title: On-chip in vitro cell-network pre-clinical cardiac toxicity using spatiotemporal human cardiomyocyte measurement on a chip.
abstract: To overcome the limitations and misjudgments of conventional prediction of arrhythmic cardiotoxicity, we have developed an on-chip in vitro predictive cardiotoxicity assay using cardiomyocytes derived from human stem cells employing a constructive spatiotemporal two step measurement of fluctuation (short-term variability; STV) of cell's repolarization and cell-to-cell conduction time, representing two origins of lethal arrhythmia. Temporal STV of field potential duration (FPD) showed a potential to predict the risks of lethal arrhythmia originated from repolarization dispersion for false negative compounds, which was not correctly predicted by conventional measurements using animal cells, even for non-QT prolonging clinical positive compounds. Spatial STV of conduction time delay also unveiled the proarrhythmic risk of asynchronous propagation in cell networks, whose risk cannot be correctly predicted by single-cell-based measurements, indicating the importance of the spatiotemporal fluctuation viewpoint of in vitro cell networks for precise prediction of lethal arrhythmia reaching clinical assessment such as thorough QT assay.
authors.affiliation: 1] Department of Biomedical Information, Division of Biosystems, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda, Tokyo 101-0062, Japan [2] [3].
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kaneko
authors.affiliation: 1] Department of Biomedical Information, Division of Biosystems, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda, Tokyo 101-0062, Japan [2].
authors.forename: Fumimasa
authors.initials: F
authors.lastname: Nomura
authors.affiliation: 1] Department of Biomedical Information, Division of Biosystems, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda, Tokyo 101-0062, Japan [2].
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Hamada
authors.affiliation: Medicinal Safety Research Laboratories, Kasai R&D Center, Daiichi-Sankyo Co. Ltd., Edogawa, Tokyo 134-8630, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Abe
authors.affiliation: Medicinal Safety Research Laboratories, Kasai R&D Center, Daiichi-Sankyo Co. Ltd., Edogawa, Tokyo 134-8630, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Takamori
authors.affiliation: Medicinal Safety Research Laboratories, Kasai R&D Center, Daiichi-Sankyo Co. Ltd., Edogawa, Tokyo 134-8630, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sakakura
authors.affiliation: Medicinal Safety Research Laboratories, Kasai R&D Center, Daiichi-Sankyo Co. Ltd., Edogawa, Tokyo 134-8630, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takasuna
authors.affiliation: Medicinal Safety Research Laboratories, Kasai R&D Center, Daiichi-Sankyo Co. Ltd., Edogawa, Tokyo 134-8630, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbuissho
authors.affiliation: 1] Division of Biotechnology, IFM, Linköping University, SE- 581 83 Linköping, Sweden [2] Cellectis Stem Cells, Cellartis AB, Arvid Wallgrens Backe 20, SE-413 46 Göteborg, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Hyllner
authors.affiliation: Cellectis Stem Cells, Cellartis AB, Arvid Wallgrens Backe 20, SE-413 46 Göteborg, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Sartipy
authors.affiliation: Department of Biomedical Information, Division of Biosystems, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda, Tokyo 101-0062, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yasuda
mesh_terms: D066126:Cardiotoxicity; D002450:Cell Communication / Q000187:drug effects; D018929:Cell Culture Techniques; D004353:Drug Evaluation, Preclinical; D006801:Humans; D066298:In Vitro Techniques; D056656:Lab-On-A-Chip Devices; D046208:Microchip Analytical Procedures; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism
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