NOTE: Team changed as of 5/1/08 (formerly was Technology Development Team) per NSBRI (6/18/08)

The dust on the surface of Mars is highly oxidative in nature, due to the UV environment on the surface, and that on the Moon has properties comparable to that of fresh-fractured quartz on Earth, a highly toxic substance. The dust is also electro-statically charged, and so will tend to stick to the outside of spacesuits, and be tracked into habitats. The lung, with its huge exposed surface area is highly vulnerable to adverse effects resulting from exposure to Mars and Moon dust.

We are engaged in a multi-faceted approach involving human and animal experiments, combined with sophisticated modeling, to provide a path to assessing the health risk of dust exposure in habitats on both the Moon and Mars. We will address the following hypotheses and objectives:

1: That total aerosol deposition in the human lung in fractional gravity will be higher than predicted by existing models (as is the case in microgravity), and that a higher than predicted alveolar deposition will result in these circumstances.

2: That aerosol deposition in the lungs of spontaneously breathing rats in fractional-G will be more peripheral (closer to the alveoli) than in 1G.

3: We will couple existing sophisticated computational fluid dynamics (CFD) models of the upper airways of humans, to our model of the alveolar region of the lung, to predict aerosol deposition under conditions matching those of the experiments performed in humans. In rats we will use detailed 3D images of the rat bronchial tree to develop an upper airway CFD model and predict aerosol deposition under conditions matching those of the experiments performed in rats. At the completion of the final year of this project we have successfully completed all 3 of the specific aims with some publications still forthcoming.

In the area of human studies of aerosol deposition in fractional gravity (SA #1) an important publication has now appeared in the European Journal of Applied Physiology. These studies showed that while deposition was reduced in fractional (lunar) gravity, that deposition which did occur was much more peripheral in the lung, with likely attendant increases in clearance time. The implications of this finding are that exposure models used for a lunar outpost cannot utilize terrestrial models. In parallel but related ground studies, we showed that breathing a reduced-density gas (in this case heliox), results in more peripheral deposition of particles. This publication has now appeared in the Journal of Aerosol Medicine. As the plans for the lunar outpost habitat are refined this has become a new and important point, as the current atmosphere design calls for a significantly lower density than sea-level air. Based on these studies, in February 2009 we flew an additional (previously unplanned study) on the Microgravity Research Aircraft. This extra set of flights was made possible by our previously more efficient use of aircraft time. In these studies we examined the regional deposition of particles under the combined influence of reduced gravity, and a reduced gas density mimicking for the first time, the lunar habitat environment with high fidelity. These extra studies are still under analysis and will be the subject of a future publication.

For the studies of deposition in rat lungs (SA #2), we flew the rat equipment in July 2008 and in September 2008. The last week of flights was cut short because of Hurricane Ike. Since then, we have not been able to complete our data collection aboard the NASA Reduced Gravity aircraft due to unavailability of flights. As a consequence, while the study of two particle sizes was planned in the original proposal, only one particle size (1 µm) was used in the experiment. Deposition in the rat lungs was assessed by magnetic resonance imaging (MRI). Preliminary MRI results from parabolic flights as well as from ground data have made two abstract presentations, one at the conference of the International Society for Aerosols in Medicine for the flight data, and the second at the International Conference of the American Thoracic Society focusing on the ground data. Future full-length publications are in development.

In the latest year, we have focused on modeling aerosol transport in the alveolar zone of the human lung (SA #3). We have developed models of up to four generations of bifurcating fully alveolated ducts. These models allow for the expansion and contraction of the airspaces during breathing and show that, even in the absence of gravity, substantial amounts of particles deposit in the alveolar cavities. Preliminary data have made an abstract poster presentation at the International Conference of the American Thoracic Society. These results are now being compiled in a manuscript. Leveraging off the NIH funding of Dr. Darquenne we have expanded the validation of our CFD models to both the flow and particle transport predictions. These results have been presented in a poster at the annual fall meeting of the Biomedical Engineering Society and also compiled in a paper published in the Journal of Aerosol Science.

