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

Abstract

Titanium implants have been widely applied in dentistry and orthopedics due to their biocompatibility and resistance to mechanical fatigue. TiO₂ nanotube arrays (TiO₂ NTAs) on titanium implant surfaces have exhibited excellent biocompatibility, bioactivity, and adjustability, which can significantly promote osseointegration and participate in its entire path. In this review, to give a comprehensive understanding of the osseointegration process, four stages have been divided according to pivotal biological processes, including protein adsorption, inflammatory cell adhesion/inflammatory response, additional relevant cell adhesion and angiogenesis/osteogenesis. The impact of TiO₂ NTAs on osseointegration is clarified in detail from the four stages. The nanotubular layer can manipulate the quantity, the species and the conformation of adsorbed protein. For inflammatory cells adhesion and inflammatory response, TiO₂ NTAs improve macrophage adhesion on the surface and induce M2-polarization. TiO₂ NTAs also facilitate the repairment-related cells adhesion and filopodia formation for additional relevant cells adhesion. In the angiogenesis and osteogenesis stage, TiO₂ NTAs show the ability to induce osteogenic differentiation and the potential for blood vessel formation. In the end, we propose the multi-dimensional regulation of TiO₂ NTAs on titanium implants to achieve highly efficient manipulation of osseointegration, which may provide views on the rational design and development of titanium implants.

Keywords: TiO2 nanotube arrays; anodization; nanostructure; osseointegration; titanium implant.

Figure 1

Schematic illustration of the implant-bone osseointegration process. According to different pivotal biological processes, we define osseointegration into four stages: protein adsorption, inflammatory cell adhesion/inflammatory response, additional relevant cells adhesion, and angiogenesis/osteogenesis. The biological process in each stage has close relation with the titanium implant surface. It should be noted that although the stage “angiogenesis” is categorized as the last stage, it indeed runs through the entire osseointegration process.

Figure 2

Schematic illustration showing the inflammatory cell adhesion and inflammatory response on TiO2 NTAs, mainly includes biological behaviors of blood platelet, neutrophil, macrophage and T lymphocyte. TiO2 NTAs can manipulate these biological behaviors by multi-dimensional regulation including diameter, spacing, etc.

Figure 3

Schematic illustration showing the angiogenesis and osteogenesis on TiO2 NTAs. For osteogenesis, MSCs and osteoblasts cultured on TiO2 NTAs are manipulated by two aspects: nano-topological signal and cytokines secreted by macrophage, and show stretched cell morphology and promoted ALP, OCN, OPN expression. For angiogenesis, there is little research directly investigating the angiogenesis function of TiO2 NTAs in bone implants, but endothelial cells on TiO2 NTAs show high activity, suggesting the potential to promote angiogenesis in osseointegration. Angiogenesis and osteogenesis on TiO2 NTAs can also manipulate under its multi-dimensional regulation, such as diameter regulation and spacing regulation.