Progress in Fetal Surgery, Tissue Engineering
By Sean Henahan, Access Excellence
ISTANBUL, Turkey (22 July 1997)- Having achieved double successes
in combined fetal surgery and tissue engineering in animal studies, Harvard
researchers are on course to conduct similar procedures in humans. These
dramatic innovations are expected to facilitate complex reparative surgeries
as well as easing the critical shortages of transplantable tissue.
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
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,
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.
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