BOSTON--July 15, 1997-- Harvard Medical School and Children's Hospital researchers have achieved the first successful repair, in animals, of congenital anomalies by combining the emerging technologies of video-guided fetal surgery and the engineering of a scarce commodity--live replacement tissue.
On July 23, Dario Fauza, a fellow at Harvard Medical School's Center for Minimally Invasive Surgery, will announce to the British Association of Paediatric Surgeons that he has removed tiny bits of bladder from a sheep fetus in utero, grown the tissue in the laboratory while the pregnancy continued, and implanted these spare parts into the newborn lambs. In May, the pediatric surgeon reported similar success with skin at the American Pediatric Surgical Association's annual meeting in Naples, Fla.
"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, where Fauza also holds an appointment.
"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.
The solution surgeons dream of is to have sufficient tissue available to repair a deformity once and for all right after the baby is born. In addition to improving the patient's prognosis, that approach would cut short the time these very ill babies stay in intensive care and reduce the disproportionate amount of resources hospitals spend on them.
Fauza started to work toward this goal by focusing on two tissues, bladder and skin. 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. Moreover, his technique can in principle be applied to any fetal tissue. Fauza is already testing it--also in lambs--on the fetal diaphragm and trachea; and ongoing tissue-engineering efforts involving almost every organ of the body may ultimately be useful for approaches in babies, as well.
Human trials--some headed by Atala--testing engineered skin and urogenital tissue on adult patients are already in place or will begin soon. Fauza's approach, he hopes, may reach that stage for infants within five years. He must show first that the engineered tissues grow and function long past the two postnatal months studied so far. But the major obstacles to human testing lie less in the tissue engineering, he says, than in the surgery.
Fetal surgery is in its infancy. To date, fewer than 100 procedures have been performed on humans, cases in which the fetus would otherwise have died. This technology--which involves making a large opening in the womb to gain access to the fetus-- needs to clear two hurdles before it will become widely applicable: Mothers enter preterm labor after surgery, and the fetus sometimes suffers head bleeds. Minimally invasive surgery reduces, but cannot yet eliminate, the risk of preterm labor. In this technique, 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.
In these first studies Fauza worked with bladder and skin tissues. For each study, he 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 divide much faster than adult cells commonly used to engineer tissues, making 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 beauty of this technique, developed by others during the past ten years, is that the scaffold dissolves harmlessly over time, leaving behind only the fresh tissue.
Studying the performance of the grafts over two months, 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. 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.
With the continuous improvement of prenatal imaging techniques, such as ultrasound and fetal MRI, the need for treatment to catch up with diagnosis will become more pressing in the coming years. Moreover, physicians are gradually recognizing the fetus as a patient as much as a baby or an adult.3I expect fetal surgery and tissue repair to become a routine part of medicine in the future," Fauza adds.
Editors: This topic can easily be turned into a feature about tissue engineering, which originated in Boston and is an area of active preclinical and clinical research at Harvard Medical School. Vacanti, who pioneered tissue engineering together with chemical engineer Robert Langer of MIT, has led the development of many different types of tissues. HMS- affiliated researchers are working on heart valves, major blood vessels, liver, various parts of the urogenital system, and others. New technologies, such as 3-D printing and the use of flow-based bioreactors, are helping the field surmount technical barriers of recent years. Call us for further information and referral to researchers at and beyond Harvard.
A black-and-white print diagram of the surgical and tissue- engineering procedures is available upon request, as is an electronic file of a color diagram. Black-and-white photos of Fauza in the OR are also available.