For medical applications of ultrasound inside the brain, it is necessary to understand the relationship between the apparent density of skull bone and its corresponding speed of sound and attenuation coefficient. Although there have been previous studies exploring this phenomenon, there is still a need to extend the measurements to cover more of the clinically relevant frequency range. The results of measurements of the longitudinal speed of sound and attenuation coefficient are presented for specimens of human calvaria. The study was performed for the frequencies of 0.27, 0.836, 1.402, 1.965 and 2.525 MHz. Specimens were obtained from fresh cadavers through a protocol with the Division of Anatomy of the University of Toronto. The protocol was approved by the Research Ethics Board of Sunnybrook Health Sciences Centre. The specimens were mounted in polycarbonate supports that were marked for stereoscopic positioning. Computer tomography (CT) scans of the skulls mounted on their supports were performed, and a three-dimensional skull surface was reconstructed. This surface was used to guide a positioning system to ensure the normal sound incidence of an acoustic signal. This signal was produced by a focused device with a diameter of 5 cm and a focal length of 10 cm. Measurements of delay in time of flight were carried out using a needle hydrophone. Measurements of effective transmitted energy were carried out using a radiation force method with a 10 μg resolution scale. Preliminary functions of speed of sound and attenuation coefficient, both of which are related to apparent density, were established using a multi-layer propagation model that takes into account speed of sound, density and thickness of the layer. An optimization process was executed from a large set of random functions and the best functions were chosen for those ones that closest reproduced the experimental observations. The final functions were obtained after a second pass of the optimization process was executed, but this time using a finite-difference time-difference solution of the Westervelt equation, which is more precise than the multi-layer model but much more time consuming for computation. For six of seven specimens, measurements were carried out on five locations on the calvaria, and for the other specimen three measurements were made. In total, measurements were carried out on 33 locations. Results indicated the presence of dispersion effects and that these effects are different according to the type of bone in the skull (cortical and trabecular). Additionally, both the speed of sound and attenuation showed dependence on the skull density that varied with the frequency. Using the optimal functions and the information of density from the CT scans, the average values (±s.d.) of the speed of sound for cortical bone were estimated to be 2384(±130), 2471(±90), 2504(±120), 2327(±90) and 2053(±40) m s−1 for the frequencies of 270, 836, 1402, 1965 and 2526 kHz, respectively. For trabecular bone, and in the same order of frequency values, the sp...

Ultrasonography is a safe, inexpensive and wide-spread diagnostic tool capable of producing real-time non-invasive images without significant biological effects. However, the propagation of higher energy, intensity and frequency ultrasound waves through living tissues can induce thermal, mechanical and chemical effects useful for a variety of therapeutic applications. With the recent development of clinically approved High Intensity Focused Ultrasound (HIFU) systems, therapeutic ultrasound is now a medical reality.  Indeed, HIFU has been used for the thermal ablation of pathological lesions; localized, minimally invasive ultrasound-mediated drug delivery through the transient formation of pores on cell membranes; the temporary disruption of skin and the blood brain barrier; the ultrasound induced break-down of blood clots; and the targeted release of drugs using ultrasound and temperature sensitive drug carriers. This review seeks to engage the pharmaceutical research community by providing an overview on the biological effects of ultrasound as well as highlighting important therapeutic applications, current deficiencies and future directions.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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A better understanding of ultrasound transmission through human skull is fundamental to develop optimal imaging and therapeutic applications. In this study, we present global attenuation values and functions that correlate apparent density calculated from computed tomography (CT) scans to shear speed of sound. For this purpose, we used a model for sound propagation based on the viscoelastic wave equation (VWE) assuming isotropic conditions. The model was validated using a series of measurements with plates of different plastic materials and angles of incidence of 0°, 15° and 50°. The optimal functions for transcranial ultrasound propagation were established using the VWE, scan measurements of transcranial propagation with an angle of incidence of 40° and a genetic optimization algorithm. Ten (10) locations over three (3) skulls were used for ultrasound frequencies of 270 kHz and 836 kHz. Results with plastic materials demonstrated that the viscoelastic modeling predicted both longitudinal and shear propagation with an average (± s.d.) error of 9(±7)% of the wavelength in the predicted delay and an error of 6.7(±5)% in the estimation of transmitted power. Using the new optimal functions of speed of sound and global attenuation for the human skull, the proposed model predicted the transcranial ultrasound transmission for a frequency of 270 kHz with an expected error in the predicted delay of 5(±2.7)% of the wavelength. The sound propagation model predicted accurately sound propagation regardless either shear or longitudinal sound transmission dominated. For 836 kHz, the model predicted accurately in average with an error in the predicted delay of 17(±16)% of the wavelength. Results indicated the high importance of the specificity of the information at a voxel level to better understand ultrasound transmission through the skull. These results and new model will be very valuable tools for the future development of transcranial applications of ultrasound therapy and imaging.

