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Sci Transl Med. 2019 Nov 6;11(517). pii: eaax5516. doi: 10.1126/scitranslmed.aax5516.

Reproducing human and cross-species drug toxicities using a Liver-Chip.

Author information

1
Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA.
2
Janssen Pharmaceutical Research and Development, Nonclinical Safety, 1400 Welsh and McKean Road, Spring House, PA 19477, USA. geraldine.hamilton@emulatebio.com motieno@its.jnj.com.
3
Janssen Pharmaceutical Research and Development, Drug Metabolism and Pharmacokinetics, 1400 Welsh and McKean Road, Spring House, PA 19477, USA.
4
Clinical Pharmacology and Safety Sciences Department, Biopharmaceuticals Science Unit, AstraZeneca, Cambridge, CB4 0WG, UK.
5
Janssen Pharmaceutical Research and Development, Nonclinical Safety, 1400 Welsh and McKean Road, Spring House, PA 19477, USA.
6
Janssen Pharmaceutical Research and Development, IPD Biology, 1400 Welsh and McKean Road, Spring House, PA 19477, USA.
7
Clinical Pharmacology and Safety Sciences Department, Biopharmaceuticals Science Unit, AstraZeneca, Gothenburg SE-431 83, Sweden.
8
Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.
9
Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
10
Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA 02139, USA.
11
Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA. geraldine.hamilton@emulatebio.com motieno@its.jnj.com.

Abstract

Nonclinical rodent and nonrodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans, contributing to drug failures in the clinic. Here, we applied microengineered Organs-on-Chips technology to design a rat, dog, and human Liver-Chip containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chip detected diverse phenotypes of liver toxicity, including hepatocellular injury, steatosis, cholestasis, and fibrosis, and species-specific toxicities when treated with tool compounds. A multispecies Liver-Chip may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.

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