First Bladders Grown in Lab Transplanted
Tuesday, April 4, 2006
Researchers said yesterday that they have grown complete urinary bladders in a laboratory and transplanted them into patients, improving their health and achieving a Holy Grail of medicine: the first cultivation of working replacements for failing solid organs in people.
The "neo-bladders," each one grown in a small laboratory container from a pinch of a patient's own cells, have been working in seven young patients for an average of almost four years, according to a report released yesterday by the British journal the Lancet. The organs have remained free of the many complications that bedevil the conventional practice of surgically constructing bladders from other tissues.
If ongoing studies continue apace, the researchers said, they hope someday to offer patients more than a dozen other homegrown organs, including blood-vessel complexes, partial kidneys and perhaps hearts.
"It was really uncharted territory in terms of how you do these things," said Anthony Atala of Wake Forest University School of Medicine in Winston-Salem, N.C., who led the work with Alan Retik at Children's Hospital and Harvard Medical School in Boston. "We're very pleased with how well they're functioning."
Experts applauded the work as a coming of age for the long-struggling field of tissue engineering and as a possible way to bypass some of the controversy over embryonic stem cells.
Those versatile cells stir political trouble because obtaining them requires the destruction of human embryos. Although embryonic cells remain the most versatile biological building blocks, it now appears that at least some tissues, and even whole organs, can be generated without using the cells at all.
Because the replacement bladders were made from patients' own cells, they did not stimulate an immune-system reaction.
"This approach allows us to avoid completely the risks of rejection and the need for immuno-suppression," said Steven Nichtberger, chief executive of Tengion Inc. in King of Prussia, Pa., which was not involved in the work described in the Lancet but was formed in 2003 to market the technology. "This brings the promise of regenerative medicine to life."
The new study involved seven children and young adults, age 4 to 19, with spina bifida, a serious birth defect of the spinal cord. Because of misconnections in the nerves to the bladder, many such patients experience urinary pressure, which causes life-threatening kidney damage.
For decades, surgeons have crafted various bladder stand-ins, often using intestinal tissue. But complications are common, including leakage, infections, stones in the bladder and bone loss -- in part because the transplanted intestinal tissue absorbs rather than excretes various waste compounds.
Colon cancers have also recently begun to emerge in some patients with intestinal-tissue bladders, a worrisome trend that has invigorated the search for alternatives.
"This has been the dream we've all had, to come up with a tissue-engineered bladder," said Tony Khoury, chief of pediatric urology at the Hospital for Sick Children in Toronto.
The bladder is a living sac made of three tissue layers: muscle on the outside, a specialized "urothelium" lining on the inside and collagen, a connective tissue protein, in between. Atala likened the process of growing a new bladder to "baking a layered cake."
The team started by taking biopsy specimens about half the size of a postage stamp from each patient's malfunctioning bladder. After teasing apart the cells in that bit of tissue and discarding the collagen, the researchers grew the muscle and urothelium cells in separate dishes for about a week.
They then seeded those cells onto spongelike biodegradable "scaffolds" made of synthetic polymer and collagen. Each scaffold was custom-designed to fit inside the patient.
Over about seven weeks in an incubator, the cells colonized the scaffold -- urothelium inside and muscle out. Surgeons then stitched the bladders into place just above the patients' old ones. There the organs continued to grow and reconfigure themselves.
"The body is the terminal incubator," said Atala, who is now a compensated Tengion board member.
The Lancet paper documents the results in each patient, showing that the outcomes improved as techniques evolved. A key advance, which began with the fourth patient, was a decision to wrap the new bladder in omentum, a kind of tissue in the body that is rich in blood vessels and so provides key nutrients and oxygen.
Despite the improvement in their conditions, the patients are not living normal lives. Because of their severe nerve abnormalities, they cannot control the muscles that regulate urine flow and so still must use catheters several times a day to empty their new bladders.
But important measures improved overall, including total urine capacity, elasticity and the bladder's ability to keep internal pressure low. Perhaps most important for quality of life, the patients now leak urine far less frequently, in some cases remaining dry for seven hours at a stretch.
"It's a huge step," Khoury said. "It shows us that it is doable."
The technique's promise for more common conditions has not been proved, several experts said. No one knows whether biopsied bladder cells from older adults -- patients losing the organ to cancer, for example -- would regenerate as nicely on laboratory-made scaffolds. It is also not clear whether doctors would want to implant new bladders made from cancer patients' cells, which might harbor tumor-promoting genetic glitches.
Getting nerves to grow into new organs also remains a challenge, though one that may be coming within reach.
"Reinnervation is certainly something to keep an eye on," said Robert Langer, a tissue engineer at the Massachusetts Institute of Technology who pioneered some of the techniques that led to the new work. He is developing new polymers that can conduct electricity -- nerve impulses, for example -- spiked with neural hormones to lure nearby nerves to connect to freshly implanted organs.