(6di) Organ-on-a-Chip Platforms to Mimic Physiology for Drug Screening

The liver is a central metabolizing organ and is susceptible to damage by chemicals and/or their metabolites that enter the body. In vitro liver platforms are essential tools that can provide insights for understanding drug metabolism, metabolite generation and resulting toxicity. While relevant, most of the successful liver platforms incorporate hepatocytes alone, thus lacking organ specific metabolism – such as contribution of other, non-parenchymal cells and ultimately can lead to their failure to predict drug induced liver injury. I am interested in developing liver-on-chip platforms that not only incorporates non-parenchymal cells, but also recapitulates the function of the liver effectively.

            The proposed research builds on the recent developments that enable multi-cell culture of primary hepatocytes with isolated non-parenchymal cells to enable development of in vitro liver models that focus on multiple cell types. I have developed a novel method to isolate and culture  primary hepatocytes with primary liver endothelial cells [1], showing the favorable outcomes of cell-cell contacts for long-term stability.  I have developed a novel approach that dramatically simplifies evaluation of liver communication with other organs in eliciting drug efficacy and toxicity [2]. This approach relies on capturing organ-organ interactions in a simple, static system that overcomes dilution effects that are present in the current interrogation systems. These findings provide a handle on an addressing an important question: what are the parameters essential for developing a functional in vitro liver platform that are essential to evaluate organ and organ-organ interactions? My research program will focus on the development of microscale platforms to integrate with other downstream organ units in a functional way. For example, is it possible to mimic the metabolic and inflammatory response to cytokine stimuli and evaluate its effect on an organ downstream (such as muscle). The ultimate objectives of this research is to design functional and physiologically relevant organ-on-chip models, to understand drug metabolism, toxicity and enable in development of effective therapeutic screening methods.

References:

1.         Bale, S.S., et al., Long Term Co-culture Strategies for Primary Hepatocytes and Liver Sinusoidal Endothelial Cells. Tissue engineering. Part C, Methods, 2014.

2.         Bale, S.S., et al., A novel low-volume two-chamber microfabricated platform for evaluating drug metabolism and toxicity. TECHNOLOGY. 0(0): p. 1-8.