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3D Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Cardiac Contractility Modulation Tool: 3D hiPSC-CM CCM Tool

Catalog of Regulatory Science Tools to Help Assess New Medical Devices 


This regulatory science tool presents a laboratory method that includes detailed characterization and protocols for evaluating contractile response in healthy 3D hiPSC-CM models.


Technical Description

The 3D human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) Cardiac Contractility Modulation (CCM) Tool, 3D hiPSC-CM CCM Tool, core elements include the ability to perform in vitro CCM contractility assays, including contraction force and kinetics, in 3D hiPSC models for various known and unknown electrophysiology pulse waveform parameters and combinations. 

Intended Purpose 

The purpose of this RST, 3D hiPSC-CM CCM Tool, is to generate the appropriate 3D in vitro environment to perform CCM contractility studies at the bench and to evaluate various electrophysiology pulse parameters using human tissues. This is important for safety and performance assessment and elucidation of molecular mechanisms of non-excitatory electrical stimulations. Moreover, this RST facilitates early-stage validation, de-risking product development and decision making through a more clinically relevant model. In addition, this RST enables physiological relevant bench testing using commercially available human cells bridging the gap between hiPSCs and medical device testing. This RST builds on the previous 2D hiPSC-CM CCM Tool in a functionally enhanced complex culture system (i.e., 3D human engineered cardiac tissues, ECTs). 

This RST is intended to be used by medical device developers, academia, and contract research organizations (CROs). It enables researchers to evaluate human contractile response in an enhanced co-culture platform comprised of human cardiomyocytes and cardiac fibroblast. This RST provides instantaneous feedback on whether various known and unknown electrophysiology pulse parameters produce a contractile response in a human cardiac tissue model in a nonclinical setting. 

This RST can be extended to various cardiac electrophysiological medical devices that deliver electrical stimulation to human myocardium through electrodes and various patient-specific disease 3D ECT models. Further, the 3D hiPSC-CM CCM tool can only evaluate the acute (i.e., seconds) effects of such stimulation.


Described in below referenced paper 3D hiPSC-CM contractility assay. This publication describes the experimental details for maintenance and culture of 3D hiPSC-CM ECTs. Moreover, the methodology to evaluate contractile properties is described for various electrophysiology pulse parameters. Demonstration of the effects of extracellular calcium challenge are provided to evaluate potential mechanisms. Detailed description of the electrical set up, pulse parameters and representative video are provided.


Device-specific verification, validation and optimization will be required to extend this RST to additional electrophysiological device signals. While the 3D hiPSC-CM CCM Tool testing was performed in a healthy 3D hiPSC-CM model optimization will be required to extend this RST to additional healthy and diseased subject lines. This RST is not developed to replace in vivo animal models or clinical studies.

Supporting Documentation

Full technical description of the tool, test conditions, and experimental data are provided in: 

Relevant Publications:

  • 3D hiPSC-CM contractility assay - Feaster TK, Feric N, Pallotta I, Narkar A, Casciola M, Graziano MP, Aschar-Sobbi R and Blinova K (2022) Acute effects of cardiac contractility modulation stimulation in conventional 2D and 3D human induced pluripotent stem cell-derived cardiomyocyte models. Front. Physiol. 13:1023563. doi: 10.3389/fphys.2022.1023563

Related Work:

  • Feaster, T. K., Casciola, M., Narkar, A., and Blinova, K. (2021). Acute effects of cardiac contractility modulation on human induced pluripotent stem cell-derived cardiomyocytes. Physiol. Rep. 9, e15085. doi:10.14814/phy2.15085
  • Narkar, A., Feaster, T. K., Casciola, M., & Blinova, K. (2022). Human in vitro neurocardiac coculture (ivNCC) assay development for evaluating cardiac contractility modulation. Physiological Reports, 10, e15498. doi:10.14814/phy2.15498
  • Feaster, T. K., Casciola, M., Narkar, A., Blinova, K. (2022). Evaluation of Cardiac Contractility Modulation Therapy in 2D Human Stem Cell-Derived Cardiomyocytes. J. Vis. Exp. (190), e64848, doi:10.3791/64848
  • Blinova, K., Stohlman, J., Krauthamer, V., Knapton, A., Bloomquist, E., and Gray, R. A. (2014). Acute effects of nonexcitatory electrical stimulation during systole in isolated cardiac myocytes and perfused heart. Physiol. Rep. 2, e12106. doi:10.14814/phy2.12106
  • Blinova, K., Dang, Q., Millard, D., Smith, G., Pierson, J., Guo, L., et al. (2018). International multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment. Cell. Rep. 24, 3582–3592. doi:10.1016/j.celrep.2018.08.079
  • Gintant, G., Kaushik, E. P., Feaster, T., Stoelzle-Feix, S., Kanda, Y., Osada, T., et al. (2020). Repolarization studies using human stem cell-derived cardiomyocytes: Validation studies and best practice recommendations. Regul. Toxicol. Pharmacol. 117, 104756. doi:10.1016/j.yrtph.2020.104756


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