BURSAC LAB/DUKE UNIVERSITY
Every 40 seconds, someone in the United States has a heart attack. Each time, up to a billion heart muscle cells suffocate. Those lost cells never regrow, leaving almost 800,000 people a year impaired for life—if they survive at all. Nenad Bursac believes he can patch some of those people up, literally.
Over the past 20 years, the bioengineer from Duke University in Durham, North Carolina, has been developing a “patch” that could take the place of the cells destroyed by a heart attack. In rodents, he has found it can hook up to the circulatory system and contract. Bursac’s patch is now about the size of a poker chip and the thickness of cardboard—big and complex enough to be tested in large animals, he declared this month at the Experimental Biology 2019 meeting in Orlando, Florida.
Like others attempting to repair damaged hearts, Bursac starts with stem cells, which can develop into specialized tissues such as heart muscle. But whereas some researchers inject hundreds of millions of individual heart muscle cells into the body, Bursac’s team and several other groups grow full-fledged pieces of heart muscle in a dish, which surgeons could attach to a damaged heart. “This could be a transformative approach,” says Ralph Marcucio, a developmental biologist at the University of California, San Francisco, School of Medicine. Bursac’s research effort “is the best in the field,” adds Martine Dunnwald, a cell biologist at the University of Iowa in Iowa City.
At one point, cardiologists thought the heart had a secret stash of stem cells that could be stimulated to repair the organ naturally, but now most biologists agree such cells don’t exist in the heart. An alternative in early clinical trials is to make heart muscle cells in a lab dish from other stem cells, inject them into the artery supplying the heart, and hope they settle in the organ and compensate for any dead tissue.
Bursac is skeptical of that approach, because the percentage of cells that survive injection and make it to the heart is very small. His approach requires open-heart surgery, but it delivers a repair that more closely matches the cell types and architecture of the real organ. “What people are now seeing is you need more structure and more cells,” says Jeffrey Jacot, a bioengineer at the University of Colorado Anschutz Medical Campus in Aurora.
Bursac started to work on heart patches as a Ph.D. student, coaxing neonatal rat cells to transform into heart muscle in a dish and contract—a first for mammals. Other researchers developed tiny heart tissue swatches for testing drugs in lab dishes. But Bursac wants to fix hearts directly. Over the years, his team has learned the best scaffolds for culturing stem cells are made of fibrin, a protein that helps form blood clots, and the best way to nurture these scaffolded cells is to gently rock them inside a suspended frame that allows the growing patch to swish back and forth in liquid media. “These cells mature and become strongly contracting,” Bursac says.
In 2016, when his lab figured out how to produce those powerful contractions, the heart patches were tiny. Then, 2 years ago, the team grew a 4-centimeter-by-4-centimeter patch—potentially big enough to repair a damaged human heart.
“The size is exciting,” says Christopher Chen, a bioengineer at Boston University. It “suggests that you can get to a scale that is clinically relevant.”
Bursac’s team also showed in rodents that blood vessels from the heart being treated can expand into the patch to keep it alive. Bursac has recently woven in more complexity, adding populations of endothelial cells, which develop into blood vessels, and fibroblast cells, which he realized can help the patch form and become stronger. A patch composed of 70% heart muscle cells, with the other two kinds of cells making up the rest, appears best so far, he reported at the meeting.
When the patch is implanted in rats and mice, its capillary network hooks up with the rodent’s circulatory system, he reported. “But we still don’t know if this can provide a survival advantage to the patch.”
Nor is it clear how—or even whether—a patch will become electrically and mechanically integrated with the original heart so they function as a true unit. Because the patch would be stitched to the outside of a damaged heart, over the scar tissue, “it is difficult to have [it] beat coordinately with existing muscle,” points out Katherine Yutzey, a cardiac biologist at Cincinnati Children’s Hospital in Ohio.
Answers may come from tests of these human heart patches in pigs or other large animals, which Bursac is conducting with bioengineer Jianyi Zhang at the University of Alabama in Birmingham. But Michelle Tallquist, a cardiovascular biologist at the University of Hawaii John A. Burns School of Medicine in Honolulu, worries that producing a patch for someone who has just suffered a heart attack could take too long—as much as 6 months if the patient’s own cells were used as the starting point.
Bursac thinks the answer could be to develop a bank of immunologically matched stem cells, which might be coaxed as needed into a heart patch in as few as 3 weeks. For him, the prize is clear. The patch can “replace dead heart cells with cells that are alive and beat and contract,” he explains. “You can see now that this could potentially go to therapy.”
Source: Science Mag