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Liver on a chip: engineering a liver sinusoid functional unit
Dissertation   Open access

Liver on a chip: engineering a liver sinusoid functional unit

Young Bok Kang
Doctor of Philosophy (Ph.D.), Drexel University
Sep 2015
DOI:
https://doi.org/10.17918/etd-6669
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Abstract

Liver--Tissue engineering Biomedical Engineering Mechanical Engineering
The liver is the largest internal organ in our body that conducts numerous metabolic activities and detoxification. Currently, liver biology, liver-related disease studies, and drug screening research are facilitated predominantly by in vitro liver-cell culture models. However, primary liver cells cultured on conventional tissue culture platforms do not maintain their viability and functions for more than a week and do not recapitulate the in vivo architecture of the liver. In order to overcome these limitations and develop an authentic and long-term liver model, we applied microfabrication and microfluidics technologies to mimic the architecture and function of a liver sinusoid where most liver activities take place. The liver sinusoid is a blood-carrying microscale channel lined with liver sinusoidal endothelial cells (LSECs). The liver cells (hepatocytes) are located outside the LSECs separated from them by the Space of Disse. Bile is secreted from the hepatocytes and transported to the intestines through bile ducts. In short, the liver sinusoid is a dual channel structure with LSECs and hepatocytes in between them. In order to engineer the liver sinusoid we conducted a stepwise study from a macroscale culture system to a microfluidic culture system and from a rat liver model to a human liver model. First, primary rat hepatocytes (PRHs) were co-cultured with endothelial cells in layers in conventional Transwell plates with the two cell layers cultured on the opposite sides of the porous membrane. Second, the layered co-culture was then transferred to a dual microchannel platform and cultured the cells with a continuous perfusion to simulate the blood sinusoid and bile duct. Finally, primary human liver cells were cultured in the dual microchannel platform realizing human liver on a chip. Morphological and biochemical analyses data support that our liver models maintain the viability and functions of hepatocytes for a long-term. We also demonstrated the utility of our human liver model via HBV replication study. Thus, we believe that our liver on a chip can find numerous applications in liver biology, liver-related disease studies, and drug screening research.

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