First is the development of better models for assessing environmental exposure to particulate matter (PM). Because of its unique structure and function, the lung is a vulnerable target for airborne particulate matter (PM). On Earth, effects of oxidative-induced lung injury are most readily seen in individuals with pre-existing lung disease (i.e. asthma, chronic obstructive pulmonary disease). However, there is little question, that even healthy individuals exposed to PM for extended periods are susceptible to oxidant-induced lung injury. Evidence suggests that short-term exposure is also of considerable risk. Short-term exposure to PM can exacerbate various pulmonary diseases and increase the risk of myocardial infarction. It is also interesting to note that the correlation of exposure with risk factor increases as one considers total suspended particles (TSP), PM smaller than 10 micron (PM10) and then PM2.5, suggesting that the smallest particles may in fact be the most significant in terms of damage.

Second is a better understanding of the fate of aerosols in the lung may also be beneficial in aerosol drug therapy as many drugs are now administered in aerosolized form. As an example, Beta-2 agonists are used in an aerosolized form for the treatment of asthma. It is long known that the effect of Beta-2 agonists as bronchodilators is enhanced if they can be delivered directly to their intended site of action. This concept of spatial targeting requires knowledge of the nature of the aerosol being delivered, and the behavior of such an aerosol in the lung. Poor spatial targeting is associated with lowered efficacy, and potential side effects. Drugs such as pentamidine or ergotamine have systemic effects that are best achieved if they can be delivered into the alveolar region of the lung, with minimum deposition in other regions. Thus it may be possible to obtain optimal results with small quantities of drugs if spatial targeting puts the drug at exactly the right place in the lung, minimizing harm caused by side effects, and minimizing the use of a potentially expensive drug.

1. Use human models to assess deposition patterns.

All planned data collection is complete in lunar gravity and results currently In Press. No data were able to be collected in Martian gravity, but the results collected suggest a largely linear response to gravity, allowing adequate extrapolation to this condition. Results show that earth-based deposition models are inappropriate for use in the lunar environment. A ground study using a reduced density carrier gas (comparable in density to that in the planned lunar habitat) also moves deposition to a more peripheral site. Based on this we investigated the effects of both reduced gravity and a low-density carrier gas to better assess deposition likely in a lunar outpost in a series of “extra” flights made possible by our more efficient use of reduced gravity flight time than initially anticipated.

2. Develop rat models to assess deposition patterns that can subsequently be used to directly assess lung damage.

We have now constructed and successfully flown the multi-animal exposure system to be flown in the Reduced Gravity Aircraft. Flights were performed in June 2008 and Sept 2008, although the latter were curtailed due to Hurricane Ike. NASA has been subsequently unable to accommodate this experiment and with the concurrence of NSBRI we have curtailed the scope of this aim to studying only 1-micron particles. As a part of the ground-testing we have been refining our MRI techniques for lung imaging of particulate-laden lungs, and data analysis is ongoing with the excised and preserved rat lungs from flight.

3. Develop more comprehensive computational models of aerosol deposition under fractional-G consistent with these data.

Comprehensive studies of aerosol transport in the conducting airways of the human lung have been conducted showing a strong dependence of aerosol transport on convective flow, a useful result in that ground based simulations and studies will be adequate for predicting the transport of aerosol to the periphery of the lung (although based on SA #1, the same cannot be said for peripheral deposition).

Leveraging off Dr. Darquenne’s NIH funded work, collaborators at the von Karman Institute (VKI) have developed a model of an alveolated bend casted in silicon that can be seen as “half” a bifurcation. In parallel, a computational model was developed at UCSD with the same geometric characteristics as that developed for the experimental study. A more complex multi-bifurcation model with three successive generations of alveolated ducts is being studied both in a physical and an in-silico model. A model of 4 generations of bifurcating alveolar ducts with moving-walls has been developed and shows the important result that even in the absence of gravity, substantial amounts of particles deposit in the alveolar cavities as a direct consequence of wall motion.

