Showing papers in "Ultrasound in Medicine and Biology in 2012"
TL;DR: It is suggested that combined ultrasound-mediated BBB disruption may significantly increase the antineoplastic efficacy of liposomal doxorubicin in the brain.
Abstract: The blood-brain barrier (BBB) inhibits the entry of the majority of chemotherapeutic agents into the brain. Previous studies have illustrated the feasibility of drug delivery across the BBB using focused ultrasound (FUS) and microbubbles. Here, we investigated the effect of FUS-enhanced delivery of doxorubicin on survival in rats with and 9L gliosarcoma cells inoculated in the brain. Each rat received either: (1) no treatment (control; N = 11), (2) FUS only (N = 9), (3) IV liposomal doxorubicin (DOX only; N = 17), or (4) FUS with concurrent IV injections of liposomal doxorubicin (FUS+DOX; N = 20). Post-treatment by magnetic resonance imaging (MRI) showed that FUS+DOX reduced tumor growth compared with DOX only. Further, we observed a modest but significant increase in median survival time after a single treatment FUS+DOX treatment (p = 0.0007), whereas neither DOX nor FUS had any significant impact on survival on its own. These results suggest that combined ultrasound-mediated BBB disruption may significantly increase the antineoplastic efficacy of liposomal doxorubicin in the brain.
232 citations
TL;DR: The in vivo influence of renal anisotropy and of urinary and vascular pressure on elasticity values using ultrasonic supersonic shear wave elastography was studied in pigs in agreement with the European Commission guidelines and directives.
Abstract: The in vivo influence of renal anisotropy and of urinary and vascular pressure on elasticity values using ultrasonic supersonic shear wave elastography was studied in pigs. Experiments were conducted in agreement with the European Commission guidelines and directives of the French Research Ministry. Six kidneys in three pigs were studied in vivo . Elasticity of renal cortex and medulla was quantified through the shear modulus ( μ ) by using the supersonic shear imaging technique with an 8 MHz linear ultrasound probe. All measurements were done peroperatively both in the axis and perpendicular to the main axis of pyramids, in normal condition, after progressive increase of urinary pressure, and after renal artery and renal vein ligation. In normal conditions, cortical (C) and medullary (M) elasticity values were always higher when acquisitions were realized with the ultrasound main axis perpendicular to main pyramid axis (C // : 7.7 ± 2.3 kPa; M // : 8.7 ± 2.5 kPa) than parallel (C ⊥ : 6.9 ± 1.4 kPa; M ⊥ : 6.6 ± 2.3 kPa), demonstrating an effect of renal anisotropy. In renal cortex, two bands were separated, inner cortex showing higher elasticity values (IC ⊥ : 8.1 ± 1.9 kPa) than outer cortex (OC ⊥ : 6.9 ± 1.4 kPa). Renal artery and renal vein ligation induced a decrease and an increase of elasticity respectively. Parenchymal elasticity increased linearly with elevation of urinary pressure. Intrarenal elasticity values vary with tissue anisotropy and, with vascular and urinary pressure levels. These parameters have to be taken into account for interpretation of tissue changes. Separation of outer and inner cortex could be attributable to perfusion differences.
212 citations
TL;DR: A novel and fully automated segmentation approach for breast ultrasound (BUS) images is proposed and an efficient region-of-interest (ROI) generation method is developed and new features to characterize lesion boundaries are proposed.
Abstract: Lesion segmentation is a challenging task for computer aided diagnosis systems. In this article, we propose a novel and fully automated segmentation approach for breast ultrasound (BUS) images. The major contributions of this work are: an efficient region-of-interest (ROI) generation method is developed and new features to characterize lesion boundaries are proposed. After a ROI is located automatically, two newly proposed lesion features (phase in max-energy orientation and radial distance), combined with a traditional intensity-and-texture feature, are utilized to detect the lesion by a trained artificial neural network. The proposed features are tested on a database of 120 images and the experimental results prove their strong distinguishing ability. Compared with other breast ultrasound segmentation methods, the proposed method improves the TP rate from 84.9% to 92.8%, similarity rate from 79.0% to 83.1% and reduces the FP rate from 14.1% to 12.0%, using the same database. In addition, sensitivity analysis demonstrates the robustness of the proposed method.
152 citations
TL;DR: A greater cross-sectional area of the median nerve at the carpal tunnel inlet (CSA-I) and a greater flattening ratio at the level of the hamate were seen in CTS wrists than in control wrists.
Abstract: Ultrasonography is widely used to diagnose carpal tunnel syndrome (CTS), a common peripheral neuropathy, but the reported diagnostic accuracy varies. This meta-analysis focused on the diagnostic test accuracy of ultrasonography for diagnosing CTS. Structured searches of PubMed for 1990-2010 were done and the data were extracted and meta-analyzed by pooling estimates of sensitivity, specificity, likelihood ratios and diagnostic odds ratios. Diagnostic performance was also judged by using a summary receiver operating characteristic curve. Twenty-eight trials involving 3995 wrists were included. A greater cross-sectional area (CSA) of the median nerve at the carpal tunnel inlet (CSA-I) and a greater flattening ratio at the level of the hamate were seen in CTS wrists than in control wrists. A CSA-I ≥9 mm(2) is the best single diagnostic criterion, with a diagnostic odds ratio of 40.4 (sensitivity 87.3%, specificity 83.3%).
