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Ultrasonics, Ferroelectrics, and Frequency Control, IEEE Transactions on

Issue 1 • Date January 2013

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  • IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control - cover

    Page(s): C1
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  • IEEE Ultrasonics, Ferroelectrics, and Frequency Control Society - Administrative Committee

    Page(s): C2
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  • IEEE Ultrasonics, Ferroelectrics, and Frequency Control Society - Elected Administrative Committee

    Page(s): C3
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  • Table of contents

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  • Information for contributors

    Page(s): 1 - 4
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  • Introduction to the special issue on ultrasound contrast agents and targeted drug delivery

    Page(s): 5 - 6
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  • 20 years of ultrasound contrast agent modeling

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    The merits of ultrasound contrast agents (UCAs) were already known in the 1960s. It was, however, not until the 1990s that UCAs were clinically approved and marketed. In these years, it was realized that the UCAs are not just efficient ultrasound scatterers, but that their main constituent, the coated gas microbubble, acts as a nonlinear resonator and, as such, is capable of generating harmonic energy. Subharmonic, ultraharmonic, and higher harmonic frequencies of the transmitted ultrasound frequency have been reported. This opened up new prospects for their use and several detection strategies have been developed to exploit this harmonic energy to discriminate the contrast bubbles from surrounding tissue. This insight created a need for tools to study coated bubble behavior in an ultrasound field and the first models were developed. Since then, 20 years have elapsed, in which a broad range of UCAs and UCA models have been developed. Although the models have helped in understanding the responses of coated bubbles, the influence of the coating has not been fully elucidated to date and UCA models are still being improved. The aim of this review paper is to offer an overview in these developments and indicate future directions for research. View full abstract»

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  • Mechanisms of the ultrasound-mediated intracellular delivery of liposomes and dextrans

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    The mechanism involved in the ultrasound-enhanced intracellular delivery of fluorescein-isothiocyanate (FITC)-dextran (molecular weight 4 to 2000 kDa) and liposomes containing doxorubicin (Dox) was studied using HeLa cells and an ultrasound transducer at 300 kHz, varying the acoustic power. The cellular uptake and cell viability were measured using flow cytometry and confocal microscopy. The role of endocytosis was investigated by inhibiting clathrin- and caveolae-mediated endocytosis, as well as macropinocytosis. Microbubbles were found to be required during ultrasound treatment to obtain enhanced cellular uptake. The percentage of cells internalizing Dox and dextran increased with increasing mechanical index. Confocal images and flow cytometric analysis indicated that the liposomes were disrupted extracellularly and that released Dox was taken up by the cells. The percentage of cells internalizing dextran was independent of the molecular weight of dextrans, but the amount of the small 4-kDa dextran molecules internalized per cell was higher than for the other dextrans. The inhibition of endocytosis during ultrasound exposure resulted in a significant decrease in cellular uptake of dextrans. Therefore, the improved uptake of Dox and dextrans may be a result of both sonoporation and endocytosis. View full abstract»

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  • Observations on the viability of C6-glioma cells after sonoporation with low-intensity ultrasound and microbubbles

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    Ultrasound (US) and microbubbles can be used to facilitate cellular uptake of drugs through a cavitation-induced enhancement of cell membrane permeability. The mechanism is, however, still incompletely understood. A direct contact between microbubbles and cell membrane is thought to be essential to create membrane perturbations lasting from seconds to minutes after US exposure of the cells. A recent study showed that the effect may even last up to 8 h after cavitation (with residual permeability up to 24 h after cavitation). In view of possible membrane damage, the purpose of this study was to further investigate the evolution of cell viability in the range of the 24-h temporal window. Furthermore, a description of the functional changes in tumor cells after US exposure was initiated to obtain a better understanding of the mechanism of membrane perturbation after sonication with microbubbles. Our results suggest that US does not reduce cell viability up to 24 h post-exposure. However, a perturbation of the entire cell population exposed to US was observed in terms of enzymatic activity and characteristics of the mitochondrial membrane. Furthermore, we demonstrated that US cavitation induces a transient loss of cell membrane asymmetry, resulting in phosphatidylserine exposure in the outer leaflet of the cell membrane. View full abstract»

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  • Microbubble attenuation and destruction: are they involved in sonoporation efficiency?

