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Project Title:  Improved Bubble Detection for EVA Reduce
Fiscal Year: FY 2009 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 07/01/2004  
End Date: 06/30/2009  
Task Last Updated: 12/09/2009 
Download report in PDF pdf
Principal Investigator/Affiliation:   Buckey, Jay C. M.D. / Dartmouth College 
Address:  Department of Medicine 
1 Medical Center Drive 
Lebanon , NH 03756-0001 
Email: jay.buckey@dartmouth.edu 
Phone: 603-650-6012  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Dartmouth College 
Joint Agency:  
Comments: Address updated 9/2008 
Co-Investigator(s)
Affiliation: 
Magari, Patrick  Creare, Inc. 
Knaus, Darin  Creare, Inc. 
MacKenzie, Todd  Dartmouth College 
Phillips, Scott  Creare, Inc. 
Pawelczyk, James  Ph.D. Pennsylvania State University 
Project Information: Grant/Contract No. NCC 9-58-TD00402 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-TD00402 
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) HHC:Human Health Countermeasures
Human Research Program Risks: (1) DCS:Risk of Decompression Sickness (IRP Rev D)
Human Research Program Gaps: (1) DCS02:We do not know the contribution of specific DCS risk factors to the development of DCS in the Space Flight Exploration Environment (IRP Rev D)
Flight Assignment/Project Notes: NOTE: End date changed to 6/30/2009 per NSBRI (5/2008)

Task Description: Decompression sickness can be a significant operational issue for NASA during extravehicular activity (EVA). Improved bubble detection and sizing technology could enhance safety and promote understanding of decompression sickness. The goal of this project is to develop and demonstrate a novel bubble detection and sizing technique—dual-frequency ultrasound (DFU).

In this project we (1) demonstrated the ability of the DFU to detect stationary microbubbles in tissue, (2) performed a comprehensive calibration of the sizing capabilities of the device using bubbles of known size, and (3) performed a mix of human and animal experiments to explore the usefulness of tissue bubble detection.

First, we demonstrated that DFU could detect both ultrasonic contrast agent and decompression bubbles in tissue. This demonstrated the ability of DFU to detect small bubbles in tissue. The next step was to assess whether bubbles could be detected after exercise in normal humans. Exercise has been postulated to create small bubbles in tissue, and these bubbles are thought to increase bubble formation and decompression sickness risk during subsequent decompression stress after exercise. But, these small bubbles had never been directly detected in tissue.

To do this, in the past year we surveyed for bubbles in the legs of human subjects before and after cycle ergometer exercise using DFU. Six normal human subjects aged (28-52) were studied. Eleven marked sites on the left thigh and calf were imaged on each subject using standard imaging ultrasound. Subjects then rested in a reclining chair for 2 hours prior to exercise. For the hour before exercise a series of baseline measurements were taken at each site using DFU. A minimum of 6 baseline measurements was taken at each site. The subjects then exercised at 80% of their age-adjusted maximal heart rate for 30 minutes on an upright bicycle ergometer. After exercise, the subjects returned to the chair and multiple post-exercise measurements were taken at the marked sites with the CDFI. Measurements continued until no further signals consistent with bubbles were returned or one hour had elapsed. All the subjects had signals consistent with bubbles at a least one site after exercise.

The most likely explanation for these results is that exercise does produce gas-filled micronuclei (bubbles). This is the first demonstration that these micronuclei can be detected after exercise, and these results have important implications for decompression sickness diagnosis and treatment.

Research Impact/Earth Benefits: The results from this study are applicable to divers, aviators, high-altitude parachutists and others who are exposed to the risk of decompression sickness.

Another application for this technology is bubble monitoring during coronary artery bypass surgery or valve replacement surgery. Patients who have coronary artery bypass surgery are at risk for having solid and gaseous emboli reach the brain when they are on the "pump" (the cardiopulmonary bypass circuit). The Creare dual-frequency ultrasound unit could be used to monitor for bubbles in the bypass circuit and could distinguish between solid and gaseous emboli.

Creare is also applying the knowledge gained on the bubble acoustics knowledge and expertise gained in this effort to a Department of Energy project to mitigate cavitation damage in the Spallation Neutron Source (SNS) being developed at Oak Ridge National Laboratory. In this facility, a large acoustic wave is produced in the mercury spallation target when proton pulses very rapidly and repeatedly enter the mercury. The acoustic wave reflects off the vessel walls and causes the mercury to cavitate which results in severe damage to the vessel when the SNS is operated at the desired full power level. Creare is characterizing the ability of various stabilized bubbles to dampen the large acoustic wave and, thereby, mitigate the resulting cavitation damage.

Task Progress & Bibliography Information FY2009 
Task Progress: The bubble detection technique exploits the resonance properties of bubbles to detect and size them using two ultrasound frequencies. Over the years, several approaches have been used to address the various tasks of the project.

