The effect of the phase of transmission on contrast agent echoes

Ultrasound contrast agents consist of a gas bubble, encapsulated by a shell for stabilization. The shell dampens the fluctuations in the bubble radius when insonified. The detection of contrast microbubbles during a medical examination can indicate whether a region is perfused with blood. Here, the authors consider the effect of the phase of sonification signal on the backscatter by the bubble echo. By transmitting two short pulses of ultrasound with opposite phases, the authors demonstrate that a unique pair of echoes can be generated by a single microbubble, and that the properties of these echoes may be useful in the discrimination of bubble and tissue echoes. Specifically, the significant echo amplitude begins coincident with each transmitted rarefactional half-cycle, and the mean frequency of this echo depends on the transmitted phase. When rarefaction is transmitted first for a 2.25 MHz signal, the mean frequency is 0.8 MHz higher for an albumin-shelled bubble and 0.9 MHz higher for a lipid-shelled bubble. The experimental results agree with the predictions of the Gilmore-Akulichev equation.     

Optical and acoustical observations of the effects of ultrasound on contrast agents

Optimal use of encapsulated microbubbles for ultrasound contrast agents and drug delivery requires an understanding of the complex set of phenomena that affect the contrast agent echo and persistence. With the use of a video microscopy system coupled to either an ultrasound flow phantom or a chamber for insonifying stationary bubbles, we show that ultrasound has significant effects on encapsulated microbubbles. In vitro studies show that a train of ultrasound pulses can alter the structure of an albumin-shelled bubble, initiate various mechanisms of bubble destruction or produce aggregation that changes the echo spectrum. In this analysis, changes observed optically are compared with those observed acoustically for both albumin and lipid-shelled agents. We show that, when insonified with a narrowband pulse at an acoustic pressure of several hundred kPa, a phospholipid-shelled bubble can undergo net radius fluctuations of at least 15%; and an albumin-shelled bubble initially demonstrates constrained expansion and contraction. If the albumin shell contains air, the shell may not initially experience surface tension; therefore, the echo changes more significantly with repeated pulsing. A set of observations of contrast agent destruction is presented, which includes the slow diffusion of gas through the shell and formation of a shell defect followed by rapid diffusion of gas into the surrounding liquid. These observations demonstrate that the low-solubility gas used in these agents can persist for several hundred milliseconds in solution. With the transmission of a high-pulse repetition rate and a low pressure, the echoes from, contrast agents can be affected by secondary radiation force. Secondary radiation force is an attractive force for these experimental conditions, creating aggregates with distinct echo characteristics and extended persistence. The scattered echo from an aggregate is several times stronger and more narrowband than echoes from individual bubbles.     

Changes in the echoes from ultrasonic contrast agents with imaging parameters

Current harmonic imaging scanners transmit a narrowband signal that limits spatial resolution in order to differentiate the echoes from tissue from the echoes from microbubbles. Because spatial resolution is particularly important in applications, including mapping vessel density in tumors, we explore the use of wideband signals in contrast imaging. It is first demonstrated that microspheres can be destroyed using one or two pulses of ultrasound. Thus, temporal signal processing strategies that use the change in the echo over time can be used to differentiate echoes from bubbles and echoes from tissue. Echo parameters, including intensity and spectral shape for narrowband and wideband transmission, are then evaluated. Through these experiments, the echo intensity received from bubbles after wideband transmission is shown to be at least as large as that for narrowband transmission, and can be larger. In each case, the echo intensity increases in a nonlinear fashion in comparison with the transmitted signal intensity. Although the echo intensity at harmonic multiples of the transmitted wave center frequency can be larger for narrowband insonation, echoes received after wideband insonation demonstrate a broadband spectrum with significant amplitude over a very wide range of frequencies.     