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    This technical note investigates the involvement of microbubble attenuation and destruction in sonoporation mechanisms. First, we evaluate sonoporation efficiency using Vevo Micromarker, and a comparison is made with BR14 and SonoVue microbubbles. Then, the acoustical properties of the microbubbles are measured to gain insight into the sonoporation mechanisms using a green fluorescent protein as a marker. Using glioblastoma cells, an unprecedented transfection rate of 70% is reached with Vevo Micromarker, corresponding to a 1.5-fold increase compared with the rate achieved with the other microbubbles. Moreover, attenuation and destruction were shown to be two key parameters in sonoporation efficiency. View full abstract»

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  • Influence of shell properties on high-frequency ultrasound imaging and drug delivery using polymer-shelled microbubbles

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    This two-part study investigated shell rupture of ultrasound contrast agents (UCAs) under static overpressure conditions and the subharmonic component from UCAs subjected to 20-MHz tonebursts. Five different polylactide-shelled UCAs with shell-thickness-to-radius ratios (STRRs) of 7.5, 30, 40, 65, and 100 nm/¿m were subjected to static overpressure in a glycerol-filled test chamber. A video microscope imaged the UCAs as pressure varied from 2 to 330 kPa over 90 min. Images were postprocessed to obtain the pressure threshold for rupture and the diameter of individual microbubbles. Backscatter from individual UCAs was investigated by flowing a dilute UCA solution through a wall-less flow phantom placed at the geometric focus of a 20-MHz transducer. UCAs were subjected to 10- and 20-cycle tonebursts of acoustic pressures ranging from 0.3 to 2.3 MPa. A method based on singular-value decomposition (SVD) was employed to obtain a cumulative subharmonic score (SHS). Different UCA types exhibited distinctly different rupture thresholds that were linearly related to their STRR, but uncorrelated with UCA size. The rupture threshold for the UCAs with an STRR = 100 nm/μm was more than 4 times greater than the UCAs with an STRR = 7.5 nm/μm. The polymer-shelled UCAs produced substantial subharmonic response but the subharmonic response to 20- MHz excitation did not correlate with STRRs or UCA-rupture pressures. The 20-cycle excitation resulted in an SHS that was 2 to 3 times that of UCAs excited with 10-cycle tonebursts. View full abstract»

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  • Nanoparticle delivery enhancement with acoustically activated microbubbles

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    The application of microbubbles and ultrasound to deliver nanoparticle carriers for drug and gene delivery is an area that has expanded greatly in recent years. Under ultrasound exposure, microbubbles can enhance nanoparticle delivery by increasing cellular and vascular permeability. In this review, the underlying mechanisms of enhanced nanoparticle delivery with ultrasound and microbubbles and various proposed delivery techniques are discussed. Additionally, types of nanoparticles currently being investigated in preclinical studies, as well as the general limitations and benefits of a microbubble- based approach to nanoparticle delivery, are reviewed. View full abstract»

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  • Doxorubicin liposome-loaded microbubbles for contrast imaging and ultrasound-triggered drug delivery

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    Targeted drug delivery under image guidance is gaining more interest in the drug-delivery field. The use of microbubbles as contrast agents in diagnostic ultrasound provides new opportunities in noninvasive image-guided drug delivery. In the present study, the imaging and therapeutic properties of novel doxorubicin liposome-loaded microbubbles are evaluated. The results showed that at scanning settings (1.7 MHz and mechanical index 0.2), these microbubbles scatter sufficient signal for nonlinear ultrasound imaging and can thus be imaged in real time and be tracked in vivo. In vitro therapeutic evaluation showed that ultrasound at 1 MHz and pressures up to 600 kPa in combination with the doxorubicin liposomeloaded microbubbles induced 4-fold decrease of cell viability compared with treatment with free doxorubicin or doxorubicin liposome-loaded microbubbles alone. The therapeutic effectiveness is correlated to an ultrasound-triggered release of doxorubicin from the liposomes and an enhanced uptake of the free doxorubicin by glioblastoma cells. The results obtained demonstrate that the combination of ultrasound and the doxorubicin liposome-loaded microbubbles can provide a new method of noninvasive image-guided drug delivery. View full abstract»

