POWRE: Modeling an Engineered Liver Tissue System: Phase I

POWRE：工程肝组织系统建模：第一阶段

• 批准号: 9753082
• 负责人: Robin Coger
• 金额: $ 8万
• 依托单位: University of North Carolina at Charlotte
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9753082&HistoricalAwards=false
• 关键词: POWRE; Modeling; Engineered; Liver; Tissue

9753082 Coger The successful operation of implantable devices (e.g., vascular grafts, pacemakers) and extracorporeal devices (e.g., dialysers, blood oxygenators) relies on understanding their impact on the function of the designated organism. Norman function of tissue (and hence organs) is regulated by a complex balance between soluble factors, cell-cell interactions, and cell-matrix interactions. Understanding the details of these interactions becomes even more complicated in organs that accomplish multiple physiological functions (e.g., the liver). In these cases, tissue engineering becomes a valuable means for studying tissue function and morphogenesis in vitro, and for affecting cell growth and function in vivo. The later application includes the development of bioartificial tissues. In the specific case of bioartificial liver development, research efforts are currently underway to provide the medical community with alternatives in treating patients with acute liver failure since less than 4100 (i.e., 4058 in 1996, 3440 in 1993) liver transplants are performed annually in the United States, although 50,000 Americans died of liver disease in 1993. A successful bioartificial liver support system must at least be able to maintain good hepatocyte function since hepatocytes are the major parenchymal cells of the liver and participate in a variety of liver functions including fat, lipid, and carbohydrate metabolism; protein and bile production, and chemical detoxification. Since hepatocytes are anchorage dependent cells, the use of matrix materials that are biodegradable and promote attachment, while simultaneously supporting acceptable levels of cell function are critical. Collagen type I and EHS matrix (e.g., Matrigel) are two such extracellular matrices (ECMs). Both yield good hepatocyte function, yet each promotes a different cell morphology (planar and aggregated, respectively). Consequently, collagen I and EHS matrix are commonly employed in in vi tro models of the liver. The proposed project focuses on the engineering of one particular liver tissue system - hepatocytes on Matrigel, and uses the double gel collagen I system is used as a comparative. In addition to the formation of aggregates, Matrigel is of particular interest because its composition resembles that of the basement membrane. Of the three processes that direct cell aggregation (i.e., soluble factors, cell-cell, and cell-matrix interactions), the proposed project specifically contrasts aspects of the cell- matrix interaction, with particular cell-cell interactions. The governing hypothesis is that cell-matrix interactions drive early aggregation, while cell-cell interactions dominate aggregation in time. In the proposed work, the physical properties of Matrigel are characterized and the forces hepatocytes exert on the ECM are quantified experimentally. The experimental results are then implemented in a predictive aggregation model based on the exerted forces (a cell-matrix parameter), ECM deformability, the density of the hepatocyte population, and degree of cell- cell contact (cell-cell parameter). ***

9753082 COGER的可植入设备（例如，血管移植物，起搏器）和体外装置（例如透析剂，血液氧化剂）的成功操作依赖于了解它们对联次生物体功能的影响。 组织（和器官）的Norman功能受到可溶性因子，细胞相互作用和细胞 - 矩阵相互作用之间的复杂平衡来调节。 在完成多种生理功能（例如肝脏）的器官中，了解这些相互作用的细节变得更加复杂。 在这些情况下，组织工程成为研究组织功能和体外形态发生以及影响细胞生长和体内功能的宝贵手段。 后来的应用包括生物人工组织的发展。 在特定的生物人工肝脏开发的情况下，目前正在进行研究工作，为医学界提供了治疗急性肝衰竭患者的替代方法，因为少于4100（即1996年的4058年，1993年的3440）在1993年进行了肝移植。美国，尽管50,000名美国人在1993年死于肝病。成功的生物人工肝支撑系统至少必须能够保持良好的肝细胞功能，因为肝细胞是肝脏的主要实质细胞，并参与包括各种肝功能，包括多种肝功能脂质和碳水化合物代谢；蛋白质和胆汁产生以及化学解毒。 由于肝细胞是锚定依赖性细胞，因此使用可生物降解并促进附着的基质材料，同时支持可接受的细胞功能水平至关重要。 I型I型和EHS矩阵（例如，基质）是两个这样的细胞外矩阵（ECM）。 两者都产生良好的肝细胞功能，但每种功能都促进了不同的细胞形态（分别是平面和聚集）。 因此，胶原蛋白I和EHS基质通常用于肝脏的VI TRO模型中。 拟议的项目着重于一种特定的肝组织系统的工程 - Matrigel上的肝细胞，并使用双凝胶胶原I系统用作比较。 除了骨料的形成外，Matrigel特别有趣，因为其组成类似于基底膜的组成。 在引导细胞聚集的三个过程（即可溶性因子，细胞 - 细胞和细胞 - 矩阵相互作用）中，所提出的项目特异性地与细胞基质相互作用的各个方面与特定的细胞 - 细胞相互作用进行了对比。 理事假设是细胞 - 矩阵相互作用驱动早期聚集，而细胞 - 细胞相互作用则占据了及时的聚集。 在拟议的工作中，表征了基质凝胶的物理特性，并通过实验对ECM上的力肝细胞施加。 然后，基于施加的力（细胞 - 矩阵参数），ECM可变形性，肝细胞群的密度和细胞 - 细胞接触程度（细胞细胞参数）的预测聚合模型中实现实验结果。 ***