An Injectable Polyurethane/Hyaluronic Acid Hybrid Hydrogel for Glucose-Responsive CAPE Release and Immune Remodeling in Diabetic Wound Healing

Diabetic wounds are typified by hyperglycemia, hypoxia, chronic inflammation, and elevated oxidative stress, all of which collectively contribute to delayed and dysregulated healing. Inspired by the structural and functional attributes of native skin, we designed a dynamic bond-crosslinked, injectable, and in situ-forming polyurethane/hyaluronic acid-based hybrid hydrogel (PUS-OHABE). In this hydrogel, caffeic acid phenethyl ester (CAPE) was grafted onto aldehyde-modified hyaluronic acid (HA) chains through dynamic borate ester bonds. This CAPE-modified HA was then combined with a side-chain hydrazide (ADH)-modified waterborne polyurethane emulsion via Schiff base reactions to form a stable hydrogel network structure. The PUS-OHABE hydrogel exhibits good self-healing ability, stability, tissue adhesion, and hemostatic capacity. Additionally, it has a unique ability to dissociate borate ester bonds in the hyperglycemic wound microenvironment to responsively release CAPE, thereby conferring antioxidant and anti-inflammatory properties. In diabetic rat models, the PUS-OHABE hydrogel enabled rapid wound healing and re-epithelialization; meanwhile, it also promoted angiogenesis, hair follicle regeneration, and extracellular matrix remodeling, thus offering a promising strategy for the design of biomaterials targeting chronic wound healing.