Development of Off-the-shelf Completely Biological Small-Diameter Blood Vessel wi

描述(申请人提供)：血管移植需求很大，因为每年全世界有1200万人死于冠状动脉疾病，占美国所有死亡人数的一半。尽管用不可生物降解的聚合物材料成功地替换了大直径血管，但在创建与冠心病相关的小血管移植物方面仍然存在关键问题。到目前为止，还没有一种生物材料和细胞组织工程血管(TEBV)能够满足患者对冠状动脉替代物的迫切需求。该项目的目标是开发一种细胞片工程策略，通过操纵具有仿生微环境参数的人类干细胞，可能适合于大规模生产完全生物和机械强度的现成小直径血管移植物。我们的中心假设是，由与生理相关的低O2浓度和流体动力学流动组成的明确定义的仿生微环境将有效地控制人类干细胞的命运，使机械强度强大的TEBV能够重复生产。我们的目标是设计一种小直径的血管，模拟自然血管中的三维细胞组织，并可用于任何患者的同种异体移植，而不存在时间问题。目标一：建立一个强大的现成TEBV制造计划。目的II：评价大鼠腹部TEBV的再生过程和远期通畅性。目的III：评价TEBV作为同种异体移植在免疫功能正常的大鼠腹主动脉模型中的免疫应答。这项研究将建立一个强大的现成的使用干细胞的小直径TEBV制造策略。完成后，这种基于细胞片的新策略将克服目前基于生物材料和细胞的方法的局限性，提供一种完全生物的小直径血管移植物，可以维持高血压，刺激功能性血管组织的再生，并诱导体内宿主组织的整合。

DESCRIPTION (provided by applicant): Vascular grafts are in great demand because coronary artery diseases cause 12 million deaths in the world each year and account for half of all deaths in the United States. Despite the successful replacement of large-diameter blood vessels with non-biodegradable polymeric materials, critical issues remain in the creation of coronary heart disease-related small vascular grafts. So far no biomaterials and cel-based tissue- engineered blood vessel (TEBV) can meet the urgent needs of patients for coronary artery substitutes. The objective of this project is to develop a cell sheet engineering strategy potentially suitable for the production of a completely biological and mechanically strong off-the-shelf small-diameter vascular graft in large scale by manipulating human stem cells with biomimetic microenvironmental parameters. Our central hypothesis is that the well-defined biomimetic microenvironments composed of physiological-relevant low O2 concentration and hydrodynamic flows would effectively control the fate of human stem cells, enabling the reproducible production of a mechanically strong TEBV. Our goal is to engineer a small-diameter blood vessel that mimics the three-dimensional cellular organization in the natural blood vessel and can be used as allografts by any patient without time concerns. Aim I: Establish a robust off-the-shelf TEBV manufacturing scheme. Aim II: Evaluate the regeneration process and long-term patency of the TEBV in a rat abdominal model. Aim III: Evaluate the immune response of the TEBV as an allograft in an immune competent rat abdominal artery model. This research will establish a robust off-the shelf small-diameter TEBV fabrication strategy using stem cells. Upon completion, this novel cell sheet-based strategy will overcome the limitations of current biomaterial- and cell-based approaches to provide a completely biological small-diameter vascular graft that can sustain the high blood pressure, stimulate the functional vascular tissue regeneration, and induce integration by the host tissue in vivo.