VASCULAR TISSUE ENGINEERING: RATIONAL DESIGN USING MODELING

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 组织工程学为心血管疾病的治疗带来了希望。对于组织工程化心血管构建，无血栓形成的内皮细胞(EC)表面将是有利的。我们的目标是，对于与血液接触的内皮细胞表面，建立可在体外预适应的内皮细胞的促止血和抗止血特性之间的关系，以及体内血栓形成和血管愈合的生理反应。为了实现这一目标，体外可变预处理的构建物的止血性能与体内结果相关，从而证明了合理设计的实用性。这些研究使用了在体外很容易从全血中分离的内皮祖细胞(EPC)，以及与血栓形成和血管移植物内膜增生相关的在体狒狒模型。为了增强或抑制调节止血功能的EPC特性，EPC生长在涂有不同基质蛋白(胶原或弹性蛋白)的常规ePTFE上，并接受可变的血流动力学预适应(静态剪切与正常剪切)。使用功能、生化、分子和组织学分析来评估由内皮祖细胞协调的止血、炎症和有丝分裂活性。我们正在评估：1)生理血流条件下天然非抗凝血液中血栓的形成，以及2)手术植入后内皮祖细胞构筑物的愈合。我们的目标不是开发改进的血管移植物。相反，通过证明体外细胞预适应可以预测地改善体内的结果-这一原理可以扩展到其他细胞类型和动物模型-这些结果将验证总体上的合理设计，并鼓励使用其他结构和试验床的研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Tissue engineering holds promise for the treatment of cardiovascular disease. For tissue-engineered cardiovascular constructs a nonthrombogenic endothelial cell (EC) surface will be advantageous. Our goal is to establish, for blood-contacting EC surfaces, relationships between pro- and anti- hemostatic properties of ECs that can be preconditioned in vitro, and physiologic responses of thrombosis and vascular healing in vivo. To achieve this goal, the hemostatic properties of constructs variably preconditioned in vitro are being correlated with in vivo outcomes, thereby documenting the utility of rational design. These studies employ baboon endothelial progenitor cells (EPCs) that are readily isolated from whole blood in vitro, and relevant in vivo baboon models of thrombosis and vascular graft intimal hyperplasia. To enhance or inhibit EPC properties that regulate hemostatic functions, EPCs are grown on conventional ePTFE coated with different matrix proteins (collagen or elastin) and subjected to variable hemodynamic preconditioning (static vs. normal shear). Hemostatic, inflammatory, and mitogenic activities that are orchestrated by EPCs are assessed using functional, biochemical, molecular, and histologic assays. We are assessing: 1) thrombus formation in native, non-anticoagulated blood under physiologic flow conditions, and 2) healing of EPC-constructs following surgical placement. It is not our goal to develop an improved vascular graft. Rather, by documenting that cellular preconditioning in vitro can predictably improve outcomes in vivo - a principle that can be extended to other cell types and animal models - these results will validate rational design in general, and encourage studies with other constructs and test beds.