Human Umbilical Cord as a Regenerative Patch for In-Utero Spina Bifida Repair

描述 子宫内脊柱裂修复术后缺乏完全获益的理解存在根本性差距， 不到一半的患者显示脊髓功能改善。该项目的长期目标是 通过再生修复，逐步改善受影响儿童的神经系统结果， 缺陷部位。本申请的总体目标是确定使用冷冻保存的人 用于子宫内脊柱裂修复的脐带（HUC）减少了修复部位的炎症和瘢痕形成， 从而改善绵羊模型中的神经学结果。核心假设是，HUC与 常规使用的方法改善了缺损部位处和缺损部位下方的脊髓的功能 妊娠绵羊脊柱裂手术模型中瘢痕形成的手术后遗症。这一假设 根据申请人实验室提供的初步数据制定。HUC是FDA批准的 具有活性成分，重链透明质酸/五聚体蛋白3， 显示出抗炎和抗瘢痕形成的特性。拟议研究的理由是， 探索HUC作为子宫内脊柱裂修复再生补片的特性， 立即转化为人类，以改善影响4000多名活产婴儿的脊柱裂的结局 每年在美国。将通过在绵羊模型中追求两个特定目标来检验假设：1） 比较使用HUC与脱细胞真皮基质进行宫内修复的组织学、放射学和临床结局 (ADM)基于补片修复的大型脊柱裂缺损皮肤闭合，2）比较相似的结果 使用HUC作为初级皮肤闭合下的硬脑膜补片与多层闭合下的硬脑膜补片。使用所建立的 妊娠绵羊脊柱裂手术模型产生了我们的初步数据，具体目标1旨在 使用组织学和先进的磁共振成像定量评估炎症、瘢痕形成， 使用经验证的德克萨斯脊髓损伤量表和羔羊膀胱控制进行评估和神经系统结局 与ADM相比，使用HUC修复。在特定目标2中，将HUC置于皮肤之间的硬脑膜替代物 闭合和神经基板或常规多层闭合将用于与上述相同的模型中， 评估将与目标1类似地进行。这种方法是创新的，因为它脱离了现状 通过利用HUC的天然再生特性来改善子宫内脊柱裂的愈合， 修复，以减少长期的神经后遗症。这项研究意义重大，因为它有望 垂直推进和扩展脊柱裂子宫内修复的益处，包括促进最小程度的 侵入性修复，以减少与目前所需的大子宫切口相关的产妇风险， approach.最终，这些知识有可能找到治疗其他疾病的新方法。 先天性解剖学出生缺陷，如唇腭裂、腹裂和腹股沟疝。

DESCRIPTION There is a fundamental gap in understanding the lack of complete benefit after in-utero spina bifida repair where fewer than half of the patients show improvement in spinal cord function. The long-term goal of this project is to incrementally improve the neurological outcomes of affected children through the regenerative repair of the defect site. The overall objective of this application is to determine whether the use of cryopreserved human umbilical cord (HUC) for in-utero spina bifida repair reduces inflammation and scar formation at the repair site, and thus improves neurological outcomes in a sheep model. The central hypothesis is that HUC compared to conventionally used methods improves the function of the spinal cord at and below the defect site and reduces the surgical sequelae of scar formation in a surgical spina bifida model in a pregnant sheep. This hypothesis has been formulated by preliminary data produced in the applicant’s laboratory. HUC is FDA approved for ophthalmological diseases and has an active component, heavy chain hyaluronic acid/pentraxin3, which demonstrates anti-inflammatory and anti-scarring properties. The rationale for the proposed research is that exploration of the properties of HUC as a regenerative patch in in-utero spina bifida repair has the potential to immediately translate into humans to improve outcomes in spina bifida, which affects over 4000 live births annually in the United States. The hypothesis will be tested by pursuing two Specific Aims in a sheep model: 1) Compare histological, radiological and clinical outcomes of in-utero repair using HUC vs. acellular dermal matrix (ADM) based patch repair for the skin closure in large spina bifida defects, and 2) Compare similar outcomes using HUC as a dural patch under the primary skin closure vs. multilayered closure. Using the established surgical spina-bifida model in pregnant sheep that generated our preliminary data, Specific Aim 1 seeks to quantitatively assess inflammation, scar formation using histology and advanced magnetic resonance imaging, and neurological outcomes using the validated Texas Spinal Cord Injury Scale and bladder control in lambs repaired with HUC compared to ADM. In Specific Aim 2, dural substitute with a HUC placed between the skin closure and neural placode or conventional multilayered closure will be used in the same model as above, and assessments will be performed similarly to Aim 1. The approach is innovative, as it departs from the status quo by utilizing the naturally occurring regenerative properties of HUC to improve healing of in-utero spina bifida repair to reduce long-term neurological sequelae. The proposed research is significant because it is expected to vertically advance and expand the benefits of in-utero repair of spina bifida including facilitating the minimally invasive repair to reduce maternal risks associated with the large uterine incision needed for the current approach. Ultimately, such knowledge has the potential to find newer approaches to the treatment of other congenital anatomical birth defects such as cleft lip/palate, gastroschisis, and diaphragmatic hernia.