Julianna C. Simon

Focused Ultrasound to Expel Calculi From the Kidney

PURPOSE A persistent stone burden after renal stone treatment may result in future patient morbidity and potentially lead to additional surgery. This problem is particularly common after treatment of lower pole stones. We describe a potential noninvasive therapeutic option using ultrasound waves to create a force sufficient to aid in stone fragment expulsion. MATERIALS AND METHODS Human stones were implanted by retrograde ureteroscopy or antegrade percutaneous access in a live porcine model. The calibrated probe of a system containing ultrasound imaging and focused ultrasound was used to target stones and attempt displacement. To assess for injury an additional 6 kidneys were exposed for 2 minutes each directly to the output used for stone movement. Another 6 kidneys were exposed to more than twice the maximum output used to move stones. Renal tissue was analyzed histologically with hematoxylin and eosin, and nicotinamide adenine dinucleotide staining. RESULTS Stones were moved to the renal pelvis or ureteropelvic junction by less than 2 minutes of exposure. Stone velocity was approximately 1 cm per second. There was no tissue injury when tissue was exposed to the power level used to move stones. Localized thermal coagulation less than 1 cm long was observed in 6 of 7 renal units exposed to the level above that used for ultrasonic propulsion. CONCLUSIONS Transcutaneous ultrasonic propulsion was used to expel calculi effectively and safely from the kidney using a live animal model. This study is the first step toward an office based system to clear residual fragments and toward use as a primary treatment modality in conjunction with medical expulsive therapy for small renal stones.

Ultrasound-guided tissue fractionation by high intensity focused ultrasound in an in vivo porcine liver model

Significance High intensity focused ultrasound (HIFU) therapy is a promising, clinically adopted method of noninvasive tissue ablation used to treat both benign and malignant conditions. This work presents, to our knowledge, the first in vivo validation of a previously developed HIFU-based method that allows for noninvasive fractionation of targeted tissue into subcellular debris—boiling histotripsy—in a large animal model. While fractionating the targeted soft tissue, boiling histotripsy is shown to spare the adjacent connective tissue structures such as blood vessels. The process can be readily targeted and monitored by B-mode ultrasound. The resulting tissue debris are liquid, which provides a potential clinical benefit over thermal ablation in the treatment of tumors that exert uncomfortable pressure on surrounding tissues. 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.

Focused Ultrasound to Expel Calculi from the Kidney: Safety and Efficacy of a Clinical Prototype Device

PURPOSE Focused ultrasound has the potential to expel small stones or residual stone fragments from the kidney, or move obstructing stones to a nonobstructing location. We evaluated the efficacy and safety of ultrasonic propulsion in a live porcine model. MATERIALS AND METHODS Calcium oxalate monohydrate kidney stones and laboratory model stones (2 to 8 mm) were ureteroscopically implanted in the renal pelvicalyceal system of 12 kidneys in a total of 8 domestic swine. Transcutaneous ultrasonic propulsion was performed using an HDI C5-2 imaging transducer (ATL/Philips, Bothell, Washington) and the Verasonics® diagnostic ultrasound platform. Successful stone relocation was defined as stone movement from the calyx to the renal pelvis, ureteropelvic junction or proximal ureter. Efficacy and procedure time was determined. Three blinded experts evaluated histological injury to the kidney in the control, sham treatment and treatment arms. RESULTS All 26 stones were observed to move during treatment and 17 (65%) were relocated successfully to the renal pelvis (3), ureteropelvic junction (2) or ureter (12). Average ± SD successful procedure time was 14 ± 8 minutes and a mean of 23 ± 16 ultrasound bursts, each about 1 second in duration, were required. There was no evidence of gross or histological injury to the renal parenchyma in kidneys exposed to 20 bursts (1 second in duration at 33-second intervals) at the same output (2,400 W/cm(2)) used to push stones. CONCLUSIONS Noninvasive transcutaneous ultrasonic propulsion is a safe, effective and time efficient means to relocate calyceal stones to the renal pelvis, ureteropelvic junction or ureter. This technology holds promise as a useful adjunct to surgical management for renal calculi.

Focused Ultrasonic Propulsion of Kidney Stones: Review and Update of Preclinical Technology

INTRODUCTION A noninvasive tool to reposition kidney stones could have significant impact in the management of stone disease. Our research group has developed a noninvasive transcutaneous ultrasound device. A review and update of the current status of this technology is provided. DISCUSSION OF TECHNOLOGY: Stone propulsion is achieved through short bursts of focused, ultrasonic pulses. The initial system consisted of an eight-element annular array transducer, computer, and separate ultrasound imager. In the current generation, imaging and therapy are completed with one ultrasound system and a commercial probe. This generation allows real-time ultrasound imaging, targeting, and propulsion. Safety and effectiveness for the relocation of calyceal stones have been demonstrated in the porcine model. ROLE IN ENDOUROLOGY: This technology may have applications in repositioning stones as an adjunct to lithotripsy, facilitating clearance of residual fragments after lithotripsy, expelling de novo stones, and potentially repositioning obstructing stones. Human trials are in preparation.

In vitro biomechanical evaluations of screw-bar-polymethylmethacrylate and pin-polymethylmethacrylate internal fixation implants used to stabilize the vertebral motion unit of the fourth and fifth cervical vertebrae in vertebral column specimens from dogs.

