Research Of Bionic And Dynamically Responsive Polycarbonate Polyurethanes For Vascular Stent Surface Modification

As an effective method of interventional therapy,cardiovascular stent implantation has been widely used in the treatment of severe atherosclerosis.However,it is found in clinical applications that the complications such as stent restenosis and late thrombosis,could severely restrict the curative effect of cardiovascular stents.Novel materials are urged to be investigated in the development of modern cardiovascular stents with better performance.Polyurethane materials have been used in the manufacture of blood-contacting interventional devices owning to their good blood compatibility.In recent years,because of the greater ability of regulation and function on biological behavior,bionic polyurethane and smart polyurethane material containing dynamic bond and dynamic response,have drawn wide attention in the biomedical application area.In this research,2-methacryloyloxyethyl phosphorylcholine(MPC)that imitates phospholipids structure and three kinds of REDOX responsive groups(-S-S-,-Se-Se-,-Te-Te-)were introduced into the molecular structure of PCU respectively.Biomimetic PCU containing phospholipids and PCU containing dynamic covalent bond that hence has the function of in-situ catalytic releasing nitric oxide(NO),have been designed and synthesized.After that,these functional PCU were used in the surface modification of metal intravascular stent substrate.Then,the composition and structure of functional PCU were characterized systematically.The properties of dynamic response and the performance of catalytic releasing NO of the materials were studied.Biology behavior evaluation in vivo and in vitro were carried out to explore the possibility of application of functional PCU in the surface modification of cardiovascular stent.It is expected that this research could provide new material sources and new strategies for the multifunctional and high-performance surface modifications of cardiovascular stent.In the research,diol(MPCDL)containing phosphorylcholine group was synthesized firstly based on Michael addition reaction.Then,polycarbonate polyurethane materials with different contents of phosphorylcholine groups(PCU-MPC)were prepared via stepwise polymerization.The successful synthesis of the materials is proved by a series of characterization methods including Fourier transforming infrared spectra(FTIR),high resolution mass spectrometry(ESI-MS),proton nuclear magnetic resonance(¹H NMR),and phosphorus nuclear magnetic resonance(³¹P NMR).The good mechanical performance and adjustable microphase separation were respectively confirmed via tensile test and differential scanning calorimetry.Results from hemocompatibility and cytocompatibility in vitro all indicated that the introduction of phosphorylcholine groups can effectively improve anti-adhesion ability of materials.The well histocompatibility of modified PCU with phosphorylcholine groups was proved via the subcutaneous experiments of rat.In this research,2-hydroxyethyl disulfide(BHS)was selected as the chain extender for preparing polycarbonate polyurethane materials containing disulfide bond(PCU-SS);on this basis,then intravascular stent coating that has the function of in-situ catalytic releasing NO was constructed.FTIR and ¹H NMR results proved the successful synthesis of materials.Scanning electron microscopy(SEM)and water contact angle(WCA)were used to characterize the morphology and the properties of hydrophilicity and hydrophobicity of the coating.The result of chemiluminescence method confirmed the reduction responsiveness and the certain ability of catalytic releasing NO of PCU-SS.A series of blood compatibility evaluations of PCU-SS showed that platelet adhesion and activation,fibrinogen adsorption and degeneration,and the blood clots formation could be inhibited to a certain degree.Cell cultures confirmed that the PCU-SS has a certain compatibility of endothelial cell(EC),which could also inhibit the smooth muscle cell(SMC)proliferation and the activity of macrophages(MA)to a certain extent.Animal experimental results showed that the histocompatibility and the ability of inhibiting intimal hyperplasia of PCU-SS were improved to a certain degree compared with unmodified samples.To further enhance the reduction response sensitivity of the PCU,realize the in-situ catalytic releasing NO ability approaches that under the condition of catalytic releasing NO of normal EC,diol(BHSe)containing double selenium bond was synthesized.Besides,polycarbonate polyurethane containing double selenium bond(PCU-Se Se)was prepared.The successful synthesis of the materials is proved by a series of characterization methods including FTIR,ESI-MS,¹H NMR and selenium nuclear magnetic resonance(⁷⁷Se NMR).The NMR results of PCU-Se Se after the treatment of oxidation and reduction proved its dual responsiveness oxidation and reduction.The results of chemiluminescence method confirmed that the PCU-Se Se could continuously catalytically releasing NO under the level of normal EC.The biocompatibility evaluation indicated that the PCU-Se Se could significantly inhibit the formation of blood clots and promote the proliferation of EC.At the same time,PCU-Se Se could significantly inhibit SMC proliferation,and MA activity.Double tellurium bond has a smaller bond energy compared with double selenium bond.In order to further regulate responsiveness of PCU containing dynamic covalent bond,a diol containing double tellurium bond(BHTe)was synthesized,and then polycarbonate polyurethane materials containing double tellurium bond(PCU-Te Te)was prepared.The successful synthesis of the materials is proved by a series of characterization methods including FTIR,ESI-MS,and NMR.The NMR results of PCU-Te Te after oxidation process confirmed that the material could realize rapid response under the condition of oxidation;the NMR results of PCU-Te Te after reduction process confirmed that the PCU-Te Te could realize the dynamic change of the structure.The results of chemiluminescence method confirmed that the PCU-Te Te could continuously and effectively releasing NO under the normal EC level.By means of a serious of biocompatibility evaluation including the test of blood and cells in vitro,and the evaluations in vivo,it is proved that PCU-Te Te could not only significantly inhibit the formation of thrombus and promote EC proliferation,but also significantly inhibit SMC proliferation,MA activity,and vascular intimal hyperplasia.In this research,three kinds of dynamic covalent bond contained polymers including PCU-SS,PCU-Se Se and PCU-Te Te were used to load model drug.The drug release behaviors under the media of different oxidation and reduction level were preliminarily investigated.These research results will provide preliminary experimental basis for the design and construction of smart coating of drug-loading intravascular stent,which may realize the adaptive drug release in personalized vessel treatment with different lesion extent.