* Micropipette-generated bubbles of optically-verifiable sizes were used as a standard with which to calibrate and validate the intravascular bubble sizing capability of the instrument. This work has been completed and presented in abstract form. It is being prepared for publication.

* Definity® stabilized bubble-based ultrasound contrast agent were used as a known source of nonlinear bubble mixing signal for tissue bubble detection validation. Solid polymer microspheres were used as comparative standard since they reflect ultrasound but do not produce nonlinear mixing signals characteristic of bubbles. Solutions of known concentrations of ultrasound contrast agent and solid polymer microspheres were injected into the thigh of an anesthetized swine and imaged using the dual-frequency ultrasound bubble detection and sizing device. These results have been published in the journal Undersea and Hyperbaric Medicine.

* A swine model of decompression sickness was used to produce nitrogen bubbles in tissue and blood. Anesthetized pigs weighing 20 kg were exposed to 4.5 ATA for 120 minutes and then brought to 1 ATA. This work has been completed and presented in abstract form. It is being prepared for publication.

* Exercise was used as a mechanism to increase levels of pre-existing extravascular bubbles in human subjects. This work has been accepted for publication in the Journal of Applied Physiology.

Bibliography Type: Description: (Last Updated: 12/02/2021) 

Show Cumulative Bibliography Listing
 
Abstracts for Journals and Proceedings Bollinger BR, Phillips SD, Donoghue TG, Wilbur JC, Knaus DA, Magari PJ, Buckey JC. "Dual-frequency ultrasound detection and sizing of 20-200 micron bubbles for studying decompression sickness." 79th Aerospace Medical Association Annual Scientific Meeting, Boston, MA, May 12-15, 2008.

Aviat Space Environ Med. 2008 Mar;79(3):317. , Mar-2008

Abstracts for Journals and Proceedings Donoghue TG, Bollinger BR, Wilbur JC, Phillips SD, Alvarenga DL, Knaus DA, Magari PJ, Buckey JC. "Decompression-induced tissue bubbles detected using dual-frequency ultrasound." 80th Aerospace Medical Association Annual Scientific Meeting, Los Angeles, CA, May 3-7 2009.

Aviat Space Environ Med. 2009 Mar;80(3):290. , Mar-2009

Abstracts for Journals and Proceedings Wilbur JC, Bollinger BR, Donoghue TG, Phillips SD, Knaus DA, Buckey JC, Magari PJ. "Evaluation of technologies for non-invasive tissue bubble detection." 79th Aerospace Medical Association Annual Scientific Meeting, Boston, MA, May 12-15, 2008.

Aviat Space Environ Med. 2008 Mar;79(3):317. , Mar-2008

Abstracts for Journals and Proceedings Wilbur JC, Phillips SD, Donoghue TG, Alvarenga DL, Knaus DA, Magari PJ, Buckey JC. "Signals consistent with microbubbles detected in normal human subjects after exercise." 2009 Undersea and Hyperbaric Medical Society Annual Meeting, Las Vegas, NV, June 25-27, 2009.

2009 Undersea and Hyperbaric Medicine Association Meeting, Las Vegas, NV, June 25-27, 2009. , Jun-2009

Articles in Peer-reviewed Journals Bollinger BR, Wilbur JC, Donoghue TG, Phillips SD, Knaus DA, Magari PJ, Alvarenga DL, Buckey JC. "Dual-frequency ultrasound detection of stationary microbubbles in tissue." Undersea Hyperb Med. 2009 Mar-Apr;36(2):127-36. PMID: 19462752 , Apr-2009
Articles in Peer-reviewed Journals Buckey JC, Knaus DA, Alvarenga DL, Kenton MA, Magari PJ. "Dual-frequency ultrasound for detecting and sizing bubbles." Acta Astronaut. 2005 May-Jun;56(9-12):1041-7. PMID: 15835064 , Jun-2005
Articles in Peer-reviewed Journals Wilbur JC, Phillips SD, Donoghue TG, Alvarenga DL, Knaus DA, Magari PJ, Buckey JC. "Signals consistent with microbubbles detected in legs of normal human subjects after exercise." J Appl Physiol. 2010 Feb;108(2):240-4. Epub 2009 Oct 29. http://dx.doi.org/10.1152/japplphysiol.00615.2009 ; PubMed PMID: 19875715 (NOTE: Originally reported as J Appl Physiol. 2009 Oct 29. [Epub ahead of print] ; October 2009) , Feb-2010
Articles in Peer-reviewed Journals Florian JP, Baisch FJ, Heer M, Pawelczyk JA. "Caloric restriction decreases orthostatic tolerance independently from 6° head-down bedrest." PLoS One. 2015 Apr 27;10(4):e0118812. eCollection 2015. http://dx.doi.org/10.1371/journal.pone.0118812 ; PubMed PMID: 25915488; PubMed Central PMCID: PMC4411149 , Apr-2015
Articles in Peer-reviewed Journals Florian JP, Baisch FJ, Heer M, Pawelczyk JA. "Caloric restriction diminishes the pressor response to static exercise." Extrem Physiol Med. 2016 Jan 20;5:2. eCollection 2016. https://doi.org/10.1186/s13728-016-0043-3 ; PubMed PMID: 26793301; PubMed Central PMCID: PMC4719559 , Jan-2016
Project Title:  Improved Bubble Detection for EVA Reduce
Fiscal Year: FY 2007 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 07/01/2004  
End Date: 06/30/2009  
Task Last Updated: 02/01/2008 
Download report in PDF pdf
Principal Investigator/Affiliation:   Buckey, Jay C. M.D. / Dartmouth College 
Address:  Department of Medicine 
1 Medical Center Drive 
Lebanon , NH 03756-0001 
Email: jay.buckey@dartmouth.edu 
Phone: 603-650-6012  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Dartmouth College 
Joint Agency:  
Comments: Address updated 9/2008 
Co-Investigator(s)
Affiliation: 
Magari, Patrick  Creare, Inc. 
Knaus, Darin  Creare, Inc. 
MacKenzie, Todd  Dartmouth College 
Phillips, Scott  Creare, Inc. 
Project Information: Grant/Contract No. NCC 9-58-TD00402 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-TD00402 
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) HHC:Human Health Countermeasures
Human Research Program Risks: (1) DCS:Risk of Decompression Sickness (IRP Rev D)
Human Research Program Gaps: (1) DCS02:We do not know the contribution of specific DCS risk factors to the development of DCS in the Space Flight Exploration Environment (IRP Rev D)
Flight Assignment/Project Notes: NOTE: End date changed to 6/30/2009 per NSBRI (5/2008)

