Significance: An ideal metal vascular stent has multiple properties for successful reendothelialization. These properties include 1) inhibiting thrombosis by preventing platelet activation/adhesion, 2) suppressing smooth muscle cell migration/proliferation, and 3) accelerating endothelial cell migration/proliferation. With an easy-to-perform, two-step surface bioengineering approach, the multifunctionalized stents reported here contain two vasoactive moieties (i.e., the nitric-oxide-generating organoselenium and the endothelial progenitor cell-targeting peptide) to satisfy all requirements. The surface engineering strategy presented here can be translated into clinical coatings for cardiovascular stents and will benefit enormously and globally the cardiovascular disease patients; it will, moreover, offer insights to engineering surfaces of blood-contacting devices.

Stenting is currently the major therapeutic treatment for cardiovascular diseases. However, the nonbiogenic metal stents are inclined to trigger a cascade of cellular and molecular events including inflammatory response, thrombogenic reactions, smooth muscle cell hyperproliferation accompanied by the delayed arterial healing, and poor reendothelialization, thus leading to restenosis along with late stent thrombosis. To address prevalence critical problems, we present an endothelium-mimicking coating capable of rapid regeneration of a competently functioning new endothelial layer on stents through a stepwise metal (copper)-catechol-(amine) (MCA) surface chemistry strategy, leading to combinatorial endothelium-like functions with glutathione peroxidase-like catalytic activity and surface heparinization. Apart from the stable nitric oxide (NO) generating rate at the physiological level ( 2.2 × 10 − 10 mol / c m 2 / min lasting for 60 days), this proposed strategy could also generate abundant amine groups for allowing a high heparin conjugation efficacy up to ∼1 μ g/cm ² , which is considerably higher than most of the conventional heparinized surfaces. The resultant coating could create an ideal microenvironment for bringing in enhanced anti-thrombogenicity, anti-inflammation, anti-proliferation of smooth muscle cells, re-endothelialization by regulating relevant gene expressions, hence preventing restenosis in vivo. We envision that the stepwise MCA coating strategy would facilitate the surface endothelium-mimicking engineering of vascular stents and be therefore helpful in the clinic to reduce complications associated with stenosis.

Endothelium can secrete vasoactive mediators and produce specific extracellular matrix, which contribute jointly to the thromboresistance and regulation of vascular cell behaviors. From a bionic point of view, introducing endothelium‐like functions onto cardiovascular stents represents the most effective means to improve hemocompatibility and reduce late stent restenosis. However, current surface strategies for vascular stents still have limitations, like the lack of multifunctionality, especially the monotony in endothelial‐mimic functions. Herein, a layer‐by‐layer grafting strategy to create endothelium‐like dual‐functional surface on cardiovascular scaffolds is reported. Typically, a nitric oxide (NO, vasoactive mediator)‐generating compound and an endothelial polysaccharide matrix molecule hyaluronan (HA) are sequentially immobilized on allylamine‐plasma‐deposited stents through aqueous amidation. In this case, the stents could be well‐engineered with dual endothelial functions capable of remote and close‐range regulation of the vascular microenvironment. The synergy of NO and endothelial glycocalyx molecules leads to efficient antithrombosis, smooth muscle cell (SMC) inhibition, and perfect endothelial cell (EC)‐compatibility of the stents in vitro. Moreover, the dual‐functional stents show efficient antithrombogenesis ex vivo, rapid endothelialization, and long‐term prevention of restenosis in vivo. Therefore, this study will provide new solutions for not only multicomponent surface functionalization but also the bioengineering of endothelium‐mimic vascular scaffolds with improved clinical outcomes.