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Burst wave lithotripsy is a method to noninvasively fragment urinary stones by short pulses of focused ultrasound. In this study, physical mechanisms of stone fracture during burst wave lithotripsy were investigated. Photoelasticity imaging was used to visualize elastic wave propagation in model stones and compare results to numerical calculations. Epoxy and glass stone models were made into rectangular, cylindrical, or irregular geometries and exposed in a degassed water bath to focused ultrasound bursts at different frequencies. A high-speed camera was used to record images of the stone during exposure through a circular polariscope backlit by a monochromatic flash source. Imaging showed the development of periodic stresses in the stone body with a pattern dependent on frequency. These patterns were identified as guided wave modes in cylinders and plates, which formed standing waves upon reflection from the distal surfaces of the stone model, producing specific locations of stress concentration in the models. Measured phase velocities compared favorably to numerically calculated modes dependent on frequency and material. Artificial stones exposed to bursts produced cracks at positions anticipated by this mechanism. These results support guided wave generation and reflection as a mechanism of stone fracture in burst wave lithotripsy.

Acoustic radiation forces can surround and trap objects to manipulate them in three dimensions. It has been demonstrated that the radiation forces can maneuver solid heavy objects similar to kidney stones in live animals under safe acoustic exposure levels. However, initial experiments identified limitations on the steering range of objects because of the array design, and tissue aberrations. Here, we present a method to design an in-house 256 multi-element array to improve the steering range of 2–5 mm stones. We modeled the acoustic field for various geometrical parameters including the element size, transducer focusing, and F-number at a frequency range from 0.5 to 1 MHz. The parameters were then used to simulate the trapping radiation forces on stone models to finalize the design of the array. The array was fabricated with a center frequency of 950 kHz and a focal distance located at 120 mm and an F-number of 1.5. A holography scan was performed to characterize the transducer output. Various trapping beams were measured and compared to simulations. The resulting radiation forces produced were on the order of the weight of the trapped 2-5 mm stone models. [Work supported by NIH P01-DK043881, K25-132416, and Applied Physics Laboratory SEED fellowship.]

Despite the growing incidence of urinary stones, the fundamental interventions for urinary stones have remained the same for several decades. However, technical innovations in ultrasound have enabled new strategies for stone management. Our team aims to employ these methods to establish a new paradigm to treat stones in an office or clinic rather than a surgical suite. Technologies include new imaging methods to detect and characterize stones, burst wave lithotripsy to fragment stones using focused ultrasound rather than shock waves, and ultrasonic propulsion to promote clearance of fragments, all using a single ultrasound platform. This presentation will describe the principles and development of these technologies, as well as the fruitful partnerships between teams of basic scientists, engineers, physicians, and industry that have enabled rapid development of these concepts to successful clinical trials. [Work supported by NIDDK P01 DK043881 and the Focused Ultrasound Foundation.]

Unlike shock wave lithotripsy, burst wave lithotripsy (BWL) uses tone bursts, consisting of many periods of a sinusoidal wave. In this work, an analytical theoretical approach to modeling mechanical stresses in a spherical stone was developed to assess the dependence of frequency and stone size on stress generated in the stone. The analytical model for spherical stones is compared against a finite-difference model used to calculate stress in nonspherical stones. It is shown that at low frequencies, when the wavelength is much greater than the diameter of the stone, the maximum principal stress is approximately equal to the pressure amplitude of the incident wave. With increasing frequency, when the diameter of the stone begins to exceed about half the wavelength in the surrounding liquid (the exact condition depends on the material of the stone), the maximum stress increases and can be more than six times greater than the incident pressure. These results suggest that the BWL frequency should be elevated for small stones to improve the likelihood and rate of fragmentation.

Burst wave lithotripsy (BWL) is a potential noninvasive treatment for breaking kidney stones. BWL requirements of high-pressure output, limited aperture for acoustic window, and specific focal length and frequency constrain the focal beam width. However, BWL is most effective only on stones smaller than the beam width. We tested a porous piezoelectric material (PZ36) to increase the output power and designed acoustic lenses that broaden the beam. A weighted iterative angular spectrum approach was used to calculate the source phase distribution needed to generate desired cross sectional focal beam profiles each of 12 mm width. The phase calculations were then 3D printed as holographic lenses placed over a circular aperture of 80-mm diameter, 350 kHz PZ36 to produce the desired beam at 85 mm depth. The difference in simulated beam width and that measured by hydrophone was

Theoretical and numerical models were developed to calculate the polariscopic integrated light intensity that forms a projection of the dynamic stress within an axisymmetric elastic object. Although the model is general, this paper addressed its application to measurements of stresses in model kidney stones from a burst wave lithotripter for stone fragmentation. The stress was calculated using linear elastic equations, and the light propagation was modeled in the instantaneous case by integrating over the volume of the stone. The numerical model was written in finite differences. The resulting images agreed well with measured images. The measured images corresponded to the maximum shear stress distribution, although other stresses were also plotted. Comparison of the modeled and observed polariscope images enabled refinement of the photoelastic constant by minimizing the error between the calculated and measured fields. These results enable quantification of the stress within the polariscope images, determination of material properties, and the modes and mechanisms of stress production within a kidney stone. Such a model may help in interpreting elastic waves in structures, such as stones, toward improving lithotripsy procedures.

