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Biological Sciences

Multi-Scale Virtual Respiratory System Models for Dosimetry Prediction

Contact: Dr. Richard A. (Rick) Corley

PNNL is a pioneer in development of the most extensive suite of 3D, multi-scale computational fluid dynamic (CFD) airflow models of animal and human respiratory systems available today.

Extrapolating Animal Exposures to Humans

Our comprehensive, experimentally derived and validated computational framework accounts for significant anatomic and physiologic differences between species.

Our multi-scale models of the respiratory system offer unprecedented high-resolution insights into how mouse-, rat-, rabbit-, monkey-, or human-specific anatomy and physiology affects how materials are inhaled, transported throughout the respiratory system, and ultimately taken up by respiratory tissues or enter into systemic blood circulation.

Simulations of airflows through the
conducting airways of a human showing
the impact of airway narrowing in the larynx (insert)

Model features include:

  • Imaging-based 4D anatomic (3D structure plus time-dependent changes) features from the external nose or mouth through the lung
  • Physiologically based pharmacokinetic (PBPK) models as cell-specific or airway tissue-specific airway boundary conditions for volatile exposures
  • Particle tracking codes for aerosol exposures and aerosol-aerosol/aerosol-volatile interactions
  • Fully transient simulations that can mimic realistic breathing patterns or the influence of altered atmospheres such as the use of medical gases.

These models can also take into account implicit heterogeneities in airway-specific airflows, the impacts of diseases such as asthma and COPD, and changes in respiratory behaviors that contribute to target site dosimetry and eventually response.

With extensive funding from the National Institutes of Health and the Department of Energy, PNNL has developed the 3D imaging and computational infrastructure (hardware and software) that makes the development and validation of individualized 3D models a practical stand-alone alternative or complement to low-resolution, non-specific or empirical approaches used in the past to predict dosimetry in the respiratory system.

Simulations of regional airflows and tissue uptake
(flux rates) of the reactive vapor, acrolein, in the
airways of a human (top), monkey (middle), and rat (bottom).

Our scientists actively participate in NIH's Multi-Scale Modeling Consortium and serve on numerous elected and appointed positions in scientific associations, National Academies of Science and EPA, boards and committees, editorial boards for scientific journals, and grant peer-review groups. Clients include NIH, EPA, DOE, and private industry.

Investigators: Rick Corley, Dan Einstein, Kevin Minard, Andrew Kuprat, Rick Jacob, James Carson, Senthil Kabilan, Justin Teeguarden, Chuck Timchalk

