Timothy L. Hall

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.

Controlled ultrasound tissue erosion

The ability of ultrasound to produce highly controlled tissue erosion was investigated. This study is motivated by the need to develop a noninvasive procedure to perforate the neonatal atrial septum as the first step in treatment of hypoplastic left heart syndrome. A total of 232 holes were generated in 40 pieces of excised porcine atrial wall by a 788 kHz single-element transducer. The effects of various parameters [e.g., pulse repetition frequency (PRF), pulse duration (PD), and gas content of liquid] on the erosion rate and energy efficiency were explored. An Isppa of 9000 W/cm/sup 2/, PDs of 3, 6, 12, and 24 cycles; PRFs between 1.34 kHz and 66.7 kHz; and gas saturation of 40-55% and 79-85% were used. The results show that very short pulses delivered at certain PRFs could maximize the erosion rate and energy efficiency. We show that well-defined perforations can be precisely located in the atrial wall through the controlled ultrasound tissue erosion (CUTE) process. A preliminary in vivo experiment was conducted on a canine subject, and the atrial septum was perforated using CUTE.

Microbubble-enhanced cavitation for noninvasive ultrasound surgery

Experiments were conducted to explore the potential of stabilized microbubbles for aiding tissue ablation during ultrasound therapy. Surgically exteriorized canine kidneys were irradiated in situ using single exposures of focused ultrasound. In each experiment, tip to eight separate exposures were placed in the left kidney. The right kidney was then similarly exposed, but while an ultrasound contrast agent was continually infused. Kidneys were sectioned and examined for gross observable tissue damage. Tissue damage was produced more frequently, by lower intensity and shorter duration exposures, in kidneys irradiated with the contrast agent present. Using 250-ms exposures, the minimum intensity that produced damage was lower in kidneys with microbubbles than those without (controls) in 10 of 11 (91%) animals. In a separate study using /spl sim/3200 W/cm/sup 2/ exposures, the minimum duration that produced damage was shorter after microbubbles were introduced in 11 of 12 (92%) animals. With microbubbles, gross observable tissue damage was produced with exposure intensity /spl ges//spl sim/800 W/cm/sup 2/ and exposure duration /spl ges/10 /spl mu/s. The overall intensity and duration tissue damage thresholds were reduced by /spl sim/2/spl times/ and /spl sim/100/spl times/, respectively. Results indicate that acoustic cavitation is a primary damage mechanism. Lowering in vivo tissue damage thresholds with stabilized microbubbles acting as cavitation nuclei may make acoustic cavitation a more predictable, and thus practical, mechanism for noninvasive ultrasound surgery.

High Speed Imaging of Bubble Clouds Generated in Pulsed Ultrasound Cavitational Therapy - Histotripsy

Our recent studies have demonstrated that mechanical fractionation of tissue structure with sharply demarcated boundaries can be achieved using short (< 20 mus), high intensity ultrasound pulses delivered at low duty cycles. We have called this technique histotripsy. Histotripsy has potential clinical applications where noninvasive tissue fractionation and/or tissue removal are desired. The primary mechanism of histotripsy is thought to be acoustic cavitation, which is supported by a temporally changing acoustic backscatter observed during the histotripsy process. In this paper, a fast-gated digital camera was used to image the hypothesized cavitating bubble cloud generated by histotripsy pulses. The bubble cloud was produced at a tissue-water interface and inside an optically transparent gelatin phantom which mimics bulk tissue. The imaging shows the following: 1) Initiation of a temporally changing acoustic backscatter was due to the formation of a bubble cloud; 2) The pressure threshold to generate a bubble cloud was lower at a tissue-fluid interface than inside bulk tissue; and 3) at higher pulse pressure, the bubble cloud lasted longer and grew larger. The results add further support to the hypothesis that the histotripsy process is due to a cavitating bubble cloud and may provide insight into the sharp boundaries of histotripsy lesions.

