Vol. 23, Issue 1: Fall 2015

Biotech: Wearing your Heart on your Chip

Isabel Marchand

From the creation of the self-driven car to the rapid, continuing progression of the Internet, scientists and science-fiction aficionados alike have dreamed of a new era of technological innovations. Fortunately, for both researchers and sci-fi fans alike, dreams of technological advancements in the context of biological systems has now become a reality. Researchers at the University of California, Berkeley recently developed a silicone-based device that accurately and successfully models the human heart. Led by Professor Kevin Healy, this bioengineering research team developed the organ-on-a-chip model in order to advance the efficiency of the drug development industry. By creating an easier mode of testing for toxicity, the time and money invested in this drug-testing aspect of drug development will be drastically minimized. Additionally, these organ chips will reduce, and possibly eliminate, the need for testing these drugs on animals and in vitro human tissue and organ samples.

Compared to purely technological industries, the drug development process is both expensive and inefficient, taking on average a decade and billions of dollars to produce just one federally approved drug. Additionally, current testing methods using animals are enveloped in scientific issues. The various physiological differences between humans and other species often complicate results, and the reliance on these simpler animal models can yield unintentionally inaccurate results that could put lives at risk and waste a decade of research and billions of dollars. Animal testing is also surrounded in bioethical issues.

This experiment was not the first to recreate human physiological functions. The Grosberg Lab, a 2011 research group at Harvard University, used mouse embryonic stem cell-derived cardiomyocytes (CMs) to recreate the structure of cardiac ventricles in 2D form. While they were successful in modeling the cardiac ventricles, this 2D form could not be recreated as a 3D model. Furthering the Grosberg Lab experiment, the Boudou group from the University of Pennsylvania was successful in creating a freestanding 3D tissue model; however, both experiments were limited by their use of animal cells, as opposed to human-derived tissue. In recent years, successful 2D models have been created that used human stem cell-derived CMs; however, there is still a lack of models that successfully recapitulate the three-dimensional physiology of in vivo human structures. Additionally, these models only statically model human physiology, and do not take into consideration nutrient cycling, tissue exposure to drugs, and oxygen transport.

Taking all of these previous experiments into consideration, the Healy Lab at UC Berkeley developed a two-part hypothesis to test if combining genetically accurate human cells with “tissue-like” drug gradients would yield a CM model accurate enough to successfully predict the pharmacological toxicity of various drugs. Researchers in the Healy Lab did so by developing a microphysiological system (MPS) that uses 3D confinement to arrange human stem cell-derived CMs into a 3D microtissue, a system that importantly mimics the flow protection of the endothelial barrier.

To accurately mimic the structure of the human heart, this chip was developed using a three-pronged concept: cardiac fibers, microcirculation, and diffusive transport to the tissue were all prioritized. The system is comprised of a central cell chamber with two adjacent media channels, and various connecting microchannels. The media channels allow for precise delivery of nutrients. In order to create a reproducible cardiac microtissue in the cell chamber, the researchers relied on a previously used method developed by the Lian Group from the University of Wisconsin. Cells were injected into the cell to promote cardiac tissue formation without extracellular or synthetic matrices.

Within twenty four hours, the human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) formed a 3D cardiac tissue that could beat spontaneously without any external stimulation. After seven days, the beating of all cells temporally aligned, and the model was comprised of multiple cell layers. Structure alignment and consistent beating are crucial for a cardiac MPS–without either of these two, the structure would not properly model the human heart, and would therefore be nonfunctional.

Upon developing this system, the researchers assayed the cardiac response with four drugs of known toxicity, ultimately showing that this human stem cell-derived system significantly improved the accuracy of toxicity testing over more involved trials and previous 2D models. The researchers assayed the toxicity of Isoproterenol, E-4031, Verapamil, and Metoprolol. These pharmacological agents were selected because together they represent four important pharmacological classes that have characteristic clinical responses and known toxicity, so the measured toxicity could be compared to known values. Measuring heart beat, the researchers obtained spontaneous and consistent beat rates between 55 and 80 beats per minute (bpm) in the MPS model across all four drug trials. The data obtained from the Isoproterenol administration showed increased beat rate and more accurate beat values compared to the data obtained from tests administered on the questionable 2D models. Additionally, the MPS data was comparable to data obtained from tests administered on slices of human heart tissue. This proves that the MPS model was more consistent with actual human tissue compared to the synthetic models.

The tests conducted using Verapamil were also significant. Verapamil is a calcium antagonist that blocks the calcium ion channels in cardiac tissue. The blocking effects differ based on drug concentration, making testing on animal-cell derived models difficult due to the high reliance on human cell physiology. Testing Verapamil with the animal systems yielded a decrease in beat rate and increase in irregular heartbeat, known as arrhythmia, as well as a complete lack of beating. Clinical observations of Verapamil, however, report very few incidences of arrhythmias. Testing Verapamil on the MPS yielded data that mirrored the clinical observations and larger scale animal testing. These findings show that the MPS system may be more efficient in modeling tests, which can lead to the MPS replacing animal testing and eradicating the unethical methods that may be undertaken with the current methods of animal testing.

Overall, the MPS creates a 3D microtissue that responds to drug testing similar to more mature hiPSC-CMs, a known accurate clinical model of the human heart. Additionally, this MPS is more viable because it uses human cells, which alleviates any inaccuracies that can arise from the discrepancies between animal and human models. These findings are ground-breaking in the realm of drug testing and medicine, with potential to greatly decrease both time and money spent on testing pharmaceuticals. Due to the quicker response of the MPS, the time spent modeling the effects of certain pharmacological agents can be shortened, and time spent on toxicity research can be greatly reduced. The MPS could also decrease money spent on these tests because it would reduce the amount of total material needed to perform these tests from various animals and lab materials to just the MPS chips. Additionally, this change in drug testing can completely eradicate the need for animal testing.

Future directions include modification of the MPS for more personalized drug testing, as a patient could use their own cells to test their own reaction to certain pharmacological agents. MPS also has the potential for development outside of the drug screening and testing world and could be used to assay other biological factors. The possibility of advancing MPS for other organs outside of the heart to test reactions with pharmaceuticals, and perhaps even environmental factors, marks it as a potentially revolutionary system for in vitro testing of biomolecular agents on the human body.

About the Author

Isabel Marchand is currently a second year Molecular Environmental Biology major in the College of Natural Resources and plans to pursue a career in either medicine or environmental health.