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Beagle Bladders and Human Hearts

Even without the technology to build extensive vascular systems, one tissue-engineered organ has made it almost all the way to human trials: the bladder. Anthony Atala, a urologist and director of tissue engineering at Children’s Hospital, Boston, decided to try to build a bladder in part because it seemed like the easiest organ to begin with. In landmark work done in the late 1990s, Atala’s team built new bladders for six beagles. The researchers started by taking a one-centimeter-square biopsy from each dog’s natural bladder, isolating the lining cells and the muscle cells from the biopsy, and culturing each cell type separately.

After a month, Atala’s team had grown enough cells-300 million of each type-to construct an artificial bladder. They used the muscle cells to sheathe the outside of a bladder-shaped polymer scaffold, and the lining cells to cover the inside. The researchers implanted each new bladder into a dog after removing the dog’s own bladder. The researchers discovered that not only did blood vessels from the surrounding tissue grow into the tissue-engineered bladder and keep its tissues healthy, but the dogs also had almost as much bladder capacity as dogs with original equipment.

The early work went so well that Atala and Cambridge, MA-based Curis hope to begin the first tests of the new bladder in humans sometime this year. Still, Atala is realistic about what he’s already accomplished. For one thing, he has not yet answered the question of how long a bioengineered bladder will last. “With the bladder, it’s going to be several years until we know what the long-term results will be,” he explains. “We certainly have a good history with skin. Twenty years down the road we know it’s fine. With cartilage in the knee, we have a four- or five-year history from the time it was first placed in patients.” But with the bladder, Atala says, “We just don’t know.”

In the meanwhile, Atala’s lab has begun to tackle the kidney and has already built small kidneylike units capable of producing urine. Still, given that the kidney is a highly complex structure that includes as many as 20 different types of cells, researchers have to clear many technical hurdles before making full-sized organs for the nearly 48,000 people waiting on kidney transplant lists in the United States alone.

Tissue-engineering a heart will also be a formidable task, but there are a couple of reasons to believe concrete steps in that direction will be made in the not-too-distant future. For one thing, the heart comprises fewer than 10 different cell types. Perhaps even more important, there are two large research consortia targeting the organ. One is the LIFE initiative (for “Living Implants from Engineering”), begun in 1998 and coordinated by the University of Toronto’s Michael Sefton, with the help of a steering committee that includes Massachusetts General Hospital’s Vacanti and MIT’s Langer. The initiative has marshaled 60 academic and government researchers from North America, Europe and Japan to work on the body’s critical pump. Says Sefton, “If we can solve the heart, then the other organs will follow.”

Sefton readily admits that a project as enormous as building the heart is, on the face of it, ridiculous. Still, he believes that by breaking the job down into component tasks-isolating human cardiac muscle cells, say, or building flexible scaffolds to support those cells-a consortium of researchers will be able to make it happen.

That model is also being tested, Sefton says, in a university/industry collaboration led by the University of Washington. Financed by a $10 million grant from the National Institutes of Health and including more than 40 researchers, the University of Washington project has broken its undertaking into a series of goals. The first is to generate a tissue-engineered patch that can be grafted onto a damaged heart. Longer term, the researchers hope to build implantable left ventricles, a goal Sefton sees as a “mini-moonshot” that could be achieved within the decade. But a fully functional bioengineered heart, Sefton says, will likely cost billions of dollars-and neither the LIFE initiative nor the University of Washington’s has raised that kind of money yet.

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