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  • Enhanced gene expression of systemically administered plasmid DNA in the liver with therapeutic ultrasound and microbubbles

    Page(s): 88 - 96
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    Ultrasound-mediated delivery (USMD) of novel therapeutic agents in the presence of microbubbles is a potentially safe and effective method for gene therapy offering many desired characteristics, such as low toxicity, potential for repeated treatment, and organ specificity. In this study, we tested the capability of USMD to improve gene expression in mice livers using glycogen storage disease Type Ia as a model disease under systemic administration of naked plasmid DNA. Image-guided therapeutic ultrasound was used in two studies to provide therapeutic ultrasound to mice livers. In the first study, involving wild-type mice, control animals received naked plasmid DNA (pG6Pase 150 μg) via the tail vein, followed by an infusion of microbubbles; the treated animals additionally received therapeutic ultrasound (1 MHz). Following the procedure, the animals were left to recover and were subsequently euthanized after 2 d and liver samples were extracted. Reverse transcription polymerase chain reaction (RT-PCR) assays were performed on the samples to quantify mRNA expression. In addition, Western blot assays of FLAG-tagged glucose-6-phosphatase (G6Pase) were performed to evaluate protein expression. Ultrasound-exposed animals showed a 4-fold increase in G6Pase RNA in the liver, in comparison with control animals. Furthermore, results from Western blot analysis demonstrated a 2-fold increased protein expression in ultrasound-exposed animals after two days ( p <; 0.05). A second pilot study was performed with G6Pase knockout mice, and the animals were monitored for correction of hypoglycemia over a period of 3 weeks before tissue analysis. The RT-PCR assays of samples from these animals demonstrated increased G6Pase RNA in the liver following ultrasound treatment. These results demonstrate that USMD can increase gene expression of systemically injected naked pDNA in the liver and also provide insight into the development of realistic approaches that can be translate- into clinical practice. View full abstract»

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  • Combining radiation force with cavitation for enhanced sonothrombolysis

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    The use of acoustic radiation force has been suggested for enhancing the delivery of therapeutic substances, whereas sonothrombolysis has been developed for years as treatment by itself, or in combination with thrombolytic agents or ultrasound contrast agents. We have examined the efficacy of using acoustic radiation force to enhance the targeting of microbubbles in cavitation-induced sonothrombolysis in a flow phantom system. A clot was targeted by microbubbles using avidin-biotin binding, and the process was observed using a confocal microscope. We found that the experimental group in which radiation force was combined with cavitation showed an additional 3% to 9% weight reduction of the thrombus relative to the cavitation group. We also found that the fluorescence intensity of the clot increased with the microbubble concentration at each acoustic setting. Microbubbles traveled 10 to 20 μm further than the control group after being exposed to radiation force, cavitation, or both. These observations confirm that radiation force helps microbubbles to distribute into a clot (as does cavitation). Therefore, combining radiation force with cavitation would provide additional thrombolysis effects (based on clot weight measurements) relative to cavitation alone. A local delivery method based on acoustic radiation force has the potential to improve the safety and efficacy of sonothrombolysis. View full abstract»

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  • Microbubble oscillations in capillary tubes

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    In diagnostic medicine, microbubbles are used as contrast agents to image blood flow and perfusion in large and small vessels. The small vessels (the capillaries) have diameters from a few hundred micrometers down to less than 10 μm. The effect of such microvessels surrounding the oscillating microbubbles is currently unknown, and is important for increased sensitivity in contrast diagnostics and manipulation of microbubbles for localized drug release. Here, oscillations of microbubbles in tubes with inner diameters of 25 μm and 160 μm are investigated using an ultra-high-speed camera at frame rates of ~12 million frames/s. A reduction of up to 50% in the amplitude of oscillation was observed for microbubbles in the smaller 25-μm tube, compared with those in a 160-μm tube. In the 25-μm tube, at 50 kPa, a 48% increase of microbubbles that did not oscillate above the noise level of the system was observed, indicating increased oscillation damping. No difference was observed between the resonance frequency curves calculated for microbubbles in 25-μm and 160-μm tubes. Although previous investigators have shown the effect of microvessels on microbubble oscillation at high ultrasound pressures, the present study provides the first optical images of low-amplitude microbubble oscillations in small tubes. View full abstract»