Remote acoustic manipulation of objects in three dimensions has been achieved through acoustic radiation forces imparted by designed acoustic beam traps. This technology can be used as a noninvasive medical tool to control foreign objects in the body. Success of this technology requires the ability to transmit complex beam shapes through the tissue while maintaining stable and robust acoustic traps. Vortex beams and other acoustic beam traps were synthesized using a 1.5 MHz, focused, multi-element array to trap and manipulate glass spheres mimicking stones. Measurements of the radiation forces agreed with calculations to within

The number and distribution of lung ultrasound (LUS) imaging artifacts—B-lines—is correlated with the presence of lung interstitial syndrome such as viral infection and pulmonary edema. The detection and quantification of B-lines is machine and operator dependent, and the mechanisms for B-line formation are not fully understood. The goals of this work were to collect RF data during LUS exams in patients with pulmonary edema and to compare to the signals and corresponding images simulated numerically to elucidate the B-line formation process. Verasonics ultrasound engine (VUE) with a phased array probe (4.5 MHz) was used to perform standard 10-zone LUS in ten patients with confirmed pulmonary edema. The RF data corresponding to each B-mode image and a series of 35 plane wave acquisitions were collected for off-line analyses. Finite element modeling of LUS pulse propagation was performed in COMSOL with fluid-filled inclusions of variable sizes and shapes in air-like medium simulating edematous lung areas. The B-mode image resulting from the simulated RF signals was reconstructed using VUE beamforming. The B-lines similar to those observed experimentally formed in simulated images only under specific conditions of sizes and shapes of water-filled areas relatively to LUS imaging wavelength. [Work supported by NIH R01EB023910.]

Combined laboratory experiment and numerical simulation are conducted on bubble clouds nucleated on the surface of a model kidney stone to quantify the energy shielding of the stone caused by cavitation during burst wave lithotripsy (BWL). In the experiment, the bubble clouds are visualized and bubble-scattered acoustics are measured. In the simulation, a compressible, multi-component flow solver is used to capture complex interactions among cavitation bubbles, the stone, and the burst wave. Quantitative agreement is confirmed between results of the experiment and the simulation. In the simulation, a significant shielding of incident wave energy by the bubble clouds is quantified. The magnitude of shielding can reach up to 90% of the energy of the incoming burst wave that otherwise would be transmitted into the stone, suggesting a potential loss of efficacy of stone comminution. There is a strong correlation between the magnitude of the energy shielding and the amplitude of the bubble-scattered acoustics, independent of the initial size and the void fraction of the bubble cloud within a range addressed in the simulation. This correlation could provide for real-time monitoring of cavitation activity in BWL.

Feasibility of ultrasonic propulsion and burst wave lithotripsy (BWL) to noninvasively reposition distal ureteral stones to facilitate passage and relieve pain was tested. Patients presenting to the clinic or emergency department were recruited. Thirteen subjects underwent ultrasonic propulsion (lower amplitude, longer duration pulses) alone, and 10 subjects also received intermittent BWL (higher amplitude, shorter duration pulses). All participants were awake and underwent a pain assessment pre- and post-procedure. For analysis, subjects were sub-categorized based on whether their stone was acute or chronic (present for ≤10 days or >10 days from their initial ED or symptomatic presentation, respectively). Seventeen subjects were enrolled in the acute study population and 6 subjects were enrolled in the chronic population. Overall, 94% of acute stones passed in an average of 3.4 days post-procedure relative to 54% in 7.5 days in the American Urological Association guidelines. 67% of chronic cases passed stones or fragments, and two surgeries were cancelled. Pain reduction was statistically significant ( p = 0.0215). Adverse events were limited to hematuria on initial urination post-procedure (BWL only, n = 3) and a mild sensation, akin to a pinprick, associated with fewer than 10 of 620 propulsion bursts ( n = 3). [Work supported by NIH-P01-DK04331.]

Acoustic radiation forces can trap and manipulate objects in three-dimensional space (3D). The state of the art in acoustic trapping has demonstrated the ability to move small or lightweight objects using single or multiple transducers. For certain medical applications, acoustic manipulation can be utilized to control foreign objects in the body, such as kidney stones. However, difficulties from these applications include the ability to control large solid objects, transmitting robust acoustic beams through the skin, and the use of a single source due to limited acoustic window in the body. The goal of this work was to use a 1.5 MHz, focused, multi-element array to synthesize specific acoustic beams to trap, levitate, and steer kidney stone models (glass spheres) in a water bath and urinary bladders of live pigs. Stable acoustic traps were investigated numerically and experimentally in water bath to design a protocol for the 3D manipulation strategies used invivo . Three programmed path were used to levitate and manipulate glass spheres in live pigs. The motion was recorded using a camera and a synchronized ultrasound imaging probe. Deviation from the intended paths was on average

We report stone comminution in the first 18 human subjects by burst wave lithotripsy (BWL). Subjects undergoing clinical ureteroscopy (URS) for at least one stone ≤12 mm on computed tomography (CT) are recruited. During the planned URS, either before or after ureteroscope insertion, BWL is administered with a handheld probe for 10 min, and any stone fragmentation and tissue injury are observed. The primary effectiveness outcome is the volume percent comminution of the stone into fragments ≤2 mm, where fragment volume is determined by μCT of basketed fragments or image processing of the URS video using the laser fiber as a size reference. The primary safety outcome is independent, blinded grading of tissue injury from the URS video. Overall, 10 of 22 stones (45%) fragmented completely in 10 min. 64% and 73% were projected to fragment completely in 15 and 40 min, respectively. For reference, shock wave lithotripsy success is about 65% to fragments ≤4 mm in 40 min. Of the other six stones, one was larger than the beamwidth, two were smaller than the wavelength, and the ureteroscope introduced air bubbles around another. Only mild reddening with some hematuria was observed ureteroscopically. [Work supported by NIH-P01-DK04331.]

