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In the context of developing boiling histotripsy (BH) as a potential clinical approach for non-invasive mechanical ablation of kidney tumors, the concept of BH dose (BHD) was quantitatively investigated in porcine and canine kidney models in vivo and ex vivo. Volumetric lesions were produced in renal tissue using a 1.5-MHz 256-element HIFU-array with various pulsing protocols: pulse duration t p = 1–10 ms, number of pulses per point ppp = 1–15. Two BHD metrics were evaluated: BHD1 = ppp, BHD2 = t p × ppp. Quantitative assessment of lesion completeness was performed by their histological analysis and assignment of damage score to different renal compartments (i.e., cortex, medulla, and sinus). Shear wave elastography (SWE) was used to measure the Young's modulus of renal compartments in vivo vs ex vivo , and before vs after BH treatments. In vivo tissue required lower BH doses to achieve identical degree of fractionation as compared to ex vivo. Renal cortex (homogeneous, low in collagen) was equal or higher in stiffness than medulla (anisotropic, collagenous), 5.8–12.2 kPa vs 4.7–9.6 kPa, but required lower BH doses to be fully fractionated. Renal sinus (fatty, irregular, with abundant collagenous structures) was significantly softer ex vivo vs in vivo , 4.9–5.1 kPa vs 9.7–15.2 kPa, but was barely damaged in either case with any tested BH protocols. BHD1 was shown to be relevant for planning the treatment of renal cortex (sufficient BHD1 = 5 pulses in vivo and 10 pulses ex vivo), while none of the tested doses resulted in complete fractionation of medulla or sinus. Post-treatment SWE imaging revealed reduction of tissue stiffness ex vivo by 27–58%, increasing with the applied dose, and complete absence of shear waves within in vivo lesions, both indicative of tissue liquefaction. The results imply that tissue resistance to mechanical fractionation, and hence required BH dose, are not solely determined by tissue stiffness but also depend on its composition and structural arrangement, as well as presence of perfusion. The SWE-derived reduction of tissue stiffness with increasing BH doses correlated with tissue damage score, indicating potential of SWE for post-treatment confirmation of BH lesion completeness. [ABSTRACT FROM AUTHOR]

Sonodynamic therapy (SDT) is currently considered as one of the promising minimally invasive treatment options for solid cancers. SDT is based on the combined use of a sonosensitizer drug and high-intensity focused ultrasound (HIFU) to produce cytotoxic reactive oxygen species (ROS) in and around neoplastic cells. Anthracycline drugs, including epirubicin (EPI), have been well known as effective sonosensitizers after interaction with focused ultrasound. Recently a new anticancer drug delivery system (DDS), NC-6300, has been developed that comprises EPI through an acid-labile hydrazone bond. In previous in vivo studies, NC-6300 showed basic drug safety and an excellent concentration property of EPI, and recently has been tested in clinical trials. For realizing minimally invasive cancer treatment, the present study demonstrated the effectiveness and feasibility of DDS-based SDT, which combined a small dose of NC-6300 and low energy of HIFU in mouse models of colon cancer and pancreatic cancer. [ABSTRACT FROM AUTHOR]

Intra- and extra-muscular hematomas result from repetitive injury as well as sharp and blunt limb trauma. The clinical consequences can be serious, including debilitating pain and functional deficit. There are currently no short-term treatment options for large hematomas, only lengthy conservative treatment. The goal of this work was to evaluate the feasibility of a high intensity focused ultrasound (HIFU)-based technique, termed histotripsy, for rapid (within a clinically relevant timeframe of 15-20 min) liquefaction of large volume (up to 20 mL) extra-vascular hematomas for subsequent fine-needle aspiration. Experiments were performed using in vitro extravascular hematoma phantoms-fresh bovine blood poured into 50 mL molds and allowed to clot. The resulting phantoms were treated by boiling histotripsy (BH), cavitation histotripsy (CH) or a combination in a degassed water tank under ultrasound guidance. Two different transducers operating at 1 MHz and 1.5 MHz with f-number = 1 were used. The liquefied lysate was aspirated and analyzed by histology and sized in a Coulter Counter. The peak instantaneous power to achieve BH was lower than (at 1.5 MHz) or equal to (at 1 MHz) that which was required to initiate CH. Under the same exposure duration, BH-induced cavities were one and a half to two times larger than the CH-induced cavities, but the CH-induced cavities were more regularly shaped, facilitating easier aspiration. The lysates contained a small amount of debris larger than 70 μm, and 99% of particulates were smaller than 10 μm. A combination treatment of BH (for initial debulking) and CH (for liquefaction of small residual fragments) yielded 20 mL of lysate within 17.5 minutes of treatment and was found to be most optimal for liquefaction of large extravascular hematomas. [ABSTRACT FROM AUTHOR]

