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New birth defect treatment studied

Hub scientists test use of fetal cells

Boston researchers are preparing to fix birth defects by using a fetus's own cells to grow replacement parts in the lab. The new parts would then be stitched into place at birth -- or even before.

The scientists, at Children's Hospital Boston, have successfully patched deformed windpipes and diaphragms in lambs, and are awaiting approval by the federal government and the hospital's ethics board to try the procedure in a human with a similar defect.

The experimental method is based on a discovery by lead researcher Dr. Dario Fauza: Fetal cells floating in the amniotic fluid that fills the womb can be coaxed in just a few weeks to grow robustly into bone, muscle, tendon -- almost any type of tissue needed for surgical reconstruction. The cells are stem cells, but not the embryonic type that have raised ethical debate.

When the technique is tried on the first baby, Fauza said, ''it will be the first tissue engineering in humans from fetal or amniotic cells for the treatment of a birth defect -- many firsts."

Tissue engineering, in which a patient's cells are cultivated into needed forms in the lab and then returned to the body, is usually touted as the future source of replacements for the worn-out parts of an aging population. But now, scientists are beginning to use the techniques to help children and babies whose bodies failed to build a part correctly in the first place. Another Children's Hospital team reported last month that it had reconstructed the bladders of seven young patients born with spina bifida through tissue engineering that did not involve fetal cells.

In fetuses and babies, ''when you fix something in them, it lasts a lifetime," said Dr. Michael Harrison, a fetal surgery pioneer at the University of California at San Francisco. ''Not just a few years at the end."

More than 100,000 babies a year are born with major birth defects in the United States, and scientists say some of them -- it is not clear how many -- could someday be helped by the technique, if it works and if it passes ethics reviews.

Such experiments, said Dr. Michael Grodin, professor of medical ethics at Boston University, present serious ethical challenges, from the risks to the mother during fetal surgery to the prospect that, even for babies with windpipe defects who are doomed to die, ''there are things worse than death," such as undergoing pain and then dying anyway.

''The most important thing is that this is research, it's not treatment," he said. ''If we knew it worked, then we wouldn't call it research."

In Fauza's animal research, as the lambs grew in their mothers' wombs, his team removed fetal cells from the amniotic fluid with a needle, isolated the right ones, and placed them in plastic containers. Researchers bathed the cells in nutrients and guided their growth with tiny polymer scaffolds. For diaphragms, they grow an oval patch of tendon cells the size of a closed fist, and for windpipes, they grow cylindrical tubes of cartilage the size of a human little finger.

By the time the lambs were born, the parts were ready to be sewn into place. And because they were made from the lambs' own cells, the lab-grown parts were not rejected by the lambs' immune system and eventually took on the normal shape of a diaphragm or windpipe. The repairs also worked when the patches were implanted while the lamb was still in the womb. Of 18 lambs that received various engineered tissue, 16 survived until the end of the experiment, some into adulthood; all those cases have been published in peer-reviewed scientific journals, Fauza said. The two that died were twins whose mother went into premature labor, he said. Such premature deliveries are the greatest risk of fetal surgery.

Still, because babies born without windpipes die immediately, and there is no current treatment, Fauza hopes that the US Food and Drug Administration will approve the experiment for such a patient relatively quickly. The agency reviews all clinical trials of tissue engineering.

But windpipe defects are rare. Of the 1,600 patients seen at the Advanced Fetal Care Center at Children's in the last five years, only three fetuses have had a fatal windpipe defect, said Luanne Nemes, the clinic's coordinator.

''The key will be whether there is a case that can be helped," said Dr. Scott Adzick, surgeon in chief of Children's Hospital of Philadelphia. ''Not to throw cold water on the whole thing, because it's very intriguing."

Diaphragm defects are much more common -- the center sees about 20 a year -- but not as deadly. The diaphragm separates the chest cavity from the abdomen. In fetuses with a hole, or hernia, in the diaphragm, organs such as the intestines can migrate into the chest, squashing the lungs and preventing them from growing.

The rationale for using tissue-engineered patches for diaphragms, Fauza said, is that it would improve on the current practice of patching diaphragm holes with Teflon.

The trouble with Teflon is that as the babies grow, the patches do not, and several operations may be needed to replace blown patches. A patch engineered from a baby's own cells, in contrast, would be expected to grow along with the baby. In lambs, Fauza said, the patch not only grew but altered its shape, conforming with the lamb's growth. The diaphragm patches would be implanted after a human baby was born, Fauza said, so the babies would face none of the added risk of prematurity that comes with fetal surgery. Major diaphragm defects require patch operations anyway, he said, and the tissue-engineered parts would add no risk because they would come from the baby's own cells.

Obtaining fetal cells from amniotic fluid also would not pose added risks for the mother or fetus in most cases. Because many mothers-to-be have their amniotic fluid drawn from their wombs with a needle anyway, to screen for genetic problems, surplus cells are often there for the taking. The procedure, amniocentesis, is also often performed when a problem is suspected with the fetus.

Fauza's research must pass the hospital's ethical review board before it can move into humans, said Susan Kornetsky, director of Clinical Research Compliance at Children's. The board reviewed the diaphragm plan in 2004, she said in an e-mail, and sent it back for revisions, as is common. It is now awaiting those revisions, which Fauza described as relatively minor. He said he is awaiting FDA approval before submitting the windpipe study and the revised plan for the diaphragm study.

Fauza said he is puzzled that no one before him proposed using fetal cells from amniotic fluid to fix birth defects. He first raised the idea when he was training at Children's in the mid-1990s, inspired by a baby boy born with a normal heart except for one grave problem: It had developed completely outside his body, and his chest was too small to enclose it. Doctors tried to cover it with skin grafts, but they did not work well and the baby died of massive infection.

''I was very frustrated that a boy with a completely normal heart died because we could not close his chest -- a simple thing," Fauza said. ''And I thought, 'My God, if I had tissue ready when he was born -- a piece of cartilage or bone or skin -- we could have closed that.' And I said, 'Why not? We can diagnose the defect in utero, why not just go ahead and get the cells?' What got me started was that tremendous frustration, which is often the case."

Fauza's work focuses on the trachea and the diaphragm because the structures needed to fix them are relatively simple. If all goes well, he said, he can imagine fixing birth defects that affect the intestines, the bladder, and blood vessels in the heart. He is trying to coax the amniotic fluid cells to make the type of neurons that could help fix spinal cord defects in patients with spina bifida.

Figuring out how to grow the tissues for each type of patch took trial and error, Fauza said. For the windpipe, the challenge was to get the stem cells to become cartilage cells. For the diaphragm patch, the key was to find a recipe that would withstand the force that breathing puts on the diaphragm. One more challenge was ensuring a blood supply for the diaphragm patch. The team stretched a piece of the abdomen -- the omentum -- over the patch, solving the problem.

At the Advanced Fetal Care Center at Children's, about 90 percent of the babies with diaphragmatic hernias survive, a rate that Dr. Rusty Jennings, the center's director, calls the best in the world. But there is still a dire need for improvements in treatments, Jennings said, and Fauza's techniques ''would have been nice three weeks ago." ''We have these kids [that] keep coming along," he said. ''We just saw a fetus recently who has quite a severe diaphragmatic hernia, and oh, my God, I don't know if we can save that baby."

Carey Goldberg can be reached at goldberg@globe.com.

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