Infection-osteogenesis crosstalk on TiO2 nanotube surfaces: mechanisms and synergistic design strategies

Titanium dioxide nanotubes (TNTs) fabricated via anodization have emerged as a versatile platform for surface modification of orthopedic and dental implants, owing to their tunable nanotopography and excellent potential for multifunctional biofunctionalization. However, the concurrent challenges of implant-associated bacterial infection and insufficient osseointegration remain formidable obstacles in clinical practice. Rather than being independent processes, bacterial infection and bone regeneration are intimately coupled through a complex signaling network—a concept increasingly recognized as the “infection-osteogenesis crosstalk.” We begin with how TNT morphology—nanotube diameter above all—differentially steers osteoblast behavior and bacterial adhesion, and how the initial protein corona and immune microenvironment set the infection-to-bone-healing trajectory. From signaling, we move to the pathways behind infection-driven osteogenic suppression: the core signaling pathways through which bacterial virulence factors suppress osteogenesis, including TLR-mediated NF-κB activation, RANKL/OPG imbalance-driven osteoclastogenesis, and biofilm hypoxia-induced metabolic reprogramming. We then look at how macrophages (M1/M2 polarization, NLRP3 inflammasome), neutrophils (NETosis), and T cells shape the host response to infection and bone repair. We close with current synergistic design strategies—metal ion doping, antimicrobial peptide loading, organic-inorganic composite coatings, temporally controlled drug release—and next-generation smart responsive surfaces including pH-responsive, photothermal/photocatalytic, enzyme-responsive, and immunomodulatory coatings. This review aims to provide a mechanistic framework for understanding infection-osteogenesis crosstalk on TNT surfaces and to guide the rational design of dual-functional implants that simultaneously combat infection and promote bone regeneration.