• We have continued to advance ultrasound technology to detect and reposition kidney stones. The imaging technology provides an alternative to imaging techniques that expose the patient to ionizing radiation on Earth and provides a user-friendly technique to detect even small stones in space. The repositioning technology provides an adjunctive treatment to surgery by which to facilitate the passage of residual fragments that may regrow to new stones, and provides a way to prophylactically remove small stones before they require surgery. The technology is also used to move a large obstructing stone to a non-obstructing location to delay the need for surgery. This year our major accomplishments were entering into the Food and Drug Administration (FDA) approval process for a human feasibility study and starting a company. In pigs we also moved a stone growing de novo, moved an obstructing stone, and moved a stone in the ureter.

• We contributed to the solicitation for a Flexible Ultrasound System (FUS), both as leaders in the platform and inventors of a required clinical capability (detecting and repositioning kidney stones), and an award for delivery of an FUS has now been granted.

• Developed a method and device to characterize the acoustic output of high intensity focused ultrasound (HIFU) devices. The University of Washington (UW) Center for Commercialization (C4C) has filed a provisional patent. The technique was added to the IEC TC87 62256 60601-2-62 standards document. The technology has now been demonstrated on several clinical HIFU systems. NIH (National Institute of Health) funding was obtained.

• Developed a method to accelerate and control tissue ablation with transcutaneous ultrasound. In particular, tissue was mechanically emulsified by millisecond bursts of HIFU at output levels that produce shock waves. C4C has filed a U.S. patent application. The Philips machine was modified to produce these outputs. Our method has several potential advantages over technique used in competitor's $11 million start-up. This year we discovered and published the mechanism by which tissue is fractionated and joined University of Washington (UW) Urology in a proposal to develop urology cancer treatments.

• We published an explanation of the mechanism of the twinkling artifact (TA) that frequently occurs during Doppler ultrasound imaging of kidney stones. These findings lead to the conclusion that bubbles cause the twinkling artifact and as such we have developed and patented several algorithms to exploit this mechanism to better detect kidney stones. Because twinkling is seen on other calcifications in the body, the result also implies bubbles may be present throughout the body, which has significant implications for decompression sickness.

• Due to cost and concerns for repeated ionizing radiation exposure from CT (computed tomography) scans on Earth, ultrasound is often used for the initial evaluation and monitoring of kidney stone patients. In space ultrasound is the only option and size of the stone is critical in treatment planning. We published work, submitted a patent application, and began preliminary work to measure the inaccuracy of ultrasound in sizing stones and develop improvements.

• Obtained funding from U.S. Army to investigate the application of shocked ultrasound to slow bone loss in a murine paralysis model. Bone loss with our best but still not optimized exposure was less than 15% which was statistically significantly lower than the over 30% loss in the control.

• We published results in a porcine model to stop bleeding in a partial nephrectomy. We secured commercialization funding and contracted a vendor to build a refined system. We obtained NIH funding to develop the technology to clinical implementation. This is the same technology we developed with the military to stop bleeding on the battlefield and provides an avenue to develop an commercial off-the-shelf (COTS) device for NASA.

Proposed plan for the next year. We have developed extensive plans to continue forward and have submitted many proposals to continue funding. The efforts are on three fronts. One is to conduct a human feasibility study. The second is to start the company. The third is to secure NSBRI funding to develop the same capabilities for the FUS and to refine and test the system for NASA's unique applications. We were subcontract on one proposal to develop the FUS but did not receive that award. The NSBRI proposal aims are to refine and validate probes to detect, reposition, and fragment kidney stones.

Tasks are 1. Implement capability to image and reposition stones on the selected FUS manufacturer's state-of-the-art kidney imaging probe. 2. Integrate a clinical mechanically scanned 4D imaging probe with the FUS and refine and validate stone imaging and repositioning. 3. Develop and integrate a prototype 2D array probe to reposition and fragment stones. 4. Refine and validate capability to displace a large blocking stone, to detect a ureter stone, to displace a ureter stone, to expel a stone attached to tissue, and to measure the size of kidney stones.

