The effect of viscoelasticity in an airway closure model.

The closure of a human lung airway is modeled as a pipe coated internally with a liquid that takes into account the viscoelastic properties of mucus. For a thick enough coating, the Plateau-Rayleigh instability blocks the airway by the creation of a liquid plug, and the pre-closure phase is dominated by the Newtonian behavior of the liquid. Our previous study with a Newtonian-liquid model demonstrated that the bifrontal plug growth consequent to airway closure induces a high level of stress and stress gradients on the airway wall, which is large enough to damage the epithelial cells, causing sub-lethal or lethal responses. In this study, we explore the effect of the viscoelastic properties of mucus by means of the Oldroyd-B and FENE-CR model. Viscoelasticity is shown to be very relevant in the post-coalescence process, introducing a second peak of the wall shear stresses. This second peak is related to an elastic instability due to the presence of the polymeric extra stresses. For high-enough Weissenberg and Laplace numbers, this second shear stress peak is as severe as the first one. Consequently, a second lethal or sub-lethal response of the epithelial cells is induced.

Effects of surfactant on propagation and rupture of a liquid plug in a tube.

Surfactant-laden liquid plug propagation and rupture occurring in lower lung airways are studied computationally using a front-tracking method. The plug is driven by an applied constant pressure in a rigid axisymmetric tube whose inner surface is coated by a thin liquid film. The evolution equations of the interfacial and bulk surfactant concentrations coupled with the incompressible Navier-Stokes equations are solved in the front-tracking framework. The numerical method is first validated for a surfactant-free case and the results are found to be in good agreement with the earlier simulations of Fujioka et al. (2008) and Hassan et al. (2011). Then extensive simulations are performed to investigate the effects of surfactant on the mechanical stresses that could be injurious to epithelial cells such as pressure and shear stress. It is found that the liquid plug ruptures violently to induce large pressure and shear stress on airway walls and even a tiny amount of surfactant significantly reduces the pressure and shear stress and thus improves cell survivability. However, addition of surfactant also delays the plug rupture and thus airway reopening.

Liquid plug formation in an airway closure model.

The closure of a human lung airway is modeled as an instability of a two-phase flow in a pipe coated internally with a Newtonian liquid. For a thick enough coating, the Plateau-Rayleigh instability creates a liquid plug which blocks the airway, halting distal gas exchange. Owing to a bi-frontal plug growth, this airway closure flow induces high stress levels on the wall, which is the location of airway epithelial cells. A parametric numerical study is carried out simulating relevant conditions for human lungs, either in ordinary or pathological situations. Our simulations can represent the physical process from pre- to post-coalescence phases. Previous studies have been limited to pre-coalescence only. The topological change during coalescence induces a high level of stress and stress gradients on the epithelial cells, which are large enough to damage them, causing sub-lethal or lethal responses. We find that post-coalescence wall stresses can be in the range of 300% to 600% greater than pre-coalescence values, so introduce a new important source of mechanical perturbation to the cells.

Liquid plug propagation in flexible microchannels: A small airway model.

In the present study, we investigate the effect of wall flexibility on the plug propagation and the resulting wall stresses in small airway models with experimental measurements and numerical simulations. Experimentally, a flexible microchannel was fabricated to mimic the flexible small airways using soft lithography. Liquid plugs were generated and propagated through the microchannels. The local wall deformation is observed instantaneously during plug propagation with the maximum increasing with plug speed. The pressure drop across the plug is measured and observed to increase with plug speed, and is slightly smaller in a flexible channel compared to that in a rigid channel. A computational model is then presented to model the steady plug propagation through a flexible channel corresponding to the middle plane in the experimental device. The results show qualitative agreements with experiments on wall shapes and pressure drops and the discrepancies bring up interesting questions on current field of modeling. The flexible wall deforms inward near the plug core region, the deformation and pressure drop across the plug increase with the plug speed. The wall deformation and resulting stresses vary with different longitudinal tensions, i.e., for large wall longitudinal tension, the wall deforms slightly, which causes decreased fluid stress and stress gradients on the flexible wall comparing to that on rigid walls; however, the wall stress gradients are found to be much larger on highly deformable walls with small longitudinal tensions. Therefore, in diseases such as emphysema, with more deformable airways, there is a high possibility of induced injuries on lining cells along the airways because of larger wall stresses and stress gradients.

