Programming the Diabetic-Infected Wound Microenvironment With a Smart Hydrogel for Ordered Healing Cascade Restoration.

Abstract

The diabetic-infected wound microenvironment, marked by elevated reactive oxygen species (ROS) levels, ongoing inflammation, and defective angiogenesis, interferes with the normal wound healing cascade and contributes to delayed and treatment-resistant repair. However, most existing wound dressings lack the capability to dynamically adapt to these spatiotemporally evolving conditions. Herein, a smart and microenvironment-programmable PVH-ST hydrogel is developed to achieve phased and spatiotemporally coordinated regulation of diabetic-infected wound healing. The hydrogel is engineered by integrating strontium (Sr)-tannic acid (ST) nanoparticles into a polyvinyl alcohol (PVA) and hyaluronic acid (HA) matrix through a boric acid-mediated multilevel dynamic crosslinking network, endowing the system with mechanical robustness suitable for daily motion. Upon wound occurrence, the PVH-ST hydrogel rapidly induces hemostasis and establishes a bioactive provisional matrix. In response to the ROS-enriched infected microenvironment, the dynamic borate bonds undergo on-demand dissociation, triggering controlled release of ST nanoparticles. Released ST nanoparticles integrate antibacterial and antioxidant functions and reduce inflammatory burden via modulation of NF-κB signaling and skewing macrophages toward an M2 pro-regenerative state. Concurrently, the sustained release of Sr²⁺ ions activates VEGF-associated angiogenic signaling and epithelialization pathways, thereby promoting vascularization and epithelial reconstruction for diabetic-infected wounds.