Ultrasound is known to overestimate kidney stone size. We explored measuring the acoustic shadow behind kidney stones combined with different ultrasound imaging modalities to improve stone sizing accuracy. A total of 45 calcium oxalate monohydrate stones were imaged in vitro at 3 different depths with the 3 different ultrasound imaging modalities of conventional ray line, spatial compound and harmonic imaging. The width of the stone and the width of the acoustic shadow were measured by 4 operators blinded to the true size of the stone.

Shadow width was a more accurate measure of true stone size than a direct measurement of the stone in the ultrasound image (p <0.0001). The ultrasound imaging modality also impacted the measurement accuracy. All methods performed similarly for shadow size while harmonic imaging was the most accurate stone size modality. Overall 78% of the shadow sizes were accurate to within 1 mm, which is similar to the resolution obtained with clinical computerized tomography.

Transcutaneous focused ultrasound (US) is used to propel kidney stones using acoustic radiation force. It is important to estimate the level of heating generated at the stone/tissue interface for safety assessment. An in-vitro experiment is conducted to measure the temperature rise in a tissue-mimicking phantom with an embedded artificial stone and subjected to a focused beam from an imaging US array. A novel optical-imaging-based thermometry method is described using an optically clear tissue phantom. Measurements are compared to the output from a fine wire thermocouple placed on the stone surface. The optical method has good sensitivity, and it does not suffer from artificial viscous heating typically observed with invasive probes and thermocouples.

Ultrasound (US) overestimates stone size when compared with CT. The purpose of this work was to evaluate the overestimation of stone size with US in an in vitro water bath model and investigate methods to reduce overestimation.

Ten human stones (3–12 mm) were measured using B-mode (brightness mode) US by a sonographer blinded to the true stone size. Images were captured and compared using both a commercial US machine and software-based research US device. Image gain was adjusted between moderate and high stone intensities, and the transducer-to-stone depth was varied from 6 to 10 cm. A computerized stone-sizing program was developed to outline the stone width based on a grayscale intensity threshold.

Overestimation with the commercial device increased with both gain and depth. Average overestimation at moderate and high gain was 1.9±0.8 and 2.1±0.9 mm, respectively (p=0.6). Overestimation increased an average of 22% with an every 2-cm increase in depth (p=0.02). Overestimation using the research device was 1.5±0.9 mm and did not vary with depth (p=0.28). Overestimation could be reduced to 0.02±1.1 mm (p<0.001) with the computerized stone-sizing program. However, a standardized threshold consistent across depth, system, or system settings could not be resolved.

Stone size is consistently overestimated with US. Overestimation increased with increasing depth and gain using the commercial machine. Overestimation was reduced and did not vary with depth, using the software-based US device. The computerized stone-sizing program shows the potential to reduce overestimation by implementing a grayscale intensity threshold for defining the stone size. More work is needed to standardize the approach, but if successful, such an approach could significantly improve stone-sizing accuracy and lead to automation of stone sizing.

Purpose
We have developed a new method of lithotripsy that uses short, broadly focused bursts of ultrasound rather than shock waves to fragment stones. This study investigated the characteristics of stone comminution by burst wave lithotripsy in vitro.

Materials and Methods
Artificial and natural stones (mean 8.2±3.0 mm, range 5–15 mm) were treated with ultrasound bursts using a focused transducer in a water bath. Stones were exposed to bursts with focal pressure amplitude 𕟮.5 MPa at 200 Hz burst repetition rate until completely fragmented. Ultrasound frequencies of 170 kHz, 285 kHz, and 800 kHz were applied using 3 different transducers. The time to achieve fragmentation for each stone type was recorded, and fragment size distribution was measured by sieving.

Results
Stones exposed to ultrasound bursts were fragmented at focal pressure amplitudes 𕟴.8 MPa at 170 kHz. Fractures appeared along the stone surface, resulting in fragments separating at the surface nearest to the transducer until the stone was disintegrated. All natural and artificial stones were fragmented at the highest focal pressure of 6.5 MPa with treatment durations between a mean of 36 seconds for uric acid to 14.7 minutes for cystine stones. At a frequency of 170 kHz, the largest artificial stone fragments were <4 mm. Exposures at 285 kHz produced only fragments <2 mm, and 800 kHz produced only fragments <1 mm.

