Dataset Information

Heritable spina bifida in sheep: A potential model for fetal repair of myelomeningocele.

ABSTRACT:

Background/purpose

In 2004, a heritable occurrence of spina bifida was reported in sheep on a farm in the United States. We maintained and characterized the spina bifida phenotype in this flock to assess its potential as an alternative surgical model.

Methods

A breeding strategy was developed in which the sheep were crossed to maintain or increase the occurrence of spina bifida. Measurements and observations were recorded regarding lesion size, birthweight, ambulatory capacity, or urological function, and necropsies were performed on spina bifida afflicted lambs in conjunction with magnetic resonance imaging to determine the character of the spina bifida defects and assess the presence of Chiari-like malformations or hydrocephalus.

Results

The defects were observed to be more prevalent in ram lambs, and the rate of spina bifida per litter could be increased through backcrossing or by selection of a productive ewe breed. The lambs displayed a range of ambulatory and urological deficits which could be used to evaluate new fetal repair methodologies. Finally, affected lambs were shown to demonstrate severe Chiari malformations and hydrocephalus.

Conclusions

We have determined that use of these sheep as a natural source for spina bifida fetuses is feasible and could supplement the deficits of current sheep models for myelomeningocele repair.

Level of evidence

Level IV.

SUBMITTER: Steele JW

PROVIDER: S-EPMC6935438 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Heritable spina bifida in sheep: A potential model for fetal repair of myelomeningocele.

Steele John W JW Bayliss Sharon S Bayliss John J Lin Ying Linda YL Wlodarczyk Bogdan J BJ Cabrera Robert M RM Asfaw Yohannes G YG Cummings Thomas J TJ Finnell Richard H RH George Timothy M TM

Journal of pediatric surgery 20190629 3

<h4>Background/purpose</h4>In 2004, a heritable occurrence of spina bifida was reported in sheep on a farm in the United States. We maintained and characterized the spina bifida phenotype in this flock to assess its potential as an alternative surgical model.<h4>Methods</h4>A breeding strategy was developed in which the sheep were crossed to maintain or increase the occurrence of spina bifida. Measurements and observations were recorded regarding lesion size, birthweight, ambulatory capacity, or ...[more]

PMID: 31301886

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Project description:Use of off-label tissue graft materials, such as acellular dermal matrix (ADM), for in utero repair of severe spina bifida (SB), where primary skin layer closure is not possible, is associated with poor neurological outcomes. The cryopreserved human umbilical cord (HUC) patch has regenerative, anti-inflammatory, and anti-scarring properties, and provides watertight SB repair. We tested the hypothesis that the HUC is a superior skin patch to ADM for reducing inflammation at the repair site and preserving spinal cord function. In timed-pregnant ewes with twins, on gestational day (GD) 75, spina bifida was created without a myelotomy (functional model). On GD 95, repair was performed using HUC vs. ADM patches (randomly assigned) by suturing them to the skin edges. Additionally, full thickness skin closure as a primary skin closure (PSC) served as a positive control. Delivery was performed on GD 140, followed by blinded to treatment neurological assessments of the lambs using the Texas Spinal Cord Injury Scale (TSCIS) for gait, proprioception, and nociception. Lambs without spina bifida were used as controls (CTL). Ex vivo magnetic resonance imaging of spines at the repair site were performed, followed by quantitative pathological assessments. Histological assessments (blinded) included Masson's trichrome, and immunofluorescence for myeloperoxidase (MPO; neutrophils) and for reactive astrocytes (inflammation) by co-staining vimentin and GFAP. The combined hind limbs' TSCIS was significantly higher in the HUC group than in ADM and PSC groups, p = 0.007. Both ADM and PSC groups exhibited loss of proprioception and mild to moderate ataxia compared to controls. MRI showed increased pathological findings in the PSC group when compared to the HUC group, p = 0.045. Histologically, the meningeal layer was thickened (inflammation) by 2-3 fold in ADM and PSC groups when compared to HUC and CTL groups, p = 0.01. There was lower MPO positive cells in the HUC group than in the ADM group, p = 0.018. Posterior column astrocyte activation was increased in ADM and PSC lambs compared to HUC lambs, p = 0.03. The HUC as a skin patch for in utero spina bifida repair preserves spinal cord function by reducing underlying inflammation when compared to ADM.

Project description:ImportanceGlobally accepted recommendations suggest that a woman should be between 19 weeks and 25 weeks plus 6 days of pregnancy to be considered eligible for fetal closure of open spina bifida. A fetus requiring emergency delivery during surgery is therefore potentially considered viable and thus eligible for resuscitation. There is little evidence, however, to support how this scenario is addressed in clinical practice.ObjectiveTo explore current policy and practice for fetal resuscitation during fetal surgery for open spina bifida in centers undertaking fetal surgery.Design, setting, and participantsAn online survey was designed to identify current policies and practices in place to support fetal surgery for open spina bifida, exploring experiences and management of emergency fetal delivery and fetal death during surgery. The survey was emailed to 47 fetal surgery centers in 11 countries where fetal spina bifida repair is currently performed. These centers were identified through the literature, the International Society for Prenatal Diagnosis center repository, and an internet search. Centers were contacted between January 15 and May 31, 2021. Individuals volunteered participation through choosing to complete the survey.Main outcomes and measuresThe survey comprised 33 questions of mixed multiple choice, option selection, and open-ended formats. Questions explored policy and practice supporting fetal and neonatal resuscitation during fetal surgery for open spina bifida.ResultsResponses were obtained from 28 of 47 centers (60%) in 11 countries. Twenty cases of fetal resuscitation during fetal surgery during the last 5 years were reported across 10 centers. Four cases of emergency delivery during fetal surgery after maternal and/or fetal complications during the last 5 years were reported across 3 centers. Fewer than half the 28 centers (n = 12 [43%]) had policies in place to support practice in the event of either imminent fetal death (during or after fetal surgery) or the need for emergency fetal delivery during fetal surgery. Twenty of 24 centers (83%) reported preoperative parental counseling on the potential need for fetal resuscitation prior to fetal surgery. The gestational age at which centers would attempt neonatal resuscitation after emergency delivery varied from 22 weeks and 0 days to more than 28 weeks.ConclusionsIn this global survey study of 28 fetal surgical centers, there was no standard practice about how fetal resuscitation or subsequent neonatal resuscitation was managed during open spina bifida repair. Further collaboration between professionals and parents is required to ensure sharing of information to support knowledge development in this area.

Dataset Information

Heritable spina bifida in sheep: A potential model for fetal repair of myelomeningocele.

Background/purpose

Methods

Results

Conclusions

Level of evidence

Publications

Heritable spina bifida in sheep: A potential model for fetal repair of myelomeningocele.

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