Mathematically Guided Experiments of Lung Mucus Transport Properties

该项目整合了一系列实验，在数学的指导和分析下，探索和推断肺呼吸道粘液的扩散和流动传输特性。这套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、协调的纤毛波以及层流和湍流推动。观察到吸入的病毒、细菌、环境颗粒物和药物载体颗粒在肺粘液中的扩散取决于颗粒大小相对于粘液的网目尺寸分布以及颗粒与粘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人的疾病进展中也不同。该项目制定了一项战略，以克服目前粘液传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、从实验数据推断方法以及直接建模和模拟工具。流动输送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珠粒波动，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，新的模型和模拟工具被用来模拟和预测实验观察到的瞬时异常扩散特性。所有项目的设计都与粘液在肺部生物学中发挥的功能一致，集成的实验-数学工具是为粘液样本的临床适用性而设计的。该工具和方法是在两种粘液模拟剂--透明质酸溶液和琼脂糖凝胶上开发和测试的，这两种粘液模拟剂的性能可以事先调整，并可以使用标准流变仪和理论进行独立测试。该项目开发了一种新的肺部健康评估和疾病治疗方法的基础。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，肺部感染是由于呼吸道粘液未能捕获、运输和清除病原体或环境颗粒造成的。因此，纤毛和气流作用下粘液层的流动，以及粘液层内不同颗粒的扩散，是支撑肺健康的基本机制。与人们普遍认为的相反，抗体提供了第二道防线。用于评估、预测和了解在生物相关条件下肺粘液层的流动和扩散传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结合在一起。集成后，这些工具将能够推断单个患者的粘液样本的流动和扩散传输特性，并能够测试恢复粘液清除的物理和药物疗法。

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.