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Project Title:  Variability in Flow Distribution within the Lung and Its Effects on Deposition and Clearance of Inhaled Particles in Normal and Reduced Gravity (Postdoctoral Fellowship) Reduce
Fiscal Year: FY 2013 
Division: Human Research 
Research Discipline/Element:
HRP SHFH:Space Human Factors & Habitability (archival in 2017)
Start Date: 11/01/2009  
End Date: 10/31/2012  
Task Last Updated: 02/19/2013 
Download report in PDF pdf
Principal Investigator/Affiliation:   Sa, Rui Carlos Ph.D. / University of California, San Diego 
Address:  Department of Medicine 
9500 Gilman Drive, MC 0852 
La Jolla , CA 92093-0852 
Email: rcsa@ucsd.edu 
Phone: 858-822-5081  
Congressional District: 53 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of California, San Diego 
Joint Agency:  
Comments: Last name ometimes seen as “Pereira de Sa” " 
Co-Investigator(s)
Affiliation: 
Prisk, G. Kim  MENTOR/University of California, San Diego  
Project Information: Grant/Contract No. NCC 9-58-PF02103 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2009 NSBRI-RFA-09-01 Postdoctoral Fellowships 
Grant/Contract No.: NCC 9-58-PF02103 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SHFH:Space Human Factors & Habitability (archival in 2017)
Human Research Program Risks: (1) Dust:Risk of Adverse Health & Performance Effects of Celestial Dust Exposure (IRP Rev F)
Human Research Program Gaps: (1) AEH Watch Item/NSBRI Research:What are the effects of lunar gravity on permissible exposure limits for inhalation of lunar dust? (Closed as of IRP Rev J)
Task Description: POSTDOCTORAL FELLOWSHIP

1) Original project aims/objectives: Our goal is to provide a better understanding of how variability in convective flow patterns in the lung affects aerosol deposition, and thus subsequent clearance between individuals. Such an understanding will allow better characterization of the normal variability in deposition and clearance rates both in 1G, and in low-gravity such as on the lunar surface. Three key factors define the toxicological risk to the lung of exposure to airborne lunar dust which is believed to be highly reactive: 1) the degree of deposition, 2) the toxicological properties of the material itself, and 3) the residence time within the lung of the particles once they have been deposited. The distribution of ventilation within the lung determines deposition. Studies by us using computational fluid dynamics (CFD) in realistic central airway trees show that ventilation varies widely at the lobar level. However, typical boundary conditions for deposition simulations assume that lung expansion is uniform, which we know to be incorrect. We have developed a Magnetic Resonance Imaging (MRI) technique that allows the quantification of regional specific ventilation in the human lung, providing realistic boundary conditions. In this proposal we will: a) map the spatial pattern of specific ventilation; b) map deposition in the supine position at 1G; and combine these with data on the spatial pattern of deposition of inhaled particles collected in low-gravity as part of our parallel NSBRI studies; c) The measured pattern of aerosol deposition will be compared with the CFD predictions, using uniform and the more realistic boundary conditions. By comparing across a number of subjects, the mechanisms underlying the observed variability in deposition and regional ventilation can be elucidated. By comparing 1G and low-gravity deposition, the magnitude of the gravitational effect can be assessed.

2) Key findings of the project: We have successfully developed, applied, and validated a Magnetic Resonance Imaging technique for quantifying specific ventilation in the human lung- Specific Ventilation Imaging - completing aim a). We are able to routinely map the spatial pattern of specific ventilation in humans, with a technique that requires no ionizing radiation, and thus allows for repeated, horizontal studies. We have used this technique to quantify the vertical, gravitational induced, gradient in specific ventilation that is present in the human lung on Earth. Our findings are in accordance with previous radiation based techniques for quantifying specific ventilation. An article describing the technique was published during the second year of the project (Journal of Applied Physiology). A patent, protecting the intellectual property of this and two other MRI methods developed at our lab is being pursued. We have mapped particle deposition for 5µm particles, when inhalation occurs in the supine position on Earth (10 subjects) and in low-gravity (5 subjects). A paper describing the low gravity results has been recently submitted to the Journal of Applied Physiology. The completion of aim c has been hampered by the missing 1µm particles deposition maps. Despite our efforts, a second parabolic flight campaign opportunity to measure 1µm particle deposition never materialized. We expect the analysis of 5µm data to lead to a publication, to be submitted in the first half of 2013.

3) Impact of key findings on original project: The successful completion of aim a) was essential to completion of the project. A paper describing deposition of coarse particles (5µm) in low-gravity and subsequent clearance has been recently submitted for publication. The analysis of the spatial distribution of ventilation and deposition in the supine posture is ongoing. The absence of 1µm particle deposition data complicates the analysis.

4) Future plans: A paper linking regional ventilation and particle deposition for 5µm particles is in preparation.

