Mathematically Guided Experiments of Lung Mucus Transport Properties

本项目通过一系列实验，在数学的指导和分析下，探索和推断肺气道粘液的扩散和流动输运特性。这套实验和相应的仪器是必要的，以跨越生物学相关的长度、时间和力尺度，用于肺粘液流动和颗粒扩散。黏液层由单个纤毛、协调的纤毛波以及层流和湍流气流推动。观察到吸入的病毒、细菌、环境颗粒和药物载体颗粒在肺黏液中的扩散，确实在很大程度上取决于相对于黏液网格大小分布的颗粒大小以及颗粒与黏液凝胶的静电相互作用。此外，肺粘液的生物物理特性在不同人群和个体的疾病进展中有所不同。该项目提出了一种策略，以克服当前粘液运输表征方法的无数限制。个别项目将推进实验设计和诊断，从实验数据推断方法，以及直接建模和仿真工具。流动输运项目结合了波动理论方法、标准蠕变流变学的惯性扩展和随机头-头波动，以跨越必要的长度、时间和力尺度。扩散输运本质上是随机的，因此概述了新的模型和模拟工具来模拟和预测实验观察到的瞬态异常扩散特性。所有项目的设计都与黏液在肺生物学中的功能相一致，并且设计了集成的实验-数学工具，用于黏液样品的临床应用。这些工具和方法是在透明质酸溶液和琼脂糖凝胶两种粘液模拟物上开发和测试的，它们的性质可以先验地调整，并通过标准流变学仪器和理论独立测试。该项目为肺部健康评估和疾病治疗的新方法奠定了基础。目前的方法是根据临床试验的统计和积累的经验证据来治疗症状。机械地说，肺部感染是气道粘液无法捕获、运输和清除病原体或环境微粒的结果。因此，纤毛和气流作用下的黏液层流动，以及黏液层内不同颗粒的扩散，是肺部健康的基本机制。与普遍的看法相反，抗体提供了第二道防线。在生物学相关条件下，评估、预测和理解肺黏液层流动和弥漫性运输的工具和数学理论尚不存在。本项目将现有的实验方法、仪器和数学理论与新仪器、数学理论和数值算法的设计和建造结合起来。整合后，这些工具将能够推断单个患者粘液样本的流动和扩散运输特性，并能够测试物理和药物治疗以恢复粘液清除。

This project integrates a set of experiments, guided and analyzed by mathematics, to probe and infer diffusive and flow transport properties of lung airway mucus. The set of experiments and corresponding instruments are necessary to span the spectrum of biologically relevant length, time and force scales for lung mucus flow and particle diffusion within. Mucus layers are propelled by individual cilia, coordinated waves of cilia, as well as by laminar and turbulent airflow. The diffusion of inhaled viruses, bacteria, environmental particulates and drug carrier particles in lung mucus is observed to depend, indeed dramatically so, on particle size relative to the mesh size distribution of mucus and on particle electrostatic interactions with the mucus gel. Furthermore, the biophysical properties of lung mucus vary across populations and with disease progression in an individual. This project lays out a strategy to overcome the myriad limitations of current approaches to mucus transport characterization. Individual projects will advance experimental design and diagnostics, inference methods from experimental data, and direct modeling and simulation tools. Flow transport projects combine wave-theoretical methods, inertial extensions of standard creep rheology, and stochastic bead-bead fluctuations in order to span the requisite length, time and force scales. Diffusive transport is inherently stochastic, for which new models and simulation tools are outlined to model and predict the transient anomalous diffusive properties that are experimentally observed. All projects are designed consistent with the functions that mucus performs in lung biology, and the integrated experimental-mathematical tools are designed for clinical applicability to mucus samples. The tools and approach are developed and tested on two mucus simulants, hyaluronic acid solutions and agarose gels, whose properties can be tuned a priori and independently tested with standard rheological instruments and theory. This project develops the underpinnings of a new approach to lung health assessment and treatment of disorders and diseases. The present approach is to treat symptoms based on the statistics of clinical trials and accumulated empirical evidence. Mechanically, lung infections are the result of a failure of airway mucus to trap, transport and clear pathogens or environmental particulates. Thus the flow of mucus layers by the action of cilia and airflow, and the diffusion of diverse particles within the mucus layer, are the fundamental mechanisms that underlie lung health. Contrary to popular belief, antibodies provide a secondary line of defense. The tools and mathematical theory for assessment, prediction, and understanding of flow and diffusive transport of lung mucus layers in biologically relevant conditions do not exist. This project incorporates existing experimental methods, instruments, and mathematical theory with the design and construction of new instruments, mathematical theory and numerical algorithms. When integrated, these tools will provide the capability to infer flow and diffusive transport properties of mucus samples from an individual patient, and the capability to test physical and drug therapies to reinstate mucus clearance.