Editors' ChoiceORGAN ON A CHIP

Heart attack on a plate

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Science Translational Medicine  27 May 2015:
Vol. 7, Issue 289, pp. 289ec88
DOI: 10.1126/scitranslmed.aac5087

Although millions of dollars are spent annually on the drug development process, many drugs still fail because of deadly side effects on the heart. A major reason for these unexpected side effects is that preclinical testing methods used in drug discovery fail to provide sufficient functional data about drug effects on human cardiac tissue, according to Stancescu et al. To address this shortcoming, the team set out to develop a human cell-based system that would enable rapid, high-throughput acquisition of a large amount of data related to cardiac function.

Previous attempts at engineering human cardiac tissue assumed that a three-dimensional structure was critical, limiting the potential for high-throughput applications. In contrast, the team reasoned that the most clinically relevant functions of the heart—electrical conduction and contractile force generation—could be measured from cells cultured in just two dimensions. Human stem cell–derived cardiac cells were patterned onto multielectrode arrays (MEA), allowing the recording of electrophysiological data including rhythm generation and action-potential waves as the cells beat spontaneously or in response to electrical stimulation. The cells also were cultured directly on micro-scale cantilevers, allowing the measurement, via atomic force microscopy, of the tiny forces produced during contraction. To achieve interassay precision, the team developed methods to culture the cells in the absence of animal serum, which is highly variable but typically considered essential for cell survival in the artificial conditions of the lab. Remarkably, the system accurately predicted the effects, at clinically relevant doses, of three drugs that are widely used in patients to treat cardiac dysfunction—norepinephrine, sotalol, and verapamil.

The main advantages of this system include the ability to measure both electrophysiological function and contractile force generation, the use of human cells, the potential for high-throughput screening, and the ability to determine the effects of drugs over several weeks. However, the system still must be validated to determine whether it can predict side effects of drugs that are not typically used to treat cardiac dysfunction, as well as the therapeutic effects of drugs on diseased cardiac tissue. Nonetheless, this system represents an important initial step toward the development of more accurate assays to accelerate the pace of drug discovery.

M. Stancescu et al., A phenotypic in vitro model for the main determinants of human whole heart function. Biomaterials 60, 20–30 (2015). [Abstract]

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