Synergistic Low-Intensity Pulsed Ultrasound-Activated Vancomycin-Loaded Microbubbles for MRSA Biofilm Eradication and Bone Regeneration in Periprosthetic Joint Infection

Periprosthetic joint infection (PJI), sustained by antibiotic-tolerant biofilms, hinders infection control and impairs bone healing. To address this, we developed a dual-action strategy combining low-intensity pulsed ultrasound (LIPUS) with vancomycin-loaded microbubbles (MBs@V) designed to concurrently eliminate methicillin-resistant Staphylococcus aureus (MRSA) biofilms and enhance bone regeneration. In vitro, LIPUS activation of MBs@V generated cavitation that effectively disrupted mature biofilm architecture, significantly enhancing intrabiofilm vancomycin penetration and bactericidal efficacy. In vivo, using a rat model of PJI with infected titanium implants, the MBs@V + LIPUS therapy demonstrated synergistic effects: it markedly reduced bacterial burden and inflammation while remodeling the immune microenvironment through polarization of macrophages toward the reparative M2 phenotype and enhancing osteogenic activity. This immunomodulation and pro-osteogenic transition fostered a reparative environment, which simultaneously enhanced peri-implant bone mineralization and improved trabecular quality. Collectively, this integrated ultrasound-mediated approach provides a multifunctional platform for effective PJI management by synergistically targeting biofilm elimination and promoting bone regeneration.