Optimized Nanointerface Engineering of Micro/Nanostructured Titanium Implants to Enhance Cell–Nanotopography Interactions and Osseointegration

The success of orthopedic implants requires rapid and complete osseointegration which relies on an implant surface with optimal features. To enhance cellular function in response to the implant surface, micro- and nanoscale topography have been suggested as essential. The aim of this study was to identify an optimized Ti nanostructure and to introduce it onto a titanium plasma-sprayed titanium implant (denoted NTPS-Ti) to confer enhanced immunomodulatory properties for optimal osseointegration. To this end, three types of titania nanostructures, namely, nanowires, nanonests, and nanoflakes, were achieved on hydrothermally prepared Ti substrates. The nanowire surface modulated protein conformation and directed integrin binding and specificity in such a way as to augment the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) and induce a desirable osteoimmune response of RAW264.7 macrophages. In a coculture system, BMSCs on the optimized micro/nanosurface exerted enhanced effects on nonactivated or lipopolysaccharide-stimulated macrophages, causing them to adopt a less inflammatory macrophage profile. The enhanced immunomodulatory properties of BMSCs grown on NTPS-Ti depended on a ROCK-medicated cyclooxygenase-2 (COX2) pathway to increase prostaglandin E2 (PGE2) production, as evidenced by decreased production of PGE2 and concurrent inhibition of immunomodulatory properties after treatment with ROCK or COX2 inhibitors. In vivo evaluation showed that the NTPS-Ti implant resulted in enhanced osseointegration compared with the TPS-Ti and Ti implants. The results obtained in our study may provide a prospective approach for enhancing osseointegration and supporting the application of micro/nanostructured Ti implants.