Gas-liquid two-phase flow patterns in rectangular polymeric microchannels: effect of surface wetting properties.

Here we map gas-liquid two-phase flow regimes observed in polymeric microchannels with different wetting properties. We utilized video and confocal microscopy to examine two-phase flow patterns produced by parallel injection of air and water through a Y-shaped junction into a rectangular microchannel made of poly(dimethylsiloxane) (PDMS). We observed seven flow regimes in microchannels with hydrophobic walls, whereas only two flow patterns were identified in hydrophilic microchannels. Our study demonstrates that surface wettability has a profound influence on the spatial distribution of air and water moving in microchannels.

Effects of inertia and gravity on liquid plug splitting at a bifurcation.

Liquid plugs may form in pulmonary airways during the process of liquid instillation or removal in many clinical treatments. During inspiration the plug may split at airway bifurcations and lead to a nonuniform final liquid distribution, which can adversely affect treatment outcomes. In this paper, a combination of bench top experimental and theoretical studies is presented to study the effects of inertia and gravity on plug splitting in an airway bifurcation model to simulate the liquid distributions in large airways. The splitting ratio, Rs, is defined as the ratio of the plug volume entering the upper (gravitationally opposed) daughter tube to the lower (gravitationally favored) one. Rs is measured as a function of parent tube Reynolds number, Rep; gravitational orientations for roll angle, phi, and pitch angle, gamma; parent plug length LP; and the presence of pre-existing plug blockages in downstream daughter tubes. Results show that increasing Rep causes more homogeneous splitting. A critical Reynolds number Rec is found to exist so that when Rep < or = Rec, Rs = 0, i.e., no liquid enters the upper daughter tube. Rec increases while Rs decreases with increasing the gravitational effect, i.e., increasing phi and gamma. When a blockage exists in the lower daughter, Rec is only found at phi = 60 deg in the range of Rep studied, and the resulting total mass ratio can be as high as 6, which also asymptotes to a finite value for different phi as Rep increases. Inertia is further demonstrated to cause more homogeneous plug splitting from a comparison study of Rs versus Cap (another characteristic speed) for three liquids: water, glycerin, and LB-400X. A theoretical model based on entrance flow for the plug in the daughters is developed and predicts Rs versus Rep. The frictional pressure drop, as a part of the total pressure drop, is estimated by two fitting parameters and shows a linear relationship with Rep. The theory provides a good prediction on liquid plug splitting and well simulates the liquid distributions in the large airways of human lungs.

Effect of gravity on liquid plug transport through an airway bifurcation model.

Many medical therapies require liquid plugs to be instilled into and delivered throughout the pulmonary airways. Improving these treatments requires a better understanding of how liquid distributes throughout these airways. In this study, gravitational and surface mechanisms determining the distribution of instilled liquids are examined experimentally using a bench-top model of a symmetrically bifurcating airway. A liquid plug was instilled into the parent tube and driven through the bifurcation by a syringe pump. The effect of gravity was adjusted by changing the roll angle (phi) and pitch angle (gamma) of the bifurcation (phi = gamma =0 deg was isogravitational). Phi determines the relative gravitational orientation of the two daughter tubes: when phi not equal to 0 deg, one daughter tube was lower (gravitationally favored) compared to the other. Gamma determines the component of gravity acting along the axial direction of the parent tube: when gamma not equal to 0 deg, a nonzero component of gravity acts along the axial direction of the parent tube. A splitting ratio Rs, is defined as the ratio of the liquid volume in the upper daughter to the lower just after plug splitting. We measured the splitting ratio, Rs, as a function of: the parent-tube capillary number (Cap); the Bond number (Bo); phi; gamma; and the presence of pre-existing plugs initially blocking either daughter tube. A critical capillary number (Cac) was found to exist below which no liquid entered the upper daughter (Rs = 0), and above which Rs increased and leveled off with Cap. Cac increased while Rs decreased with increasing phi, gamma, and Bo for blocked and unblocked cases at a given Cap > Ca,. Compared to the nonblockage cases, Rs decreased (increased) at a given Cap while Cac increased (decreased) with an upper (lower) liquid blockage. More liquid entered the unblocked daughter with a blockage in one daughter tube, and this effect was larger with larger gravity effect. A simple theoretical model that predicts Rs and Cac is in qualitative agreement with the experiments over a wide range of parameters.

