We will refine and validate probes to integrate with the NASA Flexible Ultrasound System (FUS) to address Exploration Medical Capabilities (ExMC) Gap 4.02 Nephrolithiasis.

AIM 1. Refine ultrasound probes to detect, reposition, and fragment kidney stones. AIM 2. Validate probes to visualize, reposition, and fragment stones. AIM 3. Refine and validate imaging to guide therapy.

2. Key Findings

A probe and software to image and reposition kidney stones were developed and integrated on a radiation hardened flexible ultrasound system (FUS) and demonstrated effectively on human subjects. A probe to image, reposition, and fragment stones was designed, fabricated, and integrated into an FUS and is currently in clinical trials to expel stone fragments. Software was developed and integrated on an FUS and validated in human subjects to improve kidney stone detection and size determination. The ability to reposition stones was also integrated into the partially completed NASA FUS with the NASA FUS probes and demonstrated. The work has garnered attention. Reports have been sent to NSBRI (National Space Biomedical Research Institute), FDA (Food & Drug Administration), NIH (National Institutes of Health), NASA, and OMB (Office of Management and Budget). Demonstrations have been conducted at American Urological Association (AUA) annual meetings each year, Congress twice, and several other professional societies. Over 40 papers have been published. Over 40 patent applications have been submitted. Students, residents, and fellows have trained on the project. Technology developed in this research has been licensed to a spin-off company SonoMotion Inc.

3. Impact

We have invented a technology to reposition kidney stones and demonstrated it works in people. In four of the cases, what appeared as one large stone on x-ray was two or three small passable stones. This had direct diagnostic benefit to these subjects and changed their course of treatment. In four other subjects, we moved stones out of the kidney, which they passed. This result was a direct therapeutic benefit to these subjects. One subject felt relief from a painful obstructing stone. We have shown we can produce a working prototype, develop sufficiently high-quality imaging to guide treatment, train new users, and conduct a successful clinical trial. We refined the system design, submitted for publication in vitro results quantifying the improvement, and entered a second clinical trial. The refined design also has the capability to fragment stones. This design is being commercialized. Specifically, we have now implemented our technologies with different probes making it efficient to add the probes NASA selects or to continue to refine the probes we can provide. Our imaging software can be added to an FUS or commercial imager. Our pushing capability has been added as a software upgrade to the FUS. Our advanced repositioning and fragmenting probe is readily integrated with any standard or FUS imager with minimal additional mass and software change to the system. Our final system and the system being commercialized, when validated in human in a flight analog, largely close the gap of nephrolithiasis or exploration mission and extends application to the emergency department on Earth. Our new stone sizing technique can be used on any imager by any user to improve the accuracy of stone size determination with ultrasound. Overestimated stone size leads to unnecessary surgeries, and underestimated stone size leads to obstructions and ER (emergency room) visits. Stone size similarly determines risk and course of action in space.

4. Proposed Research

We are conducting a clinical trial of S-mode software for automatic stone detection and stone sizing. We are conducting a clinical trial of expelling stone fragments. We have received approval and set up the infrastructure for an test of ultrasonic propulsion in an Emergency Department (ED) analog to a space emergency, and seek funding for that trial. We are testing safety and effectiveness in clinical simulation in animal studies of stone breaking to add this capability to our ED trial. The technology is also being tested for gallstones.

AIM 1. Refine the ultrasound probes to detect, reposition, and fragment kidney stones.

Task 1.1. Select imaging probe for stone repositioning. We enabled the capability to push stones on the as yet incomplete NASA FUS system with the NASA GE C1-6 abdominal imaging probe. These results were reported in an NSBRI Advanced Technology Demonstration: Prevention of Renal Stone Complications in Space Exploration in August 2016.

Deliverable of the grant

The capability to reposition kidney stones noninvasively has been added to the NASA flexible ultrasound system.

Task 1.2. Custom design probe to image, reposition, and fragment stones. We invented Burst Wave Lithotripsy which has fully comminuted stones of all compositions in under 20 minutes and has fragmented many stones in seconds. All work so far has been in water tanks or animals, not humans. The size fragments are controlled by the ultrasound frequency. The technique reduces peak pressure by 1/10th but increases pulse duration about five times and pulse repletion rate at least 20 times to deliver more energy more quickly and possibly without discomfort.

AIM 2. Validate probes to visualize, reposition, and fragment kidney stones.