Task Description: Assembly of the International Space Station (ISS) and lunar exploration require extensive and unprecedented extra-vehicular activity. Current spacecraft and suit designs force astronauts to move between different pressure environments, making decompression sickness (DCS) a potential risk. Current DCS risk mitigation strategies, which are highly time consuming, reduce operational efficiency. The objective of this effort is to improve EVA efficiency and safety by developing and validating new bubble detection technology using dual-frequency ultrasound. The Creare dual-frequency instrument (CDFI) can detect and size bubbles through the chest wall as they move through the heart. Also, stationary microbubbles can be detected in tissue. Potentially, this technology could be used to: (a) characterize bubble dynamics during decompression sickness (DCS), (b) detect the earliest stages of DCS, (c) develop and evaluate non-compressive countermeasures for DCS, (d) diagnose DCS in tissue or joints, and (e) mitigate DCS risk by improving preventive strategies such as oxygen pre-breathing and limiting activity at particular times.

Detecting and sizing bubbles intravascularly (a new and unique capability) allows for bubble size histograms to be constructed during the development and treatment of DCS. The change of bubble size distribution during decompression stress may indicate DCS severity. Before using the device either for quantitative research or operations, the sizing ability needs to be quantified in optimal in-vitro conditions. The calibration system developed for this project can create monodisperse distributions of microbubbles at the sizes likely to occur during decompression stress. Work in the past year has focused on resolving technical problems in the calibration setup and the calibration is moving forward.

Tissue bubble detection is also a unique capability. The CDFI potentially can detect very small bubbles (the possible precursors of larger bubbles in tissue or blood) and identify larger bubbles in areas with symptoms of pain or discomfort consistent with DCS. Last year, a significant accomplishment was the demonstration of the ability to detect ultrasound contrast bubbles (Definity®) injected into tissue (in anesthetized swine). This work has been extended significantly. In a series of studies, the power levels needed to detect bubbles in tissue were established and the concentration of injected bubbles that could be detected was determined. Also, we validated that the CDFI was specific for bubbles and did not detect ultrasonic reflectors the same size as injected bubbles. Microspheres of the same size as the bubbles were also injected into tissue and were not detected by the CDFI.

For the coming year, the plan is to: (a) complete the in-vitro calibration, (b) track bubble sizes during decompression stress in anesthetized swine, (c) determine if signals consistent with bubbles can be detected in swine muscle before or after decompression stress and (d) assess if these signals change after exercise or immobilization.

Research Impact/Earth Benefits: The results from this study are also applicable for divers, aviators, high-altitude parachutists and others who are exposed to the risk of decompression sickness.

Another application for this technology is bubble monitoring during coronary artery bypass surgery or valve replacement surgery. Patients who have coronary artery bypass surgery are at risk for having solid and gaseous emboli reach the brain when they are on the "pump" (the cardiopulmonary bypass circuit). The Creare dual-frequency ultrasound unit could be used to monitor for bubbles in the bypass circuit and could distinguish between solid and gaseous emboli. A collaboration with Dr. Donny Likosky is underway to advance this work.

The cavitation approach can be used to determine to assess the gas saturation in fluids such as hydraulic fluid, which is important for industrial and aviation applications. Creare is currently developing an instrument based on this concept for the U.S. Air Force.

