Stem cell-based biomaterials for spinal regeneration in neural tube defects

项目摘要/摘要 患有严重形式的脊柱裂的儿童，被称为脊髓膜脑膨出(MMC)，患有大量和 继发于肢体无力和瘫痪、脑积水、认知障碍、 膀胱和肠道功能障碍，以及骨科异常。尽管一项随机试验显示 为了减少产前手术后出生后脑积水，仍然迫切需要提供这些 儿童接受手术治疗，可以更好地增强神经功能。鉴于已知的 在其他脊髓损伤模型中移植的神经前体细胞的再生特性 应用羊水细胞重编程神经元治疗MMC缺陷提供了一种新的临床方法 相关的，可能是自体的替代传统的胎儿MMC修复。我们的中心假设是 胎儿神经外科手术治疗脊柱裂畸形的研究 因子(声波刺猬、神经营养因子-3)的功能可以最大限度地促进神经再生。 MMC通过植入脊髓和旁分泌作用。在具体目标1中，我们将调查短期- 神经贴片对胎儿MMC脊髓的长期旁分泌效应。在具体目标2中，我们将确定 神经贴片增强长期MMC脊髓再生和神经功能的程度 活着。这项提议的基石是由早期胎儿外科医生组成的多学科团队- 科学家(库尼萨奇博士)、学术神经外科医生(帕蒂尔博士)、高级发育神经生物学家(奥谢博士)、 和高级材料科学工程师(谢伊博士)。预期的结果将验证一个再生的 治疗脊柱裂等脊柱疾病具有较高临床转化性的医学途径 脐带受伤。

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.