Task 2.1. Validate capability to displace an obstructing stone.

Task 2.2. Validate capability to displace a ureter stone.

Task 2.3. Validate capability to comminute a stone.

These tasks were completed. A small probe embedded centrally within the Burst Wave Lithotripsy (BWL) therapy probe connected to the Verasonics FUS system provides image guidance for BWL. We have targeted and fragmented human stones surgically placed in over 10 pigs. Preclinical test results have been submitted for publication. A clinical trial of the system is underway.

AIM 3. Refine and validate imaging to guide therapy.

Task 3.1. Refine and validate capability to measure the size of kidney stones. In a series of 3 papers, we demonstrated how ultrasound imaging can be optimized to accuracy similar to CT with user controls as well as software modifications. The imaging we have implemented on the Verasonics FUS appears to size stones more accurately than clinical imagers.

Task 3.2. Refine capability to localize a stone.

Task 3.3. Refine and validate capability to detect a ureter stone. We have developed enhanced B-mode, enhanced Doppler-based twinkling, and combined them into a stone specific imaging mode called S-mode. S-mode has been published. S-mode has been used to image stones in the kidneys and ureters in human subjects. In our most recent study of hundreds of imaging frames from 40 stones and 28 subjects, the signal to noise ratio of S-mode was ten times the grayscale SNR. This paper won Best Abstract at the Engineering and Urology meeting of the AUA in 2016.

We will refine and validate probes to integrate with the NASA Flexible Ultrasound System to address Exploration Medical Capability (ExMC) Gap 4.02 Nephrolithiasis. [Ed. note 9/22/2016: This Gap was merged into the following Gap: Med13: We do not have the capability to implement medical resources that enhance operational innovation for medical needs]

AIM 1. Refine ultrasound probes to detect, reposition, and fragment kidney stones. AIM 2. Validate probes to visualize, reposition, and fragment stones. AIM 3. Refine and validate imaging to guide therapy.

2. Key Findings

Technology developed in this research has been licensed to a spin-off company SonoMotion Inc. Three articles are cited that independently review our technology. The first human trial of repositioning kidney stones was completed. A report was presented to National Space Biomedical Institute (NSBRI), FDA (Food and Drug Administration), NASA, and OMB (Office of Management and Budget). A manuscript has been submitted to the Journal of Clinical Investigation. The trial was successful. Two patients reported skin discomfort and sensation at depth with a few pushes. Otherwise, there was no pain or adverse effects associated with the treatment. Stones were localized with the system and repositioned in 14 of 15 subjects. In total, the system targeted and repositioned stones from all parts of the kidney and ureteropelvic juncture (UPJ, kidney outflow tract) including the lower pole (20 targets), midpole (10 targets), upper pole (6 targets), and renal pelvis/UPJ (7 targets). Stones were imaged and repositioned at depths as great as 11 cm. Stones were repositioned to a new location in all 6 post-lithotripsy patients, while 4 of the 6 passed over 30 stone fragments within a few days of treatment. One passed two 2 mm fragments immediately after the completion of treatment. De novo stones and stones as large as 8 mm were repositioned in awake patients and during URS, although movement was not as great as seen with residual fragments. In four of the 15 subjects, what was noted in clinical imaging as a single, potentially unpassable stone was shown to be several passable stones upon repositioning with ultrasound. One subject with a potentially obstructing UPJ stone felt relief. FDA has granted 15 more subjects for the next clinical trial. We have developed and tested new probes and systems to continue to improve and validate performance of ultrasonic propulsion. We have participated in several meetings with GE (General Electric) and ExMC about NASA's flexible ultrasound system (FUS), and have recently received the GE probe used on the FUS. We have started integrating our ultrasonic propulsion onto the GE probe. A new stone specific imaging mode was developed and reported, and a patent application was submitted. In the first step the system automatically identifies the location of stones in the image and highlights them with color during real-time scanning. In the second step, the system automatically determines the size of the kidney stone. In a series of publications, we showed that stone size could be determined more accurately by measuring the shadow width not directly the stone width in the ultrasound image. The first paper on Burst Wave Lithotripsy (BWL) was published in the Journal of Urology and reviewed in Nature Reviews Urology. Progress has been made in measuring effectiveness and safety and on image guidance. We have used preclinical data generated with NSBRI funds to obtain funding from NIH (National Institute of Health) to pursue additional clinical trials to investigate the benefit of expelling small asymptomatic kidney stones, stone clearance with repositioning, obstructing stone displacement, and stone detachment. We continue to present demonstrations of ultrasonic propulsion and BWL. We presented at the American Urological Association in 2012, 2013, 2014, and 2015 and at NSBRI's Congressional demonstration in 2014.

