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Research Article

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

Danny Bavli, Sebastian Prill, Elishai Ezra, Gahl Levy, Merav Cohen, Mathieu Vinken, Jan Vanfleteren, Magnus Jaeger, and Yaakov Nahmias
  1. aAlexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
  2. bDepartment of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
  3. cBranch Bioanalytics and Bioprocesses, Fraunhofer Institute for Cell Therapy and Immunology, Potsdam 14476, Germany;
  4. dDepartment of in Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels 1090, Belgium;
  5. eCentre for Microsystems Technology, Ghent University, Ghent B-9052, Belgium;
  6. fImec, Ghent B-9052, Belgium;
  7. gFederal Institute for Risk Assessment, Berlin 10589, Germany

See allHide authors and affiliations

PNAS April 19, 2016 113 (16) E2231-E2240; first published April 4, 2016; https://doi.org/10.1073/pnas.1522556113
Danny Bavli
aAlexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
bDepartment of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
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Sebastian Prill
cBranch Bioanalytics and Bioprocesses, Fraunhofer Institute for Cell Therapy and Immunology, Potsdam 14476, Germany;
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Elishai Ezra
aAlexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
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Gahl Levy
aAlexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
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Merav Cohen
aAlexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
bDepartment of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
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Mathieu Vinken
dDepartment of in Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels 1090, Belgium;
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Jan Vanfleteren
eCentre for Microsystems Technology, Ghent University, Ghent B-9052, Belgium;
fImec, Ghent B-9052, Belgium;
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Magnus Jaeger
cBranch Bioanalytics and Bioprocesses, Fraunhofer Institute for Cell Therapy and Immunology, Potsdam 14476, Germany;
gFederal Institute for Risk Assessment, Berlin 10589, Germany
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Yaakov Nahmias
aAlexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
bDepartment of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
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  • For correspondence: ynahmias@cs.huji.ac.il
  1. Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved March 7, 2016 (received for review November 16, 2015)

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Significance

Microfluidic organ-on-a-chip technology is poised to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Here we demonstrate a sensor-integrated platform permitting real-time tracking of the dynamics of metabolic adaptation to mitochondrial dysfunction. Our approach permits detection of chemical toxicity before any effects on cell or tissue viability can be observed.

Abstract

Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liver-on-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology.

  • microfluidics
  • liver tissue engineering
  • toxicology
  • organ-on-a-chip

Footnotes

  • ↵1D.B. and S.P. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: ynahmias{at}cs.huji.ac.il.
  • Author contributions: Y.N. designed research; D.B., S.P., E.E., G.L., M.C., and Y.N. performed research; J.V. and M.J. contributed new reagents/analytic tools; D.B., S.P., E.E., G.L., M.V., and Y.N. analyzed data; and D.B., S.P., G.L., and Y.N. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1522556113/-/DCSupplemental.

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Tracking dynamics of mitochondrial dysfunction
Danny Bavli, Sebastian Prill, Elishai Ezra, Gahl Levy, Merav Cohen, Mathieu Vinken, Jan Vanfleteren, Magnus Jaeger, Yaakov Nahmias
Proceedings of the National Academy of Sciences Apr 2016, 113 (16) E2231-E2240; DOI: 10.1073/pnas.1522556113

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Tracking dynamics of mitochondrial dysfunction
Danny Bavli, Sebastian Prill, Elishai Ezra, Gahl Levy, Merav Cohen, Mathieu Vinken, Jan Vanfleteren, Magnus Jaeger, Yaakov Nahmias
Proceedings of the National Academy of Sciences Apr 2016, 113 (16) E2231-E2240; DOI: 10.1073/pnas.1522556113
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Proceedings of the National Academy of Sciences: 113 (16)
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