Motivated by the possibility of enhancing aerosol drug delivery to mucus-obstructed lungs, the spreading of a drop of aqueous surfactant solution on a physically entangled aqueous poly(acrylamide) solution subphase that mimics lung airway surface liquid was investigated. Sodium dodecyl sulfate was used as the surfactant. To visualize spreading of the drop and mimic the inclusion of a drug substance, fluorescein, a hydrophilic and non-surface active dye, was added to the surfactant solution. The spreading progresses through a series of events. Marangoni stresses initiate the convective spreading of the drop. Simultaneously, surfactant escapes across the drop’s contact line within a second of deposition and causes a change in subphase surface tension outside the drop on the order of 1 mN/m. Convective spreading of the drop ends within 2–3 seconds of drop deposition, when a new interfacial tension balance is achieved. Surfactant escape depletes the drop of surfactant and the residual drop takes the form of a static lens of non-zero contact angle. On longer time scales, the surfactant dissolves into the subphase. The lens formed by the water in the deposited drop persists for as long as 3 minutes after the convective spreading process ends due to the long diffusional timescales associated with the underlying entangled polymer solution. The persistence of the lens suggests that the drop phase behaves as if it were immiscible with the subphase during this time period. Whereas surfactant escapes the spreading drop and advances on the subphase/vapor interface, hydrophilic dye molecules in the drop do not escape, but remain with the drop throughout the convective spreading. The quasi-immiscible nature of the spreading event suggests that the chemical properties of the surfactant and subphase are much less important than their physical properties, consistent with prior qualitative studies of spreading of different types of surfactants on entangled polymer subphases: the selection of surfactant for pulmonary delivery applications may be limited only by physical and toxicological considerations. Further, the escape of surfactant from individual drops may provide an additional spreading mechanism in the lung as hydrodynamic and/or surface pressure repulsions may drive individual droplets apart after deposition.

We investigated the phenomenon of incomplete wetting of a high energy liquid subphase by drops of pure amphiphilic molecules as well as drops of amphiphile solutions which are immiscible with the subphase. We show that amphiphiles escape across the contact line of the drop, move on the subphase/vapor interface and form a submonolayer or full monolayer external to the drop. If this monolayer is sufficiently dense, it can reduce the surface tension of the subphase, raise the contact angle of the drop and prevent the drop from fully wetting the subphase. This phenomenon is called autophobing and has been extensively studied on solid substrates. For the liquid subphase studied here, we measure the surface tensions of the three relevant interfaces before and after the drop is deposited. The measured surface tension external to the drop shows that amphiphiles can move across the contact line and form a monolayer outside of the drop. In some cases, at equilibrium, the monolayer is in a sufficiently packed state to create the nonwetting condition. In other cases, at equilibrium the monolayer density is insufficient to lower the surface tension enough to achieve the nonwetting condition. Unlike on solid substrates where the formation of the monolayer external to the drop is kinetically hindered, the amphiphiles can move rapidly across the liquid subphase by Marangoni driven surface transport and local equilbirum is achieved. However, because the amphiphile inventory and subphase area are limited, the achievement of autophobing on a liquid subphase depends not only on the instrinsic subphase/amphiphile interaction but also on the total amphiphile inventory and area of the liquid subphase.

Background: Aerosol drug delivery is a viable option for treating diseased airways, but airway obstructions associated with diseases such as cystic fibrosis cause non-uniform drug distribution and limit efficacy. Marangoni stresses produced by surfactant addition to aerosol formulations may enhance delivery uniformity by postdeposition spreading of medications over the airway surface, improving access to poorly ventilated regions. We examine the roles of different variables affecting the maximum post-deposition spreading of a dye (drug mimic). Methods: Entangled aqueous solutions of either poly(acrylamide) (PA) or porcine gastric mucin (PGM) serve as airway surface liquid (ASL) mimicking subphases for in vitro models of aerosol deposition. Measured aerosol deposition fluxes indicate that the experimental delivery conditions are representative of aerosol delivery to the conducting airways. Post-deposition spreading beyond the locale of direct aerosol deposition is tracked by fluorescence microscopy. Aqueous aerosols formulated with either nonionic surfactant (tyloxapol) or fluorosurfactant (FS-3100) are compared with surfactant-free control aerosols. Results: Significant enhancement of post-deposition spreading is observed with surfactant solutions relative to surfactant-free control solutions, provided the surfactant solution surface tension is less than that of the subphase. Amongst the variables considered-surfactant concentration, aerosol flow-rate, total deposited volume, time of delivery, and total deposited surfactant mass-surfactant mass is the primary predictor of maximum spread distance. This dependence is also observed for solutions deposited as a single, microliter-scale drop with a volume comparable to the total volume of deposited aerosol. Conclusions: Marangoni stress-assisted spreading after surfactant-laden aerosol deposition at high fluxes on a complex fluid subphase is capable of driving aerosol contents over significantly greater distances compared to surfactant-free controls. Total delivered surfactant mass is the primary determinant of the extent of spreading, suggesting a great potential to extend the reach of aerosolized medication in partially obstructed airways via a purely physical mechanism.

