A Revolutionary Therapy for Atherosclerosis: Liquid Cast Arterial Stents

动脉粥样硬化的革命性疗法：液体铸造动脉支架

• 批准号: 7830742
• 负责人: Guillermo Antonio Ameer
• 金额: $ 50万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7830742
• 关键词: Acute; Address; American; Anatomy; Anti-Inflammatory Agents; Anti-inflammatory; Area; Arteries; Atherosclerosis; Balloon Angioplasty; Balloon Occlusion; Biocompatible; Biomedical Engineering; Blood; Blood Circulation; Blood Vessels; Caliber; Catheters; Characteristics; Citrates; Citric Acid; Clinical; Coronary; Data; Development; Devices; Disease; Drug Delivery Systems; Endothelial Cells; Environment; Evaluation; FDA approved; Failure; Family suidae; Growth; Healed; Health; Healthcare; Hyperplasia; In Situ; Individual; Infusion procedures; Injection of therapeutic agent; Intervention; Knowledge; Lead; Left; Liquid substance; Medical Device; Metals; Modeling; Molds; Nature; Nitric Oxide; Operative Surgical Procedures; Outcome; Paclitaxel; Patient Care; Patients; Pharmaceutical Preparations; Platelet aggregation; Polymers; Prevalence; Process; Property; Prosthesis; Public Health; Qualifying; Radial; Recovery; Research Personnel; Secondary to; Site; Smooth Muscle Myocytes; Stenosis; Stents; Structure; Surface; System; Technology; Thrombosis; Time; Translating; Translational Research; United States National Institutes of Health; Work; base; biocompatible polymer; cell growth; coronary angioplasty; cost; design; drug development; elastomeric; ex vivo perfusion; healing; improved; in vivo; innovation; millimeter; multidisciplinary; new technology; novel; physical property; polymerization; prevent; public health relevance; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15): Translational Science, and specific Challenge Topic, 15-HL-101: Develop improved biocompatible surfaces for implantable blood-contacting medical devices. The broad, long-term objective of this proposal is to develop new and improved stent technology that will radically change the way we view arterial stenting. In 2006, more than 1.3 million Americans underwent coronary angioplasty and more than 90% of these patients received an arterial stent. While stent technology has improved over the years, failure rates remain high. We propose to develop a liquid drug-eluting biodegradable stent that will polymerize in the body and mold to the contour of the freshly angioplastied artery. We will use a biocompatible elastomeric citric acid-based polymer, polydiolcitrate (PDC) that will be diazeniumdiolated to spontaneously release nitric oxide (NO) when placed in the circulation. Given that NO inhibits platelet aggregation and vascular smooth muscle cell proliferation and stimulates endothelial cell growth, and given the biocompatible nature of PDC, this technology will serve to protect the freshly angioplastied artery from thrombosis while simultaneously promoting vascular healing. This approach will overcome the challenges of bare-metal, drug-eluting, and pre-formed biodegradable stents by being tailored to the contours of the individual artery and coat the entire surface of the artery, thereby greatly reducing the thrombogenic potential and providing the greatest surface area for drug delivery. The strength of PDC can be modified by varying the degree of acrylation, thereby giving PDC physical properties ideal for the vasculature. This stent will be simple to deliver, obviating the need for a complicated delivery device, and be cost-effective to manufacture and use. Lastly, the stent will degrade over time, leaving a healthy prosthetic- free artery. Thus, our hypothesis is that a liquid cast NO-eluting biodegradable PDC stent will have superior patency rates compared to conventional bare metal stents following percutaneous balloon angioplasty. The specific aims of this 2-year proposal are to: 1) optimize NO release from the diazeniumdiolated PDC; 2) determine the optimal conditions to polymerize the NO-PDC using thermal or photo polymerization in situ that will provide suitable stent characteristics; 3) develop a liquid cast stent system (i.e., triple balloon infusion/occlusion catheter) and evaluate this system in an ex vivo perfusion circuit; and 4) evaluate the liquid cast NO-eluting PDC stent system in a swine model of atherosclerosis to evaluate the in vivo polymerization of the device as well as overall outcome. Development of a bioactive and biodegradable liquid cast stent will lead to a radical departure in the treatment of atherosclerotic occlusive disease. Given the widespread nature of atherosclerosis, and the prevalence of arterial stenting, the innovative studies in this proposal will result in a novel technology that will directly improve patient care of millions of Americans and is, therefore, directly relevant to the public health concerns of the National Institutes of Health and the American Recovery and Reinvestment Act of 2009. PUBLIC HEALTH RELEVANCE: The development of a bioactive and biodegradable liquid cast arterial stent will lead to a radical departure in the treatment of atherosclerosis. To our knowledge, this is the first proposal to create a biodegradable arterial stent that forms in the body and is tailored to the patient's individual anatomy. Given the widespread nature of atherosclerosis, and the prevalence of arterial stenting, this highly innovative and novel translational research has the potential to impact millions of Americans. Thus, this project has tremendous relevance to public health as it will change the way we think about promoting arterial health following vascular interventions.

