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When histotripsy pulses shorter than 2 cycles are applied, the formation of a dense bubble cloud relies only on the applied peak negative pressure (p-) exceeding the "intrinsic threshold" of the medium (absolute value of 26-30 MPa in most soft tissues). It has been found that a sub-threshold high-frequency probe pulse (3 MHz) can be enabled by a sub-threshold low-frequency pump pulse (500 kHz) where the sum exceeds the intrinsic threshold, thus generating lesion-producing dense bubble clouds ("dual-beam histotripsy"). Here, the feasibility of using an imaging transducer to provide the high-frequency probe pulse in the dual-beam histotripsy approach is investigated. More specifically, an ATL L7-4 imaging transducer (Philips Healthcare, Andover, MA, USA), pulsed by a V-1 Data Acquisition System (Verasonics, Redmond, WA, USA), was used to generate the high-frequency probe pulses. The low-frequency pump pulses were generated by a 20-element 345-kHz array transducer, driven by a custom high-voltage pulser. These dual-beam histotripsy pulses were applied to red blood cell tissue-mimicking phantoms at a pulse repetition frequency of 1 Hz, and optical imaging was used to visualize bubble clouds and lesions generated in the red blood cell phantoms. The results indicated that dense bubble clouds (and resulting lesions) were generated when the p- of the sub-threshold pump and probe pulses combined constructively to exceed the intrinsic threshold. The average size of the smallest reproducible lesions using the imaging probe pulse enabled by the sub-threshold pump pulse was 0.7 × 1.7 mm, whereas that using the supra-threshold pump pulse alone was 1.4 × 3.7 mm. When the imaging transducer was steered laterally, bubble clouds and lesions were steered correspondingly until the combined p- no longer exceeded the intrinsic threshold. These results were also validated with ex vivo porcine liver experiments. Using an imaging transducer for dual-beam histotripsy can have two advantages: (i) lesion steering can be achieved using the steering of the imaging transducer (implemented with the beamformer of the accompanying programmable ultrasound system), and (ii) treatment can be simultaneously monitored when the imaging transducer is used in conjunction with an ultrasound imaging system., (Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Rapid prototyping (RP) fabrication techniques are currently widely used in diverse industrial and medical fields, providing substantial advantages in development time and costs in comparison to more traditional manufacturing processes. This paper presents a new method for the fabrication of high-intensity focused ultrasound transducers using RP technology. The construction of a large-aperture hemispherical transducer designed by computer software is described to demonstrate the process. The transducer was conceived as a modular design consisting of 32 individually focused 50.8-mm (2-in) PZT-8 element modules distributed in a 300-mm hemispherical scaffold with a geometric focus of 150 mm. The entire structure of the array, including the module housings and the hemispherical scaffold was fabricated through a stereolithography (SLA) system using a proprietary photopolymer. The PZT elements were bonded to the lenses through a quarter-wave tungsten-epoxy matching layer developed in-house specifically for this purpose. Modules constructed in this manner displayed a high degree of electroacoustic consistency, with an electrical impedance mean and standard deviation of 109 ± 10.2 Ω for the 32 elements. Time-of-flight measurements for individually pulsed modules mounted on the hemispherical scaffold showed that all pulses arrived at the focus within a 350 ns range, indicating a good degree of element alignment. Pressure profile measurements of the fully assembled transducer also showed close agreement with simulated results. The measured focal beam FWHM dimensions were 1.9 × 4.0 mm (1.9 × 3.9 mm simulated) in the transversal and axial directions respectively. Total material expenses associated with the construction of the transducer were approximately 5000 USD (as of 2011). The versatility and lower fabrication costs afforded by RP methods may be beneficial in the development of complex transducer geometries suitable for a variety of research and clinical applications.

Histotripsy produces tissue fractionation through dense energetic bubble clouds generated by short, high-pressure, ultrasound pulses. When using pulses shorter than 2 cycles, the generation of these energetic bubble clouds only depends on where the peak negative pressure (P-) exceeds the intrinsic threshold of the medium (26 to 30 MPa in soft tissue with high water content). This paper investigates a strategic method for precise lesion generation in which a low-frequency pump pulse is applied to enable a sub-threshold high-frequency probe pulse to exceed the intrinsic threshold. This pump-probe method of controlling a supra-threshold volume can be called dual-beam histotripsy. A 20-element dual-frequency (500-kHz and 3-MHz elements confocally aligned) array transducer was used to generate dual-beam histotripsy pulses in red blood cell phantoms and porcine hepatic tissue specimens. The results showed that when sub-intrinsic-threshold pump (500-kHz) and probe (3-MHz) pulses were applied together, dense bubble clouds (and resulting lesions) were only generated when their peak negative pressures combined constructively to exceed the intrinsic threshold. The smallest reproducible lesion varied with the relative amplitude between the pump and probe pulses, and, with a higher proportion of the probe pulse, smaller lesions could be generated. When the propagation direction of the probe pulse relative to the pump pulse was altered, the shape of the produced lesion changed based on the region that exceeded intrinsic threshold. Because the low-frequency pump pulse is more immune to attenuation and aberrations, and the high-frequency probe pulse can provide precision in lesion formation, this dual-beam histotripsy approach would be very useful in situations in which precise lesion formation is required through a highly attenuative and aberrative medium, such as transcranial therapy. This is particularly true if a small low-attenuation acoustic window is available for the high-frequency probe transducer.

