Elastin-derived Scaffolds for Tissue Engineered Small Diameter Vascular Grafts

用于组织工程小直径血管移植物的弹性蛋白支架

• 批准号: 8081205
• 负责人: Dan TEODOR Simionescu
• 金额: $ 6.14万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081205
• 关键词: Abdomen; Anastomosis - action; Animal Model; Animals; Aorta; Arteries; Autologous; Biocompatible Materials; Biological; Biomechanics; Biomedical Engineering; Blood; Blood Cells; Blood Vessels; Bypass; Caliber; Cardiovascular system; Cells; Clinical; Collaborations; Coronary Artery Bypass; Developing Countries; Development; Disease; Dreams; Elasticity; Elastin; Elements; Endothelial Cells; Endothelium; Engineering; Evaluation; Exhibits; Family suidae; Future; Glucose; Grant; Harvest; Head; Healed; Healthcare; Human; Human body; Hyperplasia; Implant; Injury; Legal patent; Life; Mechanics; Modeling; One-Step dentin bonding system; Operative Surgical Procedures; Outcome; Patients; Pentas; Peripheral; Pilot Projects; Polytetrafluoroethylene; Porosity; Positioning Attribute; Procedures; Process; Property; Proteins; Public Health; Rattus; Research; Research Personnel; Resistance; Rodent Model; Scientist; South Africa; Supporting Cell; Surface; Surgeon; Testing; Thick; Thrombosis; Tissue Engineering; Translating; Translations; Transplanted tissue; Tube; United States National Institutes of Health; Universities; Vascular Diseases; Vascular Graft; Veins; Work; angiogenesis; base; biomaterial compatibility; clinical application; clinically relevant; healing; implantation; improved; innovation; insight; interdisciplinary approach; lecturer; novel; novel strategies; pressure; professor; renal artery; scaffold; subcutaneous

DESCRIPTION (provided by applicant): More than 1 million small diameter vascular grafts are needed every year for peripheral or coronary bypass surgery. The conduit of choice is an autologous vein or artery, but these are not always available due to pre-existing conditions or previous harvesting. Commercially available biomaterials such as expanded polytetrafluoroethylene (ePTFE) function well as large diameter vascular grafts in the first 5 years but fail dramatically thereafter because of incomplete healing and lack of a protective endothelial layer. Clinical use of ePTFE grafts below 6 mm in diameter is associated with a high rate of narrowing at the proximal anastomosis and ultimately occlusion due to thrombosis and intimal hyperplasia. Thus, new biomaterials capable of supporting a luminal endothelial layer are needed for development of functional small diameter vascular grafts. This study is highly relevant to public health because vascular disease is a very important chapter of health care in the US as well as in third world countries such as South Africa. Long term objective: To develop "off-the-shelf" small diameter grafts that would promote formation of a stable, shear-resistant, endothelial layer to protect the graft from occlusion. Spontaneous luminal coverage with endothelial cells after implantation may occur via two independent mechanisms: 1) Trans-anastomotic endothelialization, whereby endothelial cells migrate laterally across the anastomosis to cover the luminal graft surface and 2) Trans-mural endothelialization, an angiogenic process by which endothelial cells migrate through the thickness of the scaffold to establish a neo-intima. Since trans-anastomotic endothelialization appears to be limited in human implants (as compared to animal models), both mechanisms will be investigated in proposed studies. Working hypothesis: Patent small diameter vascular grafts can be produced by engineering elastin scaffolds that promote endothelialization after implantation. The PI at Clemson University is developing porous elastin-derived vascular grafts (EDVGs) and treatment with penta-galloyl-glucose (PGG) for reversible stabilization. EDVGs were found to be non-thrombogenic in short term implantation studies, exhibited adequate elasticity, burst pressure and compliance, and also degraded slowly, facilitating healing and supporting cell repopulations in subcutaneous studies. Approach: Elastin conduits prepared in the PI's group will be implanted at the University of Cape Town into the rat infrarenal aorta to assess: (i) biocompatibility, patency and ability to support trans- anastomotic endothelialization (Aim 1), and (ii) trans-mural endothelialization in an isolated composite loop model developed by the University of Cape Town whereby the test segment is interposed in between two sections of ePTFE graft material before implantation (Aim 2). After evaluation in the rodent models, EDVGs will be implanted as carotid interposition grafts in pigs, a more clinically relevant large animal model (Aim 3). Demonstration of patency and endothelialization of these elastin-derived scaffolds has great potential for future clinical applications. The proposed research will be performed primarily in the Cardiovascular Research Unit, University of Cape Town, South Africa, in collaboration with Dr. Deon Bezuidenhout, senior lecturer and Professor Peter Zilla, head of department, both acting as co-investigators, as a logical extension of NIH grants R01HL093399 (PI, Dr. Dan Simionescu) and R21EB009835 (PI, Dr. Agneta Simionescu, co-investigator for this proposal), during the period 01/01/2011 to 12/31/2013. PUBLIC HEALTH RELEVANCE: The human body contains an extensive network of vessels that transport blood throughout the body in order to sustain function and life. When these blood vessels become blocked or damaged due to disease or injury, they are surgically replaced or bypassed, preferably by using other natural arteries and veins from the patient's own body. In a large number of cases, however, these preferred substitutes are not suitable or available, and the only current alternatives comprise tubes made of synthetic materials. In many applications these synthetic non-living materials absorb proteins and cells from the blood and become clogged, requiring replacement after 5-10 years. New and improved materials are thus needed for these patients. We are developing alternative natural replacement blood vessels by chemically treating arteries from pigs to render them suitable for use in humans. These tissue engineered blood vessels have inside surfaces which do not induce clogging and have the potential to remodel in the body, and to be repopulated by the patient's own cells, thereby creating new, living arteries. In this study we will implant our new arteries in experimental animals to test their biologic properties. Our new approach will have a global impact in the treatment of vascular disease by providing superior long- term outcomes for thousands of patients.

