title: Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction.
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.
authors.affiliation: 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;
authors.forename: Danny
authors.initials: D
authors.lastname: Bavli
authors.affiliation: Branch Bioanalytics and Bioprocesses, Fraunhofer Institute for Cell Therapy and Immunology, Potsdam 14476, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Prill
authors.affiliation: Alexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
authors.forename: Elishai
authors.initials: E
authors.lastname: Ezra
authors.affiliation: Alexander Grass Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
authors.forename: Gahl
authors.initials: G
authors.lastname: Levy
authors.affiliation: 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;
authors.forename: Merav
authors.initials: M
authors.lastname: Cohen
authors.affiliation: Department of in Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels 1090, Belgium;
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vinken
authors.affiliation: Centre for Microsystems Technology, Ghent University, Ghent B-9052, Belgium; Imec, Ghent B-9052, Belgium;
authors.forename: Jan
authors.initials: J
authors.lastname: Vanfleteren
authors.affiliation: Branch Bioanalytics and Bioprocesses, Fraunhofer Institute for Cell Therapy and Immunology, Potsdam 14476, Germany; Federal Institute for Risk Assessment, Berlin 10589, Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: Jaeger
authors.affiliation: 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.
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Nahmias
mesh_terms: D002839:Chromans / Q000009:adverse effects* / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D056656:Lab-On-A-Chip Devices; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects*; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000494:pharmacology; D000077288:Troglitazone
chemical_list: D002839:Chromans; D045162:Thiazolidinediones; D000077288:Troglitazone
keywords: liver tissue engineering; microfluidics; organ-on-a-chip; toxicology