Conclusions
Stone comminution with burst wave lithotripsy is feasible as a potential noninvasive treatment method for nephrolithiasis. Adjusting the fundamental ultrasound frequency allows control of stone fragment size.

Burst wave lithotripsy is a novel technology that uses focused, sinusoidal bursts of ultrasound to fragment kidney stones. Prior research laid the groundwork to design an extracorporeal, image-guided probe for in-vivo testing and potentially human clinical testing. Toward this end, a 12-element 330 kHz array transducer was designed and built. The probe frequency, geometry, and shape were designed to break stones up to 1 cm in diameter into fragments <2 mm. A custom amplifier capable of generating output bursts up to 3 kV was built to drive the array. To facilitate image guidance, the transducer array was designed with a central hole to accommodate co-axial attachment of an HDI P4-2 probe. Custom B-mode and Doppler imaging sequences were developed and synchronized on a Verasonics ultrasound engine to enable real-time stone targeting and cavitation detection, Preliminary data suggest that natural stones will exhibit Doppler %u201Ctwinkling%u201D artifact in the BWL focus and that the Doppler power increases as the stone begins to fragment. This feedback allows accurate stone targeting while both types of imaging sequences can also detect cavitation in bulk tissue that may lead to injury.

Objective
To provide an update on a research device to ultrasonically reposition kidney stones transcutaneously. This article reports preclinical safety and effectiveness studies, survival data, modifications of the system, and testing in a stone-forming porcine model. These data formed the basis for regulatory approval to test the device in humans.

Materials and Methods
The ultrasound burst was shortened to 50 ms from previous investigations with 1-s bursts. Focused ultrasound was used to expel 2- to 5-mm calcium oxalate monohydrate stones placed ureteroscopically in 5 pigs. Additionally, de novo stones were imaged and repositioned in a stone-forming porcine model. Acute safety studies were performed targeting 2 kidneys (6 sites) and 3 pancreases (8 sites). Survival studies followed 10 animals for 1 week after simulated treatment. Serum and urine analyses were performed, and tissues were evaluated histologically.

Results
All ureteroscopically implanted stones (6/6) were repositioned out of the kidney in 14 ± 8 minutes with 13 ± 6 bursts. On average, 3 bursts moved a stone more than 4 mm and collectively accounted for the majority of relocation. Stones (3 mm) were detected and repositioned in the 200-kg stone-forming model. No injury was detected in the acute or survival studies.

Conclusion
Ultrasonic propulsion is safe and effective in the porcine model. Stones were expelled from the kidney. De novo stones formed in a large porcine model were repositioned. No adverse effects were identified with the acute studies directly targeting kidney or pancreatic tissue or during the survival studies indicating no evidence of delayed tissue injury.

The clinical use of high intensity focused ultrasound (HIFU) therapy for noninvasive tissue ablation has been recently gaining momentum. In HIFU, ultrasound energy from an extracorporeal source is focused within the body to ablate tissue at the focus while leaving the surrounding organs and tissues unaffected. Most HIFU therapies are designed to use heating effects resulting from the absorption of ultrasound by tissue to create a thermally coagulated treatment volume. Although this approach is often successful, it has its limitations, such as the heat sink effect caused by the presence of a large blood vessel near the treatment area or heating of the ribs in the transcostal applications. HIFU-induced bubbles provide an alternative means to destroy the target tissue by mechanical disruption or, at its extreme, local fractionation of tissue within the focal region. Here, we demonstrate the feasibility of a recently developed approach to HIFU-induced ultrasound-guided tissue fractionation in an in vivo pig model. In this approach, termed boiling histotripsy, a millimeter-sized boiling bubble is generated by ultrasound and further interacts with the ultrasound field to fractionate porcine liver tissue into subcellular debris without inducing further thermal effects. Tissue selectivity, demonstrated by boiling histotripsy, allows for the treatment of tissue immediately adjacent to major blood vessels and other connective tissue structures. Furthermore, boiling histotripsy would benefit the clinical applications, in which it is important to accelerate resorption or passage of the ablated tissue volume, diminish pressure on the surrounding organs that causes discomfort, or insert openings between tissues.