Background: Cystic fibrosis (CF) is associated with the accumulation of dehydrated mucus in the pulmonary airways. This alters ventilation and aerosol deposition patterns in ways that limit drug delivery to peripheral lung regions. We investigated the use of surfactant-based, self-dispersing aerosol carriers that produce surface tension gradients to drive two-dimensional transport of aerosolized medications via Marangoni flows after deposition on the airway surface liquid (ASL). We considered the post-deposition spreading of individual aerosol droplets and two-dimensional expansion of a field of aerosol droplets, when deposited at low fluxes that are representative of aerosol deposition in the small airways. Methods: We used physically entangled aqueous solutions of poly(acrylamide) or porcine gastric mucin as simple ASL mimics that adequately capture the full miscibility but slow penetration of entangled macromolecular chains of the ASL into the deposited drop. Surfactant formulations were prepared with aqueous solutions of nonionic tyloxapol or FS-3100 fluorosurfactant. Fluorescein dye served as a model ''drug'' tracer and to visualize the extent of post-deposition spreading. Results: The surfactants not only enhanced post-deposition spreading of individual aerosol droplets due to localized Marangoni stresses, as previously observed with macroscopic drops, but they also produced largescale Marangoni stresses that caused the deposited aerosol fields to expand into initially unexposed regions of the subphase. We show that the latter is the main mechanism for spreading drug over large distances when aerosol is deposited at low fluxes representative of the small airways. The large scale convective expansion of the aerosol field drives the tracer (drug mimic) over areas that would cover an entire airway generation or more, in peripheral airways, where sub-monolayer droplet deposition is expected during aerosol inhalation. Conclusions:The results suggest that aerosolized surfactant formulations may provide the means to maximize deposited drug uniformity in and access to small airways.

Marangoni flows offer an interesting and useful means to transport particles at fluid interfaces with potential applications such as dry powder pulmonary drug delivery. In this article, we investigate the transport of partially wetted particles at a liquid/vapor interface under the influence of Marangoni flows driven by gradients in the surface excess concentration of surfactants. We deposit a microliter drop of soluble (sodium dodecyl sulfate aqueous solution) surfactant solution or pure insoluble liquid (oleic acid) surfactant on a water subphase and observe the transport of a pre-deposited particle. Following the previous observation by Wang et al. [1] that a surfactant front rapidly advances ahead of the deposited drop contact line initiates particle motion but then moves beyond the particle, we now characterize the two dominant, time- and position-dependent forces acting on the moving particle: 1) a surface tension force acting on the three-phase contact line around the particle periphery due to the surface tension gradient at the liquid/vapor interface which always accelerates the particle and 2) a viscous force acting on the immersed surface area of the particle which accelerates or decelerates the particle depending on the difference in the velocities of the liquid and particle. We find that the particle velocity evolves over time in two regimes. In the acceleration regime, the net force on the particle acts in the direction of particle motion, and the particle quickly accelerates and reaches a maximum velocity. In the deceleration regime, the net force on the particle reverses and the particle decelerates gradually and stops. We identify the parameters that affect the two forces acting on the particle, including the initial particle position relative to the surfactant drop, particle diameter, particle wettability, subphase thickness, and surfactant solubility. We systematically vary these parameters and probe the spatial and temporal evolution of the two forces acting on the particle as it moves along its trajectory in both regimes. We find that a larger particle always lags behind the smaller particle when placed at an equal initial distance from the drop. Similarly, particles more deeply engulfed in the subphase lag behind those less deeply engulfed. Further, the extent of particle transport is reduced as the subphase thickness decreases, due to the larger velocity gradients in the subphase recirculation flows.