Single Contrast Agent Research Articles

Postexcitation collapse as a characteristic of single ultrasound contrast agent destruction

Measurement of the response of single, unconstrained ultrasound contrast agents (UCAs) is useful for facilitating experiment interpretation and theoretical comparison. An experimental setup has been developed to characterize the acoustic large amplitude response of microbubbles called double passive cavitation detection (PCD) which consists of three confocally aligned transducers. The symmetric single bubble responses from within the confocal region are analyzed for the presence or absence of a postexcitation signal (PES), a rebound characteristic response to large amplitude pressures that may follow the initial harmonic UCA response. Experimental sensitivity to the PES is explored by receiving with transducers of different frequencies. Theoretical models indicate postexcitation rebound occurs following shell rupture and inertial cavitation of the UCA. The postexcitation response curves as a cavitation metric are useful for characterizing distinct collapse thresholds among UCAs which arise due to material differences; additionally, the thresholds may be considered as destruction thresholds and compared to a variety of in-vitro and in-vivo studies to aid in understanding the resultant bioeffects in these studies. (NIH Grant R37EB002641.)

Multifunctional nanoprobe to enhance the utility of optical based imaging techniques

Several imaging modalities such as optical coherence tomography, photothermal, photoacoustic and magnetic resonance imaging, are sensitive to different physical properties (i.e. scattering, absorption and magnetic) that can provide contrast within biological tissues. Usually exogenous agents are designed with specific properties to provide contrast for these imaging methods. In nano-biotechnology there is a need to combine several of these properties into a single contrast agent. This multifunctional contrast agent can then be used by various imaging techniques simultaneously or can be used to develop new imaging modalities. We reported and characterized a multifunctional nanoparticle, made from gold nanoshells, which exhibits scattering, photothermal, photoacoustic, and magnetic properties.

Imaging in Vivo Extracellular pH with a Single Paramagnetic Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Contrast Agent

The measurement of extracellular pH (pHe) has potential utility for cancer diagnoses and for assessing the therapeutic effects of pH-dependent therapies. A single magnetic resonance imaging (MRI) contrast agent that is detected through paramagnetic chemical exchange saturation transfer (PARACEST) was designed to measure tumor pH(e) throughout the range of physiologic pH and with magnetic resonance saturation powers that are not harmful to a mouse model of cancer. The chemical characterization and modeling of the contrast agent Yb(3+)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid,10-o-aminoanilide (Yb-DO3A-oAA) suggested that the aryl amine of the agent forms an intramolecular hydrogen bond with a proximal carboxylate ligand, which was essential for generating a practical chemical exchange saturation transfer (CEST) effect from an amine. A ratio of CEST effects from the aryl amine and amide was linearly correlated with pH throughout the physiologic pH range. The pH calibration was used to produce a parametric pH map of a subcutaneous flank tumor on a mouse model of MCF-7 mammary carcinoma. Although refinements in the in vivo CEST MRI methodology may improve the accuracy of pHe measurements, this study demonstrated that the PARACEST contrast agent can be used to generate parametric pH maps of in vivo tumors with saturation power levels that are not harmful to a mouse model of cancer.

Evaluation of brain tumor vessels specific contrast agents for glioblastoma imaging.

A mouse model of glioblastoma multiforme was used to determine the accumulation of a targeted contrast agent in tumor vessels. The contrast agent, consisting of superparamagnetic iron oxide coated with dextran, was functionalized with an anti-insulin-like-growth-factor binding protein 7 (anti-IGFBP7) single domain antibody. The near infrared marker, Cy5.5, was also attached for an in vivo fluorescence study. A 9.4T magnetic resonance imaging (MRI) system was used for in vivo studies on days 10 and 11 following tumor inoculation. T(2) relaxation time was used to measure the accumulation of the contrast agent in the tumor. Changes in tumor to brain contrast because of active targeting were compared with a nontargeted contrast agent. Effective targeting was confirmed with near infrared measurements and fluorescent microscopic analysis. The results showed that there was a statistically significant (P < .01) difference in normalized T(2) between healthy brain and tumor tissue 10 min, 1 h, and 2 h point postinjection of the anti-IGFBP7 single domain antibody targeted and nontargeted iron oxide nanoparticles. A statistical difference remained in animals treated with targeted nanoparticles 24 h postinjection only. The MRI, near infrared imaging, and fluorescent microscopy studies showed corresponding spatial and temporal changes. We concluded that the developed anti-IGFBP7-iron oxide single domain antibody-targeted MRI contrast agent selectively binds to abnormal vessels within a glioblastoma. T(2)-weighted MRI and near infrared imaging are able to detect the targeting effects in brain tumors.

