Construction Of Nitric Oxide Catalytic Vascular Stents Via Metal-phenolic/Catecholamine Network

Cardiovascular disease is the leading cause of death for now and even in a long future.The main treatment of cardiovascular diseases including medication,surgical and interventional treatment.Stenting implantation has become one of the most commonly methods with the advantages of minimal invasion,immediately massive effectiveness and long-term positive effect.It has been more than 30 years since the balloon angioplasty was carried out,bare metal stents,drug-eluting stents,full-biodegradable stents and various new functional stents have come out consecutively.However,the in-stent restenosis and late-stage thrombosis are still two mian complications that limit the application of stents,the surface modification of stents still has a long way to go.Nitric Oxide?NO?is an important biological molecule secreted by native endothelial cells,which can inhibit the hyperplasia of smooth muscle cells and the activation of platelet through the cGMP pathway.Modification strategies based on NO play an important role in cardiovascular surface modification.NO or NO donor loading and NO catalysis release are the two mian NO releasing strategies.Limited by the loading dose,the NO loading strategy is difficult to work for a long time on the surface of the vascular stent.Whereas,NO-catalyzed surface can continuously catalyzing release of NO from endogenous NO donors in blood,which is more suitable for the long-term surface modification.The most commonly used NO catalysts are organoselenium moieties and transition metal ions(Cu²⁺,Hg²⁺,Fe²⁺,Ag⁺etc.).However,316L stainless steel which is the substrate of commercial vascular stent is an inert metal which lacks reactive groups and is difficult to immobilize NO catalysts.On this account,we adopts metal-phenolic/catecholamine chemistry in this research.By means of the coordination of copper ions with phenolic/catecholamine,several copper-phenolic/catecholamine coatings were fabricated on the stent.In the first part of this research,three multifunctional coatings were constructed by coordination copper ions with three phenolic/catecholamine:Dopamine,Norepinephrine and Tannic acid.These coatings combined the antibacterial ability of copper ions,the anti-inflammatory of phenols,and NO catalytic ability of copper ions to assembled multiple functions on a surface.Firstly,these coatings were characterized by X-ray photoelectron spectroscopy,electron paramagnetic resonance,matrix assisted mass spectrometry,scanning electron microscope,atomic force microscope and elliptical polarimeter.Subsequently,DPPH,macrophage culture and ex-vivo experiments were carried out to detect the antibacterial,anti-inflammatory and anticoagulant functions of these coatings.Cytotoxicity and in-vivo animal experiments also demonstrated that they are safety for mammals and can be used for the surface modification of blood contact materials.In the first part,we demonstrated the feasibility of metal-phenolic/catecholamine chemistry as the NO catalyze strategy for blood contaoct material.Then inspired by mussel adhesion protein,we introduced another NO catalyts:selenothiamine?SeCA?,into the metal-phenolic/catecholamine system.We use 3,4-dihydroxy-L-phenylalanine?Dopa?to crosslink SeCA and the copper ions,and fabricate a NO-catalyzing coating.The results showed that the NO catalytic ability of the coating could be controlled by the feed concentration of Cu²⁺and the NO catalytic ability remained 44%after immersing the Dopa/SeCA/Cu^II coated 316L SS in PBS?GSNO/GSH 10?M?for 60 days which indicate that the coating was controllable and stable.The in vivo stent implantation also demonstrated impressively improved anti-thrombogenicity,anti-restenosis,and endothelialization.In order to accelerate the endothelialization of vascular stents,REDV-SH which is a short peptide that specifically promotes endothelial cell adhesion was introduced onto metal-phenolic/catecholamine coating.In the competitive adhesion of endothelial cells and smooth muscle cells,the coating with function of NO@REDV was demonstrated specificly adhesive endothelial cells to smooth muscle cells.The stent implantation for 7 days showed that the coating could effectively promote endothelialization and the 30 days stent implantation showed that the coating could inhibit intimal hyperplasia while promoting endothelial cell adhesion.The NO@REDV coatings provide a new concept for the surface modification of dual-functional stent.In summary,we fabricated three NO-catalyzing coatings with metal phenolic/catecholamine networks.These three strategies presented a progressive relationship in structure and function.Wether the in-vitro or the in-vivo experiments were carried out to discuss the feasibility and functionality of the coatings.This study provides both new concept and technical support for the design of a new generation of NO-catalyzing strategy for vascular stents.