Vessel subtype beneficial for osteogenesis enhanced by strontium-doped sodium titanate nanorods through modulating macrophage polarization

Early vascularization plays an important role in bone healing, especially in the interfacial bone formation. Many modifications have been made to titanium surfaces to promote angiogenesis. In addition, cytokines secreted by osteoblasts have been reported to enhance early angiogenesis, however, the effect is limited because osteoblasts arise after inflammation subsides. We fabricated a newly sustained release system consisting of Sr ion- loaded sodium titanate nanorods (STSr) and studied the its effect on angiogenesis via regulating macrophage subtypes. In vitro study, STSr significantly promoted angiogenesis and formation of CD31hiEmcnhi vessels by modulating the transformation of M1 macrophages toward M2 macrophages. After incubation on STSr surfaces, macrophages (RAW264.7) polarized toward M2 subtypes and expressed high levels of PDGF-BB. Furthermore, the conditioned medium from RAW264.7 cells enhanced the ability of tubule formation and migration of HUVECs and their differentiation into pro-osteogenesis vessels (CD31hiEmcnhi vessels). In vivo studies showed high expression levels of CD31hiEmcnhi surrounding implants. Accompanied with enhanced vascularization, improved bone formation and osseointegration were observed. Our study serves as a basis for the clinical application of a novel functional topography surfaces fabricated on titanium, which can be applied in new orthopedic implants for better prognoses of patients.