Tissue Engineered Nanofibrous Vascular Graft

组织工程纳米纤维血管移植物

• 批准号: 7657324
• 负责人: Song Li
• 金额: $ 35.46万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657324
• 关键词: Address; Allogenic; Aneurysm; Animal Model; Arteries; Atherosclerosis; Autologous; Biocompatible; Biocompatible Materials; Biological Markers; Biomimetics; Blood Vessels; Bone Marrow; Bone Marrow Stem Cell; Bypass; Caliber; Cell Adhesion; Cells; Collagen; Development; Endothelial Cells; Engineering; Extracellular Matrix; Failure; Goals; Laboratories; Lead; Liquid substance; Mechanics; Mesenchymal Stem Cells; Molecular Structure; Monitor; Operative Surgical Procedures; Peptides; Prevention; Procedures; Production; Property; RGD (sequence); Research; Smooth Muscle Myocytes; Source; Stem cells; Structure; Surface; Technology; Testing; Thrombosis; Tissue Engineering; Tissues; Transforming Growth Factors; Transplantation; Tubular formation; Vascular Diseases; Vascular Graft; Veins; adult stem cell; base; biodegradable polymer; cell type; common treatment; immunogenic; in vivo; innovative technologies; monolayer; nanofiber; novel; poly(lactic acid); precursor cell; prevent; repaired; response; scaffold; scale up; shear stress; stem cell differentiation; vascular tissue engineering

DESCRIPTION (provided by applicant): Blood vessel replacement is a common treatment for vascular diseases. Tissue engineering is a promising approach to the fabrication of non-thrombogenic and mechanically durable vascular grafts. Our goal is to engineer bone marrow stem cells and electrospun nanofibrous scaffolds to construct tissue-engineered vascular graft (TEVG) that closely matches the composition, structure and mechanical property of native blood vessel. Bone marrow contains vascular endothelial precursor cells (EPCs) and mesenchymal stem cell (MSC). MSC can differentiate into a variety of cell types, including vascular smooth muscle cell (SMC). We hypothesize that: (1) bone marrow stem cells can be used to derive endothelial cells (ECs) and SMCs to construct TEVGs, (2) bioactive nanofibrous scaffolds with aligned nanofibers can promote MSC differentiation, matrix remodeling and the formation of microstructure as in native vessel, and (3) mechanical loading can promote MSC differentiation, matrix remodeling and EC monolayer retention. To test our hypothesis, four Specific Aims are proposed: (1) To engineer bioactive nanofibrous scaffolds and characterize MSC-scaffold interactions; (2) To determine MSC differentiation and matrix remodeling in TEVG in response to mechanical loading; (3) To construct EC monolayer in TEVG using EPCs and determine the effect of flow on EC remodeling; (4) To determine the remodeling and patency of small-diameter TEVGs in vivo. The nanofibers in the tubular scaffolds will be aligned in the circumferential direction to mimic the matrix alignment in native blood vessels and guide the MSC alignment. RGD peptide and TGF-p will be conjugated to the nanofibers to promote matrix remodeling and MSC differentiation into SMC. Mechanical loading will be applied to the tubular scaffolds to further enhance matrix remodeling and MSC differentiation. Bone marrow derived ECs will be cultured as monolayer on the luminal surface of TEVG, and will be pre-conditioned by fluid shear stress. The mechanical property and structure of the TEVGs will be determined. Bypass surgery will be performed in animal model to determine the continued remodeling and patency of small TEVGs. Manufacturing-related issues such as Good Manufacturing Practices, biomarker monitoring, storage and caling-up will be addressed. The accomplishment of this project will lead to the development of innovative technologies to engineer stem cells and nanofibrous scaffolds for the construction of small TEVGs.

描述（由申请人提供）： 血管置换是血管疾病的常见治疗方法。组织工程是一种有前途的制造非血栓形成且机械耐用的血管移植物的方法。我们的目标是设计骨髓干细胞和电纺纳米纤维支架来构建与天然血管的成分、结构和机械性能紧密匹配的组织工程血管移植物（TEVG）。骨髓含有血管内皮前体细胞（EPC）和间充质干细胞（MSC）。 MSC可以分化成多种细胞类型，包括血管平滑肌细胞（SMC）。我们假设：（1）骨髓干细胞可用于衍生内皮细胞（EC）和SMC来构建TEVG，（2）具有对齐纳米纤维的生物活性纳米纤维支架可以促进MSC分化、基质重塑和微观结构的形成，如(3) 机械负荷可以促进 MSC 分化、基质重塑和 EC 单层保留。为了检验我们的假设，提出了四个具体目标：（1）设计生物活性纳米纤维支架并表征 MSC-支架相互作用； (2) 确定 TEVG 中 MSC 分化和基质重塑对机械负荷的响应； (3)利用EPCs在TEVG中构建EC单层并确定流动对EC重塑的影响； (4)确定小直径TEVG在体内的重塑和通畅情况。管状支架中的纳米纤维将沿圆周方向排列，以模拟天然血管中的基质排列并引导 MSC 排列。 RGD 肽和 TGF-β 将与纳米纤维缀合，以促进基质重塑和 MSC 分化为 SMC。机械负载将应用于管状支架，以进一步增强基质重塑和 MSC 分化。骨髓衍生的 EC 将在 TEVG 的管腔表面上作为单层培养，并通过流体剪切应力进行预处理。 TEVG 的机械性能和结构将被确定。将在动物模型中进行搭桥手术，以确定小型 TEVG 的持续重塑和通畅。将解决与生产相关的问题，例如良好生产规范、生物标志物监测、储存和校准。该项目的完成将促进创新技术的发展，以设计干细胞和纳米纤维支架来构建小型 TEVG。