Long-term antibacterial and biofilm dispersion activity of an injectable in situ crosslinked co-delivery hydrogel/microgel for treatment of implant infection

Titanium implant infection and biofilm formation pose substantial economic challenges on the global health system due to increased morbidity, delayed wound healing, and the need for extended antibiotic therapy or further surgical procedures. Accordingly, antimicrobial agent-loaded hydrogel delivery systems have been developed to treat implant infection, aiming at higher treating efficiency and reduced antibiotic usage. In the current study, gelatin methacryloyl (GelMA) microgels were loaded with vancomycin (Van) using a microfluidic emulsion method and then encapsulated in hydrogel with lysostaphin (Ls) to produce an injectable hydrogel/microgel co-delivery hydrogel system with bactericidal and biofilm dispersion properties. After injection, the hydrogel was crosslinked in situ within a minute at room temperature. Controlled release of encapsulated Ls and Van was observed at up to 7 days and 20 days, respectively. Ls and Van demonstrated synergy in bactericidal and biofilm dispersion activities against both methicillin-sensitive and methicillin-resistant Staphylococcus aureus strains. In addition, local release of Ls and Van led to resolution of infection within 4 weeks after one injection. Moreover, the biocompatibility and degradability of hydrogel was further demonstrated in vitro and in vivo. Overall, the advantages of co-delivery hydrogel, including injectability, antimicrobial activity, biofilm dispersion and programmed delivery, highlight its promising potential in treating implant infection.