Autologous EPC lining to improve biocompatibility of circulatory assist devices

自体 EPC 衬里可提高循环辅助装置的生物相容性

• 批准号: 7821745
• 负责人: Jeffrey H. Lawson
• 金额: $ 49.03万
• 依托单位: DUKE UNIVERSITY
• 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/7821745
• 关键词: Address; Adult; Age; Aging; Alloys; American; American Heart Association; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Area; Assisted Circulation; Autologous; Biocompatible; Biological Assay; Biological Markers; Biology; Blood; Blood Coagulation Disorders; Blood Vessels; Blood flow; Blood specimen; Cardiovascular Surgical Procedures; Cell Line; Cells; Cessation of life; Clinical; Coagulation Process; Complement Activation; Control Groups; Coronary; Devices; Diagnosis; Disease; Effectiveness; Endothelium; Family suidae; Fibrinolysis; Genes; Health; Heart; Heart Transplantation; Heart failure; Hemorrhage; Hospitalization; Implant; Infant; Inferior vena cava structure; Inflammation; Knowledge; Lead; Life; Mechanics; Medical; Medical Device; Newly Diagnosed; Operative Surgical Procedures; Organ Donor; Patients; Phase; Population; Prevalence; Property; Protein C; Proteins; Proteomics; Quality of life; Resistance; Risk; Staging; Stem cells; Stents; Surface; Survival Rate; Symptoms; Technology; Thrombin; Thrombomodulin; Thrombosis; Thrombus; Time; Titanium; Translational Research; Transplantation; Tube; United States; Woman; base; biomaterial compatibility; cofactor; implantation; improved; men; mortality; nitinol; novel; novel strategies; overexpression; peripheral blood; public health relevance; restenosis; shear stress

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. More than five million Americans, and increasingly more, suffer from heart failure yearly. Although cardiac transplantation is the best treatment for end-stage heart failure patients, not enough donor organs are available. Mechanical circulatory assist devices (MCADs) can reduce the risk of death and increase the quality of life for these patients; however, the contact of blood with their inner surface (usually titanium) often causes a coagulopathy resulting in bleeding and thrombosis. Local areas of low flow and blood stasis in most MCADs also contribute to the risk for thrombosis, especially in partial circulatory support devices that could benefit more than a million patients with less advanced heart failure. We hypothesize that a confluent lining of the patients' own endothelial progenitor cells (EPCs) will provide a more antithrombogenic and biocompatible surface and propose the following specific aims: Specific Aim 1: to genetically enhance endothelial progenitor cells, isolated from swine peripheral blood, by over-expressing the anticoagulant and anti-inflammatory protein thrombomodulin (TM) before the cells are seeded on the inside of titanium (Ti) tubes. Specific Aim 2: to surgically implant Ti tubes lined with either genetically enhanced (TM-EPC) or un-enhanced EPCs into the inferior vena cava of those pigs from which the EPCs were derived, and compare them to a group of pigs that undergoes implantation of uncoated, bare Ti tubes. A fourth group will be a control group undergoing sham operations only. Peripheral blood samples will be obtained at four time points from all pigs, and known markers of thrombosis and inflammation will be quantified with well-established bioassays. We hypothesize that known markers of thrombosis and inflammation, quantified from peripheral blood samples in these pigs, will demonstrate an improved biocompatibility of EPC-lined blood contacting surfaces. Furthermore, we anticipate that our genetically enhanced cells (TM-EPC) will render the titanium even less thrombogenic. Specific Aim 3: to perform analytical microarray-based proteomic analysis on all peripheral blood samples and to compare the four different groups and time points within each animal in order to determine the differential expression levels of a large number of known proteins associated with coagulation, fibrinolysis, inflammation and complement activation. We hypothesize that a subset of these specific proteins will reflect the effects of EPC seeding, as well as reveal differences between genetically enhanced TM-EPCs and bare Ti implants. The knowledge gained will extend our understanding of the biocompatibility of blood-contacting surfaces, and may give rise to a panel of novel biomarkers of biocompatibility of blood-contacting surfaces. According to the American Heart Association, that there are more than 5 million people living in the United States who are suffering from heart failure. Moreover, the prevalence of heart failure is steadily increasing, in part because of the aging of our population. Despite improvements in medical therapy, the mortality rate in these patients has remained extremely high, with a 5-year median survival rate of only 25% in men and 38% in women. In 2004 alone, there were over one million hospitalizations in the US with a first listed discharge diagnosis of heart failure. It is estimated that more than 250,000 of patients are in the terminal phases of this disease and suffering from severe symptoms, which cannot be alleviated even with maximal medical therapy. The results of our proposal may lead to a technology, which could alleviate the symptoms of more than one million of Americans by providing a biocompatible blood-contacting surface for mechanical circulatory assist devices for partial as well as full support of the failing heart. Furthermore, this technology could be applicable to other titanium /titanium-alloy blood-contacting surfaces, such as nitinol vascular stents. These could become resistant to in-stent restenosis and benefit millions of Americans who are being treated with coronary or vascular stents. PUBLIC HEALTH RELEVANCE: According to the American Heart Association, that there are more than 5 million people living in the United States who are suffering from heart failure. Moreover, the prevalence of heart failure is steadily increasing, in part because of the aging of our population. Despite improvements in medical therapy, the mortality rate in these patients has remained extremely high, with a 5-year median survival rate of only 25% in men and 38% in women. In 2004 alone, there were over one million hospitalizations in the US with a first listed discharge diagnosis of heart failure. It is estimated that more than 250,000 of patients are in the terminal phases of this disease and suffering from severe symptoms, which cannot be alleviated even with maximal medical therapy. The results of our proposal may lead to a technology, which could alleviate the symptoms of more than one million of Americans by providing a biocompatible blood-contacting surface for mechanical circulatory assist devices for partial as well as full support of the failing heart. Furthermore, this technology could be applicable to other titanium /titanium-alloy blood-contacting surfaces, such as nitinol vascular stents. These could become resistant to in-stent restenosis and benefit millions of Americans who are being treated with coronary or vascular stents.

