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

用于血管内手术的新型原位定制可生物降解药物洗脱支架

• 批准号: 9892106
• 负责人: Melina Rae Kibbe
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892106
• 关键词: Acute; Adherence; Adhesions; Affect; Angioplasty; Area; Arteries; Atherosclerosis; Balloon Angioplasty; Blood Platelets; Blood Vessels; Cardiac; Cardiovascular Diseases; Catheters; Cause of Death; Cells; Chemistry; Citrates; Clinical; Custom; Data; Developed Countries; Development; Disease; Drug Delivery Systems; Drug usage; Endothelial Cells; Endothelium; Engineering; Ensure; Environment; FDA approved; Failure; Family suidae; Health; Hyperplasia; In Situ; In Vitro; Individual; Industry; Inflammation; Injury; Intervention; Liquid substance; Longitudinal Studies; Measurable; Measures; Metals; Modeling; Modification; Modulus; Nitric Oxide; Nitric Oxide Donors; Operative Surgical Procedures; Paclitaxel; Patient-Focused Outcomes; Peripheral; Pharmaceutical Preparations; Polymers; Population; Process; Prosthesis; Radial; Research Personnel; S-Nitrosothiols; Safety; Secondary to; Sirolimus; Site; Solid; Stents; Surface; System; Technology; Testing; Thrombosis; Time; Translating; Vertebral column; Veterans; biodegradable polymer; biomaterial compatibility; cell growth; combat; common treatment; cost; design; diazeniumdiolate; drug development; flexibility; healing; improved; in vivo; innovation; mechanical properties; multidisciplinary; new technology; novel; novel strategies; photopolymerization; preclinical study; prevent; prototype; restenosis; safety study; stent thrombosis; thrombogenesis

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.

心血管疾病是发达国家死亡的主要原因。 动脉粥样硬化性心血管疾病是动脉支架置入术，而支架技术已得到改进。 多年来，包括药物洗脱支架的开发，失败率仍然很高，目前 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预后。 提议开发一种创新的、范式转变的支架技术，该技术将消除对 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，我们建议通过液体药物洗脱聚合物开发固体可生物降解支架 使用专门设计的三球囊导管对体内支架进行光聚合。 “设计师疗法”将根据单个动脉的轮廓进行定制，并覆盖整个动脉表面 动脉，显着降低受伤部位的血栓形成可能性并提供最大的表面 我们的可生物降解聚（十二烷二醇柠檬酸酯）（PDDC）支架将输送一氧化氮。 (NO)，一种血管保护分子，可以舒张新血管成形的动脉，从而对抗弹性 定制的支架还将通过同时抑制反冲来促进长期血管愈合。 内膜增生和血小板粘附，以及刺激内皮细胞生长。 脉动、顺应性动脉系统特有的机械特性最后，支架将降解。 时间，留下一个健康的、无假肢的、无聚合物的环境。因此，我们的假设是： 与相比，液铸、NO 洗脱、可生物降解的支架具有更高的通畅率 球囊血管成形术后的传统金属支架通过抑制血栓形成和新生内膜 通过我们的多学科研究小组和刺激再内皮化。 行业工程师，我们已经通过初步数据论证了我们项目的可行性。 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和 进行将这项技术转化为临床领域所需的体内临床前研究。 该项目的具体目标是： 1) 开发并优化 NO 洗脱、液铸 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- 的机械性能 离体洗脱、液铸 PDDC 支架；3) 检查 NO 洗脱、液铸 PDDC 的安全性和有效性 我们的新颖方法挑战了现有的动脉支架植入范式，并将导致 通过我们的初步数据，我们已经彻底改变了动脉粥样硬化闭塞性疾病的治疗方法。 考虑到退伍军人已证实患有动脉粥样硬化疾病的负担，该项目的可行性。 人口，本提案中的研究将产生一项新技术，该技术将转化为改进的 退伍军人健康。