Kimberly Ives

Pulsed cavitational ultrasound: a noninvasive technology for controlled tissue ablation (histotripsy) in the rabbit kidney.

PURPOSE The optimal minimally invasive treatment for small renal masses continues to evolve. Current ablative technologies rely on thermal mechanisms for tissue destruction. However, the creation of precise lesions is limited by inhomogeneous heating/cooling due to tissue variability, perfusion effects and tissue charring. We hypothesized that nonthermal mechanical effects of ultrasound (cavitation) can be used to progressively homogenize tissue in controlled fashion with predictable results. MATERIALS AND METHODS We developed a focused annular array ultrasound system capable of delivering high intensity (greater than 20 kW/cm) short pulses (20 microseconds) of energy to a target volume. This system operates at a repetition frequency of 100 Hz, resulting in a low time averaged power output (approximately 5 W total acoustic output). Following approval from the institutional animal care committee a series of transcutaneous ablations were performed in the normal kidneys of 10 rabbits. RESULTS Lesions created with a small number of pulses (10 or 100) produced scattered areas of damage characterized by focal hemorrhage and small areas of cellular injury in the targeted volume. Lesions created with greater numbers of pulses (1,000 or 10,000) demonstrated complete destruction of the targeted volume. Gross examination revealed that lesions contained a liquefied core with smooth walls and sharply demarcated boundaries. Histological examination demonstrated extensive areas of acellular debris surrounded by a narrow margin of cellular injury. CONCLUSIONS This pulsed cavitational ultrasound system is capable of transcutaneous nonthermal destruction of renal tissue. Refinement of this technology for noninvasive ablation of small renal masses is currently under way.

Initial Investigation of Acoustic Droplet Vaporization for Occlusion in Canine Kidney

Acoustic droplet vaporization (ADV) shows promise for spatially and temporally targeted tissue occlusion. In this study, substantial tissue occlusion was achieved in operatively exposed and transcutaneous canine kidneys by generating ADV gas bubbles in the renal arteries or segmental arteries. Fifteen canines were anesthetized, among which 10 underwent laparotomy to externalize the left kidney and five were undisturbed for transcutaneous ADV. The microbubbles were generated by phase conversion of perfluoropentane droplets encapsulated in albumin or lipid shells in the blood. A 3.5-MHz single-element therapy transducer was aligned with an imaging array in a water tank with direct access to the renal artery or a segmental artery. In vivo color flow and spectral Doppler imaging were used to identify the target arteries. Tone bursts of 1 kHz pulse repetition frequency with 0.25% duty cycle vaporized the droplets during bolus passage. Both intracardiac (IC) and intravenous (IV) injections repeatedly produced ADV in chosen arteries in externalized kidneys, as seen by B-mode imaging. Concurrent with this in two cases was the detection by pulse-wave Doppler of blood flow reversal, along with a narrowing of the waveform. Localized cortex occlusion was achieved with 87% regional flow reduction in one case using IC injections. Vaporization from IV injections resulted in a substantial echogenicity increase with an average half-life of 8 min per droplet dose. Gas bubbles sufficient to produce some shadowing were generated by transcutaneous vaporization of intrarenal artery or IV-administered droplets, with a tissue path up to 5.5 cm.

Acoustic droplet vaporization for temporal and spatial control of tissue occlusion: a kidney study

Acoustic droplet vaporization (ADV) has been introduced with the potential application of tumor treatment via occlusion and subsequent necrosis. New Zealand White rabbits were anesthetized, and their left kidney was externalized. An imaging array and single-element transducer were positioned in a tank with direct access to the kidneys vasculature and renal artery. Filtered droplet emulsions (diameter < 6 /spl mu/m) were injected intra-arterially (IA) into the left heart during insonification of the renal artery, and the extent of blood flow reduction by ADV was compared to the untreated right kidney. Flow cytometry (using colored microspheres) of kidney tissue samples and reference blood from the femoral artery allowed the quantitative estimation of regional blood flow. A maximum regional blood flow reduction in the treated region of >90% and an average organ perfusion reduction of >70% was achieved using ADV. After treatment of the left kidney, the control kidney on the contralateral side showed a maximum decrease in regional blood flow of 18% relative to the pre-ADV baseline. Image-based hyper-echogenicity from ADV of IA injections was monitored for approximately 90 minutes, and cortex perfusion was reduced by >60% of its original value for more than 1 hour. This could be enough time for the onset of cell death and possible tumor treatment via ischemic necrosis. Moreover, currently used radiofrequency tissue ablation-based tumor treatment could benefit from ADV due to the decreased heat loss via vascular cooling.