The effect of airway wall motion on surfactant delivery.

Soluble surfactant and airway surface liquid transport are examined using a mathematical model of Marangoni flows which accounts for airway branching and for cyclic airway stretching. Both radial and longitudinal wall strains are considered. The model allows for variation of the amplitude and frequency of the motion, as may occur under a variety of ventilatory situations occurring during surfactant replacement therapy. The soluble surfactant dynamics of the thin fluid film are modeled by linear sorption. The delivery of surfactants into the lung is handled by setting the proximal boundary condition to a higher concentration compared to the distal boundary condition. Starting with a steady-state, nonuniform, surfactant distribution, we find that transport of surfactant into the lung is enhanced for increasing strain amplitudes. However, for fixed amplitude, increasing frequency has a smaller effect. At small strain amplitudes, increasing frequency enhances transport, but at large strain amplitudes, increasing cycling frequency has the opposite effect.

Distribution dynamics of perfluorocarbon delivery to the lungs: an intact rabbit model.

Motivated by the goal of understanding how to most homogeneously fill the lungs with perfluorocarbon for liquid ventilation, we investigate the transport of liquid instilled into the lungs using an intact rabbit model. Perfluorocarbon is instilled into the trachea of the ventilated animal. Radiographic images of the perfluorocarbon distribution are obtained at a rate of 30 frames/s during the filling process. Image analysis is used to quantify the liquid distribution (center of mass, spatial standard deviation, skewness, kurtosis, and indicators of homogeneity) as time progresses. We compare the distribution dynamics in supine animals to those in upright animals for three constant infusion rates of perfluorocarbon: 15, 40, and 60 ml/min. It is found that formation of liquid plugs in large airways, which is affected by posture and infusion rate, can result in a more homogeneous liquid distribution than gravity drainage alone. The supine posture resulted in more homogeneous filling of the lungs than did upright posture, in which the lungs tend to fill in the inferior regions first. Faster instillation of perfluorocarbon results in liquid plugs forming in large airways and, consequently, more uniform distribution of perfluorocarbon than slower instillation rates in the upright animals.

Steady-state pleural fluid flow and pressure and the effects of lung buoyancy.

Both theoretical and experimental studies of pleural fluid dynamics and lung buoyancy during steady-state, apneic conditions are presented. The theory shows that steady-state, top-to-bottom pleural-liquid flow creates a pressure distribution that opposes lung buoyancy. These two forces may balance, permitting dynamic lung floating, but when they do not, pleural-pleural contact is required. The animal experiments examine pleural-liquid pressure distributions in response to simulated reduced gravity, achieved by lung inflation with perfluorocarbon liquid as compared to air. The resulting decrease in lung buoyancy modifies the force balance in the pleural fluid, which is reflected in its vertical pressure gradient. The data and model show that the decrease in buoyancy with perfluorocarbon inflation causes the vertical pressure gradient to approach hydrostatic. In the microgravity analogue, the pleural pressures would be toward a more uniform distribution, consistent with ventilation studies during space flight. The pleural liquid turnover predicted by the model is computed and found to be comparable to experimental values from the literature. The model provides the flow field, which can be used to develop a full transport theory for molecular and cellular constituents that are found in pleural fluid.

Respiratory fluid mechanics and transport processes.

The field of respiratory flow and transport has experienced significant research activity over the past several years. Important contributions to the knowledge base come from pulmonary and critical care medicine, surgery, physiology, environmental health sciences, biophysics, and engineering. Several disciplines within engineering have strong and historical ties to respiration including mechanical, chemical, civil/environmental, aerospace and, of course, biomedical engineering. This review draws from a wide variety of scientific literature that reflects the diverse constituency and audience that respiratory science has developed. The subject areas covered include nasal flow and transport, airway gas flow, alternative modes of ventilation, nonrespiratory gas transport, aerosol transport, airway stability, mucus transport, pulmonary acoustics, surfactant dynamics and delivery, and pleural liquid flow. Within each area are a number of subtopics whose exploration can provide the opportunity of both depth and breadth for the interested reader.