NOTE: Team changed as of 5/1/08 (formerly was Technology Development Team) per NSBRI (6/18/08)

The dust on the surface of Mars is highly oxidative in nature, due to the UV environment on the surface, and that on the Moon has properties comparable to that of fresh-fractured quartz on Earth, a highly toxic substance. The dust is also electro-statically charged, and so will tend to stick to the outside of spacesuits, and be tracked into habitats. The lung, with its huge exposed surface area is highly vulnerable to adverse effects resulting from exposure to Mars and Moon dust.

We are engaged in a multi-faceted approach involving human and animal experiments, combined with sophisticated modeling, to provide a path to assessing the health risk of dust exposure in habitats on both the Moon and Mars, addressing Risk #7 in the Bioastronautics Critical Path Roadmap. Such an assessment has profound implications on the degree of engineering (and thus cost) that will be required to limit the risk of such exposure to the inhabitants of these habitats. We will address the following hypotheses and objectives:

1: That total aerosol deposition in the human lung in fractional gravity will be higher than predicted by existing models (as is the case in microgravity), and that a higher than predicted alveolar deposition will result in these circumstances. Using the NASA Microgravity Research Aircraft, we will non-invasively measure both the total and regional deposition of inert particles (0.5 to 2 micron) in humans in fractional-G corresponding to that on the surface of the Moon and Mars.

2: That aerosol deposition in the lungs of spontaneously breathing rats in fractional-G will be more peripheral (closer to the alveoli) than in 1G. We will expose spontaneously breathing rats to fluorescent- and magnetically-labeled particles of varying sizes (between 0.5 and 2 micron) in 1G, and in fractional G corresponding to surface of the Moon and Mars, and measure the specific sites of regional deposition in the lungs using both fluorescent microscopy, and magnetic resonance imaging techniques.

3: We will couple existing sophisticated computational fluid dynamics (CFD) models of the upper airways of humans, to our model of the alveolar region of the lung, to predict aerosol deposition under conditions matching those of the experiments performed in humans. In rats we will use detailed 3D images of the rat bronchial tree to develop an upper airway CFD model which used in conjunction with an appropriately scaled alveolar model, will predict aerosol deposition under conditions matching those of the experiments performed in rats.

Nearing the completion of year 3 of this project we have flown the human studies aboard the NASA Reduced Gravity Aircraft in lunar gravity and the results have been presented as a publication now In Press in the European Journal of Applied Physiology. These studies showed that while deposition was reduced in fractional (lunar) gravity, that deposition which did occur was much more peripheral in the lung, with likely attendant increases in clearance time. The implications of this finding are that exposure models used for a lunar outpost cannot utilize terrestrial models. In parallel but related ground studies, we showed that breathing a reduced-density gas (in this case heliox), results in more peripheral deposition of particles. As the plans for the lunar outpost habitat are refined this has become a new and important point, as the current atmosphere design calls for a significantly lower density than sea-level air. These results are documented in a publication In Press in the Journal of Aerosol Medicine.

In the latest year we have built and successfully tested the flight system for 4 rats. However due to unavailability of the NASA Reduced Gravity Aircraft in the last quarter flights have not yet occurred and have been delayed to the first quarter of Year 4 of the project. As part of the testing activities we have been refining the MRI techniques for measuring deposition and have made two abstract presentations of these results, on at the International Society for Magnetic Resonance in Medicine focusing on detection of particulates, and the second at the International Conference of the American Thoracic Society focusing on the airway morphometry of the rat derived from MRI. CFD modeling (SA #3) has progressed and we have shown that adequate transport estimates for particles can be made based on convective flow patterns, a result which greatly simplifies modeling in the central airways, as convective flow patterns are largely independent of gravity level. These results were also presented late last year in abstract form at the International Conference of the American Thoracic Society. Leveraging off the NIH funding of Dr. Darquenne we have shown that our CFD models are fully-valid in a bifurcating alveolated duct system by comparing those results with results from a physical model using particle imaging velocimetry (PIV).