It is hypothesized a 2.6-mm stone was too small to break with 390-kHz burst wave lithotripsy (BWL). In clinical trial NCT03873259, a 2.6-mm stone failed to break after 10 min of 390-kHz BWL and was removed intact. Ex vivo, the stone failed to break after another 30 min at 390 kHz but broke into four pieces in 4 min at 650 kHz. A linear elastic model was used to calculate the stress created inside stones of different sizes, shapes, and compositions by shock wave lithotripsy (SWL) and different BWL frequencies. The model predicts above a threshold frequency proportionate to wave speed over stone length, the maximum principal stress inside a stone increases to more than five times the acoustic pressure applied. Thus, smaller stones may fragment at higher but not lower frequency. Amplification remains with irregularly shaped stones but is not seen with an SWL waveform. Ex vivo, stones smaller than 3 mm broke fastest at 830 kHz while larger stones broke fastest with 390 kHz followed by 830 kHz. For small stones and fragments, increasing BWL frequency many produce, amplified stress in the stone causing the stone to break to smaller fragments to pass. [Work supported by NIH-P01-DK04331 and NIH-K01-DK104854.]

Upper urinary tract stones are becoming more prevalent in cats. Surgery to address obstructing stones has poor outcomes and such stones can rarely be treated with medical therapy. Burst wave lithotripsy (BWL) is a non-invasive, ultrasound-guided, handheld focused ultrasound technology to disintegrate urinary stones, which is now in human clinical trials. In this project, we created a scaled version of the system for use on pet cats, adjusting geometric parameters and frequency of the transducer to account for differences in anatomic scale and stone size. A 650-kHz prototype transducer was fabricated, calibrated, and tested on 25 natural feline stones 2–5 mm applying 20-cycle pulses at 10 Hz pulse repetition rate with three different focal pressure amplitudes ≤8.9 MPa in an in vitro tissue phantom. The fragments were sieved in 10-min intervals to assess breakage. The results demonstrated that between 73%–96% of the stone mass was reduced to fragments i

Fragmentation of kidney stones by burst-wave lithotripsy (BWL) has shown promising results in preclinical and clinical trials. Based on initial findings, the system was upgraded to enhance imaging, target stones at deeper depths, fragment small stones, and potentially conduct dusting of stones. A 64-element, single-crystal, phased-array imaging probe is coaxially aligned with the therapy probe for image guidance and therapy feedback. Imaging is controlled through a Verasonics Vantage research ultrasound engine capable of harmonic imaging to enhance stone resolution and contrast. These features improve targeting and endpoint detection, particularly for small stones and fragments. New therapy probes were added to effectively target stones with greater skin-to-stone distance, including a higher (800 kHz) frequency transducer to effectively break

The goal is to test effectiveness and safety of transcutaneous ultrasound pulses for facilitating clearance of residual urinary stone fragments in a randomized control trial (RCT). The study is conducted in a clinic setting with the control and treatment arms undergoing all the same activities with the exception of the ultrasonic propulsion procedure and associated pain questionnaire. Subjects are followed 90 days for assessment of adverse events and for up to 5 years for stone growth and symptomatic stone visits. Twenty-six of 33 subjects have been recruited in each arm The most recent treatment is reported. The subject received shock wave lithotripsy and did not pass any fragments for 17 months. The subject was randomized to the treatment arm. Fragments began moving with the third 3-s propulsion pulse at output 2 of 5 levels. Fifty-two percent of propulsion pulses (41 of 79) resulted in fragment movement. The subject reported no pain at the beginning or end of the procedure and telephoned within 2 h to report passing 9 fragments, no hematuria, and no adverse events. The treatment results of this RCT are compelling as an immediate and casual effect was measured. [Work supported by NIH-P01-DK043881 and VA Puget Sound resources.]

Modeling and numerical simulation of bubble clouds induced by intense ultrasound waves are conducted to quantify the effect of cloud cavitation on burst wave lithotripsy, a proposed non-invasive alternative to shock wave lithotripsy that uses pulses of ultrasound with an amplitude of O(1) MPa and a frequency of O(100) kHz. A unidirectional acoustic source model and an Eulerian-Lagrangian method are developed for simulation of ultrasound generation from a multi-element array transducer and cavitation bubbles, respectively. Parametric simulations of the spherical bubble cloud dynamics reveal a new scaling parameter that dictates both the structure of the bubble cloud and the amplitude of the far-field, bubble-scattered acoustics. The simulation further shows that a thin layer of bubble clouds nucleated near a kidney stone model can shield up to 90% of the incoming wave energy, indicating a potential loss of efficacy during the treatment due to cavitation. Strong correlations are identified between the far-field, bubble-scattered acoustics and the magnitude of the shielding, which could be used for ultrasound monitoring of cavitation during treatments. The simulations are validated by companion experiments in vitro.

Non-invasive kidney stone treatments such as shock wave lithotripsy (SWL) and burst wave lithotripsy (BWL) rely on the delivery of pressure waves through tissue to the stone. In both SWL and BWL, the potential to hinder comminution by exciting cavitation proximal to the stone has been reported. To elucidate how different stones alter prefocal cavitation in BWL, different natural and synthetic stones were treated in vitro using a therapy transducer operating at 350 kHz (peak negative pressure 7 MPa, pulse length 20 cycles, pulse repetition frequency 10 Hz). Stones were held in a confined volume of water designed to mimic the geometry of a kidney calyx, with the water filtered and degassed to maintain conditions for which the cavitation threshold (in the absence of a stone) matches that from in vivo observations. Stone targeting and cavitation monitoring were performed via ultrasound imaging using a diagnostic probe aligned coaxially with the therapy transducer. Quantitative differences in the extent and location of cavitation activity were observed for different stone types—e.g., “softer” stones (natural and synthetic) that disintegrate into dusty fragments produced larger prefocal cavitation clouds. Future work will focus on correlation of such cavitation metrics with stone fragmentation. [Funding support by NIH P01-DK043881, K01-DK104854.]

