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: 8274427
• 负责人: Dan TEODOR Simionescu
• 金额: $ 5.5万
• 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/8274427
• 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.

描述（由申请人提供）：每年需要超过100万个小直径的血管移植物来进行外围或冠状动脉搭桥手术。选择的管道是自体静脉或动脉，但由于先前存在的条件或先前的收获，这些管道并不总是可用的。市售的生物材料，例如扩展的聚氟乙烯（EPTFE）在最初的5年中的大量血管移植物功能良好，但由于缺乏保护性的内皮层，但此后急剧失败。直径低于6毫米的EPTFE移植物的临床使用与近端吻合术的高较窄有关，并且由于血栓形成和内膜增生而最终遮挡。因此，需要支撑腔内皮层的新生物材料来发展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的医疗保健非常重要的一章。长期目标：开发“现成”的小直径移植物，以促进形成稳定，抗剪切的内皮层以保护移植物免受闭塞的影响。植入后可能会出现内皮细胞的自发腔覆盖范围：1）跨施施氏菌体内皮化的内皮细胞，内皮细胞在吻合术中横向迁移以覆盖腔移植物表面和2）跨膜的内皮化过程，这是通过内皮细胞通过厚度迁移的厚度，从而建立了厚度，从而迁移了厚度。由于跨施剂的内皮化似乎在人植入物中受到限制（与动物模型相比），因此将在拟议的研究中研究两种机制。工作假设：可以通过工程弹性蛋白支架来产生专利的小直径血管移植物，从而促进植入后内皮化。克莱姆森大学的PI正在开发多孔弹性蛋白的血管移植物（EDVG）和Penta-Galloyl-葡萄糖（PGG）进行可逆稳定。在短期植入研究中，发现EDVG是非紧密的，表现出足够的弹性，爆发压力和依从性，并且在皮下研究中促进了愈合和支持细胞再植物的缓慢降解。方法：在PI小组中准备的弹性蛋白渠道将在开普敦大学植入大鼠源主动脉主动脉，以评估：（i）支持的生物相容性，优势和支持跨植物内皮化（AIM 1）（AIM 1），以及（II）在分离的组合中，在分离的组合中，跨度的跨度层次化的跨度层次划分，该阶层是在分离的组合中开发的。植入前EPTFE移植物材料（AIM 2）。在啮齿动物模型中进行评估后，EDVG将被植入颈动脉介入移植物中，这是一种更临床相关的大型动物模型（AIM 3）。这些弹性蛋白衍生的脚手架的通畅和内皮化的证明具有巨大的潜力用于将来的临床应用。拟议的研究将主要在南非开普敦大学的心血管研究部门进行，并与Deon Bezuidenhout博士合作，高级讲师和系主任Peter Zilla教授，都是共同发明家，作为NIH GRANTS R01HL09339933999399993999399939993999399939939939939939939939.PID DAN9999999993999399939939939939.PID DANIIN（PISCC） R21EB009835（PI，该提案的共同投资者Agneta Simionescu博士），期间01/01/2011至12/31/2013。