Creare is also applying the knowledge gained on the bubble acoustics knowledge and expertise gained in this effort to a Department of Energy project to mitigate cavitation damage in the Spallation Neutron Source (SNS) being developed at Oak Ridge National Laboratory. In this facility, a large acoustic wave is produced in the mercury spallation target when proton pulses very rapidly and repeatedly enter the mercury. The acoustic wave reflects off the vessel walls and causes the mercury to cavitate which results in severe damage to the vessel when the SNS is operated at the desired full power level. Creare is characterizing the ability of various stabilized bubbles to dampen the large acoustic wave and, thereby, mitigate the resulting cavitation damage.

Task Progress & Bibliography Information FY2007 
Task Progress: Bubble sizing calibration

Efforts continued to calibrate the sizing capability of our dual-frequency ultrasound bubble-sizing device. Previous work has shown that bubbles can be detected and sized intravascularly in-vivo, but a careful in-vitro calibration is essential for future work with the device. Performing this calibration is technically challenging. We continue to make enhancements to the device and the experimental setup to aid in the completion of this calibration. The main challenges are producing and measuring monodisperse streams of bubbles in various sizes, and removing or understanding sources of non-linear signals that can mask bubble signals. We currently believe that the main source of non-bubble, non-linear signal is due to non-linear ultrasound propagation, which is the basis for harmonic imaging. Predicting the magnitude of this masking signal is confounded by the presence of standing waves, which are very difficult to eliminate from a calibration setup. Efforts were made to understand ultrasonic standing waves in both the tissue phantom and water tank experimental setups, and the impact that they may have on the production of sum and difference signals that indicate the presence of bubbles. In addition we have made adjustments to the calibration setup to minimize the interaction between the transmitted pump and image signals. Calibration of the sizing capability of the device is ongoing and should be completed by the end of the year.

Stationary microbubble detection in-vivo

This was the main effort of the year. Several dilutions of ultrasonic contrast agent were injected into the thigh of an anesthetized swine. The ability of the device to detect stationary microbubbles at different ultrasonic pressures and concentrations was demonstrated and characterized. The results of this effort have been submitted for publication.

Decompression Studies

Decompression studies using a swine model have been performed to detect decompression-induced bubble formation in tissue. Swine were pressurized at 4.5ATA for 2hrs and decompressed over 5 minutes. Each swine was monitored with clinical and dual-frequency ultrasound for 1-2 hours post-dive (depending on conditions). Results to date are as of yet inconclusive. It is widely speculated that bubbles form in tissue following decompression, but detecting native tissue bubbles is difficult since the concentration, locations and sizes of normally-occurring microbubbles in tissue is unknown. Current efforts to detect decompression-induced stationary bubbles in tissue are focused on determining the correct frequencies and pressures to use.

Bibliography Type: Description: (Last Updated: 12/02/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2007
Project Title:  Improved Bubble Detection for EVA Reduce
Fiscal Year: FY 2006 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 07/01/2004  
End Date: 06/30/2008  
Task Last Updated: 01/08/2007 
Download report in PDF pdf
Principal Investigator/Affiliation:   Buckey, Jay C. M.D. / Dartmouth College 
Address:  Department of Medicine 
1 Medical Center Drive 
Lebanon , NH 03756-0001 
Email: jay.buckey@dartmouth.edu 
Phone: 603-650-6012  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Dartmouth College 
Joint Agency:  
Comments: Address updated 9/2008 
Co-Investigator(s)
Affiliation: 
Magari, Patrick  Creare, Inc. 
Knaus, Darin  Creare, Inc. 
MacKenzie, Todd  Dartmouth College 
Project Information: Grant/Contract No. NCC 9-58-TD00402 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-TD00402 
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) HHC:Human Health Countermeasures
Human Research Program Risks: (1) DCS:Risk of Decompression Sickness (IRP Rev D)
Human Research Program Gaps: (1) DCS02:We do not know the contribution of specific DCS risk factors to the development of DCS in the Space Flight Exploration Environment (IRP Rev D)
Task Description: Assembly of the International Space Station (ISS) and lunar exploration require extensive and unprecedented extra-vehicular activity. Current spacecraft and suit designs force astronauts to move between different pressure environments, making decompression sickness (DCS) a potential risk. DCS risk mitigation strategies reduce operational efficiency. The objective of this effort is to improve EVA efficiency and safety by developing and validating new bubble detection technology using dual-frequency ultrasound. The Creare dual-frequency instrument (CDFI) can detect and size bubbles through the chest wall as they move through the heart. Also, signals consistent with bubbles can be detected in tissue. Potentially, this technology could be used to: (a) characterize bubble dynamics during decompression sickness (DCS), (b) detect the earliest stages of DCS, (c) develop and evaluate non-compressive countermeasures for DCS, (d) diagnose DCS in tissue or joints, and (4) mitigate DCS risk by improving preventive strategies such as oxygen pre-breathing and limiting activity at particular times.