OBJECTIVE To determine the change in stiffness as evaluated by the dorsal bending moment of cervical vertebral specimens obtained from canine cadavers after internally stabilizing the vertebral motion unit (VMU) of C4 and C5 with a traditional pin-polymethylmethacrylate (PMMA) fixation implant or a novel screw-bar-PMMA fixation implant. SAMPLE POPULATION 12 vertebral column specimens (C3 through C6) obtained from canine cadavers. PROCEDURES A dorsal bending moment was applied to the vertebral specimens before and after fixation of the VMU of C4 and C5 by use of a traditional pin-PMMA implant or a novel screw-bar-PMMA implant. Biomechanical data were collected and compared within a specimen (unaltered vs treated) and between treatment groups. Additionally, implant placement was evaluated after biomechanical testing to screen for penetration of the transverse foramen or vertebral canal by the pins or screws. RESULTS Treated vertebral specimens were significantly stiffer than unaltered specimens. There was no significant difference in stiffness between vertebral specimen groups after treatment. None of the screws in the novel screw-bar-PMMA implant group penetrated the transverse foramen or vertebral canal, whereas there was mild to severe penetration for 22 of 24 (92%) pins in the traditional pin-PMMA implant group. CONCLUSIONS AND CLINICAL RELEVANCE Both fixation treatments altered the biomechanical properties of the cervical vertebral specimens as evaluated by the dorsal bending moment. There was reduced incidence of penetration of the transverse foramen or vertebral canal with the novel screw-bar-PMMA implant, compared with the incidence for the traditional pin-PMMA implant.

In vivo tissue emulsification using millisecond boiling induced by high intensity focused ultrasound.

Shock‐wave heating and millisecond boiling in high intensity focused ultrasound fields have been shown to result in mechanical emulsification of ex‐vivo tissue. In this work, the same in situ exposures were applied in vivo in pig liver and in mice bearing 5–7 mm subcutaneous tumors (B16 melanoma) on the hind limb. Lesions were produced using a 2‐MHz annular array in the case of pig liver (shock amplitudes up to 98 MPa) and a 3.4‐MHz single‐element transducer in the case of mouse tumors (shock amplitude of 67 MPa). The parameters of the pulsing protocol (1–500 ms pulse durations and 0.01–0.1 duty factor) were varied depending on the extent of desired thermal effect. All exposures were monitored using B‐mode ultrasound. Mechanical and thermal tissue damage in the lesions was evaluated histologically using H&E and NADH‐diphorase staining. The size and shape of emulsified lesions obtained in‐vivo agreed well with those obtained in ex‐vivo tissue samples using the same exposure parameters. The lesions were suc...

Determination of tissue injury thresholds from ultrasound in a porcine kidney model

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 30,000 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 min at various intensities. The perfusion-fixed tissue was scored by three blinded independent experts. Above a threshold of 20,000 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. [Work supported by NIH DK43881, DK092197, and NSBRI through NASA NCC 9-58.]

Miniature acoustic fountain mechanism for tissue emulsification during millisecond boiling in high intensity focused ultrasound fields.

Feasibility of soft tissue emulsification using shock wave heating and millisecond boiling induced by high intensity focused ultrasound was demonstrated recently. However, the mechanism by which the bubbles emulsify tissue is not well understood. High‐speed photography of such exposures in transparent gel phantoms shows a milimeter‐sized boiling bubble, and histological analysis in tissue samples reveals sub‐micron‐sized fragments. Here, a novel mechanism of tissue emulsification by the formation of a miniature acoustic fountain within the boiling bubble is tested experimentally using a 2 MHz transducer generating up to 70 MPa positive and 15 MPa negative peak pressures at the focus. The focus was positioned at or 1–2 mm off the plane interface between air and various materials including degassed water, transparent gel, thin sliced muscle tissue phantom, and ex‐vivo tissue. Pulsing schemes with duty factors 0.001–0.1, and pulse durations 0.05–500 ms were used. Violent removal of micron‐sized fragments and...

Developing Complete Ultrasonic Management of Kidney Stones for Spaceflight

Bone demineralization, dehydration, and stasis put astronauts at an increased risk of forming kidney stones in space. The incidence of kidney stones and the potential for a mission-critical event are expected to rise as expeditions become longer and immediate transport to Earth becomes more problematic. At the University of Washington, we are developing an ultrasound-based stone management system to detect stones with S-mode™ ultrasound imaging, break stones with burst wave lithotripsy (BWL™), and reposition stones with ultrasonic propulsion (UP™) on Earth and in space. This review discusses the development and current state of these technologies, as well as integration on the flexible ultrasound system sponsored by NASA and the National Space Biomedical Research Institute.

INVESTIGATION INTO THE MECHANISMS OF TISSUE ATOMIZATION BY HIGH-INTENSITY FOCUSED ULTRASOUND

Ultrasonic atomization, or the emission of a fog of droplets, was recently proposed to explain tissue fractionation in boiling histotripsy. However, even though liquid atomization has been studied extensively, the mechanisms underlying tissue atomization remain unclear. In the work described here, high-speed photography and overpressure were used to evaluate the role of bubbles in tissue atomization. As static pressure increased, the degree of fractionation decreased, and the ex vivo tissue became thermally denatured. The effect of surface wetness on atomization was also evaluated in vivo and in tissue-mimicking gels, where surface wetness was found to enhance atomization by forming surface instabilities that augment cavitation. In addition, experimental results indicated that wetting collagenous tissues, such as the liver capsule, allowed atomization to breach such barriers. These results highlight the importance of bubbles and surface instabilities in atomization and could be used to enhance boiling histotripsy for transition to clinical use.