Mathematically Guided Experiments of Lung Mucus Transport Properties

本计画整合一组实验，以数学分析为指导，探讨与推论肺气道黏液的扩散与流动输运特性。 一组实验和相应的仪器是必要的，以跨越肺粘液流动和颗粒扩散的生物相关长度，时间和力尺度的范围。 粘液层由单独的纤毛、纤毛的协调波以及层流和湍流气流推动。 据观察，吸入的病毒、细菌、环境微粒和药物载体颗粒在肺粘液中的扩散取决于（实际上显著地取决于）相对于粘液的筛目尺寸分布的颗粒尺寸以及与粘液凝胶的颗粒静电相互作用。 此外，肺粘液的生物物理性质在不同人群中以及随着个体的疾病进展而变化。该项目提出了一种策略，以克服目前粘液运输表征方法的无数局限性。个别项目将推进实验设计和诊断，从实验数据的推理方法，直接建模和仿真工具。 流体输送项目结合了联合收割机波动理论方法、标准蠕变流变学的惯性扩展和随机珠-珠波动，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，为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粘液在肺生物学中的功能一致，并且集成的实验-数学工具被设计用于粘液样本的临床适用性。 开发的工具和方法，并测试两种粘液模拟物，透明质酸溶液和琼脂糖凝胶，其性能可以事先调整和独立测试与标准的流变仪器和理论。该项目开发了一种新的肺部健康评估和治疗疾病的方法的基础。 目前的方法是根据临床试验的统计数据和积累的经验证据来治疗症状。 从机械上讲，肺部感染是气道粘液未能捕获、运输和清除病原体或环境颗粒的结果。 因此，通过纤毛和气流的作用，粘液层的流动，以及粘液层内各种颗粒的扩散，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。 用于评估、预测和理解生物相关条件下肺粘液层的流动和扩散运输的工具和数学理论尚不存在。 该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相结合。 当集成时，这些工具将提供推断来自个体患者的粘液样品的流动和扩散运输特性的能力，以及测试物理和药物疗法以恢复粘液清除的能力。

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.