The respiratory system is one of the major interfaces between the body and the external environment. As a result, it can become a target for a broad range of environmental agents that can lead to increased morbidity and mortality. The medical field has also exploited the respiratory system/air interface as a way for either targeting drug delivery to specific regions of the respiratory tract or to provide rapid access to the systemic circulation for drugs that may not be effectively administered by other means. Furthermore, various diseases, such as COPD, or interstitial lung disease, can alter the structure and function of the respiratory system and dramatically affect how airborne agents or drugs are inhaled, deposited, or absorbed. Computational models that can effectively predict the dosimetry and ultimately the consequences of exposure to airborne agents under healthy or disease conditions in either animals or humans do not exist. As a result, this Bioengineering Research Partnership is developing the imaging and computational tools necessary for constructing and validating state-of-the-art, biologically based, multi-scale computational models of the respiratory system that incorporates the inherent species differences and heterogeneities in structure and functional relationships and the influence of disease on airflows and dosimetry predictions. In this way, computational predictions can be more rigorously tested and have a broader impact on human health risk assessments and therapeutic interventions. In light of increasing interest in nanomaterials for medical applications as well as concerns over potential human health risks, our model validation studies will focus on particulates utilizing our novel 3D imaging approaches.
Our specific aims are therefore organized around model development, experimental evaluation, and model refinement to predict: a) site-specific airflows in health rats (Aim 1);b) site-specific airflows in rats with interstitial lung disease and COPD (Aim 2);c) aerosol deposition in healthy and diseased rats (Aim 3);and d) aerosol deposition in healthy and diseased humans (Aim 4). Ultimately, we expect to deliver realistic, comprehensive, predictive models of the respiratory system that incorporate the inherent heterogeneities in anatomy, physiology, and disease. In addition, this effort will provide researchers and clinicians with a unique suite of imaging and computational tools for understanding species-specific pulmonary structure-function relationships and their effects on particle deposition and clearance.

Public Health Relevance

This project will impact human health through the development of realistic, computational models of the respiratory system that improves our understanding of disease-induced changes in airflow heterogeneities that impact aerosol deposition in rats and humans. Such models will improve human health risk assessments for environmental exposures and methods for drug delivery. This project will also produce novel, quantitative 3D imaging methods for respiratory anatomy, airflows, and nanoparticles in living systems and a suite of computational tools for image processing, mesh generation/refinement, and a multi-scale computational framework that includes bi-directional coupling of 3D computational fluid dynamics models with lower dimensional models of tissue properties and particle tracking.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (50))
Program Officer
Croxton, Thomas
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Battelle Pacific Northwest Laboratories
United States
Zip Code
Darquenne, Chantal; Fleming, John S; Katz, Ira et al. (2016) Bridging the Gap Between Science and Clinical Efficacy: Physiology, Imaging, and Modeling of Aerosols in the Lung. J Aerosol Med Pulm Drug Deliv 29:107-26
Bassingthwaighte, James B; Raymond, Gary M; Dash, Ranjan K et al. (2016) The Pathway for Oxygen: Tutorial Modelling on Oxygen Transport from Air to Mitochondrion: The Pathway for Oxygen. Adv Exp Med Biol 876:103-110
Colby, Sean M; Kabilan, Senthil; Jacob, Richard E et al. (2016) Comparison of realistic and idealized breathing patterns in computational models of airflow and vapor dosimetry in the rodent upper respiratory tract. Inhal Toxicol 28:192-202
Asgharian, Bahman; Price, Owen; Kabilan, Senthil et al. (2016) Development of a Zealand white rabbit deposition model to study inhalation anthrax. Inhal Toxicol 28:80-8
Xi, Jinxiang; Si, Xiuhua A; Kim, Jongwon et al. (2016) Anatomical Details of the Rabbit Nasal Passages and Their Implications in Breathing, Air Conditioning, and Olfaction. Anat Rec (Hoboken) 299:853-68
Darquenne, Chantal; Lamm, Wayne J; Fine, Janelle M et al. (2016) Total and regional deposition of inhaled aerosols in supine healthy subjects and subjects with mild-to-moderate COPD. J Aerosol Sci 99:27-39
Darquenne, Chantal; Hoover, Mark D; Phalen, Robert F (2016) INHALED AEROSOL DOSIMETRY: SOME CURRENT RESEARCH NEEDS. J Aerosol Sci 99:1-5
Jacob, Richard E; Lamm, Wayne J; Einstein, Daniel R et al. (2015) Comparison of CT-derived ventilation maps with deposition patterns of inhaled microspheres in rats. Exp Lung Res 41:135-45
Freed, A D; Liao, J; Einstein, D R (2014) A membrane model from implicit elasticity theory: application to visceral pleura. Biomech Model Mechanobiol 13:871-81
Bauer, Christian; Krueger, Melissa A; Lamm, Wayne J et al. (2014) Airway tree segmentation in serial block-face cryomicrotome images of rat lungs. IEEE Trans Biomed Eng 61:119-30

Showing the most recent 10 out of 57 publications