The acute respiratory distress syndrome (ARDS) is a devastating lung disease. Patients with ARDS must be placed on a mechanical ventilator to survive. However, these ventilators also exacerbate the existing lung injury and as a result the mortality for ARDS is high (~25-40%). During ARDS, small pulmonary airways become occluded with fluid and mechanical ventilation of the fluid-filled lung involves the reopening of fluid-filled airways and the propagation of microbubbles over a layer of epithelial cells lining airway walls. Previous computational and experimental studies indicate that the large spatial gradients in pressure generated near the bubble tip may cause large-scale cellular deformation, rupture of the plasma membrane and cell necrosis. However, previous computational models do not account for the complex fluid-structure interactions that occur during in-vitro or in-vivo experiments. In addition, previous studies assumed rigid-wall conditions while pulmonary airways are in reality highly compliant and changes in airway wall mechanics may significantly influence the dynamics of airway reopening and cell deformation. Furthermore, the lung consists of a large network of bifurcating airways and different bifurcation patterns may influence both the hydrodynamics of airway reopening and cellular injury/deformation especially when the effect of gravity is considered. The objective of this particular thesis is to employ sophisticated computational fluid-structure interaction models to investigate how changes in the patient's biomechanical status such as airway wall compliance, fluid properties and bifurcation patterns influence the mechanics and hydrodynamics of microbubble induced cellular deformation and injury.
We have developed several sophisticated computational models that can better represent the in-vivo or in-vitro conditions of compliant airway walls, fully coupled fluid-structure interactions and 3D structure of pulmonary airways with epithelial cells lining airway walls. We will also develop a computational model that accounts for airway bifurcation and numerous physical forces (gravity, inertia and surface tension). The specific aims of this dissertation are:
1. Develop computational fluid dynamics models that better represent in-vitro microbubble flows conditions and can be extended to study cell deformation during airway reopening conditions.
2. Identify the influence of gravity, inertia and surface tension on liquid distribution and hydrodynamic forces in bifurcating pulmonary airways.
3. Evaluate how airway wall compliance influences cellular deformation during compliant airway reopening in a fully coupled two-dimensional fluid-structure interaction model.
4. Investigate how transient hydrodynamic forces generated during microbubble flows influence epithelial cell deformation in a three-dimensional computational model.
The innovative aspects of this research program include the development of a novel computational model that 1) considers the transient flow fields generated by airway wall deformation and fully coupled fluid-structure interactions at two free surfaces (air-liquid interface and compliant wall), 2) quantifies how airway wall compliance influences cellular deformation and 3) considers an additional levels of complexity such as bifurcation patterns and three-dimensional flow patterns that exists in-vivo. Our expectations are that the development of these more sophisticated computational models will help us understand how the complex structure of the lung epithelium and pulmonary airways influence microbubble-induced injury during mechanical ventilation. As such, this project could lead to important new information about the mechanisms responsible for ventilator-induced lung injury and the development of improved treatment and therapies of patients with ARDS.