Research Impact/Earth Benefits: The overall goal of this project is to better understand how variability in convective flow patterns in the lung affects aerosol deposition and subsequent clearance between individuals. Such knowledge will help better characterize the normal variability, both on the ground and in low gravity (the lunar surface), and thus better characterize the risks of exposure to potentially toxic, aggressive dust. This improved risk assessment is important both for future lunar exploration (lunar dust is aggressive, highly reactive, and in low gravity, dust particles are likely to deposit further down in the lung, increasing residence time), as well as in Earth's gravity, where many people are exposed to airborne dust. From a different and more long-term perspective, a better understanding of the individual variability in deposition might also help optimize aerosols drug delivery, aerosols that will more accurately target specific portions of the lung. In the framework of this project, we have developed a novel MRI technique for the quantification of specific ventilation in the human lung. The technique requires a standard proton MRI machine with a 1.5 Tesla field, machines that are widely available in clinical setting. The technique does not require the use of radiation, and is therefore suitable for repeated measures. At a first stage, we are using the technique as a novel research tool, but its repercussions can be extended to the clinical setting. The recent effort to validate this MRI technique by comparing the distribution of specific ventilation obtained using our MRI technique and the identical distribution obtained using Multiple Breath Washouts (a technique that provides no spatial information) will certainly leverage its applicability. The fact that MRI does not involve radiation opens a novel diagnostic window, for it can be applied repetitively. This can be of particular importance in patient populations suffering from chronic respiratory diseases, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). Patients with chronic respiratory disease could benefit from a non invasive, zero radiation dose assessment of their lung function, that can thus be repeated time and again, allowing for a more regular follow up than the existing techniques. A patent protecting this MRI technique as well as two additional MR-sequences developed by our group is currently being pursued (provisional patent application: New method for imaging ventilation and perfusion in the lung using MRI - SD2010-320, provisional application number 61420554, PCT/US2011/063854 - R.B. Buxton, G.K. Prisk, S.R. Hopkins, R.C. Pereira de Sa, R.J. Theilmann, M.V. Cronin).

Task Progress & Bibliography Information FY2013 
Task Progress: The goal of this project is to provide a better understanding of how variability in convective flow patterns in the lung affects aerosol deposition, and thus subsequent clearance between individuals. In order to achieve the goal, three specific aims need to be addressed: a) Map the spatial pattern of specific ventilation; b) Map deposition in the supine position at 1G; combine these with data on the spatial pattern of deposition of inhaled particles collected in low-gravity (µG) as part of our existing NSBRI studies; c) The measured pattern of aerosol deposition will be compared with the Computational Fluid Dynamics (CFD) predictions, using uniform and the realistic boundary conditions. By comparing across a number of subjects, and different particles sizes, the mechanisms underlying the variability in deposition and regional ventilation can be elucidated. By comparing the data collected in 1G with data from µG, the magnitude of the gravitational effect can be assessed. In the first two years of the project we have successfully developed a Magnetic Resonance Imaging technique for quantifying specific ventilation in the human lung - Specific Ventilation Imaging (SVI), completing point a) of the initial project aims. We have used SVI to quantify the vertical, gravitational induced, gradient in specific ventilation that is present in the human lung on Earth. An article describing the technique was published in the Journal of Applied Physiology, and a patent application is pursued.

Aim 2 was completed by quantifying specific ventilation in 10 subjects, thus determining realistic boundary conditions required for addressing aim c) in an individualized subject by subject basis. We have mapped the supine deposition of 5µm particles (1G supine) in the same 10 subjects. A subset of these (N=5) participated in a NASA parabolic flight campaign, where the first maps of particle deposition in low gravity were obtained, thus completing data acquisition for 5µm particles. A second parabolic flight opportunity to acquire the µG deposition maps for 1µm particles did not materialize, despite our continuous efforts. In this project year we have completed the optimization of the analysis software and applied it to the µG and supine data. A paper describing the µG results for 5µm particle deposition and clearance was recently submitted (Journal of Applied Physiology). We have completed a validation and reliability analysis of the MR-imaging technique, by comparing heterogeneity estimated using SVI and the spatial-insensitive Multiple Breath Nitrogen Washout technique. A paper describing the validation of the SVI method will be submitted to the Journal of Applied Physiology. The analysis linking ventilation and deposition (aim c) is hampered by the missing 1µm particle deposition data; additional data analysis is ongoing. We expect a publication linking ventilation and peripheral deposition for 5µm particles to be submitted in the next ~3-4 months.

Bibliography Type: Description: (Last Updated: 01/11/2021)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Arai TJ, Sa RC, Tedjasaputra V, Prisk GK, Hopkins SR. "Ventilation-Perfusion Heterogeneity in the Lung: insights from the underlying distributions of ventilation and perfusion." American Thoracic Society 2012 International Conference, San Francisco, California, May 18-23, 2012.

Am J Respir Crit Care Med. 2012 May;185(1, Meeting Abstracts):A2684. , May-2012

Abstracts for Journals and Proceedings Darquenne C, Borja MG, Oakes JM, Breen EB, Olfert IM, Sa RC, Scadeng M, Prisk GK. "Microgravity reduces the central-to-peripheral deposition ratio of inhaled aerosols: implications for particle clearance rates." 2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012.

2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012. , Feb-2012

Abstracts for Journals and Proceedings Darquenne C, Zeman KL, Sa RC, Cooper TK, Fine JM, Bennett WD, Prisk GK. "Effect of gravity on the regional distribution of particles deposited in the human lung." 19th World Congress of the International Society for Aerosols in Medicine, Chapel Hill, NC, April 6-10, 2013.

19th World Congress of the International Society for Aerosols in Medicine, Chapel Hill, NC, April 6-10, 2013. Abstract book, P-007. , Apr-2013

Abstracts for Journals and Proceedings Darquenne C, Zeman KL, Sa RC, Cooper TK, Fine JM, Bennett WD, Prisk GK. "Removal of sedimentation decreases deposition of coarse particles in the lung periphery, reducing retention." 2013 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-14, 2013.

