Evolution and Variations of the Ovine Model of Spina Bifida

Abstract

Spina bifida is the most common congenital anomaly of the central nervous system and the first non-fatal fetal lesions to be addressed by fetal intervention. While research in spina bifida has been performed in rodent, nonhuman primate, and canine models, sheep have been a model organism for the disease. This review summarizes the history of development of the ovine model of spina bifida, previous applications, and translation into clinical studies. Initially used by Meuli et al. [Nat Med. 1995;1(4):342-7], fetal myelomeningocele defect creation and in utero repair demonstrated motor function preservation. The addition of myelotomy in this model can reproduce hindbrain herniation malformations, which is the leading cause of mortality and morbidity in humans. Since inception, the ovine models have been validated numerous times as the ideal large animal model for fetal repair, with both locomotive scoring and spina bifida defect scoring adding to the rigor of this model. The ovine model has been used to study different methods of myelomeningocele defect repair, the application of various tissue engineering techniques for neuroprotection and bowel and bladder function. The results of these large animal studies have been translated into human clinical trials including Management of Meningocele Study (MOMS) trial that established current standard of care for prenatal repair of spina bifida defects, and the ongoing trials including the Cellular Therapy for In Utero Repair of Myelomeningocele (CuRe) trial using a stem cell patch for repair. The advancement of these life savings and life-altering therapies began in sheep models, and this notable model continues to be used to further the field including current work with stem cell therapy.

Keywords: Myelomeningocele; Spina bifida; Surgical model.

Fig. 1.

Chronological evolution of ovine model for spina bifida

Fig. 2.. Representative open ovine defect creation and repair

A) Hysterotomy entry B) Defect creation (removal of skin, paraspinal muscles) C) Defect creation (lumbar laminectomy) D) Patch placement and securement E) Primary skin closure F) Hysterotomy closure

Fig. 3.. Surgical Models for Myelomeningocele defect creation and repair

Solid line represents open approach; dotted line represents fetoscopic approach. PMSC-ECM (placental mesenchymal stem cell – extracellular matrix); HUC (human-umbilical cord); SIS (small intestine submucosa) ^aOpen defect creation and fetoscopic repair can be performed during a single operation or staged (i.e., open defect, followed by fetoscopic repair later) ^bFetoscopic defect creation and repair can be performed during a single operation ^cMaterials used in fetoscopic repair as well as open repairs

Fig. 4.. Sheep Locomotor Rating Scale

I) Locomotion Categories Sheet II) Clinical Assessments Sheet III) Locomotor patterns attributed to each score ranging from complete paraplegia with no joint movement (0) to normal locomotion (15) rubric IV) Drawings of full range of motion for the lamb hindlimb (A) and open (left image) and closed (right image) positions for each individual joint: hip (B), knee (C), and ankle (D) joints. Reprinted from J Pediatr Surg, Vol 50(4), Development of a locomotor rating scale for testing motor function in sheep, Brown EG, Keller BA, Pivetti CD, et al., 617–621, 2015, with permission from Elsevier.