Bioengineer Kit Parker wants to build replacement hearts for children born with heart defects. Although that goal remains a long way off, Parker recently took a step in that direction by assembling a 1:250 scale model of the human left ventricle. The ventricle’s neatly aligned, human cells beat in time and respond to damage and a drug the way a real heart does, according to findings recently published in Nature Biomedical Engineering. For now, these mini-hearts could help test drug effects on heart muscle, and could help determine the best treatment plan for patients with irregular heartbeats (arrhythmia).
The adult heart contains layers of muscle. In each layer, the cells are lined up like bricks in a wall, so they all contract in the same direction. Multiple layers, with different cellular alignments, work together as the heart pumps. To create a single layer with this alignment in the lab, Parker and colleagues at the Wyss Institute for Biologically Inspired Engineering at Harvard University, in Boston, started with a fibrous framework. They mixed gelatin and a biodegradable polyester, spun it into nano-scale threads on a round, rotating bristle brush, and deposited it onto a bullet-shaped mold.
This procedure left plenty of space for cells to fill in between the threads. The bioengineers seeded the framework with heart muscle cells derived from human induced pluripotent stem cells. “If you organize the cells properly, they will build themselves into a muscular pump,” says Parker. Indeed, within just a few days, the cells had lined up along the fibers and started beating, about 85 times per minute. The ventricles lasted in the lab for months.
With these models, Parker and colleagues could perform many of the same experiments that heart researchers conduct with animal hearts, such as measuring how much pressure and volume the ventricles could handle. Each ventricle held about half a milliliter. The force it generated, and amount of liquid it spewed, were somewhere between 100,000 and 1 million times smaller than that of a real human heart. Its function was comparable to an early embryonic human heart, Parker says.
More importantly for the study of heart function in the lab, the tiny ventricle responded to treatments much like a human heart would. The researchers exposed the mini-hearts to isoproterenol, a drug used to treat slow heart rate. Sure enough, the ventricles in their dishes beat faster. When the bioengineers poked holes in the ventricles to simulate a heart attack, the tissues created arrhythmia just as in real hearts.
To align the cells in a lab model is “an important step forward,” says Joseph Wu, director of the Stanford Cardiovascular Institute in California. That alignment is closely involved in maintaining the correct heart rhythm. “If you want to study cardiac arrhythmia, this is perfect.”
Kevin Costa, director of cardiovascular cell and tissue engineering at the Icahn School of Medicine at Mount Sinai in New York, notes that randomly-aligned cells, as in models Costa has built, may turn out to be better for studying the mechanical contraction of the muscle. That’s because they contract in all directions, like an adult heart with many layers.
But Costa lauds the Parker group’s model for its potential to study cardiac rhythms, suggesting it’s likely to be superior to many animal models of heart function. Researchers can use these models to understand how hearts with human cells respond to treatments, even test new heart drugs, says Costa. They can also check whether novel medications might cause side effects in the heart.
Parker notes that drugs for arrhythmias can be toxic, but patient responses to the medications vary, so it’s hard for doctors to pick the right treatment. He suggests hospitals could order mini-ventricles, made from a patient’s own stem cells, and test therapeutics there before putting the patient at risk. Next, he wants to add better control of heart rate to his model.