3. Impact

We have invented a technology to reposition kidney stones and demonstrated it works in people. In four of the cases, what appeared as one large stone on x-ray was two or three small passable stones. This had direct diagnostic benefit to these subjects and changed their course of treatment. In four other subjects, we moved stones out of the kidney, which they passed. This result was a direct therapeutic benefit to these subjects. One subject felt relief from a painful obstructing stone. We have shown we can produce a working prototype, develop sufficiently high-quality imaging to guide treatment, train new users, and conduct a successful clinical trial. This opens the path to refine the system and repeat, to commercialize the system, to add refined imaging as a software upgrade, and to repeat the process with BWL to demonstrate an improved way to comminute stones in humans. Specifically, we have now implemented our technologies with different probes making it efficient to add the probes NASA selects or to continue to refine the probes we could provide. Our software continues to be refined and validated. The preclinical work funded by NSBRI enables us to pursue demonstration in humans to assess where best this technology fits into care in the clinic and in space exploration. Our new stone sizing technique can be used on any imager by any user to improve the accuracy of stone size determination with ultrasound. Overestimated stone size leads to unnecessary surgeries, and underestimated stone size leads to obstructions and Emergency Room visits. Stone size similarly determines risk and course of action in space.

4. Proposed Research

We have undertaken a prospective study to see how commonly the shadow is seen and to compare accuracy of stone size from the stone or the shadow. We are beginning a clinical trial of S-mode for automatic stone detection and stone sizing. We have built a new ultrasound propulsion probe and optimized outputs with the old probe. We are now completing preclinical testing and an FDA modification for human testing. We continue to refine the BWL probe and now have built a BWL probe for transcutaneous testing. We are testing safety and effectiveness in clinical simulation in animal studies. We are testing new image guidance technologies.

Task 1.2. Custom design probe to image, reposition, and fragment stones. Three transducers have been built and demonstrated to break stones under both in vitro and in vivo conditions. Patents have been submitted on the amplifier and probe design. The results were published in the Journal of Urology.

Task 2.1. Validate capability to displace an obstructing stone.

Task 2.2. Validate capability to displace a ureter stone. Stones were moved in humans causing a relief from releasing obstruction at the ureter. This result was reported in our report on the clinical trial. Experiments continue in pigs to improve the stone pushing capability.

Task 2.3. Validate capability to comminute a stone.

Task 2.4. Validate capability to expel an attached stone. Small stones have been implanted ureteroscopically in a kidney and fragmented transcutaneously at 5 MPa. The threshold of cavitation (as detected on B-mode) and injury was measured in 7 animals and determined to be 7 MPa at 330 kHz. Cavitation detection correlated with injury and provides safety feedback. Results have been reported at the International Symposium on Therapeutic Ultrasound.

Task 3.1. Refine and validate stone size measurement. We showed measurement of the shadow width was significantly more accurate then measurement directly of the stone width in the Image in 3 studies -- preclinical, retrospective, and prospective. Preliminary results were presented at the World Congress of Endourology in 2014 and will be presented at the American Urological Association (AUA) annual meeting in 2015. The preclinical paper is in press in the Journal of Urology.

Task 3.2. Refine capability to localize a stone. To date 12 subjects have been enrolled in a study of the ability to detect stones with S-mode and we are actively enrolling about 2 per week. The system and technique as well as preclinical studies were published in the Proceedings of the IEEE International Ultrasonics Symposium in 2014.

Task 3.3. Refine and validate capability to detect a ureter stone. Our system was further improved to improve resolution of kidney stone size on the image by several changes to the image process. Part of the paper in press also shows data supporting how to set the knobs on the ultrasound for the best sizing accuracy.

AIM 1. Refine ultrasound probes to detect, reposition, and fragment kidney stones. AIM 2. Validate probes to visualize, reposition, and fragment stones. AIM 3. Refine and validate imaging to guide therapy.