The global prevalence and incidence of renal calculi is reported to be increasing. Of the patients that undergo surgical intervention, nearly half experience symptomatic complications associated with stone fragments that are not passed and require follow-up surgical intervention. In a clinical simulation using a clinical prototype, ultrasonic propulsion was proven effective at repositioning kidney stones in pigs. The use of ultrasound to reposition smaller stones or stone fragments to a location that facilitates spontaneous clearance could therefore improve stone-free rates. The goal of this study was to determine an injury threshold under which stones could be safely repositioned.

Kidneys of 28 domestic swine were treated with exposures that ranged in duty cycle from 0%–100% and spatial peak pulse average intensities up to 30 kW/cm² for a total duration of 10 min. The kidneys were processed for morphological analysis and evaluated for injury by experts blinded to the exposure conditions.

At a duty cycle of 3.3%, a spatial peak intensity threshold of 16,620 W/cm² was needed before a statistically significant portion of the samples showed injury. This is nearly seven times the 2,400-W/cm² maximum output of the clinical prototype used to move the stones effectively in pigs.

The data obtained from this study show that exposure of kidneys to ultrasonic propulsion for displacing renal calculi is well below the threshold for tissue injury.

Purpose: Ultrasonic propulsion to reposition urinary tract calculi requires knowledge about ultrasound image capture, device manipulation, and interpretation. The purpose of this study was to validate a cognitive and technical skills curriculum to teach urologists ultrasonic propulsion to reposition kidney stones in tissue phantoms.

Materials and Methods: Ten board-certified urologists recruited from a single institution underwent a didactic session on renal ultrasound imaging. Subjects completed technical skills modules in tissue phantoms, including kidney imaging, pushing a stone through a translucent maze, and repositioning a lower pole calyceal stone. Objective cognitive and technical performance metrics were recorded. Subjects completed a questionnaire to ascertain face and content validity on a five-point Likert scale.

Results: Eight urologists (80%) had never attended a previous ultrasound course, and nine (90%) performed renal ultrasounds less frequently than every 6 months. Mean cognitive skills scores improved from 55% to 91% (p<0.0001) on pre- and post-didactic tests. In the kidney phantom, 10 subjects (100%) repositioned the lower pole calyceal stone to at least the lower pole infundibulum, while 9 (90%) successfully repositioned the stone to the renal pelvis. A mean±SD (15.7±13.3) pushes were required to complete the task over an average of 4.6±2.2 minutes. Urologists rated the curriculum's effectiveness and realism as a training tool at a mean score of 4.6/5.0 and 4.1/5.0, respectively.

Conclusions: The curriculum for ultrasonic propulsion is effective and useful for training urologists with limited ultrasound proficiency in stone repositioning technique. Further studies in animate and human models will be required to assess predictive validity.

Focused ultrasonic propulsion is a new noninvasive technique designed to move kidney stones and stone fragments out of the urinary collecting system. However, to our knowledge the extent of tissue injury associated with this technique is not known. We quantitated the amount of tissue injury produced by focused ultrasonic propulsion under simulated clinical treatment conditions and under conditions of higher power or continuous duty cycles. We compared those results to extracorporeal shock wave lithotripsy injury.

Ultrasound imaging has tissue and blood imaging modes. This report describes development of a kidney stone imaging mode. Two plane pulses generate a B-mode image. Overlaid in color are regions of high decorrelation between the pulses. Our previous data [UMB, 39, 1026-1038 (2013)] indicate the pulses excite bubbles on the stone surface, which causes the decorrelation. As such this mode automatically identifies stones in the image while scanning at a high frame rate. Further in a control box placed on the stone, highly focused beams are scanned across the stone and a harmonic B-mode image is produced to sharpen the lateral resolution. This mode is used to refine the size and shape of the stone. The first mode is used to aid visualization of stones. Our team is also using it to target and track stones that move with respiration during shock wave lithotripsy (SWL) and as an indicator of stone susceptibility to SWL since surface bubbles contribute to comminution. Improved stone sizing by the second mode aids treatment planning, and resolution of surface roughness is another indicator of stone fragility.

