Electromechanical piezoresistive sensing in suspended graphene membranes.

Monolayer graphene exhibits exceptional electronic and mechanical properties, making it a very promising material for nanoelectromechanical devices. Here, we conclusively demonstrate the piezoresistive effect in graphene in a nanoelectromechanical membrane configuration that provides direct electrical readout of pressure to strain transduction. This makes it highly relevant for an important class of nanoelectromechanical system (NEMS) transducers. This demonstration is consistent with our simulations and previously reported gauge factors and simulation values. The membrane in our experiment acts as a strain gauge independent of crystallographic orientation and allows for aggressive size scalability. When compared with conventional pressure sensors, the sensors have orders of magnitude higher sensitivity per unit area.

Clinical impact of CEUS on non-characterizable observations and observations with intermediate probability of malignancy on CT/MRI in patients at risk for HCC.

BACKGROUND: Hepatocellular carcinoma (HCC) is a unique cancer allowing tumor diagnosis with identification of definitive patterns of enhancement on contrast-enhanced imaging, avoiding invasive biopsy. However, it is still unclear to what extent Contrast-Enhanced Ultrasound (CEUS) is a clinically useful additional step when Computed tomography (CT) or Magnetic resonance imaging (MRI) are inconclusive. METHODS: A prospective international multicenter validation study for CEUS Liver Imaging Reporting and Data System (LI-RADS) was conducted between January 2018 and August 2021. 646 patients at risk for HCC with focal liver lesions were enrolled. CEUS was performed using an intravenous ultrasound contrast agent within 4 weeks of CT/MRI. Liver nodules were categorized based on LI-RADS (LR) criteria. Histology or one-year follow-up CT/MRI imaging results were used as the reference standard. The diagnostic performance of CEUS was evaluated for inconclusive CT/MRI scan in two scenarios for which the AASLD recommends repeat imaging or imaging follow-up: observations deemed non-characterizable (LR-NC) or with indeterminate probability of malignancy (LR-3). RESULTS: 75 observations on CT or MRI were categorized as LR-3 (n = 54) or LR-NC (n = 21) CEUS recategorization of such observations into a different LR category (namely, into one among LR-1, LR-2, LR-5, LR-M, or LR-TIV) resulted in management recommendation changes in 33.3% (25/75) and in all but one (96.0%, 24/25) observation, the new management recommendations were correct. CONCLUSION: CEUS LI-RADS resulted in management recommendations change in substantial number of liver observations with initial indeterminate CT/MRI characterization, identifying both non-malignant lesions and HCC, potentially accelerating the diagnostic process and alleviating the need for biopsy or follow-up imaging. CLINICALTRIALS: gov number, NCT03318380.

Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver--update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS.

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

Contrast-enhanced ultrasound for molecular imaging of angiogenesis.

INTRODUCTION: Molecular imaging of angiogenesis using contrast-enhanced ultrasound allows for functional, real-time, inexpensive imaging of angiogenesis. The addition of stabilized microbubbles as contrast agents greatly improves ultrasound signal to noise ratio/signal strength/image quality (up to 25 dB) and allows for imaging of angiogenic vasculature. METHODS: In this article recent advances in the usage of contrast-enhanced ultrasound for molecular imaging of angiogenesis are reviewed. RESULTS: The usage of commercially available agents and correlations between their imaging parameters and molecular markers of angiogenesis are reviewed. Recent developments in ultrasound contrast agents targeted to angiogenic markers for both diagnosis and monitoring are discussed. Finally, a brief overview of the emerging field of chemotherapeutic-loaded agents, which can be used with ultrasound-triggered drug delivery, is provided.

Transrectal Subharmonic Ultrasound Imaging for Prostate Cancer Detection.

