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). ***