Shock wave lithotripsy (SWL) is the most common procedure for treatment of kidney stones. SWL noninvasively delivers high-energy focused shocks to fracture stones into passable fragments. We have recently observed that lower-amplitude, sinusoidal bursts of ultrasound can generate similar fracture of stones. This work investigated the characteristics of stone fragmentation for natural (uric acid, struvite, calcium oxalate, and cystine) and artificial stones treated by ultrasound bursts. Stones were fixed in position in a degassed water tank and exposed to 10-cycle bursts from a 200-kHz transducer with a pressure amplitude of p ≤ 6.5 MPa, delivered at a rate of 40–200 Hz. Exposures caused progressive fractures in the stone surface leading to fragments up to 3 mm. Treatment of artificial stones at different frequencies exhibited an inverse relationship between the resulting fragment sizes and ultrasound frequency. All artificial and natural types of stones tested could be fragmented, but the comminution rate varied significantly with stone composition over a range of 12–630 mg/min. These data suggest that stones can be controllably fragmented by sinusoidal ultrasound bursts, which may offer an alternative treatment strategy to SWL.

The use of projection methods is increasingly accepted as a standard way of characterizing the 3D fields generated by medical ultrasound sources. When combined with hydrophone measurements of pressure amplitude and phase over a surface transverse to the wave propagation, numerical projection can be used to reconstruct 3D fields that account for operational details and imperfections of the source. Here, we use holography measurements to characterize the fields generated by two array transducers with different geometries and modes of operation. First, a seven-element, high-power therapy transducer is characterized in the continuous-wave regime using holography measurements and nonlinear forward-projection calculations. Second, a C5-2 imaging probe (Philips Healthcare) with 128 elements is characterized in the transient regime using holography measurements and linear projection calculations. Results from the numerical projections for both sources are compared with independent hydrophone measurements of select waveforms, including shocked focal waveforms for the therapy transducer. Accurate 3D field representations have been confirmed, though a notable sensitivity to hydrophone calibrations is revealed. Uncertainties associated with this approach are discussed toward the development of holography measurements combined with numerical projections as a standard metrological tool.

Previous studies have provided insight into the physical mechanisms of stone fracture in shock wave lithotripsy. Broadly focused shocks efficiently generate shear waves in the stone leading to internal tensile stresses, which in concert with cavitation at the stone surface, cause cracks to form and propagate. Here, we propose a separate mechanism by which stones may fragment from sinusoidal ultrasound bursts without shocks. A numerical elastic wave model was used to simulate propagation of tone bursts through a cylindrical stone at a frequency between 0.15 and 2 MHz. Results suggest that bursts undergo mode conversion into surface waves on the stone that continually create significant stresses well after the exposure is terminated. Experimental exposures of artificial cylindrical stones to focused burst waves in vitro produced periodic fractures along the stone surface. The fracture spacing and resulting fragment sizes corresponded well with the spacing of stresses caused by surface waves in simulation at different frequencies. These results indicate surface waves may be an important factor in fragmentation of stones by focused tone bursts and suggest that the resulting stone fragment sizes may be controlled by ultrasound frequency.

Therapeutic ultrasound has an increasing number of applications in urology, including shockwave lithotripsy, stone propulsion, tissue ablation, and hemostasis. However, the threshold of renal injury using ultrasound is unknown. The goal of this study was to determine kidney injury thresholds for a range of intensities between diagnostic and ablative therapeutic ultrasound. A 2 MHz annular array generating spatial peak pulse average intensities (ISPPA) up to 28,000 W/cm² in water was placed on the surface of in vivo porcine kidneys and focused on the adjacent parenchyma. Treatments consisted of pulses of 100 μs duration triggered every 3 ms for 10 minutes at various intensities. The perfusion-fixed tissue was scored by 3 blinded independent experts. Above a threshold of 16,620 W/cm², the majority of injury observed included emulsification, necrosis and hemorrhage. Below this threshold, almost all injury presented as focal cell and tubular swelling and/or degeneration. These findings provide evidence for a wide range of potentially therapeutic ultrasound intensities that has a low probability of causing injury. While this study did not examine all combinations of treatment parameters of therapeutic ultrasound, tissue injury appears dose-dependent.

Purpose
Focused ultrasound has the potential to expel small stones or residual stone fragments from the kidney, or move obstructing stones to a non-obstructing location. The purpose of this study was to evaluate the efficacy and safety of ultrasonic propulsion in a live porcine model.