Selected Publications

  • Einstein DR, AP Kuprat, X Jiao, JP Carson, DM Einstein, RE Jacob, and RA Corley. 2013. "An Efficient Algorithm for Mapping Imaging Data to 3D Unstructured Grids in Computational Biomechanics." International Journal for Numerical Methods in Biomedical Engineering 29(1):1-16. DOI: 10.1002/cnm.2489
  • Freed AD, and DR Einstein. 2013. "An Implicit Elastic Theory for Lung Parenchyma." International Journal of Engineering Science 62:31-47. DOI: 10.1016/j.ijengsci.2012.08.003
  • Kuprat AP, S Kabilan, JP Carson, RA Corley, and DR Einstein. 2012. "A bi-directional coupling procedure for multiscale respiratory modeling." Journal of Computational Physics. DOI: 10.1016/
  • Asgharian B, O Price, G McClellan, RA Corley, DR Einstein, RE Jacob, JR Harkema, SA Carey, E Schelegle, D Hyde, J Kimbell, and FJ Miller. 2012. "Development of a Rhesus Monkey Lung Geometry Model and Application to Particle Deposition in Comparison to Humans." Inhalation Toxicology 24(13):869-899. DOI:10.3109/08958378.2012.725782
  • Freed AD, and DR Einstein. 2012. "Hypo-Elastic Model for Lung Parenchyma." Biomechanics and Modeling in Mechanobiology 11(3-4):557-573. DOI:10.1007/s10237-011-0333-z
  • Minard KR, AP Kuprat, S Kabilan, RE Jacob, DR Einstein, JP Carson, and RA Corley. 2012. "Phase-Contrast MRI and CFD Modeling of Apparent 3He Gas Flow in Rat Pulmonary Airways." Journal of Magnetic Resonance 221:129-138. DOI:10.1016/j.jmr.2012.05.007 (Journal Cover)
  • Neradilek MB, N Polissar, DR Einstein, RW Glenny, KR Minard, JP Carson, X Jiao, RE Jacob, TC Cox, E Postlewait, and RA Corley. 2012. "Branch-based model for the diameters of the pulmonary airways: accounting for departures from self-similarity and registration errors." The Anatomical Record 295(6):1027-1044. DOI:10.1002/ar.22476
  • Corley RA, S Kabilan, AP Kuprat, JP Carson, KR Minard, RE Jacob, C Timchalk, RW Glenny, S Pipavath, TC Cox, C Wallis, R Larson, M Fanucchi, E Postlewait, and DR Einstein. 2012. "Comparative computational modeling of airflows and vapor dosimetry in the respiratory tracts of a rat, monkey, and human." Toxicological Sciences 128(2):500-516. DOI:10.1093/toxsci/kfs168
  • Jacob RE and WJ Lamm. 2011. "Stable Small Animal Ventilation for Dynamic Lung Imaging to Support Computational Fluid Dynamics Models." PLoS ONE 6(11): e27577. DOI:10.1371/journal.pone.0027577
  • Corley RA, KR Minard, S Kabilan, DR Einstein, AP Kuprat, JR harkema, J Kimbell, ML Gargas, and JH Kinzell. 2009. "Magnetic resonance imaging and computational fluid dynamics (CFD) simulations of rabbit nasal airflows for the development of hybrid CFD/PBPK models." Inhalation Toxicology 21(5-7):512-518.
  • Jacob RE, JP Carson, KM Gideon, BG Amidan, CL Smith, and KM Lee. 2009. "Comparison of two quantitative methods of discerning airspace enlargement in smoke-exposed mice." PLoS ONE, 4(8):e6670 (2009).
  • Jiao X, DR Einstein, V Dyedov, and JP Carson. 2009. "Automatic Identification and Truncation of Boundary Outlets in Complex Imaging-Derived Biomedical Geometries." Medical. & Biol. Eng. & Computing. 47(9), 989-999. NIHMS131767.
  • Carson, J.P., Kuprat, A.P., Jiao, X., Dyedov, V., Del Pin, F., Guccione, J., Ratcliffe, M., Einstein, D.R. (2009), "Adaptive Generation of Multimaterial Grids from Imaging Data for Biomedical Lagrangian Fluid-Structure Simulations." Biomech. Model. Mechanobiol. 9(2), 187-201.
  • Minard KR, RE Jacob, G Laicher, DR Einstein, AP Kuprat, and RA Corley. 2008. "MR Imaging of Apparent 3He Gas Transport in Narrow Pipes and Rodent Airways." Journal of Magnetic Resonance 194(2):182-191. DOI: 10.1016/j.jmr.2008.07.006 (Journal Cover)
  • Jacob RE, KR Minard, GJ Laicher, and C Timchalk. 2008. "3D He-3 diffusion MRI as a local in vivo morphometric tool to evaluate emphysematous rat lungs." Journal of Applied Physiology 105:1291-1300. DOI:10.1152/japplphysiol.90375.2008
  • Einstein DR, B Neradilak, N Pollisar, KR Minard, C Wallis, M Fanucchi, JP Carson, AP Kuprat, S Kabilan, R Jacob, and R Corley. 2008. "An Automated Self-similarity Analysis of the Pulmonary Tree of the Sprague-Dawley Rat." The Anatomical Record 291(12):1628-1648. DOI:10.1016/
  • Kuprat AP and DR Einstein. 2009. "An Anisotropic Scale-Invariant Unstructured Mesh Generator Auitable for Volumetric Imaging Data." Journal of Computational Physics 228(3):619-640. DOI: 10.1016/
  • Tawhai M, J Bischoff, DR Einstein, A Erdemir, T Guess, and J Reinbolt. 2009. "Multiscale Modeling in Computational Biomechanics: Determining Computational Priorities and Addressing Current Challenges." IEEE Engineering in Medicine and Biology Magazine 28(3):41-9. (Journal Cover Article) PMCID: PMC2854014.
  • Dyedov V, DR Einstein, X Jiao, AP Kuprat, JP Carson, and F del Pin. 2009. "Variational Generation of Prismatic Boundary-Layer Meshes for Biomedical Computing." International Journal for Numerical Methods in Engineering 79(8):907-945. DOI: 10.1002/nme.2583
  • Carey SA, KR Minard, LL Trease, JG Wagner, GM Garcia, CA Ballinger, J Kimbell, CG Plopper, RA Corley, E Postlewait, and JR Harkema. 2007. "Three-Dimensional Mapping of Ozone-Induced Injury in the Nasal Airways of Monkeys Using Magnetic Resonance Imaging and Morphometric Techniques." Toxicologic Pathology 35(1):27-40. DOI: 10.1080/01926230601072343
  • Jacob RE, G Laicher, and KR Minard. 2007. "3D MRI of Non-Gaussian 3He Gas Diffusion in the Rat Lung." Journal of Magnetic Resonance 188(2):357-366. DOI: 10.1016/j.jmr.2007.08.014
  • Minard KR, DR Einstein, RE Jacob, S Kabilan, AP Kuprat, C Timchalk, LL Trease, and RA Corley. 2006. "Application of Magnetic Resonance (MR) Imaging for the Development and Validation of Computational Fluid Dynamic (CFD) Models of the Rat Respiratory System." Inhalation Toxicology 18(10):787-794. DOI: 10.1080/08958370600748729

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