A rat lung model of instilled liquid transport in the pulmonary airways.

When a liquid is instilled in the pulmonary airways during medical therapy, the method of instillation affects the liquid distribution throughout the lung. To investigate the fluid transport dynamics, exogenous surfactant (Survanta) mixed with a radiopaque tracer is instilled into tracheae of vertical, excised rat lungs (ventilation 40 breaths/min, 4 ml tidal volume). Two methods are compared: For case A, the liquid drains by gravity into the upper airways followed by inspiration; for case B, the liquid initially forms a plug in the trachea, followed by inspiration. Experiments are continuously recorded using a microfocal X-ray source and an image-intensifier, charge-coupled device image train. Video images recorded at 30 images/s are digitized and analyzed. Transport dynamics during the first few breaths are quantified statistically and follow trends for liquid plug propagation theory. A plug of liquid driven by forced air can reach alveolar regions within the first few breaths. Homogeneity of distribution measured at end inspiration for several breaths demonstrates that case B is twice as homogeneous as case A. The formation of a liquid plug in the trachea, before inspiration, is important in creating a more uniform liquid distribution throughout the lungs.

Liquid plug flow in straight and bifurcating tubes.

A finite-length liquid plug may be present in an airway due to disease, airway closure, or by direct instillation for medical therapy. Air forced by ventilation propagates the plug through the airways, where it deposits fluid onto the airway walls. The plug may encounter single or bifurcating airways, an airway surface liquid, and other liquid plugs in nearby airways. In order to understand how these flow situations influence plug transport, benchtop experiments are performed for liquid plug flow in: Case (i) straight dry tubes, Case (ii) straight pre-wetted tubes, Case (iii) bifurcating dry tubes, and Case (iv) bifurcating tubes with a liquid blockage in one daughter. Data are obtainedfor the trailing film thickness and plug splitting ratio as a function of capillary number and plug volumes. For Case (i), the finite length plug in a dry tube has similar behavior to a semi-infinite plug. For Case (ii), the trailing film thickness is dependent upon the plug capillary number (Ca) and not the precursor film thickness, although the shortening or lengthening of the liquid plug is influenced by the precursor film. For Case (iii), the plug splits evenly between the two daughters and the deposited film thickness depends on the local plug Ca, except for a small discrepancy that may be due to an entrance effect or from curvature of the tubes. For Case (iv), a plug passing from the parent to daughters will deliver more liquid to the unblocked daughter (nearly double, consistently) and then the plug will then travel at greater Ca in the unblocked daughter as the blocked. The flow asymmetry is enhanced for a larger blockage volume and diminished for a larger parent plug volume and parent-Ca.

Partial prevention of monocyte and granulocyte activation in experimental vein grafts by using a biomechanical engineering approach.

Leukocytes interact with endothelial cells and contribute to the development of vascular diseases such as thrombosis and atherosclerosis. These processes are possibly influenced by mechanical factors. This study focused on the role of mechanical stretch in the activation of monocytes and granulocytes in experimental vein grafts. Two models were created by using rats: a nonengineered vein graft with increased tensile stress, which was created by grafting a jugular vein into the abdominal aorta, and an engineered vein graft with reduced tensile stress, which was created by restricting the vein graft into a cylindrical sheath constructed by using fixative-treated intestinal tissue. The density of activated monocytes and granulocytes, which attached to the endothelium, and the distribution of the intercellular adhesion molecule (ICAM)-1 in endothelial cells were examined using immunohistological assays. It was found that, in nonengineered vein grafts, the density of activated monocytes and granulocytes increased significantly compared to that in normal jugular veins at day 1, 5, 10 and 20. At each observation time, the cell density in the proximal region of the nonengineered vein grafts was significantly higher than that in the middle and distal regions, and the cell density in the distal region was significantly higher than that in the middle region. These changes were associated with ICAM-1 clustering at day 1 and 5 and focal ICAM-1 un-regulation at day 10 and 20. In engineered vein grafts, the density of activated monocytes and granulocytes decreased significantly compared to that in nonengineered vein grafts at all observation times, although it was significantly higher than that in normal jugular veins. At each observation time, the cell density in the proximal and distal regions was significantly higher than that in the middle region, but no significant difference was found between the proximal and distal regions. ICAM-1 clustering along endothelial cell borders was found at day 1 and 5, but no apparent focal ICAM-1 up-regulation was found at day 10 and 20. These results suggested that mechanical stretch due to exposure to increased tensile stress contributed to the activation of monocytes and granulocytes in experimental vein grafts, and this event could be partially prevented by reducing tensile stress using a biomechanical engineering approach.