Noninvasive Treatment of Deep Venous Thrombosis Using Pulsed Ultrasound Cavitation Therapy (Histotripsy) in a Porcine Model

PURPOSE This study evaluated histotripsy as a noninvasive, image-guided method of thrombolysis in a porcine model of deep vein thrombosis. Histotripsy therapy uses short, high-intensity, focused ultrasound pulses to cause mechanical breakdown of targeted soft tissue by acoustic cavitation, which is guided by real-time ultrasound imaging. This is an in vivo feasibility study of histotripsy thrombolysis. METHODS AND MATERIALS Acute thrombi were formed in the femoral vein of juvenile pigs weighing 30-40 kg by balloon occlusion with two catheters and thrombin infusion. A 10-cm-diameter 1-MHz focused transducer was used for therapy. An 8-MHz ultrasound imager was used to align the clot with the therapy focus. Therapy consisted of five cycle pulses delivered at a rate of 1 kHz and peak negative pressure between 14 and 19 MPa. The focus was scanned along the long axis of the vessel to treat the entire visible clot during ultrasound exposure. The targeted region identified by a hyperechoic cavitation bubble cloud was visualized via ultrasound during treatment. RESULTS Thrombus breakdown was apparent as a decrease in echogenicity within the vessel in 10 of 12 cases and in 7 cases improved flow through the vein as measured by color Doppler. Vessel histology found denudation of vascular endothelium and small pockets of hemorrhage in the vessel adventitia and underlying muscle and fatty tissue, but perforation of the vessel wall was never observed. CONCLUSIONS The results indicate histotripsy has potential for development as a noninvasive treatment for deep vein thrombosis.

Image-Guided Non-Invasive Ultrasound Liver Ablation Using Histotripsy: Feasibility Study in an In Vivo Porcine Model

Hepatocellular carcinoma is one of the fastest growing cancers worldwide. Histotripsy is a non-invasive ablation method that fractionates soft tissue through the control of acoustic cavitation. In this study, we demonstrate the feasibility of using histotripsy for non-invasive liver ablation. Fourteen ~1cm3 lesions were created in the livers of eight pigs through the intact chest in vivo without using aberration correction. Complete fractionation of liver parenchyma was observed with <;500 μm sharp boundaries. In addition, two larger volumes of 18 cm3 and 60 cm3 were generated within 60 minutes. Histotripsy liver fractionation was self-limited at the boundaries of critical structures including the gallbladder and major vessels. The liver surrounding major vessels was completely fractionated while the vessels remained intact. This work demonstrates that histotripsy is capable of noninvasively fractionating liver tissue while preserving critical anatomical structures within the liver. Results suggest histotripsy has potential for the non-invasive ablation of liver tumors.

Therapeutic Ultrasound to Noninvasively Create Intracardiac Communications in an Intact Animal Model

Objective: To determine if pulsed cavitational ultrasound therapy (histotripsy) can accurately and safely generate ventricular septal defects (VSDs) through the intact chest of a neonatal animal, with the eventual goal of developing a noninvasive technique of creating intra‐cardiac communications in patients with congenital heart disease. Background: Histotripsy is an innovative ultrasonic technique that generates demarcated, mechanical tissue fractionation utilizing high intensity ultrasound pulses. Previous work has shown that histotripsy can create atrial septal defects in a beating heart in an open‐chest canine model. Methods: Nine neonatal pigs were treated with transcutaneous histotripsy targeting the ventricular septum. Ultrasound pulses of 5‐μsec duration at a peak negative pressure of 13 MPa and a pulse repetition frequency of 1 kHz were generated by a 1 MHz focused transducer. The procedure was guided by real‐time ultrasound imaging. Results: VSDs were created in all pigs with diameters ranging from 2 to 6.5 mm. Six pigs were euthanized within 2 hrs of treatment, while three were recovered and maintained for 2–3 days to evaluate lesion maturation and clinical side effects. There were only transient clinical effects and pathology revealed mild collateral damage around the VSD with no significant damage to other cardiac or extra‐cardiac structures. Conclusions: Histotripsy can accurately and safely generate VSDs through the intact chest in a neonatal animal model. These results suggest that with further advances, histotripsy can be a useful, noninvasive technique to create intracardiac communications, which currently require invasive catheter‐based or surgical procedures, to clinically stabilize newborn infants with complex congenital heart disease.

