Construction Of Zwitterion/PLGA Composite Coating Loading Estradiol For Cardiovascular Stent Implant And Research On Functions

Although percutaneous transluminal coronary angioplasty(PTCA)with drug eluting stent(DES)achieves great success in clinic,however delayed re-endothelialization and late stent thrombosis(LST)impede advances of DES,resulting from that unselectively drug trends to mediate apoptosis on not only smooth muscle cell(SMC)but also endothelial cell(EC),leading to delayed healing process of endothelium which is able to maintain vascular homeostasis,and that polymeric coating performs undesired biocompatibility,featured by polymer induced inflammation(PII)that can stimulate SMC proliferation and inhibit endothelium healing further.Based on trouble about unselective mediation on SMC and EC apoptosis,the 17-β estradiol eluting stent system is constructed.Estradiol,as a hormone,is able to mediate vascular biologic functions,promote healing after vascular injury,suppress SMC mitosis,and contribute to EC growth.In this work,we choose Poly(trimethylene carbonate)(PTMC)as coating loading ~ 5 wt.% drug on 316 L SS platform,which can cumulatively release 42% estradiol within 45 days.While compared with PTMC,the drug loading coating(PTMC-E5)exhibits good ability to resist blood clotting,indicating estradiol’s perspective in improving hemocompatibility of material interfaces.Additionally,estradiol shows selective inhibition on SMC proliferation and promoting endothelium healing in both vitro and vivo,revealing huge potential as novel DES.In this work,Poly-(SBMA-co-BMA)is synthesized against poor biocompatibility of conventional polymeric coatings.SBMA,as a biomimetic molecule,owns promising abilities to resist biological fouling and good biocompatibility.By random radical polymerization with SBMA and BMA,functional biomimetic polymer with zwitterionic group(sulfobetaine)is achieved.The polymeric coating(Co-pSB)made by solvent evaporation method is able to expose zwitterion group on surface,performing various biological effects.Co-pSB coating reveals great hemocompatibility with the observation of inhibition on platelet adhesion as well as activation and anti-clotting in dynamic blood circulation.Meantime,Co-pSB shows strong suppression on adhesion and growth of SMC and EC on coating surface.Importantly,Co-pSB exhibits superior regulation on resistance of macrophage(MA)mediated inflammation by inhibiting MA adhesion,activation,proliferation,and downregulating TNF-α and IL-6 secretion.In addition,Co-pSB prevents EC from activation by decreasing P-selection secretion to further control inflammation because combination is block between P-selection and PSGL-1 ligand located on MA.As compared with PTMC(89μm)and PLGA(116μm),in vivo 4 weeks ‘subcutaneous embedding results reveal only 71 μm thickness of fibrous capsule for Co-pSB sample,indicating Poly-(SBMA-co-BMA)is a promising biomimetic material with good biocompatibility and minimizing inflammation.According to acknowledge advantages of bioresorbable polymer over biostable polymer,that can be disappeared and resorbed by metabolism,we construct biodegradable composite coating by blending PLGA and Poly-(SBMA-co-BMA)in ratio(PLGA/Co-pSBx,x=10%,20%,30%).After ratio blending,the composite coatings show more uniform and faster rate of polymer degradation,Correspondingly,the cumulative release of estradiol reach 56.0% as compared with 92.2% for PLGAE5.The regulatory behaviors on vascular cells growth that PLGA/Co-pSB20 coating selectively inhibits SMC adhesion and growth which barely impact on EC’s growth activity,predict better cytocompatibility as a DES coating.Moreover,PLGA/Co-pSB20 does not induce obvious inflammation and performs good hemocompatibility.Given these reasons,PLGA/Co-pSB20 can be an ideal DES coating.Additionally,the estradiol loading coating(PLGA/Co-pSB20E5)reveal really weak inflammatory signal and strong neointimal inhibition in 4 weeks’ vivo implantation(thickness: 51 μm VS PLGA:156 μm & 316 L SS:132 μm).PLGA/Co-pSB20E5 also show rapid reendothelialization suggesting PLGA/Co-pSB20E5 is able to strengthen efficiency of estradiol in vivo by minimizing inflammation’s stimulation on SMC and EC.