2013 NASA Human Research Program Investigators’ Workshop, Galveston, TX, February 12-14, 2013. , Feb-2013

Abstracts for Journals and Proceedings Darquenne C, Zeman KL, Sa RC, Cooper TK, Fine JM, Bennett WD, Prisk GK. "Effect of Gravity on Retention of Inhaled Particles in the Human Lung." American Thoracic Society 2013 International Conference, Philadelphia, PA, May 17-22, 2013.

Am J Respir Crit Care Med supplement. In press, as of February 2013. , Feb-2013

Abstracts for Journals and Proceedings Henderson AC, Sa RC, Cook FR, Arai TJ, Wagner HE, Theilmann RJ, Darquenne C, Ramsdell JW, Friedman PJ, Wagner PD. "Identification of the gas exchange defects present in Chronic Obstructive Pulmonary Disease patients noninvasively using Magnetic Resonance Imaging." American Thoracic Society 2012 International Conference, San Francisco, California, May 18-23, 2012.

Am J Respir Crit Care Med. 2012 May;185(1, Meeting Abstracts):A2039. , May-2012

Abstracts for Journals and Proceedings Henderson AC, Sa RC, Theilmann TJ, Buxton RB, Prisk GK, Hopkins SR. "The gravitational distribution of ventilation-perfusion ratio in the normal human lung is more uniform in prone than supine posture." American Thoracic Society 2013 International Conference, Philadelphia, PA, May 17-22, 2013.

Am J Respir Crit Care Med supplement. In press, as of February 2013. , Feb-2013

Abstracts for Journals and Proceedings Prisk GK, Darquenne C, Sa RC. "Human life sciences studies in sub-orbital flight: insights from parabolic flight." Next-Generation Suborbital Researchers Conference 2012, Palo Alto, California, February 27-29, 2012.

Next-Generation Suborbital Researchers Conference 2012, Palo Alto, California, February 27-29, 2012. Abstract Book. http://www.boulder.swri.edu/NSRC2012/Site1//PDF/Prisk-PSRP.pdf , Feb-2012

Abstracts for Journals and Proceedings Sa RC, Hopkins SR, Prisk GK, Darquenne C. "Validation of the distribution of specific ventilation obtained by proton MR imaging." American Thoracic Society 2012 International Conference, San Francisco, California, May 18-23, 2012.

Am J Respir Crit Care Med. 2012 May;185(1, Meeting Abstracts):A2035. , May-2012

Abstracts for Journals and Proceedings Sa RC, Prisk GK, Darquenne C. "Mapping the regional distribution of ventilation within the lung: validation of specific ventilation imaging against multiple breath nitrogen washout." 2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012.