Newer imaging and therapeutic ultrasound technologies may benefit from in situ pressure levels higher than conventional diagnostic ultrasound. One example is the recently developed use of ultrasonic radiation force to move kidney stones and residual fragments out of the urinary collecting system. A commercial diagnostic 2.3 MHz C5-2 array probe has been used to deliver the acoustic pushing pulses. The probe is a curvilinear array comprising 128 elements equally spaced along a convex cylindrical surface. The effectiveness of the treatment can be increased by using higher transducer output to provide a stronger pushing force; however nonlinear acoustic saturation can be a limiting factor. In this work nonlinear propagation effects were analyzed for the C5-2 transducer using a combined measurement and modeling approach. Simulations were based on the three-dimensional Westervelt equation with the boundary condition set to match low power measurements of the acoustic pressure field. Nonlinear focal waveforms simulated for different numbers of operating elements of the array at several output power levels were compared to fiber-optic hydrophone measurements and were found to be in good agreement. It was shown that saturation effects do limit the acoustic pressure in the focal region of a diagnostic imaging probe.

Bone loss can occur following bed rest, space flight, spinal cord injury, or age-related hormonal changes. The treatment methods for this condition include pharmaceutical interventions and exercise, neither of which is particularly effective. Other technologies include low intensity pulsed ultrasound targeted to the bone, used previously to enhance fracture healing, and whole body vibration. This study attempted to mitigate paralysis-induced bone loss indirectly, by applying pulsed focused ultrasound (pFUS) to the midbelly of a paralyzed muscle. We employed a mouse model of disuse that utilizes onabotulinumtoxin A, which induces rapid bone loss in 5 days. The pFUS treatments were performed daily for four consecutive days following paralysis. A spherically focused 2-MHz transducer produced 5-microsecond pulses at pulse repetition frequency mimicking motor neuron firing rates during walking (80 Hz) or standing (20 Hz). Two different power levels were used corresponding to peak positive focal pressures of 30 and 18 MPa. The trabecular bone changes were characterized using micro computed tomography. Our results indicated that application of pFUS at pulse repetition frequency of 20 Hz and lower amplitude setting successfully mitigated paralysis-induced bone loss. The targeted muscle tissue did not display any sign of injury. [Work supported by CDMRP SCIRP (SC090510).]

The color Doppler ultrasound twinkling artifact, a rapid color change that highlights kidney stones, was recently attributed to surface crevice microbubbles on ex vivo stones because twinkling was affected by changes in hydrostatic pressure. However, it was unclear whether crevice bubbles existed on in situ human kidney stones, and, if so, how smooth-surfaced stones could harbor the crevice bubbles that give rise to twinkling. Here, 8 human subjects with known kidney stones were exposed to 4 atmospheres absolute (ATA) while breathing air inside a hyperbaric chamber; twinkling was monitored and quantified with a research ultrasound system. At 3 and 4 ATA, twinkling was significantly reduced by an average of 35% and 39%, respectively (p = 0.04). Then, ex vivo kidney stones that twinkled were exposed to micro-computed tomography (μCT) and hypobaric pressures while submerged in water. Regions of low x-ray attenuation within the stone (i.e., microcracks) at 1 ATA expanded when the pressure was reduced to 0.1 ATA. These results support the theory that microbubbles are present on kidney stones in the human body and that microbubbles may be internal as well as external to the kidney stone. [Work supported by NSBRI through NASA NCC 9-58 and NIH DK043881.]The color Doppler ultrasound twinkling artifact, a rapid color change that highlights kidney stones, was recently attributed to surface crevice microbubbles on ex vivo stones because twinkling was affected by changes in hydrostatic pressure. However, it was unclear whether crevice bubbles existed on in situ human kidney stones, and, if so, how smooth-surfaced stones could harbor the crevice bubbles that give rise to twinkling. Here, 8 human subjects with known kidney stones were exposed to 4 atmospheres absolute (ATA) while breathing air inside a hyperbaric chamber; twinkling was monitored and quantified with a research ultrasound system. At 3 and 4 ATA, twinkling was significantly reduced by an average of 35% and 39%, respectively (p = 0.04). Then, ex vivo kidney stones that twinkled were exposed to micro-computed tomography (μCT) and hypobaric pressures while submerged in water. Regions of low x-ray attenuation within the stone (i.e., microcracks) at 1 ATA expanded when the pressure was reduced to 0.1 A...