147 citations
TL;DR: The dispersion of shear wave velocity and attenuation are strongly correlated with the degree of steatosis in a mouse liver model, ex vivo and the possibility of assessing liver steatotic using noninvasive imaging methods that are compatible with color Doppler scanners is demonstrated.
Abstract: Crawling waves, which are interfering shear wave patterns, can be generated in liver tissue over a range of frequencies. Some important biomechanical properties of the liver can be determined by imaging the crawling waves using Doppler techniques and analyzing the patterns. We report that the dispersion of shear wave velocity and attenuation, that is, the frequency dependence of these parameters, are strongly correlated with the degree of steatosis in a mouse liver model, ex vivo. The results demonstrate the possibility of assessing liver steatosis using noninvasive imaging methods that are compatible with color Doppler scanners and, furthermore, suggest that liver steatosis can be separated from fibrosis by assessing the dispersion or frequency dependence of shear wave propagations.
125 citations
TL;DR: The studies suggest that ultrasound-guided IVPA imaging can potentially be used for depth-resolved visualization of lipid deposits within the anatomical context of the vessel wall and lumen and may become an important tool for the detection of rupture-prone plaques.
Abstract: We present a preliminary study demonstrating the capability of ultrasound-guided intravascular photoacoustic (IVPA) imaging to visualize the depth-resolved distribution of lipid deposits in atherosclerotic plaques in vivo. Based on the characteristic optical absorption of lipid in the near infrared wavelength range, IVPA imaging at a single, 1720 nm, wavelength was used to provide a spatially-resolved, direct measurement of lipid content in atherosclerotic arteries. By overlaying an IVPA image with a spatially co-registered intravascular ultrasound (IVUS) image, the combined IVPA/IVUS image was used to visualize lipid distribution within the vessel wall. Ultrasound-guided IVPA imaging was performed in vivo in the abdominal aorta of a Watanabe heritable hyperlipidemic (WHHL) rabbit. Subsequently, the excised rabbit aorta filled with a solution of red blood cells (RBC) was then imaged ex vivo, and histology was obtained in the section adjacent to the imaged cross-section. To demonstrate the potential for future clinical application of IVPA/IVUS imaging, a sample of diseased human right coronary artery (RCA) was also imaged. Both in vivo and ex vivo IVPA images clearly showed the distribution of lipid in the atherosclerotic vessels. In vivo IVPA imaging was able to identify diffuse, lipid-rich plaques in the WHHL rabbit model of atherosclerosis. Furthermore, IVPA imaging at a single wavelength was able to identify the lipid core within the human RCA ex vivo. Our results demonstrate that ultrasound-guided IVPA imaging can identify lipid in atherosclerotic plaques in vivo. Importantly, the IVPA/IVUS images were obtained in presence of luminal blood and no saline flush or balloon occlusion was required. Overall, our studies suggest that ultrasound-guided IVPA imaging can potentially be used for depth-resolved visualization of lipid deposits within the anatomical context of the vessel wall and lumen. Therefore, IVUS/IVPA imaging may become an important tool for the detection of rupture-prone plaques.
114 citations
TL;DR: Investigation of the possibility of using low-intensity transcranial focused ultrasound (FUS) to selectively stimulate the rat abducens nerve located above the base of the skull shows potential for diagnostic and therapeutic applications in diseases of the peripheral nervous system.
Abstract: Nonpharmacologic and nonsurgical transcranial modulation of the nerve function may provide new opportunities in evaluation and treatment of cranial nerve diseases. This study investigates the possibility of using low-intensity transcranial focused ultrasound (FUS) to selectively stimulate the rat abducens nerve located above the base of the skull. FUS (frequencies of 350 kHz and 650 kHz) operating in a pulsed mode was applied to the abducens nerve of Sprague-Dawley rats under stereotactic guidance. The abductive eyeball movement ipsilateral to the side of sonication was observed at 350 kHz, using the 0.36-msec tone burst duration (TBD), 1.5-kHz pulse repetition frequency (PRF), and the overall sonication duration of 200 msec. Histologic and behavioral monitoring showed no signs of disruption in the blood brain barrier (BBB), as well as no damage to the nerves and adjacent brain tissue resulting from the sonication. As a novel functional neuro-modulatory modality, the pulsed application of FUS has potential for diagnostic and therapeutic applications in diseases of the peripheral nervous system.
111 citations
TL;DR: This work presents a computer aided diagnostic (CAD) based ultrasound characterization methodology (a class of Atheromatic systems) that classifies the patient into symptomatic and asymptomatic classes using two kinds of datasets: plaque regions in ultrasound carotids segmented semi-automatically and far wall gray-scale intima-media thickness regions along the common carotid artery segmented automatically.