2012 NASA Human Research Program Investigators’ Workshop, Houston, TX, February 14-16, 2012. , Feb-2012

Articles in Peer-reviewed Journals Asadi AK, Cronin MV, Sa RC, Theilmann RJ, Holverda S, Hopkins SR, Buxton RB, Prisk GK. "Spatial-temporal dynamics of pulmonary blood flow in the healthy human lung in response to altered FI(O2)." J Appl Physiol. 2013 Jan 1;114(1):107-18. Epub 2012 Oct 25. PMID: 23104691 , Jan-2013
Articles in Peer-reviewed Journals Henderson AC, Sa RC, Barash IA, Holverda S, Buxton RB, Hopkins SR, Prisk GK. "Rapid intravenous infusion of 20 mL/kg saline alters the distribution of perfusion in healthy supine humans." Respiratory Physiology and Neurobiology. 2012 Mar 15;180(2-3):331-41. Epub 2011 Dec 31. PubMed PMID: 22227320 , Mar-2012
Articles in Peer-reviewed Journals Prisk GK, Sa RC, Darquenne C. "Cardiogenic mixing increases aerosol deposition in the human lung in the absence of gravity." Acta Astronautica. 2013 Nov;92(1):15-20. (originally reported in Feb. 2013 as "In Press, Corrected Proof, Available online 12 June 2012") http://dx.doi.org/10.1016/j.actaastro.2012.05.022 , Nov-2013
Articles in Peer-reviewed Journals Tedjasaputra V, Sa RC, Arai TJ, Holverda S,Theilmann RJ, Chen WT, Wagner PD, Davis CK, Prisk CK, Hopkins SR. "The heterogeneity of regional specific ventilation is unchanged following heavy exercise in athletes." J Appl Physiol (1985). 2013 Jul 1;115(1):126-35. http://dx.doi.org/10.1152/japplphysiol.00778.2012 ; PubMed PMID: 23640585; PubMed Central PMCID: PMC3727009 , Jul-2013
Articles in Peer-reviewed Journals Sá RC, Henderson AC, Simonson TS, Arai TJ, Wagner H, Theilmann RJ, Wagner PD, Prisk GK, Hopkins SR. "Measurement of the distribution of ventilation-perfusion ratios in the human lung with proton MRI: Comparison with the multiple inert gas elimination technique." J Appl Physiol (1985). 2017 Jul;123(1):136-46. http://dx.doi.org/10.1152/japplphysiol.00804.2016 ; PubMed PMID: 28280105 , Jul-2017
Articles in Peer-reviewed Journals Hall ET, Sá RC, Holverda S, Arai TJ, Dubowitz DJ, Theilmann RJ, Prisk GK, Hopkins SR. "The effect of supine exercise on the distribution of regional pulmonary blood flow measured using proton MRI." J Appl Physiol (1985). 2014 Feb 15;116(4):451-61. Epub 2013 Dec 19. https://doi.org/10.1152/japplphysiol.00659.2013 ; PubMed PMID: 24356515; PubMed Central PMCID: PMC3921353 , Feb-2014
Articles in Peer-reviewed Journals Sá RC, Asadi AK, Theilmann RJ, Hopkins SR, Prisk GK, Darquenne C. "Validating the distribution of specific ventilation in healthy humans measured using proton MR imaging." J Appl Physiol (1985). 2014 Apr 15;116(8):1048-56. Epub 2014 Feb 6. https://doi.org/10.1152/japplphysiol.00982.2013 ; PubMed PMID: 24505099; PubMed Central PMCID: PMC4035784 , Apr-2014
Articles in Peer-reviewed Journals Asadi AK, Sá RC, Kim NH, Theilmann RJ, Hopkins SR, Buxton RB, Prisk GK. "Inhaled nitric oxide alters the distribution of blood flow in the healthy human lung, suggesting active hypoxic pulmonary vasoconstriction in normoxia." J Appl Physiol (1985). 2015 Feb 1;118(3):331-43. Epub 2014 Nov 26. https://doi.org/10.1152/japplphysiol.01354.2013 ; PubMed PMID: 25429099; PubMed Central PMCID: PMC4312852 , Feb-2015
Articles in Peer-reviewed Journals Sá RC, Zeman KL, Bennett WD, Prisk GK, Darquenne C. "Effect of posture on regional deposition of coarse particles in the healthy human lung." J Aerosol Med Pulm Drug Deliv. 2015 Dec;28(6):423-31. Epub 2015 Mar 31. https://doi.org/10.1089/jamp.2014.1189 ; PMID: 25826480 , Dec-2015
Articles in Peer-reviewed Journals Geier ET, Theilmann RJ, Darquenne C, Prisk GK, Sá RC. "Quantitative mapping of specific ventilation in the human lung using proton magnetic resonance imaging and oxygen as a contrast agent." J Vis Exp. 2019 Jun 5(148):e59579. https://doi.org/10.3791/59579 ; PMID: 31233033; PMCID: PMC6743506 , Jun-2019
Project Title:  Variability in Flow Distribution within the Lung and Its Effects on Deposition and Clearance of Inhaled Particles in Normal and Reduced Gravity (Postdoctoral Fellowship) Reduce
Fiscal Year: FY 2012 
Division: Human Research 
Research Discipline/Element:
HRP SHFH:Space Human Factors & Habitability (archival in 2017)
Start Date: 11/01/2009  
End Date: 10/31/2012  
Task Last Updated: 11/14/2011 
Download report in PDF pdf
Principal Investigator/Affiliation:   Sa, Rui Carlos Ph.D. / University of California, San Diego 
Address:  Department of Medicine 
9500 Gilman Drive, MC 0852 
La Jolla , CA 92093-0852 
Email: rcsa@ucsd.edu 
Phone: 858-822-5081  
Congressional District: 53 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of California, San Diego 
Joint Agency:  
Comments: Last name ometimes seen as “Pereira de Sa” " 
Co-Investigator(s)
Affiliation: 
Prisk, G. Kim  MENTOR/University of California, San Diego 
Project Information: Grant/Contract No. NCC 9-58-PF02103 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2009 NSBRI-RFA-09-01 Postdoctoral Fellowships 
Grant/Contract No.: NCC 9-58-PF02103 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SHFH:Space Human Factors & Habitability (archival in 2017)
Human Research Program Risks: (1) Dust:Risk of Adverse Health & Performance Effects of Celestial Dust Exposure (IRP Rev F)
Human Research Program Gaps: (1) AEH Watch Item/NSBRI Research:What are the effects of lunar gravity on permissible exposure limits for inhalation of lunar dust? (Closed as of IRP Rev J)
Task Description: POSTDOCTORAL FELLOWSHIP

1) Original project aims and objectives: Our goal is to provide a better understanding of how variability in convective flow patterns in the lung affects aerosol deposition, and thus subsequent clearance between individuals. Such an understanding will allow better characterization of the normal variability in deposition and clearance rates both in 1G, and in low-gravity such as on the lunar surface. Three key factors define the toxicological risk to the lung of exposure to airborne lunar dust which is believed to be highly reactive: 1) the degree of deposition, 2) the toxicological properties of the material itself, and 3) the residence time within the lung of the particles once they have been deposited. The distribution of ventilation within the lung determines deposition. Studies by us using computational fluid dynamics (CFD) in realistic central airway trees show that ventilation varies widely at the lobar level. However, typical boundary conditions for deposition simulations assume that lung expansion is uniform, which we know to be incorrect. We have developed a Magnetic Resonance Imaging (MRI) technique that allows the quantification of regional specific ventilation in the human lung, providing realistic boundary conditions. In this proposal we will: a) map the spatial pattern of specific ventilation; b) map deposition in the supine position at 1G; and combine these with data on the spatial pattern of deposition of inhaled particles collected in low-gravity as part of our existing NSBRI studies; c) The measured pattern of aerosol deposition will be compared with the CFD predictions, using uniform and the more realistic boundary conditions. By comparing across a number of subjects, the mechanisms underlying the observed variability in deposition and regional ventilation can be elucidated. By comparing 1G and low-gravity deposition, the magnitude of the gravitational effect can be assessed.