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  • A square-plate ultrasonic linear motor operating in two orthogonal first bending modes

    Page(s): 115 - 120
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    A novel square-plate piezoelectric ultrasonic linear motor operated in two orthogonal first bending vibration modes (B1) is proposed. The piezoelectric vibrator of the linear motor is simply made of a single PZT ceramic plate (sizes: 15 × 15 × 2 mm) and poled in its thickness direction. The top surface electrode of the square ceramic plate was divided into four active areas along its two diagonal lines for exciting two orthogonal B1 modes. The achieved driving force and speed from the linear motor are 1.8 N and 230 mm/s, respectively, under one pair orthogonal voltage drive of 150 Vp-p at the resonance frequency of 92 kHz. The proposed linear motor has advantages over conventional ultrasonic linear motors, such as relatively larger driving force, very simple working mode and structure, and low fabrication cost. View full abstract»

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  • On the potential of galileo E5 for time transfer

    Page(s): 121 - 131
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    The main global navigation satellite systems (GNSS) technique currently used for accurate time and frequency transfer is based on an analysis of the ionosphere-free combinations of dual-frequency code and carrier phase measurements in a precise point positioning (PPP) mode. This technique analyses the observations of one GNSS station using external products for satellite clocks and orbits to determine the position and clock synchronization errors of this station. The frequency stability of this time transfer is limited by the noise and multipath of the Global Positioning System (GPS) and Globalnaya Navigatsionnaya Sputnikovaya Sistema (GLONASS) codes. In the near future, Galileo will offer a broadband signal E5, with low noise in the centimeter range and with the lowest multipath error ever observed. This paper investigates new analysis procedures based on the E5 codeplus- carrier (CPC) combination for time transfer. The CPC combination with E5 provides a noise level 10 times lower than the ionosphere-free combination of Galileo E1 and E5, which is very promising for improving GNSS time transfer performances. From some tests with simulated Galileo data, it is shown here that the use of the CPC combination with E5 does not improve, at present, the medium- and long-term stability of time transfer with respect to the ionosphere-free combination of Galileo E1 and E5 codes, because of the need for a second frequency signal to correct for the ionospheric delays and ambiguities. View full abstract»

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  • Bayesian speckle tracking. Part I: an implementable perturbation to the likelihood function for ultrasound displacement estimation

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    Accurate and precise displacement estimation has been a hallmark of clinical ultrasound. Displacement estimation accuracy has largely been considered to be limited by the Cramer-Rao lower bound (CRLB). However, the CRLB only describes the minimum variance obtainable from unbiased estimators. Unbiased estimators are generally implemented using Bayes' theorem, which requires a likelihood function. The classic likelihood function for the displacement estimation problem is not discriminative and is difficult to implement for clinically relevant ultrasound with diffuse scattering. Because the classic likelihood function is not effective, a perturbation is proposed. The proposed likelihood function was evaluated and compared against the classic likelihood function by converting both to posterior probability density functions (PDFs) using a noninformative prior. Example results are reported for bulk motion simulations using a 6λ tracking kernel and 30 dB SNR for 1000 data realizations. The canonical likelihood function assigned the true displacement a mean probability of only 0.070 ± 0.020, whereas the new likelihood function assigned the true displacement a much higher probability of 0.22 ± 0.16. The new likelihood function shows improvements at least for bulk motion, acoustic radiation force induced motion, and compressive motion, and at least for SNRs greater than 10 dB and kernel lengths between 1.5 and 12λ. View full abstract»

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  • Bayesian speckle tracking. Part II: biased ultrasound displacement estimation