In the upcoming year we plan the flights of the rat plehysmograph system with aerosol exposure in low gravity. The human studies will be expanded to examine synergistic effects of low gravity and low-density gas on aerosol deposition, a new factor previously not appreciated.

First is the development of better models for assessing environmental exposure to particulate matter (PM). Because of its unique structure and function, the lung is a vulnerable target for airborne particulate matter (PM). On Earth, effects of oxidative-induced lung injury are most readily seen in individuals with pre-existing lung disease (i.e. asthma, chronic obstructive pulmonary disease). However, there is little question, that even healthy individuals exposed to PM for extended periods are susceptible to oxidant-induced lung injury. Evidence suggests that short-term exposure is also of considerable risk. Short-term exposure to PM can exacerbate various pulmonary diseases and increase the risk of myocardial infarction. It is also interesting to note that the correlation of exposure with risk factor increases as one considers total suspended particles (TSP), PM smaller than 10 micron (PM10) and then PM2.5, suggesting that the smallest particles may in fact be the most significant in terms of damage.

Second is a better understanding of the fate of aerosols in the lung may also be beneficial in aerosol drug therapy as many drugs are now administered in aerosolized form. As an example, Beta-2 agonists are used in an aerosolized form for the treatment of asthma. It is long known that the effect of Beta-2 agonists as bronchodilators is enhanced if they can be delivered directly to their intended site of action. This concept of spatial targeting requires knowledge of the nature of the aerosol being delivered, and the behavior of such an aerosol in the lung. Poor spatial targeting is associated with lowered efficacy, and potential side effects. Drugs such as pentamidine or ergotamine have systemic effects that are best achieved if they can be delivered into the alveolar region of the lung, with minimum deposition in other regions. Thus it may be possible to obtain optimal results with small quantities of drugs if spatial targeting puts the drug at exactly the right place in the lung, minimizing harm caused by side effects, and minimizing the use of a potentially expensive drug.

1. Use human models to assess deposition patterns.

All planned data collection is complete in lunar gravity and results currently In Press. No data were able to be collected in Martian gravity, but the results collected suggest a largely linear response to gravity, allowing adequate extrapolation to this condition. Results show that earth-based deposition models are inappropriate for use in the lunar environment. Ground studies using a reduced density carrier gas (comparable in density to that in the planned lunar habitat) also moves deposition to a more peripheral site. Based on this we now plan to directly investigate the effects of both reduced gravity and a low-density carrier gas to better assess deposition likely in a lunar outpost.

2. Develop rat models to assess deposition patterns that can subsequently be used to directly assess lung damage.

We have now constructed and successfully ground-tested the multi-animal exposure system to be flown in the Reduced Gravity Aircraft. We had planned to fly this in the second quarter of CY-2008, but NASA was unable to provide us with access to the Reduced Gravity Aircraft. As a consequence these flights are now in the process of being scheduled for the third quarter of CY-2008. All necessary approval paperwork has been submitted and we are essentially ready to fly. As a part of the ground-testing we have been refining our MRI techniques for lung imaging of particulate-laden lungs.

3. Develop more comprehensive computational models of aerosol deposition under fractional-G consistent with these data.

Comprehensive studies of aerosol transport in the conducting airways of the human lung have been conducted showing a strong dependence of aerosol transport on convective flow, a useful result in that ground based simulations and studies will be adequate for predicting the transport of aerosol to the periphery of the lung (although based on SA #1, the same cannot be said for peripheral deposition).

Leveraging off Dr. Darquenne’s NIH funded work, collaborators at the von Karman Institute (VKI) have developed a model of an alveolated bend casted in silicon that can be seen as “half” a bifurcation. In parallel, a computational model was developed at UCSD with the same geometric characteristics as that developed for the experimental study. A more complex multi-bifurcation model with three successive generations of alveolated ducts is being studied both in a physical and an in-silico model, the latter being a directly relevant model for the studies performed here.

