Abstract
Human iPS cell (iPSC)-derived cardiomyocytes (CMs) hold promise for drug discovery for heart diseases and cardiac toxicity tests. To utilize human iPSC-derived CMs, the establishment of three-dimensional (3D) heart tissues from iPSC-derived CMs and other heart cells, and a sensitive bioassay system to depict physiological heart function are anticipated. We have developed a heart-on-a-chip microdevice (HMD) as a novel system consisting of dynamic culture-based 3D cardiac microtissues derived from human iPSCs and microelectromechanical system (MEMS)-based microfluidic chips. The HMDs could visualize the kinetics of cardiac microtissue pulsations by monitoring particle displacement, which enabled us to quantify the physiological parameters, including fluidic output, pressure, and force. The HMDs demonstrated a strong correlation between particle displacement and the frequency of external electrical stimulation. The transition patterns were validated by a previously reported versatile video-based system to evaluate contractile function. The patterns are also consistent with oscillations of intracellular calcium ion concentration of CMs, which is a fundamental biological component of CM contraction. The HMDs showed a pharmacological response to isoproterenol, a β-adrenoceptor agonist, that resulted in a strong correlation between beating rate and particle displacement. Thus, we have validated the basic performance of HMDs as a resource for human iPSC-based pharmacological investigations.
Highlights
Heart disease is the greatest cause of death worldwide[1]
We have been investigating biomimetic cardiac tissue sheets as cardiac microtissues derived from human iPS cell (iPSC) that are composed of various cardiovascular cells using temperature-responsive culture dishes as a heart tissue surrogate to recapitulate human heart tissue function, which would serve as an optimal resource for preclinical drug discovery and safety tests[17]
We developed a heart-on-a-chip microdevice (HMD) as a novel bioassay system to evaluate the tissue function of human iPSC-derived cardiac microtissues by integrating two fundamental technologies, microelectromechanical system (MEMS)-based organ-on-a-chip technology and human iPSC technology, and we hypothesized that the HMD recapitulates heart tissue function by validating the ability of the system to respond to electrical stimulation and dose-dependent inotropic drug administration
Summary
Heart disease is the greatest cause of death worldwide[1]. The current standard treatment of heart failure includes administration of β-adrenergic receptor blockers and angiotensin receptor blockers, for which the advantageous effects on the prevention of death and major adverse cardiovascular and cerebrovascular events have been proven by large-cohort clinical studies[2,3]. We should remember that those agents had successfully passed standardized safety tests of those days before clinical use, indicating that more precise detection of cardiac side effects in earlier stages of drug development is indispensable to avoid irremediable damage to drug discovery. Recent studies of drug safety tests using human iPSC-derived cardiomyocytes (CMs) opened a gate to use human cells that show greater fidelity than those used in hERG tests[14,15]. We have been investigating biomimetic cardiac tissue sheets as cardiac microtissues derived from human iPSCs that are composed of various cardiovascular cells using temperature-responsive culture dishes as a heart tissue surrogate to recapitulate human heart tissue function, which would serve as an optimal resource for preclinical drug discovery and safety tests[17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