The applications of our technology to the control of bleeding and for tumor ablation are at least as profound. Specifically, this year we have worked with the latest clinical HIFU machine—one developed by Philips Medical. This machine is intended for many clinical applications. We have used some of our effort to characterize the output of the machine and assess its potential bio-effects. Our work provides the clinicians, who intend to use this machine, the ability to select a treatment dose. At UW alone, it helps train the clinicians and establish the specificity of what size targets are treated. With our contribution, the clinicians are then likely to pursue their own clinical studies, and regulatory approval for various tumor treatments. Before our involvement, the machine sat dormant for a year. We are also exploring the effects of HIFU on the immune system and have proposed clinical trials to combine HIFU with chemical therapeutic agents. We believe that our efforts to carefully describe outputs and bio-effects will help the U.S. catch up with the rest of the world where over 400,000 patients have been treated by HIFU. In addition, our intimate knowledge of these details enables us to consider ways in which a similar, much reduced-in-size system could be developed for NASA to reduce some critical risks to astronauts during long duration space travel.

Task 1B. Perform studies to determine pressure and temperature in ex vivo tissue exposed to HIFU: Published several papers, which led to invitation to join IEC (International Electrotechnical Commission) working group on HIFU standards and the AIUM (American Institute of Ultrasound in Medicine) sub-committee on Transiently Increased Outputs, and to measure acoustic output of Philips clinical HIFU machine. Also, discovered and submitted patent application for a method to emulsify tissue with ultrasound.

Task 2A. Develop new stone detection techniques based on radiation force and reverberation responsible for twinkling artifact: As part of our graduate student's dissertation, discovered that bubbles are responsible for the twinkling artifact. We have developed, implemented, tested, and patented new software to better detect stones.

Task 2B. Test stone sizing technology in tissue: Published paper, filed U.S. and international utility patent applications, and are negotiating licensing. We have initiated human clinical studies to test ultrasound stone sizing versus CT.

Task 3A. We utilized the YUANDE HIFU tumor ablation device as a test platform: Performed a number of studies.

Task 3B. Engineer and optimize an image-guided, two-frequency HIFU system for renal stone comminution: We will work with Exploration Medical Capabilities (ExMC) Human Research Program Element to implement on the FUS system capability to detect, reposition, and comminute stones. All are implemented in a prototype for which we are pursuing an investigational device exemption (IDE) with the FDA. We have developed a concept of expelling small stones from a kidney before they require comminution or surgery. A system to detect and reposition stones based on an OEM diagnostic ultrasound platform has been built and demonstrated to be safe and effective in studies in a porcine model. Commercialization efforts are well underway. Our technology was called a "game changer" in the plenary session of the American Urological Association (AUA) Annual meeting in May 2012.

Task 4A. Perform in vivo tests of the imaging protocols developed in Task 2: our paper is in press comparing twinkling to standard B-mode for stone detection in patients. New algorithm for stone detection implemented on clinical machine and tests of the algorithm initiated on human subjects. Data from 15 subjects has been collected.

Task 4B. Performed studies to determine the potential for HIFU-induced stone comminution as well as any associated tissue injury. We used our stone repositioning system to fragment stones in an excised porcine kidney in which they were grown. In vivo tests scheduled for Oct 22, 2012. In vivo studies of our stone clearance system have been shown to be safe and effective. Several studies of safety in pigs have been complete and are in press. These data have been presented to the FDA as part of our application for investigational device exemption for a human feasibility study.

(1) Lack of advanced therapeutic capability,

(2) lack of capability to treat renal stones, and

(3) lack of non-invasive diagnostic imaging capabilities.

The original specific aims are:

Specific Aim 1: Support ongoing leveraged efforts in Acoustic Hemostasis (AH) and HIFU Tumor Ablation (TA) by addressing fundamental scientific issues as well as to ensure NSBRI relevance.

Specific Aim 2: Develop methods and technologies that would enable detection of renal stones with ultrasound.

Specific Aim 3: Develop technology and perform in vitro studies of stone comminution.

Specific Aim 4: Utilizing technology and protocols developed in SAs 2 and 3, perform in vivo studies in a porcine model.

The main findings and associated research productivity for year 3 are:

- We have continued to advance ultrasound technology to detect and reposition kidney stones. The imaging technology provides an alternative to imaging techniques that expose the patient to ionizing radiation on earth and provides a user-friendly technique to detect even small stones in space. The repositioning technology provides an adjunctive treatment to surgery by which to facilitate the passage of residual fragments that my regrow to new stones, and provides a way to prophylactically remove small stones before they require surgery. This year, we have accomplished the following:

- Obtained approval from the University of Washington Institutional Review Board (IRB) for clinical testing of the stone detection technology.

