity with Cu + -generating reactivity. Cu 0 increased the Cu + concentration measured by the colorimetric assay in Cu 2+ -containing solutions, while the hydrogel retained radical-scavenging and superoxide dismutase- and catalase-like activities. The hydrogel had a porous, water-absorbing structure, retained Cu + -generating activity during storage, and released copper over 14 days. In vitro, Cu 0 at a nominal exposure concentration of 0.5 μmol mL −1 promoted human umbilical vein endothelial cell migration and tube formation, accompanied by increased hypoxia-inducible factor-1α and vascular endothelial growth factor expression. In RAW264.7 macrophages, Cu 0 at a nominal exposure concentration of 0.25 μmol mL −1 reduced pro-inflammatory markers and increased repair-associated markers. In a diabetic full-thickness skin wound model, Cu 0 @Alg accelerated closure, reduced oxidative damage, and increased vascular-associated staining and collagen deposition over 12 days. These results support Cu 0 @Alg as an antioxidant copper-containing dressing for diabetic wound repair. Cu 0 /Cu 2+ comproportionation is proposed as one contributor to Cu + generation in solution; however, its occurrence and contribution to wound repair have not been directly established in vivo.