Biodegradable elastic patches for congenital diaphragmatic hernia treatment

项目摘要 先天性腹股沟疝（CDH）是一种严重的出生缺陷，其特征是 隔膜这导致横膈膜的缺陷，腹部器官，如肠， 和胃的疝气会进入胸腔这可能会导致肺部压缩，并损害其功能。 发展，这可能导致致命的肺发育不全。CDH影响所有种族和民族。在联合 仅在美国，每天就有五个孩子患有这种先天缺陷，每三个新生儿中就有一个患有这种缺陷。 毁灭性的死亡CDH治疗需要手术干预，以使疝出的器官返回到 腹腔，修复缺损。在某些情况下，隔膜中的缺陷可以通过缝合闭合。 隔膜边缘在一起。然而，如果缺陷太大或者如果隔膜的部分完全 如果缺失，则必须使用修复补片来修复缺损。这些补丁大多是由合成，生物 惰性/非活性材料，如聚丙烯网、增强硅橡胶片、聚乙烯网和 聚四氟乙烯（商品名Gore-Tex）。然而，由于合成贴片不会随孩子一起生长， 裂开和复发性疝是常见的。可生物降解的合成补片，如聚乳酸， 机械上不顺从并且具有不足的再生潜力。脱细胞组织补片，例如 小肠粘膜下层（SIS）和脱细胞隔膜的机械强度弱且降解迅速。到 为了解决这些问题，我们的目标是开发一种新型的可生物降解的，生物活性的，弹性的贴片，不仅匹配 天然隔膜的机械性能，但也具有CDH修复的再生潜力。 具体地，将生物可降解弹性聚合物和脱细胞猪隔膜组合以形成生物可降解弹性聚合物。 纤维性斑块该聚合物将提供具有弹性和可控降解的坚固机械支撑 而脱细胞的膈肌细胞外基质（ECM）将提供膈肌组织特异性生物活性， 支持细胞和组织生长。这种新的补丁将能够随着呼吸沿着与本地 更重要的是，它将与孩子一起成长。本研究提出两个目标。在目标1中，我们 系统地表征天然隔膜的生物力学和生物活性，然后开发纤维 含有隔膜特异性ECM生物活性并与天然隔膜机械匹配的贴片。在Aim中 2、我们将使用一种手术建立的大鼠腰椎缺损模型来评估在体内和体外的治疗效果。 新型贴剂的体内驱替功能。这个项目是创新和翻译，作为成功的 该项目的完成将建立一个新的方法，以产生一个可生物降解的，弹性和生物活性 为先天性先天性心脏病患儿提供了一种新的治疗策略。

Project summary Congenital diaphragmatic hernia (CDH) is a serious birth defect characterized by incomplete development of the diaphragm. This results in a defect in the diaphragm through which abdominal organs, such as the intestines and stomach, can herniate into the chest. This can cause compression of the lungs and impairs their development, which can result in fatal pulmonary hypoplasia. CDH affects all races and ethnicities. In the United States alone, five children are born with this birth defect every day, and one of every three newborns with this devastating condition dies. CDH treatment requires surgical intervention to return the herniated organs to the abdominal cavity and to repair the defect. In some cases, the defect in the diaphragm can be closed by suturing the diaphragm edges together. However, if the defect is too large or if portions of the diaphragm are completely missing, a prosthetic patch must be used to fix the defect. These patches are most made of synthetic, biologically inert/inactive materials like polypropylene mesh, reinforced silastic sheet, polyethylene mesh and polytetrafluoroethylene (trade name Gore-Tex). However, as synthetic patches do not grow with the child, dehiscence and recurrent herniation are common. Biodegradable synthetic patches, such as polylactide, are mechanically incompliant and possess insufficient regenerative potential. Decellularized tissue patches, such as small intestinal submucosa (SIS) and decellularized diaphragm, are mechanically weak and degrade rapidly. To address these problems, we aim to develop a novel biodegradable, bioactive, elastic patch that not only matches the mechanical properties of the native diaphragm but also comes with regenerative potential for CDH repair. Specifically, a biodegradable elastic polymer and decellularized porcine diaphragm will be combined to form a fibrous patch. The polymer will provide robust mechanical support with elasticity and controllable degradation while the decellularized diaphragm extracellular matrix (ECM) will offer diaphragm tissue-specific bioactivity to support cell and tissue growth. This novel patch will be able to move with respiration along with the native diaphragm and more importantly will grow with the child. Two aims are proposed in this study. In Aim 1, we will systematically characterize the biomechanics and bioactivity of the native diaphragm, and then develop a fibrous patch that contains diaphragm-specific ECM bioactivity and mechanically matches the native diaphragm. In Aim 2, we will use an established surgically created diaphragmatic defect rat model to evaluate the in vivo and ex vivo diaphragmatic functions of the novel patch. This project is innovative and translational, as successful completion of this project will establish a new methodology to generate a biodegradable, elastic and bioactive diaphragmatic patch, and provide a novel therapeutic strategy to treat children born with CDH.