Self-assembly of ultrasonically synthesized gold nanoparticles on protein microbubbles for multiple imaging applications.

Air-filled lysozyme microbubbles can be synthesized in an aqueous medium by emulsification followed by cross-linking of protein molecules under high-intensity ultrasound. The efficiency of formation, size distribution, and morphology of the microbubbles can be controlled by manipulating the experimental conditions, namely, power and length of sonication [Zhou et al., Soft Matter (in press); Med Cavalieri et al., Current Topics in Medicinal Chemistry, 12, 1198–1210 (2010)]. Gold nanoparticles have been sonochemically synthesized and stabilized with bovine serum albumin and polyvinylpyrrolidone. Gold nanoparticles (NPs) have been assembled on the surface of microbubbles in a deposition process. The functionalization of the surface of bubbles endowed the microbubbles with gold plasmon absorption and fluorescence emission. The NP-coated bubbles showed enhanced response when irradiated by 1 MHz ultrasound. We envisage that these stable, multifunctional microbubbles may have important applications in medical diagnostics where multiple imaging methods using a single contrast agent can be advantageous.

Where Contrast Agent Concentration Really Matters – A Comparison of CT and MRI

First pass contrast-enhanced magnetic resonance imaging (MRI) and computed tomography (CT) are influenced by parameters that characterize the injected bolus. The aim of this study was to assess the role of contrast agent concentration and the differences between MRI and CT. We systematically evaluated the published literature to define the differences between MRI and CT with regards to the influence of contrast agent concentration and flow rate on signal enhancement and image quality. Subsequently, we used a simulation model to simulate bolus dispersion in the human body for contrast agents with different concentration. We performed this simulation for different injection times (3-25 seconds) as well as for single and double contrast agent dose, and calculated the effect of contrast agent concentration and dose on the increase of local contrast agent concentration. Although CT studies have shown that even a moderate increase in contrast agent concentration leads to higher peak concentration in the tissue or artery of interest, MRI studies have failed to show a marked benefit of higher concentration. The simulation demonstrated that the use of high concentrated contrast agent leads to an increase in local contrast agent concentration within the tissue or artery of interest, only if injection time is long (in CT commonly >10 seconds) compared with the time constant of bolus dispersion (about 5 seconds in humans). If the injection time is shorter (in MRI commonly 1-4 seconds), the local contrast agent concentration is mainly affected by the injected dose. Contrast agent concentration is a key parameter for the optimization of dynamic imaging techniques such as angiography or perfusion in CT, whereas in dynamic MRI, contrast agent dose and relaxivities are the leading parameters.

Determination of postexcitation thresholds for single ultrasound contrast agent microbubbles using double passive cavitation detection

This work presents experimental responses of single ultrasound contrast agents to short, large amplitude pulses, characterized using double passive cavitation detection. In this technique, two matched, focused receive transducers were aligned orthogonally to capture the acoustic response of a microbubble from within the overlapping confocal region. The microbubbles were categorized according to a classification scheme based on the presence or absence of postexcitation signals, which are secondary broadband spikes following the principle oscillatory response of the ultrasound contrast agent and are indicative of the transient collapse of the microbubble. Experiments were conducted varying insonifying frequencies (0.9, 2.8, 4.6, and 7.1 MHz) and peak rarefactional pressures (200 kPa to 6.2 MPa) for two types of contrast agents (Definity and Optison). Results were fit using logistic regression analysis to define pressure thresholds where at least 5% and 50% of the microbubble populations collapsed for each frequency. These thresholds were found to occur at lower pressures for Definity than for Optison over the range of frequencies studied; additionally, the thresholds occurred at lower pressures with lower frequencies for both microbubble types in most cases, though this trend did not follow a mechanical index scaling.

