Liquid plug propagation in flexible microchannels: A small airway model

Zheng, Ying; Fujioka, Hideki; Bian, Shiyao; Torisawa, Yu-suke; Takayama, Shuichi; Grotberg, J. B.

doi:10.1063/1.3183777

Cited by 40 publications

(30 citation statements)

References 57 publications

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“…Also, plug rupture and reformation at airway bifurcations could be different from those in the tubular sections of the airway (21). Interaction between plugs and the airway walls during air ventilation would also need to be carefully studied to enable more accurate liquid delivery in actual lungs (21,42). Although it would be technically challenging, the contact angles of liquid plugs and collars would need to be more precisely determined in the airways, especially within distal airways and alveoli.…”

Section: Discussionmentioning

confidence: 99%

Targeted delivery of liquid microvolumes into the lung

Kim

O’Neill

Dorrello

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The ability to deliver drugs to specific sites in the lung could radically improve therapeutic outcomes of a variety of lung diseases, including cystic fibrosis, severe bronchopneumonia, chronic obstructive pulmonary disease, and lung cancer. Using conventional methods for pulmonary drug administration, precise, localized delivery of exact doses of drugs to target regions remains challenging. Here we describe a more controlled delivery of soluble reagents (e.g., drugs, enzymes, and radionuclides) in microvolume liquid plugs to targeted branches of the pulmonary airway tree: upper airways, small airways (bronchioles), or the most distal alveoli. In this approach, a soluble liquid plug of very small volume (<1 mL) is instilled into the upper airways, and with programmed air ventilation of the lungs, the plug is pushed into a specific desired (more distal) airway to achieve deposition of liquid film onto the lung epithelium. The plug volume and ventilation conditions were determined by mathematical modeling of plug transport in a tubular geometry, and targeted liquid film deposition was demonstrated in rat lungs by three different in vivo imaging modalities. The experimental and modeling data suggest that instillation of microvolumes of liquid into a ventilated pulmonary airway could be an effective strategy to deliver exact doses of drugs to targeted pathologic regions of the lung, especially those inaccessible by bronchoscopy, to increase in situ efficacy of the drug and minimize systemic side effects.pulmonary drug delivery | lung disease | liquid instillation | lung airway | alveoli E ffective treatment strategies for lung diseases such as cystic fibrosis, tuberculosis, bronchopneumonia, and lung cancer would involve a small, highly concentrated dose of drug delivered directly to the pathologic site (1, 2). Unfortunately, delivery of a precise drug dose to specific sites in the lung is challenging using conventional systemic drug administration methods, resulting in inefficient treatments for many lung diseases (3, 4). For example, orally administered drugs often require high doses to achieve therapeutic effects due to first-pass metabolism, which in turn leads to systemic side effects (5). Although drugs administered i.v. can avoid first-pass metabolism, they can still incur a range of side effects (6).On the other hand, inhalation of aerosolized drugs has the advantage of noninvasively bringing a drug locally into the lung, and so it has been a first-line treatment option for many lung diseases in the outpatient setting (7,8). In particular, dry powder inhalers can allow for local delivery of drugs in specific lung regions (9). Because properties of powders such as particle size, density, and cohesiveness strongly affect particle transport behavior, dry powders should be prepared with appropriate properties conducive to delivery into specific locations in the structurally complex pulmonary airway tree (10).Alternatively, microvolumes of a liquid plug containing the drug could be instilled into the lung using ...

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Section: Discussionmentioning

confidence: 99%

Targeted delivery of liquid microvolumes into the lung

Kim

O’Neill

Dorrello

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Numerical simulations of liquid plug propagation in a rigid channel (Fujioka & Grotberg 2004Fujioka, Takayama & Grotberg 2008) confirmed that sharp peaks in wall stresses and stress gradients were present in the transition region of the plug during plug propagation. In addition, experimental and numerical studies of plug propagation in flexible microchannels (Zheng et al 2009) predicted a higher level of wall stresses and stress gradients along a highly deformable wall as compared to a rigid channel wall.…”

Section: Introductionmentioning

confidence: 96%

Numerical study of flow fields in an airway closure model

et al. 2011

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The liquid lining in small human airways can become unstable and form liquid plugs that close off the airways. Direct numerical simulations are carried out on an airway model to study this airway instability and the flow-induced stresses on the airway walls. The equations governing the fluid motion and the interfacial boundary conditions are solved using the finite-volume method coupled with the sharp interface method for the free surface. The dynamics of the closure process is simulated for a viscous Newtonian film with constant surface tension and a passive core gas phase. In addition, a special case is examined that considers the core dynamics so that comparisons can be made with the experiments of Bian et al. (J. Fluid Mech., vol. 647, 2010, p. 391). The computed flow fields and stress distributions are consistent with the experimental findings. Within the short time span of the closure process, there are large fluctuations in the wall shear stress. Furthermore, dramatic velocity changes in the film during closure indicate a steep normal stress gradient on the airway wall. The computational results show that the wall shear stress, normal stress and their gradients during closure can be high enough to injure airway epithelial cells.

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“…Furthermore, plug rupture imposed a higher risk of cellular injury than plug propagation alone. Additional experimental and theoretical studies on plug propagation in flexible microchannels by Zheng et al [26] indicate higher risk of injury for greater flexibility, which is a feature of airways in emphysema, for example.…”

Section: Introductionmentioning

confidence: 97%

Adaptive Lagrangian–Eulerian computation of propagation and rupture of a liquid plug in a tube

Hassan

Uzgoren

Fujioka

et al. 2010

Numerical Methods in Fluids

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SUMMARYLiquid plug propagation and rupture occurring in lung airways can have a detrimental effect on epithelial cells. In this study, a numerical simulation of a liquid plug in an infinite tube is conducted using an Eulerian-Lagrangian approach and the continuous interface method. A reconstruction scheme is developed to allow topological changes during plug rupture by altering the connectivity information about the interface mesh. Results prior to the rupture are in reasonable agreement with the study of Fujioka et al. in which a Lagrangian method is used. For unity non-dimensional pressure drop and a Laplace number of 1000, rupture time is shown to be delayed as the initial precursor film thickness increases and rupture is not expected for thicknesses larger than 0.10 of tube radius. During the plug rupture process, a sudden increase of mechanical stresses on the tube wall is recorded, which can cause tissue damage. The peak values of those stresses increase as the initial precursor film thickness is reduced. After rupture, the peaks in mechanical stresses decrease in magnitude as the plug vanishes and the flow approaches a fully developed behavior. Increasing initial pressure drop is shown to linearly increase maximum variations in wall pressure and shear stress. Decreasing the pressure drop and increasing the Laplace number appear to delay rupture because it takes longer for a fluid with large inertial forces to respond to the small pressure drop.

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Liquid plug propagation in flexible microchannels: A small airway model

Cited by 40 publications

References 57 publications

Targeted delivery of liquid microvolumes into the lung

Targeted delivery of liquid microvolumes into the lung

Numerical study of flow fields in an airway closure model

Adaptive Lagrangian–Eulerian computation of propagation and rupture of a liquid plug in a tube

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