2. Key Findings. A new stone specific imaging mode was developed, reported, and a patent submitted. In the first step the system automatically identifies the location of stones in the image and highlights them with color during real-time scanning. In the second step, the system automatically determines the size of the kidney stone. Published a clinical study showing reduced false positives with S-mode. Submitted a paper showing improved accuracy in stone size determination with our system. Presented and submitted a patent and paper showing stone size measurement across the shadow behind the stone is more accurate than measurement not across the image of the stone itself. Hence anyone can improve his or her stone size measurement. Published several preclinical safety and effectiveness studies of repositioning stones. Published a study of training techniques and outcomes for reposition stones. Initiated first clinical study of repositioning stones and reported preliminary results. In summary, stones were moved in all six subjects. No subjects observed any discomfort associated with the procedure. Invented, reported, patented, and submitted paper on a new method to comminute kidney stones, termed Burst Wave Lithotripsy BWL. Published paper 'Pulse focused ultrasound treatment of muscle mitigates paralysis-induced bone loss in the adjacent bone: a study in a mouse model.' Since the start of the clinical trial we have doubled the effectiveness of ultrasonic propulsion as measured by vertical stone displacement. Simultaneously we have reduced the channels needed. We have published and used a numerical model of radiation force and the acoustic field in tissue to design an improved probe. We have begun implementing BWL on the flexible ultrasound system. We have participated in several meetings with GE and ExMC about NASA's flexible ultrasound system (FUS). We stand by to integrate GE probe into our FUS and refine and validate ultrasonic propulsion on these probes. We await a probe and a probe description (pin-out) from GE. We continue to present demonstrations of ultrasonic propulsion and BWL. We presented at the American Urological Association in 2012, 2013, and 2014 and at NSBRI's Congressional demonstration in 2014.

3. Impact. We have invented a technology to reposition kidney stones and demonstrated it works in people. In 3 of the 6 cases, what appeared as one large stone on x-ray was 2 or 3 small passable stones. This had direct diagnostic benefit to these subjects and changed their course of treatment. In two other subjects we moved stones out of the kidney, which they passed and which was a direct therapeutic benefit to these subjects. We have shown we can produce a working prototype, develop sufficiently high-quality imaging to guide treatment, train new users, and conduct a successful clinical trial. This opens the path to refine the system and repeat, to commercialize the system, to add refined imaging as a software upgrade, and to repeat the process with BWL to demonstrate an improved way to comminute stones in humans. Specifically, we have now implemented our technologies with different probes making it efficient to add the probes NASA selects or to continue to refine the probes we could provide. Our software continues to be refined and validated. The preclinical work funded by NSBRI enables us to pursue demonstration in humans to assess where best this technology fits into care in the clinic and in space exploration.

4. Proposed Research. We have undertaken a retrospective study to see how commonly the shadow is seen and to compare accuracy of stone size from the stone or the shadow. We are beginning a clinical trial of S-mode for automatic stone detection and stone sizing. Our numerical codes and bench top testing will be used to optimize radiation force used to move stones. We will characterize the acoustic and thermal outputs of the new probes. We plan preclinical safety and effectiveness studies of imaging, repositioning, and comminution studies with improved probe outputs. Preclinical data will be resubmitted to FDA for a second clinical trial with the improved probe and outputs. We will work toward clinical trials with BWL. We have used preclinical data generated with NSBRI funds to apply to NIH to pursue additional clinical trials to investigate the benefit of expelling small asymptomatic kidney stones, stone clearance with repositioning, obstructing stone displacement, and stone detachment.

AIM 2. Validate probes to visualize, reposition, and fragment stones. Task 2.1. Validate capability to displace an obstructing stone. Pursuing initial test in current clinical trial and applying for follow-on trial. Pre-clinical investigations of safety and effectiveness conducted with upgraded outputs. Task 2.2. Validate capability to displace a ureter stone. Followed schedule and did not pursue in year 1. Task 2.3. Validate capability to comminute a stone. Invented, patented, and reported burst wave lithotripsy BWL. Appears to have faster comminution than SWL, comminute stones that are difficult to break with SWL, have effectiveness and safety feedback, and be operable in a safe range. Task 2.4. Validate capability to expel a stone attached to tissue. Enhanced outputs and developed BWL to address this task. Testing underway.

AIM 3. Refine and validate imaging to guide therapy. Task 3.1. Refine and validate capability to measure stone size. Reported and patented significant enhancement with our technology and technique. Task 3.2. Refine capability to localize a stone. Initiated clinical validation now at the end of year 1. Task 3.3. Refine and validate capability to detect a ureter stone. Followed schedule and did not pursue in year 1.