Optimization of acquisition trajectories for 3D rotational coronary venography

Rotational coronary X-ray imaging on C-arm systems provides a multitude of diagnostic projections from the vascular tree with a single contrast agent bolus. The acquisition trajectory is typically limited to a circular arc with a fixed caudo-cranial angulation. This may cause sub- optimal projection directions for specific vessel segments for all acquired views, e.g., those segments orthogonal to the axis of rotation. In this paper, a method is presented to calculate a patient-independent acquisition trajectory with respect to vessel foreshortening and overlap for multiple vessel segments of the coronary tree. This method can be applied to artery as well as vein anatomy. Rotational coronary venograms of 14 patients have been used to generate three-dimensional mesh representations with a semi-automatic two view modeling algorithm. The venous tree is divided into seven different vessel segments. Foreshortening and overlap of every segment are calculated and combined for all patients in a measure called obstruction value. The weighted obstruction values of all vessel segments define a cost function for the entire two-dimensional angular range of the C-arm system. Viterbi's algorithm is used to calculate an optimal trajectory with respect to this cost function. The method is validated by leave-one-out cross-validation on the 14 rotational venography data sets and on simulated venograms of a segmented computed tomography (CT) data set. Projection images with a foreshortening value below 10% and overlap below 20% are rated 'optimal'. In 12 (85.7%) data sets, 43% more optimal images were acquired using the presented method compared to the standard circular arc trajectory. As well, in 13 (92.8%) data sets 38% more vessel segments can be optimally visualized in the acquired images. The test on the CT data set showed that the resulting average root-mean-square error of the extracted centerline points of the segmented CT data set compared to the error based on the views from the circular arc was reduced from 2.52 to 1.55 mm. In a first test, the method proved to deliver improved image quality by reducing foreshortening and overlap of vessel segments and may therefore also improve the centerline extraction accuracy of the semi-automatic two view modeling method.

Peripheral Magnetic Resonance Angiography With Continuous Table Movement in Combination With High Spatial and Temporal Resolution Time-Resolved MRA With a Total Single Dose (0.1 mmol/kg) of Gadobutrol at 3.0 T

To prove the concept of peripheral continuous table movement (CTM) MR-angiography (MRA) in combination with high spatial and temporal resolution time-resolved TWIST-MRA in a single MR-examination at 3.0 T with a single dose (0.1 mmol/kg) of gadobutrol in total. We included 22 consecutive patients (15 m/7 f, mean age: 64 years) referred for peripheral MRA with clinical symptoms of peripheral arterial occlusive disease Fontaine stages II-IV. All of them underwent both CTM-MRA (TR: 2.4 ms/TE: 1.0 ms/flip angle: 21 degree) of the entire run-off vessels and TWIST-MRA (TR: 2.8 ms/TE: 1.1 ms/flip angle: 20 degree) of the calf station during a single MR-examination. All examinations were performed on a 3.0 T MR system (Tim Trio). Spatial resolution of the CTM-MRA datasets was technically limited to an acquired resolution of 1.2 x 1.2 x 1.96 mm3 reconstructed to 1.2 mm isotropic. The TWIST-MRA was acquired with 1.1 x 1.1 x 1.35 mm3 and reconstructed to 1.1 mm isotropic with a temporal resolution of 5.5 seconds in the calf station. A total of 0.1 mmol/kg BW gadobutrol diluted 1:1 with saline was injected at a flow rate of 1.5 mL/s of which 0.07 mmol/kg was administered for the CTM-MRA and 0.03 mmol/kg for the TWIST-MRA. CTM-MRA run off datasets were qualitatively assessed using a 4 point scale (4 = excellent, 1 = nondiagnostic) followed by TWIST-MRA datasets for the calf using the same scale. Additional relevant findings only visible in the TWIST-MRA were documented. All datasets could be evaluated with a total of 397 assessable segments. CTM-MRA was diagnostic in 99% (393/397 segments) with image quality judged as excellent in 54% (213/397 segments), good in 42% (14/397), and moderate in 4% (14/397) of analyzed segments respectively. Nondiagnostic image quality was seen in 1% (4/397 segments). Venous overlay in the calf station was found in 27% (6/22 patients). TWIST-MRA was diagnostic in 100% (115/115 segments), throughout with good or excellent image quality. In 14 of 22 patients additional relevant findings were detected by TWIST-MRA. Single-dose gadobutrol CTM-MRA in combination with a high spatial and temporal resolution TWIST-MRA at 3.0 T is a reliable technique with good image quality. Despite the use of single dose contrast agent large field of view coverage and dynamic images can be acquired. Because of its robustness, this imaging approach of the vasculature has great potential for a broad clinical use.

