Marcel Arditi

Influence of Bubble Size Distribution on the Echogenicity of Ultrasound Contrast Agents: A Study of Sonovue™

Gorce J-M, Arditi M, Schneider M. Influence of bubble size distribution on the echogenicity of ultrasound contrast agents: A study of SonoVue™. Invest Radiol 2000;35:661–671. RATIONALE AND OBJECTIVES.To study the relative contributions of different bubble size classes to SonoVue™’s echogenicity in fundamental acoustic imaging modes. SonoVue™ is a contrast agent, previously known as BR1, with a bubble size distribution extending from approximately 0.7 to 10 &mgr;m. METHODS.A model for the acoustic response of SonoVue™ was determined and validated for a set of experimental data. This model was used to simulate the acoustic response of a standard batch of SonoVue™ as the sum of responses of nonoverlapping bubble size classes. RESULTS.The simulation was first validated for a standard SonoVue™ bubble size distribution. When this distribution was considered as five size classes with equal numbers of bubbles, it was found that bubbles smaller than 2 &mgr;m accounted for 60% of the total number but contained only 5% of the total gas volume. The simulation results indicated marked differences in the acoustic contributions from these classes, with 80% of the acoustic efficacy provided by bubbles 3 to 9 &mgr;m in diameter. The study also compared bubble distributions in number, surface, and volume, with the distribution computed in terms of acoustic efficacy. CONCLUSIONS.This study shows why bubble volume is a much better indicator of SonoVue™’s efficacy than is bubble count. A low threshold in diameter was found for SonoVue™ microbubbles at approximately 2 &mgr;m, under which size bubbles do not contribute appreciably to the echogenicity at medical ultrasound frequencies.

BR1: A new ultrasonographic contrast agent based on sulfur hexafluoride-filled microbubbles

RATIONALE AND OBJECTIVESThe basic characteristics of BR1, a novel echo contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles have been evaluated. METHODSThe authors determined the physicochemical properties (bubble concentration, bubble size distribution, resistance to pressure, and stability) and the acoustic properties (backscatter and attenuation coefficients) of BR1. The diagnostic value of BR1 was evaluated further in minipigs. Left heart images were recorded before and after injection of different doses of BR1. RESULTSBR1 is formulated as a lyophilized product, which after addition of saline, provides a suspension containing 2 × 108 SF6 microbubbles/mL with a number mean diameter of 2.5 µm. More than 90% of the bubbles are below 8 µm. The use of SF6 rather than air provides an improved resistance to pressure increases such as the ones occuring in the left heart during systole. After reconstitution, the echogenicity and the bubble characteristics are unchanged for more than 8 hours. The high echogenicity remains almost constant over the entire medical frequency range ( 1−10 MHz). BR1 injections in animals resulted in a homogenous, dose-dependent opacification of the left heart. CONCLUSIONSConsidering its high echogenicity, outstanding stability, and resistance to pressure changes, BR1 is a very promising ultrasound contrast agent.

A new formalism for the quantification of tissue perfusion by the destruction-replenishment method in contrast ultrasound imaging

A new formalism is presented for the destruction-replenishment perfusion quantification approach at low mechanical index. On the basis of physical considerations, best-fit methods should be applied using perfusion functions with S-shape characteristics. These functions are first described for the case of a geometry with a single flow velocity, then extended to the case of vascular beds with blood vessels having multiple flow velocity values and directions. The principles guiding the analysis are, on one hand, a linearization of video echo signals to overcome the log-compression of the imaging instrument, and, on the other hand, the spatial distribution of the transmit-receive ultrasound beam in the elevation direction. An in vitro model also is described; it was used to confirm experimentally the validity of the approach using a commercial contrast agent. The approach was implemented in the form of a computer program, taking as input a sequence of contrast-specific images, as well as parameters related to the ultrasound imaging equipment used. The generated output is either flow-parameter values computed in regions-of-interest, or parametric flow-images (e.g., mean velocity, mean transit time, mean flow, flow variance, or skewness). This approach thus establishes a base for extracting information about the morphology of vascular beds in vivo, and could allow absolute quantification provided that appropriate instrument calibration is implemented.

