Researchers at the University of California at Berkeley have developed the prototype of a better mousetrap for in vitro drug studies that could someday transform the screening of cardiovascular drug candidates. The ultimate goal is to replace the use of animals to screen drug candidates for safety and efficacy, reducing both the time and cost to speed therapies through the development pipeline.
Kevin Healy, professor of bioengineering and materials science and engineering, and colleagues designed a cardiac microphysiological system (MPS) that encompasses key attributes required for an in vitro system to predict cardiotoxicity – a principal stumbling block for in vitro studies, since it's the culprit in approximately one-third of drugs withdrawn from development for safety reasons.
The heart-on-a-chip contains cells with a human genetic background; physiologically relevant tissue structure; and computationally predictable perfusion, mimicking human vasculature. The system also lends itself to biological, electrophysiological and physiological analysis.
The researchers used heart cells derived from human-induced pluripotent stem (iPS) cells, housing the network of pulsating cardiac muscle cells in an inch-long silicone device. The cardiac MPS is designed so that its 3-D structure is comparable to the geometry and spacing of connective tissue fiber in a human heart. When the differentiated human heart cells are added into a loading area, the system's confined geometry helps align the cells in multiple layers and in a single direction.
Within 24 hours after the heart cells were loaded into the chamber, they began beating on their own at a normal physiological rate of 55 to 80 beats per minute.
Microfluidic channels on either side of the cell area serve as models for blood vessels, mimicking the exchange of nutrients and drugs with human tissue via diffusion. The setup could one day allow researchers to monitor the removal of metabolic waste products from the cells, as well.
The project, which was detailed in a paper in Scientific Reports, was funded through the Tissue Chip for Drug Screening Initiative, an interagency collaboration launched by the National Institutes of Health to develop 3-D human tissue chips that model the structure and function of human organs.
Anurag Mathur, a postdoctoral scholar in Healy's lab and a fellow at the California Institute for Regenerative Medicine, said the genesis for the cardiac MPS was the team's desire to create an "intelligent" in vitro system that would overcome the high failure rate associated with the use of "gold standard" animal models for preclinical testing.
"The heart rate of a mouse is in the range of 600 beats per minute," Mathur observed. "For a healthy human being, the heart rate is in the range of 60 to 80 beats per minute." That gulf, he said, is partly responsible for myriad disconnects between preclinical and clinical testing.
Of course, safety studies still are essential before drug candidates can advance to human trials. The research team sought to "take cues from the human body for the organ that we were designing, mimic the minimal structural and functional unit of that organ on the lab scale and see if we got a response that would be relevant to a clinical response," Mathur told BioWorld Today.
The system is not a simple cell culture where tissue is bathed in a static bath of liquid, he added. "We designed this system so that it is dynamic," Mathur said. "It replicates how tissue in our bodies actually gets exposed to nutrients and drugs."
The research team demonstrated proof of concept for the cardiac MPS by monitoring the reaction of the heart cells to the 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.
The baseline beat rate for the heart tissue consistently fell within 55 to 80 beats per minute, a range considered normal for adult humans. Responses after exposure to the drugs were predictable. For example, after 30 minutes of exposure to isoproterenol, a drug used to treat bradycardia, the beat rate of the heart tissue increased from 55 to 124 beats per minute.
The next step is to increase throughput of the system so it can be developed as a high-content tool to screen multiple drugs. The research team also is working on a standardized process for collecting iPS cells to ensure consistent quality. Once those items are in place, the team will seek to partner directly with biopharma companies to test the device in real-world drug development – potentially, in the next six to 12 months.
"We've already demonstrated the power of the technology," Mathur said. "Once the model is in use by a biotech or pharma, it will still need to be adapted to their standard of testing. When you develop a new technology, you have to make sure it's easily integrated into a company's work flow."
Mathur said the researchers are considering both licensing deals with biopharmas and a potential start-up to advance the technology. For example, he suggested pharmas could provide one or more compounds for screening by the cardiac MPS system "to see if there is concordance with their own cardiovascular findings."
Longer term, the cardiac MPS also could be used to model human genetic diseases or to screen for an individual's reaction to one or more particular drugs, according to Mathur. The researchers also envision using the system to model complex multi-organ interactions – for example, assessing whether a drug works in the heart, but is later metabolized by the liver in a way that causes toxicity.