Optimal dosage of ultrasound contrast agent for ultrasound surgery: Thermal effect of linear plane wave

The optimal dosage of ultrasound contrast agent model for ultrasound surgery was explored. A specific ultrasound contrast agent Albunex ® was chosen for simulation. The model was developed based on a dilute bubbly liquid model proposed by Ye and Ding [Z. Ye, L. Ding, Acoustic dispersion and attenuation relations in bubbly mixture, J. Acoust. Soc. Am. 98 (3) (1995) 1629–1636]. The numerical simulation suggests that 2 MHz is more efficient than 1 MHz to thermally treat cancer in deep tissue with the optimal dosage of 3 ml. On the other hand, the simulation also suggests 3 MHz center frequency with the optimal dosage of 1.6 ml is adequate for prostate cancer treatment with transrectal equipment. The simulation is expected to valid up to 2 MPa incident pressure due to the limitation of the linearized UCA model. Even though it is developed from a single ultrasound contrast agent, this model is expected to be useful for any ultrasound contrast agent as long as the necessary parameters are provided.

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.

Combined optical and acoustical characterization of single ultrasound contrast agent microbubbles

Contrast enhancement in medical ultrasound imaging is provided by the non‐linear characteristics of coated microbubbles used as Ultrasound Contrast Agents (UCA). Optical time‐resolved observations of the UCA microbubble dynamics have revealed new non‐linear bubble behavior such as "compression only" and "thresholding" behavior. Up to now, the contributions of such behavior to the non‐linear acoustic response of UCA microbubbles is not known. Theoretically, the sound emission of an oscillating microbubble is derived from the unsteady Bernoulli equation and mass conservation assuming incompressible and irrotational flow. An experimental validation of this relation between the radial dynamics and the sound emission of a microbubble is not straightforward. We present a combined optical and acoustical setup to characterize individual BR‐14 (Bracco Research S.A., Geneva, Switzerland) UCA microbubbles. The bubbles were isolated in a capillary fiber by an active flow control. During insonation the radial response of the single microbubble was recorded with the Brandaris ultra high‐speed camera while the resulting acoustic response was measured with an accurately calibrated sensitive transducer. The sound emission calculated from the measured radius‐time curves gives excellent quantitative agreement with the directly measured sound emission for both the linearly oscillating microbubbles and bubbles displaying "compression‐only" and "thresholding" behavior, which indeed resulted in a strong non‐linear sound emission.

Nanoparticles as Contrast Agents for MRI of Atherosclerotic Lesions

Nanoparticle contrast agents for MRI may aid in identifying atherosclerotic lesions that give rise to ischemic events by means of penetration and retention in the plaque. These imaging agents may provide valuable information regarding plaque characteristics which can help determine the risk of plaque rupture. By increasing molecular flexibility or adding a means of specifically targeting ligands via antibody or peptide, nanoparticles can enhance certain regions of the atherosclerotic plaque. The development of single contrast agents detectable with multiple imaging modalities may further improve our ability to detect and characterize atherosclerosis in clinical and preclinical applications. These exciting developments may help in the realization of MRI as a powerful tool in the prevention of cardiovascular morbidity and mortality.