OBJECTIVE: To assess the prostate cancer (CaP) detection rates of contrast-enhanced, transrectal subharmonic ultrasound imaging (SHI). MATERIALS AND METHODS: This IRB-approved study enrolled 55 subjects. The initial 5 subjects were studied for SHI optimization, while the remaining 50 were evaluated with contrast-enhanced sonography using continuous SHI, color, and power Doppler as well as conventional grayscale, continuous color, and power Doppler and SHI combined with maximum flash replenishment. A maximum of 6 directed biopsy cores were obtained from sites of greatest asymmetrical enhancement, followed by spatially distributed cores in a double sextant distribution. Subharmonic time-intensity parameters, including time to peak intensity, peak intensity, and estimated perfusion were also evaluated for each directed biopsy core. Receiver operating characteristic curve analysis and conditional logistic regression were employed to assess the benefit of each modality and the quantitative SHI parameters. RESULTS: Cancer was detected in 22 of 50 subjects. Among subjects with clinically significant CaP (n = 11), targeted cores were more likely to be positive (odds ratio 1.39, P = .02). The majority of patients detected by SHI demonstrated significant CaP (5/8); SHI remained an independent marker of malignancy in a multivariate logistic regression model (P = .027). Receiver operating characteristic curve analysis of imaging findings compared to biopsy results yielded diagnostic accuracies ranging from 0.59 to 0.80 for all imaging modalities with the highest being for quantitative subharmonic perfusion estimates. CONCLUSION: This first-in-humans study provides a preliminary estimate of the diagnostic accuracy of SHI for detection of clinically significant CaP (up to 80%).

3D micro-scale deformations of wood in bending: synchrotron radiation muCT data analyzed with digital volume correlation.

A micro-scale three-point-bending experiment with a wood specimen was carried out and monitored by synchrotron radiation micro-computed tomography. The full three-dimensional wood structure of the 1.57x3.42x0.75mm(3) specimen was reconstructed at cellular level in different loading states. Furthermore, the full three-dimensional deformation field of the loaded wood specimen was determined by digital volume correlation, applied to the reconstructed data at successive loading states. Results from two selected regions within the wood specimen are presented as continuous displacement and strain fields in both 2D and 3D. The applied combination of synchrotron radiation micro-computed tomography and digital volume correlation for the deformation analysis of wood under bending stress is a novel application in wood material science. The method offers the potential for the simultaneous observation of structural changes and quantified deformations during in situ micro-mechanical experiments. Moreover, the high spatial resolution allows studying the influence of anatomical features on the fracture behaviour of wood. Possible applications of this method range from bio-mechanical observations in fresh plant tissue to fracture mechanics aspects in structural timber.

Application of the compound probability density function for characterization of breast masses in ultrasound B scans.

The compound probability density function (pdf) is investigated for the ability of its parameters to classify masses in ultrasonic B scan breast images. Results of 198 images (29 malignant and 70 benign cases and two images per case) are reported and compared to the classification performance reported by us earlier in this journal. A new parameter, the speckle factor, calculated from the parameters of the compound pdf was explored to separate benign and malignant masses. The receiver operating characteristic curve for the parameter resulted in an A(z) value of 0.852. This parameter was combined with one of the parameters from our previous work, namely the ratio of the K distribution parameter at the site and away from the site. This combined parameter resulted in an A(z) value of 0.955. In conclusion, the parameters of the K distribution and the compound pdf may be useful in the classification of breast masses. These parameters can be calculated in an automated fashion. It should be possible to combine the results of the ultrasonic image analysis with those of traditional mammography, thereby increasing the accuracy of breast cancer diagnosis.

Endosonographic and color Doppler flow imaging alterations observed within irradiate rectal cancer.

PURPOSE: To correlate the endosonographic and color Doppler flow imaging alterations observed in irradiated rectal cancers with the pathologic features of radiation response, and to evaluate the potential impact of altered blood flow on the integrity of the surgical anastomosis. METHODS AND MATERIALS: Endosonography with color and pulsed wave Doppler was performed on 20 rectal cancer masses before and after high dose preoperative radiation (XRT). Pre- and post-XRT observations included comparing alterations in tumor size, sonographic echotexture, color Doppler flow, and pulsatility indices. Comparisons were made with pathologic findings in the irradiated specimens and with the incidence of anastomotic failure. RESULTS: Compared to pre-XRT observations, irradiated rectal cancers decreased in size and became either mixed in echogenicity with less apparent color Doppler flow (16 of 20) or unchanged in color Doppler flow and echotexture (4 of 20). Those with less flow (16 of 20) were imaged later (mean = 90.2 +/- 12.1 days) than those without change in color Doppler flow (mean = 21.7 +/- 2.7 days). Pathologically, the group of four without change in color Doppler signal had features of acute inflammation which were not observed in 16 of 20 imaged later. Based on pulsatility index measurements, both high and low resistance vessels were detected and confirmed by immunohistochemical staining, and features of postradiation obliterative vasculitis were observed. Only one primary anastomosis in 14 patients with decreased flow failed. CONCLUSIONS: The sonographic and color Doppler flow imaging alterations observed within irradiated rectal cancer correlated with changes of postradiation obliterative vasculitis. The apparent diminished local blood flow within high and low resistance vessels post-XRT did not result in an increased incidence of anastomotic failures.

