Epithelium damage and protection during reopening of occluded airways in a physiologic microfluidic pulmonary airway model.

Airways of the peripheral lung are prone to closure at low lung volumes. Deficiency or dysfunction of pulmonary surfactant during various lung diseases compounds this event by destabilizing the liquid lining of small airways and giving rise to occluding liquid plugs in airways. Propagation of liquid plugs in airways during inflation of the lung exerts large mechanical forces on airway cells. We describe a microfluidic model of small airways of the lung that mimics airway architecture, recreates physiologic levels of pulmonary pressures, and allows studying cellular response to repeated liquid plug propagation events. Substantial cellular injury happens due to the propagation of liquid plugs devoid of surfactant. We show that addition of a physiologic concentration of a clinical surfactant, Survanta, to propagating liquid plugs protects the epithelium and significantly reduces cell death. Although the protective role of surfactants has been demonstrated in models of a propagating air finger in liquid-filled airways, this is the first time to study the protective role of surfactants in liquid plugs where fluid mechanical stresses are expected to be higher than in air fingers. Our parallel computational simulations revealed a significant decrease in mechanical forces in the presence of surfactant, confirming the experimental observations. The results support the practice of providing exogenous surfactant to patients in certain clinical settings as a protective mechanism against pathologic flows. More importantly, this platform provides a useful model to investigate various surface tension-mediated lung diseases at the cellular level.

Microprinted feeder cells guide embryonic stem cell fate.

We introduce a non-contact approach to microprint multiple types of feeder cells in a microarray format using immiscible aqueous solutions of two biopolymers. Droplets of cell suspension in the denser aqueous phase are printed on a substrate residing within a bath of the immersion aqueous phase. Due to their affinity to the denser phase, cells remain localized within the drops and adhere to regions of the substrate underneath the drops. We show the utility of this technology for creating duplex heterocellular stem cell niches by printing two different support cell types on a gel surface and overlaying them with mouse embryonic stem cells (mESCs). As desired, the type of printed support cell spatially direct the fate of overlaid mESCs. Interestingly, we found that interspaced mESCs colonies on differentiation-inducing feeder cells show enhanced neuronal differentiation and give rise to dense networks of neurons. This cell printing technology provides unprecedented capabilities to efficiently identify the role of various feeder cells in guiding the fate of stem cells.

Numerical simulations investigating the regional and overall deposition efficiency of the human nasal cavity.

Numerical simulations have been carried out on a model of the right passageway of an anonymous, adult male's nasal cavity, constructed from magnetic resonance imagery (MRI) scans. Steady, laminar, inspiratory flow was assumed to simulate inhalation. Analysis shows smoothly varying streamlines with a peak in velocity magnitude occurring in the nasal valves and a peak in vorticity magnitude immediately posterior. Dilute, uniform concentrations of inertial (1 microm < or = d(ae) < or = 10 microm) particles were released at the nostril and tracked via a Lagrangian tracking algorithm. Deposition efficiency is shown to increase with particle size and flow rate. Preferential deposition is seen in the anterior third of the nasal cavity for large Stokes number particles. An empirical expression for particle deposition is proposed that incorporates particle size, flow rate, and nose anatomy.

Steady Displacement of Long Gas Bubbles in Channels and Tubes Filled by a Bingham Fluid.

Bingham fluids behave like solids below a von Mises stress threshold, the yield stress, while above it they behave like Newtonian fluids. They are characterized by a dimensionless parameter, Bingham number (Bn), which is the ratio of the yield stress to a characteristic viscous stress. In this study, the non-inertial steady motion of a finite size gas bubble in both a plane 2D channel and an axi-symmetric tube filled by a Bingham fluid has been studied numerically. The Bingham number, Bn, is in the range 0 ≤ Bn ≤ 3, where Bn=0 is the Newtonian case, while the Capillary number which is the ratio of a characteristic viscous force to the surface tension has values Ca=0.05, 0.10, and 0.25. The volume of all axi-symmetric and 2D bubbles has been chosen to be identical for all parameter choices and large enough for the bubbles to be long compared to the channel/tube width/diameter. The Bingham fluid constitutive equation is approximated by a regularized equation. During the motion, the bubble interface is separated from the wall by a static liquid film. The film thickness scaled by the tube radius (axi-symmetric)/half of the channel height (2D) is the dimensionless film thickness, h. The results show that increasing Bn initially leads to an increase in h, however, the profile h versus Bn can be monotonic or non-monotonic depending on Ca values and 2D/axi-symmetric configurations. The yield stress also alters the shape of the front and rear of the bubble and suppresses the capillary waves at the rear of the bubble. The yield stress increases the magnitude of the wall shear stress and its gradient and therefore increases the potential for epithelial cell injuries in applications to lung airway mucus plugs. The topology of the yield surfaces as well the flow pattern in the bubble frame of reference varies significantly by Ca and Bn.

Fine structures in sheared granular flows.

Computer simulations were used to investigate shear flows of large numbers of viscoelastic, monosized, spherical particles in unbounded and bounded systems with solid fractions ranging from 0.16 to 0.59. A modified hard-sphere model with inelastic, instantaneous particle interactions was found to replicate some results predicted by kinetic theory in an unbounded shear flow at low and moderate solids fractions. This model was found to predict features such as particle lateral diffusive motion even for systems at solid fractions as high as 0.56. However, for higher solid fractions where phenomena such as jamming could occur, a particle dynamics model accounting for particle contacts of finite duration has been developed, in which the viscoelastic behavior of the particles was represented using a nonlinear Hertzian model. The nonlinear viscoelastic model was found to give more reasonable predictions for cluster formation than previously reported linear models, especially when accounting for surface friction in the model. However, neither frictionless nor frictional particle models could predict particle ordering in unbounded flows. As such, simulations were performed for bounded systems using both the modified hard-sphere model and the nonlinear particle dynamic model. For a bounded shear flow, particle ordering could be predicted by the hard-sphere model even in the absence of both particle friction and gravity, with the local solid fraction and wall separation distance governing the flow stability. For these conditions chain formation was found to be quite likely in the disordered layers for frictional particles. The interesting stick-slip dynamics could be clearly observed in the normal stress signal at the bottom wall. Interpretations were proposed for the complex processes observed, which could lay the foundation for further investigations in sheared dense granular systems.

Combination of fluid and solid mechanical stresses contribute to cell death and detachment in a microfluidic alveolar model.

Studies using this micro-system demonstrated significant morphological differences between alveolar epithelial cells (transformed human alveolar epithelial cell line, A549 and primary murine alveolar epithelial cells, AECs) exposed to combination of solid mechanical and surface-tension stresses (cyclic propagation of air-liquid interface and wall stretch) compared to cell populations exposed solely to cyclic stretch. We have also measured significant differences in both cell death and cell detachment rates in cell monolayers experiencing combination of stresses. This research describes new tools for studying the combined effects of fluid mechanical and solid mechanical stress on alveolar cells. It also highlights the role that surface tension forces may play in the development of clinical pathology, especially under conditions of surfactant dysfunction. The results support the need for further research and improved understanding on techniques to reduce and eliminate fluid stresses in clinical settings.