To improve in vitro lithotripsy models, we investigated the effects of multiple experimental variables on stone fragmentation. We performed timed burst wave lithotripsy (BWL) and shock wave lithotripsy (SWL) exposures in a water tank with the following variable parameters: water gas content (60, 30, and 15% O2), temperature (20 and 37°C), stone holder degree of enclosure (open wire basket, polyvinyl chloride (PVC) open-ended gel, and similar material anatomically accurate artificial kidney), and stone type (Begostone at 2 mixture ratios, calcite, calcium oxalate monohydrate (COM), and uric acid). At least 3 stones were treated for each condition, with fragmentation defined as percent stone mass

Histotripsy is a therapy that focuses short-duration, high-amplitude pulses of ultrasound to incite a localized cavitation cloud that mechanically breaks down tissue. To investigate the mechanism of cloud formation, high-speed photography was used to observe clouds generated during single histotripsy pulses. Pulses of 5-20 cycles duration were applied to a transparent tissue phantom by a 1-MHz spherically focused transducer. Clouds initiated from single cavitation bubbles that formed during the initial cycles of the pulse, and grew along the acoustic axis opposite the propagation direction. Based on these observations, we hypothesized that clouds form as a result of large negative pressure generated by the backscattering of shockwaves from a single bubble. The positive-pressure phase of the wave inverts upon scattering and superimposes on the incident negative-pressure phase to create this negative pressure and cavitation. The process repeats with each cycle of the incident wave, and the bubble cloud elongates toward the transducer. Finite-amplitude propagation distorts the incident wave such that the peak-positive pressure is much greater than the peak-negative pressure, which exaggerates the effect. The hypothesis was tested with two modified incident waves that maintained negative pressure but reduced the positive pressure amplitude. These waves suppressed cloud formation which supported the hypothesis.

This study is aimed at developing a method to controllably manipulate kidney stones in the human body using a single ultrasound source. Calculation and measurement of the lateral force on a sphere using various acoustic beams (vortex and radially-varying phased beams) were compared. A 256-element, 1.5-MHz array was used to synthesize the beams. Spheres of 1–6 mm (6 < ka < 20) diameter made of glass, ceramic, or brass were positioned on an acoustically matched platform at the focus rigidly attached to the transducer by a frame. The transducer and platform were rotated to the angle at which the trapped sphere fell. The acoustic power was

Burst wave lithotripsy (BWL) is an experimental method to noninvasively fragment urinary stones by short pulses of focused ultrasound. We are investigating physical mechanisms of stone fracture during BWL to better optimize this procedure. In this study, we used photoelasticity imaging as a method to visualize elastic wave dynamics in model stones. Epoxy and glass stone models were made into cylindrical, rectangular, or irregular geometries and exposed in a degassed water bath to focused ultrasound bursts at different frequencies. A high-speed camera was used to record images of the stone during exposure through a circular polariscope backlit by a monochromic flash source. Results showed development of periodic stresses in the stone body with a pattern dependent on frequency. These were identified as guided wave modes in cylinders and plates, which formed standing waves upon reflection from the distal surfaces of the stone model, causing periodic stress positions. Measured phase velocities compared favorably to specific numerically calculated modes dependent on frequency and material. Artificial stones exposed to BWL produced cracks at positions anticipated by this mechanism. These results support guided wave production and reflection as a mechanism of stone fracture in BWL. [Work supported by K01 DK104854 and P01 DK043881.]

Tissue water content has been observed to influence ultrasonic atomization efficiency, which raises questions regarding ex vivo tissue storage time and viability. Here, we investigate the influence of tissue preservation solutions on acoustic properties and atomization efficiency. Samples from ten bovine livers were immediately submerged in phosphate-buffered saline (PBSaline), phosphate-buffered sucrose (PBSucrose), phosphate-buffered raffinose (PBRaffinose), or ViaSpan® clinical organ transplantation solution; no solution was also tested. Acoustic attenuation, sound speed, water content, and atomization efficiency were evaluated on either day 1 or day 2. For atomization efficiency, samples were partially submerged in water with the liver-air interface aligned with a 2-MHz focused transducer operating with 10-ms pulses at 1 Hz and peak pressures of 65/-16 MPa. Overall, no difference in atomization efficiency was observed. Water content in tissue was 66–78%, with PBSaline showing a significant increase between days (p = 0.0013). Only tissues in no solution showed a significant difference between days in acoustic attenuation (p = 0.0003). Sound speed measurements had more variation with only ViaSpan and PBSucrose showing no significant differences. As ViaSpan and PBSurcrose showed the most similarities in the tested acoustic properties, PBSurcose may be a low-cost alternative to the clinical ViaSpan solution for preserving ex vivo tissues. [Work supported by NIH DK043881 and EB017857.]Tissue water content has been observed to influence ultrasonic atomization efficiency, which raises questions regarding ex vivo tissue storage time and viability. Here, we investigate the influence of tissue preservation solutions on acoustic properties and atomization efficiency. Samples from ten bovine livers were immediately submerged in phosphate-buffered saline (PBSaline), phosphate-buffered sucrose (PBSucrose), phosphate-buffered raffinose (PBRaffinose), or ViaSpan® clinical organ transplantation solution; no solution was also tested. Acoustic attenuation, sound speed, water content, and atomization efficiency were evaluated on either day 1 or day 2. For atomization efficiency, samples were partially submerged in water with the liver-air interface aligned with a 2-MHz focused transducer operating with 10-ms pulses at 1 Hz and peak pressures of 65/-16 MPa. Overall, no difference in atomization efficiency was observed. Water content in tissue was 66–78%, with PBSaline showing a significant increase be...

