PROJECT SUMMARY/ABSTRACT Children with a severe form of spina bifida, known as myelomeningocele (MMC), suffer from substantial and life-long morbidities secondary to lower limb weakness and paralysis, hydrocephalus, cognitive impairment, bladder and bowel dysfunction, and orthopedic abnormalities. Although a randomized trial has shown a reduction of postnatal hydrocephalus after prenatal surgery, there remains a critical need to provide these children with an operative treatment that can better enhance neurologic function. Given the known regenerative properties of neural progenitor cells transplanted in other models of spinal cord injury, the application of neurons reprogrammed from amniotic fluid cells to treat MMC defects offers a novel, clinically relevant, and potentially autologous alternative to conventional fetal MMC repair. Our central hypothesis is that fetal neurosurgical treatment of spina bifida defects using a composite, cell-based neural patch with trophic factor (sonic hedgehog, neurotrophin-3) functionality can maximally enhance neuronal regeneration within the MMC spinal cord through engraftment and paracrine effects. In Specific Aim 1, we will investigate the short- term paracrine effects of neural patches on the fetal MMC spinal cord. In Specific Aim 2, we will determine the extent to which neural patches augment long-term MMC spinal cord regeneration and neurologic function in vivo. The cornerstone of this proposal is the multidisciplinary team composed of an early-stage, fetal surgeon- scientist (Dr. Kunisaki), academic neurosurgeon (Dr. Patil), senior developmental neurobiologist (Dr. O'Shea), and senior materials science engineer (Dr. Shea). The expected outcomes will have validated a regenerative medicine approach with high potential for clinical translation in the treatment of spina bifida and other spinal cord injuries.