描述（由申请人提供）：外周或冠状动脉搭桥手术每年需要超过100万个小直径血管移植物。选择的管道是自体静脉或动脉，但由于预先存在的条件或先前的收获，这些并不总是可用的。市售的生物材料如膨胀型聚四氟乙烯（ePTFE）在前5年内作为大直径血管移植物发挥良好的功能，但此后由于愈合不完全和缺乏保护性内皮层而急剧失效。直径小于6 mm的ePTFE移植物的临床使用与近端吻合口狭窄率高以及血栓形成和内膜增生导致的最终闭塞相关。因此，需要能够支持管腔内皮层的新生物材料用于开发功能性小直径血管移植物。这项研究与公共卫生高度相关，因为血管疾病是美国以及南非等第三世界国家医疗保健的一个非常重要的章节。长期目标：开发“现成”小直径移植物，促进形成稳定、抗剪切的内皮层，以保护移植物免受闭塞。植入后内皮细胞自发性管腔覆盖可能通过两种独立的机制发生：1）经吻合内皮化，其中内皮细胞横向迁移穿过吻合口以覆盖管腔移植物表面; 2）透壁内皮化，一种血管生成过程，其中内皮细胞迁移穿过支架的厚度以建立新内膜。由于经吻合口内皮化似乎在人体植入物中受到限制（与动物模型相比），因此将在拟定研究中研究这两种机制。工作假设：专利的小直径血管移植物可以通过工程弹性蛋白支架来产生，其在植入后促进内皮化。克莱姆森大学的PI正在开发多孔弹性蛋白衍生的血管移植物（EDVG），并使用五没食子酰葡萄糖（PGG）进行可逆稳定治疗。在短期植入研究中发现EDVG无血栓形成，表现出足够的弹性、爆破压和顺应性，并且在皮下研究中缓慢降解，促进愈合并支持细胞再生。方法：PI组制备的弹性蛋白导管将在开普敦大学植入大鼠肾下主动脉，以评估：（i）生物相容性、开放性和支持经吻合内皮化的能力（目标1），及（ii）反式-由开普敦大学开发的隔离复合环模型中的壁内皮化，其中测试段插入ePTFE移植物材料的两个部分之间植入前（目标2）。在啮齿动物模型中进行评价后，将EDVG作为颈动脉间置移植物植入猪体内，这是一种临床相关性更高的大型动物模型（目的3）。这些弹性蛋白衍生支架的通畅性和内皮化的证明具有未来临床应用的巨大潜力。拟议的研究将主要在南非开普敦大学心血管研究中心进行，与高级讲师Deon Bezuidenhout博士和系主任Peter Zilla教授合作，作为NIH赠款R 01 HL 093399的合理延伸，两人均担任共同研究者（PI，Dr. Dan Simionescu）和R21 EB 009835（PI，Dr. Agneta Simionescu，本提案的共同研究者），在2011年1月1日至2013年12月31日期间。 公共卫生相关性：人体包含广泛的血管网络，将血液输送到整个身体，以维持功能和生命。当这些血管由于疾病或损伤而阻塞或受损时，它们被手术替换或旁路，优选地通过使用来自患者自身身体的其他天然动脉和静脉。然而，在大量情况下，这些优选的替代品是不合适的或不可用的，并且当前唯一的替代品包括由合成材料制成的管。在许多应用中，这些合成的非生命材料会从血液中吸收蛋白质和细胞并堵塞，需要在5-10年后更换。因此，这些患者需要新的和改进的材料。我们正在通过化学处理猪的动脉来开发替代天然替代血管，使其适合用于人类。这些组织工程血管的内表面不会引起堵塞，并有可能在体内重塑，并由患者自己的细胞重新填充，从而产生新的活动脉。在这项研究中，我们将把我们的新动脉植入实验动物体内，以测试它们的生物学特性。我们的新方法将通过为数千名患者提供上级长期结局，在血管疾病治疗方面产生全球影响。