Editors' ChoiceDrug Delivery

Super model

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Science Translational Medicine  30 Sep 2015:
Vol. 7, Issue 307, pp. 307ec168
DOI: 10.1126/scitranslmed.aad3626

Many serious lung diseases, including cystic fibrosis and lung cancer, would benefit from precise delivery of drugs to pathologic regions of the lung. Conventional drug delivery techniques such as oral or intravenous administration can cause systemic side effects, and aerosol inhalers that do directly target the lungs can only be used with certain types of drugs. Small volumes of liquid drug formulation can be administered directly to the lungs, but a lack of control over the process has stymied widespread use of this approach. To address this challenge, Kim et al. reasoned that mathematical modeling of fluid flow in a tube could be used to determine the delivery parameters required to precisely target liquids to specific regions of the lung.

The team started with a conceptual framework of how a liquid plug would travel and coat the walls of the airways in a ventilated lung: As the patient breathes in, air pressure would push the plug into a bronchus leading from the windpipe, depositing a thin film as it travels and splitting into smaller plugs at bifurcations. Eventually, each plug would rupture as its volume decreased relative to the size of its leading front. Then, when the patient exhales, the decreasing diameter of the airways would cause the plug to reform, and transport would continue with the next breath until the surface tension and viscosity of the liquid prevented further movement. Thus, it was theoretically possible to control the distance that the liquid traveled into the depths of the lung by manipulating ventilation parameters and the starting volume of the first plug. To test this hypothesis, the team used measurements of water flowing through glass capillary tubes to experimentally validate the relationships between liquid volume, the thickness of the deposited film, and the critical volume at which a plug would rupture as a function of airway diameter and applied pressure. These measurements allowed calculation of the starting volume and air pressure required to push liquid into any desired depth of the bronchial tree, which was verified using infusion of fluorescent dye into the lungs of rats and subsequent in vivo imaging.

Additional layers of complexity are required to adapt the model to pathologic human lungs, but this study demonstrates that mathematical modeling can allow precise control over drug delivery to a complex organ.

J. Kim et al., Targeted delivery of liquid microvolumes into the lung. Proc. Natl. Acad. Sci. U.S.A. 112 11530–11535 (2015). [Abstract]

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