Biodegradability and Biocompatibility of a Shape Memory Polymer Wrap to Improve Saphenous Vein Graft Patency in Peripheral and Coronary Artery Bypass Grafting Surgeries

项目摘要/摘要 外周动脉疾病(PAD)在美国影响着近1200万人。最常见的一种 外科治疗是外周动脉旁路移植术(PABG)。一些患者有资格接受侵入性较小的治疗 治疗方案，如血管成形术，但钙化病变的患者不是。在接受了PABG的患者中， 大约20%的人在第一年内失败，50%的人在5年内失败。这项提议的重点是改善结果 在需要PABG的患者中。 目前的PABG手术有几个主要缺点：吻合口质量很高 取决于外科医生的经验，静脉移植物不适合高压、大流量 动脉循环的环境。这项建议评估了形状记忆聚合物(SMP)的外静脉 WRAP(SelfWrap)来解决这些缺点。自包裹是以规定的角度制造的，在 可支持缝合的动、静脉分支，可能减少对缝合质量的依赖 和手术经验。更重要的是，SelfWrap为静脉提供第一次机械支撑 暴露在动脉压力下。减轻静脉移植物的壁张力可以减少新生内膜增生(NH)， 从而减轻了移植物失败的风险。自缠绕的形状记忆特性是 使该装置能够适合患者特定的血管解剖结构，并提供非缩窄性机械 支持，即使动脉和静脉分支在整个心脏周期中跳动。 用绵羊评价自体包裹作为动静脉瘘血管周围包裹的初步结果 用于血液透析通路的(AVF)支持这些说法。28天后，经自包裹治疗的动静脉曲张 明显高于未经处理的动静脉瘘的流速和血管直径。 然而，如果SelfWrap具有显著的长期降级，那么所有这些都与其商业化无关 和/或可泄漏问题。为此，生物降解、可浸出物测试后的风险评估以及 6个月植入的生物相容性结果在本方案中进行了评估。接下来将进行这些测试 早期评估细胞毒性、急性全身毒性和可植入生物相容性的颁奖前活动 时间点。FDA做出的突破性设备指定决定，以及与 FDA进一步通知我们的监管检测策略也将在颁奖前完成。除了第一个目标外， 组织学、血流动力学和生物力学数据将在兔PABG模型中收集，以进一步 验证SelfWrap设备在PABG环境中的解剖和生理性能良好。 如果成功完成本建议书中的目标，将通知VenoStent，Inc.是否需要进行任何更改 在继续进行其他GLP生物兼容性测试之前，SelfWrap的制造工艺或设计，进一步 制造工作，并在非GLP和GLP大型动物PABG模型中进行测试。

PROJECT SUMMARY/ABSTRACT Peripheral artery disease (PAD) affects nearly 12 million people in the United States. One of the most common surgical therapies is peripheral artery bypass grafting (PABG). Some patients are eligible for less invasive treatment options like angioplasty, but patients with calcified lesions are not. In patients that do receive PABG, approximately 20% fail within the first year and 50% within 5 years. This proposal focuses on improving outcomes in patients who require PABG. There are a couple major shortcomings in current PABG procedures: the quality of the anastomosis is highly dependent on surgeon experience, and vein grafts are not conditioned for the high pressure, high flow environment of the arterial circulation. This proposal evaluates a shape memory polymer (SMP) external vein wrap (SelfWrap) to address these shortcomings. SelfWrap is manufactured with a prescribed angle between the artery and vein branches which can support the sutures, possibly reducing dependence on quality of the sutures and surgical experience. More importantly, SelfWrap provides mechanical support to the vein upon its first exposure to arterial pressures. Mitigating wall tension in the vein graft can reduce neointimal hyperplasia (NH), thereby alleviating risk of graft failure. The shape memory characteristics of SelfWrap are a critical aspect that enables the device to form-fit to the patient-specific vascular anatomy and provide non-constrictive mechanical support, even as the artery and vein branches pulse throughout the cardiac cycle. Preliminary results collected in sheep when evaluating SelfWrap as a perivascular wrap on arteriovenous fistulas (AVF) used for hemodialysis access support these claims. At 28 days, AVFs treated with SelfWrap had significantly higher flow rates and larger vessel diameters than untreated AVFs. However, none of this is relevant towards commercializing SelfWrap if it has significant long-term degradation and/or leachables issues. For this reason, biodegradation, a risk assessment following leachables testing, and biocompatibility results from a 6-month implantation are evaluated in the present proposal. These tests will follow pre-award activities assessing cytotoxicity, acute systemic toxicity, and implantable biocompatibility at earlier timepoints. A Breakthrough Devices Designation decision from the FDA and a pre-submission meeting with the FDA to further inform our regulatory testing strategy will also be completed pre-award. In addition to the first aim, histological, hemodynamic, and biomechanical data will be collected in a rabbit model PABG model to further validate that the SelfWrap device performs well in the PABG environment, both anatomically and physiologically. Successful completion of the aims in this proposal will inform VenoStent, Inc. if there are any changes needed for SelfWrap’s manufacturing process or design prior to continuing onto other GLP biocompatibility tests, furthering manufacturing efforts, and testing in non-GLP and GLP large animal PABG models.