Miniature Device to Promote Lung Development

描述（由申请人提供）：先天性膈疝（CDH）影响2000名新生儿中的1名。CDH是一种疾病，其中部分横膈膜无法形成，使腹部器官迁移到胸部，导致受影响婴儿肺部发育不全。尽管在对这种疾病的管理方面取得了很大进展，但发病率和死亡率仍然很高。来自全球50多个中心的汇总结果表明，采用标准的产后治疗，总生存率为68%。幸存者的特殊发病率包括神经发育、营养、感音神经性听力和肺功能缺陷。这种疾病的公共卫生影响也很显著，因为在最近的一项研究中，CDH已被确定为代价第三高的出生缺陷。这种先天性异常的严重后果导致其他人寻求在出生前纠正CDH或其主要后果肺发育不全的方法，以允许更正常的产后功能。迄今为止，最有希望的子宫内治疗包括完全阻断胎儿气管，这已被证明可以促进肺部生长。然而，这一过程损害了对肺正常发育起关键调节作用的阶段性机械力。为了克服这一点，我们建议使用微型瓣膜来提供动态气管闭塞（dTO）以促进肺生长。在初步实验中，在胎羊CDH模型中，使用定制设计的改良脑室-腹膜分流阀将气管压力维持在6-8 mmHg，同时允许肺液流出。与完全闭塞相比，dTO导致改善（接近正常）的肺形态计量学和功能。在这里，我们建议进一步定义最佳肺生长的压力特性，并创建一个微型设备，允许微创部署。为了制造该器件，将使用MEMS（微电子机械系统）微制造技术制造微阀，该技术可以精确控制器件的几何形状和性能规格。第一阶段的具体目标是：(1)建立开启压力在2-10 mmHg范围内的微阀设计；(2)确定最佳肺部发育的阀压设置。

DESCRIPTION (provided by applicant): Congenital diaphragmatic hernia (CDH) affects 1 in 2000 newborns. CDH is a disorder in which part of the diaphragm fails to form, allowing abdominal organs to migrate into the chest, resulting in lung hypoplasia (underdevelopment) in affected infants. Although great strides have been made in the management of this disease, significant morbidity and mortality persist. Pooled results from over 50 centers worldwide indicate overall survival to be 68% with standard, postnatal therapy. Specific morbidities in survivors include neurodevelopmental, nutritional, sensorineural hearing, and pulmonary function deficiencies. The public health impact of this disease is also significant, in that CDH has been identified as the third-most-costly of birth defects in a recent study. The severe consequences of this congenital anomaly have led others to pursue methods of correcting CDH or its main consequence, lung hypoplasia, prior to birth, allowing for more normal postnatal function. The most promising in utero therapy developed thus far consists of complete occlusion of the fetal trachea, which has been shown to encourage lung growth. However, this procedure impairs the phasic mechanical forces that are known to critically regulate proper lung development. To overcome this, we propose the use of a miniature valve to provide dynamic tracheal occlusion (dTO) to promote lung growth. In preliminary experiments, a custom-designed, modified ventriculoperitoneal shunt valve was used to maintain a tracheal pressure of 6-8 mmHg, yet allow for efflux of lung fluid, in a fetal lamb CDH model. Compared to complete occlusion, dTO resulted in improved (near-normal) lung morphometrics and function. Here, we propose to further define the pressure characteristics for optimal lung growth and to create a miniature device that will allow for minimally invasive deployment. To create the device, a microvalve will be made using MEMS (micro electro mechanical systems) microfabrication techniques that allow for precise control of device geometry and performance specifications. The Phase I Specific Aims are to: (1) Establish microvalve designs with opening pressures in the range of 2-10 mmHg and (2) Determine valve pressure setting for optimal lung development. PUBLIC HEALTH RELEVANCE: Congenital diaphragmatic hernia (CDH) afflicts approximately 1 in 2000 newborns. As common as cystic fibrosis and spina bifida, CDH incurs significant long-term morbidity, mortality, and socioeconomic costs due to poor fetal lung development. The ultimate goal of the proposed STTR project is to apply novel technologies to develop a miniature device for treatment of CDH.