Novel in situ custom biodegradable drug-eluting stents for endovascular surgery

心血管疾病是发达国家的主要死因。的常见治疗 动脉粥样硬化性心血管疾病是动脉支架的放置。虽然支架技术已经改进， 多年来，包括药物洗脱支架的开发，失败率仍然很高， 技术与重大挑战有关。因此，非常需要新的支架技术 这将改善经皮心脏和外周血管介入治疗后的患者结局。我们 建议开发一种创新的、范式转变的支架技术， 在动脉系统中放置永久性金属支架以治疗严重动脉粥样硬化。 具体来说，我们建议从液体药物洗脱聚合物中开发一种固体可生物降解支架， 使用特别设计的三重气囊导管在体内光聚合支架。这 “设计师疗法”将根据个体动脉的轮廓量身定制，并覆盖整个动脉表面。 动脉，显著降低损伤部位血栓形成的可能性，并提供最大的表面积 药物输送区。我们的可生物降解聚（十二烷二醇柠檬酸盐）（PDDC）支架将提供一氧化氮 (NO)，一种血管保护分子，可以舒张新鲜血管成形术的动脉，从而对抗弹性血管扩张。 后座力定制形成的支架还将通过同时抑制血管的生长来促进长期血管愈合。 新生内膜增生和血小板粘附，以及刺激内皮细胞生长。支架将具有 脉动顺应性动脉系统特有的机械性能。最后，支架将降解超过 时间，留下一个健康的，无假肢，无聚合物的环境。因此，我们的假设是 液体浇铸、NO洗脱、可生物降解支架的通畅率上级 通过抑制血栓形成和新生内膜， 增生和刺激再内皮化。通过我们的多学科研究团队， 我们已经通过初步数据证明了我们项目的可行性。是 现在是时候专注于开发和优化聚合物支架的药物释放能力， 进行必要的体内临床前研究，以将该技术转化为临床竞技场。因此 本项目的具体目标是：1）开发和优化NO洗脱，液体铸造PDDC支架， 二醇二氮烯鎓和S-亚硝基硫醇化学; 2）评估和调整NO-二醇二氮烯鎓和S-亚硝基硫醇化学的机械性能; 体外洗脱、液体浇铸PDDC支架; 3）检查NO洗脱、液体浇铸PDDC支架的安全性和有效性 体内支架。我们的新方法挑战了动脉支架植入术的现有模式， 动脉粥样硬化闭塞性疾病治疗的根本性偏离。通过我们的初步数据， 证明了这个项目的可行性。考虑到退伍军人动脉粥样硬化疾病的负担 人口，本提案中的研究将产生一种新技术， 退伍军人健康

Cardiovascular disease is the leading cause of death in developed countries. A common treatment for atherosclerotic cardiovascular disease is placement of an arterial stent. While stent technology has improved over the years, including the development of drug-eluting stents, failure rates remain high and current technologies are associated with significant challenges. Thus, there is a great need for new stent technology that will improve patient outcomes following percutaneous cardiac and peripheral vascular interventions. We propose to develop an innovative, paradigm-shifting stent technology that will obviate the need for placement of permanent metal stents in the arterial system for the treatment of severe atherosclerosis. Specifically, we propose to develop a solid biodegradable stent from a liquid drug-eluting polymer by photo-polymerizing the stent in the body using a specially designed triple balloon catheter. This “designer therapy” will be tailored to the contours of the individual artery and coat the entire surface of the artery, significantly reducing the thrombogenic potential at the site of injury and providing the greatest surface area for drug delivery. Our biodegradable poly(dodecanediol citrate) (PDDC) stent will deliver nitric oxide (NO), a vasoprotective molecule that will vasodilate the freshly angioplastied artery, thereby combating elastic recoil. The custom-formed stent will also promote long-term vascular healing by simultaneously inhibiting neointimal hyperplasia and platelet adhesion, and stimulating endothelial cell growth. The stent will have mechanical properties specific for the pulsatile, compliant arterial system. Lastly, the stent will degrade over time, leaving a healthy, prosthetic-free, polymer-free environment in its place. Thus, our hypothesis is that a liquid-cast, NO-eluting, biodegradable stent will have a superior patency rate compared to conventional metal stents following balloon angioplasty by inhibiting thrombosis and neointimal hyperplasia, and stimulating re-endothelialization. Through our multidisciplinary team of investigators and industry engineers, we have already demonstrated the feasibility of our project through preliminary data. It is now time to focus on developing and optimizing the drug releasing capacity of the polymeric stent and conducting the in vivo preclinical studies necessary to translate this technology to the clinical arena. Thus, the specific aims of this project are: 1) Develop and optimize a NO-eluting, liquid-cast PDDC stent using diazeniumdiolate and S-nitrosothiol chemistry; 2) Evaluate and tune the mechanical properties of the NO- eluting, liquid-cast PDDC stent ex vivo; 3) Examine the safety and efficacy of the NO-eluting, liquid-cast PDDC stent in vivo. Our novel approach challenges the existing paradigm for arterial stenting and will lead to a radical departure in the treatment of atherosclerotic occlusive disease. Through our preliminary data, we have demonstrated the feasibility of this project. Given the burden of atherosclerotic disease in the veteran population, the studies in this proposal will result in a new technology that will be translated to improved veteran health.