The dust on the surface of Mars is highly oxidative in nature, due to the UV environment on the surface, and that on the Moon has properties comparable to that of fresh-fractured quartz on Earth, a highly toxic substance. The dust is also electro-statically charged, and so will tend to stick to the outside of spacesuits, and be tracked into habitats. The lung, with its huge exposed surface area is highly vulnerable to adverse effects resulting from exposure to Mars and Moon dust.

We are engaged in a multi-faceted approach involving human and animal experiments, combined with sophisticated modeling, to provide a path to assessing the health risk of dust exposure in habitats on both the Moon and Mars, addressing Risk #7 in the Bioastronautics Critical Path Roadmap. Such an assessment has profound implications on the degree of engineering (and thus cost) that will be required to limit the risk of such exposure to the inhabitants of these habitats. We will address the following hypotheses and objectives:

1: That total aerosol deposition in the human lung in fractional gravity will be higher than predicted by existing models (as is the case in microgravity), and that a higher than predicted alveolar deposition will result in these circumstances. Using the NASA Microgravity Research Aircraft, we will non-invasively measure both the total and regional deposition of inert particles (0.5 to 2 micron) in humans in fractional-G corresponding to that on the surface of the Moon and Mars.

2: That aerosol deposition in the lungs of spontaneously breathing rats in fractional-G will be more peripheral (closer to the alveoli) than in 1G. We will expose spontaneously breathing rats to fluorescent- and magnetically-labeled particles of varying sizes (between 0.5 and 2 micron) in 1G, and in fractional G corresponding to surface of the Moon and Mars, and measure the specific sites of regional deposition in the lungs using both fluorescent microscopy, and magnetic resonance imaging techniques.

3: We will couple existing sophisticated computational fluid dynamics (CFD) models of the upper airways of humans, to our model of the alveolar region of the lung, to predict aerosol deposition under conditions matching those of the experiments performed in humans. In rats we will use detailed 3D images of the rat bronchial tree to develop an upper airway CFD model which used in conjunction with an appropriately scaled alveolar model, will predict aerosol deposition under conditions matching those of the experiments performed in rats.

Nearing the completion of year 2 of this project we have flown the human studies aboard the Microgravity Research Aircraft and the results have been presented in abstract form at the International Conference of the American Thoracic Society (SA #1). These studies showed that while deposition was reduced in fractional (lunar) gravity, that deposition which did occur was much more peripheral in the lung, with likely attendant increases in clearance time. The implications of this finding are that exposure models used for a lunar outpost cannot utilize terrestrial models. CFD modeling (SA #3) has progressed and we have shown that adequate transport estimates for particles can be made based on convective flow patterns, a result which greatly simplifies modeling in the central airways, as convective flow patterns are largely independent of gravity level. These results were also presented in abstract form at the International Conference of the American Thoracic Society. Proof of concept flights of the rat plethysmograph system necessary for SA #2 was successfully completed in this year, and the building of the system is currently in progress. In the upcoming year we see the first flights of the rat plehysmograph system with aerosol exposure in low gravity. The human studies will be published and CFD development and further simulations will be on-going in parallel.

1. Use human models to assess deposition patterns. The human studies, which were an extension of previous studies in microgravity performed by us, flew on the Microgravity Research Aircraft in this year. Data collection is complete is lunar gravity and results are in preparation for publication. No data were able to be collected in Martian gravity, but the results collected suggest a largely linear response to gravity, allowing adequate extrapolation to this condition. Results show that earth-based deposition models are inappropriate for use in the lunar environment.

2. Develop rat models to assess deposition patterns that can subsequently be used to directly assess lung damage. As part of the flights during this year, an engineering evaluation of the rodent aerosol exposure system was performed, and highlighted a number of potential issues to be addressed in the final design. However, overall the prototype system performed well, and we are now in the process of building the multi-animal exposure system to be flown in the upcoming year of the project.