2) Key findings: We have successfully applied the MRI technique for quantifying specific ventilation in the human lung- Specific Ventilation Imaging- completing aim a). We have used this technique to quantify the vertical, gravitational induced, gradient in specific ventilation that is present on the human lung on earth. Our findings are in accordance with previous radiation based techniques for quantifying specific ventilation. An article describing the technique was published during the second year in the Journal of Applied Physiology. A patent, protecting the intellectual property of this and two other MRI methodologies developed at our lab is currently actively pursued. During the second year we have mapped particle deposition for 4µm particles, when inhalation occurs in the supine position (10 subjects) and recently in low-gravity (6 subjects), addressing aim b).

3) Impact of key findings on original project: The successful completion of aim a) was essential to completion the project. The data for addressing aim b was recently collected for 4µm particles. Data analysis is under way. These results allow us to start CFD modeling, addressing aim c).

4) Research plan for the coming year: We have collected deposition data for 4µm particles (aim b). A second parabolic flight campaign (1µm particles) is expected in the spring 2012. MATLAB based software tools for the analysis of this data developed by the fellow are in use for the analysis of ground (1-G) data. Further development and optimization of these tools for application to low-gravity acquired data is underway. Computational Fluid Dynamic modeling will begin soon. The third year will be dedicated to the analysis of the outcomes of these models, and establishing a metric for comparison with the measured deposition patterns. We expect that, by imposing realistic instead of idealized boundary conditions, we will significantly improve our ability to predict particle deposition. Time will be dedicated to compiling and writing these results into a scientific publication.

Research Impact/Earth Benefits: The overall goal of this project is to better understand how variability in convective flow patterns in the lung affect aerosol deposition and subsequent clearance between individuals. Such knowledge will help better characterize the normal variability, both on the ground and in low gravity (the lunar, martian or asteroid surface), and thus better characterize the risks of exposure to potentially toxic, aggressive dust. This improved risk assessment is important both in earth's gravity, where many people are exposed to airborne dust, as well as in future planetary exploration (lunar dust is aggressive, highly reactive, and in low gravity, dust particles are likely to deposit further down in the lung, increasing residence time; little is know at this time on the toxicological properties of martian or asteroid dust). From a different and more long-term perspective, an improved fundamental understanding of the individual spatial variability in particle deposition might also help optimize aerosols drug delivery, helping optimizing aerosols mixes that will more accurately target specific portions of the lung. Individualized targeting of aerosol medication in chronic diseases such as asthma has the potential to increase the efficiency of the drug delivery, decreasing the inhaled dose and minimizing side effects. In the framework of this project, we have developed a novel MRI technique for the quantification of specific ventilation in the human lung. The technique requires a standard proton MRI machine with a 1.5 Tesla field, machines that are widely available in clinical setting. The technique does not require the use of radiation, and is therefore suitable for repeated measures. At a first stage, we are using the technique as a novel research tool, but its repercussions can be extended to the clinical setting. The fact that it does not involve radiation opens a novel diagnostic window, for it can be applied repetitively. This can be of particular importance in patient populations suffering from chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Patients with chronic respiratory disease could benefit from a non invasive, zero radiation dose assessment of their lung function, that can thus be repeated time and again, allowing for a more regular follow up than the existing techniques. A patent protecting the intellectual property of this MRI technique as well as two additional MR-sequences developed by our group is currently being pursued (provisional patent application: "New method for imaging ventilation and perfusion in the lung using MRI" - SD2010-320, provisional application number 61420554 - R.B. Buxton, G.K. Prisk, S.R. Hopkins, R.C. Pereira de Sá, R.J. Theilmann, M.V. Cronin).

Task Progress & Bibliography Information FY2012 
Task Progress: The goal of this project is to provide a better understanding of how variability in convective flow patterns in the lung affects aerosol deposition, and thus subsequent clearance between individuals. In order to achieve this goal, three specific aims need to be addressed: a) map the spatial pattern of specific ventilation; b) map deposition in the supine position at 1G; and combine these with data on the spatial pattern of deposition of inhaled particles collected in low-gravity as part of our existing NSBRI studies. c) The measured pattern of aerosol deposition will be compared with Computational Fluid Dynamics (CFD) predictions, using uniform and the more realistic boundary conditions. By comparing across a number of subjects, the mechanisms underlying the observed variability in deposition and regional ventilation can be elucidated. By comparing the data collected in 1G with data from low-gravity, the magnitude of the gravitational effect can be assessed.

In the first year we have successfully developed a Magnetic Resonance Imaging technique for quantifying specific ventilation in the human lung - Specific Ventilation Imaging, completing point a) of the initial project aims. We have used this technique to quantify the vertical, gravitational induced, gradient in specific ventilation that is present on the human lung on earth. An article describing the technique and the first physiological results obtained was published in the Journal of Applied Physiology during the second year of the project. This novel MRI technique was included in a provisional patent application: "New method for imaging ventilation and perfusion in the lung using MRI" (provisional application number 61420554). During this second year we quantified specific ventilation in the entire pool of subjects available (parabolic flight certified) for the low-gravity deposition experiments (N=10). The data thus obtained allowed us to determined realistic boundary conditions required for addressing aim c) in a individualized subject by subject basis.