Enhanced detection of blood flow in the normal canine prostate using an ultrasound contrast agent.

RATIONALE AND OBJECTIVES: To evaluate the sonographic appearance of normal prostate vascularity in dogs before and after injection of a new ultrasound contrast agent, NC100100. METHODS: Thirty-five intravenous injections of NC100100, in doses ranging from 0.00625 to 0.05 microL microbubbles/kg, were administered to seven anesthetized mongrel male dogs. Transrectal color Doppler imaging and power Doppler imaging were used to perform the assessment. The visibility of the vascular pattern of the prostate was assessed, including dynamics of contrast inflow, blood flow symmetry, and duration times. RESULTS: Before contrast administration, the vascular pattern was poorly visualized in all cases. After contrast injection, the visibility of the vascular architecture improved significantly for both modalities. Independent of the imaging method used, higher doses tended to be more effective than lower doses. Contrast kinetics in the prostate vessels was demonstrated with a mean time from injection of the ultrasound contrast agent to enhancement of the Doppler signals in the subcapsular arteries (+/-1 SD) of 13+/-3 seconds, and the ultrasound contrast agent reached the central periurethral veins 3 to 6 seconds later. A spokelike radial pattern of internal prostatic vessels observed with enhanced ultrasound could also be seen on silicone microfil x-ray images. The Doppler enhancement persisted for a mean time ( +/-1 SD) of 904 seconds (approximately 15 minutes) +/- 225 seconds and tended to increase with increasing dose. CONCLUSIONS: NC100100 significantly improves the detection of blood flow in the normal canine prostate and allows more accurate depiction of the vascular architecture of the prostate.

Computer aided classification of masses in ultrasonic mammography.

Frequency compounding was recently investigated for computer aided classification of masses in ultrasonic B-mode images as benign or malignant. The classification was performed using the normalized parameters of the Nakagami distribution at a single region of interest at the site of the mass. A combination of normalized Nakagami parameters from two different images of a mass was undertaken to improve the performance of classification. Receiver operating characteristic (ROC) analysis showed that such an approach resulted in an area of 0.83 under the ROC curve. The aim of the work described in this paper is to see whether a feature describing the characteristic of the boundary can be extracted and combined with the Nakagami parameter to further improve the performance of classification. The combination of the features has been performed using a weighted summation. Results indicate a 10% improvement in specificity at a sensitivity of 96% after combining the information at the site and at the boundary. Moreover, the technique requires minimal clinical intervention and has a performance that reaches that of the trained radiologist. It is hence suggested that this technique may be utilized in practice to characterize breast masses.

Assessment of hybrid speckle reduction algorithms.

A consequence of employing coherent detection methods in medical ultrasound imaging systems is the occurrence of interference effects in the received echo field, which produce the speckle artefact. Speckle can severely degrade the information content of the image, and its efficient removal from ultrasound pulse-echo images is the focus of a number of research projects. Traditionally, the approach towards speckle reduction in pulse-echo images has been based on two classes of technique, either employing some form of spatial/frequency compounding or a data (image) filter. Both approaches have inherent shortcomings, and two alternative techniques are suggested here: 'local frequency diversity' and 'frequency differencing'. These algorithms deterministically identify where speckle occurs, and correct for speckle only within short, localized, corrupted segments of the A-line. This provides the potential for real-time implementation. Simulated and clinical in vivo images have been obtained, and the capabilities of the alternative speckle reduction algorithms are assessed against the more conventional approaches.

Ultrasonic characterization of the nonlinear properties of contrast microbubbles.

