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Liver-Chip: Reproducing Human and Cross-Species Toxicities

Kyung-Jin Jang, Monicah A. Otieno, Janey Ronxhi, Heng-Keang Lim, Lorna Ewart, Konstantia Kodella, Debora Petropolis, Gauri Kulkarni, Jonathan E. Rubins, David Conegliano, Janna Nawroth, Damir Simic, Wing Lam, Monica Singer, Erio Barale, Bhanu Singh, Manisha Sonee, Anthony J. Streeter, Carl Manthey, Barry Jones, Abhishek Srivastava, Linda C. Andersson, Dominic Williams, Hyoungshin Park, Riccardo Barrile, Josiah Sliz, Anna Herland, Suzzette Haney, Katia Karalis, Donald E. Ingber, Geraldine A. Hamilton
doi: https://doi.org/10.1101/631002
Kyung-Jin Jang
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Monicah A. Otieno
2Janssen Pharmaceutical Research and Development, Nonclinical Safety, 1400 Welsh and McKean Road, Spring House, PA 19477, USA
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  • For correspondence: geraldine.hamilton@emulatebio.com MOtieno@its.jnj.com
Janey Ronxhi
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Heng-Keang Lim
3Janssen Pharmaceutical Research and Development, Drug Metabolism & Pharmacokinetics, 1400 Welsh and McKean Road, Spring House, PA 19477, USA
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Lorna Ewart
4Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK
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Konstantia Kodella
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Debora Petropolis
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Gauri Kulkarni
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Jonathan E. Rubins
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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David Conegliano
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Janna Nawroth
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Damir Simic
2Janssen Pharmaceutical Research and Development, Nonclinical Safety, 1400 Welsh and McKean Road, Spring House, PA 19477, USA
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Wing Lam
3Janssen Pharmaceutical Research and Development, Drug Metabolism & Pharmacokinetics, 1400 Welsh and McKean Road, Spring House, PA 19477, USA
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Monica Singer
2Janssen Pharmaceutical Research and Development, Nonclinical Safety, 1400 Welsh and McKean Road, Spring House, PA 19477, USA
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Erio Barale
2Janssen Pharmaceutical Research and Development, Nonclinical Safety, 1400 Welsh and McKean Road, Spring House, PA 19477, USA
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Bhanu Singh
2Janssen Pharmaceutical Research and Development, Nonclinical Safety, 1400 Welsh and McKean Road, Spring House, PA 19477, USA
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Manisha Sonee
2Janssen Pharmaceutical Research and Development, Nonclinical Safety, 1400 Welsh and McKean Road, Spring House, PA 19477, USA
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Anthony J. Streeter
2Janssen Pharmaceutical Research and Development, Nonclinical Safety, 1400 Welsh and McKean Road, Spring House, PA 19477, USA
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Carl Manthey
5Janssen Pharmaceutical Research and Development, IPD Biology, 1400 Welsh and McKean Road, Spring House, PA 19477, USA
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Barry Jones
4Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK
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Abhishek Srivastava
4Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK
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Linda C. Andersson
9Drug Safety and Metabolism, IMED Biotech Unit, Gothenburg, Sweden
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Dominic Williams
4Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge, UK
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Hyoungshin Park
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Riccardo Barrile
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Josiah Sliz
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Anna Herland
6Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA
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Suzzette Haney
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Katia Karalis
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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Donald E. Ingber
6Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA
7Vascular Biology Program and Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
8Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA 02139, USA
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Geraldine A. Hamilton
1Emulate Inc., 27 Drydock Avenue, Boston, MA 02210, USA
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  • For correspondence: geraldine.hamilton@emulatebio.com MOtieno@its.jnj.com
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Abstract

Nonclinical rodent and non-rodent 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 Organ-on-Chip (Organ-Chip) technology to design rat, dog, and human Liver-Chips 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-Chips detected diverse phenotypes of liver toxicity including hepatocellular injury, steatosis, cholestasis, and fibrosis as well as species-specific toxicities when treated with tool compounds. Multi-species Liver-Chips 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.

One Sentence Summary Microengineered Organ-Chip technology has been used to design rat, dog and human Liver-Chips that recapitulate species-specific liver toxicities.

Footnotes

  • Note: Emulate®, Human Emulation System®, S-1™, ER-1™, and ER-2™ are trademarks of Emulate, Inc., and any other trademarks used herein remain with their respective holders. The technology disclosed in this document may be covered by one or more patents or patent applications, and no license to these is granted herein. You are solely responsible for determining whether you have all intellectual property rights that are necessary for your intended use of any of the disclosed materials, and whether you are required to obtain any additional intellectual property rights from a third party. Further information is available by contacting the authors.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 15, 2019.
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Liver-Chip: Reproducing Human and Cross-Species Toxicities
Kyung-Jin Jang, Monicah A. Otieno, Janey Ronxhi, Heng-Keang Lim, Lorna Ewart, Konstantia Kodella, Debora Petropolis, Gauri Kulkarni, Jonathan E. Rubins, David Conegliano, Janna Nawroth, Damir Simic, Wing Lam, Monica Singer, Erio Barale, Bhanu Singh, Manisha Sonee, Anthony J. Streeter, Carl Manthey, Barry Jones, Abhishek Srivastava, Linda C. Andersson, Dominic Williams, Hyoungshin Park, Riccardo Barrile, Josiah Sliz, Anna Herland, Suzzette Haney, Katia Karalis, Donald E. Ingber, Geraldine A. Hamilton
bioRxiv 631002; doi: https://doi.org/10.1101/631002
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Liver-Chip: Reproducing Human and Cross-Species Toxicities
Kyung-Jin Jang, Monicah A. Otieno, Janey Ronxhi, Heng-Keang Lim, Lorna Ewart, Konstantia Kodella, Debora Petropolis, Gauri Kulkarni, Jonathan E. Rubins, David Conegliano, Janna Nawroth, Damir Simic, Wing Lam, Monica Singer, Erio Barale, Bhanu Singh, Manisha Sonee, Anthony J. Streeter, Carl Manthey, Barry Jones, Abhishek Srivastava, Linda C. Andersson, Dominic Williams, Hyoungshin Park, Riccardo Barrile, Josiah Sliz, Anna Herland, Suzzette Haney, Katia Karalis, Donald E. Ingber, Geraldine A. Hamilton
bioRxiv 631002; doi: https://doi.org/10.1101/631002

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