Ultrasound-Responsive Biomimetic Microbubbles Against Implant-Related Infections.

The structure of bacterial biofilms and extracellular polymeric substances (EPS) hinder the penetration of antibacterial agents, inhibit the phagocytic activity and inflammatory response of immune cells, and ultimately weaken the effect of the host immune system in combating bacterial biofilm infections. A cell-like structure was developed by encapsulating red blood cell membrane fragments on the surface of microbubbles prepared with ferriferous oxide nanoparticles (Fe3O4 NPs) and then loading hydroxyurea (EMB-Hu). The characteristics of EMB-Hu were studied by confocal microscopy, scanning electron microscopy, etc. The bactericidal effect was investigated by bacterial plate counting, live/dead staining, crystal violet staining, etc. The activation state of macrophages was studied by flow cytometry, Elisa, etc. Finally, a mouse subcutaneous implant infection model was established to verify the antibacterial and immune activation effects. Under ultrasound (US) stimulation, EMB-Hu oscillates in a stable manner, presenting as a kind of "exocytosis" of cells, which releases antibacterial agents while destroying bacterial biofilms and enhances the penetration of active antibacterial substances (ROS and NO) within the biofilms. Additionally, the "exocytosis" of EMB-Hu under US stimulation can activate pro-inflammatory macrophage polarization and enhance macrophage phagocytosis to clear the disrupted biofilms. This study prepared a cell-like microbubble that generates an "exocytosis" mechanism under ultrasonic stimulation to overcome the biofilm barrier and activate macrophages for inflammation, ultimately achieving a good therapeutic effect on implant infections caused by methicillin-resistant Staphylococcus aureus (MRSA) biofilms.