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    Ultrasonic displacement estimates have numerous clinical uses, including blood flow estimation, elastography, therapeutic guidance, and acoustic radiation force imaging (ARFI). These clinical tasks could be improved with better ultrasonic displacement estimates. Traditional ultrasonic displacement estimates are limited by the Cramer-Rao lower bound (CRLB). The CRLB can be surpassed using biased estimates. In this paper, a framework for biased estimation using Bayes' theorem is described. The Bayesian displacement estimation method is tested against simulations of several common types of motion: bulk, step, compression, and acoustic-radiation-force-induced motion. Bayesian estimation is also applied to in vivo ARFI of cardiac ablation lesions. The Bayesian estimators are compared with the unbiased estimator, normalized cross-correlation. As an example, the peak displacement of the simulated acoustic radiation force response is reported because this position results in the noisiest estimates. Estimates were made with a 1.5-λ kernel and 20 dB SNR on 100 data realizations. Estimates using normalized cross-correlation and the Bayes' estimator had mean-square errors of 17 and 7.6 μm2, respectively, and contextualized by the true displacement magnitude, 10.9 μm. Biases for normalized cross-correlation and the Bayes' estimator are -0.12 and -0.28 μm, respectively. In vivo results show qualitative improvements. The results show that with small amounts of additional information, significantly improved performance can be realized. View full abstract»

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  • Fully automated segmentation and tracking of the intima media thickness in ultrasound video sequences of the common carotid artery

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    The robust identification and measurement of the intima media thickness (IMT) has a high clinical relevance because it represents one of the most precise predictors used in the assessment of potential future cardiovascular events. To facilitate the analysis of arterial wall thickening in serial clinical investigations, in this paper we have developed a novel fully automatic algorithm for the segmentation, measurement, and tracking of the intima media complex (IMC) in B-mode ultrasound video sequences. The proposed algorithm entails a two-stage image analysis process that initially addresses the segmentation of the IMC in the first frame of the ultrasound video sequence using a model-based approach; in the second step, a novel customized tracking procedure is applied to robustly detect the IMC in the subsequent frames. For the video tracking procedure, we introduce a spatially coherent algorithm called adaptive normalized correlation that prevents the tracking process from converging to wrong arterial interfaces. This represents the main contribution of this paper and was developed to deal with inconsistencies in the appearance of the IMC over the cardiac cycle. The quantitative evaluation has been carried out on 40 ultrasound video sequences of the common carotid artery (CCA) by comparing the results returned by the developed algorithm with respect to ground truth data that has been manually annotated by clinical experts. The measured IMTmean ± standard deviation recorded by the proposed algorithm is 0.60 mm ± 0.10, with a mean coefficient of variation (CV) of 2.05%, whereas the corresponding result obtained for the manually annotated ground truth data is 0.60 mm ± 0.11 with a mean CV equal to 5.60%. The numerical results reported in this paper indicate that the proposed algorithm is able to correctly segment and track the IMC in ultrasound CCA video sequences, and we were encouraged by the stability of our technique when applied - o data captured under different imaging conditions. Future clinical studies will focus on the evaluation of patients that are affected by advanced cardiovascular conditions such as focal thickening and arterial plaques. View full abstract»

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  • A flexible annular-array imaging platform for micro-ultrasound

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    Micro-ultrasound is an invaluable imaging tool for many clinical and preclinical applications requiring high resolution (approximately several tens of micrometers). Imaging systems for micro-ultrasound, including single-element imaging systems and linear-array imaging systems, have been developed extensively in recent years. Single-element systems are cheaper, but linear-array systems give much better image quality at a higher expense. Annular-array-based systems provide a third alternative, striking a balance between image quality and expense. This paper presents the development of a novel programmable and real-time annular-array imaging platform for micro-ultrasound. It supports multi-channel dynamic beamforming techniques for large-depth-of-field imaging. The major image processing algorithms were achieved by a novel field-programmable gate array technology for high speed and flexibility. Real-time imaging was achieved by fast processing algorithms and high-speed data transfer interface. The platform utilizes a printed circuit board scheme incorporating state-of-the-art electronics for compactness and cost effectiveness. Extensive tests including hardware, algorithms, wire phantom, and tissue mimicking phantom measurements were conducted to demonstrate good performance of the platform. The calculated contrast-to-noise ratio (CNR) of the tissue phantom measurements were higher than 1.2 in the range of 3.8 to 8.7 mm imaging depth. The platform supported more than 25 images per second for real-time image acquisition. The depth-of-field had about 2.5-fold improvement compared to single-element transducer imaging. View full abstract»