Surfactant effects in model airway closure experiments.

The capillary instability that occurs on an annular film lining a tube is studied as a model of airway closure. Small waves in the film can amplify and form a plug across the tube. This dynamical behavior is studied using theoretical models and bench-top experiments. Our model predicts the initial growth rate of the instability and its dependence on surfactant effects. In experiments, an annular film is formed by infusion of water into an initially oil-filled glass capillary tube. The thickness of the oil film varies with the infusion flow rate. The instability growth rate and closure time are measured for a range of film thicknesses. Our theory predicts that a thinner film and higher surfactant activity enhance stability; surfactant can decrease the growth rate to 25% of its surfactant-free value. In experiments, we find that surfactant can decrease the growth rate to 20% and increase the closure time by a factor of 3.8. Functional values of a critical film thickness for closure support the theory that it increases in the presence of surfactant.

Surfactant-spreading and surface-compression disturbance on a thin viscous film.

Spreading of a new surfactant in the presence of a pre-existing surfactant distribution is investigated both experimentally and theoretically for a thin viscous substrate. The experiments are designed to provide a better understanding of the fundamental interfacial and fluid dynamics for spreading of surfactants instilled into the lung. Quantitative measurements of spreading rates were conducted using a fluorescent new surfactant that was excited by argon laser light as it spread on an air-glycerin interface in a petri dish. It is found that pre-existing surfactant impedes surfactant spreading. However, fluorescent microspheres used as surface markers show that pre-existing surfactant facilitates the propagation of a surface-compression disturbance, which travels faster than the leading edge of the new surfactant. The experimental results compare well with the theory developed using lubrication approximations. An effective diffusivity of the thin film system is found to be Deff = (E*gamma)/(mu/H), which indicates that the surface-compression disturbance propagates faster for larger background surfactant concentration, gamma, larger constant slope of the sigma*-gamma* relation, -E*, and smaller viscous resistance, mu/H. Note that sigma* and gamma* are the dimensional surface tension and concentration, respectively, mu is fluid viscosity, and H is the unperturbed film thickness.

A theoretical study of surfactant and liquid delivery into the lung.

A computational study is presented for the transport of liquids and insoluble surfactant through the lung airways, delivered from a source at the distal end of the trachea. Four distinct transport regimes are considered: 1) the instilled bolus may create a liquid plug that occludes the large airways but is forced peripherally during mechanical ventilation; 2) the bolus creates a deposited film on the airway walls, either from the liquid plug transport or from direct coating, that drains under the influence of gravity through the first few airway generations; 3) in smaller airways, surfactant species form a surface layer that spreads due to surface-tension gradients, i.e., Marangoni flows; and 4) the surfactant finally reaches the alveolar compartment where it is cleared according to first-order kinetics. The time required for a quasi-steady-state transport process to evolve and for the subsequent delivery of the dose is predicted. Following fairly rapid transients, on the order of seconds, steady-state transport develops and is governed by the interaction of Marangoni flow and alveolar kinetics. Total delivery time is approximately 24 h for a typical first dose. Numerical solutions show that both transit and delivery times are strongly influenced by the strength of the preexisting surfactant and the geometric properties of the airway network. Delivery times for follow-up doses can increase significantly as the level of preexisting surfactant rises.

Influence of intravenous perfluorocarbon administration on the dynamic behavior of lung surfactant.

