An adult-fetal skin interface heals without scar formation in sheep

K M Sullivan  1 , M Meuli, T E MacGillivray, N S Adzick

Fetal skin heals by regeneration rather than by adult-type scarring. Prior studies indicate that scarless healing is an intrinsic property of fetal tissue.

Journal: Surgery (Volume 118, Issue 1, Pages 82-86)

Date: 01/07/1995

1 Fetal Treatment Center, University of California, San Francisco 94143-0570, USA.

Creation of myelomeningocele in utero: a model of functional damage from spinal cord exposure in fetal sheep

Martin Meuli a, b, c, d, e Claudia Meuli-Simmen a, b, c, d, e Charles D Yingling a, b, c, d, e Grover M Hutchins a, b, c, d, e Kathleen McBiles Hoffman a, b, c, d, e Michael R Harrison a, b, c, d, e N. Scott Adzick a, b, c, d, e


A recent study in human fetuses with myelomeningocele (MMC) suggested that the primary malformation is not neural but a failed closure of the posterior vertebral column and paraspinal soft tissue, which leads to exposure and secondary destruction of the spinal cord. The goal of this study was to test whether chronic exposure of the normal spinal cord to the amniotic space produces a lesion similar to human MMC. In fetal sheep at 75 days' gestation (group A) and 60 days' gestation (group B) (term = 150 days), the lumbar spinal cord was exposed to the amniotic cavity by excising skin and paraspinal soft tissues, and by performing a laminectomy. Some animals from both groups were fetectomized and assessed morphologically at 100 days' gestation. The remainder were delivered near term and assessed clinically, electrophysiologically, and morphologically. In group A, all animals showed MMC-type pathology. The exposed spinal cord was herniated out of the spinal canal and rested on the dorsal membranes of a cystic sac. The neural tissue was stretched and flattened out. Histologically, the hallmarks of the spinal cord were not discernable and the cytoarchitecture was lost. These changes were less severe at 100 days than at term. The three survivors in group A were paraplegic. In group B, the two survivors and two fetuses harvested at 100 days had healed skin wounds and near normal spinal cord histology. The other animal harvested at 100 days had a MMC-type lesion with less severe histological changes. The two survivors had a mild paraparesis. In conclusion, surgical exposure of the normal spinal cord to the amniotic space in a 75-day sheep fetus results in a MMC-type pathology at birth, which clinically and morphologically resembles human MMC. The creation of a spina bifida-type lesion in a 60-day-old fetus may result in spontaneous healing and minimal neurological deficit at birth. This “healing experiment of nature” suggests that in utero repair of MMC might prevent spinal cord damage and spare neurological function.

Journal: Journal of Pediatric Surgery (Volume 30, Issue 7, Pages 1028-1033)

Date: 01/07/1995

a Fetal Treatment Center, University of California San Francisco, CA, USA

b the Department of Anesthesia, University of California San Francisco, CA, USA

c the Animal Care Facility, University of California, San Francisco, CA, USA

d Microsurgical Laboratory, Davies Medical Center, San Francisco, CA, USA

e the Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

In utero surgery rescues neurological function at birth in sheep with spina bifida

M Meuli  1 , C Meuli-Simmen, G M Hutchins, C D Yingling, K M Hoffman, M R Harrison, N S Adzick

We hypothesize that the neurologic deficit associated with open spina bifida is not directly caused by the primary defect but rather is due to chronic mechanical and chemical trauma since the unprotected neural tissue is exposed to the intrauterine environment. We report here that exposure of the normal spinal cord to the amniotic cavity in midgestational sheep fetuses leads to a human-like open spina bifida with paraplegia at birth, indicating that the exposed neural tissue is progressively destroyed during pregnancy. When open spina bifida was repaired in utero at an intermediate stage, the animals had near-normal neurologic function. The spinal cord was deformed but largely preserved. These findings suggest that secondary neural tissue destruction during pregnancy is primarily responsible for the functional loss and that timely in utero repair of open spina bifida might rescue neurologic function.

Journal: Nature Medicine 1, 342-347 (1995)

Date: 01/04/1995

1 Fetal Treatment Center, University of California, San Francisco 94143-0570, USA.

Scar formation in the fetal alimentary tract

M Meuli  1 , H P Lorenz, M H Hedrick, K M Sullivan, M R Harrison, N S Adzick

The aim of this study was to determine whether the fetal alimentary tract shares the unique scarless healing properties of fetal skin. Full-thickness incisional gastric wounds were created and sutured closed in fetal lambs at 60, 75, and 120 days' gestation (full term, 145 days), and in adult control sheep. At the time of harvest, 14 days postwounding, dense fibrous adhesions were found intraperitoneally in all fetal and adult animals. Histologically, all fetal and adult gastric wounds healed with pronounced scar formation. In contrast to the adult wound, there was no significant inflammatory response in the fetal wounds. Because scar formed in the absence of inflammation in fetal gastric wounds, there is no obvious relation between scarring and the inflammatory response at this location. This study shows that not all fetal tissues exhibit scarless repair properties.

Journal: Journal of Pediatric Surgery (Volume 30, Issue 3, Pages 392-395)

Date: 01/03/1995

1 Fetal Treatment Center, University of California, San Francisco 94143, USA.

A model of scarless human fetal wound repair is deficient in transforming growth factor beta

K M Sullivan  1 , H P Lorenz, M Meuli, R Y Lin, N S Adzick

Human fetal skin heals via scarless regeneration, whereas adult skin heals with scar. Scarless repair may reflect a distinct cytokine milieu. We studied the role of the cytokine transforming growth factor beta (TGFβ) using an established model of scarless human fetal skin repair in which human fetal skin is transplanted into a subcutaneous pocket on the flank of an adult nude mouse. In this model, wounded 16-week-gestation human fetal skin heals without scar, whereas wounded adult skin heals with scar. Seven days after transplantation, incisional wounds were made in the skin grafts. In the first phase of the study, wounds were harvested from 1 hour to 4 weeks postwounding, and immunohistochemistry was performed for TGFβ (isoform nonspecific), TGFβ1, and TGFβ2. Scarfree wounds in the fetal skin grafts did not show TGFβ staining. In contrast, wounds in adult grafts that heal with scar demonstrated isoform nonspecific TGFβ staining from 6 hours through 21 days, TGFβ1 from 6 hours through 21 days, and TGFβ2 from 12 hours through 7 days. In the second phase of the study, a slow-release disk with 0.01, 0.1, 1.0, or 10 μg of TGFβ1 was placed beneath the fetal skin graft at the time of wounding. Fourteen days postwounding, there was marked scarring in the fetal grafts treated with TGFβ1, and the size of the scar was proportional to the amount of TGFβ1 applied. The relative lack of TGFβ, a cytokine known to promote fibrosis, may be one reason why the fetus heals by regeneration rather than scarring. In contrast, the fibrosis characteristic of postnatal wound repair may be associated with an excess of TGFβ. These findings suggest that anti-TGFβ therapeutic strategies may ameliorate scar formation in children and adults.

Journal: Jourlan of Pediatric Surgery (Volume 30, Issue 2, Pages 198-203)

Date: 01/02/1995

1 Fetal Treatment Center, University of California, San Francisco 94143-0570, USA.