High-resolution Myocardial Perfusion Imaging in Mice with High-frequency Echocardiographic Detection of a Depot Contrast Agent

High-resolution methods for assessing myocardial perfusion in murine models of cardiovascular disease are needed. We hypothesized that regional hypoperfusion could be assessed with ultrahigh-frequency myocardial contrast echocardiography (MCE) and a novel strategy of depot contrast enhancement. MCE was performed with 30-MHz transthoracic imaging 10 seconds and 10 minutes after intravenous administration of microbubbles in control mice, and in mice after left anterior descending coronary artery ligation. MCE was also performed using size-segregated microbubbles. Microbubble behavior in the microcirculation was evaluated with intravital microscopy. In control mice anterior myocardial enhancement was robust at 10 seconds, but left ventricular cavity attenuation precluded evaluation of posterior segments. After 10 minutes, left ventricular cavity signal cleared but myocardial enhancement persisted, permitting analysis of all segments. The degree of enhancement at 10 min was related to microbubble size, implying retention of large microbubbles transiting pulmonary arteriovenous shunts. Intravital microscopy confirmed capillary lodging of large microbubbles. Infarct size by delayed MCE correlated with fluorescent nanospheres (r = 0.94, P < .001). We conclude that complete assessment of regional myocardial perfusion in the mouse heart is possible with high-frequency MCE and a single intravenous contrast agent injection. This technique can be used for characterizing murine models of myocardial infarction and left ventricular remodeling.

In vivo photoacoustic flow cytometry for monitoring of circulating single cancer cells and contrast agents

A new photoacoustic flow cytometry was developed for real-time detection of circulating cells, nanoparticles, and contrast agents in vivo. Its capability, integrated with photothermal and optical clearing methods, was demonstrated using a near-infrared tunable laser to characterize the in vivo kinetics of Indocyanine Green alone and single cancer cells labeled with gold nanorods and Indocyanine Green in the vasculature of the mouse ear. In vivo applications are discussed, including selective nanophotothermolysis of metastatic squamous cells, label-free detection of melanoma cells, study of pharmokinetics, and immune response to apoptotic and necrotic cells, with potential translation to humans. The threshold sensitivity is estimated as one cancer cell in the background of 10(7) normal blood cells.

Intraoperative brain ultrasound: A new approach to study flow dynamics in intracranial aneurysms

The aim was to evaluate the potential of contrast-enhanced ultrasound to visualize the hemodynamics in intracranial aneurysms during neurosurgical intervention and to quantify the ultrasound data using digital particle image velocimetry (DPIV) technique. Aneurysms were scanned through the intact dura mater, preclipping and again postclipping after closure of the dura. After intravenous injection of Optison™, angio-like views of the vascular tree surrounding the aneurysm, including the aneurysm sac, were obtained. Single ultrasound contrast agent microbubbles could be visualized in the aneurysm sac and the flow dynamics could be assessed in vivo. Spatial and temporal distributions of the velocity in the aneurysm and in the parent vessels were measured with DPIV using the backscattered signals from the microbubbles. Subsequently, the fluid stresses, vorticity, circulation, etc., were calculated from the velocity fields. We demonstrate in this paper that intraoperative contrast-enhanced ultrasound can be used to quantify the flow dynamics within an aneurysm. (E-mail: thoelscher@ucsd.edu)

Comparison of errors associated with single‐ and multi‐bolus injection protocols in low‐temporal‐resolution dynamic contrast‐enhanced tracer kinetic analysis

Accurate sampling of the arterial input function (AIF) in low-temporal-resolution quantitative dynamic contrast-enhanced MRI (DCE-MRI) studies is crucial for accurate and reproducible parameter estimation. However, when conventional AIFs are sampled at low temporal resolution, they introduce an unpredictable degree of error. An alternative double contrast agent (CA) bolus injection protocol designed to compensate for temporal mis-sampling of the AIF and tissue uptake curve was simulated in addition to a commonly used single CA bolus injection protocol. A range of tissue uptake curves for each AIF form were generated using a distributed parameter model, and Monte Carlo simulation studies were performed over a range of offset times (to mimic temporal mis-sampling), temporal resolutions and SNR in order to compare the performance of both AIF forms in compartmental modeling. Insufficient data sampling of the single bolus AIF at temporal resolutions in excess of 9 s leads to large errors, which can be reduced by employing an additional, appropriately administered, second CA bolus injection.

