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Patch Shows Promise as Novel Method for In Utero Myelomeningocele Repair

A patch made from cryopreserved human umbilical cord may prove to be a novel method for treating myelomeningocele in utero, according to researchers at McGovern Medical School at UTHealth.

The findings were published in July 2016 in Obstetrics & Gynecology,1 the journal of the American Congress of Obstetricians and Gynecologists. Made of the donated outer layer of the umbilical cord of healthy newborns, the patch was used for repairs performed at Children’s Memorial Hermann Hospital.

“The umbilical cord contains a specific natural material called heavy chain hyaluronic acid/pentraxin3, which has regenerative properties,” says lead author Ramesha Papanna, M.D., M.P.H., an assistant professor in the department of Obstetrics, Gynecology and Reproductive Sciences at McGovern Medical School and maternal-fetal medicine specialist at The Fetal Center at Children’s Memorial Hermann Hospital. “It allows the local tissue to grow in at the repair site instead of healing by scar formation, which occurs with traditional repair methods. This decrease in scar formation may help improve the spinal cord function further and reduce the need for future surgeries to remove the effects of the scar tissue on the spinal cord.”

Spina Bifida memorial hermannAccording to the National Institute of Neurological Disorders and Stroke, myelomeningocele – characterized by the incomplete development of the coverings of the brain, spinal cord or meninges – is the most common neural tube defect in the United States, affecting 1,500 to 2,000 of the more than 4 million babies born each year. The defect can result in paralysis, urinary or bowel dysfunction, and mental retardation.

In 2011, a landmark clinical trial – the Management of Myelomeningocele Study (MOMS) sponsored by the National Institutes of Health – found that if a fetus underwent in utero surgery to close the defect, the serious complications associated with spina bifida could be lessened or even reversed. In cases where the defect was too large to close with the fetus’ existing skin, a patch was necessary.

But in some cases, scar tissue may cause adherence of the patch to the underlying spinal cord, which could result in a loss of neurologic function as the child ages. Further surgery is often needed to remove the scar tissue.

“The use of this patch for fetal repair heralds a new era for fetal spina bifida repair,” says Kenneth Moise, M.D., coauthor, professor and co-director of The Fetal Center at Children’s Memorial Hermann Hospital and McGovern Medical School. “For the first time, a bioscaffold has been successfully employed to allow the fetus to heal itself.

The implications for the future of a minimally invasive approach to fetal spina bifida repair and even neonatal spina bifida repair are enormous.”

“WITHIN TWO WEEKS, THE SKIN HAD HEALED OVER THE PATCH SPONTANEOUSLY. THE CHILD HAD NORMAL MOVEMENTS OF THE LOWER EXTREMITIES AND BLADDER CONTROL FUNCTION, AND THERE WAS A COMPLETE REVERSAL OF THE CHIARI II MALFORMATION.”

Dr. Stephen Fletcher

In the first case study, the skin lesion in the fetus measured 5 centimeters by 6 centimeters and there was evidence of Chiari II malformation, a complication of spina bifida in which the brain stem and the cerebellum protrude into the spinal canal or neck area. Chiari II can lead to problems with feeding, swallowing or breathing control.

At 24 weeks gestation, the patient underwent fetal surgery performed by Stephen Fletcher, D.O., co-author, associate professor in McGovern Medical School’s Department of Pediatric Surgery and a pediatric neurosurgeon affiliated with Memorial Hermann Mischer Neuroscience Institute and Children’s Memorial Hermann Hospital, and KuoJen Tsao, M.D., associate professor and The Children’s Fund Distinguished Professor in Pediatric Surgery and codirector of The Fetal Center. Dr. Moise and Dr. Papanna also participated in the surgery.

“The lesion was closed with skin edges sutured to the human umbilical cord patch in a watertight fashion, and the mother was discharged on postoperative day 5,” Dr. Fletcher says. “The baby was born at 37.5 weeks and the patch was intact with no leakage of fluid. At the site of the lesion it appeared semi-translucent with incomplete regeneration of the skin, but within two weeks, the skin had healed over the patch spontaneously. The child had normal movements of the lower extremities and bladder control function, and there was a complete reversal of the Chiari II malformation.”