Material and Methods
Calcium oxalate monohydrate kidney stones and laboratory model stones (2–8 mm) were ureteroscopically implanted within the renal pelvicalyceal system of 12 kidneys in eight domestic swine. Transcutaneous ultrasonic propulsion was performed using a Philips HDI C5-2 imaging transducer and Verasonics diagnostic ultrasound platform. Successful stone relocation was defined as stone movement from the calyx to the renal pelvis, ureteropelvic junction (UPJ) or proximal ureter. Efficacy and procedure time were determined. Three blinded experts evaluated for histologic injury to the kidney in control, sham, and treatment arms.

Results
All stones were observed to move during treatment, and 65% (17/26) were relocated successfully to the renal pelvis (3), UPJ (2), or ureter (12). Average successful procedure time was 14±8 min and required 23±16 ultrasound bursts of ~1 sec duration. There was no evidence of gross or histologic injury to the renal parenchyma in kidneys exposed to 20 bursts (1 sec duration, 33 sec intervals) at the same output (2400 W/cm²) used to push stones.

Conclusions
Non-invasive transcutaneous ultrasonic propulsion is a safe, effective, and time-efficient means to relocate calyceal stones to the renal pelvis, UPJ, or ureter. This technology holds promise as a useful adjunct to the surgical management of renal calculi.

Laser vibrometry is a practical method to detect surface displacement. The method enables a direct measurement of acoustic field parameters such as acoustic particle displacement or acoustic particle velocity. Unlike other sensors, e.g., hydrophones, laser vibrometers are completely non-contact. Such devices are capable of measuring displacements from centimeters to sub nanometers at frequencies from near dc to 10 s of megahertz and have been proven to establish a primary standard for calibrating hydrophones [Bacon, IEEE Trans. UFFC, 35 (1988)]. In this technique, an ultrasonic transducer radiates an acoustic wave which is detected by a thin plastic membrane - a pellicle. The pellicle is effectively transparent to the acoustic beam so that the vibration of the pellicle follows the particle motion in the sound wave, but is reflective to the optical beam of the vibrometer allowing for a measurement. The present talk will report on measurements of nonlinearly distorted sawtooth waves in water performed with two commercial Polytec laser vibrometers: a scanning 24 MHz bandwidth system and a non-scanning 600 MHz bandwidth system. It is shown that appropriately chosen optical targets - pellicle or thick glass block with flat sides - allow resolution of both shock front and the smooth part of the waveform.

Residual fragments remain in over 50% of treatments for lower pole kidney stones. A second-generation device based on a diagnostic ultrasound system and scanhead has been developed with a unique algorithm for stone detection and the capability to focus ultrasound to expel residual fragments. Focused ultrasound was applied to a bead on string in a water tank as well as to human stones (<5 mm) implanted in the lower pole of a live porcine model via retrograde ureteroscopy. Histological samples were collected and scored in a blinded fashion for therapeutic exposures and for super-therapeutic levels. The in-vitro bead was visually observed to move under focused ultrasound. Even with progressive manual displacement of the bead, the system continuously tracked and caused bead movement in real time. In the live porcine model, stones were expelled from the lower pole to the ureteropelvic junction in seconds to minutes using pulses at a duty factor of 0.02 and 8 W total acoustic power. Injury was observed no more frequently than in controls. Occurrence of injury rose slightly above control at a duty factor of 0.02 and 80 W and at a duty factor of 1 and 8 W.

Recent interest in using High Intensity Focused Ultrasound (HIFU) for surgical applications such as hemostasis and tissue necrosis has stimulated the development of image-guided systems for non-invasive HIFU therapy. Seeking an all-ultrasound therapeutic modality, we have developed a clinical HIFU system comprising an integrated applicator that permits precisely registered HIFU therapy delivery and high quality ultrasound imaging using two separate arrays, a multi-channel signal generator and RF amplifier system, and a software program that provides the clinician with a graphical overlay of the ultrasound image and therapeutic protocol controls. Electronic phasing of a 32 element 2 MHz HIFU annular array allows adjusting the focus within the range of about 4 to 12 cm from the face. A central opening in the HIFU transducer permits mounting a commercial medical imaging scanhead (ATL P7-4) that is held in place within a special housing. This mechanical fixture ensures precise coaxial registration between the HIFU transducer and the image plane of the imaging probe. Recent enhancements include development of an acoustic lens using numerical simulations for use with a 5-element array. Our image-guided therapy system is very flexible and enables exploration of a variety of new HIFU therapy delivery and monitoring approaches in the search for safe, effective, and efficient treatment protocols.