Catalytic Metal-Phenolic Surface Chemistry For Generating Therapeutic Gas On Cardiovascular Stents

Vascular stent for interventional therapy has become an important mean of cardiovascular disease treatment because of its advantages such as small trauma and significant effect.However,due to the lack of biocompatibility,the restenosis rate of bare metal stent?BMS?was 20-30%after the stent implantation for 3-6 months.Drug eluting stents?DES?effectively inhibited the proliferation of smooth muscle cells?SMCs?by releasing drugs.Therefore,the restenosis rate of the stent was reduced to about 10%.In addition to inhibiting the smooth muscle,the drugs released from the stent had a bad effect including inhibiting the growth of endothelial cells,greatly delaying the process of endothelialization and increasing the risk of late thrombus.The clinical application of stent is still facing two major complications of restenosis and late thrombosis at present.A healthy and intact endothelium is the key to maintain the homeostasis of blood vessel microenvironment,coagulation balance and normal growth of SMCs.The function of endothelial cells is strongly dependent on the sustained release of signaling molecules nitric oxide?NO?.This is due to the fact that NO has many important physiological functions,such as upregulating platelet and smooth muscle cell cyclic guanosine monophosphate?cGMP?synthesis to achieve anticoagulant and inhibiting the proliferation of smooth muscle cells,and promoting the repair of damaged endothelial tissue.And these functions are exactly necessary for the ideal vascular stents.Therefore,the function of the vascular stents with the continuous and stable release of NO by means of surface modification is expected to solve the clinical complications of vascular stent.Therefore,the vascular stent function of sustained and stable release of NO similar to natural vascular endothelial cells which is given by surface modification is expected to solve the clinical complications of vascular stent.Copper ion which has the activity of highly efficient catalyzing the release of NO from the NO donor-nitroso alcohol in the blood is used to modify the surface function of the blood contact materials to realize the biomimetic function of endothelial cells.However,the lack of reactive functional groups on the surface of metal scaffolds makes it difficult and challenging to immobilized copper ions on the surface.Dopamine?DA?has been widely used in the surface modification of biomaterials because of its self-polymerization,adhesion to broad-spectrum materials and chelating with transition metal ions.Based on this,this paper is established in the innovative surface modification technology.A metal catechol surface chemical modification method with endogenous NO donor catalytic release function has been developed to realize the biomimetic function of endothelial cell function on the surface of metal 316L stainless steel scaffold.The NO-generating coating containing Cu^II-DA coordination compound was deposited on the surface of 316L stainless steel scaffold by"one step dip coating"by using the ability of dopamine self polymerization and chelating metal ions.The precise regulation of NO catalytic release rate on the surface of the scaffold is achieved by changing the stoichiometric ratio of DA and Cu^II to adjust the content of copper ions in the Cu^II-DA coating.In addition,the coating can maintain long-term,sustained,and stable NO release activity.Applied to the surface modification of the stent,the coating not only has an excellent adhesion ability,but also exhibits excellent compliance during the stenting process without coating damage,peeling,and shedding.The systemic blood and cell compatibility evaluations indicated that Cu^II-DA inhibited platelet adhesion/activation by selectively catalyzing NO release as well as selectively promoted endothelial cell growth and inhibits smooth muscle cell adhesion,proliferation,and migration.At the same time,we found that NO has a strict dose requirement for the growth behavior of endothelial cells.When the rate of NO release exceeded 6×10^-1010 mol cm^-2 min^-1,the proliferation of endothelial cells began to decline.The blood circulation resulted in the half-body show that the coating modified scaffold material had excellent antithrombotic ability.The results of in vivo stenting demonstrated that the vascular stent modified by the Cu^II-DA coating could rapidly promote endothelial regeneration and effectively inhibit the proliferation of intima and stent restenosis.