- Obtained NIH Funding for regulatory consultants (Drug and Device Development Co. and Institute of Translational Health Sciences) to help us prepare an application to the U.S. Food and Drug Administration (FDA) for an Investigational Device Exemption (IDE) for an investigator-driven, pilot clinical trial of detecting and repositioning stones.

- Collected and documented about half the required safety data for the IDE application.

- Developed three iterations of a business plan culminating in one funded by NASA and NSBRI to be completed by Virtual Incubation Company, LLC. Our approach has been to not start a company yet, but instead to leverage university resources (research team, Center for Commercialization, Entrepreneur-in-Residence, and non-diluting state, federal and foundation funding to remove risk and attain the critical inflection point of "first in man." The business plans center on commercial partnerships or a start-up as well as NASA implementation at that inflection point.

- Filed a U.S. patent application that encompassed all the technologies.

- Developed a prototype from commercial-off-the-shelf (COTS) hardware, which will arguably accelerate production and regulatory approval of an eventual commercial product.

- The hardware for our prototype has advantages for space flight, namely radiation hardening, and with the ExMC Imaging Integration Team and the manufacturer, we are developing a system suitable for deployment and testing on ISS. We use the HDI-5000 probes currently available on ISS. The ultrasound system is a single box that was adapted to work with the IBM Lenovo laptops currently used on ISS. The system is open-architecture, software based, COTS technology, meaning that other NASA or NSBRI countermeasures could easily be implemented on it and upgrades do not require up-mass. Proposals for flight-testing, for integration of NSBRI countermeasures on the platform, for implementation of new technology, and for radiation testing were submitted with NSBRI, NSBRI researchers, ExMC, and NASA Glenn.

- Successfully completed a collaboration with Siemens of a DARPA-funded Phase II project to develop an automated system to detect and control bleeding on the battlefield and in remote environments. Phase III funding is pending. NSBRI funding was used to automate the detection and treatment for ease-of-use in a portable system. That work was published in year 2. The results were presented at international meetings.

- Developed a method and device to characterize the acoustic output of high intensity focused ultrasound (HIFU) devices. The University of Washington (UW) Center for Commercialization (C4C) has filed a provisional patent. The technique was added to the IEC 60601-2-62 standards document. The technology was demonstrated on a Philips clinical HIFU system.

- Developed a method to accelerate and control tissue ablation with transcutaneous ultrasound. In particular, tissue was mechanically emulsified by millisecond bursts of HIFU at output levels that produce shock waves. C4C has filed a U.S. patent application. The Philips machine was modified to produce these outputs. Our method has several potential advantages over technique used in competitor's $11 million start-up.

- Negotiations are underway among UW, Philips, and a drug company for clinical trials for pancreatic cancer. Our measurements were used to define the "dose" to be applied to patients.

- Completed initial investigation of HIFU-induced, tumor-specific auto-immune response in collaboration with Fred Hutchinson Cancer Research Institute.

- Demonstrated with statistical significance in a small cohort that application of shocked ultrasound waves accelerated wound healing in a rat model over sham exposures.

- Obtained funding from US Army to investigate the application of shocked ultrasound to slow bone loss in a murine paralysis model. Our new approach was found to significantly slow, and in some cases halt, bone loss.

The applications of our technology to the control of bleeding and for tumor ablation are at least as profound. Specifically, this year we have worked with the latest clinical HIFU machine - one developed by Philips Medical. This machine is intended for many clinical applications. We have used some of our effort to characterize the output of the machine and assess its potential bio-effects. Our work provides the clinicians, who intend to use this machine, the ability to select a treatment dose. At UW alone, it helps train the clinicians and establish the specificity of what size targets are treated. With our contribution, the clinicians are then likely to pursue their own clinical studies, and regulatory approval for various tumor treatments. Before our involvement, the machine sat dormant for a year. We are also exploring the effects of HIFU on the immune system and have proposed clinical trials to combine HIFU with chemical therapeutic agents. We believe that our efforts to carefully describe outputs and bio-effects will help the US catch up with the rest of the world where over 400,000 patients have been treated by HIFU. In addition, our intimate knowledge of these details enables us to consider ways in which a similar, much reduced-in-size system could be developed for NASA to reduce some critical risks to astronauts during long duration space travel.