Detecting and sizing bubbles intravascularly (a new and unique capability) allows for bubble size histograms to be constructed during the development and treatment of DCS. The change of bubble size distribution during decompression stress may indicate DCS severity. Before using the device either for quantitative research or operations, the sizing ability needs to be quantified in optimal in-vitro conditions. The calibration system developed for this project can create monodisperse distributions of microbubbles at the sizes likely to occur during decompression stress. Work in the past year has focused on improving the optical sizing capability (used for comparison to the ultrasonically determined size), developing tissue equivalent phantoms, and reducing standing waves in the in-vitro test setup. A full calibration is currently underway.

Tissue bubble detection is also a unique capability. The CDFI potentially can detect very small bubbles (the possible precursors of larger bubbles in tissue or blood) and identify larger bubbles in areas with symptoms of pain or discomfort consistent with DCS. Interpreting tissue bubble signals, however, requires knowledge of other potential sources of false bubble signals in tissue. Work in this past year has identified the mechanisms for false positive signals and methods to minimize them have been developed. A significant accomplishment was the demonstration of the ability to detect contrast bubbles (Definity®) injected into tissue (in anesthetized swine). Bubble signals were returned only from the area where Definity® had been injected and not from other areas, including tissues like bone, which strongly reflects ultrasound. False bubble signals were not detected. This demonstrated the ability of the system to detect stationary bubbles in tissue.

In the past year the first human tissue bubble studies were performed. Additionally, a new technique to measure gas saturation in tissue is being explored. In-vitro work has shown that the point at which bubbles are created by cavitation varies with gas saturation. This offers a potential new way to determine gas saturation in tissue, which could potentially lead to a new way to assess DCS risk.

For the coming year, the plan is to: (a) complete the in-vitro calibration, (b) track bubble sizes during decompression stress in anesthetized swine, (c) determine if signals consistent with bubbles can be detected in human muscle and assess if these signals change after exercise or immobilization and (d) develop the cavitation threshold as a method to measure gas saturation in tissue or blood.

Research Impact/Earth Benefits: The results from this study are also applicable for divers, aviators, high-altitude parachutists and others who are exposed to the risk of decompression sickness.

Another application for this technology is bubble monitoring during coronary artery bypass surgery or valve replacement surgery. Patients who have coronary artery bypass surgery are at risk for having solid and gaseous emboli reach the brain when they are on the "pump" (the cardiopulmonary bypass circuit). The Creare dual-frequency ultrasound unit could be used to monitor for bubbles in the bypass circuit and could distinguish between solid and gaseous emboli. A collaboration with Dr. Donny Likosky is underway to advance this work.

The cavitation approach can be used to determine to assess the gas saturation in fluids such as hydraulic fluid, which is important for industrial and aviation applications. Creare is currently developing an instrument based on this concept for the U.S. Air Force.

The bubble generator that has been developed for this project is currently being supplied to a large industrial manufacturer in the pharmaceuticals industry to calibrate a Doppler-based detector, which monitors a manufacturing process.

Creare is also applying the knowledge gained on the bubble acoustics knowledge and expertise gained in this effort to a Department of Energy project to mitigate cavitation damage in the Spallation Neutron Source (SNS) being developed at Oak Ridge National Laboratory. In this facility, a large acoustic wave is produced in the mercury spallation target when proton pulses very rapidly and repeatedly enter the mercury. The acoustic wave reflects off the vessel walls and causes the mercury to cavitate which results in severe damage to the vessel when the SNS is operated at the desired full power level. Creare is characterizing the ability of various stabilized bubbles to dampen the large acoustic wave and, thereby, mitigate the resulting cavitation damage.

Task Progress & Bibliography Information FY2006 
Task Progress: Tissue Bubble Detection

The detection of frequent, unexplained false bubble signals had been complicating bubble detection. Work in the past year successfully identified the mechanism underlying a major source of false bubble signals. These signals originated from previously undetected electrical interference. After solving this problem an in-vivo test of tissue bubble detection was performed using Definity® ultrasonic contrast agent. Experiments in a water tank showed that a small amount of Definity® produced bubble signals, while water did not. Subsequently, Definity® was injected into thigh tissue in an anesthetized swine. Measurements were taken at several points on the thigh and bubble signals were only returned from the area where Definity® had been injected. False bubble signals were not detected, even from strong ultrasound reflectors like bone.

Calibration

Previous in-vivo studies have shown that bubbles can be detected and sized transthoracically during decompression stress. Before the information from in-vivo studies can be used scientifically, however, a calibration of the device against bubbles of known size is essential. This calibration, however, is technically challenging since it requires (1) streams of small bubbles of known size, (2) phantoms that match tissue attenuation characteristics and (3) the elimination of standing ultrasonic waves from the test setup, which can confound the results.

This past year, tissue-like phantoms were built using special polyurethane formulations that mimic the attenuation properties of tissue. Measurements were taken to determine the presence and magnitude of standing ultrasonic waves created in the phantom and test setup during calibration. Once this was characterized, countermeasures were employed to minimize standing waves. Currently, an initial set of calibration data is under review to ascertain whether all the technical factors involved in calibration have been solved.

