Fetal Tissue Engineering to Treat Spina Bifida Before Birth

摘要 脊柱裂（SB）是美国终身儿童瘫痪的最常见原因， 每天大约有四名婴儿出生时就患有这种严重的神经先天性缺陷。SB结果来自 在怀孕的第四周，神经管的不完全闭合，留下了脆弱的神经。 不受典型的骨层和结缔组织保护的脊髓组织。暴露的脊柱 脐带承受子宫内的化学和机械创伤，使儿童终身瘫痪，肠和 膀胱失禁、肌肉骨骼畸形和由于后脑疝引起的认知障碍。直到 最近，还没有SB的治疗方法和出生后暴露的脊髓、硬脑膜和皮肤的手术闭合 主要用于预防脑脊液感染（脑膜炎）。治疗模式 在NIH资助的脊髓脊膜膨出管理研究（MOMS）-一项多中心，前瞻性， 随机对照临床试验-证明SB缺陷的子宫内修复是安全的， 后脑脑疝的风险和CSF分流的需要，以及患者在远端 神经功能虽然有希望，但在MOMS试验中看到的运动功能改善是有限的， 58%接受产前修复的儿童仍然不能独立行走。我们最近 临床前研究表明，用妊娠早期胎盘来源的间充质基质细胞治疗 在胎羊模型中，在子宫内修复期间使用私营军事和保安干细胞（PMSC）治疗出生时SB相关的运动功能。然而，在这方面， 我们还发现，在标准子宫内手术修复时， 在胎羊模型中，挽救的运动功能、运动恢复在出生后随时间下降。详细 放射学和组织学分析表明，运动功能下降后的发展， 严重的脊柱后凸，脊髓压迫和栓系由于缺乏骨骼和结缔组织，这是 与人类临床结果一致。在这项研究中，我们建议开发一种多功能， 生物工程支架，提供神经保护，抗栓系和骨再生功能于一体 治疗来解决这个复杂的疾病问题。我们的中心假设是子宫内移植 利用独特的胎儿发育环境的多功能生物工程支架将提供 针对病情发展进行综合治疗，在出生前治愈SB。如果成功完成， 这种疗法将显著降低保健费用并改善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.