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J Control Release. 2019 Jun 27;307:282-291. doi: 10.1016/j.jconrel.2019.06.035. [Epub ahead of print]

Visualizing treatment delivery and deposition in mouse lungs using in vivo x-ray imaging.

Author information

1
Chair of Biomedical Physics, Department of Physics, Technical University of Munich, James-Franck-Str. 1, 85748 Garching, Germany; Munich School of BioEngineering, Technical University of Munich, Boltzmannstr. 11, 85748 Garching, Germany; Institute for Advanced Study, Technical University of Munich, Lichtenbergstr. 2 a, 85748, Garching, Germany. Electronic address: regine.gradl@tum.de.
2
Chair of Biomedical Physics, Department of Physics, Technical University of Munich, James-Franck-Str. 1, 85748 Garching, Germany; Munich School of BioEngineering, Technical University of Munich, Boltzmannstr. 11, 85748 Garching, Germany.
3
Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Max-Lebsche-Platz 31, 81377 München, Germany; Institute of Lung Biology and Disease, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
4
Chair of Biomedical Physics, Department of Physics, Technical University of Munich, James-Franck-Str. 1, 85748 Garching, Germany; Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 München, Germany.
5
Munich School of BioEngineering, Technical University of Munich, Boltzmannstr. 11, 85748 Garching, Germany.
6
Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, Australia; Respiratory and Sleep Medicine, Women's and Children's Hospital, 72 King William Road, SA 5006, North Adelaide, Australia.
7
Chair of Biomedical Physics, Department of Physics, Technical University of Munich, James-Franck-Str. 1, 85748 Garching, Germany; Munich School of BioEngineering, Technical University of Munich, Boltzmannstr. 11, 85748 Garching, Germany; Institute for Advanced Study, Technical University of Munich, Lichtenbergstr. 2 a, 85748, Garching, Germany; Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str. 22, 81675 München, Germany.
8
Chair of Biomedical Physics, Department of Physics, Technical University of Munich, James-Franck-Str. 1, 85748 Garching, Germany; Institute for Advanced Study, Technical University of Munich, Lichtenbergstr. 2 a, 85748, Garching, Germany; School of Physics and Astronomy, Monash University, Clayton, Victoria 3800, Australia.

Abstract

The complexity of lung diseases makes pre-clinical in vivo respiratory research in mouse lungs of great importance for a better understanding of physiology and therapeutic effects. Synchrotron-based imaging has been successfully applied to lung research studies, however longitudinal studies can be difficult to perform due to limited facility access. Laboratory-based x-ray sources, such as inverse Compton x-ray sources, remove this access limitation and opens up new possibilities for pre-clinical small-animal lung research at high spatial and temporal resolution. The in vivo visualization of drug deposition in mouse lungs is of interest, particularly in longitudinal research, because the therapeutic outcome is not only dependent on the delivered dose of the drug, but also on the spatial distribution of the drug. An additional advantage of this approach, when compared to other imaging techniques, is that anatomic and dynamic information is collected simultaneously. Here we report the use of dynamic x-ray phase-contrast imaging to observe pulmonary drug delivery via liquid instillation, and by inhalation of micro-droplets. Different liquid volumes (4 μl, 20 μl, 50 μl) were tested and a range of localized and global distributions were observed with a temporal resolution of up to 1.5 fps. The in vivo imaging results were confirmed by ex vivo x-ray and fluorescence imaging. This ability to visualize pulmonary substance deposition in live small animals has provided a better understanding of the two key methods of delivery; instillation and nebulization.

KEYWORDS:

Fluorescence imaging; Lung imaging; Treatment delivery; X-ray imaging; in vivo small animal imaging

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