Abstract: Plaques in the carotid artery result in stenosis, which is one of the main causes for stroke. Patients have to be carefully selected for stenosis treatments as they carry some risk. Since patients with symptomatic plaques have greater risk for strokes, an objective classification technique that classifies the plaques into symptomatic and asymptomatic classes is needed. We present a computer aided diagnostic (CAD) based ultrasound characterization methodology (a class of Atheromatic systems) that classifies the patient into symptomatic and asymptomatic classes using two kinds of datasets: (1) plaque regions in ultrasound carotids segmented semi-automatically and (2) far wall gray-scale intima-media thickness (IMT) regions along the common carotid artery segmented automatically. For both kinds of datasets, the protocol consists of estimating texture-based features in frameworks of local binary patterns (LBP) and Law's texture energy (LTE) and applying these features for obtaining the training parameters, which are then used for classification. Our database consists of 150 asymptomatic and 196 symptomatic plaque regions and 342 IMT wall regions. When using the Atheromatic-based system on semiautomatically determined plaque regions, support vector machine (SVM) classifier was adapted with highest accuracy of 83%. The accuracy registered was 89.5% on the far wall gray-scale IMT regions when using SVM, K-nearest neighbor (KNN) or radial basis probabilistic neural network (RBPNN) classifiers. LBP/LTE-based techniques on both kinds of carotid datasets are noninvasive, fast, objective and cost-effective for plaque characterization and, hence, will add more value to the existing carotid plaque diagnostics protocol. We have also proposed an index for each type of datasets: AtheromaticPi, for carotid plaque region, and AtheromaticWi, for IMT carotid wall region, based on the combination of the respective significant features. These indices show a separation between symptomatic and asymptomatic by 4.53 units and 4.42 units, respectively, thereby supporting the texture hypothesis classification.
110 citations
TL;DR: Real-time shear wave ultrasound elastography for cervical lymphadenopathy in routine clinical practice appears unsuitable for cancer screening but may detect a subset of malignant nodes, and elastograms of benign nodes were homogeneously soft or markedly heterogeneous with some including regions lacking elasticity signal.
Abstract: A pilot study of real-time shear wave ultrasound elastography (SWE) for cervical lymphadenopathy in routine clinical practice was conducted on 55 nodes undergoing conventional ultrasound (US) with US-guided needle aspiration for cytology. Elastic moduli of stiffest regions in nodes were measured on colour-coded elastograms, which were correlated with cytology. Malignant nodes (n = 31, 56.4%) were stiffer (median 25.0 kPa, range 6.9-278.9 kPa) than benign nodes (median 21.4 kPa, range 8.9-30.2 kPa) (p = 0.008, Mann Whitney U test). A cut-off of 30.2 kPa attained highest accuracy of 61.8%, corresponding to 41.9% sensitivity, 100% specificity and 0.77 area under the receiver operating characteristic curve. Qualitatively, elastograms of benign nodes were homogeneously soft; malignant nodes were homogeneously soft or markedly heterogeneous with some including regions lacking elasticity signal. SWE is feasible for neck nodes. It appears unsuitable for cancer screening but may detect a subset of malignant nodes. The cause of spatial heterogeneity of malignant nodes on SWE is yet to be established.
102 citations
TL;DR: This study assessed acoustic radiation force impulse (ARFI) reproducibility and the factors influencing it and found that the correlation of repeated ARFI measurements was higher, but not significantly so, in cases in which intraoperator Reproducibility was assessed compared with the ones in which interoperator reproducible was studied.
Abstract: Our study assessed acoustic radiation force impulse (ARFI) reproducibility and the factors influencing it. The intra- and interoperator reproducibility were studied in 33 and 58 patients, respectively. Intraclass correlation coefficient (ICC) was used to assess ARFI reproducibility. The overall intraoperator agreement was better than the interoperator one: ICC 0.90 vs. ICC 0.81. The correlation of repeated ARFI measurements was higher, but not significantly so, in cases in which intraoperator reproducibility was assessed compared with the ones in which interoperator reproducibility was studied: r = 0.848 vs. r = 0.694 (p = 0.08). For both intra- and interoperator reproducibility, the ICCs were smaller in women vs. men (0.88 vs. 0.91 and 0.67 vs. 0.86, respectively), in patients with high body mass index (BMI) ≥25 kg/m² vs. <25 kg/m² (0.88 vs. 0.91 and 0.79 vs. 0.82, respectively), in patients with ascites vs. no ascites (0.80 vs. 0.93 and 0.78 vs. 0.84, respectively) and in noncirrhotic vs. cirrhotic patients (0.77 vs. 0.82 and 0.70 vs. 0.83, respectively).
100 citations
TL;DR: Carotid longitudinal displacement, estimated with this approach, is impaired in the periodontal disease group, independent of established cardiovascular risk factors and other noninvasive measures of arterial stiffness, and may represent an important marker of cardiovascular risk.
Abstract: The recently discovered longitudinal displacement of the common carotid arterial wall (i.e., the motion along the same plane as the blood flow), may be associated with incident cardiovascular events and represents a novel and relevant clinical information. At present, there have only been a few studies that have been conducted to investigate this longitudinal movement. We propose here a method to assess noninvasively the wall bi-dimensional (two-dimensional [2-D], cross-sectional and longitudinal) motion and present an original approach that combines a robust speckle tracking scheme to guidance by minimal path contours segmentation. Our method is well suited to large clinical population studies as it does not necessitate strong imaging prerequisites. The aim of this study is to describe the association between the longitudinal displacement of the carotid arterial wall and cardiovascular risk factors, among which periodontal disease. Some 126 Indigenous Australians with periodontal disease, an emerging risk factor, and 27 healthy age- and sex-matched non-indigenous control subjects had high-resolution ultrasound scans of the common carotid artery. Carotid intima-media thickness and arterial wall 2-D motion were then assessed using our method in ultrasound B-mode sequences. Carotid longitudinal displacement was markedly lower in the periodontal disease group than the control group (geometric mean (IQR): 0.15 mm (0.13) vs. 0.42 mm (0.30), respectively; p < 0.0001), independent of cardiovascular risk factors, cross-sectional distensibility and carotid intima-media thickness (p < 0.0001). A multivariable model indicated that the strongest correlates of carotid longitudinal displacement in adults with periodontal disease were age (β-coefficient = −.235, p = .03), waist (β-coefficient = −.357, p = 0.001), and pulse pressure (β-coefficient = .175, p = 0.07), independent of other cardiovascular risk factors, cross-sectional distensibility and pulse wave velocity. Carotid longitudinal displacement, estimated with our approach, is impaired in the periodontal disease group, independent of established cardiovascular risk factors and other noninvasive measures of arterial stiffness, and may represent an important marker of cardiovascular risk.
