Clog-busters

Small, artificial blood vessels are meant to offer hope to cardiac-bypass patients. The problem is that these tiny synthetic vessels tend to clog. Now, biomedical engineer Donald Elbert and his team at Washington University, in St. Louis, have developed a new material designed to trick the body into building vessels from its own cells.

The root of the clogging problem is thermodynamics, Elbert says. When a vessel is made of modified Teflon–or anything besides the body’s own cells–clotting proteins in the blood bump into the vessel walls, stick, unfold, and become active, setting off clotting reactions. The clots are too small to block large vessels, and in fact, Teflon aortas are common. But in vessels narrower than six millimeters across, clots make clogs. Consequently, cardiac-bypass patients can’t receive small artificial-vessel implants. Instead, small vessels have to be harvested from the patient’s body so that blood can be rerouted. This is an extra surgery, and eventually, the patient may run out of vessels to harvest.

Elbert’s solution is a novel coating for the inside of artificial vessels. It’s primarily made of substances found in the human body. Polyethylene glycol, the only synthetic ingredient, is a many-armed polymer used in toothpaste and shampoo. When exposed to blood, it repels nearly all clotting proteins that try to stick to it. Albumin, a blood protein, is included to attach polyethylene glycols together. Polyethylene glycol’s arms link to two biologically active ingredients. One of the ingredients is a protein fragment that acts like Velcro, binding endothelial cells, which line human blood vessels, to the artificial lining. The other bioactive ingredient is an enzyme found in blood that can grab a fatty substance, or lipid, from the bloodstream and convert it into a lipid called sphingosine-1-phosphate that sends growth and survival signals to endothelial cells.

Making the concoction is “simple,” Elbert says. All the ingredients are mixed in water and left overnight. By morning, they form a gel.

Elbert imagines that a synthetic graft lined with the coating could then be sewn into an existing blood vessel. Polyethylene glycol would repel most clotting proteins for some time. Meanwhile, the enzyme would make and release the lipid that signals endothelial cells, encouraging them to grow onto the graft edges. The protein fragments would hold the cells on the surface. The gel would release more lipid, signaling the cells to divide and colonize. “After a month or two, the whole inner surface of the graft would hopefully be lined with a layer of cells,” Elbert says. The cells would exude chemicals to hinder clotting, as they do naturally in the body.

Other researchers are fighting the clotting problem in different ways, Elbert notes. “A lot of people are trying to make blood vessels by tissue engineering,” he says. Tissue engineers remove cells from a patient’s vessels, grow them on a porous tube, and nurture the structure until it’s strong enough to reimplant. Clots don’t clog these vessels because they’re lined with endothelial cells. “That works,” says Elbert. But growing a human blood vessel in a lab is slow and “incredibly expensive.” And the vessels can be fragile–blood flow can rip cells off, causing clotting. Others have tried making synthetic vessels out of clot-resistant materials. These are cheap and sturdy. And they resist clots for some time. But after several years, they can clog. Neither method has fully succeeded in animals.

Unlike other alternatives, Elbert says, vessels lined with his team’s material would be cheap, easy, durable, non-clotting, and non-immunogenic. So far, his gel has passed some initial tests in the laboratory. Endothelial cells migrate quickly on top of the gel. The cells stick to it, even inside a flow chamber, which simulates the shearing force of blood flow.

Elbert adds that his team’s gel may also help the body grow new vessel networks. Chicken-egg membranes treated with it grew new webs of vessels. “One could imagine putting the material next to the heart after a heart attack, allowing the lipid to diffuse into the heart wall and form new vessels that would help the heart survive,” he says.

“It’s way too early to know” how Elbert’s vessels or gel will perform in the human body, cautions Robert Langer, professor of chemical and biological engineering at MIT. Many formulations have looked promising in the lab, only to fail in animals, he says. “The key is animal studies, particularly pigs.”

Safety is also a concern, adds Omolola Eniola-Adefeso, assistant professor of chemical engineering at the University of Michigan. She worries that Elbert’s lipid, which sends many signals in the body, could disrupt normal body processes.

“One has to be extremely careful,” agrees Elbert. Large quantities of the lipid can suppress the immune system and trigger cell death. He plans to determine how much he can deliver to stimulate endothelial cells without overloading. Tests will begin in animals in 2007 and continue for at least four years, he says.

As for the clotting problem, “there are as many engineers working on it as there are bioengineering departments across the country,” says Eniola-Adefeso. So far, she says, Elbert’s “is the most promising approach.”