For the treatment of acute and chronic liver failure, there is a critical need for temporary and permanent modes of liver support. The long-term objective of the proposed research is to enhance our basic understanding of hepatocyte behavior in bioartificial liver (BAL) devices in order to provide a rational basis for the development of an effective extracorporeal device which contains functional hepatocytes. In our prior studies, we have developed a number of stable hepatocyte culture systems and have used these systems to investigate various critical technologies for the development of a BAL device. We have also begun an evaluation of the effects of plasma exposure on hepatocyte function in order to understand the behavior of cultured hepatocytes under ex vivo conditions. In our reactor design efforts, we have focused on combining microtechnology techniques with the use of co-cultures of hepatocytes and mesenchymal cells, which, in preliminary experiments, showed an upregulation of hepatospecific function when compared to cultures of hepatocytes alone. For our proposed studies, we hypothesize that the placement of specific patterns of hepatocytes and mesenchymal cells can have a substantial effect on hepatic cell function and therefore reactor performance. First, we will study mechanisms by which mesenchymal-parenchymal interactions contribute to hepatospecific function. Through a thorough mechanistic study we aim to understand the means by which co-culture mediates its effect on hepatocytes, and use this fundamental knowledge to optimize a co-culture system with high-levels of stable differential functional output. Second, we will elucidate mechanisms by which plasma exposure limits hepatospecific function, and develop techniques which help maintain a stable hepatocyte phenotype during extracorporeal plasma perfusion. Third, we will investigate the use of novel a BAL device based on microfabricated hepatocyte co-cultures in the treatment of a number of hepatic insufficiency animal models. Through a combined program of understanding the determining factors in successful hepatocyte co-culture and developing a new approach in BAL device design using micropatterning techniques, we hope to both enhance our basic science base in the area of hepatic tissue engineering and provide a solid foundation for the design of extracorporeal BAL systems for treatment of liver failure.
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