Multiscale simulation of the respiratory epithelium: towards the development of a numerical tool to model human lungs

哮喘或慢性阻塞性肺病等慢性呼吸道疾病是影响近10亿人的主要健康问题，由于城市社会污染的增加，这一数字还在继续增长。这些呼吸问题的根源是发生在肺部的运输现象，称为“粘膜纤毛清除”（MCC），具有迷人的物理学，涉及通过上皮的质量交换，嵌入在双流体环境中的微观柔性纤毛的协调跳动以及可变形管道中的时间依赖性呼吸气流。 本计划的长期目标是开发新的数值工具，能够研究人体肺部的流动动力学。与心脏相比，这些器官对数值方法来说更具挑战性，主要是因为它们的多尺度性质（从纤毛长度的几微米到气管直径的厘米）和复杂的几何形状（23代二分分支）。 通过我以前的发现补助金，第一个求解器的基础上耦合格子玻尔兹曼/浸没边界法已经开发出来。在不同性质的两相流体介质中模拟了纤毛地毯的跳动。结果表明，纤毛的协调运动（异时性）可能是由于一个简单的流体动力学的反作用。与主流相比，沿相反方向移动的异时波被发现以更少的能量消耗更好地输送支气管粘液。然而，仍然需要数值的发展，以模拟更有代表性的条件下，在上皮细胞表面，然后为整个呼吸道。它包括支气管粘液的非牛顿行为、上皮表面（多孔介质）的质量交换、三维纤毛跳动模式、呼吸期间支气管树的弹性性质和叠加气流的建模。在微观尺度上获得的新的见解将有助于开发一个宏观模型，能够模拟几代人在上部的支气管树。这些微观和宏观尺度的模型将系统地进行比较，从新的实验设施在舍布鲁克大学开发的实验数据。八名高素质的人员将在该计划期间接受培训，并在一个非常刺激的环境中发展，与工程师，生物学家和临床医生互动。在加拿大，哮喘是第三大最常见的慢性疾病，有300万患者，给国家带来约16亿美元的成本。从机械角度更好地了解MCC可能有助于更好地管理此类疾病。它还将为涉及纤毛或鞭毛协调运动的其他应用铺平道路：海洋动物的流体推进，微流体设备中的泵送和混合以及其他人体器官（大脑，输卵管，眼睛）中的流体运输。

Chronic respiratory diseases such as asthma or chronic obstructive pulmonary disease are a major health problem affecting almost 1 billion people, a number that continues to grow due to the increased pollution in urban societies. At the root of these respiratory problems is a transport phenomenon that takes place in the lungs, named the "mucociliary clearance" (MCC), with a fascinating physics involving mass exchanges through the epithelium, the coordinated beating of microscopic flexible cilia embedded in a two-fluid environment and the time-dependent respiratory air flow in deformable conduits. The long-term objective of this present program is to develop new numerical tools able to investigate the flow dynamics in human lungs. Compared to heart, these are an even more challenging organ for numerical methods mainly because of their multiscale nature (from few microns for the cilia length to centimeters for the trachea's diameter) and complex geometry (23 generations of dichotomous branching). Through my former Discovery grant, a first solver based on the coupled lattice Boltzmann / immersed boundary method has been developed. The beating of cilia carpets has been simulated in a two-phase fluid medium with different properties. The results showed that a coordinated motion of cilia (metachrony) may emerge due to a simple hydrodynamic retroaction. Metachronal waves moving in the opposite direction compared to the main flow were found to better transport bronchial mucus with less energy consumption. Numerical developments are however still required to simulate more representative conditions at the epithelium surface then for the whole respiratory tract. It includes the modelling of the non-Newtonian behavior of bronchial mucus, the mass exchanges at the epithelium surface (porous medium), the three-dimensional cilia beating pattern, the elastic nature of the bronchial tree during breathing and the superimposed air flow. The new insights gained at the microscopic scale will serve to develop a macroscale model able to simulate several generations in the upper part of the bronchial tree. These micro- and macroscale models will be systematically compared to experimental data from new experimental facilities developed at Université de Sherbrooke. Eight highly qualified personnel will be trained during this program and evolved in a very stimulating environment, interacting with engineers, biologists and clinicians. In Canada, asthma is the third most common chronical disease with 3 millions of patients, inducing around $1.6 billion costs to the country. A better understanding of MCC from a mechanical point of view may serve to better manage such diseases. It will also pave the road to other applications where the coordinated motion of cilia or flagella is involved: the fluid propulsion of marine animals, the pumping and mixing in microfluidic devices and the fluid transport in other human organs (brain, Fallopian tubes, eyes).