Interrod spacing dependent angiogenesis and osseointegration of Na2TiO3 nanorods-patterned arrays via immunoregulation

Abstract Nanorods-arrayed coatings show topographical parameters-dependent immunomodulation that plays a key role in angiogenesis and consequent osseoinegration, while immunomodulation by interrod spacing, as a solely altered topographic parameter of an array, has not been clarified yet. In this context, four kinds of nanorods-arrayed coatings, appearing similar surface roughness and hydrophilia, were hydrothermally grown on Ti. The coatings comprise a bilayer structure with compact nanogranular Na2TiO3 as an inner layer and Na2TiO3 nanorods-patterned array as an outer layer. The nanorods in the coatings exhibit identical rod diameter and length but different interrod spacing values of ~ 45, 75, 140, and 245 nm, respectively. Compared to Ti, the arrayed coatings promote adhesion and filopodia formation of macrophages to accelarate their transformation from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. Moreover, the accelaration is more pronounced by the coatings with nanoscale interrod spacing (especially ~ 75 nm) compared to those with submicro-scale spacing. The rapid phenotypic switch of macrophages on the arrayed coatings trigers the increase in their secretion of pro-angiogenic factors, including PDGF-BB, ANG1 and SDF-1, to enhance recruitment and angiogenesis of human umbilical vein endothelial cells (HUVECs) in co-culture condition, and the enhancment is the most pronounced for HUVECs in response to macrophages on ~ 75 nm spaced nanorods-arrayed coating. Owing to the favorable immune microenvironment induced by the coating and consequently enhanced angiogenesis, ~ 75 nm spaced nanorods-arrayed coating exhibits the best osseoinetegration in rat femoral condyles. Our work provides insights into the surface structural design of an orthopedic implant favoring osseointegration.