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.
