The zebrafish embryo as a new model for biomaterial-associated infection and novel treatment strategies

Biomaterials (medical devices) are widely used in modern medicine. However, the presence of biomaterials may derange local immune responses in the host, thereby facilitating so-called biomaterial-associated infection (BAI). To fill the large gap between in vitro cell-based assays and mammalian animal models for studying host-biomaterial interactions and BAI, we developed zebrafish embryo models for in vivo visualization and intravital analysis of early immune cell responses to biomaterials and the early stage BAI using fluorescence microscopy. Our results showed that the embryo models allow to detect differences in immune cell responses to different biomaterial microspheres and to assess increase in infection susceptibility due to such microspheres, indicating their usefulness for biocompatibility testing and studying BAI. Intracellular survival of bacteria is involved in the pathogenesis of BAI. To improve efficacy of antibiotics against intracellular bacteria, we developed a gelatin nanosphere-based system for local/intracellular delivery of antibiotics (e.g. vancomycin). This delivery system enhanced internalization of vancomycin both by human macrophages in vitro and zebrafish macrophages in vivo, and improved efficacy of vancomycin against (intracellular) staphylococcal infection in zebrafish embryos. Moreover, we for the first time utilized photochemical internalization (PCI) technique to enhance cytosolic release and increase intracellular efficacy of an antibiotic, gentamicin. PCI-induced cytosolic release of gentamicin was observed in vitro in mouse macrophages. PCI enhanced efficacy of gentamicin against (intracellular) staphylococcal infection both in mouse macrophages and in zebrafish embryos. These approaches, assessed using the zebrafish embryo models, have strong potential for treatment of BAI through effectively targeting intracellular bacteria