Histotripsy: Minimally Invasive Technology for Prostatic Tissue Ablation in an In Vivo Canine Model

OBJECTIVES Symptoms of benign prostatic hyperplasia affect men increasingly as they age. Minimally invasive therapies for the treatment of benign prostatic hyperplasia continue to evolve. We describe histotripsy, a noninvasive, nonthermal, focused ultrasound technology for precise tissue ablation, and report the initial results of using histotripsy for prostatic tissue ablation in an in vivo canine model. METHODS An annular 18-element, 750-kHz, phased-array ultrasound system delivered high-intensity (22 kW/cm(2)), ultrasound pulses (15 cycles in 20 ms) at pulse repetition frequencies of 100 to 500 Hz to canine prostates. Eight lateral lobe and nine periurethral treatments were performed in 11 anesthetized dogs. Diagnostic ultrasound transducers provided in-line and transrectal imaging. Retrograde urethrography was performed before and after the periurethral treatments. After treatment, the prostates were grossly examined, sectioned, and submitted for histologic examination. RESULTS In the lateral lobe treatments, a well-demarcated cavity containing liquefied material was present at the ablation site. Microscopically, the targeted volume was characterized by the presence of histotripsy paste (debris, absent cellular structures). A narrow margin of cellular injury was noted, beyond which no tissue damage was apparent. The periurethral treatments resulted in total urethral ablation or significant urethral wall damage, with visible prostatic urethral defects on retrograde urethrography. Real-time ultrasound imaging demonstrated a dynamic hyperechoic zone at the focus, indicative of cavitation and suggesting effective tissue ablation. CONCLUSIONS The results of our study have shown that histotripsy is capable of precise prostatic tissue destruction and results in subcellular fractionation of prostate parenchyma. Histotripsy can also produce prostatic urethral damage and thereby facilitate drainage of finely fractionated material per urethra, producing immediate debulking.

Quantitative ultrasound backscatter for pulsed cavitational ultrasound therapy-histotripsy

Histotripsy is a well-controlled ultrasonic tissue ablation technology that mechanically and progressively fractionates tissue structures using cavitation. The fractionated tissue volume can be monitored with ultrasound imaging because a significant ultrasound backscatter reduction occurs. This paper correlates the ultrasound backscatter reduction with the degree of tissue fractionation characterized by the percentage of remaining normal-appearing cell nuclei on histology. Different degrees of tissue fractionation were generated in vitro in freshly excised porcine kidneys by varying the number of therapeutic ultrasound pulses from 100 to 2000 pulses per treatment location. All ultrasound pulses were 15 cycles at 1 MHz delivered at 100 Hz pulse repetition frequency and 19 MPa peak negative pressure. The results showed that the normalized backscatter intensity decreased exponentially with increasing number of pulses. Correspondingly, the percentage of normal appearing nuclei in the treated area decreased exponentially as well. A linear correlation existed between the normalized backscatter intensity and the percentage of normal appearing cell nuclei in the treated region. This suggests that the normalized backscatter intensity may be a potential quantitative real-time feedback parameter for histotripsy-induced tissue fractionation. This quantitative feedback may allow the prediction of local clinical outcomes, i.e., when a tissue volume has been sufficiently treated.

Optical and acoustic monitoring of bubble cloud dynamics at a tissue-fluid interface in ultrasound tissue erosion

Short, high-intensity ultrasound pulses have the ability to achieve localized, clearly demarcated erosion in soft tissue at a tissue-fluid interface. The primary mechanism for ultrasound tissue erosion is believed to be acoustic cavitation. To monitor the cavitating bubble cloud generated at a tissue-fluid interface, an optical attenuation method was used to record the intensity loss of transmitted light through bubbles. Optical attenuation was only detected when a bubble cloud was seen using high speed imaging. The light attenuation signals correlated well with a temporally changing acoustic backscatter which is an excellent indicator for tissue erosion. This correlation provides additional evidence that the cavitating bubble cloud is essential for ultrasound tissue erosion. The bubble cloud collapse cycle and bubble dissolution time were studied using the optical attenuation signals. The collapse cycle of the bubble cloud generated by a high intensity ultrasound pulse of 4-14 micros was approximately 40-300 micros depending on the acoustic parameters. The dissolution time of the residual bubbles was tens of ms long. This study of bubble dynamics may provide further insight into previous ultrasound tissue erosion results.