3. Develop more comprehensive computational models of aerosol deposition under fractional-G consistent with these data. A new workstation dedicated to the computational simulations was installed and equipped with Computational Fluid Dynamics software allowing for aerosol transport simulations in the conducting airways as well as in the alveolar region of the lung. Comprehensive studies of aerosol transport in the conducting airways of the human lung have been conducted showing a strong dependence of aerosol transport on convective flow, a useful result in that ground based simulations and studies will be adequate for predicting the transport of aerosol to the periphery of the lung (although based on SA #1, the same cannot be said for peripheral deposition).

The dust on the surface of Mars is highly oxidative in nature, due to the UV environment on the surface, and that on the Moon has properties comparable to that of fresh-fractured quartz on Earth, a highly toxic substance. The dust is also electro-statically charged, and so will tend to stick to the outside of spacesuits, and be tracked into habitats. The lung, with its huge exposed surface area is highly vulnerable to adverse effects resulting from exposure to Mars and Moon dust.

We are engaged in a multi-faceted approach involving human and animal experiments, combined with sophisticated modeling, to provide a path to assessing the health risk of dust exposure in habitats on both the Moon and Mars, addressing Risk #7 in the Bioastronautics Critical Path Roadmap. Such an assessment has profound implications on the degree of engineering (and thus cost) that will be required to limit the risk of such exposure to the inhabitants of these habitats. We will address the following hypotheses and objectives:

1: That total aerosol deposition in the human lung in fractional gravity will be higher than predicted by existing models (as is the case in microgravity), and that a higher than predicted alveolar deposition will result in these circumstances. Using the NASA Microgravity Research Aircraft, we will non-invasively measure both the total and regional deposition of inert particles (0.5 to 2 micron) in humans in fractional-G corresponding to that on the surface of the Moon and Mars.

2: That aerosol deposition in the lungs of spontaneously breathing rats in fractional-G will be more peripheral (closer to the alveoli) than in 1G. We will expose spontaneously breathing rats to fluorescent- and magnetically-labeled particles of varying sizes (between 0.5 and 2 micron) in 1G, and in fractional G corresponding to surface of the Moon and Mars, and measure the specific sites of regional deposition in the lungs using both fluorescent microscopy, and magnetic resonance imaging techniques.

3: We will couple existing sophisticated computational fluid dynamics (CFD) models of the upper airways of humans, to our model of the alveolar region of the lung, to predict aerosol deposition under conditions matching those of the experiments performed in humans. In rats we will use detailed 3D images of the rat bronchial tree to develop an upper airway CFD model which used in conjunction with an appropriately scaled alveolar model, will predict aerosol deposition under conditions matching those of the experiments performed in rats.

At the completion of year 1 of this project we have flown the first series of human studies aboard the Microgravity Research Aircraft (scheduled for mid-June at time of writing). These will encompass both total and regional deposition experiments (specific aim #1). As the only available flight profiles aboard the Aircraft are presently a mixture of microgravity and fractional-gravity profiles, we will use the microgravity phases of the flights to perform engineering evaluation so the plethysmographic system to be used for studies associated with specific aim #2. In pursuit of specific aim #3 (CFD) we have begun the development of a detailed atlas of the upper airway geometry in rats (using MRI imaging). In parallel, we have begun the coupling of the CFD codes for central and peripheral airways. Limited simulations in fractional gravity have been performed to generate preliminary data and test development progress. We have installed the upgraded CFD processing workstation to support these activities.

In the upcoming year we will continue the flights aboard the Microgravity Research Aircraft, to complete the human studies (Specific Aim #1). Flights are currently scheduled for September, with subsequent flight opportunities not yet defined by the Reduced Gravity Office. We will complete engineering evaluations of the rat plethysmographic system and expect to fly the first rat exposure studies in CY 2007. CFD development will be on-going in parallel.

