A full-blooded assault on cardiac disease has been constricted by inefficient drug testing. To widen the development pipeline—and quicken the flow of new cardiac drugs—researchers have introduced a new way to test for cardiotoxicity. Instead of using nonhuman animals models or ordinary cell cultures, these researchers say, it may be better to use a cardiac microphysiological system—a heart-on-a-chip.
The heart-on-a-chip consists of a network of pulsating cardiac muscle cells housed in an inch-long silicone device. It has been found to be effective in modeling human heart tissue, and it has demonstrated its viability as a drug-screening tool in tests with cardiovascular medications.
These findings appeared March 9 in the journal Scientific Reports, in an article entitled, “Human iPSC-based Cardiac Microphysiological System for Drug Screening Applications.” As the title indicates, the cells used in the heart-on-a-chip were derived from human induced pluripotent stem cells, the adult stem cells that can be coaxed to become many different types of tissue.
The use of human cells overcomes many of the limitations of existing drug-screening models. For example, nonhuman animal models often fail to predict human reactions to new drugs because of the fundamental differences in biology between species. Also, cell cultures often fail to capture the dynamics of how tissues are exposed to nutrients and drugs.
Exactly how these limitations can be overcome by the heart-on-a-chip was explained by the authors of the Scientific Reports article. For example, Kevin Healy, Ph.D., a professor of bioengineering at the University of California, Berkeley, noted that the heart-on-a-chip can better emulate the ion channels through which heart cells conduct electrical currents.
“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,” said Dr. Healy. “It takes about $5 billion on average to develop a drug, and 60 percent of that figure comes from upfront costs in the research and development phase. Using a well-designed model of a human organ could significantly cut the cost and time of bringing a new drug to market.”
As for mimicking the exchange of nutrients and drugs that takes place between blood flows and human tissue, the heart-on-a-chip is capable of aligning cells in multiple layers and in a single direction, positioned between microfluidic channels that serve as models for blood vessels.
“This system is not a simple cell culture where tissue is being bathed in a static bath of liquid,” explained study lead author Anurag Mathur, Ph.D., a postdoctoral scholar in Healy's lab and a California Institute for Regenerative Medicine fellow. The Healy team’s members added that in the future, their setup could also be used to monitor the removal of metabolic waste products from the cells.
In their article, the investigators emphasized that their heart-on-a-chip was well suited to drug testing applications because it has the following attributes:
- cells with a human genetic background.
- physiologically relevant tissue structure (such as aligned cells).
- computationally predictable perfusion mimicking human vasculature.
- multiple modes of analysis (biological, electrophysiological, and physiological).
The researchers put the system to the test by monitoring the reaction of the heart cells to four well-known cardiovascular drugs: isoproterenol, E-4031, verapamil, and metoprolol. They used changes in the heart tissue's beat rate to gauge the response to the compounds.
“Pharmacological studies using the cardiac microphysiological system,” wrote the authors, “show half maximal inhibitory/effective concentration values that are more consistent with the data on tissue scale references compared to cellular scale studies.”
The baseline beat rate for the heart tissue consistently fell within 55 to 80 beats per minute, a range considered normal for adult humans. They found that the responses after exposure to the drugs were predictable. For example, after half an hour of exposure to isoproterenol, a drug used to treat bradycardia (slow heart rate), the beat rate of the heart tissue increased from 55 to 124 beats per minute.
The researchers noted that their heart-on-a-chip could be adapted to model human genetic diseases or to screen for an individual's reaction to drugs. They are also studying whether the system could be used to model multi-organ interactions. A standard tissue culture plate could potentially feature hundreds of microphysiological cell culture systems.
“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,” said Dr. Healy.
The engineered heart tissue remained viable and functional over multiple weeks. Given that time, it could be used to test various drugs, Dr. Healy added.