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首页> 外文学位 >Toward engineering a neoendothelium with circulating progenitor cells on a novel biodegradable elastomer.
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Toward engineering a neoendothelium with circulating progenitor cells on a novel biodegradable elastomer.

机译：致力于在新型可生物降解的弹性体上设计具有循环祖细胞的新内皮。

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摘要

Approximately 500,000 coronary artery and 100,000 upper and lower limb bypass procedures are performed yearly to address heart attacks and side effects due to peripheral artery disease. To deal with this problem, surgeons commonly use synthetic vascular grafts made from expanded poly(tetrafluoroethylene) (ePTFE). The use of this synthetic graft in small diameter applications (5 mm) remains a challenge due to low patency rates, resulting from graft thrombosis, intimal hyperplasia, and eventual graft occlusion and failure. This has led to considerable efforts in the field of vascular tissue engineering to modify and improve the long term success rate of synthetic grafts for small diameter applications.;One such modification involves the introduction of a polymeric material in the inner lumen of the graft that provides a substrate for cell attachment as well as improving the biocompatibility of the synthetic graft. Our laboratory has designed a novel biodegradable, elastomeric copolymer, poly (1,8-octanediol co-citrate) (POC), with mechanical and degradation properties suitable for vascular tissue engineering. The hemocompatibility of POC in vitro and its ability to support the attachment of human aortic endothelial cell cells under fluid flow was assessed. The hemocompatibility evaluation included assessments, such as platelet adhesion and activation, protein adsorption properties, plasma clotting, and hemolysis. Further, to assess the inflammatory potential of POC, the release of interleukin-1a and tumor necrosis factor-alpha from a monocytic cell line was measured. The results described herein are encouraging and suggest that POC is hemocompatible, does not elicit a significant inflammatory response, and is an adequate candidate for vascular applications.;In addition to evaluating the hemocompatibility of our candidate biomaterial, POC, we also address one of the main challenges in vascular tissue engineering; the identification of a suitable cell source that can provide the biological components of the vasculature to the non-biological graft. In this work, we assess the feasibility of using endothelial progenitor cells found in circulating blood to generate a functional endothelium. Adult progenitor cells have emerged as a potentially promising cell source but very little is known about their functional potential; particularly on a biomaterial surface. As such, EPCs were isolated from porcine and human blood and biochemically differentiated into endothelial-like cells in vitro. The differentiated endothelial-like cell phenotype and function when cultured on POC was compared to mature endothelial cells also cultured on POC. Specifically, we assessed the endothelial-like cell morphology and the expression of EC specific markers. Further, we evaluated the anti-thrombogenic functional ability of the cells, including EC specific factor synthesis and secretion, as well as the ability for the cells to inhibit platelet adhesion, and retard plasma and whole blood clotting