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

Abstract

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.

Nanostructured Titanium Implant Surface Facilitating Osseointegration from Protein Adsorption to Osteogenesis: The Example of TiO2 NTAs

“…So far, TiO 2 NTAs have been suggested to affect protein adsorption, cell behaviors like adhesion, proliferation and differentiation through the recognition between cell and implant surface. 23 , 40–42 In detail, the TiO 2 NTAs impact the osteointegration via protein adsorption, 52 platelet activation, 42 inflammatory response 16 and osteogenic property. 53 Hence, in this review, the biological role of TiO 2 NTAs at each stage in osseointegration will be discussed.…”

“…For instance, it is demonstrated that TiO 2 NTAs of 30 nm diameter show noticeably weakened pro-inflammatory properties on macrophage polarization, since the adsorbed fibronectin, which is reported to be involved in the manipulation of integrin-induced macrophage behavior on biomaterial, displayed different conformations as the nanotube size changed, specific in the changing of exposed Arg-Gly-Asp (RGD) domain. 52 , 81 TiO 2 NTAs of 30 nm diameter allow the maximum exposure of RGD domain in fibronectin. 52 Hence, TiO 2 NTAs can regulate the protein conformation, which is also significant in protein adsorption, even more critical than the adsorbed concentration.…”

“… 52 , 81 TiO 2 NTAs of 30 nm diameter allow the maximum exposure of RGD domain in fibronectin. 52 Hence, TiO 2 NTAs can regulate the protein conformation, which is also significant in protein adsorption, even more critical than the adsorbed concentration.…”

“…Considering that protein conformation plays a more significant role in protein function, we thus believe that a diameter of about 30 nm is more suitable for the function of relevant protein. 52 …”

Influence of Bioinspired Lithium-Doped Titanium Implants on Gingival Fibroblast Bioactivity and Biofilm Adhesion

“…A significant increase in the expression of fibronectin for the Li_Ti surface was also observed. Elevated fibronectin levels as an indicator of effective adhesion are well-established in the literature [54][55][56][57]. Indeed, it is the one glycoprotein produced by fibroblasts that regulates the adhesion process [58], acting as a "glue" for cell attachment.…”