Radial modulation of microbubbles for ultrasound contrast imaging

Over the past few years, extensive research has been carried out in the field of ultrasound contrast imaging. In addition to the development of new types of ultrasound contrast agents, various imaging methods dedicated to contrast agents have been introduced, and some of them are now commercially available. In this study, we present results of an imaging technique that is capable of detecting echoes from microbubbles and eliminating those emanating from nonoscillating structures (tissue), thereby enhancing contrast imaging. The method is based on mixing a low frequency (LF) modulator signal and a high frequency (HF) imaging signal to effectively modulate the size of the contrast microbubble through its volumetric oscillations using the LF signal and to probe the radial motion using the HF imaging signal. To evaluate the performances and limitations of the method, high-speed optical observations and acoustic measurements were carried out on soft-shelled microbubbles. The results showed that, by incorporating the modulator signal, the bubbles respond differently compared to the HF excitation alone. The decorrelation between the signals obtained at the compression and expansion phase of the modulator signal is significantly high to be used as a parameter to detect contrast microbubbles and discriminate them from tissue. The echo received from a solid reflector shows identical responses during the compression and rarefaction phase of the LF signal. In conclusion, these results demonstrate the feasibility of this fully linear approach for improving the contrast detection.     

Mechanisms of contrast agent destruction

Various applications of contrast-assisted ultrasound, including blood vessel detection, perfusion estimation, and drug delivery, require controlled destruction of contrast agent microbubbles. The lifetime of a bubble depends on properties of the bubble shell, the gas core, and the acoustic waveform impinging on the bubble. Three mechanisms of microbubble destruction are considered: fragmentation, acoustically driven diffusion, and static diffusion. Fragmentation is responsible for rapid destruction of contrast agents on a time scale of microseconds. The primary characteristics of fragmentation are a very large expansion and subsequent contraction, resulting in instability of the bubble. Optical studies using a novel pulsed-laser optical system show the expansion and contraction of ultrasound contrast agent microbubbles with the ratio of maximum diameter to minimum diameter greater than 10. Fragmentation is dependent on the transmission pressure, occurring in over 55% of bubbles insonified with a peak negative transmission pressure of 2.4 MPa and in less than 10% of bubbles insonified with a peak negative transmission pressure of 0.8 MPa. The echo received from a bubble decorrelates significantly within two pulses when the bubble is fragmented, creating an opportunity for rapid detection of bubbles via a decorrelation-based analysis. Preliminary findings with a mouse tumor model verify the occurrence of fragmentation in vivo. A much slower mechanism of bubble destruction is diffusion, which is driven by both a concentration gradient between the concentration of gas in the bubble compared with the concentration of gas in the liquid, as well as convective effects of motion of the gas-liquid interface. The rate of diffusion increases during insonation, because of acoustically driven diffusion, producing changes in diameter on the time scale of the acoustic pulse length, thus, on the order of microseconds. Gas bubbles diffuse while they are not being insonified, termed static diffusion. An air bubble with initial diameter of 2 microns in water at 37 degrees C is predicted to fully dissolve within 25 ms. Clinical ultrasound contrast agents are often designed with a high molecular weight core in an attempt to decrease the diffusion rate. C3F8 and C4F10 gas bubbles of the same size are predicted to fully dissolve within 400 ms and 4000 ms, respectively. Optical experiments involving gas diffusion of a contrast agent support the theoretical predictions; however, shelled agents diffuse at a much slower rate without insonation, on the order of minutes to hours. Shell properties play a significant role in the rate of static diffusion by blocking the gas-liquid interface and decreasing the transport of gas into the surrounding liquid. Static diffusion decreases the diameter of albumin-shelled agents to a greater extent than lipid-shelled agents after insonation.     

Pulse subtraction time delay imaging method for ultrasound contrast agent detection

Detection of contrast agent in perfused tissues has been an important research topic for many years. Currently available methods are mostly based on the strong nonlinear scattering of contrast agent microbubbles. These methods selectively extract those parts of the spectrum that show the largest difference in nonlinearity between contrast agent and tissue. The method introduced in this paper expands this extraction approach in that it additionally exploits differences in system behavior between tissue and contrast bubbles. The resonant nature of contrast bubbles implies that the response of a contrast bubble is stateful, i.e., the response not only depends on the current input, but also on all previous inputs. Tissue does not show this dependence on previous inputs. Our method is based on a 3 pulse design in which the echoes from 2 nonoverlapping pulses are subtracted from a third pulse. With this method we aim to separate and suppress those parts in an echo signal that originate from tissue while leaving the part originating from contrast bubbles relatively undisturbed. Simulation results show increases up to 30 dB in contrast-to-tissue ratio (CTR) with this method relative to single pulse echoes. This was confirmed in an in vitro experiment that showed an increase of approximately 12 dB in CTR.     