Abstract: An optically transparent tissue-mimicking (TM) phantom whose acoustic properties are close to those of tissue was constructed for visualizing therapeutic effects by high intensity focused ultrasound (HIFU). The TM phantom was designed to improve a widely used standard bovine serum albumin (BSA) polyacrylamide hydrogel (PAG), which attenuated ultrasound far less than tissue and, unlike tissue, did not scatter ultrasound. A modified recipe has been proposed in the study by adding scattering glass beads with diameters of 40–80 μm (0.002% w/v) and by raising the concentration of acrylamide (30% v/v). The TM BSA-PAG constructed has an acoustic impedance of 1.67 MRayls, a speed of sound of 1576 m/s, an attenuation coefficient of 0.52 dB/cm at 1 MHz, a backscattering coefficient of 0.242 × 10−3 1/sr/cm at 1 MHz and a nonlinear parameter (B/A) of 5.7. These parameters are close to those of liver. The thermal and optical properties are almost the same as the standard BSA-PAG. The characteristic features of the thermal lesions by HIFU were observed to be more accurately visualized in the TM BSA-PAG than in the standard BSA-PAG. In conclusion, the proposed TM BSA-PAG acoustically mimics tissue better than the standard BSA-PAG and is expected to be preferentially used for assuring if a clinical HIFU device produces the thermal lesion as planned. [Copyright &y& Elsevier]

Abstract: The temperature dependence of an agar/gelatin phantom was evaluated. The purpose was to predict the material property response to high-intensity focused ultrasound (HIFU) for developing ultrasound guided dosing and targeting feedback. Changes in attenuation, sound speed, shear modulus and thermal properties with temperature were examined from 20°C to 70°C for 3 weeks post-manufacture. The attenuation decreased with temperature by a power factor of 0.15. Thermal conductivity, diffusivity and specific heat all increased linearly with temperature for a total change of approximately 16%, 10% and 6%, respectively. Sound speed had a parabolic dependence on temperature similar to that of water. Initially, the shear modulus irreversibly declined with even a slight increase in temperature. Over time, the gel maintained its room temperature shear modulus with moderate heating. A stable phantom was achieved within 2 weeks post-manufacture that possessed quasi-reversible material properties up to nearly 55°C. [Copyright &y& Elsevier]

Abstract: High intensity focused ultrasound (HIFU) induced inertial cavitation has been shown to improve release and cellular uptake of drugs. The effects of magnetite nanoparticle agglomerates (290±10nm diameter), silica coated magnetite nanoparticle agglomerates (320±10nm diameter) and silica particles (320±10nm diameter) suspended in MilliQ water on the degree of inertial cavitation due to HIFU were investigated. The HIFU transducer was operated at a frequency of 1.1MHz, 1.67kHz pulse repetition frequency, with applied duty cycles (DC) between 0% and 5% and different peak negative focal pressures (PNFPs) applied up to 7.2MPa. The inertial cavitation dose (ICD: time averaged root-mean-squared broadband noise amplitude in the frequency domain) was measured in the presence and absence of nanoparticles when subjected to HIFU. Magnetite nanoparticle agglomerates caused a significant increase in the ICD above 2.7MPa PNFP compared with MilliQ water, silica coated magnetite agglomerates and silica particles. With the dramatic increase in ICD on introduction of these magnetite agglomerates, this technique could provide a method of HIFU triggered drug delivery by enhancing inertial cavitation. The superparamagnetic properties of these particles offer the possibility of magnetic targeting to the site of disease. [Copyright &y& Elsevier]

Abstract: Cloud cavitation is potentially the most destructive form of cavitation. When the cloud cavitation is acoustically forced into a collapse, it has the potential to concentrate a very high pressure, more than 100 times the acoustic pressure, at its center. We experimentally investigate a method to control the collapse of high intensity focused ultrasound (HIFU)–induced cloud cavitation to fragment kidney stones. Our study examines a novel two-frequency wave designed to control the cloud cavitation (cavitation control [C-C] waveform); a high-frequency ultrasound pulse (1 to 4 MHz) to create the cloud cavitation and a low-frequency trailing pulse (545 kHz) following the high-frequency pulse to force the cloud into collapse. High-speed photography has revealed that a localized distribution of the cloud cavitation can be produced within 1 mm on the solid surface by the high-frequency pulse. The low-frequency ultrasound was irradiated to the high-frequency–induced cloud cavitation. A subsequent shock wave emitted from the cloud cavitation was observed both in the shadowgraph photography and the remote hydrophone measurement. Furthermore, in vitro erosion tests of model and natural stones were conducted. In the case of model stones, the erosion rate of the C-C waveform showed a distinct advantage with the combined high- and low-frequency waves over either wave alone. Natural stones were eroded and most of the resulting fragments were less than 1 mm in diameter. The results show that the control of the cloud cavitation has untapped potential for the lithotripsy applications upon further optimization of the ultrasound parameters and complementary in vivo studies. (E-mail: teichiro@fel.t.u-tokyo.ac.jp) [Copyright &y& Elsevier]

Abstract: This study was conducted to demonstrate the feasibility of high intensity focused ultrasound (HIFU) application to control post-liver-biopsy hemorrhage. Anesthetized Yorkshire pigs (n = 3; mean weight = 23.0 kg) were used and the liver organ was exposed surgically by an open laparotomy. Core biopsies were performed on the hepatic parenchyma with 14-gauge (n = 41) and 18-gauge (n = 33) core biopsy needles. The focus of HIFU (4.23 MHz) field was applied for 15 to 45 s to the needle entry site in the liver immediately after needle retraction. Blood loss from a biopsy site was determined using surgical sponges as absorbent applied at the site. Mean blood loss for control sites was 6.16 g (14-gauge, n = 20) and 1.22 g (18-gauge, n = 10). Virtually no blood loss was measured for biopsies after HIFU application (n = 44) for using needles of both sizes. Our results indicate that intraoperative HIFU application could successfully induce hemostasis after liver biopsy in a porcine model. (E-mail: cheri.deng@cwru.edu) [Copyright &y& Elsevier]