We have mapped the deposition of 4µm particles (1G supine) in the same pool of subjects (N=10). A subset of these subjects (N=6) participated in a recent NASA parabolic flight campaign, where maps of particle deposition in low gravity were obtained for the first time, thus completing data acquisition for 4µm particles. Low-gravity deposition maps for 1µm particles, and the corresponding post-flight controls are expected to occur during a parabolic flight campaign tentatively scheduled for the spring 2012. The analysis of the acquired data is ongoing using MATLAB based software analysis tools developed during the first and second year of the project. The constraints of parabolic-flight acquired data imposed, as expected, additional customization and optimization. The implementation of the necessary changes is currently underway. We expect to start the CFD modeling component of the project shortly.

Bibliography Type: Description: (Last Updated: 01/11/2021)  Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Henderson AC, Sa RC, Barash IA, Holverda S, Buxton RB, Hopkins SR, Prisk GK. "Rapid intravenous infusion of 20 ml/kg saline alters the distribution of perfusion in healthy supine humans." American Thoracic Society (ATS) 2011 Conference, Denver, CO, May 13-18, 2011.

Am J Respir Crit Care Med 2011 May;183:A3572. , May-2011

Abstracts for Journals and Proceedings Prisk GK, Cronin MV, Henderson AC, Holverda S, Theilmann RJ, Arai TJ, Dubowitz DJ, Hopkins SR, Buxton RB, Sa RC. "Quantifying regional ventilation with proton MRI." The 2011 International Functional Pulmonary Imaging Workshop, Philadelphia, PA, February 28 - March 2, 2011.

The 2011 International Functional Pulmonary Imaging Workshop, Philadelphia, PA, February 28 - March 2, 2011. Abstract Book, February 2011. , Feb-2011

Abstracts for Journals and Proceedings Prisk GK, Sa RC, Bennett WD, Darquenne C. "Deposition and subsequent clearance of aerosols in reduced gravity." 18th International Academy of Astronautics (IAA) Humans in Space Symposium, Houston, TX, April 11-15, 2011.

18th IAA Humans in Space Symposium, Houston, TX, April 11-15, 2011. , Apr-2011

Abstracts for Journals and Proceedings Prisk GK, Sa RC, Holverda S, Dubowitz D, Cronin MV, Hopkins SR, Buxton RB. "Spatial-temporal heterogeneity of pulmonary blood flow is altered by changes in FIO2." American Thoracic Society (ATS) 2011 Conference, Denver, CO, May 13-18, 2011.

Am J Respir Crit Care Med 2011 May;183:A5188. , May-2011

Abstracts for Journals and Proceedings Sa RC, Darquenne C, Prisk GK. "Imaging ventilation within the lung to predict deposition of inhaled particles in normal and reduced gravity." 18th International Academy of Astronautics (IAA) Humans in Space Symposium, Houston, TX, April 11-15, 2011.

18th IAA Humans in Space Symposium, Houston, TX, April 11-15, 2011. , Apr-2011

Articles in Peer-reviewed Journals Sa RC, Cronin MV, Henderson AC, Holverda S, Theilmann RJ, Arai TJ, Dubowitz DJ, Hopkins SR, Buxton RB, Prisk GK. "Vertical distribution of specific ventilation in normal supine humans measured using oxygen-enhanced proton MRI." J Appl Physiol. 2010 Dec;109(6):1950-9. Epub 2010 Oct 7. PubMed PMID: 20930129 , Dec-2010
Project Title:  Variability in Flow Distribution within the Lung and its Effects on Deposition and Clearance of Inhaled Particles in Normal and Reduced Gravity (Postdoctoral Fellowship) Reduce
Fiscal Year: FY 2011 
Division: Human Research 
Research Discipline/Element:
HRP SHFH:Space Human Factors & Habitability (archival in 2017)
Start Date: 11/01/2009  
End Date: 10/31/2011  
Task Last Updated: 12/06/2011 
Download report in PDF pdf
Principal Investigator/Affiliation:   Sa, Rui Carlos Ph.D. / University of California, San Diego 
Address:  Department of Medicine 
9500 Gilman Drive, MC 0852 
La Jolla , CA 92093-0852 
Email: rcsa@ucsd.edu 
Phone: 858-822-5081  
Congressional District: 53 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of California, San Diego 
Joint Agency:  
Comments: Last name ometimes seen as “Pereira de Sa” " 
Co-Investigator(s)
Affiliation: 
Prisk, G. Kim  MENTOR/University of California, San Diego 
Project Information: Grant/Contract No. NCC 9-58-PF02103 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2009 NSBRI-RFA-09-01 Postdoctoral Fellowships 
Grant/Contract No.: NCC 9-58-PF02103 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:
No. of Master's Candidates:
No. of Bachelor's Candidates:
No. of PhD Degrees:
No. of Master's Degrees:
No. of Bachelor's Degrees:
Human Research Program Elements: (1) SHFH:Space Human Factors & Habitability (archival in 2017)
Human Research Program Risks: (1) Dust:Risk of Adverse Health & Performance Effects of Celestial Dust Exposure (IRP Rev F)
Human Research Program Gaps: (1) AEH Watch Item/NSBRI Research:What are the effects of lunar gravity on permissible exposure limits for inhalation of lunar dust? (Closed as of IRP Rev J)
Task Description: POSTDOCTORAL FELLOWSHIP

