HEPREGEN
Grant: $499,800 - National Institutes of Health - Sep. 30, 2009
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Award Description: TOWARDS A MINIATURIZED HUMAN LIVER ARRAY FOR HIGH-THROUGHPUT SCREENING Animal studies are proving to be insufficient for predicting human liver responses primarily due to significant species-specific differences in liver functions. Therefore, a plethora of in vitro human liver models have been developed over the last three decades to supplement testing on animals. Of the several liver models currently available, those utilizing primary hepatocytes strike a good balance between their potential to predict the diverse human responses seen in vivo and their simplicity of use in various culture formats. However, primary hepatocytes are notoriously difficult to maintain in conventional models as their phenotypic functions display a precipitous decline within a few hours after isolation from the native microenvironment of the liver. Indeed, unstable hepatocytes in these models have been shown to be poor predictors of clinical outcomes. We have utilized microfabrication technologies and tissue engineering techniques to develop a human liver model with precise microscale cytoarchitecture and optimal stromal interactions that displays phenotypic stability for several weeks in vitro as compared to a few hours in conventional cultures. Here, we propose to further develop and optimize these microscale human liver cultures and couple them with miniaturization strategies and assay technologies for cost-effective high-throughput screening (HTS) applications. Since drug-induced liver injury (DILI) is a leading cause of acute liver failures and the high attrition rate of pharmaceuticals, we will optimize our miniaturized human livers specifically for the in vitro screening of genotype-specific and clinically-relevant drug disposition and coupled DILI. The technologies we develop here may find broad utility in the development of several classes of therapeutic compounds (drugs, biologics), in evaluating the disposition and injury potential of environmental toxicants, in fundamental investigations of liver physiology and disease, and in personalized medicine for liver disease. In the future, continued combination of microtechnology with tissue engineering may spur the development of other tissue models and their integration into the so-called ?human-on-a-chip?.
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