Task 1B. Perform studies to determine pressure and temperature in ex vivo tissue exposed to HIFU: Published paper "Shock-induced heating and millisecond boiling in gels and tissue due to high intensity focused ultrasound", Michael Canney, et al., Ultrasound Med. & Biol., 36, 250-267 (2010), which led to invitation to join IEC working group on HIFU standards and to measure acoustic output of Philips clinical HIFU machine. Also, discovered and submitted patent application for method to emulsify tissue with ultrasound.

Task 2A. Develop new stone detection techniques based on radiation force and reverberation responsible for twinkling artifact: As part of our graduate student's dissertation, efforts continue toward understanding the origins of the twinkling artifact and to further refine the algorithms we have developed, implemented, tested, and patented.

Task 2B. Test stone sizing technology in tissue: Published paper, M.D. Sorensen, et al., "Proof of Principle of a Prototype Ultrasound Technology to Size Stone Fragments During Ureteroscopy," J. Endourology, 2009, 1161-1164; filed U.S. and international utility patent applications, and are negotiating licensing. We have initiated human clinical studies to test ultrasound stone sizing versus CT.

Task 3A. Utilize the YUANDE HIFU tumor ablation device as a test platform: Performed a number of studies.

Task 3B. Engineer and optimize an image-guided, two-frequency HIFU system for renal stone comminution: We are working with ExMC to fly one platform that detects, repositions, and comminutes stones. All are implemented in a prototype for which we are pursuing an investigational device exemption (IDE) with the FDA. We have developed a concept of expelling small stones from a kidney before they require comminution or surgery. A system to detect and reposition stones based on an OEM diagnostic ultrasound platform has been built and demonstrated to be safe and effective in studies in a porcine model. Commercialization efforts have begun. An update report on progress won best poster at the American Urology Association meeting.

Task 4A. Perform in vivo tests of the imaging protocols developed in Task 2: Paper in preparation comparing twinkling to standard B-mode for stone detection in patients. New algorithm for stone detection implemented on clinical machine and tests of the algorithm initiated on human subjects.

Task 4B. Perform studies to determine the potential for HIFU-induced stone comminution as well as any associated tissue injury: In vivo studies of our stone clearance system have been shown to be safe and effective. A safety study in pigs is complete and a study of safety under realistic clinical conditions in pigs has just begun. These data will be presented to the FDA to pursue a clinical trial.

(1) Lack of advanced therapeutic capability,

(2) lack of capability to treat renal stones, and

(3) lack of non-invasive diagnostic imaging capabilities.

The original specific aims are:

Specific Aim 1: Support ongoing leveraged efforts in Acoustic Hemostasis (AH) and HIFU Tumor Ablation (TA) by addressing fundamental scientific issues as well as to ensure NSBRI relevance.

Specific Aim 2: Develop methods and technologies that would enable detection of renal stones with ultrasound.

Specific Aim 3: Develop technology and perform in vitro studies of stone comminution.

Specific Aim 4: Utilizing technology and protocols developed in SAs 2 and 3, perform in vivo studies in a porcine model.

The key findings and associated research productivity for year 1 are:

• Successfully completed a collaboration with Siemens of a DARPA-funded Phase II project to develop an automated system to detect and control bleeding on the battlefield. Phase III funding is pending. Leveraged this effort to build automated bleeding detection and ultrasound-based treatment monitoring with NSBRI funding. Paper published, presentation made, and Record of Invention submitted.

• Conducted in vitro and animal tests toward transcutaneous tumor ablation treatment with HIFU. Completing initial investigation of HIFU-induced, tumor-specific immune response in collaboration with Fred Hutchinson Cancer Research Institute and initiated a second animal study on Philips clinical HIFU system with Seattle Cancer Care Alliance. Characterized the acoustic output and optimized exposure parameters of the Philips machine. Efforts are underway for commercially sponsored clinical trials for pancreatic cancer. Utilized NSBRI funding to develop modeling and characterization tools, test ultrasound guidance, replicate acoustic output with smaller instrumentation, and initiate additional research. Papers published and others are pending approval by commercial collaborators.

• Developed new method to emulsify tissue with transcutaneous ultrasound. Our method has several potential advantages over the technique used in competitor's $11 million start-up. Our method also has promise as a potential surgical tool. Submitted provisional patent and published papers.