1) Original aims and objectives: Our goal is to provide a better understanding of how variability in convective flow patterns in the lung affects aerosol deposition, and thus subsequent clearance between individuals. Such an understanding will allow better characterization of the normal variability in deposition and clearance rates both in 1G, and in low-gravity such as on the lunar surface. Three key factors define the toxicological risk to the lung of exposure to airborne lunar dust which is believed to be highly reactive: 1) the degree of deposition, 2) the toxicological properties of the material itself, and 3) the residence time within the lung of the particles once they have been deposited. The distribution of ventilation within the lung determines deposition and subsequent clearance. Studies by us using computational fluid dynamics (CFD) in realistic central airway trees show that ventilation varies widely at the lobar bronchiole level. However, typical boundary conditions for deposition simulations assume that lung expansion is uniform, which we know to be incorrect. We developed a MRI technique that allows the quantification of regional specific ventilation in the human lung providing realistic boundary conditions and an accurate prediction of particle deposition.

In this proposal we will: a) map the spatial pattern of specific ventilation, b) map deposition in the supine position at 1G, and combine these with data on the spatial pattern of deposition of inhaled particles collected in low-gravity as part of our existing NSBRI studies; c) The measured pattern of aerosol deposition will be compared with the CFD predictions, using uniform and the more realistic boundary conditions. By comparing across a number of subjects, the mechanisms underlying the observed variability in deposition and regional ventilation can be elucidated. By comparing the data collected in 1G with data from low-gravity, the magnitude of the gravitational effect can be assessed.

2) Key findings: In this first year we have successfully developed a Magnetic Resonance Imaging technique for quantifying specific ventilation in the human lung - Specific Ventilation Imaging. We have thus completed point a) of the initial project aims. We are now capable of routine mapping the spatial pattern of specific ventilation in humans. We have used this technique to quantify the vertical, gravitational induced, gradient in specific ventilation that is present on the human lung on earth, in a total of 8 subjects. An article describing the technique is currently under review with the Journal of Applied Physiology.

Moreover, we have completed the integration of hardware and software required for the completion of aim b) and we have completed ground tests of the system. The completion of this specific goal is dependent on the availability of parabolic flights. We are currently waiting for NASA to provide such opportunity.

3) Impact of key findings on original project: The successful completion of aim a) was essential to the rest of the project.

4) Research plan for the coming year: Deposition and clearance: the parabolic flight campaign is likely to happen in March or April 2011. The constraints imposed by parabolic flights render the existing deposition and clearance analysis software inadequate. Based on preliminary 1G data of deposition and clearance, I am developing new software tools for the analysis of deposition and clearance. These tools will allow us, for example, to triage events by gravity level, but also to correct for subject movement or misalignment.

Specific Ventilation Imaging (SVI) allows to measure realistic boundary conditions for lobar ventilation. During this year, we will simulate deposition using computational fluid dynamics models, based on these realistic boundary conditions. Comparison with 1G supine and low-gravity deposition will follow, once the low-gravity data is available.

Research Impact/Earth Benefits: The overall goal of this project is to better understand how variability in convective flow patterns in the lung affects aerosol deposition and subsequent clearance between individuals. Such knowledge will help better characterize the normal variability, both on the ground and in low gravity (the lunar surface), and thus better characterize the risks of exposure to potentially toxic, aggressive dust. This improved risk assessment is important both for future lunar exploration (lunar dust is aggressive, highly reactive, and in low gravity, dust particles are likely to deposit further down in the lung, increasing residence time), as well as in earth's gravity, where many people are exposed to airborne dust.

From a different and more long-term perspective, a better understanding of the individual variability in deposition might also help optimize aerosols drug delivery, aerosols that will more accurately target specific portions of the lung.

In the framework of this project, we have developed a novel MRI technique for the quantification of specific ventilation in the human lung. The technique requires a standard proton MRI machine with a 1.5 Tesla field, machines that are widely available in clinical setting. The technique does not require the use of radiation, and is therefore suitable for repeated measures. At a first stage, we are using the technique as a novel research tool, but its repercussions can be extended to the clinical setting. The fact that it does not involve radiation, opens a novel diagnostic window, for can be applied repetitively. This can be of particular importance in patient populations suffering from chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD). Patients with chronic disease could benefit from a noninvasive, zero radiation dose assessment of their lung function, allowing for a more regular follow up than the existing techniques.

Task Progress & Bibliography Information FY2011 
Task Progress: The goal of this project is to provide a better understanding of how variability in convective flow patterns in the lung affects aerosol deposition, and thus subsequent clearance between individuals. In order to achieve this goal, three specific aims need to be addressed: a) map the spatial pattern of specific ventilation; b) map deposition in the supine position at 1G; and combine these with data on the spatial pattern of deposition of inhaled particles collected in low-gravity as part of our existing NSBRI studies. c) The measured pattern of aerosol deposition will be compared with the CFD predictions, using uniform and the more realistic boundary conditions. By comparing across a number of subjects, the mechanisms underlying the observed variability in deposition and regional ventilation can be elucidated. By comparing the data collected in 1G with data from low-gravity, the magnitude of the gravitational effect can be assessed.

