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

项目总结/摘要 患有严重形式的脊柱裂的儿童，称为脊髓脊膜膨出（MMC）， 继发于下肢无力和瘫痪、脑积水、认知障碍、 膀胱和肠道功能障碍以及矫形畸形。尽管一项随机试验显示， 减少产前手术后的产后脑积水，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 移植到其他脊髓损伤模型中的神经祖细胞的再生特性， 应用从羊水细胞重编程的神经元治疗MMC缺陷提供了一种新的、临床上有效的方法， 相关，并且可能是常规胎儿MMC修复的自体替代方案。我们的核心假设是， 应用复合细胞神经补片和营养因子治疗脊柱裂的胎儿神经外科治疗 因子（音刺猬，神经营养因子-3）的功能可以最大限度地增强神经细胞内的神经再生。 MMC通过脊髓植入和旁分泌作用。在具体目标1中，我们将研究短- 胚胎MMC脊髓神经补片的旁分泌效应。在具体目标2中，我们将确定 神经补片增强长期MMC脊髓再生和神经功能的程度 vivo.这项提议的基石是由一名早期胎儿外科医生组成的多学科团队- 科学家（国崎博士），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）， 高级材料科学工程师（Shea博士）。预期的结果将验证再生 在治疗脊柱裂和其他脊柱疾病方面具有高度临床转化潜力的医学方法 脊髓损伤

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.