In-stent restenosis (ISR) is the leading cause of stent failure and is a direct result of a dysfunctional vascular endothelium and subsequent overgrowth of vascular smooth muscle tissue. TiO2 nanotubular (NT) arrays have been shown to affect vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) in vitro by accelerating VEC cell proliferation and migration while suppressing VSMCs. This study investigates for the first time the potentially beneficial effects of TiO2 NT arrays on vascular tissue in vivo. TiO2 NT arrays (NT diameter: 90 ± 5 nm, height: 1800 ± 300 nm) were grown on the surface of titanium stents and characterized in terms of surface morphology and stability. Stents were implanted into the iliofemoral artery using an overinflation model (rabbit). After 28 days, stenosis rates were determined. The data show a statistically significant reduction of stenosis by 30% compared to the control. Tissue in the presence of TiO2 NTs appears more mature, and less neointima is present between struts. In addition, the extra cellular matrix secreted by cells at the interface of the NT arrays shows complete integration into the nanostructured surface. These results document the accelerated restoration of a functional endothelium in the presence of TiO2 NT arrays and substantiate their beneficial impact on vascular tissue in vivo. Our findings suggest that TiO2 NT arrays can be used as a drug-free approach for keeping stents patent long-term and have the potential to address ISR.
Keywords: anti-inflammatory; in-stent restenosis; nanoengineered surface; pro-healing; titania nanotubes.