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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.00934

Considerations for an in vitro, cell-based testing platform for detection of drug-induced inotropic effects in early drug development. Part 2: Designing and fabricating microsystems for assaying cardiac contractility with physiological relevance using human iPSC-cardiomyocytes

 Alexandre Ribeiro1*,  Brian Guth2, Michael Engwall3,  Sandy Eldridge4,  C. M. Foley5, Liang Guo6,  Gary Gintant5, John Koerner1,  Stanley T. Parish7, Jennifer Pierson7,  Mathew Brock8, 9,  Khuram Chaudhary10,  Yasunari Kanda11 and Brian Berridge12
  • 1United States Food and Drug Administration, United States
  • 2North-West University, South Africa
  • 3Amgen (United States), United States
  • 4National Institutes of Health (NIH), United States
  • 5AbbVie (United States), United States
  • 6Leidos Biomedical Research, Inc., United States
  • 7Health and Environmental Sciences Institute (HESI), United States
  • 8Genentech, Inc., United States
  • 9MyoKardia, Inc., United States
  • 10GlaxoSmithKline (United States), United States
  • 11National Institute of Health Sciences (NIHS), Japan
  • 12National Institute of Environmental Health Sciences (NIEHS), United States

Contractility of the myocardium engines the pumping function of the heart and is enabled by the collective contractile activity of its muscle cells: cardiomyocytes. The effects of drugs on the contractility of human cardiomyocytes in vitro can provide mechanistic insight that can support the prediction of clinical cardiac drug effects early in drug development. Cardiomyocytes differentiated from human induced pluripotent stem cells have high potential for overcoming the current limitations of contractility assays because they attach easily to extracellular materials and last long in culture, while having human- and patient-specific properties. Under these conditions, contractility measurements can be non-destructive and minimally-invasive, which allow assaying sub-chronic effects of drugs. For this purpose, the function of cardiomyocytes in vitro must reflect physiological settings, which is not observed in cultured cardiomyocytes derived from induced pluripotent stem cells because of the fetal-like properties of their contractile machinery. Primary cardiomyocytes or tissues of human origin fully represent physiological cellular properties, but are not easily available, do not last long in culture and do not attach easily to force sensors or mechanical actuators. Microengineered cellular systems with a more mature contractile function have been developed in the last 5 years to overcome this limitation of stem cell derived cardiomyocytes, while simultaneously measuring contractile endpoints with integrated force sensors/actuators and image-based techniques. Known effects of engineered microenvironments on the maturity of cardiomyocyte contractility have also been discovered in the development of these systems. Based on these discoveries, here we review design criteria of microengineered platforms of cardiomyocytes derived from pluripotent stem cells for measuring contractility with higher physiological relevance. These criteria involve the use of electromechanical, chemical and morphological cues, co-culture of different cell types and three-dimensional cellular microenvironments. We further discuss the use and the current challenges for developing and improving these novel technologies for predicting clinical effects of drugs based on contractility measurements with cardiomyocytes differentiated form induced pluripotent stem cells. Future research should establish contexts of use in drug development for novel contractility assays with stem cell derived cardiomyocytes.

Keywords: microenvironment, Cellular alignment, sarcomere, co-culture, Electrical Stimulation

Received: 15 Mar 2019; Accepted: 22 Jul 2019.

Copyright: © 2019 Ribeiro, Guth, Engwall, Eldridge, Foley, Guo, Gintant, Koerner, Parish, Pierson, Brock, Chaudhary, Kanda and Berridge. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Alexandre Ribeiro, United States Food and Drug Administration, Silver Spring, United States,