Surfactant Driven Post-Deposition Spreading of Aerosols on Complex Aqueous Subphases. 2: Low Deposition Flux Representative of Aerosol Delivery to Small Airways

Abstract

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.

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

“…The calculated average aerosol deposition fluxes for all experiments were well within the ''low-flux regime'' as defined in our previous publication. (13) Droplet coalescence is not expected in this regime. Instead, postdeposition dispersal of a field of distinct droplets is expected.…”

“…At this concentration, the mucin is above its entanglement concentration in water. (13) The mixed solutions were kept between 2 and 8°C and used within 10 days of preparation.…”

“…(4)(5)(6)(7)(8) Recently, Marangoni stresses have been harnessed to enhance the surface transport of mock drugs deposited from surfactant-laden aerosols onto surfaces that mimic the key features of the airway surface liquid (ASL). (9)(10)(11)(12)(13)(14)(15) Researchers have been studying the use of Marangoni flows to cause surface transport for years. (16)(17)(18)(19) Marangoni flows occur when surface stresses are generated by a gradient in surface tension along an interface.…”

“…Prior work from our group has examined how the aerosol deposition flux affects the postdeposition flow behavior of the aerosol contents. (13,14) Two different deposition flux regimes were studied. In the high-flux regime, which occurs in the larger airways, aerosol droplets deposit so quickly that they coalesce into a single, large drop before spreading.…”

“…In the low-flux regime, occurring in the smaller airways of the lung, each individual aerosol droplet spreads out before the next drop deposits. (13) This creates a spreading field of droplets that do not coalesce after deposition. The transition between these two regimes occurs at deposition fluxes of *0.01 lL/(cm 2 $s).…”