processes. Finally, we assessed the ability of the cells to withstand physiological shear stress of 10 dynes/cm2 when cultured on a POC-modified-ePTFE vascular graft. Collectively, our results show that the endothelial-like cells derived from circulating blood progenitor cells function similar to mature endothelial cells, they secrete anti-thrombogenic factors and delay clotting processes. The results shown in this thesis are the foundation for future clinical studies in the creation of an autologous endothelial cell-seeded vascular graft.;The last study described in this dissertation is a preliminary in vivo study using autologous porcine endothelial-like cell seeded POC-modified ePTFE graft. The seeded grafts were implanted in a porcine carotid artery bypass for up to 28 days. Because of the inherent limitations associated with in vitro studies, this study represents the culmination of all of the previous experiments and allows us to evaluate the cells in a physiological and clinically relevant manner. Our results indicate that the explanted cell seeded grafts remained patent for up to 28 days. As we had hoped, the cells did not detach from the graft, nor did the graft occlude via thrombus formation. Although the results of this study are preliminary, they provide the basis for future in vivo studies, which will be more comprehensive.;Significantly more research needs to be done, however, the work described in this dissertation has provided a better understanding of the function of endothelial-like cells cultured on a biomaterial of interest for vascular tissue engineering. Further, this work provides evidence that EPCs combined with our polymer, POC are a viable strategy for improving the long term success of synthetic vascular grafts.
机译：每年执行约500,000例冠状动脉手术和100,000例上肢和下肢旁路手术，以解决由于周围动脉疾病引起的心脏病发作和副作用。为了解决该问题，外科医生通常使用由膨胀的聚四氟乙烯（ePTFE）制成的合成血管移植物。由于通畅率低（由于移植物血栓形成，内膜增生以及最终的移植物闭塞和衰竭），在小直径应用（<5 mm）中使用这种合成移植物仍然是一个挑战。这导致了在血管组织工程领域的巨大努力，以修改和提高用于小直径应用的合成移植物的长期成功率。；其中一种修饰涉及在移植物的内腔中引入聚合材料，从而提供用于细胞附着的底物以及改善合成移植物的生物相容性。我们的实验室设计了一种新型的可生物降解的弹性体共聚物，聚（1,8-辛二醇-柠檬酸酯）（POC），具有适合血管组织工程的机械和降解性能。评估了POC在体外的血液相容性及其在流体流动下支持人主动脉内皮细胞附着的能力。血液相容性评估包括血小板粘附和活化，蛋白质吸附特性，血浆凝结和溶血等评估。另外，为了评估POC的炎性潜力，测量了单核细胞系中白介素-1a和肿瘤坏死因子-α的释放。本文所述结果令人鼓舞，并表明POC具有血液相容性，不会引起明显的炎症反应，并且是血管应用的合适候选药物。;除了评估我们候选生物材料POC的血液相容性之外，我们还解决了其中一种血管组织工程的主要挑战；确定可以为非生物移植物提供脉管系统生物学成分的合适细胞来源。在这项工作中，我们评估了使用循环血液中发现的内皮祖细胞产生功能性内皮的可行性。成体祖细胞已成为潜在的有希望的细胞来源，但对其功能潜力知之甚少。特别是在生物材料表面上。这样，从猪和人的血液中分离出EPC，并在体外生化分化为内皮样细胞。与在POC上培养的成熟内皮细胞相比，在POC上培养时分化的内皮样细胞表型和功能也得到了比较。具体来说，我们评估了内皮样细胞的形态和EC特异性标志物的表达。此外，我们评估了细胞的抗血栓形成功能，包括EC特异性因子的合成和分泌，以及细胞抑制血小板粘附，延迟血浆和全血凝固过程的能力。最后，我们评估了在POC修饰的ePTFE血管移植物中培养细胞时细胞承受10达因/平方厘米的生理切应力的能力。总的来说，我们的结果表明，源自循环血祖细胞的内皮样细胞的功能类似于成熟的内皮细胞，它们分泌抗血栓形成因子并延迟凝血过程。本论文显示的结果为建立自体内皮细胞种血管移植物的未来临床研究奠定了基础。本论文描述的最后一项研究是利用自体猪内皮样细胞接种的POC-进行的体内初步研究。改性ePTFE接枝。播种的移植物被植入猪颈动脉旁路中长达28天。由于与体外研究相关的固有局限性，该研究代表了所有先前实验的高潮，并使我们能够以生理和临床相关的方式评估细胞。我们的结果表明，已植入细胞的移植物在长达28天的时间内仍保持专利。正如我们希望的那样，细胞不会从移植物上脱落，移植物也不会通过血栓形成而闭塞。尽管这项研究的结果是初步的，但它们为将来的体内研究提供了基础，该研究将更加全面。；需要进行大量研究，但是，本文所描述的工作已经使人们对功能有了更好的理解。在用于血管组织工程的目标生物材料上培养的内皮样细胞的数量此外，这项工作提供了证据，证明EPC与我们的聚合物POC结合是提高合成血管移植物长期成功率的可行策略。

著录项

  • 作者

    Allen, Josephine.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Engineering Biomedical.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 242 p.
  • 总页数 242
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物医学工程;
  • 关键词

  • 入库时间 2022-08-17 11:38:26

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