Continuum-kinetic-microscopic model of lung clearance due to core-annular fluid entrainment

The human lung is protected against aspirated infectious and toxic agents by a thin liquid layer lining the interior of the airways. This airway surface liquid is a bilayer composed of a viscoelastic mucus layer supported by a fluid film known as the periciliary liquid. The viscoelastic behavior of the mucus layer is principally due to long-chain polymers known as mucins. The airway surface liquid is cleared from the lung by ciliary transport, surface tension gradients, and airflow shear forces. This work presents a multiscale model of the effect of airflow shear forces, as exerted by tidal breathing and cough, upon clearance. The composition of the mucus layer is complex and variable in time. To avoid the restrictions imposed by adopting a viscoelastic flow model of limited validity, a multiscale computational model is introduced in which the continuum-level properties of the airway surface liquid are determined by microscopic simulation of long-chain polymers. A bridge between microscopic and continuum levels is constructed through a kinetic-level probability density function describing polymer chain configurations. The overall multiscale framework is especially suited to biological problems due to the flexibility afforded in specifying microscopic constituents, and examining the effects of various constituents upon overall mucus transport at the continuum scale

Continuum-kinetic-microscopic model of lung clearance due to core-annular fluid entrainment

The human lung is protected against aspirated infectious and toxic agents by a thin liquid layer lining the interior of the airways. This airway surface liquid is a bilayer composed of a viscoelastic mucus layer supported by a fluid film known as the periciliary liquid. The viscoelastic behavior of the mucus layer is principally due to long-chain polymers known as mucins. The airway surface liquid is cleared from the lung by ciliary transport, surface tension gradients, and airflow shear forces. This work presents a multiscale model of the effect of airflow shear forces, as exerted by tidal breathing and cough, upon clearance. The composition of the mucus layer is complex and variable in time. To avoid the restrictions imposed by adopting a viscoelastic flow model of limited validity, a multiscale computational model is introduced in which the continuum-level properties of the airway surface liquid are determined by microscopic simulation of long-chain polymers. A bridge between microscopic and continuum levels is constructed through a kinetic-level probability density function describing polymer chain configurations. The overall multiscale framework is especially suited to biological problems due to the flexibility afforded in specifying microscopic constituents, and examining the effects of various constituents upon overall mucus transport at the continuum scale

Engineering Systems to Study the Mechanics of Cilia- and Airflow-mediated Mucus Clearance

The pulmonary airway surface liquid layer is comprised of two components: 1) inhaled pathogens that are stuck to a mucus layer and 2) a periciliary layer (PCL) that provides an environment for mucociliary clearance (MCC) out of the lungs. The mechanisms of how the beating of cilia from adjacent ciliated cells is coordinated are poorly understood. In Chapter 2, the perfusion of fluid flow along the apical surface of airway cells was hypothesized to yield airway cultures that transported mucus uni-directionally. To test this hypothesis, perfusion protocols were performed during ciliogenesis and post-ciliation phase of in vitro human bronchial epithelial (HBE) airway models. The length of exposure of fluid shear stress on the apical surface of airway epithelial cultures yielded transient or permanent unidirectional mucus transport in the direction of fluid flow cue. These characteristics matched in vivo biology and remained unseen in standard tissue culturing protocols. In addition to MCC, two other modes of mucus clearance have been studied namely cough clearance (CC) and proposed here, a third mechanism: cilia-independent "gas-liquid transport" (GLT). In Chapter 3, a system was engineered to deliver laminar, humidified airflow across the surface of HBE cultures, which emulated peak expiratory flow rates associated with exhalation. In the GLT models, three conditions of mucosal hydration were tested to represent a variety of clearance models between health and disease: from well-hydrated, normal-like mucus, in situ mucus, to dehydrated mucus, which represented severe Cystic Fibrosis (CF) mucus. At healthy mucus concentrations (2-4%), GLT rate was much faster at clearing mucus than MCC. In contrast, under conditions of severe dehydration, CF-like, GLT failed to produce significant mucus transport, as observed with MCC. In Chapter 4, the effect of mucus clearance with air velocities associated with cough was investigated and captured using high-speed photography. CC was also observed to decrease as mucus concentration increased. Together, the methods developed in this dissertation will help researchers to culture HBE cells with transport characteristics similar to in vivo behavior and help clinicians to better evaluate drug therapeutics on airway clearance for treating muco-obstructive diseases like CF.Doctor of Philosoph

Characterization of large LPG pool fires and mucus clearance dynamics in upper airway using CFD method

A large pool fire can be generated if there is a liquefied petroleum gas (LPG) leakage during transportation or at storage sites, while the underlying mechanisms of how the hazardous matter can be generated from the LPG pool fire and delivered dose into the human lung, and evaluation of the exposure risks are still ambiguous. Thus, it is necessary to systematically study the LPG pool fire rheology and the generation, transport, and deposition of the generated aerosolized toxicants from the pool fire to the human respiratory system. To partially address the above-mentioned concerns, this study has conducted novel research efforts to investigate the characteristics of large LPG pool fires and cough-driven mucus transport behaviors in upper lung airways, which can be employed to assess the health risks from LPG fires to the pulmonary system future work. Specifically, Chapter I reviewed the previous studies concerning the LPG pool fires and mucus movement behaviors in lung airways using experimental methods and numerical approaches, as well as presented the research objectives. Chapter II was to develop an experimentally validated CFD model to estimate the surface emissive power, and predict the incident radiation from large LPG pool fires to the surrounded objects and develop the reasonable minimum distances between the pool fire and objects using CFD simulations. Chapter III performed numerical simulations using an experimentally validated CFD model to simulate large LPG pool fires and predict the fire configuration characteristics, including flame height and flame tilt. The impacts of pool diameter and wind velocity on the fire configuration characteristics were investigated. Based on the CFD results and the parametric analysis, new correlations are proposed to provide more accurate estimations of flame height and tilt specifically for large LPG pool fires. Chapter IV has built an experimentally validated Volume of Fluid (VOF) model to conduct a quantitative analysis to investigate the effects of cough intensity and initial mucus thicknesses on the mucus transport and clearance in a mouth-to-trachea airway geometry. The VOF model developed in this work can be further refined and integrated with Discrete Phase Models (DPMs) to predict the mucus clearance effect on inhaled toxic particles from LPG pool fires explicitly. In addition, Chapter V summarized the essentials of the research work done and outlined the future work