Patterned cardiomyocytes on microelectrode arrays as a functional, high information content drug screening platform

Abstract

Cardiac side effects are one of the major causes of drug candidate failures in preclinical drug development or in clinical trials and are responsible for the retraction of several already marketed therapeutics. Thus, the development of a relatively high-throughput, high-information content tool to screen drugs and toxins would be important in the field of cardiac research and drug development. In this study, recordings from commercial multielectrode arrays were combined with surface patterning of cardiac myocyte monolayers to enhance the information content of the method; specifically, to enable the measurement of conduction velocity, refractory period after action potentials and to create a functional reentry model. Two drugs, 1-Heptanol, a gap junction blocker, and Sparfloxacin, a fluoroquinone antibiotic, were tested in this system. 1-Heptanol administration resulted in a marked reduction in conduction velocity, whereas Sparfloxacin caused rapid, irregular and unsynchronized activity, indicating fibrillation. As shown in these experiments, patterning of cardiac myocyte monolayers solved several inherent problems of multielectrode recordings, increased the temporal resolution of conduction velocity measurements, and made the synchronization of external stimulation with action potential propagation possible for refractory period measurements. This method could be further developed as a cardiac side effect screening platform after combination with human cardiomyocytes.

In vitro detection of cardiotoxins or neurotoxins affecting ion channels or pumps using beating cardiomyocytes as alternative for animal testing

“…Amiodarone inhibited neuronal activity in rat cortical neurons [37]. Measuring effects on the beating rate or on the generation of action potentials as additional parameters, using for example multielectrode arrays [38], will most likely result in a more sensitive assay and might even result in an assay able to detect a wider range of neurotoxins. Ultimately, a model capable of detecting an extensive range of marine neurotoxins shall present a large variety of ion channels/pumps as well as neuronal receptors, the principal targets of such toxins.…”

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

“…In some cases, it can be valuable to electrically ‘pace’ CMs so that their beating rate (defined RR‐like interval because it reflects the analogue ECG parameter) is standardized and constant rather than irregular, as often occurs if beating is spontaneous. However, in contrast to isolated cells or neuronal networks, clusters of hPSC‐CMs seeded on MEA cannot efficiently be paced in all available devices, because the hardware is not suitable (Natarajan et al , 2011). Although methods for electrical stimulation have been implemented in some custom‐made MEAs (Kaneko et al , 2012) and impedance‐based systems (Xi et al , 2011), these are not yet widely used.…”

Modeling Life

“…The current microCCA has >10,000 cells per compartment which provides sufficient material for diagnosis, but requires the sacrifice of the unit. On line analysis either optically 18 or electrically 15 allows readout without having to sacrifice the unit and is compatible with measurement of time course.…”

“…Also there are serum-free defined media that will support long-term culture of difficult to culture cell types. 15 Another constraint, but not a strong one with the development of a broad range of analytic devices, is analysis based on relatively few cells. The current microCCA has >10,000 cells per compartment which provides sufficient material for diagnosis, but requires the sacrifice of the unit.…”