Cavitation

The amount of dissolved inert gas within a tissue strongly influences whether bubbles will form in the tissue during decompression stress. At present, however, no method exists to assess gas saturation within tissue.

As the amount of ultrasonic energy sent into the tissue increases, it reaches a point where bubbles form spontaneously. This bubble formation process is called cavitation. When the bubbles cavitate, ultrasonic signals at multiple harmonics can be detected indicating that cavitation has occurred. Work in the past year has explored whether the point at which bubbles cavitate within a fluid could be used to assess gas saturation. We have shown that the bubble cavitation threshold (as measured by the returned ultrasonic signals) decreases with increasing gas saturation in the liquid. Further work is underway to determine if this method could be useful to measure gas saturation in tissue and hence as a measure for DCS risk.

Bibliography Type: Description: (Last Updated: 12/02/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Buckey JC, Knaus DA, Alvarenga DL, Kenton MA, Magari PJ. "Dual-frequency ultrasound for detecting and sizing bubbles." Acta Astronaut. 2005 May-Jun;56(9-12):1041-7. PMID: 15835064 , May-2005
Project Title:  Improved Bubble Detection for EVA Reduce
Fiscal Year: FY 2005 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 07/01/2004  
End Date: 06/30/2008  
Task Last Updated: 10/27/2005 
Download report in PDF pdf
Principal Investigator/Affiliation:   Buckey, Jay C. M.D. / Dartmouth College 
Address:  Department of Medicine 
1 Medical Center Drive 
Lebanon , NH 03756-0001 
Email: jay.buckey@dartmouth.edu 
Phone: 603-650-6012  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Dartmouth College 
Joint Agency:  
Comments: Address updated 9/2008 
Co-Investigator(s)
Affiliation: 
Magari, Patrick  Creare 
Kenton, Marc  Creare 
Knaus, Darin  Creare 
MacKenzie, Todd  Dartmouth College 
Project Information: Grant/Contract No. NCC 9-58-TD00402 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-TD00402 
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) HHC:Human Health Countermeasures
Human Research Program Risks: (1) DCS:Risk of Decompression Sickness (IRP Rev D)
Human Research Program Gaps: (1) DCS02:We do not know the contribution of specific DCS risk factors to the development of DCS in the Space Flight Exploration Environment (IRP Rev D)
Task Description: Assembly of the International Space Station (ISS) and future space exploration require extensive and unprecedented extra-vehicular activity. Current spacecraft and suit designs force astronauts to move between different pressure environments, making decompression sickness (DCS) a potential risk. DCS risk mitigation strategies reduce operational efficiency. The objective of this effort is to improve EVA efficiency and safety by developing and validating new bubble detection technology using dual-frequency ultrasound. The Creare dual-frequency instrument (CDFI) can detect and size bubbles through the chest wall as they move through the heart. Also, signals consistent with bubbles can be detected in tissue. Potentially, this technology could be used to: (a) characterize bubble dynamics during decompression sickness (DCS), (b) detect the earliest stages of DCS, (c) develop and evaluate non-compressive countermeasures for DCS, (d) diagnose DCS in tissue or joints, and (4) mitigate DCS risk by improving preventive strategies such as oxygen pre-breathing and limiting activity at particular times. Detecting and sizing bubbles intravascularly (a new and unique capability) allows for bubble size histograms to be constructed during the development and treatment of DCS. The change of bubble size distribution during decompression stress may indicate DCS severity. Before using the device either for quantitative research or operations, the sizing ability needs to be quantified in optimal in-vitro conditions. Work in the past year has focused on performing a comprehensive calibration of the device. A major hurdle overcome in the present grant period was the ability to create monodisperse distributions of microbubbles at the sizes likely to occur during decompression sickness. This is achieved by shearing bubbles off the tip of a fine glass micropipette with a stream of water. The velocity of the shearing water stream is used to adjust the size of the bubble generated. Monodisperse bubbles as small as 40 microns have been generated in this manner. Smaller sizes can also be generated, but with a broader size distribution. Tissue bubble detection is also a unique capability. The CDFI can potentially detect very small bubbles (the possible precursors of larger bubbles in tissue or blood) and identify larger bubbles in areas with symptoms of pain or discomfort consistent with DCS. Interpreting tissue bubble signals, however, requires knowledge on other potential sources of false bubble signals in tissue. In the present grant period a major effort has been made to understand the sources of weakly nonlinear signals (potential false bubble signals). These efforts included the complete elimination of any potential nonlinear sources of mixing in the signal processing (e.g. amplifier clipping, impedance mismatches). Work this year has also lead to human use approval for the device. For the coming year, the plan is to: (a) complete the in-vitro calibration, (b) track bubble sizes during decompression stress in anesthetized swine, (c) determine if signals consistent with bubbles can be detected in human muscle and assess if these signals change after exercise or immobilization.

