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A Biological Replacement for Pacemakers

Scientists have engineered tissue from muscle cells that can transmit electrical signals through the heart.

Approximately 200,000 people in the United States get pacemakers every year – but having a battery-operated machine control the heart is far from optimum, especially for children, because it requires repeat operations.

Engineered tissue provides an electrical connection between the atria (not shown) and ventricles (at left). The implanted cells appear in green alone, while the cardiac cells are in red and green. Such tissue-engineered implants might substitute for pacemakers. (Courtesy of Douglas Cowan, Children’s Hospital Boston.)

According to new findings, muscle cells from a patient’s own tissue could one day be used to treat some heart problems. Scientists at Children’s Hospital Boston have devised a way to grow skeletal muscle cells that, when implanted into the hearts of rats, transmit the heart’s vital electrical signals. The therapy could eventually help people with abnormal heart rhythms.

When the heart beats, electrical pulses are first generated at the top of the heart and propagate through the muscle, causing the upper chambers of the heart to contract. The signal then reaches a small piece of tissue, called the atrioventricular (AV) node, and slows for a split second, allowing the lower chambers, or ventricles, of the heart to fill with blood. The signal is then propagated to the ventricles, allowing them to contract.

Unfortunately, the function of the AV node sometimes goes awry. In patients with a condition known as complete heart block, which can be triggered by one of several factors: heart disease, a developmental defect, or injury during surgery, the AV node is damaged enough that the electrical signal is not transmitted from the upper to lower chambers, and the heart fails to function properly.

Pacemakers implanted into the heart can often fix the problem – they sense the electrical signal in the heart’s upper chamber and then stimulate the lower chamber to contract. But in children, pacemakers have certain drawbacks. The child can quickly outgrow the device and the batteries must be replaced every three to five years, requiring repeat surgeries. “We wanted to try to create a [cellular] electrical bridge for children with AV node problems,” says Douglas Cowen, a cell biologist at Children’s Hospital who led the new study.

“One of the major benefits of a biological alternative to a pacemaker is that it would grow with the child,” says David Lathrop, leader of the arrhythmias research group at the National Heart Lung and Blood Institute, a division of the National Institutes of Health in Bethesda, MD.

Other groups are also developing biological alternatives to pacemakers. But Cowen’s technique may offer advantages because it directly transmits the heart’s own electrical signals, rather than generating a new electrical signal, as a pacemaker does. “The approach Cowen takes more closely resembles the normal conduction pathway of the heart,” says Lathrop. “It’s too early to say which is better at this point.” He adds that both techniques need further development and are years away from clinical testing.

Cowen and team took skeletal muscle cells from rats and transferred them to a specially designed collagen scaffold. When in the scaffold, the cells align themselves into a conduit and express a protein that creates small pores between the cells, allowing them to transmit electrical signals.

When sections of this engineered tissue were transplanted into rat hearts, the new cells integrated into the existing heart tissue, making electrical connections with existing cells. (The rats did not have heart block; Cowen says rat hearts are too small to have pacemakers, which are necessary to keep a rat with heart block alive long enough to transplant the cells.) The researchers used optical imaging of the heart to show that the new cells were electrically active, essentially forming an alternative conduction circuit. The results appear in the July issue of the American Journal of Pathology.

Cowan and team are still working out some kinks in the therapy. They need to design a cell implant that will mimic the brief time delay of the AV node, which is crucial for proper heart functioning. They are now testing out different types of cells, such as stem cells from blood or bone marrow, which could be directed to differentiate into a cell that more closely resembles a heart cell. The scientists initially chose skeletal muscle cells because they’re an easily acquired resource – such cells could be obtained from patients needing a pacemaker by a routine muscle biopsy and don’t need to be cultured under special conditions, as is the case with stem cells.

The researchers are also testing the therapy in larger animals, whose hearts more closely resemble those of humans. They will induce heart block in these animals and implant them with both pacemakers and engineered skeletal tissue to determine if the engineered tissue can take over for the pacemaker.

“The less hardware you put in someone, the better,” says Ivan Vesely, a biomedical engineer who specializes in cardiac tissue engineering at Children’s Hospital Los Angeles. “So if the only problem is a missing conduction pathway, it makes a lot of sense to try to reengineer that pathway, rather than turning the whole heart over to a pacemaker.”

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