Bioadaptation of implants to In vitro and In vivo oxidative stress pathological conditions via nanotopography-induced FoxO1 signaling pathways to enhance Osteoimmunal regeneration

Varieties of pathological conditions, including diabetes, are closely related to oxidative stress (OS), but the osseointegration or bioadaptation of implants to OS and the related mechanism remain poorly explored. In this study, the antioxidation and osteoimmune regeneration of titanium implants with micro/nanotopographies were evaluated under H2O2-, lipopolysaccharide (LPS)- and hyperglycemia-mediated cellular OS models and in diabetic rats as a representative animal model of OS. TiO2 nanotube (TNT) coating on titanium implants directly induced superior osteogenic differentiation of bone mesenchymal stem cells (MSCs) and osseointegration compared with microscale sand blasted-acid etched topography (SLA) under OS, attributed to higher superoxide dismutase 2 activity, the neutralization of intracellular reactive oxygen species (ROS), and less apoptosis. Mechanistically, the oxidation resistance on TNT is driven by upregulated forkhead box transcription factor O1 (FoxO1), which is abolished after knockdown of FoxO1 via shRNA in MSCs. Indirectly, TNT also alleviates OS in macrophages, therefore inducing a higher portion of the M2 phenotype under OS with increased secretion of the anti-inflammatory cytokine IL-10, further promoting the osseoimmunity capacity compared with SLA. The current study not only suggests the potential application of TiO2 nanotube-coated titanium implants in compromised conditions but also provides a systematic evaluation strategy for the future development of bone biomaterials.