The accuracy of high-intensity focused ultrasound (HIFU) lesion prediction modelling was evaluated for a truncated spherical transducer designed for prostate cancer treatment The modelling adapted the bio heat transfer equation (BHTE) to take into account the activity of cavitation bubbles generated during HIFU exposure. This modelling was used to predict the lesions produced by three different transducer geometries: fixed-focus, concentric-ring and 1.5D phased-array. Lesions were predicted for different ultrasound exposure conditions close to those used in prostate cancer treatment. Twenty-one in vitro and nine in vitro experiments were performed on pig liver to validate the accuracy of the predictions. A good match was found between the predicted and experimental lesion shapes. Lesion dimensions (maximum depth and length, area at the centre of the lesion or central surface area) were measured on experimental and predicted lesions. The central surface area was predicted by the model with a range of error of 0.15-6.5% for in vitro tests and 0.97-9% in vivo. For comparison, BHTE without bubbles had a range of error of 0.4-55.5% (in vitro) and 9-25.5% (in vivo). The model should be accurate enough to predict HIFU lesions under ultrasound exposure conditions used in prostate cancer treatment.

Shear mode transmission through the skull has been previously proposed as a new trans-skull propagation technique for noninvasive therapeutic ultrasound (Clement 2004 J. Acoust. Soc. Am. 115 1356-64). The main advantage of choosing shear over longitudinal mode resides on the fact that there is less wavefront distortion with the former. In the present study, the regions of the brain suitable for shear-mode transmission were established for a simple focused ultrasound device. The device consists of a spherically curved transducer that has a focal length of 10 cm, an aperture between 30 degrees and 60 degrees and operates at 0.74 MHz. The regions suitable for shear-mode transmission were determined by the shear wave acoustic windows that matched the shape of the device acoustic field. The acoustic windows were calculated using segmentation and triangulation of outer and inner faces of skull from 3D-MRI head datasets. Nine heads of healthy adults were analyzed. The surface considered for the calculations was the head region found above the supra-orbital margin. For every inspected point in the brain volume, the axis of the device was determined by the vector between this inspection point and a point located in the center of the brain. Numerical predictions of the acoustic field, where shear-mode conversion through the skull was considered, were obtained and compared to the case of water-only conditions. The brain tissue that is close to the skull showed suitable acoustic windows for shear waves. The central region of the brain seems to be unreachable using shear-mode. Analysis of the acoustic fields showed a proportional relation between the acoustic window for shear mode and the effective degree of focusing. However, this relation showed significant differences among specimens. In general, highly focused fields were obtained when the acoustic window for shear waves (A(SW)) intersected more than 67% of the entering acoustic window (A(TX)) of the device. The average depth from the inner surface of the skull showing this intersection value was 13 +/- 10 mm (mean +/- SD). The differences of the degree of focusing observed among patients suggest that the intersection A(SW) intersection A(TX) can be used as a preliminary criterion for screening and calculation of the acoustic fields should confirm the degree of focusing patient by patient. In conclusion, shear waves provide a useful method for trans-cranial focusing in regions close to the skull surface.

High-risk types of human papillomavirus (HPV), such as HPV16, have been found in nearly all cases of cervical cancer. Therapies targeted at blocking the HPV16 E6 protein and its deleterious effects on the tumour suppressor pathways of the cell can reverse the malignant phenotype of affected keratinocytes while sparing uninfected cells. Through a strong interdisciplinary collaboration between engineering and biology, a novel, non-invasive intracellular delivery method for the HPV16 E6 antibody, F127-6G6, was developed. The method employs high intensity focused ultrasound (HIFU) in combination with microbubbles, in a process known as sonoporation. In this proof of principle study, it was first demonstrated that sonoporation antibody delivery into the HPV16 positive cervical carcinoma derived cell lines CaSki and SiHa was possible, using chemical transfection as a baseline for comparison. Delivery of the E6 antibody using sonoporation significantly restored p53 expression in these cells, indicating the antibody is able to enter the cells and remains active. This delivery method is targeted, non-cytotoxic, and non-invasive, making it more easily translatable for in vivo experiments than other transfection methods.

This paper presents a practical implementation of an integrated MRI-compatible CMOS amplifier capable of directly driving a piezoelectric ultrasound transducer suitable for high-intensity focused ultrasound (HIFU) therapy. The amplifier operates in Class DE mode without the need for an output matching network. The integrated amplifier has been implemented with the AMS AG H35 CMOS process. A class DE amplifier design methodology for driving unmatched piezoelectric loads is presented along with simulation and experimental results. The proposed design achieves approximately 90% efficiency with over 800 mW of output power at 1010 kHz. The total die area including pads is 2 mm(2). Compatibility with MRI was validated with B1 imaging of a phantom and the amplifier circuit.