Surviving Lambs with Myelomeningocele Repaired in utero with Placental Mesenchymal Stromal Cells for 6 Months: A Pilot Study

Abstract

<b><i>Background:</i></b> Fetal repair of myelomeningocele (MMC) with placental mesenchymal stromal cells (PMSCs) rescues ambulation in the ovine model up to 48 h postnatally. Outcomes past 48 h are unknown as MMC lambs have not been survived past this timepoint. <b><i>Objective:</i></b> We aimed to survive lambs for 6 months following the fetal repair of MMC with PMSCs. <b><i>Methods:</i></b> Fetal MMC lambs were repaired with PMSCs. Lambs received either no additional treatment or postnatal bracing and physical therapy (B/PT). Motor function was assessed with the sheep locomotor rating (SLR). Lambs with an SLR of 15 at birth were survived for 6 months or until a decline in SLR less than 15, whichever came first. All lambs underwent a perimortem MRI. <b><i>Results:</i></b> The lambs with no postnatal treatment (<i>n</i> = 2) had SLR declines to 7 and 13 at 29 and 65 days, respectively, and were euthanized. These lambs had a spinal angulation of 57° and 47°, respectively. The B/PT lamb (<i>n</i> = 1) survived for 6 months with a sustained SLR of 15 and a lumbar angulation of 42°. <b><i>Conclusion:</i></b> Postnatal physical therapy and bracing counteracted the inherent morbidity of the absent paraspinal muscles in the ovine MMC model allowing for survival and maintenance of rescued motor function of the prenatally treated lamb up to 6 months.

Early investigations into improving bowel and bladder function in fetal ovine myelomeningocele repair

“…However, long-term outcomes would be informative regarding the durability of our findings. We have previously shown that the improvements in distal motor function afforded by in utero application of the PMSC-ECM to the spinal cord are durable to 6 months of age [ 43 ] and we hypothesize that the bowel and bladder functionality observed in this study may be similarly durable.…”

“…In particular, to prevent the natural healing of the MMC defect that is seen in the fetus [ 41 ], surgical MMC defect creation involves removal of the paraspinal muscles in addition to the lamina and dura, resulting in increasing spinal column angulation and instability with growth of the animal [ 42 ]. This limits the ability to study long-term outcomes due to the intense rehabilitation and veterinary care required to sustain these animals long-term [ 43 ]. However, long-term outcomes would be informative regarding the durability of our findings.…”

A Novel Model of Fetal Spinal Cord Exposure Allowing for Long-Term Postnatal Survival

“…It is possible that the application of placental mesenchymal stromal cells seeded on to extracellular matrix improved the motor function in these animals, as we have demonstrated in other models [22-24]. However, even with the incorporation of placental mesenchymal stromal cells we have previously been able to survive only 1 lamb for a long term with our prior fetal surgical model [27].…”

“…Occasionally, studies followed lambs up to 1 week of age [20]. In our prior attempts at long-term survival, 5 out of 6 lambs began developing worsening motor function within 1 week [27]. We have previously demonstrated the long-term survival to 6 months of 1 lamb that underwent in utero MMC defect creation and repair, which was possible with the addition of physical therapy and bracing orthotic devices [27].…”

“…In our prior attempts at long-term survival, 5 out of 6 lambs began developing worsening motor function within 1 week [27]. We have previously demonstrated the long-term survival to 6 months of 1 lamb that underwent in utero MMC defect creation and repair, which was possible with the addition of physical therapy and bracing orthotic devices [27]. While this is an important advancement, physical therapy is resource intensive, and challenging to provide for multiple lambs simultaneously, which limits the ability of researchers to evaluate long-term outcomes with sufficiently large sample sizes.…”