Advisory Committee Chair
Joel L Berry
Advisory Committee Members
Andrew D Penman
Andra R Frost
Shannon Bailey
Joanne Murphy-Ullrich
Document Type
Thesis
Date of Award
2015
Degree Name by School
Master of Biomedical Engineering (MBE) School of Engineering
Abstract
Drug development is an expensive and time consuming process, requiring an average of over $1 billion and up to fifteen years of work for each newly released product. Drug-induced liver toxicity is the leading cause of post-market drug withdrawals despite the fact that extensive animal testing and clinical trials are required prior to approval of a novel drug or therapy. Due to both the specificity and genetic variability of hepatic regulation and metabolism in humans, animal models and single-cell hepatocyte testing cannot fully predict the metabolic response of a novel compound. In vitro organ culture in a three dimensional (3D) microenvironment has been shown to better model physical and chemical properties of a particular tissue, compared to standard single cell-type, monolayer culture models. In addition, cellular and tissue response to metabolic challenges, particularly drug sensitivity, vary between 3D organ models and two dimensional (2D) cellular monolayers. Studies have been performed on hepatocyte culture but the complex and numerous functions of the liver may require the presence of other hepatic cell types including sinusoidal endothelial cells, stellate cells, Kupffer cells and the extracellular matrix environment to accurately reproduce a physiologic response. An improvement over current methods would be to culture fragments of liver tissue in which these cells are present. A novel 3D bioreactor design was developed and tested with primary rat liver fragments and immortalized HepG2 hepatocarcinoma cells. Tissue was embedded in a collagen/Matrigel hydrogel, polymerized around flow channels. The construct was perfused in a closed loop system in which perfusate was regularly sampled. Viable HepG2 cells were maintained for 17 days in culture and demonstrated albumin production and CYP3A4 metabolism. The approach is complementary to existing 2D cell culture, pre-clinical animal models, and existing microfluidic devices.
Recommended Citation
Miller, Lindsay Mckinney, "A Three Dimensional Microphysiologic Liver Model For Toxicity Testing" (2015). All ETDs from UAB. 2473.
https://digitalcommons.library.uab.edu/etd-collection/2473