Lab-Grown Bladders Successful in Humans
In a major advance toward the development of artificial organs, bladders grown from patients’ own cells in the laboratory have been successfully implanted in seven children with spina bifida and shown to function for five years or longer, researchers reported today.
The achievement, reported online in the international medical journal the Lancet, marks the first time that artificial organs more complicated than skin and bone have been implanted in humans. It brings much closer the day when scientists may be able to grow new organs for people who have lost them to disease or injury.
Clinical trials of the bladder-building process could begin later this year. The team that invented it is using the same method to grow blood vessels, kidneys, livers and other organs -- some of which have already been implanted in animals.
“This work marks a new age in regenerative medicine,” said Dr. Len Horovitz of Lenox Hill Hospital in New York City, who was not involved in the research.
“This is the first tissue engineering product that has withstood the test of time,” added Dr. Gordon McLorie, chief of urology at Children’s Hospital of Michigan, who also was not involved. He and his colleagues “have been waiting to see what the long-term outcome will be ... and are eager to use it when it becomes available,” he said.
The bladder is a much simpler organ than a liver or a kidney, but the success of the artificial tissues in humans suggests that it may be possible to grow more complicated organs and reduce the backlog of patients waiting for replacements.
An estimated 54,200 Americans develop bladder cancer each year and treatment often entails removal of the bladder. Many others lose their bladders as a result of congenital defects, infectious diseases, injuries, diabetes and heavy metal poisoning.
Surgeons now replace the bladder by building a fluid reservoir using tissue from the bowel, but that produces many problems, including reabsorption of toxins, formation of stones and kidney damage due to pressure buildup in the reservoir.
Dr. Anthony Atala and his colleagues at the Wake Forest University School of Medicine in North Carolina have been working to overcome this problem by growing bladder cells in the laboratory.
They begin by biopsying a small piece of bladder, about half the size of a postage stamp. The tissue has three layers: muscle on the outside, a collagen supporting layer in the center and specialized urothelial cells on the inside to hold the urine.
The team isolates the muscle and urothelial cells and grows them in the lab for about 30 days. The cells involved are not stem cells, but more specialized progenitor cells, which in this case have the capacity to grow only into other bladder cells.
Meanwhile, using CT imaging of the patient to determine the size of the bladder, they construct a scaffolding of a biodegradable polymer. The muscle and urothelial cells are then seeded onto the exterior and interior of the scaffold, respectively, and the entire construct grown in an incubator for two to three weeks.
A team of surgeons then removes scarred and diseased tissue from the patient’s own bladder and uses the artificial tissue to rebuild the organ. As the final step, they wrap the rebuilt organ in omentum, a membrane from the interior of the abdomen rich in blood vessels that supplies nutrients and oxygen to the tissue until it can grow its own vessels.
Keeping the cells alive until they can establish their own blood supply has been the major impediment in past attempts to produce bladders. The omentum seems to have overcome this difficulty, said Dr. Tony Khoury of the Hospital for Sick Children in Toronto.
The study’s patients all had spina bifida, a birth defect that leads to incomplete closure of the spine. Their bladder tissue is hard, causing high pressures to build up and be transmitted to the kidney, where they cause kidney damage. They also have urinary leakage.
Atala’s team transplanted their synthetic bladders in nine children from 4 to 19 years old. Two of the patients dropped out of the study and could not be followed.
In each of the seven patients studied, however, the tissue functioned successfully, ballooning as a real bladder does up to 10 times the normal size as it filled, without increasing pressure. The bladders also stopped leakage.
“It is rewarding when you see the improved quality of life in these patients,” Atala said.
The patients were studied for an average of 4.6 years before the team published its report.
“We have to make sure the vessels last a long time,” Atala said. “We’ve already shown that in animals, and now we have shown it in humans.”
The technology was developed by Atala when he was at Children’s Hospital Boston. That institution holds a patent on the process. The patent was licensed in 2003 to Tengion Inc. of King of Prussia, Penn., which was formed to develop the technology.
Gary Sender, Tengion’s chief financial officer, said the company had raised $39 million for the project and would apply to the Food and Drug Administration this summer to begin formal clinical trials.
Atala, meanwhile, is working on constructing 20 other organs in the laboratory. He has already produced functioning kidneys that have been implanted in cows, where they successfully produce urine.
The next product, he said, will probably be artificial blood vessels.
