Biomimetic Janus Cardiovascular Stents For Regulating Vascular Tissue Regenerative Repair

Cardiovascular diseases are a serious threat to human health because of their high mortality and disability rates.The accelerated aging process of society and people’s unhealthy diet and living habits have led to a continuous rise in the incidence and death of cardiovascular diseases in China.Vascular stent intervention has been widely used because of its significant advantages of minimally invasive,high efficacy,low risk,and fast recovery.After more than 30 years of development through newer iterations,vascular stents have undergone development from bare metal stents(BMS),drug-eluting stents(DES)(first and second generation),and the restenosis rate within the stent has been reduced from 40% to about 20-30% and then to less than 10%.However,vascular stents not only cause damage to the vessel,trigger coagulation and inflammation during implantation,but the use of anti-proliferative drugs also inhibits regenerative repair of the endothelial layer,leading to late thrombosis(LST),in-stent restenosis(ISR),and delayed endothelialization.To achieve regeneration of endothelial tissue with normal physiological function,repair of the diseased vessel is first required.Therefore,endowing vascular stents with multiple functions including anticoagulation,effective regulation of inflammation at the lesion site,and specific and selective inhibition of SMCs while promoting the growth of ECs can create a favorable microenvironment for promoting the regeneration of endothelial cells with normal physiological functions,which is the key to solve the problems of clinical stent restenosis and late thrombosis.It was found that nitric oxide(NO),as a signaling molecule secreted by the endothelium,has a wide range of physiological activities such as inhibiting platelet activation and adhesion,promoting intimal repair,and regulating vascular homeostasis;rosmarinic acid(RA),a water-soluble polyphenolic compound,has good anti-inflammatory,antibacterial and antioxidant functions and has great potential in the inflammatory treatment of cardiovascular diseases.Therefore,NO and RA are the preferred biomolecules for modifying vascular scaffolds.We propose a novel surface modification strategy "Janus-double-sided modification",the functionalization of the inner and outer surfaces of stents by surface modification techniques.In this paper,we designed and synthesized a novel amino-rich adhesion molecule(PAMCA)based on the synergistic adhesion effect of phenolamine chemistry using a mussel-inspired bionic strategy,and constructed an amino-rich coating(PAMCA)on the inner surface of the vascular stent through its special adhesion properties.DOTA,which has multiple biological functions of specific and selective anticoagulation,inhibition of smooth muscle cells(SMCs)proliferation and promotion of endothelial cells(ECs)growth;on the outer surface of the scaffold,the smooth muscle bionanostructure is loaded with anti-inflammatory molecule RA using femtosecond laser treatment,which enables its effective long-term elution at the lesion site to regulate inflammation and maintain vascular homeostasis;RA can also play a certain anticoagulant role.RA can also play a certain anticoagulant role,complementing NO to achieve a more superior anticoagulant and antiproliferative effect.The material science characterization verified the successful synthesis of the adhesion molecule PAMCA,the successful preparation of the coating,and the functional stability of the coating;the hemocompatibility evaluation showed that the modified samples could effectively inhibit the activation and adhesion of fibrinogen and platelets;the cytocompatibility experiments showed that the coating could significantly inhibit the excessive proliferation of smooth muscle,promote the proliferation and adhesion of endothelial cells,inhibit the proliferation of macrophages,and effectively regulate the inflammation In vivo animal studies have demonstrated that our double-sided modified vascular scaffold promotes rapid formation of a natural endothelial layer,significantly inhibits ISR and regulates inflammation.All of these functions are desirable for the surface of cardiovascular stent materials,and no similar studies have been reported on the use of this double-sided modification strategy with regenerative repair of diseased vascular tissues for vascular scaffolds,and we expect this modification strategy to open a new pathway for surface engineering of vascular implants for better clinical outcomes.