Although blood vessels may seem like mere plumbing compared to organs like the brain or eye, they are complex and dynamic components of the body, and building vessels from scratch has been a challenge for scientists in the field of tissue engineering. Having the ability to create vessels from patients’ own cells would be a boon for cardiovascular bypass surgery, for restoring circulation to blood-starved limbs or as replacements for failing vascular grafts used in kidney dialysis.
Two recent Yale studies, both published in the February 21 issue of the Proceedings of the National Academy of Sciences, have moved vessel engineering closer to clinical application. In one, researchers created a tiny, water-rich scaffold that can nurture and shape microvascular networks to provide tissues with a new blood supply; in the other, scientists demonstrated that they could tweak a molecule to prolong the life of blood vessel cells from elderly donors without causing those cells to spiral toward the uncontrolled cell growth seen in cancer.
“A microvascular network is fundamentally important for tissue engineering,” says Erin Lavik, Sc.D., assistant professor of biomedical engineering and co-author of one of the studies, but “stability of microvascular networks has been a challenge.”
To create new blood vessels, tissue engineers generally build scaffolds from polymers and seed them with human blood vessel cells. Like trellises that train rosebushes, vessel scaffolds guide cell growth to create a tubular structure that blood can flow through.
Because Lavik’s team wanted to build networks of the tiniest vessels, they devised a “micro-scaffold” from a hydrogel, a gelatin-like material that can be chemically treated to form numerous pores (see photo). As their name implies, hydrogels are mostly water, which makes them highly compatible with the body’s tissues.
In collaboration with Joseph A. Madri, M.D., Ph.D., professor of pathology and of molecular, cellular and developmental biology, Lavik and colleagues seeded the gels with blood vessel cells and implanted them under the skin of mice. After six weeks, using a technique known as intravital fluorescence microscopy, the team observed red blood cells flowing through functional and stable vessel networks that had formed in the pores of the hydrogel implant.
Using more conventional scaffolds, scientists have been able to build larger human blood vessels outside the body from a donor’s own cells, but cells taken from older people—those most in need of new vessels—are less viable than cells from younger people, which results in weaker vessels.
Last year, researchers led by Laura E. Niklason, M.D., Ph.D., associate professor of anesthesiology and biomedical engineering, used gene therapy techniques to deliver telomerase, an enzyme that extends cells’ normal lifespan, to blood vessel cells from older donors.
The technique extended the life of the cells, even those taken from patients as old as 85. In addition, Niklason showed that it was possible to culture new arteries for these older patients in vitro after the cell lifespan was extended.
However, it is well known that telomerase is highly active in cancer cells, which gave Niklason pause about moving the technique toward the clinic. “One of the outstanding questions is, ‘How safe is this?’” she says. “One of the main reasons tumors can grow forever is because they can activate telomerase.”
In the February study, which involved nine mostly elderly patients, Niklason’s team took cells obtained during a coronary bypass procedure and added telomerase. The group was reassured to discover that, in so doing, they had not produced cancerous cells. “Just turning on telomerase by itself is not enough to create cancer,” Niklason says. “It’s necessary, but not sufficient.”
Niklason says much more work is needed, but that techniques like hers may one day enable the making of replacement tissue the way replacement parts are now made for automobiles.
Yale advances in blood vessel engineering don’t end there. Christopher K. Breuer, M.D., assistant professor of surgery and pediatrics, has received a $625,000 grant from the National Heart, Lung and Blood Institute to develop new vessels for patients with serious cardiovascular disease.
In a technique Breuer is pioneering with W. Mark Saltzman, Ph.D., chair and Goizueta Foundation Professor of Chemical and Biomedical Engineering, Breuer is creating more stable and reliable grafts for cardiovascular operations by treating vessel scaffolds with a cocktail of proteins that stimulate cell growth and promote vessel formation.