Detection of Cardiac Right-to-Left Shunts by Contrast-Enhanced Harmonic Carotid Duplex Sonography

Paradoxical embolization by cardiac right-to-left shunts (RLS) is increasingly recognized as an important factor for embolic stroke. Contrast-enhanced transcranial Doppler sonography (ce-TCDS) is an established diagnostic tool for RLS detection but is frequently limited because of an inadequate temporal acoustic bone window. The purpose of this study was to determine whether extracranial sonography (ECS) using harmonic frequencies improves detection of RLS. Extracranial color duplex sonography using harmonic frequencies enables visualization of even single ultrasound contrast agent microbubbles because of oscillation. Patients with stroke and positive RLS findings on transesophageal echocardiography underwent a simultaneous extracranial and transcranial sonographic examination of the proximal common carotid artery (CCA) and middle cerebral artery (MCA) on the same side. A Valsalva strain was performed for 10 seconds after intravenous bolus injection of a galactose-based nontranspulmonary contrast agent. The B-mode frame sequences of the transverse plane of the CCA obtained by harmonic ECS and the ce-TCDS recordings of high-intensity transient signals from the MCA were analyzed offline. In all patients with RLS, the shunts could be identified by harmonic ECS. A close correlation could be seen between the count of visualized microbubbles in the CCA and the number of high-intensity transient signals detected on ce-TCDS in the ipsilateral MCA. The results of this study indicate that contrast-enhanced ultrasound harmonic imaging of the CCA using a Valsalva strain might be an optional screening tool for detection of cardiac RLS in patients with insufficient acoustic bone windows.

Ressonância magnética de alta resolução espacial para estudo arterial periférico com aquisição segmentar e contínua: Mobitrak

O objetivo é apresentar uma técnica recente para a avaliação de obstruções arteriais dos membros inferiores por ressonância magnética em um único momento e com a utilização de dose dupla do meio de contraste paramagnético administrado de forma lenta através de bomba injetora. O método baseia-se em um "software" e "hardware" denominado Mobitrak, disponível nos aparelhos de alto campo de ressonância da Philips, que permite a avaliação de uma grande extensão vascular a partir de aquisições de alta resolução, segmentares e contínuas. A seqüência utilizada é um gradiente eco (FFE) que permite a programação de três segmentos simultaneamente, com pequena sobreposição nas intersecções desses segmentos. Essa seqüência dinâmica é obtida em duas fases, uma previamente ao contraste e outra durante a injeção lenta deste, com subtração do sinal dos tecidos adjacentes e reconstruções em 3D. O método apresenta vários benefícios, como: melhor visualização dos segmentos tibiofibulares, estudo de toda a aorta e o membro inferior em uma única visita do paciente, com baixo volume de meio de contraste.

Theoretical and experimental investigation of the behaviour of ultrasound contrast agent particles in whole blood

The majority of the existing models for the behaviour of ultrasound (US) contrast agents consider a single contrast agent particle (CAP) surrounded by an infinite, homogeneous and Newtonian fluid. In vivo, however, CAPs are suspended within the confines of blood vessels, in fluid containing both other CAPs and a high volume fraction of cells of comparable size. The aim of this work was to investigate the influence of blood cells upon CAP acoustic response to determine how existing models should be modified for the purposes of improving CAP design. A new model for a CAP surrounded by a cluster of cells was derived and solved numerically. Broadband US attenuation measurements were then made in suspensions of Optison® (Amersham PLC, Bucks, UK) in plasma and in whole blood. Both the theoretical and experimental results indicate that the presence of blood cells has a relatively small effect upon CAP dynamics and hence acoustic response. This implies that it is justifiable to model blood as homogeneous and Newtonian for the purposes of CAP design.(E-mail: e_stride@meng.ucl.ac.uk)