Biodegradable elastic patches for congenital diaphragmatic hernia treatment

项目总结 摘要先天性横隔性疝气是一种严重的出生缺陷，其特征是发育不完全。 横隔膜。这会导致横隔膜的缺陷，腹部器官，如肠道，通过横隔膜 和胃，可以突出到胸腔内。这可能会导致肺部受压，并损害他们的 发展，这可能导致致命的肺发育不良。CDH影响所有种族和民族。在美国 仅在美国，每天就有五个孩子出生时就有这种出生缺陷，每三个新生儿中就有一个患有这种缺陷 毁灭性的情况就会消失。CDH治疗需要手术干预，以使突出的器官恢复到 并修复腹膜腔内的缺陷。在某些情况下，横隔膜的缺陷可以通过缝合来闭合。 隔膜的边缘在一起。然而，如果缺陷太大或如果横隔膜的部分完全 缺失时，必须使用假体补片来修复缺陷。这些贴片大多是由生物合成的 惰性/非活性材料，如聚丙烯网、增强硅胶板、聚乙烯网和 聚四氟乙烯(商标为Gore-Tex)。然而，由于合成贴片不会随着孩子的成长而生长， 裂开和复发的腹股沟很常见。可生物降解的合成贴片，如聚乳酸，是 机械上不顺从，再生潜力不足。脱细胞组织贴片，如 小肠粘膜下层(SIS)和去细胞的横隔膜，机械强度弱，降解快。至 针对这些问题，我们的目标是开发一种新型的可生物降解、生物活性、弹性的贴片，不仅匹配 天然隔膜的机械性能不仅具有CDH修复的再生潜力，而且还具有再生潜力。 具体地说，一种可生物降解的弹性聚合物和脱细胞猪膜将结合在一起，形成一个 纤维斑块。该聚合物将提供坚固的机械支撑，具有弹性和可控的降解 而脱细胞的横隔膜细胞外基质(ECM)将提供横隔膜组织特异性生物活性 支持细胞和组织的生长。这种新颖的贴片将能够随着呼吸而移动 更重要的是，横隔膜会随着孩子的成长而成长。本研究提出了两个目标。在目标1中，我们将 系统地表征天然横隔膜的生物力学和生物活性，进而形成一种纤维 包含特定于隔膜的ECM生物活性的补丁，并在机械上与本地隔膜匹配。在AIM 2，我们将使用已建立的手术建立的横隔膜缺损大鼠模型来评估体内和外部 活体横隔膜功能的新型贴片。该项目具有创新性和翻译性，非常成功 该项目的完成将建立一种新的方法学，以产生可生物降解、有弹性和生物活性的 横隔膜贴片，为先天性CDH的治疗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.