Observation of contrast agent response to chirp insonation with a simultaneous optical-acoustical system

Rayleigh-Plesset analysis, ultra-high speed photography, and single bubble acoustical recordings previously were applied independently to characterize the radial oscillation and resulting echoes from a microbubble in response to an ultrasonic pulse. In addition, high-speed photography has shown that microbubbles are destroyed over a single pulse or pulse train by diffusion and fragmentation. In order to develop a single model to characterize microbubble echoes based on oscillatory and destructive characteristics, an optical-acoustical system was developed to simultaneously record the optical image and backscattered echo from each microbubble. Combined observation provides the opportunity to compare predictions for oscillation and echoes with experimental results and identify discrepancies due to diffusion or fragmentation. Optimization of agents and insonating pulse parameters may be facilitated with this system. The mean correlation of the predicted and experimental radius-time curves and echoes exceeds 0.7 for the parameters studied here. An important application of this new system is to record and analyze microbubble response to a long pulse in which diffusion is shown to occur over the pulse duration. The microbubble response to an increasing or decreasing chirp is evaluated using this new tool. For chirp insonation beginning with the lower center frequency, low-frequency modulation of the oscillation envelope was obvious. However, low-frequency modulation was not observed in the radial oscillation produced by decreasing chirp insonation. Comparison of the echoes from similar sized microbubbles following increasing and decreasing chirp insonation demonstrated that the echoes were not time-reversed replicas. Using a transmission pressure of 620 kPa, the -6 dB echo length was 0.9 and 1.1 micros for increasing and decreasing chirp insonation, respectively (P = 0.02). The mean power in the low-frequency portion of the echoes was 8 (mV)2 and 13 (mV)2 for increasing and decreasing chirp insonation, respectively (P = 0.01).     

Shear stress induced by a gas bubble pulsating in an ultrasonic field near a wall

Some of the effects that therapeutic ultrasound has in medicine and biology may be associated with steady oscillations of gas bubbles in liquid, very close to tissue surface. The bubble oscillations induce on the surface steady shear stress attributed to microstreaming. A mathematical simulation of the problem for both free and capsulated bubbles, known as contrast agents, is presented here. The simulation is based on a solution of Laplace's equation for potential flow and existing models for microstreaming. The solution for potential flow was obtained numerically using a boundary integral method. The solution provides the evolution of the bubble shape, the distribution of the velocity potential on the surface, and the shear stress along the surface. The simulation shows that significant shear stresses develop on the surface when the bubble bounces near the tissue surface. In this case, pressure amplitude of 20 kPa generates maximal steady shear stress of several kilo Pascal. Substantial shear stress on the tissue surface takes place inside a circular zone with a radius about half of the bubble radius. The predicted shear stress is greater than stress that causes hemolysis in blood and several orders of magnitude greater than the physiological stress induced on the vessel wall by the flowing blood.     

Nonlinear radial oscillations of micro-bubbles in a compressible UCM medium

The nonlinear oscillations of acoustically forced spherical gas bubbles in an upper-convected Maxwell (UCM) compressible fluid are investigated. The nonlinear viscoelastic model used is suitable for large-amplitude excitation of bubbles that cannot be captured by linear models. The effects of acoustic excitation are studied for compressible nonlinear viscoelastic media, which increases the complexity and nonlinearity of the behavior. The Keller–Miksis equation is used to model the dynamics of a single bubble. The constitutive equations of compressible UCM are used for viscoelastic media. These governing equations are non-dimensionalized and coupled to determine the bubble dynamic behavior. The set of derived non-dimensionalized integro-differential equations developed are numerically solved simultaneously using the fourth-order Runge–Kutta method featured by the automatic variable time step-size module. The combined effects of compressibility and viscoelasticity of the fluid on bubble radius are investigated. The results show that the combination of compressibility and nonlinear viscoelasticity for bubble radial oscillations makes forced bubble dynamics more applicable for human needs, especially for large deformations in highly non-Newtonian fluids like industrial polymers or even tissue-like media. It can be seen that compressibility controls the oscillations at higher forcing amplitudes. The relevance and importance of these bubble dynamics to biomedical ultrasound applications and light emissions by sonoluminescence and other industries are evident.     