Intravenous administration of perfluorocarbon (PFC) compounds can lead to pulmonary hyperinflation and respiratory distress in some mammals. This study was designed to quantify the effects of two PFC emulsions on the dynamic behavior of lung surfactant and to demonstrate that PFC is retained in the liquid lining the lung. New Zealand White rabbits received isotonic saline (3 ml/kg), Fluosol (15 ml/kg) or Oxygent (90% perfluorooctyl-bromide emulsion, 3 ml/kg). After seven days we euthanized the animals and lavaged the lungs. Surface tension-surface area relationships (sigma-A loops) were measured with the lavage fluid placed in a Wilhelmy plate-oscillating bellows apparatus. Loop hysteresis area after Fluosol administration was 334 +/- 92 dyne-cm, significantly greater than after saline (203 +/- 36 dyne-cm) but not Oxygent (274 +/- 66 dyne-cm). Loop hysteresis slope was higher with Oxygent (0.8 +/- 0.4 dyne/cm3) than after saline (0.6 +/- 0.3 dyne/cm3) or Fluosol (0.5 +/- 0.1 dyne/cm3). 282 MHz 19F NMR spectral analysis demonstrates that both PFCs tested appear only in the extracellular fraction of the lavage fluid. These results show that pulmonary elimination of intravascular PFC leads to PFC presence in the liquid lining the airways where it alters surfactant dynamic mechanical behavior.

Perfluorocarbon induced alterations in pulmonary mechanics.

Perfluorocarbon (PFC) compounds induce pulmonary hyperinflation and respiratory distress in some animals following intravenous administration. This study was designed to quantify the effects of two PFC emulsions on lung volumes and compliance and to identify the mechanism of pulmonary hyperinflation. New Zealand White rabbits received isotonic saline (3 ml/kg), Fluosol (15 ml/kg) or Oxygent (90% perfluorooctyl-bromide emulsion, 3 ml/kg). After seven days we measured functional residual capacity, vital capacity, lung compliance and thoracic gas volume. Gross and microscopic histologic examination of the lungs was performed. Functional residual capacity after Fluosol administration was 16.0 +/- 4.0 ml/kg, significantly greater than after saline (3.4 +/- 1.0 ml/kg) or Oxygent (4.0 +/- 1.4 ml/kg). Vital capacity was lower with Fluosol (30 +/- 5.0 ml/kg) than after saline (37 +/- 3.0 ml/kg) or Oxygent (37 +/- 2.0 ml/kg). Thoracic gas volume increased from 9 +/- 1.0 ml/kg (saline) to 16 +/- 13 ml/kg (Oxygent) and 33 +/- 7.0 ml/kg (Fluosol). Lung compliance was the same after saline (1.6 +/- 0.5 ml.cm H2O-1.kg-1) and Oxygent (1.5 +/- 0.3 ml.cm H2O-1.kg-1) but lower after Fluosol (0.9 +/- 0.1 ml.cm H2O-1.kg-1). Gross pathology demonstrated foam exudation from airways of animals receiving PFCs and intra-alveolar foam was identified by light microscopy. These results show intra-airway foam formation causes gas trapping and shifts tidal breathing to a less compliant region of the pressure-volume curve.

Mechanical forces alter growth factor release by pleural mesothelial cells.

The mesothelial cells that form the visceral pleura of the lung are subjected to physical forces such as stretch due to lung expansion and fluid shear stress due to the sliding motion of the lung against the chest wall. In this study, the effect of mechanical forces on the production of growth factors by mesothelial cells was investigated. Rat visceral pleura mesothelial (RVPM) cells were exposed to fluid shear stress by perfusing a column of cell-covered beads. RVPM cells grown on a silicone elastomer were subjected to cyclic strain by applying an oscillating vacuum to the bottom of the wells using the Flexercell apparatus. Fluid shear stress (5.2-15.7 dyn/cm2) stimulated the release of endothelin-1 (ET-1) by RVPM cells two- to fivefold over static cells. ET-1 secretion by RVPM cells was also stimulated approximately twofold by cyclic stretch (20% maximum strain, 30 cycles/min). RVPM cells released significant levels of platelet-derived growth factor (PDGF), but there was no effect of either shear stress or cyclic strain on PDGF release. These results suggest that the production of growth factors by pleural mesothelial cells is regulated in part by physical forces.