Better Blood Vessels

New artificial blood vessels could help a wider range of patients.

Researchers have developed artificial blood vessels that are derived from human cells but appear to have long shelf lives and are unlikely to provoke an immune response. Such vessels could someday prove valuable to patients undergoing heart-bypass operations, dialysis, or other procedures in which portions of blood vessels, or vascular grafts, may be needed.

Substitute blood vessels: Researchers have created artificial vessels (top) that are derived from human cells but appear to have long shelf lives. To create these vessels, the researchers use donor cells to produce a collagen matrix, then remove the cells. The cross section (bottom) shows the vessel material after cell removal and storage.

In a typical bypass operation, surgeons take veins from a patient’s leg and use them to reroute blood around blocked arteries. But suitable veins can be hard to find, especially in patients who have had previous bypass surgeries or are obese or diabetic. “I’ve spent a lot of time in the OR watching surgeons dig around in a patient’s leg and try to find suitable vessels,” says Laura Niklason, the lead researcher on the new technology and an anesthesiologist and biomedical engineer at Yale University. In heart-bypass surgery, typically “it’s the leg incision, more than the chest incision, that causes patients problems.”

Now, Niklason and her team have developed a potential alternative in which donor cells are used to create a collagen matrix but are then removed, so the final product is acellular.

“It’s an incredibly important and creative approach,” says Robert Langer, a renowned engineer and Institute Professor at MIT. “She’s taking advantage of some of the things cells can do” while ending up with an acellular material. (Niklason was a fellow in Langer’s lab from 1995 to 1998.)

Niklason developed the new vessels under the auspices of a company called Humacyte, which she founded in 2004. She and her team took cells from a tissue bank and placed them on biodegradable scaffolds, which had been shaped into tubes of different diameters. The cells laid down collagen matrices as they grew. After roughly eight weeks, the team washed the cells away, leaving behind tubes made of acellular material. In theory, if the grafts are implanted in humans, they should be repopulated by the patients’ own endothelial cells, which would reduce the likelihood of clots. But it is not yet clear how the grafts will behave in humans.

This material is likely to be compatible with the body and with blood because it is derived from human cells. But it will probably not provoke an immune response because it is acellular. It is also likely to last much longer on the shelf than a cellular product would.

So far, Niklason has created and studied the properties of these vessel substitutes using cells from dogs, pigs, and humans. But she has only implanted them in animals. “She still has to prove this in a human,” says Robert Nerem, director of the Parker H. Petit Institute for Bioengineering and Bioscience at the Georgia Institute of Technology. “Having said that, I consider what she’s doing to be very exciting.”

Synthetic materials like Teflon and Dacron have also been used in bypass operations, but they’re only helpful for large vessels like the aorta. They do not work for narrower vessels like the coronary arteries because at smaller diameters they readily cause blood clots.

Niklason’s grafts would be less likely to form clots because they would “recreate the environment that the blood normally sees,” says Langer.

Another experimental approach is to grow blood vessels on demand using individual patients’ own cells as the starting material. Researchers at Cytograft, based in California, proved that they could create vascular grafts with this strategy, and they have used it successfully to treat a small number of dialysis patients outside the United States, according to data published in October in the New England Journal of Medicine. (Dialysis patients are often given vascular grafts to facilitate blood flow to the dialysis machine during the procedure.)

These vessels from Cytograft promise very high compatibility with a patient’s body since they are made from his or her own cells. But they currently take between six and nine months to grow and may turn out to be prohibitively expensive and difficult to apply in less specialized settings. “To reach the wide patient population that is in need, we can’t simply talk about doing this in major academic medical centers,” Nerem says. “It has to be out there in community hospitals, in the whole health-care system. And for that to happen, these products will need to be available off the shelf.”

If successful, Niklason’s product would offer a more efficient, less expensive alternative to growing vessels from scratch for individual patients, says Langer. (Cytograft says that it is also pursuing an approach that would use donor cells to create an off-the-shelf product.)

So far, Niklason and her team have mainly tested their approach in dogs. Using canine smooth muscle cells, they created a dog version of the grafts and implanted them in nine surgical procedures: two coronary grafts, three arterial patches, and four carotid-bypass grafts. In one of the dogs, a clot formed, and the graft was removed after roughly a week. In the other dogs, the new vessels did not cause complications and appeared to remain viable for up to a year, according to data presented this week at a meeting of the American Heart Association.

Niklason says that her team has also created vascular grafts from human cells and implanted them into several baboons, although that work is not yet public.

Going forward, she and her team will need to test the human-derived vessels in larger animals for longer periods of time. The goal is to win FDA approval and begin further tests in humans, perhaps within the next two years, Niklason says.

Another major challenge would be to scale up the manufacturing processes so that the grafts can be produced more efficiently in greater quantities.

“We’ll just have to see how this plays out,” says Nerem. Niklason and her team “still have a lot of work to do.”

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