Fetal Tissue Engineering to Treat Spina Bifida Before Birth

胎儿组织工程在出生前治疗脊柱裂

基本信息

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
项目类别：
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

项目摘要

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) 是美国儿童终生瘫痪的最常见原因，每天大约有四个孩子出生时患有这种毁灭性的神经先天缺陷。 SB 结果来自妊娠第四周神经管不完全闭合，留下脆弱的神经脊髓组织不受典型的骨和结缔组织层的保护。暴露的脊柱脐带会造成宫内化学和机械损伤，导致儿童终生瘫痪，肠道和膀胱失禁、肌肉骨骼畸形和后脑疝引起的认知障碍。直到最近，没有治疗SB和产后手术闭合暴露的脊髓、硬脑膜和皮肤主要目的是预防脑脊液感染（脑膜炎）。治疗范例 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 - 证明子宫内修复 SB 缺陷是安全的，可减少后脑疝的风险和脑脊液分流的需要，并且患者的远端功能有所改善神经功能。尽管前景乐观，但 MOMS 试验中看到的运动功能改善有限， 58%接受产前修复的孩子仍然无法独立行走。我们最近的临床前研究表明，妊娠早期胎盘来源的间充质基质细胞治疗 (PMSC) 在子宫内修复过程中可以治愈胎儿羔羊模型出生时 SB 相关的运动功能。然而，我们还发现，在标准子宫手术修复时用 PMSC 治疗 SB 病变时挽救了运动功能，但在胎儿羔羊模型中，运动恢复随着出生后的时间而下降。详细的放射学和组织学分析表明，运动功能在发展后下降由于缺乏骨骼和结缔组织而导致严重的脊柱后凸、脊髓受压和束缚，与人类临床发现一致。在这项研究中，我们建议开发一种多功能、生物工程支架集神经保护、抗束缚和骨再生功能于一身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发展进行综合治疗，并在出生前治愈SB。如果成功完成，该疗法将显着降低 SB 患者的医疗费用并提高其生活质量。