• Developed second prototype to detect and reposition kidney stones with ultrasound. This is a proposed new treatment for stones in microgravity for early detection as well as to reposition them near the exit of the kidney for natural clearance. It also has significant earthbound clinical and commercialization potential. Human studies of the detection algorithm have begun and approval in principle for treatment in human subjects has been granted pending final acoustic output measurements. Safety and efficacy has been demonstrated in pigs. An intellectual-property package has been prepared by UW for potential licensing. A business/commercialization plan has been developed. A commercial partner has been identified and initial investigation into the regulatory and reimbursement pathways has taken place. This information was shared during NASA's meetings to identify the next ultrasound system for ISS as our capabilities to address gaps could be integrated directly into certain existing ultrasound systems.

• A miniaturized device to size stone fragments for safe extraction has been tested in a porcine kidney: Submitted U.S. utility patent application and published paper. This topic has been the subject of licensing negotiations between the University of Washington and a potential commercial sponsor.

Ultrasound for treating bleeding, benign and malignant tumors, and stone disease are revolutionary therapies; as such, our approach is to leverage funding to demonstrate that they are clinically safe and efficacious. In particular, we utilized NSBRI funding to understand the acoustic exposures needed to develop light-weight instrumentation for potential use in microgravity. NSBRI has also embraced the commercialization of our system to detect and reposition stones, and great progress has been made this year. The earthbound, as well as the space application is to enable the passage of stones and residual fragments and thus prevent complications from impacted stones. We licensed revolutionary diagnostic ultrasound hardware from an Original Equipment Manufacturer and added a few changes of our own. With NSBRI's help, we made the case that if similar hardware were selected as the ultrasound system on ISS, our capability to detect and treat stones could be immediately deployed (TRL/CRL level 9) for emergency treatment of urolithiasis.

To summarize, in our acoustic hemostasis effort, we have results ready to publish, expect to continue our substantial DARPA-funded effort working toward human subjects testing, and will utilize our NSBRI-developed systems in animal studies. On our HIFU ablation studies, animal experiments should soon be completed and published this year, and all pieces should be in place for and IDE/IRB to initiate human studies. On stone disease, our device is expected to be tested on human subjects; a new transducer will be developed; acoustic output characterization for regulatory approval will begin, and it is planned to transfer some of this technology to a new start-up.

The applications of our technology to the control of bleeding and for tumor ablation are at least as profound. Specifically, this year we have worked with the latest clinical HIFU machine - one developed by Philips Medical. This machine is intended for many clinical applications. We have used some of our effort to characterize the output of the machine and assess its potential bio-effects. Our work provides the clinicians, who intend to use this machine, the ability to select a thermal dose. At UW alone, it helps train the clinicians and establish the specificity of what size targets are treated. With our contribution, the clinicians are then likely to pursue their own clinical studies and with Philips backing regulatory approval for various tumor treatments. Before our involvement, the machine sat dormant for a year. We are also exploring the effect of HIFU on the immune system and have proposed clinical trials to combine HIFU with chemotherapy agents. We believe that our efforts to carefully describe outputs and bio-effects will help the US catch up with the rest of the world where over 400,000 patients have been treated by HIFU. In addition, our intimate knowledge of these details enable us to consider ways in which a similar, much reduced-in-size system could be developed for NASA to reduce some major risks to astronauts.

The control of bleeding with ultrasound has great potential to save lives from both civilian and battlefield trauma. Our most directed work leverages DARPA funding and is in partnership with a commercial entity. This ambitious project seeks to develop a fully autonomous system that would both detect bleeding and induce hemostasis without major user involvement.

Task 1B. Perform studies to determine pressure and temperature in ex vivo tissue exposed to HIFU. Paper M.S. Canney, et al., "Millisecond boiling produced by high intensity focused ultrasound," Ultrasound Med. Biol., 2009 and others led to invitation to join IEC working group on HIFU standards and to measure acoustic output of Philips clinical HIFU machine. Also, discovered method to emulsify tissue with ultrasound.

Task 2A. Develop new stone detection techniques based on radiation force and reverberation responsible for twinkling artifact and vibroacoustography. As part of our graduate student's dissertation, efforts continue to understand the origins of the twinkling artifact and to further refine the algorithms we have developed, implemented, tested, and submitted to UW for patent submission.

