Behavior Of Ultrasound Contrast Agents Research Articles

Ultrasonic Characterization of Ibidi μ-Slide I Luer Channel Slides for Studies With Ultrasound Contrast Agents.

Understanding and controlling the ultrasound contrast agent (UCA)'s response to an applied ultrasound pressure field are crucial when investigating ultrasound imaging sequences and therapeutic applications. The magnitude and frequency of the applied ultrasonic pressure waves affect the oscillatory response of the UCA. Therefore, it is important to have an ultrasound compatible and optically transparent chamber in which the acoustic response of the UCA can be studied. The aim of our study was to determine the in situ ultrasound pressure amplitude in the ibidi μ -slide I Luer channel, an optically transparent chamber suitable for cell culture, including culture under flow, for all microchannel heights (200, 400, 600, and [Formula: see text]). First, the in situ pressure field in the 800- [Formula: see text] high channel was experimentally characterized using Brandaris 128 ultrahigh-speed camera recordings of microbubbles (MBs) and a subsequent iterative processing method, upon insonification at 2 MHz, 45° incident angle, and 50-kPa peak negative pressure (PNP). Control studies in another cell culture chamber, the CLINIcell, were compared with the obtained results. The pressure amplitude was -3.7 dB with respect to the pressure field without the ibidi μ -slide. Second, using finite-element analysis, we determined the in situ pressure amplitude in the ibidi with the 800- [Formula: see text] channel (33.1 kPa), which was comparable to the experimental value (34 kPa). The simulations were extended to the other ibidi channel heights (200, 400, and [Formula: see text]) with either 35° or 45° incident angle, and at 1 and 2 MHz. The predicted in situ ultrasound pressure fields were between -8.7 and -1.1 dB of the incident pressure field depending on the listed configurations of ibidi slides with different channel heights, applied ultrasound frequencies, and incident angles. In conclusion, the determined ultrasound in situ pressures demonstrate the acoustic compatibility of the ibidi μ -slide I Luer for different channel heights, thereby showing its potential for studying the acoustic behavior of UCAs for imaging and therapy.

The Wash-Out of Contrast-Enhanced Ultrasound for Evaluation of Hypoxic Ischemic Injury in Neonates and Infants: Preliminary Findings.

We evaluated the use of quantitative contrast-enhanced ultrasound (CEUS) to study wash-out behavior of ultrasound contrast agents in the pediatric brain in cases of hypoxic ischemic injury (HII). Six neonates and young infants were imaged using CEUS for suspected HII in the Neonatal Intensive Care Unit/Pediatric Intensive Care Unit. After receiving a bolus of ultrasound contrast agent Lumason (Bracco Diagnostics Inc.), analysis was performed in the whole brain, cortex, cortical/subcortical gray and white matter and central gray nuclei to quantify wash-out metrics and ratios. On magnetic resonance imaging clinical imaging findings, 3 children were classified as unaffected and 3 with classical imaging findings consistent with HII. A lower wash-out rate was found in the case of HII compared with the unaffected cases. Here, we present initial work exploring the wash-out behavior for differentiation between unaffected and HII in the brain. These preliminary findings are indicative of altered hemodynamics in HII and are promising for the potential use of CEUS to quantitatively differentiate between the unaffected and HII brain. Little is known about the CEUS wash-out dynamics, especially in the setting of the pediatric brain injury. Our preliminary findings are encouraging and warrant further investigation into the mechanisms behind delayed clearance of the ultrasound contrast agent in the setting of HII.

Passive Underwater Noise Attenuation Using Large Encapsulated Air Bubbles.

Measurements demonstrating low-frequency underwater sound attenuation using arrays of large, tethered, stationary encapsulated bubbles to surround a sound source were compared with various effective medium models for the acoustic dispersion relationship in bubbly liquids. Good agreement was observed between measurements for the large bubbles (on the order of 10 cm) at frequencies below 1 kHz and a model originally intended to describe the acoustic behavior of ultrasound contrast agents. The primary goal is to use the model for designing encapsulated-bubble-based underwater noise abatement systems and to reduce uncertainty in system performance.

Acoustic characterization of monodisperse lipid-coated microbubbles: relationship between size and shell viscoelastic properties.

The acoustic attenuation spectrum of lipid-coated microbubble suspensions was measured in order to characterize the linear acoustic behavior of ultrasound contrast agents. For that purpose, microbubbles samples were generated with a very narrow size distribution by using microfluidics techniques. A performance as good as optical characterization techniques of single microbubbles was achieved using this method. Compared to polydispersions (i.e., contrast agents used clinically), monodisperse contrast agents have a narrower attenuation spectrum, which presents a maximum peak at a frequency value corresponding to the average single bubble resonance frequency. The low polydispersity index of the samples made the estimation of the lipid viscoelastic properties more accurate since, as previously reported, the shell linear parameters may change with the equilibrium bubble radius. The results showed the great advantage of dealing with monodisperse populations rather than polydisperse populations for the acoustic characterization of ultrasound contrast agents.

