From the AGA Journals

Bioengineered liver models screen drugs and study liver injury

Publish date: March 13, 2018

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Thirty to 50 new drugs are approved in the United States annually, which costs approximately $2.5 billion/drug in drug development costs. Nine out of 10 drugs never make it to market, and of those that do, adverse events affect their longevity. Hepatotoxicity is the most frequent adverse drug reaction, and drug-induced liver injury, which can lead to acute liver failure, occurs in a subset of affected patients. Understanding a drug’s risk of hepatotoxicity before patients start using it can not only save lives but also conceivably reduce the costs incurred by pharmaceutical companies, which are passed on to consumers.

Dr. Rotonya Carr Assistant professor of medicine, division of gastroenterology, University of Pennsylvania

Dr. Rotonya Carr

In Cellular and Molecular Gastroenterology and Hepatology, Underhill and Khetani summarize available and emerging cell-based, high-throughput systems that can be used to predict hepatotoxicity. These modalities include cellular microarrays of single cells; cocultures of liver parenchymal and nonparenchymal cells; organoids (3-D organ-like structures); and liver-on-a-chip devices (complex perfusion bioreactors that allow for modulation of the cellular micro-environment). These in vitro systems have not only enabled investigators to screen multiple drugs at the same time but also have informed the clinical translation of these technologies. For example, the extracorporeal liver assist device – essentially, a liver bypass – and similar bioartificial liver devices can in principal temporarily perform some of the major liver functions while a patient’s native liver heals from drug-induced liver injury or other hepatic injury.

However, just as we have seen with the limitations of the in vitro systems, bioartificial livers are unlikely to be successful unless they integrate the liver’s complex functions of protein synthesis, immune surveillance, energy homeostasis, and nutrient sensing. The future is bright, though, as biomedical scientists and bioengineers continue to push the envelope by advancing both in vitro and bioartificial technologies.

Rotonya Carr, MD, is an assistant professor of medicine in the division of gastroenterology at the University of Pennsylvania, Philadelphia. She receives research support from Intercept Pharmaceuticals.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY


Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

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