Burst wave lithotripsy (BWL) is a new non-invasive method for stone comminution using bursts of sub-megahertz ultrasound. A porcine model of urolithiasis and techniques to implement BWL treatment have been developed to evaluate its effectiveness and acute safety. Five human calcium oxalate monohydrate stones (6–7 mm) were hydrated, weighed, and surgically implanted into the kidneys of three pigs. Transcutaneous stone treatments were performed with a BWL transducer coupled to the skin via an external water bath. Stone targeting and treatment monitoring were performed with a co-aligned ultrasound imaging probe. Treatment exposures were applied in three 10-minute intervals for each stone. If sustained cavitation in the parenchyma was observed by ultrasound imaging feedback, treatment was paused and the pressure amplitude was decreased for the remaining time. Peak negative focal pressures between 6.5 and 7 MPa were applied for all treatments. After treatment, stone fragments were removed from the kidneys. At least 50% of each stone was reduced to

Our goal is an office-based, handheld ultrasound system to target, detach, break, and/or expel stones and stone fragments from the urinary space to facilitate natural clearance. Repositioning of stones in humans (maximum 2.5 MPa, and 3-second bursts) and breaking of stones in a porcine model (maximum 50 cycles, 20 Hz repetition, 30 minutes, and 7 MPa peak negative pressure) have been demonstrated using the same 350-kHz probe. Repositioning in humans was conducted during surgery with a ureteroscope in the kidney to film stone movement. Independent video review confirmed stone movements (≥ 3 mm) in 14 of 15 kidneys (93%). No serious or unanticipated adverse events were reported. Experiments of burst wave lithotripsy (BWL) effectiveness on breaking human stones implanted in the porcine bladder and kidney demonstrated fragmentation of 4 of 4 stones on post mortem dissection. All clinical pathology, hematology, and urinalysis for a 1-week survival study with the BWL exposures in 10 specific pathogen free pigs were within normal limits. These results demonstrate that repositioning of stones with ultrasonic propulsion and breaking of stones with BWL are safe and effective. [Work supported by NIH P01 DK043881, K01 DK104854, and R44 DK109779.]

Recently, our group proposed the color Doppler ultrasound twinkling artifact originates from stable crevice bubbles on the kidney stone surface because overpressure suppressed twinkling on ex vivo stones (Lu et al., Ultrasound Med. Biol. 2013). However, the hypothesis is not fully accepted because the bubbles were not directly observed. Here, the submicron-sized bubbles predicted by the crevice-bubble hypothesis are enlarged in ex vivo kidney stones by exposure to a pre-focal, off-axis lithotripter pulse (p + = 1.5 MPa, p-=2.5 MPa) or hypobaric static pressures (0.021 MPa, absolute) to simultaneously capture their appearance by high-speed photography and ultrasound imaging. In rough stones that twinkle, consecutive lithotripter pulses caused more than 50% of bubbles to grow reproducibly from specific locations on the stone surface, suggesting the bubbles were pre-existing. Conversely, on smooth stones that did not twinkle, repeated lithotripter pulses initiated bubbles from varying locations on the stone...

Both mechanically induced acoustic cavitation and thermally induced boiling can occur during high intensity focused ultrasound (HIFU) medical therapy. The goal was to monitor the temperature as boiling was approached using magnetic resonance imaging (MRI). Tissue phantoms were heated for 20 s in a 4.7-T magnet using a 2-MHz HIFU source with an aperture and radius of curvature of 44 mm. The peak focal pressure was 27.5 MPa with corresponding beam width of 0.5 mm. The temperature measured in a single MRI voxel by water proton resonance frequency shift attained a maximum value of only 73 degrees C after 7 s of continuous HIFU exposure when boiling started. Boiling was detected by visual observation, by appearance on the MR images, and by a marked change in the HIFU source power. Nonlinear modeling of the acoustic field combined with a heat transfer equation predicted 100 degrees C after 7 s of exposure. Averaging of the calculated temperature field over the volume of the MRI voxel (0.3 x 0.5 x 2 mm(3)) yielded a maximum of 73 degrees C that agreed with the MR thermometry measurement. These results have implications for the use of MRI-determined temperature values to guide treatments with clinical HIFU systems.

Acoustic characterization of high intensity focused ultrasound (HIFU) fields is important both for the accurate prediction of ultrasound induced bioeffects in tissues and for the development of regulatory standards for clinical HIFU devices. In this paper, a method to determine HIFU field parameters at and around the focus is proposed. Nonlinear pressure waveforms were measured and modeled in water and in a tissue-mimicking gel phantom for a 2 MHz transducer with an aperture and focal length of 4.4 cm. Measurements were performed with a fiber optic probe hydrophone at intensity levels up to 24,000 W/cm(2). The inputs to a Khokhlov-Zabolotskaya-Kuznetsov-type numerical model were determined based on experimental low amplitude beam plots. Strongly asymmetric waveforms with peak positive pressures up to 80 MPa and peak negative pressures up to 15 MPa were obtained both numerically and experimentally. Numerical simulations and experimental measurements agreed well; however, when steep shocks were present in the waveform at focal intensity levels higher than 6000 W/cm(2), lower values of the peak positive pressure were observed in the measured waveforms. This underrepresentation was attributed mainly to the limited hydrophone bandwidth of 100 MHz. It is shown that a combination of measurements and modeling is necessary to enable accurate characterization of HIFU fields.

The importance of nonlinear acoustic wave propagation and ultrasound-induced cavitation in the acceleration of thermal lesion production by high intensity focused ultrasound was investigated experimentally and theoretically in a transparent protein-containing gel. A numerical model that accounted for nonlinear acoustic propagation was used to simulate experimental conditions. Various exposure regimes with equal total ultrasound energy but variable peak acoustic pressure were studied for single lesions and lesion stripes obtained by moving the transducer. Static overpressure was applied to suppress cavitation. Strong enhancement of lesion production was observed for high amplitude waves and was supported by modeling. Through overpressure experiments it was shown that both nonlinear propagation and cavitation mechanisms participate in accelerating lesion inception and growth. Using B-mode ultrasound, cavitation was observed at normal ambient pressure as weakly enhanced echogenicity in the focal region, but was not detected with overpressure. Formation of tadpole-shaped lesions, shifted toward the transducer, was always observed to be due to boiling. Boiling bubbles were visible in the gel and were evident as strongly echogenic regions in B-mode images. These experiments indicate that nonlinear propagation and cavitation accelerate heating, but no lesion displacement or distortion was observed in the absence of boiling.

