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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.

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Summary

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.

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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.