Christopher Hunter

Dependence of inertial cavitation induced by high intensity focused ultrasound on transducer F-number and nonlinear waveform distortion

Pulsed high intensity focused ultrasound was shown to enhance chemotherapeutic drug uptake in tumor tissue through inertial cavitation, which is commonly assumed to require peak rarefactional pressures to exceed a certain threshold. However, recent studies have indicated that inertial cavitation activity also correlates with the presence of shocks at the focus. The shock front amplitude and corresponding peak negative pressure (p -) in the focal waveform are primarily determined by the transducer F-number: less focused transducers produce shocks at lower p -. Here, the dependence of inertial cavitation activity on the transducer F-number was investigated in agarose gel by monitoring broadband noise emissions with a coaxial passive cavitation detector (PCD) during pulsed exposures (pulse duration 1 ms, pulse repetition frequency 1 Hz) with p- varying within 1-15 MPa. Three 1.5 MHz transducers with the same aperture, but different focal distances (F-numbers 0.77, 1.02, 1.52) were used. PCD signals were processed to extract cavitation probability, persistence, and mean noise level. At the same p -, all metrics indicated enhanced cavitation activity at higher F-numbers; specifically, cavitation probability reached 100% when shocks formed at the focus. These results provide further evidence supporting the excitation of inertial cavitation at reduced p - by waveforms with nonlinear distortion and shocks.

Impact of stone characteristics on cavitation in burst wave lithotripsy

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.]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 lo...

Effect of high intensity focused ultrasound transducer F-number and waveform non-linearity on inertial cavitation activity

Enhanced chemotherapeutic drug delivery has been shown using pulsed high intensity focused ultrasound (pHIFU) without contrast agents. The threshold of these inertial cavitation effects has recently been correlated to the formation of shocks at the focus. The shock amplitude and corresponding peak negative pressure (p-) are primarily determined by the transducers F-number with less focused (higher F-number) transducers producing shocks at lower p-. Here, the dependence of inertial cavitation activity on F-number was investigated in gel phantoms using passive cavitation detection (PCD) and high-speed photography. HIFU transducers with the same aperture but different F-numbers (0.77, 1.02, and 1.52), operable at three driving frequencies (1 MHz, 1.5 MHz, and 1.9 MHz), were utilized with driving conditions consisting of 1 ms pulses delivered every second and p- from 1 to 15 MPa. Broadband noise emissions recorded by PCD were batch-processed to extract cavitation probability and persistence while concurrent imaging was performed in the focal pHIFU region. At the same p-, both PCD metrics and the imaging revealed enhanced cavitation activity at higher F-numbers. These results support the use of less focused, smaller-footprint transducers for achieving desired cavitation-aided drug delivery. [Work supported by NIH R01EB023910, K01DK104854, R01EB007643, and RFBR 17-54-33034.]Enhanced chemotherapeutic drug delivery has been shown using pulsed high intensity focused ultrasound (pHIFU) without contrast agents. The threshold of these inertial cavitation effects has recently been correlated to the formation of shocks at the focus. The shock amplitude and corresponding peak negative pressure (p-) are primarily determined by the transducers F-number with less focused (higher F-number) transducers producing shocks at lower p-. Here, the dependence of inertial cavitation activity on F-number was investigated in gel phantoms using passive cavitation detection (PCD) and high-speed photography. HIFU transducers with the same aperture but different F-numbers (0.77, 1.02, and 1.52), operable at three driving frequencies (1 MHz, 1.5 MHz, and 1.9 MHz), were utilized with driving conditions consisting of 1 ms pulses delivered every second and p- from 1 to 15 MPa. Broadband noise emissions recorded by PCD were batch-processed to extract cavitation probability and persistence while concurrent i...

Burst wave lithotripsy: An in vivo demonstration of efficacy and acute safety using a porcine model

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 <2 mm fragments. 100% of four stones were reduced to <4 mm fragments. Magnetic resonance imaging showed minimal injury to the functional renal volume. This study demonstrated that BWL can be used to effectively fragment kidney stones with minimal injury. [Funding support: NIH P01-DK043881, NIH K01-DK104854.] 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 ...

Nonlinear ultrasound fields generated by a 256-element spiral array for boiling histotripsy

Boiling histotripsy (BH) is a HIFU approach that uses millisecond-long ultrasound bursts with high-amplitude shocks to mechanically fractionate tissue. In this work, the performance of a BH pre-clinical system operating at 1.5 MHz was characterized by hydrophone measurements in water and lesion formation capabilities were tested in ex vivo tissue. The system comprises a 256 element array driven by Verasonics Ultrasound Engine with a 1.2 kW external power source enhanced by an additional capacitor bank. The maximum pulse average acoustic power of the system was 2.2 kW (as measured by radiation force balance), sustained for 10 ms with <15% drop in amplitude. At the focus, a fully developed shock of 100 MPa amplitude formed at 275 W acoustic power. The steering range defined at -3 dB in both linear and nonlinear beam was 19 mm laterally and 38 mm axially forming the region where 100 MPa shocks can be achieved with less than twofold increase in acoustic power. Within the axial steering range, shock formation characteristics varied substantially due to changes in the effective transducer F-number. The system was successfully used to produce volumetric BH lesions in ex vivo tissue using electronic steering only. [Work supported by NIH R01EB7643, R01GM122859, and R01EB025187.]Boiling histotripsy (BH) is a HIFU approach that uses millisecond-long ultrasound bursts with high-amplitude shocks to mechanically fractionate tissue. In this work, the performance of a BH pre-clinical system operating at 1.5 MHz was characterized by hydrophone measurements in water and lesion formation capabilities were tested in ex vivo tissue. The system comprises a 256 element array driven by Verasonics Ultrasound Engine with a 1.2 kW external power source enhanced by an additional capacitor bank. The maximum pulse average acoustic power of the system was 2.2 kW (as measured by radiation force balance), sustained for 10 ms with <15% drop in amplitude. At the focus, a fully developed shock of 100 MPa amplitude formed at 275 W acoustic power. The steering range defined at -3 dB in both linear and nonlinear beam was 19 mm laterally and 38 mm axially forming the region where 100 MPa shocks can be achieved with less than twofold increase in acoustic power. Within the axial steering range, shock formation ...

