A Revolutionary Therapy for Atherosclerosis: Liquid Cast Arterial Stents

描述（由申请人提供）：该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设备开发改进的生物相容性表面。这项提议的广泛、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置入的看法。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。虽然近年来支架技术有所进步，但失败率仍然很高。我们建议开发一种液体药物洗脱生物可降解支架，它将在体内聚合，并与新血管成形术动脉的轮廓相适应。我们将使用一种生物相容性的弹性柠檬酸基聚合物，聚双酸盐（PDC），当它被放置在循环系统中时，它将被重氮离解，自发释放一氧化氮（NO）。考虑到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，考虑到PDC的生物相容性，该技术将有助于保护新血管成形术动脉免受血栓形成，同时促进血管愈合。这种方法将克服裸金属、药物洗脱和预先形成的可生物降解支架的挑战，根据单个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潜力，并为药物输送提供最大的表面积。PDC的强度可以通过改变丙烯酸化程度来改变，从而使PDC具有适合血管系统的物理性能。这种支架易于输送，无需复杂的输送装置，而且制造和使用成本低廉。最后，支架会随着时间的推移而降解，留下一条没有假体的健康动脉。因此，我们的假设是，与经皮球囊血管成形术后的传统裸金属支架相比，液体铸造no洗脱可生物降解PDC支架将具有更高的通畅率。这项为期2年的提案的具体目标是：1)优化重氮分离PDC的NO释放；2)确定NO-PDC原位热聚合或光聚合的最佳条件，以提供合适的支架特性；3)开发液体铸型支架系统（即三重球囊输注/闭塞导管），并在离体灌注回路中评估该系统；4)在猪动脉粥样硬化模型中评估液态铸造no洗脱PDC支架系统，以评估该装置的体内聚合和总体结果。生物活性和可生物降解的液体铸造支架的发展将导致动脉粥样硬化性闭塞疾病治疗的根本转变。鉴于动脉粥样硬化的广泛性和动脉支架植入术的普遍性，本提案中的创新研究将产生一种新技术，将直接改善数百万美国人的病人护理，因此，与国家卫生研究院和2009年美国复苏和再投资法案的公共卫生问题直接相关。

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.