Injectable ε-Polylysine/Hyaluronic Acid Hydrogels with Resistance-Preventing Antibacterial Activity for Treating Wound Infections

Abstract

The growing threat of antimicrobial resistance has created an urgent demand for nonantibiotic biomaterials capable of preventing infections without promoting bacterial resistance. In this study, we developed injectable, covalently cross-linked hydrogels composed of ε-poly-l-lysine (ε-PL) and hyaluronic acid (HA) for localized wound infection treatment. These hydrogels combine the inherent antibacterial properties of ε-PL with the biocompatibility of HA, forming a shear-thinning, self-recovering system suitable for syringe-based administration. We first evaluated the antibacterial activity of pure ε-PL, determining minimum inhibitory and bactericidal concentrations (MIC/MBC) and evaluating resistance development against ATCC and clinically isolated multidrug-resistant strains (MRSA, ESBL-E. coli, P. aeruginosa). Notably, no resistance emerged in any strain after the serial passages. Hydrogels formed at varying ε-PL/HA ratios demonstrated strong immediate and long-term bactericidal activity while maintaining high cytocompatibility with murine and human fibroblasts. The hydrogels significantly reduced biofilm formation of S. aureus and MRSA within 24 h, achieving reductions comparable to or greater than vancomycin-gentamicin controls. Rheological analysis confirmed injectability, stability, and tunable stiffness. This study presents the first demonstration that ε-PL-based hydrogels can prevent resistance development in multidrug-resistant pathogens, offering a safe and antibiotic-free approach for infection control. The combination of antibacterial efficacy, resistance prevention, and biocompatibility makes these hydrogels promising candidates for wound infection management.