Particle kinetics in the postnatally developing lung

描述（由申请人提供）：关于儿童肺部颗粒沉积的知识对于现实估计儿童气溶胶暴露造成的健康风险以及确定吸入治疗药物的正确剂量至关重要，但这一问题很少受到关注。目前，假设儿童的肺是成人肺的小尺寸版本，并且按比例缩小的成人肺模型用于评估沉积效率。然而，众所周知，在出生后的发育过程中，肺不仅在尺寸上生长，而且还经历了戏剧性的结构变化。我们以前的研究提供的证据表明，肺外周的结构是颗粒行为的主要决定因素;特别是，我们发现了一种新的颗粒运输机制-混沌混合-，在成人肺的完全肺泡化的管道中运行。我们假设肺解剖结构的年龄相关变化，如进行性肺泡化，导致颗粒混合和沉积的重大变化，预测沉积峰值出现在非常年幼的儿童，他们的肺已经大部分肺泡化，但尺寸仍然很小。为了验证这一假设，我们建议进行一项研究，结合理论和实验方法，建立在我们的专业知识。(1)我们将进行分析和数值分析，以阐明渐进的肺泡和混沌流动现象和相关混合的外观之间的关系。(2)我们将在简化和良好控制的物理模型中测试这些数学预测的结果，该模型具有可扩展的壁和不同程度的肺泡。(3)将使用处于不同肺泡形成阶段的发育中仔猪的离体肺进行吸入暴露和流动可视化实验。这些方法的结果一起将给我们一个全面的看法肺泡的几何形状和混乱的混合机制在肺中的外观，可能会导致突然变化的颗粒沉积的程度之间的关系。同时，本项目的研究结果可能为现实和合理的儿童吸入剂量测定奠定基础-这是一个具有重要临床意义的问题。

DESCRIPTION (provided by applicant): Knowledge on particle deposition in children's lungs is essential for realistic estimates of health risks posed by aerosol exposure of children, and also to determine the correct dose for therapeutic drugs delivered by inhalation, but this problem has received little attention. Currently, it is assumed that children's lungs are a small-size version of the adult one, and scaled-down adult lung models are used for the assessment of deposition efficiency. It is well established, however, that during postnatal development the lungs are not only growing in size, but they also undergo dramatic structural changes. Our previous studies provided evidence that the structure of the lung periphery is a major determinant of particle behavior; particularly, we have discovered a new mechanism of particle transport -chaotic mixing-, operating in the fully alveolated ducts of adult lungs. We hypothesize that age-associated changes in lung anatomy, such as progressive alveolation, lead to major changes in particle mixing and deposition, predicting that deposition peaks in very young children with lungs that have become largely alveolated already but are still small in size. To test this hypothesis, we propose to perform a study combining theoretical and experimental approaches building on our expertise. (1) We will perform analytical and numerical analyses to elucidate the relationship between progressive alveolation and the appearance of chaotic flow phenomena and associated mixing. (2) We will test the findings of these mathematical predictions in simplified and well-controlled physical models with expandable walls and different degrees of alveolation. (3) Excised lungs of developing piglets at different stages of alveolation will be used to do inhalation exposure and flow visualization experiments. The results of these approaches taken together will give us a comprehensive view of the relationship between alveolar geometry and the appearance of chaotic mixing mechanisms in the lung that may result in a sudden change in the extent of particle deposition. At the same time the findings of this project may lay down the foundation for realistic and rationally based inhalation dosimetry in children - a matter of great clinical importance.