Non-invasive pulsed cavitational ultrasound for fetal tissue ablation: feasibility study in a fetal sheep model

Currently available fetal intervention techniques rely on invasive procedures that carry inherent risks. A non‐invasive technique for fetal intervention could potentially reduce the risk of fetal and obstetric complications. Pulsed cavitational ultrasound therapy (histotripsy) is an ablation technique that mechanically fractionates tissue at the focal region using extracorporeal ultrasound. In this study, we investigated the feasibility of using histotripsy as a non‐invasive approach to fetal intervention in a sheep model.

A novel canine model for prostate cancer

No existing animal model fully recapitulates all features of human prostate cancer. The dog is the only large mammal, besides humans, that commonly develops spontaneous prostate cancer. Canine prostate cancer features many similarities with its human counterpart. We sought to develop a canine model of prostate cancer that would more fully represent the features of human prostate cancer than existing models.

Histotripsy Effects on the Bladder Trigone: Functional and Histologic Consequences in the Canine Model

BACKGROUND Histotripsy is an extracorporeal therapeutic ultrasound (US) technology, where high-amplitude acoustic energy is applied to targeted tissue. Previous research has demonstrated the feasibility, safety, and effectiveness of histotripsy tissue homogenization and debulking of the prostate in the canine model. Before translating this technology for human use, it is prudent to examine the susceptibility of critical periprostatic structures to cavitation injury in the event of histotripsy mistargeting. In this study, we sought to characterize the tissue effects and biologic response of directly treating the bladder trigone with histotripsy. MATERIALS AND METHODS In eight anesthetized canines, 750,000 histotripsy pulses were applied uniformly across a 2×1.5-cm area encompassing the bladder trigone and ureteral orifices. Prostate and bladder trigone were harvested immediately after treatment (2 subjects) or at 14 days (6 subjects). Flexible cystourethroscopy, US imaging, and creatinine levels were obtained at intervals until harvest, 14 days after treatment. In one control subject, harvested at 2 days, the same treatment algorithm was applied to the prostate. RESULTS Transrectal US imaging revealed a cavitation bubble cloud on the surface of the bladder trigone and progressive development of tissue edema during treatment. Flexible cystourethroscopy immediately after treatment confirmed edema and erythema of the trigone. In the six subjects survived 2 weeks after treatment, one incidence of transient, self-limited ureteral obstruction was noted based on hydronephrosis and creatinine levels. At harvest, ureteral orifices were confirmed patent by passage of a guide wire. Histologic evaluation revealed hemorrhage acutely with mild localized fibrosis at 14 days. CONCLUSIONS In this study, designed along the lines of a worst-case, destructive testing scenario, direct targeting of the bladder trigone with supratherapeutic histotripsy failed to induce significant tissue damage or clinical complication. These results are reassuring and will guide treatment strategy in upcoming human clinical trials of histotripsy treatment for benign prostatic hyperplasia.

Histotripsy for the treatment of BPH: evaluation in a chronic canine model

Histotripsy was evaluated as a non-invasive BPH treatment. The prostates of 20 canine subjects were targeted with one of three histotripsy doses. Prostates were harvested immediately, 7 days, or 28 days after treatment and assessed for changes. Lower treatment doses were found to produced scattered cellular disruption and hemorrhage that was sometimes reversible. Higher doses perforated the urethra and produced cavities in the glandular prostate that healed to leave an enlarged urinary channel.