Contrast imaging by non-overlapping dual frequency band transmit pulse complexes

SURF contrast imaging, as described previously in the literature, is a contrast agent detection technique achieved by processing of the received signals from transmitted dual frequency band pulse complexes with overlapping high-frequency (HF) and low-frequency (LF) pulses. The transmitted HF pulses are used for image reconstruction, whereas the transmitted LF pulses are used to manipulate the scattering properties of the contrast agent. As with harmonic contrast agent detection techniques, nonlinear wave propagation will, in most situations, also limit the specificity with the SURF contrast technique when transmitting overlapping HF and LF pulses. The present paper proposes an alternative SURF contrast imaging technique using transmit dual frequency band pulse complexes with non-overlapping HF and LF pulses. If the frequency of the LF manipulation pulse is close to the bubble resonance frequency, numerical simulations indicate a significant ring-down effect of the LF bubble radius response. Utilizing this bubble ring-down effect and transmitting the HF pulse just after the LF pulse, a contrast agent specificity approaching infinity accompanied by a contrast agent sensitivity only for contrast bubbles having resonance frequencies within a narrow frequency range may be obtained.     

Nonlinear propagation of ultrasound through microbubble contrast agents and implications for imaging

Microbubble contrast agents produce nonlinear echoes under ultrasound insonation, and current imaging techniques detect these nonlinear echoes to generate contrast agent images accordingly. For these techniques, there is a potential problem in that bubbles along the ultrasound transmission path between transducer and target can alter the ultrasound transmission nonlinearly and contribute to the nonlinear echoes. This can lead to imaging artefacts, especially in regions at depth. In this paper we provide insight, through both simulation and experimental measurement, into the nonlinear propagation caused by microbubbles and the implications for current imaging techniques. A series of investigations at frequencies below, at, and above the resonance frequency of microbubbles were performed. Three specific effects on the pulse propagation (i.e., amplitude attenuation, phase changes, and harmonic generation) were studied. It was found that all these effects are dependent on the initial pulse amplitude, and their dependence on the initial phase of the pulse is shown to be insignificant. Two types of imaging errors are shown to result from this nonlinear propagation: first, that tissue can be misclassified as microbubbles; second, the concentration of microbubbles in the image can be misrepresented. It is found that these imaging errors are significant for all three pulse frequencies when the pulses transmit through a microbubble suspension of 6 cm in path length. It also is found that the first type of error is larger at the bubble resonance frequency.     

Shape oscillation of bubbles in a row excited by ultrasonic vibration

Behaviors of bubble(s) exposed to an ultrasonic vibration are focused. Size of the bubbles interested in the present study is of O(1 mm) in diameter. The bubbles were injected through the micro syringe to the test fluid (water or water/surfactant mixture) filled in the rectangular tank. Ultrasonic vibration was irradiated to the bubble(s) after the detachment of the bubble from the tip of the syringe; thus the bubbles were exposed to the periodic oscillation in rising the test fluid. The authors clearly detect radial and shape oscillations under the large-amplitude vibration by use of high-speed camera. Preferable mode number of the shape oscillation, and the transition process from the radial to the shape oscillation are discussed.     

Optical observations of acoustical radiation force effects on individual air bubbles