Modeling of the dynamics of microbubble contrast agents in ultrasonic medicine: Survey

The survey is devoted to a new field of bubble dynamics that studies the behavior of ultrasound contrast agents. This name denotes man-made encapsulated microbubbles applied in diagnostic and therapeutic ultrasonic medicine to enhance the quality of ultrasonic images and to deliver drugs to target sites in the human body. The survey analyzes theoretical models that are currently applied for the description of the bubble shell, the interaction of bubbles with blood vessel walls, and the acoustical action of bubbles on the cell membrane.

Modeling complicated rheological behaviors in encapsulating shells of lipid-coated microbubbles accounting for nonlinear changes of both shell viscosity and elasticity

It has been accepted that the dynamic responses of ultrasound contrast agent (UCA) microbubbles will be significantly affected by the encapsulating shell properties (e.g., shell elasticity and viscosity). In this work, a new model is proposed to describe the complicated rheological behaviors in an encapsulating shell of UCA microbubbles by applying the nonlinear ‘Cross law’ to the shell viscous term in the Marmottant model. The proposed new model was verified by fitting the dynamic responses of UCAs measured with either a high-speed optical imaging system or a light scattering system. The comparison results between the measured radius–time curves and the numerical simulations demonstrate that the ‘compression-only’ behavior of UCAs can be successfully simulated with the new model. Then, the shell elastic and viscous coefficients of SonoVue microbubbles were evaluated based on the new model simulations, and compared to the results obtained from some existing UCA models. The results confirm the capability of the current model for reducing the dependence of bubble shell parameters on the initial bubble radius, which indicates that the current model might be more comprehensive to describe the complex rheological nature (e.g., ‘shear-thinning’ and ‘strain-softening’) in encapsulating shells of UCA microbubbles by taking into account the nonlinear changes of both shell elasticity and shell viscosity.

Use of Intravital Microscopy to Study the Microvascular Behavior of Microbubble‐Based Ultrasound Contrast Agents

The study describes the use of intravital microscopy (IVM) to assess the behavior of ultrasound contrast agents (UCAs), including targeted UCAs, in the microcirculation of rodents. IVM was performed on various exteriorized organs: hamster cheek pouch, rat mesentery, liver, spinotrapezius muscle, and mouse cremaster muscle. A dorsal skin-fold chamber with MatBIII tumor cells was also implanted in rats. Nontargeted UCAs (SonoVue(®) and BR14) and targeted UCAs (BR55 and P-selectin targeted microbubbles) were tested. IVM was used to measure microbubble size, determine their persistence, and observe their behavior in the blood circulation. Intravenous and intra-arterial injections of high doses of UCAs did not modify the local microvascular hemodynamics. No microbubble coalescence and no increased size were observed. Adhesion of some microbubbles to leukocytes was observed in various microcirculation models. Microbubbles are captured by Kupffer cells in the liver. Targeted microbubbles were shown to adhere specifically to endothelial receptors without compromising local blood flow. These results support the safety of both targeted and nontargeted UCAs as no microvascular flow alteration or plugging of microvessels were observed. They confirm that binding observed with targeted microbubbles are due to the binding of these microbubbles to specific endothelial receptors.

Temperature-Dependent Differences in the Nonlinear Acoustic Behavior of Ultrasound Contrast Agents Revealed by High-Speed Imaging and Bulk Acoustics

Previous work by the authors has established that increasing the temperature of the suspending liquid from 20°C to body temperature has a significant impact on the bulk acoustic properties and stability of an ultrasound contrast agent suspension (SonoVue, Bracco Suisse SA, Manno, Lugano, Switzerland). In this paper the influence of temperature on the nonlinear behavior of microbubbles is investigated, because this is one of the most important parameters in the context of diagnostic imaging. High-speed imaging showed that raising the temperature significantly influences the dynamic behavior of individual microbubbles. At body temperature, microbubbles exhibit greater radial excursion and oscillate less spherically, with a greater incidence of jetting and gas expulsion, and therefore collapse, than they do at room temperature. Bulk acoustics revealed an associated increase in the harmonic content of the scattered signals. These findings emphasize the importance of conducting laboratory studies at body temperature if the results are to be interpreted for in vivo applications.

A model for the dynamics of ultrasound contrast agents in vivo.

