Photo-crosslinkable hydrogel with programmable dual time-phase drug release for accelerated healing of infected diabetic wounds
Yufei Xue, Fan Li, Hui Liu, Hongli Chen, Ka Bian, Hua Bai, Nicolas H. Voelcker, Bo Peng, Lin Li, Xuekang Yang
Abstract
• Diabetic wounds always come with persistent bacterial infections and chronic inflammation. • Conventional photo-crosslinking methods often complicate hydrogel modification. • Photo-crosslinking agent greatly simplifies the modification process of hydrogel. • Dual-drug release strategy provides hydrogel with antibacterial and anti-inflammatory effect. • Facile release of ciprofloxacin and prolonged release of metformin accelerates wound healing. Chronic diabetic wounds remain a critical unmet challenge in clinical care, largely due to persistent bacterial infections and unresolved inflammation, leading to impaired healing. While photo-crosslinkable hydrogels offer localized therapeutic delivery, existing systems often face limitations in ease of modification and comprehensive multi-functional efficacy. Herein, we present a light-activated hydrogel dressing featuring programmable, dual time-phase drug release and simplified modification of crosslinking matrices to address these barriers in a synergistic manner. This intelligent system integrates a ciprofloxacin-caged photo-crosslinker (PCA-CIP), hyaluronic acid (HA), and metformin-loaded poly(lactic-co-glycolic acid) nanoparticles (MET@NPs). Upon brief photo-irradiation, the hydrogel rapidly crosslinks (<52 s), releasing ciprofloxacin immediately at the wound site for rapid anti-bacterial action. Concurrently, MET@NPs enable sustained delivery of metformin to modulate inflammation over an extended period. This spatiotemporally coordinated release, characterized by an initial burst of antibiotics followed by prolonged anti-inflammatory activity, fosters a favorable microenvironment for tissue regeneration. In both in vitro and full-thickness diabetic wound models, the hydrogel exhibits strong tissue adhesion, potent infection control, durable immunomodulation, and significantly enhanced healing. This work demonstrates the clinical promise of dual time-phase hydrogels as precision-engineered wound therapies for diabetes-related complications.