Apr. 19, 1999 DURHAM, N.C. -- A Duke University Medical Center researcher, using a novel "bioreactor" system that mimics the fetal environment, has used cells taken from adult pigs' arteries to grow blood vessels that look and act like the real thing.
When implanted back into the same animals, the arteries functioned much like native vessels, said Dr. Laura Niklason, who published the results of her team's experiments in the April 16 issue of the journal Science.
While there are many biological and technical hurdles to be overcome before such an approach could be considered for use in humans, such as to treat heart disease, the researchers said this development represents a significant advance in the field of tissue engineering.
"We are very excited that after many years, we have produced a bio-engineered tissue that appears functional in animals," said Niklason, an anesthesiologist and bioengineer at Duke.
The engineered vessels, which were grown in a bioreactor that provided nutrients and pulsed the growing vessels much like a heart would, were as strong as native vessels, could hold a suture without ripping and responded to drugs in much the same manner as native vessels would.
The series of experiments was funded by two grants from the National Institutes of Health and one from the Foundation for Anesthesia Education and Research.
"While we still have much work to accomplish before moving into human studies, these results not only demonstrated the feasibility of culturing autologous arteries, but also that the pulsatile approach was very effective," Niklason said.
To create the arteries, Niklason fashioned a tube from a thin sheet of a biodegradable polymer which, like a sponge, is 97 percent air. Smooth muscle cells were collected from the animal arteries and were impregnated throughout the polymer tube. Once placed within the bioreactor, the tube was bathed with similar nutrients found in native vessels.
"The bioreactor pulsed the nutrient solution through and around the tube, approximating as much as possible the conditions that exist within the developing animal fetus," Niklason said.
After eight to 10 weeks within the bioreactor, the smooth muscle cells proliferated and filled all the spaces within the polymer scaffolding, most of which had dissolved by that time. To complete the artery, Niklason then added endothelial cells, which line the interior of blood vessels, to the inside of the tube. Several days later, the arteries were ready for implantation back into the pigs.
"To the naked eye, the vessels looked exactly like native vessels," Niklason said. "The surgeons who sewed them in told me the way they held a suture was also comparable. Additionally, the arteries also withstood blood pressures the same as native vessels."
To see if arteries grown in the pulsing environment worked better than those grown in a static system, Niklason implanted arteries grown both ways back into the pigs. She followed their performance for four weeks.
"While all the vessels remained open after two weeks, the non-pulsed vessels began to show signs of thrombosis (clotting) by the third week," she said. "The pulsed vessels remained open for the four weeks."
Niklason conducted the bulk of her experiments while she was research affiliate at the Massachusetts Institute of Technology in the lab of Dr. Robert Langer, one of the leading researchers in tissue engineering.
"This is certainly a major advance," Langer said. "Most tissue culture systems are static - Dr. Niklason has taken it one step farther and made a system that acts like a living body. The bioreactor she developed demonstrates that we can begin to grow cells and tissues in a more physiological way outside the body.
"This very innovative approach to tissue engineering will set the stage for future advances," he added. "Dr. Niklason and others are bringing the field to the point where we will be able to solve more complex problems."
Both Langer and Niklason are quick to point out that it is too early to determine if and when bio-engineered blood vessels will become a clinical reality. The major problem facing researchers is that while pig smooth muscle cells grow easily and rapidly outside the body in tissue culture, similar human cells are more difficult to grow, Niklason said.
Also, Niklason pointed out, while the cells used to grow the arteries are from the same animal that ultimately receives the artery, the culture process may change them. Further studies will need to be conducted on how the body will react to these cells, which tend to be more immature than their native counterparts.
The most obvious initial use of bio-engineered vessels would be in peripheral or coronary artery bypass surgeries, where veins are used to carry blood around clogged arteries. Because veins are physiologically different than arteries, they are not ideal candidates for bypass. Also, because of co-existing diseases which effect blood vessels, many heart patients do not possess sufficient veins for bypass procedures.
Joining Niklason and Langer in the study were: Dr. Jinming Gao, Case Western Reserve University, Cleveland; Dr. William Abbott and Dr. Stuart Houser, Massachusetts General Hospital, Boston; Dr. Karen Hirschi, Baylor College of Medicine, Houston; and Dr. Robert Marini, MIT.
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