Parametric imaging for characterizing focal liver lesions in contrast-enhanced ultrasound

The differentiation between benign and malignant focal liver lesions plays an important role in diagnosis of liver disease and therapeutic planning of local or general disease. This differentiation, based on characterization, relies on the observation of the dynamic vascular patterns (DVP) of lesions with respect to adjacent parenchyma, and may be assessed during contrast-enhanced ultrasound imaging after a bolus injection. For instance, hemangiomas (i.e., benign lesions) exhibit hyper-enhanced signatures over time, whereas metastases (i.e., malignant lesions) frequently present hyper-enhanced foci during the arterial phase and always become hypo-enhanced afterwards. The objective of this work was to develop a new parametric imaging technique, aimed at mapping the DVP signatures into a single image called a DVP parametric image, conceived as a diagnostic aid tool for characterizing lesion types. The methodology consisted in processing a time sequence of images (DICOM video data) using four consecutive steps: (1) pre-processing combining image motion correction and linearization to derive an echo-power signal, in each pixel, proportional to local contrast agent concentration over time; (2) signal modeling, by means of a curve-fitting optimization, to compute a difference signal in each pixel, as the subtraction of adjacent parenchyma kinetic from the echo-power signal; (3) classification of difference signals; and (4) parametric image rendering to represent classified pixels as a support for diagnosis. DVP parametric imaging was the object of a clinical assessment on a total of 146 lesions, imaged using different medical ultrasound systems. The resulting sensitivity and specificity were 97% and 91%, respectively, which compare favorably with scores of 81 to 95% and 80 to 95% reported in medical literature for sensitivity and specificity, respectively.

POLYMERIC MICROBALLOONS AS ULTRASOUND CONTRAST AGENTS : PHYSICAL AND ULTRASONIC PROPERTIES COMPARED WITH SONICATED ALBUMIN

Air-filled polymeric microballoons were prepared with number-mean diameters of approximately 3 microns, volume-mean diameters of approximately 5 microns, and narrow particle-size distributions (standard deviation [SD] = 1.2 microns in number and SD = 2.0 microns in volume). More than 99% of the particles were below 8 microns. These particles were found to be highly echogenic for ultrasound, showing backscatter coefficients at 7.5 MHz, similar to the ones obtained with sonicated albumin microspheres. However, at 2.25 MHz, microballoons were less echogenic than albumin microspheres. These results are consistent with ultrasound attenuation measurements, which showed a maximum at 8 to 9 MHz for the microballoons compared with a reported value of 3.5 to 4.5 MHz for albumin microbubbles. Polymeric microballoons were found to be stable in plasma or under applied pressure as evidenced by unchanged particle concentration and echogenicity. Albumin microspheres were particularly unstable to applied pressure (150 mm Hg) and showed a rapid decrease in both particle counts and echogenicity.

Subharmonic scattering of phospholipid-shell microbubbles at low acoustic pressure amplitudes

Subharmonic scattering of phospholipid-shell microbubbles excited at relatively low acoustic pressure amplitudes (<;30 kPa) has been associated with echo responses from compression-only bubbles having initial surface tension values close to zero. In this work, the relation between subharmonics and compression-only behavior of phospholipid-shell microbubbles was investigated, experimentally and by simulation, as a function of the initial surface tension by applying ambient overpressures of 0 and 180 mmHg. The microbubbles were excited using a 64-cycle transmit burst with a center frequency of 4 MHz and peak-negative pressure amplitudes ranging from 20 of 150 kPa. In these conditions, an increase in subharmonic response of 28.9 dB (P <; 0.05) was measured at 50 kPa after applying an overpressure of 180 mmHg. Simulations using the Marmottant model, taking into account the effect of ambient overpressure on bubble size and initial surface tension, confirmed the relation between subharmonics observed in the pressure-time curves and compression-only behavior observed in the radius-time curves. The trend of an increase in subharmonic response as a function of ambient overpressure, i.e., as a function of the initial surface tension, was predicted by the model. Subharmonics present in the echo responses of phospholipid-shell microbubbles excited at low acoustic pressure amplitudes are indeed related to the echo responses from compression-only bubbles. The increase in subharmonics as a function of ambient overpressure may be exploited for improving methods for noninvasive pressure measurement in heart cavities or big vessels in the human body.

In-vivo perfusion quantification by contrast ultrasound: Validation of the use of linearized video data vs. raw RF data

Perfusion quantification software commonly analyzes log-compressed video images provided by ultrasound systems. Compared to analysis of raw RF signals, errors in perfusion parameter estimates may be introduced, even when proper linearization is applied to reverse the log-compression. In this work, the effects of log-compression, demodulation, scan conversion and 8-bit quantization have been investigated, in terms of the errors introduced on perfusion parameter estimates. An in-vivo contrast bolus sequence was processed using both raw RF data and linearized video data. The outcome is that linearizing log-compressed video sequences can provide estimates as accurate as processing RF data under two conditions: a) system gain should be such as to prevent both excessive truncation of pixel values to minimum level and saturation to maximum level; b) the dynamic range of log-compression should be 45 dB or higher.