Cavitation plays a varied but important role in lithotripsy. Cavitation facilitates stone comminution, but can also form an acoustic barrier that may shield stones from subsequent shock waves. In addition, cavitation damages tissue. Spark-gap lithotripters generate cavitation with both a direct and a focused wave. The direct wave propagates as a spherically diverging wave, arriving at the focus ahead of the focused shock wave. It can be modeled with the same waveform (but lower amplitude) as the focused wave. We show with both simulations and experiments that bubbles are forced to grow in response to the direct wave, and that these bubbles can still be large when the focused shock wave arrives. A baffle or "suppressor" that blocks the propagation of the direct wave is shown to significantly reduce the direct wave pressure amplitude, as well as direct wave-induced bubble growth. These results are applicable to spark-gap lithotripters and extracorporeal shock wave therapy devices, where cavitation from the direct wave may interfere with treatment. A simple direct-wave suppressor might therefore be used to improve the therapeutic efficacy of these devices.

Mechanical erosion of soft tissues into subcellular debris has been demonstrated with pulsed high-intensity focused ultrasound, facilitated by either boiling or cavitation bubbles. In this work, we propose acoustic streaming as a primary cause of tissue erosion at a tissue-fluid interface. Bovine liver tissue and polyacrylamide gels were sonicated in a degassed water bath, with the focus positioned at the tissue/fluid interface. Pulses with duration between 1 to 104 μs and constant duty cycle of 0.5% were applied from a 1 MHz transducer generating focal pressures |p- | ≤17 MPa and p+ ≤90 MPa. Results showed a strongly nonlinear change in erosion with pulse duration, being greatest for pulse lengths between 50-500 μs. For longer pulses (>1 ms), high-speed videos showed streaming velocities >10 m/s. Moreover, lesions >1cm in depth were produced in tissue phantoms even with a single pulse and tissue disruption was evident where no bubbles were observed at the tissue-fluid interface. Enhancement of erosion wa...

Overpressure has been shown to reduce the color-Doppler ultrasound twinkling artifact on ex vivo human kidney stones, leading to the hypothesis that surface crevice microbubbles cause twinkling. For the first time, we investigate the effect of overpressure on in situ human kidney stones. Thus far, five human subjects with kidney stones known to twinkle have been imaged with a Philips/ATL P4-2 transducer and Verasonics ultrasound system for 45 minutes in a hyperbaric chamber. Subjects breathed ambient air while exposed to a maximum pressure of 4 atmospheres absolute (ATA), except for a scheduled decompression stop at 1.6 ATA where subjects breathed pure oxygen. Twinkling was quantified in terms of Doppler power over 2 min intervals before pressurization (baseline), at 4 ATA, and at 1.6 ATA. Preliminary results (averaged over 3 of the 5 subjects) indicate no change in twinkling at 4 ATA compared to baseline levels (ratio of Doppler powers = 1.09±0.27). Twinkling almost doubled, though, during the pure oxyge...

Hyperbaric pressures of 0.3–10 MPa (absolute) have been shown to reduce the magnitude of the color Doppler ultrasound twinkling artifact on ex vivo human kidney stones, supporting the hypothesis that surface crevice microbubbles cause twinkling. For the first time, we investigate the etiology of twinkling on in situ human kidney stones. Eight human subjects with kidney stones known to twinkle were imaged with a Philips/ATL P4-2 transducer and Verasonics ultrasound system for 45 minutes while inside a hyperbaric chamber. Subjects breathed ambient air while the pressure in the chamber cycled to a maximum pressure of 0.4 MPa, with a scheduled decompression stop at 0.16 MPa where subjects breathed pure oxygen. Preliminary results show no change in the twinkling amplitude at 0.4 MPa compared to the baseline measurements before pressurization; however, a statistically significant increase in the twinkling amplitude was observed when subjects breathed pure oxygen at 0.16 MPa (p = 0.046). The increase in the twinkling amplitude upon changing respiratory gas composition further supports the crevice microbubble hypothesis of twinkling. Higher pressures than explored in this study may be needed to reduce twinkling on in situ human kidney stones. [Work supported by the National Space Biomedical Research Institute through NASA NCC 9-58 and NIH grant DK043881.]

Varying ethanol concentration with depth, Hobaek et al. [AIP Proc. 838, 2006)] simulated the atmospheric sound speed profile scaled in a water tank and mimicked sonic boom propagation. Some limitations of their groundbreaking design included complexity, fragility, size, safety, one-dimensionality, tonal bursts instead of impulsive shocks, and the inability to scale density, absorption, turbulence, or other nonlinearities. Recognizing the time and cost savings of scaled overflight experiments in a laboratory environment, this work is meant to address certain limitations and investigate the Mach cut-off phenomena. Our primary advances are to use gel layers instead of fluid mixtures and lithotripter shock pulses. We defocused and modified a Dornier Compact S lithotripter to vary source angle in a 500-liter polycarbonate tank, measured shocks with a fiber optic hydrophone, and developed fluid-like gels with negligible shear-wave generation and robustness against cavitation. The sound speed, attenuation, inhomogeneity, and nonlinearity are adjustable within each gel layer. The result is a more flexible, controllable, and durable atmospheric analogue. [Work supported by the FAA. The opinions, findings, conclusions, and recommendations expressed in this material are those of the authors and do not necessarily reflect the views of ASCENT FAA Center of Excellence sponsor organizations.]Varying ethanol concentration with depth, Hobaek et al. [AIP Proc. 838, 2006)] simulated the atmospheric sound speed profile scaled in a water tank and mimicked sonic boom propagation. Some limitations of their groundbreaking design included complexity, fragility, size, safety, one-dimensionality, tonal bursts instead of impulsive shocks, and the inability to scale density, absorption, turbulence, or other nonlinearities. Recognizing the time and cost savings of scaled overflight experiments in a laboratory environment, this work is meant to address certain limitations and investigate the Mach cut-off phenomena. Our primary advances are to use gel layers instead of fluid mixtures and lithotripter shock pulses. We defocused and modified a Dornier Compact S lithotripter to vary source angle in a 500-liter polycarbonate tank, measured shocks with a fiber optic hydrophone, and developed fluid-like gels with negligible shear-wave generation and robustness against cavitation. The sound speed, attenuation, inhom...