Previous studies dealing with contrast agent microbubbles have demonstrated that ultrasound (US) can significantly influence the movement of microbubbles. In this paper, we investigated the influence of the acoustic radiation force on individual air bubbles using high-speed photography. We emphasize the effects of the US parameters (pulse length, acoustic pressure) on different bubble patterns and their consequences on the translational motion of the bubbles. A stream of uniform air bubbles with diameter ranging from 35 microm to 79 microm was generated and insonified with a single US pulse emitted at a frequency of 130 kHz. The bubble sizes have been chosen to be above, below, and at resonance. The peak acoustic pressures used in these experiments ranged from 40 kPa to 120 kPa. The axial displacements of the bubbles produced by the action of the US pulse were optically recorded using a high-speed camera at 1 kHz frame rate. The experimental results were compared to a simplified force balance theoretical model, including the action of the primary radiation force and the fluid drag force. Although the model is quite simple and does not take into account phenomena like bubble shape oscillations and added mass, the experimental findings agree with the predictions. The measured axial displacement increases quasilinearly with the burst length and the transmitted acoustic pressure. The axial displacement varies with the size and the density of the air bubbles, reaching a maximum at the resonance size of 48 microm. The predicted displacement values differ by 15% from the measured data, except for resonant bubbles for which the displacement was overestimated by about 40%. This study demonstrates that even a single US pulse produces radiation forces that are strong enough to affect the bubble position.     

Harmonic chirp imaging method for ultrasound contrast agent

Coded excitation is currently used in medical ultrasound to increase signal-to-noise ratio (SNR) and penetration depth. We propose a chirp excitation method for contrast agents using the second harmonic component of the response. This method is based on a compression filter that selectively compresses and extracts the second harmonic component from the received echo signal. Simulations have shown a clear increase in response for chirp excitation over pulse excitation with the same peak amplitude. This was confirmed by two-dimensional (2-D) optical observations of bubble response with a fast framing camera. To evaluate the harmonic compression method, we applied it to simulated bubble echoes, to measured propagation harmonics, and to B-mode scans of a flow phantom and compared it to regular pulse excitation imaging. An increase of approximately 10 dB in SNR was found for chirp excitation. The compression method was found to perform well in terms of resolution. Axial resolution was in all cases within 10% of the axial resolution from pulse excitation. Range side-lobe levels were 30 dB below the main lobe for the simulated bubble echoes and measured propagation harmonics. However, side-lobes were visible in the B-mode contrast images.     

Review of shell models for contrast agent microbubbles

Micrometer-scale encapsulated gas bubbles, known as ultrasound contrast agents, are used in ultrasound medical diagnostics for enhancing blood-tissue contrast during an ultrasonic examination. They are also employed in therapy as an activator of drug incorporation or extravasation. Adequate modeling of the effect of encapsulation is of primary importance because it is the encapsulating shell that determines many of the functional properties of contrast agents. In this review, existing approaches to the modeling of the radial motion of an encapsulated bubble are discussed and comparative analysis of available shell models is conducted. The capabilities of the shell models are evaluated in the context of recent experimental observations, such as compression-only behavior and the dependence of shell material properties on initial bubble radius. It is shown that for early shell models, the main problem is that the behavior of encapsulation is described by linear elastic and viscous laws, whereas recent experimental data attest to complicated rheological properties inherent in shell materials. Currently, a trend toward models involving nonlinear laws for shell elasticity and viscosity is observed. In particular, nonlinear models have been proposed that allow one to reproduce compression-only behavior. However, the problem of the radius dependence of shell material parameters remains unsolved.     

Acoustic signatures of submicron contrast agents

Previous studies have revealed that hard-shelled submicron contrast agents exhibit large relative expansions and strong acoustical echoes that can be observed experimentally, and predicted by theoretical simulations. In this paper, we study harmonic imaging and pulse-pair imaging techniques designed to assist in the differentiation of these contrast agents from tissue. For harmonic imaging, we apply a high-sensitivity, narrowband strategy that differentiates the microbubble from tissue based on the generation of strong harmonic echoes. For pulse-pair imaging, we apply high spatial resolution, wideband strategies using phase inversion, which relies on the frequency differences observed in response to phase-inverted pulses, and signal subtraction, which takes advantage of the amplitude differences in response to identical pulses. The bubble-to-phantom signal amplitude ratio in the absence of motion approaches 20 dB using phase inversion and 30 dB using signal subtraction; both techniques are robust for up to 50 microm of simulated motion. With the experience gained in these studies, we hope to advance the development of multi-pulse or shaped-pulse techniques that are optimized for specific clinical applications.     

