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‘Heart-on-a-chip’ and potential for new drug testing.
A new ‘heart-on-a-chip’ system may provide a highly effective in vitro model for screening of cardiovascular medications and for testing cardiotoxicity of other pharmaceuticals, according to a new study in the journal Scientific Reports. The cardiac microphysiological system (MPS) was developed by a research team led by bioengineering professor Kevin Healy of the University of California at Berkeley.

Currently, new drug development relies heavily on animal models and animal-derived cell lines. This makes the process inefficient and expensive, as inter-species differences in key biological pathways and pharmacokinetic properties mean that animal models cannot completely mimic human physiology. Ion channels, for example, are key for conducting cardiac electrical currents and can vary widely in type and number between humans and animals. Prof Healy explained: "Many cardiovascular drugs target those channels, so these differences often result in inefficient and costly experiments that do not provide accurate answers about the toxicity of a drug in humans." These types of differences lead to issues including inaccurate prediction of human cardiotoxicity of new drugs. As a result, about one third of pharmaceuticals withdrawals due to safety concerns are related to cardiotoxicity. On average, a new drug takes 10-15 years and approximately $5 billion to produce, with many of the costs being incurred in the preclinical and clinical development. The current study aimed to address the gap in availability of reliable in vitro systems based on a human genetic background for prediction of cardiac effects of drugs.

In the current study, the research team used human induced pluripotent stem cells to derive human cardiac tissue. Differentiated human heart cells were added to the loading area of the cardiac MPS structure, which was designed to be comparable to the geometry and spacing of connective tissue fibres in a human heart. Microfluidic channels were used as models for blood vessels, to mimic nutrient and drug exchange by diffusion. The confined geometry of the system allowed cells to be aligned in multiple layers and in a single direction, making it physiologically relevant. Lead author Anurag Mathur, a postdoctoral scholar in Prof Healy's lab explained: "This system is not a simple cell culture where tissue is being bathed in a static bath of liquid. We designed this system so that it is dynamic; it replicates how tissue in our bodies actually gets exposed to nutrients and drugs."

Within 24 hours of loading the heart cells, they began beating independently at a normal physiological rate of 55 to 80 beats per minute. In order to test the responsiveness of their system, the research team used four well-characterised cardiovascular drugs, namely isoproterenol, E-4031, verapamil and metoprolol and measured changes in the heart tissue's beat rate. Beat rate changes were predictable and consistent with data on tissue scale references as opposed to cellular scale studies.

The study authors noted, for example, that the system could be adapted for modelling of human genetic diseases or for individual drug screening. They are also interested in the system’s potential for study of multi-organ interactions. They envisage accommodating hundreds of microphysiological cell culture systems on a single standard tissue culture plate. Prof Healy explained: "Linking heart and liver tissue would allow us to determine whether a drug that initially works fine in the heart might later be metabolized by the liver in a way that would be toxic." The viability and functionality of the engineered heart tissue over many weeks adds to the system’s versatility and suggest that the system could be used for assessing various drugs. In conclusion, the authors of the study: “anticipate the widespread adoption of MPSs for drug screening and disease modelling.”

Reference: Mathur A. et al. (2015).  Human iPSC-based Cardiac Microphysiological System for Drug Screening Applications. Scientific Reports  5, Article number: 8883. doi:10.1038/srep08883

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