Research Impact/Earth Benefits: If the bubble detection and sizing instrument proves to be effective for monitoring during cardiopulmonary bypass, this could be a significant benefit to patients. Currently, many patients experience decreases in cognitive function after cardiopulmonary bypass, and this is thought to be due to emboli reaching the brain. Improved monitoring could help reduce these emboli and their consequences. The results from this study are also applicable for divers, aviators and others who are exposed to the risk of decompression sickness. Another application for this technology is bubble monitoring during coronary artery bypass surgery or valve replacement surgery. Patients who have coronary artery bypass surgery are at risk for having solid and gaseous emboli reach the brain when the are on the "pump" (the cardiopulmonary bypass circuit). The Creare dual-frequency ultrasound unit could be used to monitor for bubbles in the bypass circuit and could distinquish between solid and gaseous emboli. An application has been submitted to the NIH to advance this work. In addition to its NASA application, this technology could be used to improve the safety and efficiency of diving operations.

Task Progress & Bibliography Information FY2005 
Task Progress: Highly reflective targets -- strong versus weak mixers The Creare Dual Frequency Instrument (CDFI) exploits the fact that resonating bubbles are strong nonlinear mixers. Other objects and materials can be weak nonlinear mixers. In most cases weak mixers generate negligible mixing signals. If driven hard enough, however, a weak mixer can produce a detectable nonlinear mixing signal. Effort has been devoted over the last year to understanding weak sources of nonlinear signals to ensure that they do not affect either the calibration of the instrument or the bubble sizing measurements adversely. The CDFI electronics have been studied systematically to eliminate any potential electronic sources of mixing. In-vitro studies have examined the relationship of ultrasound power to non-linear mixing by weak mixers. Calibration bubbles Efforts have also been underway to calibrate the instrument by validating the mixing signals produced bubbles of known sizes. A major hurdle overcome in the present grant period was the ability to create monodisperse microbubble distributions at sizes likely to occur during decompression sickness (40 microns to 245 microns). This has been achieved by shearing bubbles off the tip of a fine glass micropipette with a stream of water. These bubble streams have been used to generate a calibration for the CDFI suitable for intravascular DCS studies. Further efforts will be undertaken to refine and expand this calibration for smaller bubble sizes. Human use approval A major advance during the present grant period was obtaining Dartmouth and Creare IRB approval for using the CDFI for extravascular human testing. The steps undertaken to obtain this approval included the full characterization of the transducers used in the CDFI to understand their power output, as well as a modification of the CDFI control software to calculate and display the mechanical and thermal indexes of the instrument’s output. The CDFI was designated as “non significant risk” by the Dartmouth IRB and thus did not require Investigational Device Exemption (IDE) from the FDA. Human use approval is especially important for the extravascular (tissue) bubble studies. For the initial studies, the conduct of extravascular bubble detection experiments is less complex with humans since the experiments will require voluntary exercise. In-vivo bubble sizes The CDFI has been used to show qualitative bubble size differences in in-vivo studies. Two separate bubble detection studies were used to compare the detected sizes of Definity™ contrast agent “bubbles” with DCS bubbles. In both studies, the right ventricular outflow track of an anesthetized swine was monitored. In one study, Definity™ ultrasound contrast bubbles were injected continuously, in the other, bubbles were monitored during DCS (grade 3-4). Bubble signals were detected at the small end of the bubble size scale during the Definity™ scan

Bibliography Type: Description: (Last Updated: 12/02/2021) 

Show Cumulative Bibliography Listing
 
Articles in Peer-reviewed Journals Buckey JC, Knaus DA, Alvarenga DL, Kenton MA, Magari PJ. "Dual-frequency ultrasound for detecting and sizing bubbles." Acta Astronaut. 2005 May-Jun;56(9-12):1041-7. PMID: 15835064 , May-2005
Patents US Patent 6,457,331 Patent Oct-2004 Kline-Schoder, R. and P. J. Magari "Bubble Measuring Instrument and Method"
Presentation Bollinger, B. R., Buckey, JC., Alvarenga, D. L., Knaus, D. A., Kenton, M. A., and P. J. Magari "Improved bubble detection for EVA" N/A

Jan-2005

Presentation Buckey, JC., Knaus, D. A., Alvarenga, D. L., Kenton, M. A., Bollinger B., and P. J. Magari "Bubble detection and sizing using dual-frequency ultrasound" N/A