Stable and transient subharmonic emissions from isolated contrast agent microbubbles

Ultrasound contrast agents (UCAs) have been widely studied in recent years in order to improve and develop new, sophisticated imaging techniques for clinical applications. In order to improve the understanding of microbubble-ultrasound interactions, an acoustic dynamic characterization of UCA microbubble behavior was performed in this work using a high frame-rate acquiring and processing system. This equipment is connected to a commercial scanner that provides RF beam-formed data with a frame-rate of 30 Hz. Acquired RF sequences allows us to follow the dynamics of cavitation mechanisms in its temporal evolution during different insonifying conditions. The experimental setup allowed us to keep the bubbles free in a spatial region of the supporting medium, thus avoiding boundary effects that can alter the ultrasound field and the scattered echo from bubbles. The work focuses on the study of subharmonic emission from an isolated bubble of contrast agent. In particular, the acoustic pressure threshold for a subharmonic stable emission was evaluated for a subset of 50 microbubbles at 3.3 MHz and at 5 MHz of insonation frequencies. An unexpected second pressure threshold, which caused the stand still of the subharmonic emission, was detected at 3.3 MHz and 5 MHz excitation frequencies. A transient subharmonic emission, which is hypothesized as being related to the formation of new free gas bubbles, was detected during the ultrasound-induced destruction of microbubbles. An experimental procedure was devised in order to investigate these behaviors and several sequences of RF echo signals and the related spectra, acquired from an isolated bubble in different insonation conditions, are presented and discussed in this paper.     

Transient bubble domain configuration in garnet materials observed using high speed photography

The dynamic domain configurations of bubbles in garnet materials have been studied using a sampling optical microscope capable of single exposure photographs with a 10 nsec exposure time. The microscope is an integral part of a sampling system so that the transient shape of the bubble is recorded at various times after a field pulse or, for bubbles in field access devices, during a clock cycle. A triggerable flowing nitrogen gas laser pumping a low Q Rodamine 6G Dye laser is used as an illumination source giving light pulses of ∼1.5 KW for 10 nsec. This light is sufficient to expose Kodak 4 × 16 mm movie film. Standard pulse generators (HP 214A) are used to make free bubble radial velocity measurements. A modified generator allows free bubble collapse measurement to be made. For bubbles propagating at operating frequency within field access devices, a standard bubble exerciser is used, synchronized to the sampling system. In this case, special samples with an internal mirror and epi-mode illumination are used. Illustrative results of bubble domain shapes in a chevron propagating structure and a 90° chevron expander detector are included.     

Transient subharmonic and ultraharmonic acoustic emission during dissolution of free gas bubbles

This work concerns the study of free gas bubble behavior, a basic step in contrast agent study. In order to improve the understanding of microbubble-ultrasound interaction, we propose an acoustic dynamic observation of microbubble behavior performed by a high frame-rate acquiring and processing system. Results from ultrasonic observations of free gas microbubbles are discussed and compared with theoretical simulation. Peculiar radio frequency (RF) echo signals back-propagated from bubbles during dissolution up to their destruction are shown and their behavior is discussed. In particular, the different orders of subharmonic emissions related to changes in bubble sizes during dissolution were observed.     

Heat transfer near the contact line during boiling in microgravity

Although significant progress has been made, the mechanisms of heat transfer responsible for enhancement during nucleate boiling are not fully understood. The primary barriers to a complete understanding of the heat transfer during boiling are due to difficulties associated with performing rapid microscale measurements, ambiguity due to the interaction of previous and neighbouring bubbles, uncertainty with regard to gravitational effects and the complexity associated with theoretical modelling that often results in empiricism/adjustable parameters being introduced into the theoretical/numerical works. In this investigation, a numerical simulation of hemispherical bubble growth on a heated surface in μ-gravity has been performed. The simulations agree well with R113 μ-gravity measurements provided by [1]. The simulations indicate that during the bubble expansion phase, the heat transfer coefficient along the boiling surface in the vicinity of the triple interface is substantial. The maximum heat transfer coefficient reaches values over 3500 W/m²K and decays with radial distance from the vapour-liquid interface. This is over 10 times larger than the effective thermal conductance due to diffusion in the undisturbed region. The increase in the local heat transfer coefficient is complimented by the fact that the effective area of enhancement around the bubble increases with bubble radius enhancing the thermal conductance of single bubble events.