Human iPSC-based cardiac microphysiological system for drug screening applications
Anurag Mathur1, Peter Loskill1, Kaifeng Shao2
11] 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.
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.
Insights
Developing advanced cardiac microphysiological systems (MPS) using human cells offers a more accurate in vitro model for predicting cardiotoxicity during drug discovery, reducing reliance on animal testing.
Area of Science:
- Biomedical Engineering
- Drug Discovery
- Toxicology
Background:
- High failure rates in drug development are linked to inaccurate safety and efficacy testing in non-human animal models.
- Non-human animal models poorly represent human biology, necessitating improved in vitro systems for predicting drug-induced toxicity.
- Cardiotoxicity is a major cause of pharmaceutical withdrawals, highlighting the need for predictive cardiac safety systems.
Purpose of the Study:
- To present a novel cardiac microphysiological system (MPS) designed for accurate prediction of drug-induced cardiotoxicity.
- To develop an ideal in vitro system that addresses limitations of current drug testing methodologies.
- To improve the reliability of preclinical safety assessments in pharmaceutical development.
Main Methods:
- Development of a cardiac MPS utilizing human induced pluripotent stem cell-derived cardiac tissue.
- Incorporation of physiologically relevant features: human genetic background, aligned cell structure, and computationally modeled perfusion.
- Employment of multi-modal analysis including biological, electrophysiological, and physiological assessments.
Main Results:
- The cardiac MPS maintained human cardiac tissue viability and function for multiple weeks.
- Pharmacological studies yielded IC₅₀/EC₅₀ values more consistent with tissue-scale data compared to cellular-scale studies.
- The system demonstrated enhanced predictive accuracy for cardiotoxicity compared to traditional methods.
Conclusions:
- The developed cardiac MPS represents a significant advancement in in vitro cardiotoxicity prediction.
- This system offers a more human-relevant platform for drug screening and disease modeling.
- Widespread adoption of such microphysiological systems is anticipated to enhance drug safety and reduce development failures.
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