Engineering multifunctional chitosan-based hydrogels for integrated antimicrobial therapy and endogenous stem cell-driven tissue repair in infectious keratitis

Bacterial keratitis is a major contributor to preventable blindness worldwide, with infections caused by Pseudomonas aeruginosa posing significant challenges due to the formation of biofilms and insufficient tissue regeneration following antimicrobial therapy. Conventional treatments predominantly target the infection while neglecting the promotion of healing processes, often resulting in corneal scarring and subsequent vision impairment. Therefore, therapeutic approaches for condition should extend beyond antibacterial measures to include strategies that facilitate early limbal stem cell participation in tissue regeneration. In this study, we present a dual-functional hydrogel system that integrates quaternized ultra-highly deacetylated chitosan (QUDCS) with oxidized dextran (OD) and stromal cell-derived factor-1 (SDF-1). This system effectively eradicates bacterial biofilms while simultaneously promoting the recruitment of endogenous stem cells for corneal regeneration. The hydrogel exhibits rapid gelation and mechanical properties similar to corneal tissue, along with significant antimicrobial activity mediated by electrostatic membrane disruption. The sustained release of SDF-1 establishes chemotactic gradients that attract limbal stem cells, thereby activating Wnt/β-catenin signaling pathways and enhancing cellular proliferation and regenerative potential. This integrated therapeutic platform represents a paradigm shift from traditional monotherapy to advanced biomaterial systems that simultaneously address infection and facilitate molecular-level tissue regeneration. It offers transformative potential for the treatment of infectious ocular diseases and other biofilm-associated infections that necessitate concurrent antimicrobial intervention and tissue repair. Graphical abstract. Schematic illustration of the SDF-1/QUDCS/OD hydrogel system and its dual therapeutic mechanisms in P. aeruginosa keratitis. The hydrogel forms via Schiff base reaction between quaternized ultra-highly deacetylated chitosan (QUDCS) and oxidized dextran (OD), encapsulating stromal cell-derived factor-1(SDF-1). Upon application, the hydrogel provides mechanical support to prevent corneal perforation while exerting antibacterial effects through electrostatic disruption of bacterial membranes and biofilm penetration. Concurrently, sustained SDF-1 release establishes chemotactic gradients that recruit limbal epithelial stem cells (LESCs) and limbal niche cells (LNCs) from the peripheral cornea, promoting tissue regeneration through activation of the Wnt/β-catenin signaling pathway. • The SDF-1/QUDCS/OD hydrogel eliminates bacterial biofilms and promotes tissue regeneration in P. aeruginosa keratitis. • Utilizing autologous limbal stem cells early in tissue repair reduces corneal scarring and enhances transparency. • Exogenous SDF-1 promotes limbal stem cells homing by activating the Wnt/β-catenin signaling pathway.