Size-Confined Effects of Nanostructures on Fibronectin-Induced Macrophage Inflammation on Titanium Implants

Macrophage activation determines the fate of biomaterials implantation. Though researches have shown that fibronectin (FN) is highly involved in integrin-induced macrophage activation on biomaterials, the mechanism of how nanosized structure affects macrophage behavior is still unknown. Here, titanium dioxide nanotube structures with different sizes are fabricated to investigate the effects of nanostructure on macrophage activation. Compared with larger sized nanotubes and smooth surface, 30 nm nanotubes exhibit considerable lesser pro-inflammatory properties on macrophage differentiation. Confocal protein observation and molecular dynamics simulation show that FN displays conformation changes on different nanotubes in a feature of "size-confined," which causes the hiding of Arg-Gly-Asp (RGD) domain on other surfaces. The matching size of nanotube with FN allows the maximum exposure of RGD on 30 nm nanotubes, activating integrin-mediated focal adhesion kinase (FAK)-phosphatidylinositol-3 kinase γ (PI3Kγ) pathway to inhibit nuclear factor kappa B (NF-κB) signaling. In conclusion, this study explains the mechanism of nanostructural-biological signaling transduction in protein and molecular levels, as well as proposes a promising strategy for surface modification to regulate immune responses on bioimplants.