Task 2B. Test stone sizing technology in tissue. Published paper M.D. Sorensen, et al., "A Proof of Principle of a Prototype Ultrasound Technology to Size Stone Fragments During Ureteroscopy," J. Endourology 2010; filed U.S. and international utility patent applications, and are negotiating licensing.

Task 3A. Utilize the YUANDE HIFU tumor ablation device as a platform for determining the acoustic protocols necessary for ultrasound-based stone comminution. This project is ongoing.

Task 3B. Engineer and optimize an image-guided, two-frequency HIFU system for renal stone comminution. We have focused on moving small stones within the kidney with ultrasound to facilitate natural stone clearance. A system to detect and reposition stones based on an OEM diagnostic ultrasound platform has been built and demonstrated to be safe and effective in a porcine model. Commercialization effort has begun. Results were reported at the American Urology and Laparoendoscopy Society meetings. Efforts to generate shorter higher amplitude pulses such as those used in shock wave lithotripsy (SWL) to break stones have begun, both to add a useful capability as well as to pursue a SWL regulatory pathway.

Task 4A. Perform in vivo tests of the imaging protocols developed in Task 2. Paper in preparation comparing twinkling to standard B-mode for stone detection in patients. New algorithm for stone detection implemented on clinical machine and tests of the algorithm initiated on human subjects.

Task 4B. Perform studies to determine the potential for HIFU-induced stone comminution as well as any associated tissue injury. In vivo studies of our stone clearance system have been shown to be safe and effective. A new assay and ultrasound imaging technology are being tested by a graduate student to quantify tissue injury. Stone clearance and injury measurements will begin on human subjects.

(1) Lack of advanced therapeutic capability,

(2) lack of capability to treat renal stones, and

(3) lack of non-invasive diagnostic imaging capabilities.

The original specific aims are:

Specific Aim 1: Support ongoing leveraged efforts in Acoustic Hemostasis (AH) and HIFU Tumor Ablation (TA) by addressing fundamental scientific issues as well as to ensure NSBRI relevance.

Specific Aim 2: Develop methods and technology that would enable detection of renal stones with ultrasound.

Specific Aim 3: Develop technology and perform in vitro studies of stone comminution.

Specific Aim 4: Utilizing technology and protocols developed in SAs 2 and 3, perform in vivo studies in a porcine model.

(2) The key findings and associated research productivity for year 1 are:

- Developed an automated ultrasound guided high intensity focused ultrasound (HIFU) system to detect and stop bleeding: Published paper.

- Began initial investigation of HIFU induced tumor specific immune response in collaboration with Fred Hutchinson Cancer Research Institute: Obtained NIH funding to support a Postdoctoral fellow on the work.

- Developed a body of evidence on methods to accelerate HIFU therapy with the use of shock waves: Papers published.

- Tested new Doppler ultrasound-based kidney stone detection method in vitro, in animals, and in humans: Filed 3 Records of Invention with the University of Washington TechTransfer Office.

- Developed method to use focused ultrasound to move kidney stones and stone fragments within the kidney to expedite stone clearance: Presented work to American Urology Association.

- Miniaturized device to size stone fragments for safe extraction and tested operation in kidney: Submitted U.S. utility patent application and published paper.

- Developed correlation between ultrasound-induced and monitored vasoconstriction; discovered that vasoconstriction reduces injury during stone fragmentation therapy: Published paper.

- Participated in the generation of a white paper through gap analysis of medical risk 4.15 (Lack of lithotripsy or other capability to treat a renal stone) by the JSC Exploration Medical Capability element of the Human Research Program.

- Copyrighted and licensed technology describing new HIFU sources and test equipment.

(3) These findings are self-explanatory, but we wish to highlight the broader impact on kidney stone disease. Our new detection technique requires only a software change, at most, to existing ultrasound technology on board ISS. It is sensitive and easy to use. Our belief is that this approach will provide NASA with the capability to detect even small, asymptomatic stones. The next phase of our work will be to use focused ultrasound (which could also be generated with only modest software reprogramming of the existing ISS ultrasound device) to dislodge the stone and push it toward the opening of the ureter where it could be naturally passed. In this way, a potential critical clinical problem would be solved by early diagnosis and prevention, rather than by last-minute and difficult therapy. This methodology has obvious and significant earthbound utility as well.