The nonlinear properties of microbubble contrast agents have been used to create contrast-specific imaging modalities such as harmonic imaging and subharmonic imaging. Thus, a better understanding of the nonlinear performance of contrast microbubbles may enhance the diagnostic capabilities of medical ultrasound (US) imaging. The first and second harmonic, the 1/2 order subharmonic and the 3/2 order ultraharmonic components in spectra of scattered signals from Optison microbubbles insonified at 2 and 4 MHz have been investigated using an in vitro laboratory pulse-echo system. The development of these signal components over time is quite different for 2-MHz insonification compared to 4-MHz insonification. Scattered subharmonic and ultraharmonic signals are much more time-dependent than first and second harmonic echoes. The dependence of the first and second harmonic, subharmonic and ultraharmonic components on acoustic pressure for 2-MHz insonification is similar to that for 4-MHz insonification. The first and second harmonic components increase linearly with acoustic pressure (in double logarithmic scales) and the subharmonic and ultraharmonic amplitudes undergo rapid growths in the intermediate acoustic pressure range and much slower increases at both lower and higher acoustic pressures.

Ultrasound contrast agents: a review.

During the past 25 years, many attempts have been made to establish effective ultrasound contrast agents for both cardiac and noncardiac applications. The ideal ultrasound contrast agent would be: (a) nontoxic; (b) injectable intravenously; (c) capable of passing through the pulmonary, cardiac and capillary circulations; and (d) stable for recirculation. A variety of potential ultrasound contrast agents have been or are now under development. Present and future ultrasound contrast agents should provide for increased diagnostic capabilities in a variety of normal and abnormal vessels and organs throughout the body. These agents will enhance tumor vascularity, delineate areas of ischemia, as well as improve visualization of vascular stenosis. Future developments with modification of ultrasound equipment should increase the capabilities of these agents to improve imaging as well as Doppler sensitivity.

Quantitative ultrasonic diagnosis of silicone breast implant rupture: an in vitro feasibility study.

Ultrasound is useful in evaluating the integrity of silicone breast implants. However, extensive operator experience is required. A system for computer-assisted diagnosis is being developed to reduce operator dependence. Feasibility was examined by measuring the ultrasonic properties of breast implants in vitro. Silicone gels from 45 explanted implants (26 intact and 19 ruptured) were placed in sealed acoustic test chambers and 60 RF A-lines were acquired from each. Velocity of sound, attenuation and integrated backscatter (IB) were estimated. Receiver operating characteristic (ROC) analysis was performed. The mean speed of sound was 1060 m/s +/- 50.1 m/s in intact implants and 1115 m/s +/- 74.3 m/s in ruptured ones (p < 0.003). Differences in attenuation were not statistically significant. The mean IB was -83.9 dB +/- 7.94 dB in intact and -77.2 dB +/- 9.07 dB in ruptured implants (p < 0.006). The area under the ROC curve (Az) was 0.70 and 0.73 for IB and velocity, respectively, while combining the two yielded Az = 0.81. Changes in speed of sound and IB, with changes in integrity of breast implants, have been demonstrated in vitro. The results indicate the potential for quantitative assessment of silicone breast implants performed in vivo.

Destruction of contrast microbubbles and the association with inertial cavitation.

The destruction of insonified Sonazoid microbubbles and its association with inertial cavitation in vitro utilizing an active acoustic detector was investigated. The experimental observation indicated that contrast microbubbles could be damaged at moderate acoustic pressures of 0.6-1.6 MPa (0.4-1.0 in mechanical index, MI). A damaged bubble could be dissolved into the medium on the order of 1 ms, implying that the destruction at moderate pressures is a relatively slow (relative to inertial bubble collapse), nonviolent dissolution process following the disruption of encapsulating surface materials. Inertial cavitation events in the presence of contrast microbubbles were observed using multiple highly intense ultrasound (US) pulses (>1.6 MPa). This observation suggested that intense US might disintegrate contrast microbubbles, and fragments of disintegrated microbubbles could be activated by an upcoming highly intense imaging pulse. The above results imply that inertial cavitation is unlikely to take place in the presence of Sonazoid contrast microbubbles when exposed to diagnostic US with an MI <1.

Tissue classification with generalized spectrum parameters.

This paper presents performance comparisons between breast tumor classifiers based on parameters from a conventional texture analysis (CTA) and the generalized spectrum (GS). The computations of GS-based parameters from radiofrequency (RF) ultrasonic scans and their relationship to underlying scatterer properties are described. Clinical experiments demonstrate classifier performances using 22 benign and 24 malignant breast mass regions taken from 40 patients. Linear classifiers based on parameters from the front edge, back edge and interior tumor regions are examined. Results show significantly better performances for GS-based classifiers, with improvements in empirical receiver operating characteristic (ROC) areas of greater than 10%. The ROC curves show GS-based classifiers achieving a 90% sensitivity level at 50% specificity when applied to the back-edge tumor regions, an 80% sensitivity level at 65% specificity when applied to the front-edge tumor regions, and a 100% sensitivity level at 45% specificity when applied to the interior tumor regions.