A Second Case

In the second case, performed by the same team, the patient’s fetus had a lesion of 4 centimeters by 5 centimeters and Chiari II malformation. The expectant mother underwent surgery at 25 weeks gestation, and the procedure and application of the patch were similar to the first case. The baby was delivered at 37.5 weeks with complete covering of the lesion with the patch but without skin grown into the patch. As with the first case, the skin grew over the patch and by day 30 was completely healed. There was normal motor and urinary function and the Chiari II malformation was completely reversed.

Both cases were approved by the U.S. Food and Drug Administration under Expanded Access use, by the Fetal Therapy Board of The Fetal Center at Children’s Memorial Hermann Hospital and by the UTHealth Institutional Review Board prior to the surgery. The clinical cases were the culmination of seven years of research after Dr. Papanna and co-author Lovepreet K. Mann, M.B.B.S., an instructor in McGovern Medical School’s Department of

The lesion was closed with skin edges sutured to the human umbilical cord patch in a watertight fashion. The skin grew over the patch and by day 30 was completely healed. 

Obstetrics, Gynecology and Reproductive Sciences, began brainstorming ideas about possible patch materials. Their research led them to their co-author Scheffer C.G. Tseng, M.D., Ph.D., of Ocular Surface Center and TissueTech, Inc., in Miami, Fla., who was using human amniotic membrane and umbilical cord – donated by mothers of healthy infants – to repair corneas. The patch is approved by the FDA for corneal repair.

“This patch acts as a scaffold, which is watertight and allows native tissue to regenerate in an organized manner, and also has anti-scarring, anti-inflammatory properties,” Mann says. “Preventing the scarring could prevent tethering, which can in turn prevent further damage to the cord.”

The patch was first tested in animal models by a team of researchers that included Dr. Papanna, Dr. Fletcher, Dr. Mann, Dr. Moise and Saul Snowise, M.D., a maternal-fetal fellow who has since joined McGovern Medical School as an assistant professor in the department of Obstetrics, Gynecology and Reproductive Sciences.

First in Texas

In 2011, after the national MOMS trial for fetal surgery was ended early because of positive results, physicians at McGovern Medical School and The Fetal Center were the first in Texas to perform the newly approved surgery. Since then, the team has performed more than 40 fetal surgeries to treat spina bifida.

Dr. Mann said the team was taken aback at first by the lack of skin covering the patch at the birth of the first infant, but she could see the child’s legs moving and recognized it was an early success that they hope will continue as the baby grows. “If we can make a small change and improve the quality of life for the child, that will mean we really accomplished something.”

The team has since completed two additional surgeries using the patch, and Dr. Fletcher has used the new patch in surgeries to untether the spinal cord of children who had previous spina bifida surgery. Discussions are ongoing with the FDA for an IDE application to allow for a clinical trial based on the pilot results from the first four patients. 

Currently, the team members are working on finding ways to make the skin heal inside the uterus and different ways to deploy the patch over the defect site through less-invasive means. “We’ve made progress at an incredibly rapid pace,” Dr. Papanna says. “Taking an idea from the lab to human use typically takes about a decade. We’ve been able to reduce that time to two and a half years. We have a good system in place with strong collaborators, all of whom have a track record of success in their fields.”

Research collaborators from other institutions and disciplines across the country include Sanjay Prabhu, M.B.B.S., assistant professor of pediatric neuroradiology at Harvard Medical School; Raymond Grill, Ph.D., associate professor of neurobiology and anatomical sciences at the University of Mississippi; and Russell Stewart, Ph.D., professor of biomedical engineering at the University of Utah.

“Children’s Memorial Hermann Hospital is about patients. If they’re not here, we’re not here,” Dr. Papanna says.

“There’s still plenty of work to do. What we’ve done to date in showing real benefit to children is just the tip of the iceberg. We want all babies who undergo the fetal surgery to be able to walk at age 3. Right now, the percentage is less than half. Our goal is to take it to 100 percent.”

1. Papanna R, Fletcher S, Moise KJ Jr, Mann LK, Tseng SC. Cryopreserved Human Umbilical Cord for In Utero Myeloschisis Repair. Obstet Gynecol. 2016 Aug;128(2):325-30.