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  • Probing heterogeneity of cortical bone with ultrasound axial transmission

    Page(s): 187 - 193
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    In clinical examination of long cortical bones based on ultrasound axial transmission, the parameter currently used as indicator of bone fragility is the velocity of the first arriving signal (VFAS). VFAS is inherently related to the material properties of the bone site. However, experimental uncertainties may hide the true sensitivity of VFAS to elastic characteristics of bone. Measurements are performed with a multi-element compact array placed in contact with the bone. Therefore, VFAS measurements may be biased by variability imposed by geometrical irregularities of the sample below the probe and/or by probe misalignment. In this paper, we test the assumption that despite experimental errors, VFAS variations resulting from material properties can be measured. The methodology was to compare VFAS and velocities of compression bulk waves (VBWs) on carefully matched sites around the circumference of a test sample (bovine femur). VBW was mapped on bone cross-sections using a through-transmission technique. VBW and VFAS were highly correlated [R2 = 0.80, root mean square error = 23 m·s-1, p <; 10-5] and the slope of the linear regression was close to 1 except in a part of the circumference with a pronounced curvature. In measurements performed with the same protocol as for clinical measurements, regions with different material properties (reflected by VBW) could be identified. This work demonstrates that within-specimen variations of material properties can be assessed with a technique available for in vivo measurements. View full abstract»

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  • A high-performance ultrasonic system for the simultaneous transmission of data and power through solid metal barriers

    Page(s): 194 - 203
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    This paper presents a system capable of simultaneous high-power and high-data-rate transmission through solid metal barriers using ultrasound. By coaxially aligning a pair of piezoelectric transducers on opposite sides of a metal wall and acoustically coupling them to the barrier, an acoustic-electric transmission channel is formed which prevents the need for physical penetration. Independent data and power channels are utilized, but they are only separated by 25.4 mm to reduce the system's form factor. Commercial off-the-shelf components and evaluation boards are used to create realtime prototype hardware and the full system is capable of transmitting data at 17.37 Mbps and delivering 50 W of power through a 63.5-mm thick steel wall. A synchronous multi-carrier communication scheme (OFDM) is used to achieve a very high spectral efficiency and to ensure that there is only minor interference between the power and data channels. Also presented is a discussion of potential enhancements that could be made to greatly improve the power and data-rate capabilities of the system. This system could have a tremendous impact on improving safety and preserving structural integrity in many military applications (submarines, surface ships, unmanned undersea vehicles, armored vehicles, planes, etc.) as well as in a wide range of commercial, industrial, and nuclear systems. View full abstract»

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  • Properties of acoustic plate modes in YZ LiNbO3

    Page(s): 204 - 207
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    Properties of acoustic plate modes (APMs) in YZ LiNbO3 were calculated and measured. It was found that these modes have a dominant longitudinal component of mechanical motion concentrated near both surfaces of a plate. A delay line with double-electrode interdigital transducers (IDTs) was used for the measurements. Because of good matching to the load, strong triple-transit signals (TTS) were generated and insertion loss of about 7 dB was achieved at a frequency of about 131.4 MHz. Using water and glycerin solutions, insertion loss changes against viscosity were measured for this mode. In a viscosity range from about 1 mPa·s to 1000 mPa·s, an insertion loss change of about 16 dB was obtained. High sensitivity of viscosity measurement over a wide range makes the APMs in YZ LiNbO3 attractive for application in viscosity sensors. View full abstract»

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Aims & Scope

IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control focuses on the theory, design, and application on generation, transmission, and detection of bulk and surface mechanical waves.

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Editor-in-Chief
Steven Freear
s.freear@leeds.ac.uk