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Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):E2231-40. doi: 10.1073/pnas.1522556113. Epub 2016 Apr 4.

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

Author information

1
Alexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; Department of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
2
Branch Bioanalytics and Bioprocesses, Fraunhofer Institute for Cell Therapy and Immunology, Potsdam 14476, Germany;
3
Alexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
4
Department of in Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels 1090, Belgium;
5
Centre for Microsystems Technology, Ghent University, Ghent B-9052, Belgium; Imec, Ghent B-9052, Belgium;
6
Branch Bioanalytics and Bioprocesses, Fraunhofer Institute for Cell Therapy and Immunology, Potsdam 14476, Germany; Federal Institute for Risk Assessment, Berlin 10589, Germany.
7
Alexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; Department of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel; ynahmias@cs.huji.ac.il.

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.

KEYWORDS:

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

PMID:
27044092
PMCID:
PMC4843487
DOI:
10.1073/pnas.1522556113
[Indexed for MEDLINE]
Free PMC Article

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