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: 8485708
• 负责人: Dan TEODOR Simionescu
• 金额: $ 5.23万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8485708
• 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 万个小直径血管移植物用于外周或冠状动脉搭桥手术。选择的导管是自体静脉或动脉，但由于预先存在的条件或之前的采集，这些导管并不总是可用的。商用生物材料，例如膨体聚四氟乙烯 (ePTFE)，在前 5 年内可作为大直径血管移植物发挥良好作用，但此后由于愈合不完全和缺乏保护性内皮层而急剧失效。临床使用直径低于 6 毫米的 ePTFE 移植物会导致近端吻合处的高狭窄率，并最终因血栓形成和内膜增生而闭塞。因此，开发功能性小直径血管移植物需要能够支撑管腔内皮层的新型生物材料。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部分。长期目标：开发“现成的”小直径移植物，促进稳定、抗剪切的内皮层的形成，以保护移植物免于闭塞。植入后内皮细胞自发的管腔覆盖可能通过两种独立的机制发生：1) 跨吻合口内皮化，即内皮细胞横向迁移穿过吻合口以覆盖管腔移植物表面；2) 跨壁内皮化，这是一种血管生成过程，内皮细胞通过该过程形成血管壁。细胞迁移穿过支架的厚度以建立新内膜。由于经吻合内皮化似乎在人体植入物中受到限制（与动物模型相比），因此在拟议的研究中将研究这两种机制。工作假设：专利小直径血管移植物可以通过设计弹性蛋白支架来生产，以促进植入后的内皮化。克莱姆森大学的 PI 正在开发多孔弹性蛋白衍生血管移植物 (EDVG) 和五没食子酰葡萄糖 (PGG) 处理以实现可逆稳定。在短期植入研究中发现 EDVG 不形成血栓，表现出足够的弹性、爆裂压力和顺应性，并且在皮下研究中降解缓慢，促进愈合并支持细胞再生。方法：PI 小组准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、通畅性和支持经吻合内皮化的能力（目标 1），以及（ii）反式- 开普敦大学开发的隔离复合环模型中的壁内皮化，其中测试部分在植入前插入 ePTFE 移植材料的两部分之间（目标 2）。在啮齿动物模型中进行评估后，EDVG 将作为颈动脉介入移植物植入猪体内，这是一种更具临床相关性的大型动物模型（目标 3）。这些弹性蛋白衍生支架的通畅和内皮化的证明对于未来的临床应用具有巨大的潜力。拟议的研究将主要在南非开普敦大学心血管研究中心与高级讲师 Deon Bezuidenhout 博士和系主任 Peter Zilla 教授合作进行，两人均担任共同研究者，作为合乎逻辑的研究NIH 延长拨款 R01HL093399（PI，Dan Simionescu 博士）和 R21EB009835（PI，Agneta Simionescu 博士，该提案的联合研究员），期间为2011年1月1日至2013年12月31日。

项目成果

Platform technologies for decellularization, tunic-specific cell seeding, and in vitro conditioning of extended length, small diameter vascular grafts.

• DOI: 10.1089/ten.tec.2014.0047
• 发表时间: 2014-12
• 期刊: Tissue engineering. Part C, Methods
• 作者: George Fercana;D. Bowser;Margarita Portilla;E. Langan;C. Carsten;D. Cull;L. Sierad;D. Simionescu

The performance of cross-linked acellular arterial scaffolds as vascular grafts; pre-clinical testing in direct and isolation loop circulatory models.

• DOI: 10.1016/j.biomaterials.2014.04.062
• 发表时间: 2014-08
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Pennel, Timothy;Fercana, George;Bezuidenhout, Deon;Simionescu, Agneta;Chuang, Ting-Hsien;Zilla, Peter;Simionescu, Dan
• 通讯作者: Simionescu, Dan

Development and initial characterization of a chemically stabilized elastin-glycosaminoglycan-collagen composite shape-memory hydrogel for nucleus pulposus regeneration.

• DOI: 10.1002/jbm.a.35104
• 发表时间: 2014-12
• 期刊: Journal of biomedical materials research. Part A
• 作者: J. Mercuri;Caroline P. Addington;Richard Pascal;S. Gill;D. Simionescu

Knitted nitinol represents a new generation of constrictive external vein graft meshes.

针织镍钛诺代表了新一代收缩性外静脉移植网。

• DOI: 10.1016/j.jvs.2011.05.023
• 发表时间: 2011
• 期刊: Journal of vascular surgery
• 影响因子: 4.3
• 作者: Zilla,Peter;Moodley,Loven;Wolf,MichaelF;Bezuidenhout,Deon;Sirry,MazinS;Rafiee,Nasser;Lichtenberg,Wilhelm;Black,Melanie;Franz,Thomas
• 通讯作者: Franz,Thomas