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Tissue engineering a patch to repair neural tube damage during in utero surgery for spina bifida

Supervisors: Dr Gabriel Galea, Professor Paolo De Coppi and Professor Nicola Elvassore

Project:

Surgery on the unborn child requires either access via a large opening incision or, more recently, using minimal access or fetoscopy. A randomized trial demonstrated improved neonatal outcomes following open prenatal over postnatal repair of spina bifida. Maternal laparotomy and hysterotomy, with temporary exposure of the fetus (Adzick et al. 2011) is very limited by the high associated risks of maternal morbidity and is a serious obstacle. Fetoscopic coverage with a patch has been developed (Kohl et al. 2010) but is technically difficult, less successful and has a high risk for preterm birth (Verbeek et al. 2012). The latter is probably due to the requirement for multiple ports compared to the 6 cm hysterotomy incision that causes less rupture. To increase the acceptability of fetal repair and ameliorate neurological outcome, a combined approach using a single access technique and a regenerative medicine approach is required. Stem cells could be derived from the amniotic fluid (De Coppi et al. 2007), reprogrammed to induced pluripotent stem cells (IPSC) and differentiated to produce neurons which could be used either for improved functional repair (apply gel to the defect for tissue engineering) and also for disease modelling. In particular, in vitro bioengineered systems have been established in the laboratory to functionally test differentiated neurons derived from iPSC of affected patients vs controls. Ultimately, this work could lead to improve our knowledge in spina bifida and translate clinically to produce a better repair which could achieve earlier in gestation (Watanabe et al. 2011).

References:

  1. Adzick NS, Thom EA, Spong CY, Brock JW 3rd, Burrows PK, Johnson MP, Howell LJ, Farrell JA, Dabrowiak ME, Sutton LN, Gupta N, Tulipan NB, D'Alton ME, Farmer DL; MOMS Investigators. A randomized trial of prenatal versus postnatal repair of myelomeningocele. N Engl J Med. 2011 Mar 17;364(11):993-1004.

  2. De Coppi P, Bartsch G Jr, Siddiqui MM, Xu T, Santos CC, Perin L, Mostoslavsky G, Serre AC, Snyder EY, Yoo JJ, Furth ME, Soker S, Atala A. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol. 2007 Jan;25(1):100-6.

  3. Kohl T. Minimally invasive fetoscopic interventions: an overview in 2010. Surg Endosc. 2010 Aug;24(8):2056-67.

  4. Verbeek RJ, Heep A, Maurits NM, Cremer R, Hoving EW, Brouwer OF, van der Hoeven JH, Sival DA. Fetal endoscopic myelomeningocele closure preserves segmental neurological function. Dev Med Child Neurol. 2012 Jan;54(1):15-22.

  5. Watanabe M, Li H, Kim AG, Weilerstein A, Radu A, Davey M, Loukogeorgakis S, Sánchez MD, Sumita K, Morimoto N, Yamamoto M, Tabata Y, Flake AW. Complete tissue coverage achieved by scaffold-based tissue engineering in the fetal sheep model of Myelomeningocele. Biomaterials. 2016 Jan;76:133-43.