描述（由申请人提供）：此申请应解决广泛的挑战领域（15）转化科学和特定挑战主题，15-HL-101：开发改进的可植入血液接触医疗设备的生物相容性表面。每年有超过500万美国人，越来越多的美国人遭受心力衰竭。尽管心脏移植是最终心力衰竭患者的最佳治疗方法，但没有足够的供体器官可用。机械循环辅助设备（MCADS）可以降低死亡的风险并提高这些患者的生活质量；但是，血液与它们的内表面（通常是钛）的接触通常会导致凝血病，导致出血和血栓形成。在大多数MCAD中，流量低下和血液暂停的地方也有助于血栓形成的风险，尤其是在部分循环系统支撑装置中，这些设备可能受益于超过一百万心力衰竭患者。我们假设患者自身内皮祖细胞（EPC）的融合衬里将提供一个更抗抗浓度和生物相容性的表面，并提出以下特定目的：具体目的1：通过遗传性增强内皮祖细胞，通过猪外围血液中的过度表达和抗抗激素（抗抗激素），并提高遗传性的内皮祖细胞，并提高抗抗抗流的蛋白质（抗抗激素）。细胞在钛（Ti）管的内部播种。具体目的2：将外科手术植入TI管衬有遗传增强（TM-EPC）或未增强的EPC，将EPC塞入源自EPCS的猪的下腔静脉中，并将它们与一组猪进行比较，并将其与一群经历未含糖的裸露Ti管植入的猪。第四组将是仅接受假操作的对照组。外周血样本将在所有猪的四个时间点获得，并且已知的血栓形成和炎症标记将通过完善的生物测定量化。我们假设通过这些猪的外周血样本定量的血栓形成和炎症的已知标记将证明EPC衬里血接触表面的生物相容性提高。此外，我们预计我们的遗传增强细胞（TM-EPC）将使钛的血栓形成更少。特定目的3：对所有外周血样本进行基于分析微阵列的蛋白质组学分析，并比较每只动物中的四个不同的组和时间点，以确定与凝血，纤维蛋白溶解，炎症，炎症和补体激活相关的大量已知蛋白质的差异表达水平。我们假设这些特定蛋白的子集将反映EPC播种的作用，并揭示了遗传增强的TM-EPC和裸露Ti植入物之间的差异。获得的知识将扩展我们对接触血液表面的生物相容性的理解，并可能引起一系列新型的伴有血液接触表面生物相容性的生物标志物。根据美国心脏协会的说法，美国有超过500万人患有心力衰竭。此外，心力衰竭的患病率逐渐增加，部分原因是我们人群的老化。尽管医疗疗法有所提高，但这些患者的死亡率仍然很高，男性的中位生存率仅为25％，女性的生存率仅为25％。仅在2004年，美国就有超过100万个住院治疗，并首先列出了心力衰竭的出院诊断。据估计，超过25万名患者处于这种疾病的末期，并且患有严重症状，即使使用最大药物治疗也无法缓解。我们的提案结果可能会导致一项技术，该技术可以通过为机械循环辅助设备提供生物相容性的血液接触表面来减轻超过一百万美国人的症状，以部分部分，并全力支持失败的心脏。此外，该技术可能适用于其他钛 /钛合金血液接触表面，例如尼替尼血管支架。这些可能会抗固定的再狭窄，并使数百万接受冠状动脉或血管支架治疗的美国人受益。 公共卫生相关性：根据美国心脏协会的说法，美国有超过500万人患有心力衰竭。此外，心力衰竭的患病率逐渐增加，部分原因是我们人群的老化。尽管医疗疗法有所提高，但这些患者的死亡率仍然很高，男性的中位生存率仅为25％，女性的生存率仅为25％。仅在2004年，美国就有超过100万个住院治疗，并首先列出了心力衰竭的出院诊断。据估计，超过25万名患者处于这种疾病的末期，并且患有严重症状，即使使用最大药物治疗也无法缓解。 我们的提案结果可能会导致一项技术，该技术可以通过为机械循环辅助设备提供生物相容性的血液接触表面来减轻超过一百万美国人的症状，以部分部分，并全力支持失败的心脏。此外，该技术可能适用于其他钛 /钛合金血液接触表面，例如尼替尼血管支架。这些可能会抗固定的再狭窄，并使数百万接受冠状动脉或血管支架治疗的美国人受益。