(4) Our future plans will focus on continued automation, cancer treatment, and the prevention of complications from kidney stones. We have obtained access to a programmable ultrasound imager that we will program to test our new stone detection algorithms. The immune response study, initiated by seed funds from our NSBRI cost match, will be continued under NIH sponsorship; hopefully, it will be determined that HIFU can induce a systemic tumor-specific immune response in mice. Investigation and improvement of the stone detection technique will continue by direct comparison of simulation and measurement. The technique to detect stones at pre-symptomatic levels will be tested against standard ultrasound, fluoroscopy, and CT in patients. Acceleration of stone passage by focused ultrasound will be investigated in a porcine animal model.

Specifically our work this year has provided the following Earthbound benefits, viz.,

1. We demonstrated a way to automate the detection and treatment of bleeding.

2. We have designed and initiated a study to test the hypothesis that HIFU can generate a systemic immune response and have high hopes for progress in this area.

3. We have offered the HIFU community significant insight into how to plan, execute and monitor HIFU treatments. For earthbound HIFU, we have raised considerable concern over the accuracy of the gold standard (MR thermometry) used to "ensure" heating only where desired.

4. Our efforts to develop a Doppler ultrasound-based, kidney stone detection method has several applications. It appears at least as good a fluoroscopy in targeting and could therefore replace this approach and its ionizing radiation. It also can be used real-time and therefore could compensate for respiratory motion during treatment. Lastly, an accurate ultrasound imaging system could be used in the urologist's office to localize stones and to replace the need for CT scans.

5. Our new method to use focused ultrasound to move kidney stones could be used whenever residual stones are observed after treatment. These stones get trapped and do not pass naturally. They then serve as a nucleus for future stones.

6. Our miniaturized device to size stone fragments may soon be used during ureteroscopy to determine stone size before attempting to extract stones too large to pass through a finite-sized lumen.

7. We have licensed new HIFU sources and test equipment to a vendor who will provide these tools to researchers, clinicians, regulators, and manufacturers to accelerate the implementation of clinical HIFU applications.

Task 1A1. Perform studies of bleeding detection in a flow-phantom model. A model and a method to excise but not detach the femoral arteries in live pigs have been developed.

Task 1B1. Perform studies to determine pressure and temperature in ex vivo tissue exposed to HIFU. A paper co-authored by M.S. Canney, V. A. Khokhlova, O.V. Bessonova, M. R. Bailey, and L. A. Crum, entitled "Millisecond boiling produced by high intensity focused ultrasound," was submitted in February 2009 to the journal Ultrasound in Medicine and Biology.

Task 2A. Develop new stone detection techniques based on radiation force and reverberation responsible for the twinkling artifact and vibroacoustography. We have completed considerable data collection and have begun an analysis of the data to improve understanding of the mechanisms and algorithms for use. Three records of invention describing the evidence for this new understanding have been filed. We also reported progress in the following paper: A. Shah, M. Paun, J. Kucewicz, O. A. Sapozhnikov, M. Dighe, H. A. McKay, M. D. Sorensen, and M. R. Bailey, "Investigation of an ultrasound imaging technique to target kidney stones in lithotripsy," J. Acoust. Soc. Am., 125(4, Pt. 2), 2620 (2009).

Task 2B. Investigate stone-sizing technology in tissue. We have submitted for publication our progress in this task in the following article: M.D. Sorensen, J.M.H. Teichman, and M.R. Bailey, "A Proof of Principle of a Prototype Ultrasound Technology to Size Stone Fragments During Ureteroscopy," J. Endourology in press 2009, We have also filed U.S. and international utility patent applications, and are negotiating licensing.

Task 3A. Utilize the YUANDE HIFU tumor ablation device as a platform for determining the acoustic protocols necessary for ultrasound-based stone comminution. No significant progress to report. For business reasons, effort has shifted to a second clinical device.

Task 3B. Engineer and optimize an image-guided, two-frequency HIFU system for renal stone comminution. In year one, we have focused on moving small stones within the kidney with ultrasound to facilitate natural stone clearance. Results were reported at the American Urology and Laparoendoscopic Surgeons meetings. Stone comminution work is scheduled to continue later in the Research Project.

Task 4A. Perform in vivo tests of the imaging protocols developed in Task 2. Investigations are underway for stone detection not only in animals but in humans. Human protocols have been approved and added to the grant.

Task 4B. Perform studies to determine the potential for HIFU-induced stone comminution as well as any associated tissue injury. In vivo studies of stone clearance are underway.