Improved Immunoregulation of Ultra-Low-Dose Silver Nanoparticle-Loaded TiO(2) Nanotubes via M2 Macrophage Polarization by Regulating GLUT1 and Autophagy

INTRODUCTION: The bone regeneration of endosseous implanted biomaterials is often impaired by the host immune response, especially macrophage-related inflammation which plays an important role in the bone healing process. Thus, it is a promising strategy to design an osteo-immunomodulatory biomaterial to take advantage of the macrophage-related immune response and improve the osseointegration performance of the implant. METHODS: In this study, we developed an antibacterial silver nanoparticle-loaded TiO(2) nanotubes (Ag@TiO(2)-NTs) using an electrochemical anodization method to make the surface modification and investigated the influences of Ag@TiO(2)-NTs on the macrophage polarization, osteo-immune microenvironment as well as its potential molecular mechanisms in vitro and in vivo. RESULTS: The results showed that Ag@TiO(2)-NTs with controlled releasing of ultra-low-dose Ag(+) ions had the excellent ability to induce the macrophage polarization towards the M2 phenotype and create a suitable osteo-immune microenvironment in vitro, via inhibiting PI3K/Akt, suppressing the downstream effector GLUT1, and activating autophagy. Moreover, Ag@TiO(2)-NTs surface could improve bone formation, suppress inflammation, and promote osteo-immune microenvironment compared to the TiO(2)-NTs and polished Ti surfaces in vivo. These findings suggested that Ag@TiO(2)-NTs with controlled releasing of ultra-low-dose Ag(+) ions could not only inhibit the inflammation process but also promote the bone healing by inducing healing-associated M2 polarization. DISCUSSION: Using this surface modification strategy to modulate the macrophage-related immune response, rather than prevent the host response, maybe a promising strategy for implant surgeries in the future.