By Sean Henahan, Access Excellence

Speaking at a conference here, Dario Fauza, a fellow at Harvard Medical School's Center for Minimally Invasive Surgery reported that he has successfully removed bladder tissue from a sheep fetus in utero, grown the tissue in the laboratory while the pregnancy continued, and implanted these engineered tissues into the newborn lambs. Dr. Fauza also recently reported similar success with skin transplants.

"This is the first time someone engineered tissue from a fetus and used that  tissue to treat the newborn," says Fauza, who worked with Anthony Atala, HMS assistant professor of surgery and assistant in urology at Children's Hospital in Boston.

Fauza removed a pea-sized tissue sample from five fetuses, about two-thirds into the ewe's pregnancy. When researchers cultured the cells in Atala's laboratory, they found that they divided much faster than adult cells commonly used to engineer tissues. This makes them highly suitable for this approach. Shortly before the ewes were due, the cells were seeded onto a synthetic, feltlike textile serving as a porous scaffold for tissue assembly. Fauza then implanted these constructs into the newborn lambs, in which he had earlier created defects like those seen in humans. The scaffold dissolved harmlessly over time, leaving behind only the fresh tissue.

Over a  two month period post-operatively, the researchers found that the lab-grown skin healed faster than the control, was stronger, and had a complex architecture resembling normal skin. The engineered bladder  functioned better than the control, especially at keeping internal pressure low. This is important since high bladder pressure can cause urine reflux and kidney damage in children who receive standard surgical repair of these defects, says Atala, who has researched bladder tissue engineering for the past seven years.

"This work is an important conceptual innovation, and the results are really very exciting," comments Joseph Vacanti, HMS professor of surgery and senior associate of surgery at Children's Hospital, where he directs the organ transplantation program as well as the Laboratory for Transplantation and Tissue Engineering. Vacanti was not involved in this study, but has pioneered the broader field of tissue engineering, which aims to fabricate tissues and organs for use in people of all ages.

"For me as a pediatric surgeon, the shortage of suitable tissue is the most  pressing problem in trying to repair defects in babies," says Vacanti. Babies are so small that surgeons cannot borrow skin from elsewhere on the body, as they do with older patients. The dearth of donor organs for transplantation is most acute for infants. And the current, makeshift practice of fixing defects with other tissue types, for example, patching up a bladder with a piece of intestine, can cause the children serious problems later.

Two of the most difficult problems encountered by pediatric surgeons are congenital bladder anomalies and fetal cancers. Fauza designed his research with these problems in mind. Bladder tissue is needed for better repair of anomalies in which the developing bladder fuses with the body wall and opens to the outside. Skin is needed to close wounds after removal of fetal cancers as well as for the repair of defects in which the body wall fails to close, exposing the heart or intestines.

Though each of these malformations is rare, together they pose a significant problem for referral centers, says Fauza. In addition, this technique might be applied to any fetal tissue. Research is already underway in lambs to create tissue from fetal diaphragms and trachea. Moreover, ongoing tissue-engineering efforts involving almost every organ of the body may ultimately prove useful for babies, as well.

Dr. Atala and others have already begun testing engineered skin and urogenital tissue on adult patients. Dr. Fauza expects to see studies conducted in infants within five years. However, first he needs to demonstrate  that the engineered tissues grow and function longer than the two postnatal months studied so far. The major remaining obstacles to human testing have more to do the details of the surgical procedures than with tissue engineering, Fauza notes.

Fetal surgery is still considered experimental. It involves making a large opening in the womb to gain access to the fetus, performing a surgery, then closing the womb again. Several hurdles remain. One problem is that mothers enter preterm labor following fetal surgery, another is that the fetus sometimes suffers head bleeds. Innovative methods of minimally invasive surgery reduce, but cannot yet eliminate, some of the risk of preterm labor. To accomplish this, surgeons insert a camera lens and scissors one-twelfth of an inch wide through tiny incisions in the uterus and operate on the fetus guided by video images projected on a screen. Fewer than 100 fetal surgeries have ever been performed on humans, all cases in which the fetus would otherwise have died.

"I expect fetal surgery and tissue repair to become a routine part of medicine in the future," Fauza adds.

The Harvard research coincides with an announcement by Japanese researchers of  the creation of an artificial womb capable of incubating goat fetuses.The artificial womb is a plastic tank designed to replace oxygen and clean the fetus' blood with a dialysis machine connected to the umbilical cord. The researchers report keeping goat fetuses alive for up to three weeks in the experimental device. The researchers estimate it will be at least ten years before the concept might be tried in humans.

The research was presented July 22, 1997 at the 44th Annual International Congress of the British Association of Paediatric Surgeons in Istanbul, Turkey. The artificial womb research was published in the Journal of the Japan Medical Association.