In vitro platforms for evaluating liver toxicity

Shyam Sundhar Bale, Lawrence Vernetti, Nina Senutovitch, Rohit Jindal, Manjunath Hegde, Albert Gough, William J. McCarty, Ahmet Bakan, Abhinav Bhushan, Tong Y. Shun, Inna Golberg, Richard DeBiasio, O. Berk Usta, D. Lansing Taylor, Martin L. Yarmush

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

The liver is a heterogeneous organ with many vital functions, including metabolism of pharmaceutical drugs and is highly susceptible to injury from these substances. The etiology of drug-induced liver disease is still debated although generally regarded as a continuum between an activated immune response and hepatocyte metabolic dysfunction, most often resulting from an intermediate reactive metabolite. This debate stems from the fact that current animal and in vitro models provide limited physiologically relevant information, and their shortcomings have resulted in “silent” hepatotoxic drugs being introduced into clinical trials, garnering huge financial losses for drug companies through withdrawals and late stage clinical failures. As we advance our understanding into the molecular processes leading to liver injury, it is increasingly clear that (a) the pathologic lesion is not only due to liver parenchyma but is also due to the interactions between the hepatocytes and the resident liver immune cells, stellate cells, and endothelial cells; and (b) animal models do not reflect the human cell interactions. Therefore, a predictive human, in vitro model must address the interactions between the major human liver cell types and measure key determinants of injury such as the dosage and metabolism of the drug, the stress response, cholestatic effect, and the immune and fibrotic response. In this mini-review, we first discuss the current state of macro-scale in vitro liver culture systems with examples that have been commercialized. We then introduce the paradigm of microfluidic culture systems that aim to mimic the liver with physiologically relevant dimensions, cellular structure, perfusion, and mass transport by taking advantage of micro and nanofabrication technologies. We review the most prominent liver-on-a-chip platforms in terms of their physiological relevance and drug response. We conclude with a commentary on other critical advances such as the deployment of fluorescence-based biosensors to identify relevant toxicity pathways, as well as computational models to create a predictive tool.

Original languageEnglish (US)
Pages (from-to)1180-1191
Number of pages12
JournalExperimental Biology and Medicine
Volume239
Issue number9
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

Keywords

  • Drug-induced liver injury
  • hepatotoxicity
  • high content screening
  • liver on chip
  • predictive modeling

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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  • Cite this

    Bale, S. S., Vernetti, L., Senutovitch, N., Jindal, R., Hegde, M., Gough, A., McCarty, W. J., Bakan, A., Bhushan, A., Shun, T. Y., Golberg, I., DeBiasio, R., Usta, O. B., Taylor, D. L., & Yarmush, M. L. (2014). In vitro platforms for evaluating liver toxicity. Experimental Biology and Medicine, 239(9), 1180-1191. https://doi.org/10.1177/1535370214531872