Bioengineering Catalytically Active Grafts for Vascular Surgery

用于血管手术的生物工程催化活性移植物

• 批准号: 8967095
• 负责人: Melina Rae Kibbe
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8967095
• 关键词: Address; Affect; American; Animal Model; Arterial Injury; Ascorbic Acid; Autologous; Biocompatible; Biomedical Engineering; Blood; Blood Chemical Analysis; Blood Vessels; Bypass; Caring; Cavia; Citrates; Data; Development; Drug Delivery Systems; Engineering; Failure; Formulation; Generations; Goals; Gold; Health; Healthcare; Hospitalization; Human; Hyperplasia; Impairment; Implant; In Vitro; Inflammation; Interdisciplinary Study; Investigation; Ions; Lead; Light; Metals; Modeling; Modification; Morbidity - disease rate; Nitric Oxide; Nitric Oxide Donors; Operative Surgical Procedures; Outcome; Patient Care; Patient-Focused Outcomes; Performance; Peripheral; Peripheral arterial disease; Pharmaceutical Preparations; Plasma; Polymers; Polytetrafluoroethylene; Procedures; Prosthesis; Prosthesis Failure; Quality of life; Reaction; S-Nitrosothiols; Safety; Stenosis; Surface; Technology; Therapeutic Agents; Thrombosis; Time; Vascular Graft; Veins; Veterans; antiproliferative agents; ascorbate; biomaterial compatibility; copolymer; diazeniumdiolate; feeding; graft failure; graft function; hemodynamics; improved; in vivo; inhibitor/antagonist; innovation; limb amputation; new technology; nitrosative stress; novel; novel strategies; pre-clinical; prevent; public health relevance; small molecule; standard care

DESCRIPTION (provided by applicant): The gold standard for the treatment of severe peripheral artery disease remains bypass grafting with autologous vein. However, when vein is not available, prosthetic grafts must be utilized and are associated with very high failure rates, approaching 70% at just 2 years. The primary cause of failure of prosthetic grafts is development of neointimal hyperplasia. It is well established tht nitric oxide (NO) is a potent inhibitor of neointimal hyperplasia. The two main classes of NO donors that have been used to inhibit neointimal hyperplasia locally are diazeniumdiolates and S-nitrosothiols (RSNO). Graft modifications with either class of NO donors have shown only limited improvement in graft function due to a short duration of NO release. However, RSNO remain attractive because they are present in human plasma and can release NO upon reaction with light, metal ions, or L-ascorbic acid (AA). Thus, to overcome the limitation of drug delivery duration, we propose to develop and evaluate a catalytically active graft that will release NO at the blood-material interface for an extended duration of time by immobilizing AA to the luminal surface of the graft. This concept takes advantage of the limitless reservoir of circulating RSNO that will react with AA on the graft surface to release NO. We hypothesize that a catalytically active prosthetic graft engineered to incorporate AA on the lumen surface will utilize endogenous circulating RSNO to generate NO at the blood-material interface and inhibit the formation of neointimal hyperplasia. To confirm the feasibility of our approach, we synthesized a first generation poly(1,8 octanediol-citrate-ascorbate) (POCA) copolymer and demonstrated prolonged generation of NO upon contact with RSNO solutions in vitro. Preliminary data show 30% POCA degradation at 2 months. This is important, as NO will be released as long as POCA is present on the graft. By the time POCA is completely degraded, the NO will have simulated endogenous endothelialization of the graft, thereby abrogating the need for external NO release. Supporting our approach, we implanted a POCA graft using a guinea pig aortic interposition model and found less graft hyperplasia at 1 month. Thus, given our promising preliminary data, we propose to investigate our hypothesis with the following Specific Aims: 1) synthesize and characterize biocompatible AA containing polydiolcitrate copolymers that catalyze the conversion of RSNO to NO and use these copolymers to fabricate catalytically active ePTFE grafts; 2) evaluate the safety, biocompatibility, and efficacy of the catalytically active POCA-ePTFE graft at inhibiting neointimal hyperplasia in vivo; and 3) evaluate the biocompatibility and efficacy of an optimized catalytically active POCA-ePTFE graft at inhibiting neointimal hyperplasia in an atherosclerotic animal model in vivo. Currently, prosthetic grafts are a poor substitute for autologous vein and there is a significant need to develop novel strategies to improve prosthetic graft patency rates. Through a multidisciplinary collaboration, we have demonstrated the feasibility of our approach. Successful completion of the studies described in this proposal will provide an innovative approach to locally generate NO, an important therapeutic agent, while overcoming limitations of other graft modification approaches, and directly lead to preclinical investigations. Once validated, this technology has the potential to positively impact veteran health care.

描述（由申请人提供）： 治疗严重外周动脉疾病的金标准仍然是自体静脉旁路移植术。然而，当静脉不可用时，必须使用假体移植物，并且失败率非常高，仅 2 年就接近 70%。假体移植失败的主要原因是新内膜增生的发生。众所周知，一氧化氮（NO）是新内膜增生的有效抑制剂。用于局部抑制新生内膜增生的两类主要的 NO 供体是二醇二氮烯鎓和 S-亚硝基硫醇 (RSNO)。由于 NO 释放持续时间短，使用任一类 NO 供体进行的移植物修饰仅显示出对移植物功能的有限改善。然而，RSNO 仍然具有吸引力，因为它们存在于人血浆中，并且在与光、金属离子或 L-抗坏血酸 (AA) 反应时可以释放 NO。因此，为了克服药物输送持续时间的限制，我们建议开发和评估一种催化活性移植物，通过将 AA 固定到移植物的管腔表面，该移植物将在血液-材料界面长时间释放 NO。这一概念利用了循环 RSNO 的无限储量，RSNO 将与移植物表面的 AA 发生反应，释放 NO。我们假设，将 AA 掺入管腔表面的催化活性假体移植物将利用内源性循环 RSNO 在血液-物质界面处产生 NO，并抑制新内膜增生的形成。为了证实我们的方法的可行性，我们合成了第一代聚（1,8辛二醇-柠檬酸-抗坏血酸）（POCA）共聚物，并证明在体外与RSNO溶液接触时可以延长NO的产生时间。初步数据显示，2 个月后 POCA 降解了 30%。这很重要，因为只要移植物上存在 POCA，就会释放 NO。当 POCA 完全降解时，NO 将模拟移植物的内源性内皮化，从而消除外部 NO 释放的需要。为了支持我们的方法，我们使用豚鼠主动脉介入模型植入 POCA 移植物，并发现 1 个月时移植物增生较少。因此，鉴于我们有希望的初步数据，我们建议通过以下具体目标来研究我们的假设：1）合成并表征含有生物相容性AA的聚二醇柠檬酸酯共聚物，该共聚物催化RSNO转化为NO，并使用这些共聚物制造催化活性的ePTFE接枝物； 2) 评价催化活性POCA-ePTFE移植物在体内抑制内膜增生的安全性、生物相容性和功效； 3) 评估优化的催化活性 POCA-ePTFE 移植物在体内动脉粥样硬化动物模型中抑制新生内膜增生的生物相容性和功效。目前，假体移植 自体静脉的替代品效果较差，因此迫切需要开发新的策略来提高假体移植物的通畅率。通过多学科合作，我们证明了我们方法的可行性。该提案中描述的研究的成功完成将为局部生成NO（一种重要的治疗剂）提供创新方法，同时克服其他移植物修饰方法的局限性，并直接导致临床前研究。一旦经过验证，这项技术有可能对退伍军人的医疗保健产生积极影响。