Histotripsy of the Prostate: Dose Effects in a Chronic Canine Model

OBJECTIVES To develop the technique of histotripsy ultrasound therapy as a noninvasive treatment for benign prostatic hyperplasia and to examine the histotripsy dose-tissue response effect over time to provide an insight for treatment optimization. We have previously demonstrated the feasibility of prostate histotripsy fractionation in a canine model. METHODS Various doses of histotripsy were applied transabdominally to the prostates of 20 canine subjects. Treated prostates were then harvested at interval time points from 0 to 28 days and assessed for histologic treatment response. RESULTS The lowest dose applied was found to produce only scattered cellular disruption and necrosis, whereas higher doses produced more significant regions of tissue effect that resulted in sufficient fractionation of tissue so the material could be voided with urination. Urethral tissue was more resistant to the lower histotripsy doses than was parenchymal tissue. Treatment of the urethra at the lowest doses appeared to heal, with minimal long-term sequelae. CONCLUSIONS Histotripsy was effective at fractionating parenchymal and urethral tissue in the prostate, in the presence of a sufficient dose. Further development of this technique could lead to a noninvasive method for debulking the prostate to relieve symptoms associated with benign prostatic hyperplasia.

Evolution of bubble clouds induced by pulsed cavitational ultrasound therapy - Histotripsy

Mechanical tissue fractionation can be achieved using successive, high-intensity ultrasound pulses in a process termed histotripsy. Histotripsy has many potential clinical applications where noninvasive tissue removal is desired. The primary mechanism for histotripsy is believed to be cavitation. Using fast-gated imaging, this paper studies the evolution of a cavitating bubble cloud induced by a histotripsy pulse (10 and 14 cycles) at peak negative pressures exceeding 21 MPa. Bubble clouds are generated inside a gelatin phantom and at a tissue-water interface, representing two situations encountered clinically. In both envi ronments, the imaging results show that the bubble clouds share the same evolutionary trend. The bubble cloud and individual bubbles in the cloud were generated by the first cycle of the pulse, grew with each cycle during the pulse, and continued to grow and collapsed several hundred microseconds after the pulse. For example, the bubbles started under 10 mum, grew to 50 mum during the pulse, and continued to grow > 100 mum after the pulse. The results also suggest that the bubble clouds generated in the two environments differ in growth and collapse duration, void fraction, shape, and size. This study furthers our understanding of the dynamics of bubble clouds induced by histotripsy.

A real-time measure of cavitation induced tissue disruption by ultrasound imaging backscatter reduction

A feedback method for obtaining real-time information on the mechanical disruption of tissue through ultrasound cavitation is presented. This method is based on a substantial reduction in ultrasound imaging backscatter from the target volume as the tissue structure is broken down. Ex-vivo samples of porcine liver were exposed to successive high-intensity ultrasound pulses at a low duty cycle to induce mechanical disruption of tissue parenchyma through cavitation (referred to as histotripsy). At the conclusion of treatment, B-scan imaging backscatter was observed to have decreased by 22.4 plusmn 2.3 dB in the target location. Treated samples of tissue were found to contain disrupted tissue corresponding to the imaged hypoechoic volume with no remaining discernable structure and a sharp boundary. The observed, substantial backscatter reduction may be an effective feedback mechanism for assessing treatment efficacy in ultrasound surgery using pulsed ultrasound to create cavitation