Multifunctional Intelligent Hydrogels Based on MnO2 Nanozymes and Ca2+ Signal Regulation for Diabetic Wound Repair

Abstract

Diabetic refractory wounds are a prevalent and severe complication of diabetes, whose pathological progression is jointly mediated by multiple factors, including oxidative stress imbalance, chronic inflammation, impaired angiogenesis, bacterial infection, and biofilm formation. Current clinical hydrogel dressings generally suffer from drawbacks such as single-function performance, potential toxicity of nano-components, static networks incompatible with dynamic wound conditions, and the absence of bionic repair signals. Therefore, they cannot simultaneously satisfy the dual repair requirements of complex pathological microenvironments and dynamic mechanical properties for diabetic wounds. In this study, a multi-functional dynamically responsive composite hydrogel (MC group) with high-efficiency antioxidant, antibacterial, and pro-angiogenic capacities was fabricated. Using SDS-C18 micelles as hydrophobic units, a rigid–flexible dual-network framework was constructed with polyvinyl alcohol (PVA) and methacrylated hyaluronic acid (HAMA). Manganese dioxide nanozymes were introduced to scavenge reactive oxygen species (ROS) and mitigate oxidative stress. Calcium-ion-mediated dynamic micelle reconstruction was adopted to regulate the hydrophilic–hydrophobic balance, while achieving antibacterial effects and facilitating tissue regeneration. In vitro experiments verified that the MC hydrogel possesses mechanical properties well-matched to human soft tissues (fracture stress: 25 kPa) and excellent biocompatibility (cell viability > 100%, hemolysis rate: only 0.13%). It also exhibits prominent antioxidant activity (DPPH radical-scavenging rate: 36.95%), antibacterial performance (>99.86% bactericidal rate against Staphylococcus aureus, survival rate of Escherichia coli reduced to 15.95%), and cell-migration-promoting activity (endothelial cell migration rate of 83.72% and mouse fibroblast migration rate of 90.88% within 24 h). In the full-thickness skin defect model of diabetic mice, the wound-healing rate reached 99% on day 16. Moreover, it promoted ordered collagen deposition, skin appendage regeneration, and functional microvascular reconstruction, thereby accomplishing high-quality tissue repair. This design synergistically intervenes in multiple pathological links of diabetic wounds, overcomes several key limitations of existing dressings, and provides an innovative strategy for developing smart dressings.