First is the development of better models for assessing environmental exposure to particulate matter (PM). Because of its unique structure and function, the lung is a vulnerable target for airborne particulate matter (PM). On Earth, effects of oxidative-induced lung injury are most readily seen in individuals with pre-existing lung disease (i.e. asthma, chronic obstructive pulmonary disease). However, there is little question, that even healthy individuals exposed to PM for extended periods are susceptible to oxidant-induced lung injury. Evidence suggests that short-term exposure is also of considerable risk. Short-term exposure to PM can exacerbate various pulmonary diseases and increase the risk of myocardial infarction. It is also interesting to note that the correlation of exposure with risk factor increases as one considers total suspended particles (TSP), PM smaller than 10 micron (PM10) and then PM2.5, suggesting that the smallest particles may in fact be the most significant in terms of damage.

Second is a better understanding of the fate of aerosols in the lung may also be beneficial in aerosol drug therapy as many drugs are now administered in aerosolized form. As an example, Beta-2 agonists are used in an aerosolized form for the treatment of asthma. It is long known that the effect of Beta-2 agonists as bronchodilators is enhanced if they can be delivered directly to their intended site of action. This concept of spatial targeting requires knowledge of the nature of the aerosol being delivered, and the behavior of such an aerosol in the lung. Poor spatial targeting is associated with lowered efficacy, and potential side effects. Drugs such as pentamidine or ergotamine have systemic effects that are best achieved if they can be delivered into the alveolar region of the lung, with minimum deposition in other regions. Thus it may be possible to obtain optimal results with small quantities of drugs if spatial targeting puts the drug at exactly the right place in the lung, minimizing harm caused by side effects, and minimizing the use of a potentially expensive drug.

1. Use human models to assess deposition patterns.

The human studies, which are an extension of previous studies in microgravity performed by us, are ready to fly on the Microgravity Research Aircraft. Actual flight has been delayed by non-availability of the aircraft. First flight is scheduled for mid-June 2006, and will include both total and regional deposition studies in lunar gravity

2. Develop rat models to assess deposition patterns that can subsequently be used to directly assess lung damage.

As part of the flights scheduled for mid-June an engineering evaluation of the rodent aerosol exposure system will be performed. This system has been developed based on laboratory systems modified for flight and numerous aspects require testing in the flight environment prior to actual rodent flight. As such several key design decisions have been delayed pending engineering evaluation. It is anticipated that flight availability will increase in the next FY and as such the delays experienced this year can be readily compensated for. In parallel we have been developing and refining our high resolution imaging capability in mouse and rat lungs, with a paper recently submitted for publication in this area with Dr Scadeng.

3. Develop more comprehensive computational models of aerosol deposition under fractional-G consistent with these data.

A new workstation dedicated to the computational simulations has been purchased and equipped with Computational Fluid Dynamics software allowing for aerosol transport simulations in the conducting airways as well as in the alveolar region of the lung. In this first year, simulations have focused on the human lung. Flow patterns have been computed in both the conducting airways and a model of a portion of the human acinus for the same breathing conditions as those that will be used in the experimental human studies to be carried during parabolic flights in June 2006. Aerosol transport and deposition in the three-dimensional model of conducting airways have also been simulated both in a microgravity and normal gravity, these gravitational environments representing a lower and upper bound to lunar and Martian gravity. Simulations of aerosol transport in lunar gravity are now being performed.

The dust on the surface of Mars is highly oxidative in nature, due to the UV environment on the surface, and that on the Moon has properties comparable to that of fresh-fractured quartz on Earth, a highly toxic substance. The dust is also electro-statically charged, and so will tend to stick to the outside of spacesuits, and be tracked into habitats. The lung, with its huge exposed surface area is highly vulnerable to adverse effects resulting from exposure to Mars and Moon dust.

We are engaged in a multi-faceted approach involving human and animal experiments, combined with sophisticated modeling, to provide a path to assessing the health risk of dust exposure in habitats on both the Moon and Mars, addressing Risk #7 in the Bioastronautics Critical Path Roadmap. Such an assessment has profound implications on the degree of engineering (and thus cost) that will be required to limit the risk of such exposure to the inhabitants of these habitats. We will address the following hypotheses and objectives:

1: That total aerosol deposition in the human lung in fractional gravity will be higher than predicted by existing models (as is the case in microgravity), and that a higher than predicted alveolar deposition will result in these circumstances. Using the NASA Microgravity Research Aircraft, we will non-invasively measure both the total and regional deposition of inert particles (0.5 to 2 micron) in humans in fractional-G corresponding to that on the surface of the Moon and Mars.

