Engineered cardiac tissue needs a steady supply of oxygen and nutrients to survive after being grafted onto the heart. In an effort to tackle this problem, researchers from Ben-Gurion University of the Negev, Tel-Aviv University, and Soroka University Medical Center in Israel have developed a method that uses the body as a bioreactor to build working blood vessels in a bioengineered cardiac patch. The results, published this week in the Proceedings of the National Academy of Sciences, represent a crucial step toward generating a bioengineered material capable of repairing damaged heart tissue.
Several labs around the world have been working on ways to engineer living heart tissue by seeding a three-dimensional scaffold with heart muscle cells or with stem cells that can be coaxed into forming these cardiac myocytes. “What they haven’t generally focused on is strategies to create the infrastructure to support these myocytes,” says Frederick Schoen, professor of health sciences and technology at Harvard Medical School and the Brigham and Women’s Hospital. That infrastructure includes blood vessels that bring oxygen to the immigrant myocytes as they try to integrate into the existing heart tissue. Without that vascular support, most of the implanted cells will die.
“In a healthy heart, every single myocyte is flanked by two capillaries,” says Gordana Vunjak-Novakovic, professor of biomedical engineering at Columbia University. In implants without blood vessels, only the outermost cells can grab oxygen. As a result, these patches “look like an M&M candy,” Vunjak-Novakovic says. “Healthy cells on the outside, dead cells on the inside.”
To encourage vascularization in engineered cardiac patches, the Israeli researchers infused a myocyte-seeded scaffold with growth factors that promote cell survival and the growth of new blood vessels. They then implanted each cardiac patch into a living rat’s omentum, the blood-vessel-rich membrane that connects and supports the abdominal organs. Within a week, the patches were populated with mature blood vessels. The researchers then excised the vascularized patches and transplanted them onto the hearts of rats with myocardial infarctions. One month later, the patches appeared not only to survive, but to be well integrated with the animals’ cardiac tissue. The patches improved the rats’ cardiac activity, the myocytes formed muscle fibers that were able to contract, and the researchers could see red blood cells inside the blood vessels, “which means they, too, were fully functional,” says Smadar Cohen, professor of biotechnology engineering at Ben-Gurion University and senior author of the study.
Vunjak-Novakovic is enthusiastic about the research. “They’ve made nature work for them,” she says. “And they’ve demonstrated that vascular supply makes all the difference for the functionality of engineered heart tissue.”
In some ways, the blood vessels might be more important than the myocytes. “That’s the elephant in the room that we don’t tend to talk about,” says Harvard’s Schoen. “Nobody knows if the myocytes are necessary. Perhaps if you can inject something that revascularizes the damaged area of the heart, that might be all you need.”
Indeed, in Cohen’s study, rats that received a vascularized patch without myocytes also showed improvement in their cardiac function. These myocyte-free patches also integrated into the local tissue and thickened the scar that’s left after an infarction. That strengthening alone may relieve some of the stretching of the damaged heart muscle wall and thus improve contractility, Cohen says.
With or without myocytes, the approach is not yet ready for the clinic. “It’s a significant research advance that demonstrates an approach to growing vasculature in an engineered tissue,” Schoen says. “But we’re not significantly closer to making engineered heart muscle patches for patients who have heart disease.” For one, the strategy requires two rounds of surgery: one to implant the patch in the abdomen and a second to move it to the heart. And Cohen points out that patients with coronary disease are generally in no condition to tolerate that sort of invasive treatment.
But the model could help scientists better understand the molecular mechanisms that drive vascularization–and that could allow the growth of a ready-made patch with blood vessels in place prior to implantation. Better still, Cohen says, would be a material that could induce regeneration in the heart itself–something she and her colleagues are working on. “I think all these approaches should be technically possible,” says Cohen. “We just need to do more good science to find the best one.”