All ETDs from UAB

Advisory Committee Chair

Joel L Berry

Advisory Committee Members

Shannon M Bailey

Andra R Frost

Palaniappan Sethu

Document Type

Thesis

Date of Award

2017

Degree Name by School

Master of Science in Biomedical Engineering (MSBME) School of Engineering

Abstract

Development of almost all novel effective drug compounds is immensely expensive and time consuming. The process is slowed by the ineffectiveness of current toxicity testing methods, with 80% of drugs undergoing late-stage failure in clinical trials or post-market withdrawal. The leading cause of these failures and withdrawals is due to drug-induced liver injury. Much of drug metabolism occurs in the liver, but there are incredible differences among the metabolic pathways in humans, animal models, and two-dimensional testing platforms. Thus, the current methods are limited to accurately predict in vivo metabolic response of a novel compound. Three dimensional (3D) in vitro organ culture has been shown to better model the physical and chemical properties of a specific tissue as compared to two dimensional (2D) monolayer culture models. Primary hepatocytes, a particularly polar cell type, have proven to better maintain their phenotype when cultured in three dimensions rather than on a tissue culture plate. Thus, cellular and tissue response to metabolic changes varies between 2D cellular monolayers and 3D organ models. Maintenance of the extracellular matrix provides chemical and physical signals to the cells and provides improvement upon the current in vitro and animal testing methods used. A novel 3D bioreactor was designed and tested with immortalized human hepatocellular carcinoma (HepG2) cells. Cells were embedded in a collagen/Matrigel extracellular matrix (ECM) and polymerized around flow channels. Media was perfused to the sample via these microchannels through a closed flow loop system. Cells were maintained for 7 days in culture. This approach is designed as a complement to current pre-clinical testing methods.

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