Evolution of interfacial mechanics of lung surfactant mimics progression of acute respiratory distress syndrome.

How acute respiratory distress syndrome progresses from underlying disease or trauma is poorly understood, and there are no generally accepted treatments resulting in a 40% mortality rate. However, during the inflammation that accompanies this disease, the phospholipase A2 concentration increases in the alveolar fluids leading to the hydrolysis of bacterial, viral, and lung surfactant phospholipids into soluble lysolipids. We show that if the lysolipid concentration in the subphase reaches or exceeds its critical micelle concentration, the surface tension, γ, of dipalmitoyl phosphatidylcholine (DPPC) or Curosurf monolayers increases and the dilatational modulus, [Formula: see text], decreases to that of a pure lysolipid interface. This is consistent with DPPC being solubilized in lysolipid micelles and being replaced by lysolipid at the interface. These changes lead to [Formula: see text] which is the criterion for the Laplace instability that can lead to mechanical instabilities during lung inflation, potentially causing alveolar collapse. These findings provide a mechanism behind the alveolar collapse and uneven lung inflation during ARDS.

Microtensiometer for Confocal Microscopy Visualization of Dynamic Interfaces.

Adsorption of surface-active molecules to fluid-fluid interfaces is ubiquitous in nature. Characterizing these interfaces requires measuring surfactant adsorption rates, evaluating equilibrium surface tensions as a function of bulk surfactant concentration, and relating how surface tension changes with changes in the interfacial area following equilibration. Simultaneous visualization of the interface using fluorescence imaging with a high-speed confocal microscope allows the direct evaluation of structure-function relationships. In the capillary pressure microtensiometer (CPM), a hemispherical air bubble is pinned at the end of the capillary in a 1 mL volume liquid reservoir. The capillary pressure across the bubble interface is controlled via a commercial microfluidic flow controller that allows for model-based pressure, bubble curvature, or bubble area control based on the Laplace equation. Compared to previous techniques such as the Langmuir trough and pendant drop, the measurement and control precision and response time are greatly enhanced; capillary pressure variations can be applied and controlled in milliseconds. The dynamic response of the bubble interface is visualized via a second optical lens as the bubble expands and contracts. The bubble contour is fit to a circular profile to determine the bubble curvature radius, R, as well as any deviations from circularity that would invalidate the results. The Laplace equation is used to determine the dynamic surface tension of the interface. Following equilibration, small pressure oscillations can be imposed by the computer-controlled microfluidic pump to oscillate the bubble radius (frequencies of 0.001-100 cycles/min) to determine the dilatational modulus The overall dimensions of the system are sufficiently small that the microtensiometer fits under the lens of a high-speed confocal microscope allowing fluorescently tagged chemical species to be quantitatively tracked with submicron lateral resolution.

Flow regime transitions and effects on solute transport in surfactant-driven Marangoni flows.

HYPOTHESIS: Surfactant-driven Marangoni flow on liquid films is predicted to depend on subphase depth and initial surface tension difference between the subphase and deposited surfactant solution drop. Changes in flow behavior will impact transport of soluble species entrained in the Marangoni flow along the surface. In extreme cases, the subphase film may rupture, limiting transport. Understanding this behavior is important for applications in drug delivery, coatings, and oil spill remediation. EXPERIMENTS: A trans-illumination optical technique measured the subphase height profiles and drop content transport after drop deposition when varying initial subphase depth, surfactant concentration, and subphase viscosity. FINDINGS: Three distinct flow regimes were identified depending on the subphase depth and surfactant concentration and mapped onto an operating diagram. These are characterized as a "central depression" bounded by an outwardly traveling ridge, an "annular depression" bounded by a central dome and the traveling ridge, and an "annular dewetting" when the subphase ruptures. Well above the critical micelle concentration, transitions between regimes occur at characteristic ratios of gravitational and initial surface tension gradient stresses; transitions shift when surfactant dilution during spreading weakens the stress before the completion of the spreading event. Drop contents travel with the ridge, but dewetting hinders transport.

