Growing spare parts for sick children’s hearts

Creating a living, growing organ from scratch sounds like the stuff of science fiction. But a pair of Yale physician-scientists are making it happen, coaxing cells to form artificial blood vessels that can be used to repair or replace faulty blood vessels in the body. Christopher K. Breuer, M.D., assistant professor of surgery and pediatrics, and Toshiharu Shinoka, M.D., Ph.D., associate professor and director of pediatric cardiovascular surgery at Yale-New Haven Children’s Hospital, have spearheaded this project, and they think their work can one day lead to the building of more complex organs.

“We figure if you start with blood vessels, that’s going to be the first step in making just about anything,” says Breuer. “Plus, there’s an immediate need for vessels in vascular and cardiovascular surgery.”

The blood vessels Breuer and Shinoka have created rely on stem cells harvested from a patient’s own bone marrow, though the team hopes that by understanding how vessels form, they can soon create an “off-the-shelf” version that will not require harvesting cells. Either way, the engineered vessels are not prone to the immunological problems that affect transplanted tissue, such as inflammation or rejection. And they are living organs, an especially important characteristic in pediatric surgery because the vessels can grow as a child grows and can last a lifetime.

Typically, if a child is born with certain defects, such as a heart with two chambers instead of four, doctors first try to mold the child’s own tissue into new vessels that can be used as grafts. “Whenever you use the child’s own tissue, you get very good results,” says Breuer. “But the problem is these children usually require multiple grafts and you never have enough tissue.” The alternative has been to use synthetic Gore-Tex grafts, which often have biocompatibility problems, leading to infections and blood clotting, or biological grafts from animals, which tend to calcify and need replacement as often as every few years.

To tackle these problems, Breuer and his colleagues designed a three-dimensional scaffolding in the tubular shape of a vein. The researchers coat this matrix with stem cells from bone marrow and sew it where needed, in place of a damaged or missing vessel. As blood begins to flow through the tube, the stem cells send out a signal that recruits all the right types of cells from elsewhere in the body to form a blood vessel around the scaffolding. As the vessel forms, the original matrix dissolves.

“The stuff we make the scaffolding out of is also what they make absorbable sutures out of,” explains Breuer. “So we already know how the body reacts to this material, and that it’s safe.”

The resulting vessel, which can also be used to treat ischemic heart disease, or stroke, is almost indistinguishable from any other vessel in the body. It can grow over time and it constricts when treated with certain drugs. Additionally, the researchers showed that the elasticity of the engineered vessels matches that of the body’s own vessels. “That is really important,” says Breuer. “If you have blood flowing and it goes from this really stretchy tube to this really stiff tube, you tend to have problems; the grafts tend to narrow and cause blood clotting.”

Over the past six years, Shinoka has used the process successfully in 47 children in Japan. No complications have arisen, he said, and no patients have needed replacement grafts. “They’re fine,” he said, “and they’ve avoided many medications that patients with traditional grafts need to take to prevent stenosis.”

Shinoka and Breuer expect to hear soon about a U.S. Food and Drug Administration application they’ve filed to conduct clinical trials of their grafts at Yale, but they continue to pursue improvements in their techniques.

Breuer says that his next goal is to figure out what chemical from bone marrow is attracting cells to the scaffolding. He hopes to isolate that chemical and build it into the matrix so that the step of drawing bone marrow from each patient becomes unnecessary. “That would make this even simpler and increase the utility,” he said. “We would have immediate off-the-shelf availability when a patient needed a graft.”

And if he succeeds in that, Breuer and Shinoka plan to build a tissue-engineered heart valve. Over 80,000 heart valves are surgically replaced each year in the United States because they leak or don’t open fully. And within 10 years of valve replacement, most patients need a second surgery. Breuer and Shinoka hope their valves would reduce post-operative problems. “It’s significantly harder than making a blood vessel from a biomechanical standpoint,” Breuer says, “but we’ve done the basic feasibility studies to show that you can do it.”