In this first year we have successfully developed a Magnetic Resonance Imaging technique for quantifying specific ventilation in the human lung - Specific Ventilation Imaging. We have thus completed point a) of the initial project aims. We are now capable of routine mapping the spatial pattern of specific ventilation in humans. We have used this technique to quantify the vertical, gravitational induced, gradient in specific ventilation that is present on the human lung on earth, in a total of 8 subjects. An article describing the technique and presenting the first results obtained with it is currently under review with the Journal of Applied Physiology. The data thus obtained allowed us to determine the realistic boundary conditions required for addressing aim c).

Moreover, in this year we have completed the integration of hardware and software required for the completion of aim b) and we have completed ground tests of the system. The completion of this specific aim (b) is dependent on the availability of parabolic flights. We are currently waiting for NASA to provide such opportunity; the parabolic flight campaign is likely to take place in March or April 2011.

The constraints imposed by parabolic flights render the existing deposition and clearance analysis software inadequate. Based on preliminary 1G data of deposition and clearance acquired in 3 subjects, I have started developing new software tools for the analysis of deposition and clearance. These tools will allow us, for example, to triage events by gravity level, but also to correct for subject movement or misalignment induced by the parabolic profile. This is an ongoing work that will continue through the second year.

Bibliography Type: Description: (Last Updated: 01/11/2021)  Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Sa RC, Cronin MV, Henderson AC, Holverda S, Theilmann RJ, Arai TJ, Dubowitz DJ, Hopkins SR, Buxton RB, Prisk GK. "Vertical distribution of specific ventilation in normal supine humans measured using oxygen-enhanced proton MRI." J Appl Physiol. In press, February 2010. , Feb-2010
Project Title:  Variability in Flow Distribution within the Lung and its Effects on Deposition and Clearance of Inhaled Particles in Normal and Reduced Gravity (Postdoctoral Fellowship) Reduce
Fiscal Year: FY 2010 
Division: Human Research 
Research Discipline/Element:
HRP SHFH:Space Human Factors & Habitability (archival in 2017)
Start Date: 11/01/2009  
End Date: 10/30/2011  
Task Last Updated: 12/22/2009 
Download report in PDF pdf
Principal Investigator/Affiliation:   Sa, Rui Carlos Ph.D. / University of California, San Diego 
Address:  Department of Medicine 
9500 Gilman Drive, MC 0852 
La Jolla , CA 92093-0852 
Email: rcsa@ucsd.edu 
Phone: 858-822-5081  
Congressional District: 53 
Web:  
Organization Type: UNIVERSITY 
Organization Name: University of California, San Diego 
Joint Agency:  
Comments: Last name ometimes seen as “Pereira de Sa” " 
Co-Investigator(s)
Affiliation: 
Prisk, G. Kim  MENTOR/University of California, San Diego 
Project Information: Grant/Contract No. NCC 9-58-PF02103 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2009 NSBRI-RFA-09-01 Postdoctoral Fellowships 
Grant/Contract No.: NCC 9-58-PF02103 
Project Type: GROUND 
Flight Program:  
TechPort: No 
No. of Post Docs:
No. of PhD Candidates:  
No. of Master's Candidates:  
No. of Bachelor's Candidates:  
No. of PhD Degrees:  
No. of Master's Degrees:  
No. of Bachelor's Degrees:  
Human Research Program Elements: (1) SHFH:Space Human Factors & Habitability (archival in 2017)
Human Research Program Risks: (1) Dust:Risk of Adverse Health & Performance Effects of Celestial Dust Exposure (IRP Rev F)
Human Research Program Gaps: (1) AEH Watch Item/NSBRI Research:What are the effects of lunar gravity on permissible exposure limits for inhalation of lunar dust? (Closed as of IRP Rev J)
Task Description: POSTDOCTORAL FELLOWSHIP

The goal of this project to provide a better understanding of how variability in convective flow patterns in the lung affects aerosol deposition, and thus subsequent clearance between individuals. Such an understanding will allow better characterization of the normal variability in deposition and clearance rates both in Earths gravity, and in low-gravity such as on the lunar surface. Three key factors define the toxicological risk to the lung of exposure to airborne lunar dust which is believed to be highly reactive:

1. The degree of deposition; 2. The toxicological properties of the material itself, and; 3. The residence time within the lung of the particles once they have been deposited.

The distribution of ventilation within the lung determines deposition and subsequent clearance. Previous studies using computational fluid dynamics in realistic central airway trees show that ventilation varies widely at the lobar bronchiole level. However, typical boundary conditions for deposition simulations assume that lung expansion is uniform, which we know to be incorrect. This group has developed a MRI technique that allows the quantification of regional specific ventilation in the human lung providing realistic boundary conditions and an accurate prediction of particle deposition.

Specific Aims

1. Map the spatial pattern of specific ventilation, and;

2. Map deposition in the supine position at Earths gravity; and combine these with data on the spatial pattern of deposition of inhaled particles collected in low-gravity as part of Dr. Prisk's existing NSBRI studies.

The measured pattern of aerosol deposition will be compared with the computational fluid dynamics predictions, using uniform and the more realistic boundary conditions. By comparing across a number of subjects, the mechanisms underlying the observed variability in deposition and regional ventilation can be elucidated. By comparing the data collected in Earth's gravity with data from low-gravity, the magnitude of the gravitational effect can be assessed.

Research Impact/Earth Benefits: 0

Task Progress & Bibliography Information FY2010 
Task Progress: New project for FY2010.

Bibliography Type: Description: (Last Updated: 01/11/2021)  Show Cumulative Bibliography Listing
 
 None in FY 2010