Fetal Tissue Engineering to Treat Spina Bifida Before Birth

摘要 脊柱裂(SB)是美国儿童终身瘫痪的最常见原因， 每天大约有四个孩子出生时就有这种破坏性的神经先天性缺陷。某人由以下原因引起 妊娠第四周神经管不完全闭合，使脆弱的人神经紧张 脊髓的组织，没有典型的骨层和结缔组织的保护。裸露的脊椎 脐带遭受宫内化学和机械创伤，使儿童终身瘫痪，肠和 膀胱大小便失禁，肌肉骨骼畸形，以及因后脑脱出而导致的认知障碍。直到 最近，没有治疗SB和出生后手术缝合暴露的脊髓，硬脑膜和皮肤 主要用于预防脑脊液感染(脑膜炎)。治疗范式 在NIH资助的脊髓脊膜膨出管理研究(MOMS)后发生了变化-一项多中心、前瞻性、 随机对照临床试验表明，宫内修复SB缺陷是安全的，减少了 后脑脱出的风险和脑脊液分流术的需要，以及患者在远端的改善 神经功能。虽然很有希望，但在MOMS试验中看到的运动功能改善是有限的， 在接受产前修复的儿童中，58%的儿童仍然无法独立行走。我们最近 临床前研究表明，妊娠早期胎盘来源的间充质基质细胞治疗 (PMSCs)在宫内修复期间治愈出生时SB相关的运动功能的胎羊模型。然而， 我们还发现，在标准的宫内手术修复时间用PMSCs治疗SB病变时 胎羊模型出生后运动功能恢复随时间延长呈下降趋势。详细 放射学和组织学分析表明，在发展成骨性痴呆后，运动功能下降。 由于缺乏骨骼和结缔组织，严重的脊柱后凸，脊髓受压和拴系，这是 与人类的临床结果一致。在这项研究中，我们建议开发一种多功能、 集神经保护、抗栓系和骨再生功能于一体的生物工程支架 治疗来解决这个复杂的疾病问题。我们的中心假设是在子宫内移植 一种利用独特的胎儿发育环境的多功能生物工程支架将提供 对疾病的发展进行综合治疗，在出生前治愈某人。如果成功完成， 这种疗法将显著降低医疗成本，提高SB患者的生活质量。

ABSTRACT Spina bifida (SB) is the most common cause of lifelong childhood paralysis in the United States, and approximately four children are born with this devastating neurological congenital defect daily. SB results from the incomplete closure of the neural tube during the fourth week of gestation, leaving the delicate nervous tissue of the spinal cord unprotected by the typical layers of bone and connective tissue. The exposed spinal cord sustains intrauterine chemical and mechanical trauma, leaving children with lifelong paralysis, bowel and bladder incontinence, musculoskeletal deformities, and cognitive disabilities due to hindbrain herniation. Until recently, there was no treatment of SB and postnatal surgical closure of the exposed spinal cord, dura and skin was primarily intended to prevent infection of the cerebrospinal fluid (meningitis). The treatment paradigm changed after the NIH funded Management of Myelomeningocele Study (MOMS) - a multicenter, prospective, randomized, controlled clinical trial - demonstrated that in utero repair of the SB defect was safe, decreased the risk of hindbrain herniation and the need for CSF shunting, and that patients showed improvement in distal neurologic function. While promising, the motor function improvements seen in the MOMS trial were limited, and 58% of children who underwent prenatal repair were still unable to walk independently. Our recent preclinical studies showed that treatment with early gestation placental derived mesenchymal stromal cells (PMSCs) during in utero repair cures SB-associated motor function at birth in a fetal lamb model. However, we also found that while treating the SB lesion with PMSCs at the time of standard in utero surgical repair rescued motor function, locomotor recovery declined over time after birth in the fetal lamb model. Detailed radiological and histological analyses showed that locomotor function decreased after the development of severe kyphosis, cord compression and tethering due to the lack of bone and connective tissue, which is consistent with human clinical findings. In this study, we propose to develop a multifunctional, bioengineered scaffold to provide neuroprotection, anti-tethering and bone regeneration functions in one treatment to solve this complicated disease problem. Our central hypothesis is that in utero transplantation of a multifunctional bioengineered scaffold that utilizes the unique fetal developmental environment will provide a comprehensive treatment to the disease development and cure SB before birth. If successfully accomplished, this therapy will significantly lower healthcare costs and improve the quality of life of patients with SB.