Human iPSC-based cardiac microphysiological system for drug screening applications.
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.
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.
Anurag
A
Mathur
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.
Peter
P
Loskill
Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA.
Kaifeng
K
Shao
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.
Nathaniel
N
Huebsch
Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA.
SoonGweon
S
Hong
Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA.
Sivan G
SG
Marcus
Department of Bioengineering and California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, California 94720, USA.
Natalie
N
Marks
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.
Mohammad
M
Mandegar
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.
Bruce R
BR
Conklin
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.
Luke P
LP
Lee
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.
Kevin E
KE
Healy
D001681:Biological Assay / Q000295:instrumentation; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation*; D004867:Equipment Design; D019544:Equipment Failure Analysis; D017022:Flow Injection Analysis / Q000295:instrumentation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D056656:Lab-On-A-Chip Devices; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D046888:Tissue Array Analysis / Q000295:instrumentation*
D002317:Cardiovascular Agents