TL;DR: The data indicate that ultrasound measurement of SAT thickness proportionally reflects segmental fat mass and accurately predicts % body fat in young adults.
Abstract: This study evaluated the ability of ultrasound measurement of subcutaneous adiposity to accurately determine whole body and segmental body fat in young adults aged 18–29 years. Subcutaneous adipose tissue (SAT) thickness was measured by ultrasound at five body sites in 135 subjects (83 men, 52 women) and compared with the corresponding segmental fat mass measured by dual energy X-ray absorptiometry (DXA). Ultrasound measures of SAT thickness were strongly correlated to segmental fat mass and total percentage (%) body fat (r = 0.697–0.907, p
TL;DR: Results indicated that the removal of the cavitation memory resulted in more efficient treatments and homogeneous lesions, and complete disruption of a tissueVolume with fewer pulses.
Abstract: Cavitation memory effects occur when remnants of cavitation bubbles (nuclei) persist in the host medium and act as seeds for subsequent events. In pulsed cavitational ultrasound therapy, or histotripsy, this effect may cause cavitation to repeatedly occur at these seeded locations within a target volume, producing inhomogeneous tissue fractionation or requiring an excess number of pulses to completely homogenize the target volume. We hypothesized that by removing the cavitation memory, i.e., the persistent nuclei, the cavitation bubbles could be induced at random locations in response to each pulse; therefore, complete disruption of a tissue volume may be achieved with fewer pulses. To test the hypothesis, the cavitation memory was passively removed by increasing the intervals between successive pulses, ∆t, from 2, 10, 20, 50 and 100, to 200 ms. Histotripsy treatments were performed in red blood cell tissue phantoms and ex vivo livers using 1-MHz ultrasound pulses of 10 cycles at P-/P+ pressure of 21/59 MPa. The phantom study allowed for direct visualization of the cavitation patterns and the lesion development process in real time using high-speed photography; the ex vivo tissue study provided validation of the memory effect in real tissues. Results of the phantom study showed an exponential decrease in the correlation coefficient between cavitation patterns in successive pulses from 0.5 ± 0.1 to 0.1 ± 0.1 as ∆t increased from 2-200 ms; correspondingly, the lesion was completely fractionated with significantly fewer pulses for longer ∆ts. In the tissue study, given the same number of therapy pulses, complete and homogeneous tissue fractionation with well-defined lesion boundaries was achieved only for ∆t ≥ 100 ms. These results indicated that the removal of the cavitation memory resulted in more efficient treatments and homogeneous lesions.
TL;DR: The use of attenuation and a principal component analysis of the BSC to detect and quantify hepatic steatosis in vivo in a rabbit model of fatty liver is explored.
Abstract: Nonalcoholic fatty liver disease (NAFLD) affects more than 30% of Americans, and with increasing problems of obesity in the United States, NAFLD is poised to become an even more serious medical concern. At present, accurate classification of steatosis (fatty liver) represents a significant challenge. In this study, the use of high-frequency (8 to 25 MHz) quantitative ultrasound (QUS) imaging to quantify fatty liver was explored. QUS is an imaging technique that can be used to quantify properties of tissue giving rise to scattered ultrasound. The changes in the ultrasound properties of livers in rabbits undergoing atherogenic diets of varying durations were investigated using QUS. Rabbits were placed on a special fatty diet for 0, 3, or 6 weeks. The fattiness of the livers was quantified by estimating the total lipid content of the livers. Ultrasonic properties, such as speed of sound, attenuation, and backscatter coefficients, were estimated in ex vivo rabbit liver samples from animals that had been on the diet for varying periods. Two QUS parameters were estimated based on the backscatter coefficient: effective scatterer diameter (ESD) and effective acoustic concentration (EAC), using a spherical Gaussian scattering model. Two parameters were estimated based on the backscattered envelope statistics (the k parameter and the μ parameter) according to the homodyned K distribution. The speed of sound decreased from 1574 to 1565 m/s and the attenuation coefficient increased from 0.71 to 1.27 dB/cm/MHz, respectively, with increasing fat content in the liver. The ESD decreased from 31 to 17 μm and the EAC increased from 38 to 63 dB/cm3 with increasing fat content in the liver. A significant increase in the μ parameter from 0.18 to 0.93 scatterers/mm3 was observed with increasing fat content in the liver samples. The results of this study indicate that QUS parameters are sensitive to fat content in the liver.
TL;DR: Simple to use, with good interobserver agreement, elastography has all the requisites to become an important complement of conventional US examination in the near future.
