Spatiotemporal dual-delivery of therapeutic gas and growth factor for prevention of vascular stent thrombosis and restenosis

Abstract

Injury of endothelium is an inevitable consequence of cardiovascular stent implantation, which increases the incidence of in-stent restenosis (ISR) and late stent thrombosis (LST). Rapid and complete re-endothelialization, along with long-term suppression of smooth muscle cells (SMCs) are mandatory to alleviate these complications. To this goal, we designed a multi-functional stent coating, consisting of a vascular endothelial growth factor/CuII-dopamine(VEGF/CuII-DA) complex network for a spatiotemporal delivery of VEGF and nitric oxide (NO). We fabricated such network using a two-step stent-coating process: first a CuII-DA network with NO catalytic activity via metal-catecholamine coordination chemistry, followed by conjugation of VEGF onto the CuII-DA network via imine formation. The conjugated VEGF significantly accelerated the early-stage endothelial cell (EC) migration/growth for the first 7 days, forming a new and complete endothelial layer on the lumen. Furthermore, Cu ions sustainably decomposed endogenous S-nitrosothiols (RSNOs) in the bloodstream into NO for over 30 days, suppressing SMC migration/proliferation and ultimately preventing ISR and LST. Altogether, such designed stent coating provides options for a phase-adjusted endothelial repair during cardiovascular treatment.