Fetal Tissue Engineering to Treat Spina Bifida Before Birth

胎儿组织工程在出生前治疗脊柱裂

• 批准号: 9923771
• 负责人: Aijun Wang
• 金额: $ 34.34万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923771
• 关键词: Animal Model; Animals; Biocompatible Materials; Biological Process; Biomedical Engineering; Birth; Bladder; Bladder Dysfunction; Bone Diseases; Bone Growth; Bone Regeneration; Bone Tissue; Caring; Cartilage; Cerebrospinal Fluid; Cerebrospinal fluid shunts procedure; Chemicals; Child; Childhood; Clinical; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Congenital Abnormality; Connective Tissue; Defect; Deformity; Development; Disease; Distal; Dura Mater; Environment; Fetal Tissues; Fetus; Foundations; Funding; Gold; Growth; Health Care Costs; Histologic; Human; In Vitro; Incontinence; Infection prevention; Intestines; Kyphosis deformity of spine; Lesion; Life; Locomotor Recovery; Magnetic Resonance Imaging; Measures; Mechanics; Medicine; Meningitis; Meningomyelocele; Methods; Modeling; Motor; Musculoskeletal; Nature; Nerve Tissue; Nervous System Physiology; Neural Tube Closure; Neurodegenerative Disorders; Neurologic; Neurons; Operative Surgical Procedures; Oryctolagus cuniculus; Osteoblasts; Osteogenesis; Outcome; Paralysed; Patients; Placenta; Pregnancy; Preventive care; Property; Quality of life; Radiology Specialty; Randomized Controlled Clinical Trials; Rattus; Recovery of Function; Research; Resolution; Risk; Skin; Solid; Spinal Cord; Spinal Dysraphism; Spinal cord injury; Structure; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Therapeutic; Time; Tissue Engineering; Trauma; Treatment Efficacy; Tretinoin; United States; United States National Institutes of Health; Variant; Vertebral column; Walking; base; bone; cognitive disability; combinatorial; density; experience; experimental study; fetal; functional outcomes; hindbrain; improved; in utero; in utero transplantation; in vivo; malformation; mesenchymal stromal cell; microCT; motor function improvement; neuron apoptosis; neuroprotection; novel; novel strategies; novel therapeutics; osteogenic; postnatal; pre-clinical; preclinical study; prenatal; prospective; recruit; regenerative; repaired; scaffold; spinal cord compression; stem cells; tissue regeneration; treatment group; tumor

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.

抽象的 脊柱裂（SB）是美国终身瘫痪的最常见原因， 每天大约有四个孩子出生于这种毁灭性神经系统缺陷。 SB的结果 妊娠的第四周神经管的闭合不完整，留下了紧张的紧张 脊髓的组织不受典型的骨和结缔组织层的保护。暴露的脊柱 绳索承受宫内化学和机械创伤，使儿童患有终身瘫痪，肠和 膀胱尿失禁，肌肉骨骼畸形和因后脑疝引起的认知障碍。直到 最近，裸露的脊髓，硬脑膜和皮肤的SB和出生后手术闭合治疗 主要旨在防止感染脑脊液（脑膜炎）。治疗范式 在NIH资助的脊髓脑元素研究（MOMS）的管理之后，有所改变 - 多中心，潜在的， 随机，对照临床试验 - 证明在SB缺陷的子宫修复中是安全的，减少了 后脑疝的风险和CSF分流的需求，并且患者的远端有所改善 神经功能。虽然有希望，但在妈妈试验中看到的运动功能改进有限， 58％的接受产前修复的儿童仍无法独立行走。我们最近 临床前研究表明，用早期妊娠胎盘衍生的间充质细胞治疗 （PMSC）在子宫修复期间，可以在胎儿羊肉模型中治愈与SB相关的运动功能。然而， 我们还发现，在子宫手术修复标准时用PMSC处理SB病变时 救出的运动功能，在胎儿羔羊模型中出生后的时间随着时间的流逝而下降。详细的 放射学和组织学分析表明，发展后运动功能降低 由于缺乏骨骼和结缔组织而导致的严重脑膜病，绳索压缩和绑扎 与人类临床发现一致。在这项研究中，我们建议开发多功能的， 生物工程脚手架以提供神经保护，抗螺旋和骨再生功能 治疗以解决这个复杂的疾病问题。我们的中心假设是在子宫移植 利用独特胎儿发育环境的多功能生物工程脚手架将提供 综合治疗疾病发展并在出生前治愈SB。如果成功完成， 这种疗法将显着降低医疗保健成本，并改善SB患者的生活质量。