Abstract: Elastography is a new diagnostic tool in the evaluation of thyroid nodules. Aim of the study was to evaluate the accuracy and reliability of elastography in discriminating thyroid lesions and the interobserver variability. One hundred thirty-two nodules in 115 patients selected for thyroid surgery underwent conventional ultrasound and elastographic evaluation. Elastography score was divided in four categories (totally elastic nodule, mainly elastic, mainly rigid and totally rigid) according to signal distribution. Three independent operators conducted the study. Final histology showed 92 benign nodules and 40 malignant. On elastography, 77/92 benign nodules were classified as score 1 or 2 and 34/40 malignant nodules as score 3 or 4 (sensitivity 85%, specificity 83.7%, positive predictive value [PPV] 69.3%, negative predictive value [NPV] 92.7%). Rate of concordance between operators was good (K test: 0.64, p < 0.0001). Simple to use, with good interobserver agreement, elastography has all the requisites to become an important complement of conventional US examination in the near future.
TL;DR: The present results indicate that using a customized US template provides reliable measures of leg muscle CSA and, thus, could be used to characterize muscle C SA and volume.
Abstract: This study examined the reliability and validity of using customized templates to acquire panoramic ultrasound (US) images for determining cross-sectional area (CSA) and volume in the vastus lateralis (VL), rectus femoris (RF), medial gastrocnemius (MG) and lateral gastrocnemius (LG). Panoramic US and magnetic resonance imaging (MRI) images were analyzed by two trained investigators. The inter-experimenter reliability (coefficient of variation [CV]) of panoramic US ranged from 2.4% to 4.1% and the intraclass correlation (ICC) ranged from 0.963 to 0.991, whereas the inter-experimenter CV of MRI ranged from 2.8% to 3.8% and the ICC from 0.946 to 0.986. Bland-Altman plots demonstrated high agreement between US and MRI; however, values obtained from MRI were systematically larger than those obtained from US. The present results indicate that using a customized US template provides reliable measures of leg muscle CSA and, thus, could be used to characterize muscle CSA and volume.
TL;DR: Findings suggest US signals through integrin receptors to the MAPK/Erk pathway via a mechanotransduction pathway involving FAK, Src, p130Cas and CrkII, suggesting integrins and Src are upstream of Erk in an US-mediated mechanotranduction pathway.
Abstract: Chondrocytes are mechanosensitive cells that require mechanical stimulation for proper growth and function in in vitro culture systems. Ultrasound (US) has emerged as a technique to deliver mechanical stress; however, the intracellular signaling components of the mechanotransduction pathways that transmit the extracellular mechanical stimulus to gene regulatory mechanisms are not fully defined. We evaluated a possible integrin/mitogen-activated protein kinase (MAPK) mechanotransduction pathway using Western blotting with antibodies targeting specific phosphorylation sites on intracellular signaling proteins. US stimulation of chondrocytes induced phosphorylation of focal adhesion kinase (FAK), Src, p130 Crk-associated substrate (p130Cas), CrkII and extracellular-regulated kinase (Erk). Furthermore, pre-incubation with inhibitors of integrin receptors, Src and MAPK/Erk kinase (MEK) reduced US-induced Erk phosphorylation levels, indicating integrins and Src are upstream of Erk in an US-mediated mechanotransduction pathway. These findings suggest US signals through integrin receptors to the MAPK/Erk pathway via a mechanotransduction pathway involving FAK, Src, p130Cas and CrkII.
TL;DR: US interstitial syndrome can be reproduced in histologically normal lungs that are deflated to a critical level (>0.45 g/mL) of density, which is not achievable under physiologic conditions.
Abstract: Ultrasound (US) interstitial syndrome is a sonographic lung pattern characterized by the presence of acoustic artifacts (B-lines and white lung). The purpose of this study was to demonstrate how interstitial syndrome is determined by acoustic interactions in lungs of variable density and in healthy organs deflated to a nonphysiologic level of density. Normal rabbit lungs were studied ex vivo by US at varying known degrees of inflation, and their histologic appearances were described. In this experimental setting, US interstitial syndrome recognizes a mechanism related to tissue density or porosity. Artifacts (B-lines and white lung) appear in the normal rabbit lung through air-dependent increases in density. As in pathologic conditions, US interstitial syndrome can be reproduced in histologically normal lungs that are deflated to a critical level (>0.45 g/mL) of density, which is not achievable under physiologic conditions.
TL;DR: Pulse-echo ultrasound, laser Doppler vibrometry and Schlieren imaging were applied to noninvasively characterize common in vitro experimental configurations to characterize any possible temperature rise during the ultrasound exposures and Lamb waves may be a mechanism for stimulating the cells.
Abstract: Therapeutic ultrasound is a clinically applied method to improve fracture healing and holds great potential as a manipulator of biologic material relevant to tissue engineering approaches. Unfortunately, the cell stimulating property of ultrasound is not known, which inhibits the optimal use of this technique. Additionally, many in vitro studies in this field use ultrasound configurations that are vulnerable to errors during calibration and use. These errors arise from the structural simplicity and incomplete characterization of these configurations. In this study, pulse-echo ultrasound, laser Doppler vibrometry and Schlieren imaging were applied to noninvasively characterize common in vitro experimental configurations. Fine wire thermocouple measurements were conducted to characterize any possible temperature rise during the ultrasound exposures. The results quantified the frequency dependent sound transmission through culture wells and the standing wave effect within the cell volume. These effects can cause uncertainty of up to 700% in the actual ultrasound exposure experienced by the cell. A temperature rise of 2.7°C was measured from an ultrasound configuration commonly used in vitro ultrasound studies. Furthermore, wave mode conversion in culture wells was observed, emphasizing the complexity of these sonications. Similar type Lamb waves have been observed in bone in vivo. Thus, Lamb waves may be a mechanism for stimulating the cells.