Acoustic characterization of single ultrasound contrast agent microbubbles

Individual ultrasound contrast agent microbubbles (BR14) were characterized acoustically. The bubbles were excited at a frequency of 2 MHz and at peak-negative pressure amplitudes of 60 and 100 kPa. By measuring the transmit and receive transfer functions of both the transmit and receive transducers, echoes of individual bubbles were recorded quantitatively and compared to simulated data. At 100 kPa driving pressure, a second harmonic response was observed for bubbles with a size close to their resonance size. Power spectra were derived from the echo waveforms of bubbles of different sizes. These spectra were in good agreement with those calculated from a Rayleigh-Plesset-type model, incorporating the viscoelastic properties of the phospholipid shell. Small bubbles excited below their resonance frequency have a response dominated by the characteristics of their phospholipid shell, whereas larger bubbles, excited above resonance, have a response identical to those of uncoated bubbles of similar size.

Effects of Acoustic Radiation Force on the Binding Efficiency of BR55, a VEGFR2-Specific Ultrasound Contrast Agent

This work describes an in vivo study analyzing the effect of acoustic radiation force (ARF) on the binding of BR55 VEGFR2-specific contrast-agent microbubbles in a model of prostatic adenocarcinoma in rat. A commercial ultrasound system was modified by implementing high duty-cycle 3.5-MHz center frequency ARF bursts in a scanning configuration. This enabled comparing the effects of ARF on binding in tumor and healthy tissue effectively in the same field of view. Bubble binding was established by measuring late-phase enhancement in amplitude modulation (AM) contrast-specific imaging mode (4 MHz, 150 kPa) 10 min after agent injection when the unbound bubbles were cleared from the circulation. Optimal experimental conditions, such as agent concentration (0.4 × 10(8)-1.6 × 10(8) bubbles/kg), acoustic pressure amplitude (26-51 kPa) and duty-cycle (20%-95%) of the ARF bursts, were evaluated in their ability to enhance binding in tumor without significantly increasing binding in healthy tissue. Using the optimal conditions (38 kPa peak-negative pressure, 95% duty cycle), ARF-assisted binding of BR55 improved significantly in tumor (by a factor of 7) at a lower agent dose compared with binding without ARF, and it had an insignificant effect on binding in healthy tissue. Thus, the high binding specificity of BR55 microbubbles for targeting VEGFR2 present at sites of active angiogenesis was confirmed by this study. Therefore, it is believed that based on the results obtained in this work, ultrasound molecular imaging using target-specific contrast-agent microbubbles should preferably be performed in combination with ARF.

Differentiation of Focal Liver Lesions: Usefulness of Parametric Imaging with Contrast-enhanced US

PURPOSE To evaluate whether parametric imaging with contrast material-enhanced ultrasonography (US) is superior to visual assessment for the differential diagnosis of focal liver lesions (FLLs). MATERIALS AND METHODS This study had institutional review board approval, and verbal patient informed consent was obtained. Between August 2005 and October 2008, 146 FLLs in 145 patients (63 women, 82 men; mean age, 62.5 years; age range, 22-89 years) were imaged with real-time low-mechanical-index contrast-enhanced US after a bolus injection of 2.4 mL of a second-generation contrast agent. Clips showing contrast agent uptake kinetics (including arterial, portal, and late phases) were recorded and subsequently analyzed off-line with dedicated image processing software. Analysis of the dynamic vascular patterns (DVPs) of lesions with respect to adjacent parenchyma allowed mapping DVP signatures on a single parametric image. Cine loops of contrast-enhanced US and results from parametric imaging of DVP were assessed separately by three independent off-site readers who classified each lesion as benign, malignant, or indeterminate. Sensitivity, specificity, accuracy, and positive and negative predictive values were calculated for both techniques. Interobserver agreement (κ statistics) was determined. RESULTS Sensitivities for visual interpretation of cine loops for the three readers were 85.0%, 77.9%, and 87.6%, which improved significantly to 96.5%, 97.3%, and 96.5% for parametric imaging, respectively (P < .05, McNemar test), while retaining high specificity (90.9% for all three readers). Accuracy scores of parametric imaging were higher than those of conventional contrast-enhanced US for all three readers (P < .001, McNemar test). Interobserver agreement increased with DVP parametric imaging compared with conventional contrast-enhanced US (change of κ from 0.54 to 0.99). CONCLUSION Parametric imaging of DVP improves diagnostic performance of contrast-enhanced US in the differentiation between malignant and benign FLLs; it also provides excellent interobserver agreement.