Injectable vancomycin-conjugated polysaccharide-protein hydrogel for targeted antibacterial therapy in musculoskeletal infections.

Musculoskeletal infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA), remain a major clinical challenge owing to antibiotic resistance and biofilm formation within implant-associated bone microenvironments. In this study, we developed an injectable, biodegradable, thermoresponsive vancomycin (VA)-loaded hydrogel based on genipin (GP)-crosslinked gelatin (GLT) and hyaluronic acid (HA), designated GLT/HA/GP + VA, for localized and sustained antibacterial drug delivery. The GLT/HA/GP + VA hydrogel exhibited in situ gelation at 37 °C and sustained vancomycin release, with cumulative release of approximately 600-700 μg/mL at 72 h in the 2.5% VA formulation. Compared with vancomycin-loaded bone cement, which declined to near-baseline levels by Day 3, the hydrogel maintained sustained drug retention over 28 days. In vitro, the VA-loaded hydrogels showed favorable cytocompatibility (>95% cell viability), retained approximately 50% of their volume at Day 12, and demonstrated significantly greater antibacterial efficacy than cement-based controls, with superior quantitative zones of inhibition (p < 0.0001), together with dose-dependent antibiofilm activity against Staphylococcus aureus (S. aureus). In vivo MRI and histological analyses confirmed progressive biodegradation, with more than 50% of the hydrogel volume remaining at Day 21, as well as effective local drug retention, minimal inflammatory response, and negligible systemic toxicity. Collectively, these findings indicate that the GLT/HA/GP + VA hydrogel represents a promising biomacromolecular platform for targeted and sustained antimicrobial therapy in musculoskeletal infection management.