Bubble clouds can shield kidney stones from insonification, and limit stone breakage during burst-wave lithotripsy (BWL), a recently proposed technique that uses focused ultrasound pulses with an amplitude of O(1-10) MPa and frequency of O(0.1) MHz. We use numerical simulations to quantify the magnitude of such shielding. In the simulations, we solve for the radial evolution of Lagrangian bubbles coupled to a compressible fluid using volume-averaging techniques. The resulting equations are discretized on an Eulerian grid. In particular, we quantify the reduction in acoustic energy flux incident on a rigid, plane wall that models the stone surface. We consider a burst wave with an amplitude of 6 MPa and a bubble cloud of diameter O(1) mm. The size distribution of nuclei, the number density of bubbles, and the distance of the cloud from the wall are varied, We show that a cloud containing O(10) bubbles with a diameter of O(10) um can reduce the total energy flux by more than 50%, largely independent of distribution of nuclei. Finally, we compare the simulation results with high-speed images and hydrophone measurements of bubble clouds from companion experiments. [Work supported by NIH 2P01-DK043881.]Bubble clouds can shield kidney stones from insonification, and limit stone breakage during burst-wave lithotripsy (BWL), a recently proposed technique that uses focused ultrasound pulses with an amplitude of O(1-10) MPa and frequency of O(0.1) MHz. We use numerical simulations to quantify the magnitude of such shielding. In the simulations, we solve for the radial evolution of Lagrangian bubbles coupled to a compressible fluid using volume-averaging techniques. The resulting equations are discretized on an Eulerian grid. In particular, we quantify the reduction in acoustic energy flux incident on a rigid, plane wall that models the stone surface. We consider a burst wave with an amplitude of 6 MPa and a bubble cloud of diameter O(1) mm. The size distribution of nuclei, the number density of bubbles, and the distance of the cloud from the wall are varied, We show that a cloud containing O(10) bubbles with a diameter of O(10) um can reduce the total energy flux by more than 50%, largely independent of dist...

Most progress in acoustic trapping and levitation has been achieved with the use of multiple sound sources, standing waves, and low density or very small objects. Repositioning kidney stones in the human body is an important clinical application where acoustic levitation could be employed; however, it requires manipulation of larger and heavier objects. The goal of this work was to calibrate the acoustic output of a 1.5-MHz, 256-element array designed in our laboratory for HIFU research, which is also capable of generating vortex beams to manipulate mm-sized objects in water and to move them in any direction without moving the source. Electrical circuits were developed for matching each element of the array to an output channel of a Verasonics ultrasound engine to allow for efficient power transfer to the transducer. Acoustic holography was used to calibrate and equalize outputs across all channels. Manipulation of artificial kidney stone targets made of plastic, glass, or cement (2—8 mm) and comparable i...

An approach that combines numerical modeling with measurements is gaining acceptance for field characterization in medical ultrasound. The general method is suitable for accurate simulation of the fields radiated by therapeutic transducers in both water and tissue. Here, three characterization methods are compared. Simulations based on the 3D Westervelt equation with a boundary condition determined from acoustic holography measurements are used as the most accurate benchmark method. Two simplified methods are based on an axially symmetric nonlinear parabolic formulation, either the KZK equation or its wide-angle extension. Various approaches for setting a boundary condition to the parabolic models are presented and discussed. Simulation results obtained with the proposed methods are compared for a typical therapeutic array and a strongly focused single-element transducer, with validation measurements recorded by a fiber optic hydrophone at the focus at increasing acoustic outputs. It is shown that the wid...

The color Doppler ultrasound twinkling artifact, which is thought to arise from microbubbles on and within the stone, has the potential to improve kidney stone detection in space; however, bubbles are known to be sensitive to the elevated levels of carbon dioxide (CO2) found on space vehicles. Here, we investigate the effect of respiratory gas composition on twinkling in swine implanted with kidney stones. Thirteen swine were initially exposed to either 100% oxygen (O2) or room air and then to air with elevated CO2 at 0.8%, 0.54%, or 0.27%. Stones were imaged with a Verasonics ultrasound system and ATL P4-2 transducer. The 9 swine initially breathing 100% O2 showed a significant reduction in twinkling when exposed to air with elevated CO2, with the degree of decrease in twinkling occurring in the order: 0.8%>0.54%>0.27% CO2. An additional 4 swine were oscillated between air with 0.04% CO2 (normal air) and 0.5% CO2. A reduction in twinkling was observed over the course of the experiment. The effect of respiratory gas composition should be further investigated before using twinkling to diagnose a kidney stone in space. [Work supported by NSBRI through NASA NCC 9-58 and NIH DK043881.]