Surfactant-induced Marangoni transport of lipids and therapeutics within the lung.

Understanding the fundamentals of surface transport on thin viscous films has important application in pulmonary drug delivery. The human lung contains a large-area interface between its complex fluid lining and inhaled air. Marangoni flows driven by surface tension gradients along this interface would promote enhanced distribution of inhaled therapeutics by carrying them from where they are deposited in the upper airways, along the fluid interface to deeper regions of the lung. Motivated by the potential to improve therapies for acute and chronic lung diseases, we review recent progress in modeling and experimental studies of Marangoni transport induced by the deposition of surfactant-containing microliter drops and liquid aerosols (picoliter drops) onto a fluid interface. The roles of key system variables are identified, including surfactant solubility, drop miscibility with the subphase, and the thickness, composition and surface properties of the subphase liquid. Of particular interest is the unanticipated but crucial role of aerosol processing to achieve Marangoni transport via phospholipid vesicle dispersions, which are likely candidates for a biocompatible delivery system. Progress in this field has the potential to not only improve outcomes in patients with chronic and acute lung diseases, but also to further our understanding of surface transport in complex systems.

Aerosolizing Lipid Dispersions Enables Antibiotic Transport Across Mimics of the Lung Airway Surface Even in the Presence of Pre-existing Lipid Monolayers.

BACKGROUND: Secondary lung infections are the primary cause of morbidity associated with cystic fibrosis lung disease. Aerosolized antibiotic inhalation is potentially advantageous but has limited effectiveness due to altered airway aerodynamics and deposition patterns that limit drug access to infected regions. One potential strategy to better reach infected areas is to formulate aerosols with surfactants that induce surface tension gradients and drive postdeposition drug dispersal via Marangoni transport along the airway surface liquid (ASL). Since this relies on surfactant-induced surface tension reduction, the presence of endogenous lipid monolayers may hinder drug dispersal performance. METHODS: Tobramycin solutions were formulated with dipalmitoylphosphatidylcholine (DPPC), a major component of endogenous pulmonary surfactant, to drive postdeposition aerosol dispersal across a model ASL based on a liquid layer or "subphase" of aqueous porcine gastric mucin (PGM) solution with predeposited DPPC monolayers to mimic the endogenous surfactant. In vitro subphase samples were collected from regions outside the aerosol deposition zone and assayed for tobramycin concentration using a closed enzyme donor immunoassay. The motion of a tracking bead across the subphase surface and the corresponding decrease in surface tension on aerosol deposition were tracked both with and without a predeposited DPPC monolayer. The surface tension/area isotherm for DPPC on PGM solution subphase was measured to aid in the interpretation of the tobramycin dispersal behavior. RESULTS AND CONCLUSIONS: Transport of tobramycin away from the deposition region occurs in aerosols formulated with DPPC whether or not predeposited lipid is present, and tobramycin concentrations are similar in both cases across biologically relevant length scales (∼8 cm). When DPPC is deposited from an aerosol, it induces ultralow surface tensions (<5 mN/m), which drive Marangoni flows, even in the presence of a dense background layer of DPPC. Therefore, aerosolized phospholipids, such as DPPC, will likely be effective spreading agents in the human lung.

Aggregation and separation in ternary particle/oil/water systems with fully wettable particles.

We report that a variety of ternary particle/liquid/liquid mixtures heavily aggregate or separate completely if (1) the particles are fully or almost fully wetted by one fluid, and (2) if the wetting fluid volume fraction is comparable to the particle volume fraction. Aggregation and separation do not happen if the particles are partially wetted by both fluids, in which case Pickering emulsions appear at all compositions. Rheological and geometric criteria for aggregation are proposed and compared with a state diagram of a ternary system composed of oil, water, and hydrophilic glass particles. Analogies are drawn to wet granulation and spherical agglomeration, two particle processing operations in which wetting phenomena are important.