TL;DR: An analysis of the response of MicroMarker™ bubbles suggests that these bubbles exhibit "expansion-dominated" oscillations, in contrast to "compression-only" oscillation observed for similar bubbles at lower frequencies (f < 11 MHz).
Abstract: There are a range of contrast ultrasound applications above 10 MHz, a frequency regime in which nonlinear microbubble behavior is poorly understood. Lipid-encapsulated microbubbles have considerable potential for use at higher frequencies because they have been shown to exhibit pronounced nonlinear activity at frequencies up to 40 MHz. The objective of this work was to investigate the influence of agent formulation on the subharmonic response of lipid-encapsulated microbubbles at high frequencies with a view to providing information relevant to improving contrast agent design and imaging performance. An optical-acoustical setup was used to measure the subharmonic emissions from small (d < 3 μm) individual lipid-encapsulated microbubbles as a function of transmit pressure, size and composition. In this study, five agent formulations (Definity™, MicroMarker™ and three in-house agents manipulated to exhibit different levels of shell microstructure heterogeneity) were insonified at 25 MHz over a peak negative pressure (Pn) range of 0.02–1.2 MPa. All agents exhibited distinctly different subharmonic behavior, both in terms of amplitude and active sizes. MicroMarker™ exhibited the strongest, broadest and most consistent subharmonic response, 22% greater in power than that of Definity™ and as much as 50% greater than the in-house formulations. No clear relation between in-house agents’ shell microstructure and nonlinear response was found, other than the variability in the nonlinear response itself. An analysis of the response of MicroMarker™ bubbles suggests that these bubbles exhibit “expansion-dominated” oscillations, in contrast to “compression-only” oscillations observed for similar bubbles at lower frequencies (f < 11 MHz).
TL;DR: The phantom study showed that pseudoenhancement may be present during vascular CEUS and that the degree of pseudoenHancement is influenced by the size and concentration of the microbubbles.
Abstract: The present study describes the presence of pseudoenhancement during contrast-enhanced ultrasound (CEUS) imaging of human carotid arteries and the reproduction of this pseudoenhancement in vitro. Seventy patients underwent bilateral CEUS examination of the carotid arteries using a Philips iU22 ultrasound system equipped with a L9-3 ultrasound probe and SonoVue microbubble contrast. During CEUS of the carotid arteries, we identified enhancement in close proximity to the far wall, parallel to the main lumen. The location of this enhancement does not correlate to the anatomical location of a parallel vessel. To corroborate the hypothesis that this is a pseudoenhancement artifact, the enhancement was recreated in a tissue-mimicking material phantom, using the same ultrasound system, settings and contrast agent as the patient study. The phantom study showed that pseudoenhancement may be present during vascular CEUS and that the degree of pseudoenhancement is influenced by the size and concentration of the microbubbles. During vascular CEUS, identification of the artifact is important to prevent misinterpretation of enhancement in and near the far wall.
TL;DR: MEUS provides a new, simple physical method for anti-angiogenic therapy and may have great potential for clinical applications.
Abstract: Tumor angiogenesis is of vital importance to the growth and metastasis of solid tumors. The angiogenesis is featured with a defective, leaky and fragile vascular construction. Microbubble enhanced ultrasound (MEUS) cavitation is capable of mechanical disruption of small blood vessels depending on effective acoustic pressure amplitude. We hypothesized that acoustic cavitation combining high-pressure amplitude pulsed ultrasound (US) and circulating microbubble could potentially disrupt tumor vasculature. A high-pressure amplitude, pulsed ultrasound device was developed to induce inertial cavitation of circulating microbubbles. The tumor vasculature of rat Walker 256 was insonated percutaneously with two acoustic pressures, 2.6 MPa and 4.8 MPa, both with intravenous injection of a lipid microbubble. The controls were treated by the ultrasound only or sham ultrasound exposure. Contrast enhanced ultrasound (CEUS) and histology were performed to assess tumor circulation and pathological changes. The CEUS results showed that the circulation of Walker 256 tumors could be completely blocked off for 24 hours in 4.8 MPa treated tumors. The CEUS gray scale value (GSV) indicated that there was significant GSV drop-off in both of the two experimental groups but none in the controls. Histology showed that the tumor microvasculature was disrupted into diffuse hematomas accompanied by thrombosis, intercellular edema and multiple cysts formation. The 24 hours of tumor circulation blockage resulted in massive necrosis of the tumor. MEUS provides a new, simple physical method for anti-angiogenic therapy and may have great potential for clinical applications.
TL;DR: This study applied submental ultrasonography to measure changes in dysphagic stroke patients' tongue thickness and hyoid bone displacement when swallowing 5 mL of water and correlated the results with the severity of clinical dysphagia.
Abstract: This study applied submental ultrasonography (SUS) to measure changes in dysphagic stroke patients' tongue thickness and hyoid bone displacement when swallowing 5 mL of water and correlated the results with the severity of clinical dysphagia. We included 60 stroke patients (30 tube-feeding-dependent and 30 on regular oral intake) and 30 healthy controls. An additional 10 healthy people were recruited to assess the reliability of SUS. Measurements of hyoid bone displacement using videofluoroscopic swallowing study (VFSS) and SUS were compared for 12 stroke patients to assess the correlation between the two methods. Changes in tongue thickness and hyoid bone displacement were significantly less in the tube-feeding group. Those with a tongue thickness change of less than 1.0 cm and hyoid bone displacement of less than 1.5 cm were likely to be tube-feeding. SUS showed good intra-rater/inter-rater reliability and correlated well with VFSS measurement. SUS can be an adjunct assessment tool of swallowing.