May-2004

Project Title:  Improved Bubble Detection for EVA Reduce
Fiscal Year: FY 2004 
Division: Human Research 
Research Discipline/Element:
HRP HHC:Human Health Countermeasures
Start Date: 07/01/2004  
End Date: 06/30/2008  
Task Last Updated: 07/21/2006 
Download report in PDF pdf
Principal Investigator/Affiliation:   Buckey, Jay C. M.D. / Dartmouth College 
Address:  Department of Medicine 
1 Medical Center Drive 
Lebanon , NH 03756-0001 
Email: jay.buckey@dartmouth.edu 
Phone: 603-650-6012  
Congressional District:
Web:  
Organization Type: UNIVERSITY 
Organization Name: Dartmouth College 
Joint Agency:  
Comments: Address updated 9/2008 
Co-Investigator(s)
Affiliation: 
Magari, Patrick  Creare 
Kenton, Marc  Creare 
Knaus, Darin  Creare 
Project Information: Grant/Contract No. NCC 9-58-TD00402 
Responsible Center: NSBRI 
Grant Monitor:  
Center Contact:   
Solicitation / Funding Source: 2003 Biomedical Research & Countermeasures 03-OBPR-04 
Grant/Contract No.: NCC 9-58-TD00402 
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) HHC:Human Health Countermeasures
Human Research Program Risks: (1) DCS:Risk of Decompression Sickness (IRP Rev D)
Human Research Program Gaps: (1) DCS02:We do not know the contribution of specific DCS risk factors to the development of DCS in the Space Flight Exploration Environment (IRP Rev D)
Task Description: Assembly of the International Space Station (ISS) and future space exploration require extensive and unprecedented extra-vehicular activity. Current spacecraft and suit designs force astronauts to move between different pressure environments, making decompression sickness (DCS) a potential risk. DCS risk mitigation strategies reduce operational efficiency. The objective of this effort is to improve EVA efficiency and safety by developing and validating new bubble detection technology using dual-frequency ultrasound. The Creare dual-frequency instrument (CDFI) can detect and size bubbles through the chest wall as they move through the heart. Also, signals consistent with bubbles can be detected in tissue. Potentially, this technology could be used to: (a) characterize bubble dynamics during decompression sickness (DCS), (b) detect the earliest stages of DCS, (c) develop and evaluate non-compressive countermeasures for DCS, (d) diagnose DCS in tissue or joints, and (4) mitigate DCS risk by improving preventive strategies such as oxygen pre-breathing and limiting activity at particular times. Detecting and sizing bubbles intravascularly (a new and unique capability) allows for bubble size histograms to be constructed during the development and treatment of DCS. The change of bubble size distribution during decompression stress may indicate the progression of DCS. Preliminary data indicate the CDFI may identify bubbles earlier than current Doppler or imaging ultrasound techniques. One goal of this project is to demonstrate the capabilities of the CDFI in DCS. Experiments using anesthetized swine after decompression will be performed to test the CDFI. An accurate and reliable way to assess intravascular bubbles may offer a way to evaluate non-compressive therapies, such as perfluorocarbons, for DCS. Studies on the effect of perfluorocarbons on bubble size and frequency during DCS will be performed in swine exposed to decompression stress. Tissue bubble detection is also a unique capability. The CDFI can potentially detect very small bubbles (the possible precursors of larger bubbles in tissue or blood) and to identify larger bubbles in areas with symptoms of pain or discomfort consistent with DCS. A goal of this project is to validate tissue bubble detection for both very small (50 micron) bubbles. In-vitro tests and studies using swine exposed to compression and decompression will be performed to validate the CDFI in tissue.

Research Impact/Earth Benefits: This technical approach offers an improved way to detect bubbles in blood. The ability to detect bubbles in tissue, once validated, would be a completely new capability..

In addition to its NASA application, this technology could be used to improve the safety and efficiency of diving operations.

Task Progress & Bibliography Information FY2004 
Task Progress: The objective of this project is to improve EVA efficiency and safety through the in-vivo validation of a unique ultrasonic bubble-sizing and detection instrument. This instrument exploits bubble resonance by using two frequencies of ultrasound (dual-frequency ultrasound) to detect and size bubbles in tissue and blood. The original aims of the project were to: (a) establish the appropriate transducer configurations, electronic settings and instrument enhancements to detect and size bubbles reliably in-vivo, (b) compare the new bubble monitoring technique to Doppler, and use it to investigate decompression sickness and (c) develop the capability to size small bubbles in tissue.

a. establish the appropriate transducer configurations, electronic settings and instrument enhancements to detect and size bubbles reliably in-vivo--experiments demonstrated that bubbles could be detected as they move through the right ventricle and right atrium. These experiments established the technical knowledge (transducer position relative to anatomical features, equipment settings, etc.) needed to monitor bubbles during subsequent decompression experiments.

b. compare the new bubble monitoring technique to Doppler, and use it to investigate decompression sickness -- aim has been advanced by comparing the signals obtained with the dual frequency device to a standard clinical ultrasound instrument.

c. develop the capability to size small bubbles in tissue-- aim has been advanced through a variety of in vitro and in vivo studies.

The newly developed ability to construct bubble size histograms has a major impact on our research. The histograms provide a novel way to study the time course and treatment of decompression sickness as it is manifested in the bubbles that form in the vasculature. Currently, no other technique exists that allows for bubble size histograms to be constructed during decompression stress.

Bibliography Type: Description: (Last Updated: 12/02/2021) 

Show Cumulative Bibliography Listing
 
 None in FY 2004