2: That aerosol deposition in the lungs of spontaneously breathing rats in fractional-G will be more peripheral (closer to the alveoli) than in 1G. We will expose spontaneously breathing rats to fluorescent- and magnetically-labeled particles of varying sizes (between 0.5 and 2 micron) in 1G, and in fractional G corresponding to surface of the Moon and Mars, and measure the specific sites of regional deposition in the lungs using both fluorescent microscopy, and magnetic resonance imaging techniques.

3: We will couple existing sophisticated computational fluid dynamics (CFD) models of the upper airways of humans, to our model of the alveolar region of the lung, to predict aerosol deposition under conditions matching those of the experiments performed in humans. In rats we will use detailed 3D images of the rat bronchial tree to develop an upper airway CFD model which used in conjunction with an appropriately scaled alveolar model, will predict aerosol deposition under conditions matching those of the experiments performed in rats.

At the completion of year 1 of this project we have flown the first series of human studies aboard the Microgravity Research Aircraft (scheduled for mid-June at time of writing). These will encompass both total and regional deposition experiments (specific aim #1). As the only available flight profiles aboard the Aircraft are presently a mixture of microgravity and fractional-gravity profiles, we will use the microgravity phases of the flights to perform engineering evaluation so the plethysmographic system to be used for studies associated with specific aim #2. In pursuit of specific aim #3 (CFD) we have begun the development of a detailed atlas of the upper airway geometry in rats (using MRI imaging). In parallel, we have begun the coupling of the CFD codes for central and peripheral airways. Limited simulations in fractional gravity have been performed to generate preliminary data and test development progress. We have installed the upgraded CFD processing workstation to support these activities.

In the upcoming year we will continue the flights aboard the Microgravity Research Aircraft, to complete the human studies (Specific Aim #1). Flights are currently scheduled for September, with subsequent flight opportunities not yet defined by the Reduced Gravity Office. We will complete engineering evaluations of the rat plethysmographic system and expect to fly the first rat exposure studies in CY 2007. CFD development will be on-going in parallel.

First is the development of better models for assessing environmental exposure to particulate matter (PM). Because of its unique structure and function, the lung is a vulnerable target for airborne particulate matter (PM). On Earth, effects of oxidative-induced lung injury are most readily seen in individuals with pre-existing lung disease (i.e. asthma, chronic obstructive pulmonary disease). However, there is little question, that even healthy individuals exposed to PM for extended periods are susceptible to oxidant-induced lung injury. Evidence suggests that short-term exposure is also of considerable risk. Short-term exposure to PM can exacerbate various pulmonary diseases and increase the risk of myocardial infarction. It is also interesting to note that the correlation of exposure with risk factor increases as one considers total suspended particles (TSP), PM smaller than 10 micron (PM10) and then PM2.5, suggesting that the smallest particles may in fact be the most significant in terms of damage.

Second is a better understanding of the fate of aerosols in the lung may also be beneficial in aerosol drug therapy as many drugs are now administered in aerosolized form. As an example, Beta-2 agonists are used in an aerosolized form for the treatment of asthma. It is long known that the effect of Beta-2 agonists as bronchodilators is enhanced if they can be delivered directly to their intended site of action. This concept of spatial targeting requires knowledge of the nature of the aerosol being delivered, and the behavior of such an aerosol in the lung. Poor spatial targeting is associated with lowered efficacy, and potential side effects. Drugs such as pentamidine or ergotamine have systemic effects that are best achieved if they can be delivered into the alveolar region of the lung, with minimum deposition in other regions. Thus it may be possible to obtain optimal results with small quantities of drugs if spatial targeting puts the drug at exactly the right place in the lung, minimizing harm caused by side effects, and minimizing the use of a potentially expensive drug.