TL;DR: This study characterized the acoustic properties of an International Electromechanical Commission (IEC) agar-based tissue mimicking material at ultrasound frequencies in the range 10–47 MHz to enhance understanding in the use of this TMM as a tissue equivalent material for high frequency ultrasound applications.
Abstract: This study characterized the acoustic properties of an International Electromechanical Commission (IEC) agar-based tissue mimicking material (TMM) at ultrasound frequencies in the range 10–47 MHz. A broadband reflection substitution technique was employed using two independent systems at 21°C ± 1°C. Using a commercially available preclinical ultrasound scanner and a scanning acoustic macroscope, the measured speeds of sound were 1547.4 ± 1.4 m∙s−1 and 1548.0 ± 6.1 m∙s−1, respectively, and were approximately constant over the frequency range. The measured attenuation (dB∙cm−1) was found to vary with frequency f (MHz) as 0.40f + 0.0076f2. Using this polynomial equation and extrapolating to lower frequencies give values comparable to those published at lower frequencies and can estimate the attenuation of this TMM in the frequency range up to 47 MHz. This characterisation enhances understanding in the use of this TMM as a tissue equivalent material for high frequency ultrasound applications.
TL;DR: Vector flow can measure the angle for spectral angle correction, thus eliminating the bias from the radiologist performing the angle setting with spectral estimation, and the flow angle limitation in velocity estimation is eliminated, so that flow at any angle can be measured.
Abstract: The purpose of this study is to show whether a newly introduced vector flow method is equal to conventional spectral estimation. Thirty-two common carotid arteries of 16 healthy volunteers were scanned using a BK Medical ProFocus scanner (DK-2730, Herlev, Denmark) and a linear transducer at 5 MHz. A triplex imaging sequence yields both the conventional velocity spectrum and a two-dimensional vector velocity image. Several clinical parameters were estimated and compared for the two methods: Flow angle, peak systole velocity (PS), end diastole velocity (ED) and resistive index (RI). With a paired t-test, the spectral and vector angles did not differ significantly (p = 0.658), whereas PS (p = 0.034), ED (p = 0.004) and RI (p < 0.0001) differed significantly. Vector flow can measure the angle for spectral angle correction, thus eliminating the bias from the radiologist performing the angle setting with spectral estimation. The flow angle limitation in velocity estimation is also eliminated, so that flow at any angle can be measured.
TL;DR: The quantitative analysis of small bowel wall contrast enhancement after microbubble contrast agent injection may differentiate inflammatory from fibrotic ileal strictures in patients with Crohn's disease.
Abstract: We analysed the value of contrast-enhanced ultrasound to differentiate inflammatory from fibrotic ileal strictures in patients with Crohn's disease (CD). Twenty-eight patients (17 male and 11 female; mean age ± SD, 48.5 ± 17.17 years) with a biopsy-proven diagnosis of CD were included. In each patient, the terminal ileal loop was scanned by a convex-array probe (2-5 MHz) before and after sulphur hexafluoride-filled microbubble injection. The digital cine-clip registered after microbubble injection during the first-pass dynamic enhancement was quantified in gray-scale levels by a dedicated software through manually drawn regions-of-interest (ROIs) encompassing the anterior bowel wall. Time-intensity curves from patients with inflammatory and fibrotic ileal strictures, fitted according to the theoretical gamma variate curve, were compared. Inflammatory vs. fibrotic ileal strictures differed in the percentage of maximal enhancement (45.86 ± 5.32 vs. 37.33 ± 16.24%; p 0.05). The quantitative analysis of small bowel wall contrast enhancement after microbubble contrast agent injection may differentiate inflammatory from fibrotic ileal strictures in patients with CD.
TL;DR: It is concluded that the literature does not support the hypothesis that efficient intracellular uptake of molecules can be achieved with high cell viability after US exposure in vitro, which poses a challenge to future applications of US that require efficient intrACEllular delivery.
Abstract: Most applications of therapeutic ultrasound (US) for intracellular delivery of drugs, proteins, DNA/ RNA and other compounds would benefit from efficient uptake of these molecules into large numbers of cells without killing cells in the process. In this study we tested the hypothesis that efficient intracellular uptake of mole- cules can be achieved with high cell viability after US exposure in vitro. A search of the literature for studies with quantitative data on uptake and viability yielded 26 published papers containing 898 experimental data points. Analysis of these studies showed that just 7.7% of the data points corresponded to relatively efficient uptake (.50% of cells exhibiting uptake). Closer examination of the data showed that use of Definity US contrast agent (as opposed to Optison) and elevated sonication temperature at 37 � C (as opposed to room temperature) were asso- ciated with high uptake, which we further validated through independent experiments carried out in this study. Although these factors contributed to high uptake, almost all data with efficient uptake were from studies that had not accounted for lysed cells when determining cell viability. Based on retrospective analysis of the data, we showed that not accounting for lysed cells can dramatically increase the calculated uptake efficiency. We further argue that if all the data considered in this study were re-analyzed to account for lysed cells, there would be essentially no data with efficient uptake. We therefore conclude that the literature does not support the hypoth- esis that efficient intracellular uptake of molecules can be achieved with high cell viability after US exposure in vitro, which poses a challenge to future applications of US that require efficient intracellular delivery. (E-mail: prausnitz@gatech.edu) 2012 World Federation for Ultrasound in Medicine & Biology.