Histotripsy is an ultrasound ablation method that depends on the initiation of a dense cavitation bubble cloud to fractionate soft tissue. Previous work has demonstrated that a cavitation cloud can be formed by a single acoustic pulse with one high-amplitude negative cycle, when the negative pressure amplitude exceeds a threshold intrinsic to the medium. The intrinsic thresholds in soft tissues and tissue phantoms that are water based are similar to the intrinsic threshold of water over an experimentally verified frequency range of 0.3–3 MHz. Previous work studying the histotripsy intrinsic threshold has been limited to experiments performed at room temperature (~20°C). In this study, we investigate the effects of temperature on the histotripsy intrinsic threshold in water, which is essential to accurately predict the intrinsic thresholds expected over the full range of in vivo therapeutic temperatures. Based on previous work studying the histotripsy intrinsic threshold and classical nucleation theory, we hypothesize that the intrinsic threshold will decrease with increasing temperature. To test this hypothesis, the intrinsic threshold in water was investigated both experimentally and theoretically. The probability of generating cavitation bubbles was measured by applying a single pulse with one high-amplitude negative cycle at 1 MHz to distilled degassed water at temperatures ranging from 10 °C to 90 °C. Cavitation was detected and characterized by passive cavitation detection and high-speed photography, from which the probability of cavitation was measured versus pressure amplitude. The results indicate that the intrinsic threshold (the negative pressure at which the cavitation probability $=\,0.5$ ) significantly decreases with increasing temperature, showing a nearly linear decreasing trend from 29.8 ± 0.4 MPa at 10 °C to 14.9±1.4 MPa at 90 °C. Overall, the results of this study support our hypothesis that the intrinsic threshold is highly dependent on the temperature of the medium, which may allow for better predictions of cavitation generation at body temperature in vivo and at the elevated temperatures commonly seen in high-intensity focused ultrasound regimes. [ABSTRACT FROM PUBLISHER]

In diagnostic ultrasound, broadband transducers capable of short acoustic pulse emission and reception can improve axial resolution and provide sufficient bandwidth for harmonic imaging and multi-frequency excitation techniques. In histotripsy, a cavitation-based ultrasound therapy, short acoustic pulses (<2 cycles) can produce precise tissue ablation wherein lesion formation only occurs when the applied peak negative pressure exceeds an intrinsic threshold of the medium. This paper investigates a frequency compounding technique to synthesize nearly monopolar (half-cycle) ultrasound pulses. More specifically, these pulses were generated using a custom transducer composed of 23 individual relatively-broadband piezoceramic elements with various resonant frequencies (0.5, 1, 1.5, 2, and 3 MHz). Each frequency component of the transducer was capable of generating 1.5-cycle pulses with only one high-amplitude negative half-cycle using a custom 23-channel high-voltage pulser. By varying time delays of individual frequency components to allow their principal peak negative peaks to arrive at the focus of the transducer constructively, destructive interference occurs elsewhere in time and space, resulting in a monopolar pulse approximation with a dominant negative phase (with measured peak negative pressure [P?]: peak positive pressure [P+] = 4.68: 1). By inverting the excitation pulses to individual elements, monopolar pulses with a dominant positive phase can also be generated (with measured P+: P? = 4.74: 1). Experiments in RBC phantoms indicated that monopolar pulses with a dominant negative phase were able to produce very precise histotripsy-type lesions using the intrinsic threshold mechanism. Monopolar pulses with a dominant negative phase can inhibit shock scattering during histotripsy, leading to more predictable lesion formation using the intrinsic threshold mechanism, while greatly reducing any constructive interference, and potential hot-spots elsewhere. Moreover, these monopolar pulses could have many potential benefits in ultrasound imaging, including axial resolution improvement, speckle reduction, and contrast enhancement in pulse inversion imaging. [ABSTRACT FROM AUTHOR]