TiO-Based Nanotopographical Cues Attenuate the Restenotic Phenotype in Primary Human Vascular Endothelial and Smooth Muscle Cells

Coronary and peripheral stents are implants that are inserted into blocked arteries to restore blood flow. After stent deployment, the denudation of the endothelial cell (EC) layer and the resulting inflammatory cascade can lead to restenosis, the renarrowing of the vessel wall due to the hyperproliferation and excessive matrix secretion of smooth muscle cells (SMCs). Despite advances in drug-eluting stents (DES), restenosis remains a clinical challenge and can require repeat revascularizations. In this study, we investigated how vascular cell phenotype can be modulated by nanotopographical cues on the stent surface, with the goal of developing an alternative strategy to DES for decreasing restenosis. We fabricated TiO nanotubes and demonstrated that this topography can decrease SMC surface coverage without affecting endothelialization. In addition, to our knowledge, this is the first study reporting that TiO nanotube topography dampens the response to inflammatory cytokine stimulation in both endothelial and smooth muscle cells. We observed that compared to flat titanium surfaces, nanotube surfaces attenuated tumor necrosis factor alpha (TNF)-induced vascular cell adhesion molecule-1 (VCAM-1) expression in ECs by 1.8-fold and decreased TNF-induced SMC growth by 42%. Further, we found that the resulting cellular phenotype is sensitive to changes in nanotube diameter and that 90 nm diameter nanotubes leads to the greatest magnitude in cell response compared to 30 or 50 nm nanotubes.