TL;DR: Acoustic radiation force impulse imaging holds promise for guidance of targeted prostate needle biopsy and focal therapy, as well as aiding assessment of changes during watchful waiting/active surveillance.
Abstract: Reliably detecting prostate cancer (PCa) has been a challenge for current imaging modalities Acoustic radiation force impulse (ARFI) imaging is an elasticity imaging method that uses remotely generated, focused acoustic beams to probe tissue stiffness A previous study on excised human prostates demonstrated ARFI images portray various prostatic structures and has the potential to guide prostate needle biopsy with improved sampling accuracy The goal of this study is to demonstrate the feasibility of ARFI imaging to portray internal structures and PCa in the human prostate in vivo Custom ARFI imaging sequences were designed and implemented using a modified Siemens Antares™ scanner with a three-dimensional (3-D) wobbler, end-firing, trans-cavity transducer, EV9F4 Nineteen patients were consented and imaged immediately preceding surgical prostatectomy Pathologies and anatomic structures were identified in histologic slides by a pathologist blinded to ARFI data and were then registered with structures found in ARFI images The results demonstrated that when PCa is visible, it generally appears as bilaterally asymmetric stiff structures; benign prostatic hyperplasia (BPH) appears heterogeneous with a nodular texture; the verumontanum and ejaculatory ducts appears softer compared with surrounding tissue, which form a unique 'V' shape; and the boundary of the transitional zone (TZ) forms a stiff rim separating the TZ from the peripheral zone (PZ) These characteristic appearances of prostatic structures are consistent with those found in our previous study of prostate ARFI imaging on excised human prostates Compared with the matched B-mode images, ARFI images, in general, portray prostate structures with higher contrast With the end-firing transducer used for this study, ARFI depth penetration was limited to 22 mm Image contrast and resolution were decreased as compared with the previous ex vivo study due to the small transducer aperture Even with these limitations, this study suggests ARFI imaging holds promise for guidance of targeted prostate needle biopsy and focal therapy, as well as aiding assessment of changes during watchful waiting/active surveillance
TL;DR: This model uniquely provides a means to systematically evaluate multiple acoustic and microbubble parameters for the optimization of microvascular sonothrombolysis and may obviate the need for adjunctive rt-PA and could have important clinical cost and safety benefits.
Abstract: Ultrasound (US) mediated microbubble (MB) destruction facilitates thrombolysis of the epicardial coronary artery in acute myocardial infarction (AMI) but its effect on microvascular thromboemboli remains largely unexplored. We sought to define the acoustic requirements for effective microvascular sonothrombolysis. To model microembolization, microthrombi were injected and entrapped in a 40 μm pore mesh, increasing upstream pressure, which was measured as an index of thrombus burden. MBs (2.0 × 10 6 MBs/mL) were then infused while pulsed US (1 MHz) was delivered to induce MB destruction immediately adjacent to the thrombus. Upstream pressure decreased progressively during US delivery, indicating a reduction in thrombus burden. More rapid and complete lysis occurred with increasing peak negative acoustic pressure (1.5 MPa > 0.6 MPa) and increasing pulse length (5000 cycles > 100 cycles). Additionally, similar lytic efficacy was achieved at 1.5 MPa without tPA as was at 1.0 MPa with tPA. This model uniquely provides a means to systematically evaluate multiple acoustic and microbubble parameters for the optimization of microvascular sonothrombolysis. This treatment approach for thrombotic microvascular obstruction may obviate the need for adjunctive rt-PA and could have important clinical cost and safety benefits.
TL;DR: The response to BV can be identified soon after initiation of treatment, often within 3 days, by use of CEUS molecular imaging techniques, which may allow for earlier and more effective determination of efficacy of antiangiogenic therapy.
Abstract: Agents targeting vascular endothelial growth factor (VEGF) have been validated as cancer therapeutics, yet efficacy can differ widely between tumor types and individual patients. In addition, such agents are costly and can have significant toxicities. Rapid noninvasive determination of response could provide significant benefits. We tested if response to the anti-VEGF antibody bevacizumab (BV) could be detected using contrast-enhanced ultrasound imaging (CEUS). We used two xenograft model systems with previously well-characterized responses to VEGF inhibition, a responder (SK-NEP-1) and a non-responder (NGP), and examined perfusion-related parameters. CEUS demonstrated that BV treatment arrested the increase in blood volume in the SK-NEP-1 tumor group only. Molecular imaging of α(V)β(3) with targeted microbubbles was a more sensitive prognostic indicator of BV efficacy. CEUS using RGD-labeled microbubbles showed a robust decrease in α(V)β(3) vasculature following BV treatment in SK-NEP-1 tumors. Paralleling these findings, lectin perfusion assays detected a disproportionate pruning of smaller, branch vessels. Therefore, we conclude that the response to BV can be identified soon after initiation of treatment, often within 3 days, by use of CEUS molecular imaging techniques. The use of a noninvasive ultrasound approach may allow for earlier and more effective determination of efficacy of antiangiogenic therapy.