Titania nanotubes promote osteogenesis via mediating crosstalk between macrophages and MSCs under oxidative stress

Before mesenchymal stem cells (MSCs) adhere to the surface of an implant and differentiate into osteoblasts, monocytes (especially macrophages) arrive at the bone injury site and interact with the implant and subsequent MSCs. In our previous study, large titania nanotubes (TNT₁₁₀) had been verified to endow superior oxidation resistance to osteoblasts. The early regulation between macrophages and MSCs by surface nanotubes under oxidative stress (OS) was evaluated further in this study. Cellular and molecular results show that TNT₁₁₀ greatly increased early inflammation of macrophages by activating integrin/FAK-mediated MAPK and NFκB signals and simultaneously promoted their gene expression of SDF1, IL-8, and CCL2 (chemokines) compared with 30 nm nanotubes and titanium substrates. Co-culture results show that more MSCs were recruited by those chemokines and may promote osteogenic self-differentiation, reducing early inflammation of macrophages by accelerating their M1-to-M2 transition in the TNT₁₁₀ group. All findings reveal that the early cellular behavior of macrophages and MSCs was effectively regulated by TNT₁₁₀, indicating large nanotubes would be more suitable to prevent oxidative damages.