Quantitative acoustic characterization of a new surfactant-based ultrasound contrast agent.

The acoustic properties of a new ultrasound contrast agent, ST68, have been investigated. ST68 is a sonicated mixture of nonionic surfactants (Span-type and Tween-type) consisting of stabilized microbubbles with a mean diameter of 3.8 microns and a concentrations of 7.1 x 10(8) bubbles/mL. A pulsatile flow system was used to acquire data in vitro. The acoustic properties of ST68, as a function of time, frequency and dose, were calculated. Enhancement changed nonlinearly with contrast agent dose; maximum was 13.1 dB +/- 1.0 dB for a dose of 0.30 microL/mL of suspending medium. Attenuation reached approximately 11 dB/cm for dosages above 0.27 microL/mL and for frequencies between 2.5 and 6.0 MHz. In vivo, i.v. injections of ST68 were given to 4 rabbits (doses from 0.01 to 0.23 mL/kg). A clear increase in flow signal intensity was observed for 1 to 2 min. An in vivo dose-response curve was calculated from audio Doppler signals obtained with a 10-MHz cuff transducer placed around the distal aorta. Maximum enhancement was 18.3 dB +/- 3.13 dB for a 0.13 mL/kg dose. Moreover, ST68 appears to follow a simple relationship between in vivo enhancement and dose. In conclusion, ST68 is capable of producing marked vascular enhancement. Its acoustic properties have been characterized in vitro and in vivo.

Volume flow estimation using time domain correlation and ultrasonic flowmetry.

A comparison of two volumetric blood flow measurement techniques, CVI-Q (based on time domain correlation) and ultrasonic flowmetry, has been performed in vitro and in vivo. A pulsatile flowpump was used to simulate carotid and femoral type waveforms which were measured simultaneously using the two methods. Five dogs had their common carotid and femoral arteries exposed, and the instantaneous maximum volume flow and the mean flow were measured. Each vessel was partially occluded halfway through the experiment, simulating a 90% stenosis. In vitro, both techniques achieved absolute errors below +/- 5% for flow rates over 100 mL/min, but ultrasonic flowmetry had statistically significant larger errors for slower flow rates. In vivo correlation coefficients ranging from 0.73 to 0.95 were obtained with regression line slopes close to unity. The two techniques were in reasonable agreement, but with standard deviations of 20% to 28%. These studies indicate that noninvasive CVI-Q measurements of blood flow in the carotid and femoral arteries are linear and accurate compared to invasive ultrasonic flowmetry.

Pressure dependence of subharmonic signals from contrast microbubbles.

Noninvasive pressure estimation in heart cavities and in major vessels would provide clinicians with a valuable tool for assessing patients with heart and vascular diseases. Some microbubble-based ultrasound contrast agents are particularly well suited for pressure measurements because their substantial compressibility enables microbubbles to vary significantly in size in response to changes in pressure. Pressure changes should then affect reflectivity of microbubbles after intravenous injection of a contrast agent. This has been demonstrated with a galactose-based contrast agent using 2.0-MHz ultrasound tone bursts. Preliminary results indicate that, over the pressure range of 0-186 mmHg, the subharmonic amplitude of scattered signals decreases by as much as 10 dB under optimal acoustic settings and the first and second harmonic amplitudes decrease by less than 3 dB. An excellent correlation between the subharmonic amplitude and the hydrostatic pressure suggests that the subharmonic signal may be utilized for noninvasive detection of pressure changes.

Use of the K-distribution for classification of breast masses.

The K-distribution had been introduced as a valid model to represent the statistics of the envelope of the backscattered echo from phantom and tissue. This paper investigates the efficacy of the parameters of this statistical model; namely, the effective number and the effective cross-section, to characterize breast lesions as benign or malignant. Based on the normalized values of the effective number and the effective scattering cross-section, images containing benign and malignant masses were classified for a data set from 52 patients having breast masses/lesions. The receiver operating characteristic (ROC) curves were then obtained to test the classification based on these two parameters. The results indicate that the parameters of the K-distribution may be useful in classification of the breast lesions as benign and malignant.