Design and characterization of a research phantom for shock-wave enhanced irradiations in high intensity focused ultrasound therapy

The use of shock waves for enhancing thermal effects and mechanically ablating tissue is gaining increased attention in high intensity focused ultrasound (HIFU) therapies for applications such as tumor treatment, drug delivery, and immunotherapy. For abdominal targets, the presence of ribs and inhomogeneous adipose tissue can affect shock formation through aberration, absorption, and diffraction. The goal of this study was to design and characterize a phantom that simulates an abdominal body wall, ribs, and target tissues for investigating the impact of different structures on shock formation in situ.

MP62-07 IDENTIFICATION OF FACTORS AFFECTING IN VITRO LITHOTRIPSY EXPERIMENTS TOWARDS AN IMPROVED MODEL

INTRODUCTION AND OBJECTIVES: Extracorporeal Shock Wave Lithotripsy (SWL) is performed in only few centres across Australia including Monash Health. Currently patients fast for 2 hours prior to the procedure. On the day of procedure, bowel gas can obscure visualisation of the calculus resulting in 8% of cases being cancelled. This study aims to review whether bowel preparation or fasting for six hours prior to SWL will improve stone visualisation on the day of treatment, reduce cancellations and improve calculi clearance rates. METHODS: This is a single centre, randomised controlled trial, with ethics approval granted from Monash Health Human Research and Ethics Committee (approval number: 16324A). Patients who were selected for SWL were then consented for participation in the trial. Patients were randomly allocated to one of the three arms of the trial; 1. Two sachets of Sodium Picosulphate, 2. Six hours of fasting or 3. Fasting for two hours. Sodium Picosulphate sachets were provided by Fresenius-Kabi. Patients were included into the study if they had intrarenal calculi measuring between 8-12mm. Patients were excluded from the study, if they were over 75 years of age, had more than three medical co-morbidities or had any cardiac/renal conditions. At six weeks post SWL, all patients had a CT KUB to assess stone clearance and completed a survey on their subjective experience of the trial. Statistical analysis was performed using SPSS, t-test. RESULTS: Sixty patients were recruited in total, twenty into each of the three arms. In the bowel preparation group, there were no cancellations on the day of SWL treatment. All stones were fragmented, with one patient needing a repeat treatment for a 5mm intra-renal fragment. Of the patients who were fasting for either the six hours or the two hours, each group had two cancellations on the day of the procedure for poor visualisation of the calculus. This was a statistically significant difference of p1⁄40.03between thebowel preparationand fastinggroups.Therewere nocomplications related to thebowel preparationor fasting. Therewasno loss to follow-up. Patient satisfaction was high across all three groups, including those who received bowel preparation. CONCLUSIONS: Giving bowel preparation within twelve hours of SWL appears to be an effective method of reducing bowel gas interference and improving the calculi visualisation at the time of SWL, resulting in fewer cancellations. Fasting for extended periods of time does not seem to make a significant difference. We are in the process of recruiting more patients to the study.

Improving environmental and stone factors toward a more realistic in vitro lithotripsy model

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 <2 mm. Begostone (2:1 powder:water ratio) treated with BWL at 20°C vs. 37°C showed 75±13% vs. 62±6% breakage, respectively. Using the same stone type, gas concentrations of 60, 30, and 15% O2 showed breakage of 23±4%, 55±8%, and 82±16%, respectively. More enclosed kidney phantoms showed decreasing lithotripsy efficacy of 94±11%, 64±21%, and 13±2% breakage in basket, PVC, and anatomic phantoms, respectively. 2:1 Begostone most closely mimicked COM stone breakage. SWL exposures produced similar trends. This work indicates the importance of controlling multiple variables during in vitro lithotripsy experiments. [Work supported by NIH P01 DK043881 and K01 DK104854.]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 <2 mm. Begostone (2:1 powder:water ratio) treated with BWL at 20°C vs. 37°C showed 75±13% vs. 62±6% breakage, respectively. Using the same stone type, gas concentrations of 60, 30, and 15% O2 showed breakage of 23±4%, 55±8%, and 82±16%, respectively. More enclosed kidney phantoms showed decreasing lithotripsy effic...

A multi-element HIFU array system: Characterization and testing for manipulation of kidney stones

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...

Design of transmission-mode measurements for estimating ultrasound attenuation and nonlinearity in liver

Previously, it has been shown that ultrasound measurements of sound speed and nonlinearity can be used to quantify the fatty and non-fatty components of liver tissue. In addition, it has been proposed that ultrasound attenuation measurements can be used to distinguish fatty components comprising either sub-micron lipid droplets (microsteatosis) or much larger cell-sized droplets (macrosteatosis). To perform all of these measurements, a caliper device is being developed based on a transmission-mode approach. Design challenges are posed by competing requirements: sub-megahertz frequencies for optimal detection of microsteatosis and nonlinearity estimation based on waveform distortion over relatively short distances. To meet these challenges, a design is proposed in which ultrasound at 667 kHz is generated by a 50 mm piezoceramic disk and all measurements are made in the plane-wave regime. Given geometrical and physical constraints, all analysis was performed in the time domain. The nonlinearity coefficient ...