Motivated by a new approach to enhance pulmonary aerosol drug delivery, the project will establish the fundamental mechanisms controlling surface tension gradient driven (Marangoni) flows to induce post-deposition transport of aerosol across subphases that mimic the lung airway surface liquid (ASL). While inhaled aerosol drugs can deliver substantial doses of medication directly to the lungs, altered patterns of ventilation cause inhaled drugs to deposit non-uniformly in diseased lungs. Some lung regions receive very high local doses while other regions go untreated. This demands new methods to cause post-deposition spreading in order to be effective. The research under a current NSF grant has shown that surfactant induced Marangoni stresses enhance spreading of millimeter scale drops across subphases mimicking the ASL. In this renewal proposal, the PIs extend their research to address how the aerosol droplet flux to the subphase couples with individual droplet spreading dynamics to produce the maximum spreading on ASL mimic subphases.
Intellectual Merit: Through the previous NSF grant, the PIs have obtained a complete picture of how millimeter scale drops of surfactant solutions spread across complex subphases and what properties control the final spread area. These results present a clear set of material selection and dosing criteria for developing successful therapies. They set the stage for the present proposal where we will determine the conditions for optimizing the final spread area from aerosol deposition of micron scale droplets. While dispersion of aerosol in a branched system such as the lung is well studied, the post-deposition spreading of the droplets is not. The research under the current grant uses single droplets and has confirmed that surfactant greatly enhances the post-deposition transport of aqueous droplet contents on aqueous polymeric subphases. However, to determine the conditions that will optimize the spreading of aerosol droplets, they address a number of fundamental issues. Do the same spreading mechanisms determined to operate at the millimeter scale operate at the 10 micron scale? How do adjacent aqueous surfactant solution drops on a complex aqueous subphase coalesce after deposition? How do the timescales of droplet deposition, spreading, and coalescence on an entangled aqueous polymeric subphase compete to control the final spread area? The research addresses two specific aims: 1) Determine the droplet scale processes and properties that control the lateral interactions of aerosol droplets after deposition on complex subphases. 2) Determine how aerosol deposition flux and total dose determine the final extent of post-deposition spreading. The project will culminate this work by developing empirical quantitative correlations for the extent of post-deposition spreading with the critical parameters and time scales identified in previous aims.
Broader Impacts: Just as the earlier work in determining the fundamental spreading mechanisms of millimeter scale drops has established the basis for materials selection for surfactant-enhanced pulmonary drug delivery methods, the research here provides new options in not only the composition of aerosol formulations but also the administration protocols such as breathing patterns to optimize drug spreading to all regions of a diseased lung. Thus, the proposed research will become a formulation design tool for surfactants to be tested as self-dispersing carriers for aerosol drug delivery. This technology will benefit the treatment of any number of obstructive lung diseases, including cystic fibrosis, asthma,pneumonia and other acute or chronic pulmonary infections. While this research focuses on fundamental physical mechanisms of enhanced drug spreading, the team collaborates with pulmonary medicine specialists in the University of Pittsburgh School of Medicine where our new fundamental findings will guide in vivo studies. By regularly attending seminars and meetings with clinical investigators, students will be trained in a highly interdisciplinary environment. As part of the this grant, the investigators will plan a two to three day workshop to bring together the clinical and the science and engineering communities to exchange ideas on understanding and harnessing mechanisms for exogenous fluid movement in the lung. The investigators will mentor an undergraduate research student during each academic year and summer and at least two middle school students each year in the Carnegie Mellon/Colfax Physics Concepts Outreach Program.
