| Percutaneous coronary intervention can effectively treat arterial obstructive disease caused by atherosclerosis and decrease the mortality associated with myocardial infarction.After several generations of development of drug-eluting stents（DES）,the incidence of late complications after stent implantation remains at a level that needs to be reduced,and the risk of death caused by complications is high.The occurrence of late complications is related to the early sudden release and insufficient late release of anti-inflammatory or anti-proliferative drugs loaded after DES implantation,and the passive diffusion release of drugs cannot effectively meet the needs of the target vessel repair process of stent implantation.The local microenvironment of the target vascular site presents different states in different pathological and repair processes after stent implantation.Understanding the change in the local microenvironment as the trigger factor for stent drug release can enhance the regulation of drug administration.In this study,based on the changes in reactive oxygen species（ROS）levels and related enzyme expression levels in the pathological microenvironment of vascular stent implantation in atherosclerotic lesions,three types of responsive drug-loading coatings were designed and constructed on the surface of vascular stents.ROS and enzyme response of the coating were systematically evaluated.Biological evaluation was carried out in vitro in a simulated pathological environment to explore the biological function of the coating,and the performance of coating-modified vascular stents in vivo was evaluated.By constructing microenvironment-responsive drug-eluting stents,controllable and intelligent drug release can be achieved,thereby providing a research basis and theoretical guidance for the development of new vascular stents.In this study,an ROS-responsive drug-loading coating（EGCG-Cys-Pi）was prepared using epigallocatechin gallate（EGCG）and cystamine dihydrochloride cross-linked coating as the carrier and pitavastatin calcium as the drug.The disulphide bond in the cystamine molecule provides the coating with oxidation response ability.In the oxidative stress microenvironment,ROS levels increase,disulphide bonds gradually oxidise under the action of ROS and break the bond to form sulfonic radical（-SO3H）.The material properties,ROS response,and biological functions of the modified coatings were studied.The results showed that the EGCG-Cys-Pi coating was successfully constructed on the surface of the vascular stent material and had ROS response ability,which could accelerate the drug release rate under the action of ROS.In an oxidised environment,the EGCG-Cys-Pi coating protects cells in the form of antioxidants and is sensitive to ROS,accelerating drug release and achieving drug cytological functions.In addition,the coatings exhibited good anti-inflammatory properties.The EGCG-Cys-Pi coating effectively promotes endothelialisation and reduces the risk of in-stent restenosis when used in animals.In the blood evaluation,the modified coating showed good blood compatibility,but the existence of disulphide bonds in the coating caused the coating to easily react with cysteine-containing proteins,and there was a certain risk of stent thrombosis.To further improve the sensitivity of the modified coating to ROS,the disulphide bond（251 k J/mol）in the coating was replaced with a diselenide bond（172 k J/mol）with a lower bond energy to construct an ROS-sensitive coating（EGCG-Se Cys-Pi）with a diselenide bond as the response core.The material properties of the EGCG-Se Cys-Pi-modified coatings were evaluated comprehensively.The dynamic changes in the drug release level and quality of the EGCG-Se Cys-Pi coating in the oxidising environment proved that the EGCG-Se Cys-Pi coating had a better ROS response than the EGCG-Cys-Pi coating.In vitro cell evaluation proved that the EGCG-Se Cys-Pi-modified coating had a good ability to promote endothelial growth and inhibit smooth muscle and could maintain this trend in the oxidation environment.The EGCG-Se Cys-Pi coating exhibits good anti-inflammatory properties.In vitro blood evaluation proved that the EGCG-Se Cys-Pi-modified coating had better blood compatibility than the EGCG-Cys-Pi coating and reduced thrombosis on the surface of the stent material.Animal experiments have demonstrated the biocompatibility of the EGCG-Se Cys-Pi coating,which has the potential to promote endothelialisation and inhibit restenosis in stents.In this study,high expression of type II collagenase in the service environment of vascular stents was used as the triggering factor for drug release,and a drug-loading coating responding to type II collagenase was constructed.The amino-rich coating was constructed with dopamine（DA）and polyethylenimine（PEI）,and the repeated layering self-assembly of gelatin and heparin on the surface of the coating was formed by electrostatic interaction.The Gel/Hep-RAPA enzyme responsive drug elution coating was constructed by loading rapamycin.The drug release rate and dynamic changes in the coating quality of the Gel/Hep-RAPA coating were detected under the action of type II collagenase,and the surface morphology of the coating was observed by SEM,which proved that the Gel/Hep-RAPA coating had a type II collagenase response ability.The in vitro cell evaluation showed that the Gel/Hep-RAPA coating had good endothelial cell safety and significantly inhibited smooth muscle cell proliferation.A model of atherosclerosis with high expression of type II collagenase was constructed in the carotid artery of New Zealand white rabbits and stent implantation was performed.The results showed that Gel/Hep-RAPA coating could effectively reduce the risk of stent restenosis. |