The Rayleigh-Plesset (RP) equation for a clean gas bubble in an incompressible and infinite liquid has previously been applied to approximately simulate the behavior of ultrasound contrast agents (UCA) in vivo, and extended RP equations have been proposed to account for the effects of the UCA shell or surrounding soft tissue. These models produce results that are consistent with experimental measurements for low acoustic pressure scenarios. For applications of UCAs in therapeutic medicine, the transmitted acoustic pulse can have a peak negative pressure (PNP) up to a few megapascals, resulting in discrepancies between measurements and predictions using these extended RP equations. Here, a model was developed to describe the dynamics of UCAs in vivo while taking account of the effects of liquid compressibility, the shell and the surrounding tissue. Liquid compressibility is approximated to first order and the shell is treated either as a Voigt viscoelastic solid or a Newtonian viscous liquid. Finite deformation of the shell and tissue is derived. Dynamics of UCAs with a shell of lipid, polymer, albumin and liquid are investigated for typical therapeutic ultrasound pulses. The effects of liquid compressibility and shell and tissue parameters are analyzed.

Characterization of Acoustic Properties of PVA-Shelled Ultrasound Contrast Agents: Linear Properties (Part I)

This work examines the linear acoustic behavior of ultrasound contrast agents made of three types of poly (vinyl alcohol) (PVA) shelled microbubbles manufactured at different pH and temperature conditions. Backscattered power, attenuation coefficient and phase velocity of ultrasonic waves propagating through suspensions of PVA contrast agents were measured at temperature values ranging between 24°C and 37°C in a frequency range from 3 MHz to 13 MHz. Enhancement of the backscattered power higher than 20 dB and displaying a weak dependence on temperature was observed. Attenuation and phase velocity, on the other hand, showed higher sensitivity to temperature variations. A modified version of the Church model, which accounts for the dispersion of the dynamic modulus of the PVA shells, was developed to simultaneously fit the attenuation and phase velocity data at 24°C. The frequency dependence of the storage modulus was found to be that of semiflexible polymeric networks. On the other hand, the frequency dependence of the dynamic loss modulus suggests that additional mechanisms, which may be related to the finite dimensions of the shell and/or to its inhomogeneity, may play a significant role in the dissipation of the acoustic energy. For the microbubbles of interest, this model predicts frequency dependent resonance frequency higher than 100 MHz. (E-mail: dmitryg@kth.se)

A model for the dynamics of ultrasound contrast agents in soft tissue.

For a bubble suspended in an incompressible and infinite liquid, the dynamics of a clean gas bubble can be described by the Rayleigh–Plesset (RP) equation. The RP equation has been applied to approximately simulate the behavior of ultrasound contrast agents (UCAs) in blood, and extended RP equations have been proposed to account for the effects of the UCA shell and surrounding soft tissue. These models produce consistent results with experimental measurements for low acoustic pressure scenarios. For applications of UCAs in therapeutic medicine, the transmitted acoustic pulse can have a peak negative pressure up to a few megapascals, resulting in violent oscillations of UCAs and discrepancies between measurements and predictions using these extended RP equations. Based on the Keller equation, we developed a new model to describe the dynamics of UCAs in the body while taking account of liquid compressibility and shell and soft tissue effects. Liquid compressibility is approximated to the first order, and the shell is treated either as a layer of visco‐elastic solid or a viscous liquid. Finite deformation of the shell is included. Typical UCAs with a lipid or albumin shell are investigated, and the effects of soft tissue and blood are examined.

Experimental and theoretical investigations of ultrasound contrast agent dynamics between parallel plates and within rectangular channels.

The behavior of ultrasound contrast agent (UCA) microbubbles in confining environments is relevant for applications including ultrasound imaging and targeted microbubbles. In this presentation, measurements from experiments investigating the radial dynamics of UCA microbubbles positioned between parallel plates and within rectangular microchannels will be compared with model simulations. The radial motion of several UCA bubbles was recorded with high‐speed imaging at 15 million frames per second over a range of insonation frequencies at various offset distances from the plates or channel walls. The behavior of each individual bubble was observed in both parallel plate and microchannel environments, thereby isolating effects due purely to the confinement. Several plastics and polymers with well‐defined material properties were used to construct the plates and channels, making the dataset suitable for model validation. Measurements show that the oscillation amplitude and natural frequency of the bubbles dep...

