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Sci Rep. 2015 Mar 9;5:8883. doi: 10.1038/srep08883.

Human iPSC-based cardiac microphysiological system for drug screening applications.

Author information

1
1] Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA [2] Department of Materials Science and Engineering, University of California at Berkeley, Berkeley, California 94720, USA.
2
Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA.
3
1] Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA [2] Department of Medicine, Division of Genomic Medicine, UCSF, San Francisco, California 94143, USA.
4
1] Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA [2] Department of Electrical Engineering and Computer Science, University of California at Berkeley, Berkeley, California 94720, USA.

Abstract

Drug discovery and development are hampered by high failure rates attributed to the reliance on non-human animal models employed during safety and efficacy testing. A fundamental problem in this inefficient process is that non-human animal models cannot adequately represent human biology. Thus, there is an urgent need for high-content in vitro systems that can better predict drug-induced toxicity. Systems that predict cardiotoxicity are of uppermost significance, as approximately one third of safety-based pharmaceutical withdrawals are due to cardiotoxicty. Here, we present a cardiac microphysiological system (MPS) with the attributes required for an ideal in vitro system to predict cardiotoxicity: i) cells with a human genetic background; ii) physiologically relevant tissue structure (e.g. aligned cells); iii) computationally predictable perfusion mimicking human vasculature; and, iv) multiple modes of analysis (e.g. biological, electrophysiological, and physiological). Our MPS is able to keep human induced pluripotent stem cell derived cardiac tissue viable and functional over multiple weeks. Pharmacological studies using the cardiac MPS show half maximal inhibitory/effective concentration values (IC₅₀/EC₅₀) that are more consistent with the data on tissue scale references compared to cellular scale studies. We anticipate the widespread adoption of MPSs for drug screening and disease modeling.

PMID:
25748532
PMCID:
PMC4352848
DOI:
10.1038/srep08883
[Indexed for MEDLINE]
Free PMC Article

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