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.

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.

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.

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.

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.

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.

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.

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.