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: 9794740
• 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: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794740
• 关键词: Address; Affect; American; Animal Model; Arterial Injury; Ascorbic Acid; Autologous; Biomedical Engineering; Blood; Blood Chemical Analysis; Blood Vessels; Bypass; Caring; Cavia; Citrates; Clinical; Data; Development; Drug Delivery Systems; Endothelium; Engineering; Failure; Fibrinolytic Agents; Formulation; Generations; Goals; Gold; Health; Healthcare; Hospitalization; Human; Hyperplasia; Immobilization; 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; 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; hemocompatibility; hemodynamics; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; limb amputation; mortality; new technology; nitrosative stress; novel; novel strategies; pre-clinical; prevent; public health relevance; response to injury; small molecule; standard care; surgery outcome

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，并且与非常高的失败率相关，仅2年就接近70%。人工血管移植失败的主要原因是新生内膜增生。一氧化氮（nitric oxide，NO）是一种有效的抑制血管内膜增生的物质。已用于局部抑制新生内膜增生的两种主要类别的NO供体是二醇二氮烯鎓和S-亚硝基硫醇（RSNO）。由于NO释放的持续时间短，用任一类NO供体进行的移植物修饰仅显示出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，为了克服药物递送持续时间的限制，我们建议开发和评估一种催化活性移植物，该移植物通过将AA固定到移植物的管腔表面上而在血液-材料界面处释放NO持续延长的时间。这个概念利用了循环RSNO的无限储存，它将与移植物表面的AA反应释放NO。我们假设，设计成在管腔表面掺入AA的催化活性假体移植物将利用内源性循环RSNO在血液中产生NO材料界面并抑制新生内膜增生的形成。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-柠檬酸盐-抗坏血酸盐）（波卡）共聚物，并证明了在体外与RSNO溶液接触后NO的产生时间延长。初步数据显示2个月时波卡降解30%。这一点很重要，因为只要移植物上存在波卡，NO就会释放。到波卡完全降解时，NO将模拟移植物的内源性内皮化，从而消除对外部NO释放的需要。支持我们的方法，我们使用豚鼠主动脉间置模型植入波卡移植物，并在1个月时发现移植物增生较少。因此，考虑到我们有希望的初步数据，我们提出研究我们的假设，具有以下具体目的：1）合成和表征生物相容的含AA的聚二醇柠檬酸酯共聚物，其催化RSNO转化为NO，并使用这些共聚物制备催化活性的ePTFE接枝物; 2）评价催化活性POCA-ePTFE移植物在体内抑制新生内膜增生的安全性、生物相容性和有效性;和3）评价优化的催化活性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，假体移植物是 是自体静脉的不良替代品，并且非常需要开发新的策略来提高假体移植物的通畅率。通过多学科的合作，我们已经证明了我们的方法的可行性。成功完成本提案中描述的研究将提供一种创新的方法来局部产生NO，一种重要的治疗剂，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。一旦得到验证，这项技术有可能对退伍军人的医疗保健产生积极影响。