描述（由申请人提供）：本申请涉及广泛的挑战领域（15）：转化科学，以及特定的挑战主题15-HL-101：为植入式血液接触医疗器械开发改进的生物相容性表面。这项提案的广泛的长期目标是开发新的和改进的支架技术，这将从根本上改变我们对动脉支架术的看法。2006年，超过130万美国人接受了冠状动脉成形术，其中90%以上的患者接受了动脉支架。虽然支架技术多年来有所改进，但失败率仍然很高。我们建议开发一种液体药物洗脱的可生物降解支架，它将在体内固定，并根据新血管成形术的动脉轮廓成型。我们将使用一种生物相容性弹性体柠檬酸基聚合物，聚二醇柠檬酸盐（PDC），当置于循环中时，它将被二醇二氮烯鎓化以自发释放一氧化氮（NO）。鉴于NO抑制血小板聚集和血管平滑肌细胞增殖并刺激内皮细胞生长，并且鉴于PDC的生物相容性，该技术将用于保护新鲜血管成形术的动脉免于血栓形成，同时促进血管愈合。这种方法将克服裸金属、药物洗脱和预成型可生物降解支架的挑战，通过根据个体动脉的轮廓进行定制并覆盖动脉的整个表面，从而大大降低血栓形成的可能性并为药物递送提供最大的表面积。PDC的强度可以通过改变丙烯酸酯化程度来改变，从而使PDC具有理想的脉管系统物理性能。该支架易于输送，避免了对复杂输送装置的需要，并且制造和使用成本有效。最后，支架会随着时间的推移而降解，留下一个健康的没有假体的动脉。因此，我们的假设是，经皮球囊血管成形术后，液体铸造NO洗脱可生物降解PDC支架的通畅率上级传统裸金属支架。这项为期2年的提案的具体目标是：1）优化二醇二氮烯鎓 PDC的NO释放; 2）确定使用原位热聚合或光聚合来固定NO-PDC的最佳条件，这将提供合适的支架特性; 3）开发液体浇铸支架系统（即，三气囊输注/闭塞导管），并在离体灌注回路中评价该系统;和4）在猪动脉粥样硬化模型中评价液体浇铸NO洗脱PDC支架系统，以评价装置的体内聚合以及总体结果。生物活性和可生物降解的液体铸造支架的开发将导致动脉粥样硬化闭塞性疾病的治疗的根本性改变。鉴于动脉粥样硬化的广泛性和动脉支架植入术的流行，本提案中的创新研究将产生一种新技术，该技术将直接改善数百万美国人的患者护理，因此，与美国国立卫生研究院和2009年美国复苏和再投资法案的公共卫生问题直接相关。 公共卫生相关性：生物活性和可生物降解的液体铸造动脉支架的发展将导致动脉粥样硬化治疗的根本性转变。据我们所知，这是第一个创建可生物降解动脉支架的提案，该支架在体内形成，并根据患者的个体解剖结构量身定制。鉴于动脉粥样硬化的广泛性和动脉支架植入术的流行，这项高度创新和新颖的转化研究有可能影响数百万美国人。因此，该项目与公共卫生具有巨大的相关性，因为它将改变我们对血管介入后促进动脉健康的看法。