Discussion of the application of finite Volterra series for the modeling of the oscillation behavior of ultrasound contrast agents

Ultrasound contrast agents consist of microbubbles with diameters in the micrometer range. Excited by ultrasound, these bubbles exhibit highly nonlinear oscillation. While well developed physical models for microbubble oscillation exist, the efficiency of pulse sequences for sensitive microbubble detection is discussed based on simple mathematical models of general nonlinearity. Typically, Taylor series are used to model microbubble nonlinearity for the development of detection schemes. Recently, pulse sequences were proposed which exploit nonlinear memory of microbubbles, a property that cannot be modeled by a Taylor series but can be explained using a Volterra series. Therefore, this paper discusses and evaluates the usage of Volterra series for the modeling of the scattering behavior of contrast agent microbubbles. A numerically stable linear estimation algorithm is implemented to determine a third order Volterra model for a free gas bubble with a resting radius r 0 = 1 μ m . For insonification pressures up to 100 kPa, the identified model allowed for a mean-square error of less than −16 dB with respect to the reference signal. Analysis of the response to narrowband signals showed that the achievable mean-square error is further reduced for the bandwidth available to typical ultrasound transducers used for clinical diagnostics.

TH-B-I-609-01: Imaging Ultrasound Contrast Agents

Purpose: Existing Dopplerultrasound techniques are capable of detecting blood flow in large vessels with velocities high enough (>3 cm/sec) to enable removal of tissue signals. Microbubbleultrasound contrast agents can be administered intravenously to increase the backscatter from blood. The nonlinear behavior of ultrasound contrast agents enable discrimination from tissue both nearly stationary microbubbles in the microcirculation and higher velocitymicrobubbles in the larger vasculature. The visualization of blood flow in both the macro‐ and micro‐circulation has been used to assess organ function and characterize tumors. Method and Materials:Imaging techniques for ultrasound contrast agents have been developed utilizing both the nonlinear and transient nature of contrast agents. These techniques are based on detecting microbubble nonlinear responses to the acoustic field of diagnosticultrasound. Different multi‐pulse transmit sequences will be described that have been used detect the nonlinear activity of the microbubbles (harmonic imaging, pulse inversion, amplitude modulation, and coded excitation). Only low amplitude acoustic fields may be used for interrogation to avoid bubble destruction and enable continuous contrast agent imaging. The difficulties of detecting nonlinear activity with low excitations are addressed. Dopplerimaging techniques are used in cases where transient properties of contrast agents are to be imaged. With these techniques high acoustic amplitude is used to intentionally destroy the contrast microbubbles and form an image. Once the bubbles in a region are destroyed, the user must wait for the area to be replenished before forming another image or move to a new imaging plane. Results: While destruction techniques have an excellent signal to noise ratio (SNR), clinical use is difficult due to the destruction of contrast agent. Nonlinear imaging techniques are clinically easier to use, but suffer from SNR and are often penetration limited. A number of different ultrasound contrast agents have been approved for clinical use in Europe and Asia and are in the Federal Drug Administration approval process in the US. Most these contrast agents can be imaged in real‐time using the nonlinear imaging techniques. Conclusion:Ultrasound contrast agents can be used to imageblood flow in both the micro‐ and macro‐ circulations. Clinical examples of imagingultrasound contrast agent with both low and high amplitude techniques will be presented for both radiology and cardiology applications.

Contrast harmonic imaging

The behavior of ultrasound contrast agents depends highly on the acoustic pressure of the insonified ultrasound wave. For low pressure the expansion and compression is linear to the pressure, for medium acoustic pressure nonlinear behavior starts to occur and for high pressures, but still in the diagnostic range transient scattering can be noticed, resulting in an enhanced scattering followed by a disappearance of the bubble. The nonlinear and transient regime can be utilized for imaging of the contrast agent in or nearby tissue. The magnitude of the nonlinear signal from the contrast has to compete with the nonlinear component of the ultrasound wave, which is generated during propagation. It is shown that contrast is superior to tissue when using low frequencies and imaging the third or fourth harmonic of the transmitted frequency.

Behavior of ultrasound contrast agents near the fragmentation threshold

Understanding the destruction process of ultrasound contrast agents is important in therapeutic ultrasound applications (such as ultrasound-enhanced drug delivery), as well as in certain imaging applications (such as ‘‘flash echo’’ imaging of the myocardium). In the destruction of OptisonTM microbubbles, our observations suggest that there are two pressure thresholds: a lower threshold which leads to shell rupture and the production of daughter (derivative) bubbles, and a higher threshold leading to the onset of the inertial cavitation (IC) activity. Slightly above the shell-disruption (SD) threshold, the acoustic scattering signal decreases, presumably due in part to the partial dissolution of the derivative bubbles. The extent of the quiescent region, the IC pressure threshold, and the strength of the subsequent cavitation activity are all highly dependent on the acoustic pulse parameters. It is found that for pressure amplitudes in excess of the IC threshold, a longer pulse length or a higher pressure level will decrease the duration of this quiescent period. By controlling the bubbles’ response through fine-tuning the acoustic parameters near the SD and IC threshold, one could design an ultrasound system which would optimize the desirable effects of contrast agents for imaging and therapy applications. [Work supported in part by ONR and WTC.]