A new study has developed multispecies liver-on-a-chip models (liver-chips) to address challenges in drug development such as species-specific differences in drug metabolism and toxicity. This technology could lead to better predictions of liver toxicities to determine human risk.
Before moving into human clinical trials, new drug candidates must undergo safety evaluation in animal models, typically rat and dog. However, toxicities in humans are not always correctly predicted with these models, particularly those related to drug-induced liver injury (DILI), or the results from different models might be discordant. This situation leads to drug failures in trials and the clinic, and to substantial costs for drug development, highlighting a need for better predictive alternatives.
One solution is organ-on-chip technology, which recreates the 3D microenvironment and function of organs. In collaboration with pharmaceutical companies, Donald Ingber and colleagues at Emulate led by Geraldine Hamilton, who have previously worked on several organ-on-chip models, aimed to develop rat, dog and human liver-chips to address these challenges.
Microfluidic liver-chips were microengineered to contain species-specific primary hepatocytes and liver sinusoidal endothelial cells, with or without Kupffer cells and/or hepatic stellate cells, and all cultured under physiological fluid flow. After assessing physiological function and relevance of the liver-chips, the investigators explored prediction of species-specific DILI responses. The liver-chips successfully detected DILI phenotypes including hepatocellular injury, steatosis, cholestasis and fibrosis.
“We confirmed that rat, dog, and human liver-chips recapitulated species-specific toxicities that were also observed in previous animal and human studies by our pharma partners,” reports Ingber. “In addition, because we can carry out high-resolution imaging in our chips, we uncovered a potential mechanism of toxicity of one compound that was not previously appreciated,” he says.
“The liver-chips successfully detected DILI phenotypes”
In tests of other experimental compounds, one induced fibrosis in the rat liver-chip but did not alter function of the human liver-chip, demonstrating species-specific differences. “The hope in the future is that if the human liver-chips can be further validated in terms of their mimicry of human hepatotoxicities relative to animal models, this could progressively reduce, and eventually replace, the use of animals in toxicity studies,” concludes Ingber.
Jang, K.-J. et al. Reproducing human and cross-species drug toxicities using a Liver-Chip. Sci. Transl Med. 11, eaax5516 (2019)
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Dickson, I. Multispecies liver-on-a-chip for improved drug toxicity testing. Nat Rev Gastroenterol Hepatol 17, 4 (2020). https://doi.org/10.1038/s41575-019-0244-5
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