Daniel A. King

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.

Comparison between maximum radial expansion of ultrasound contrast agents and experimental postexcitation signal results

Experimental postexcitation signal data of collapsing Definity microbubbles are compared with the Marmottant theoretical model for large amplitude oscillations of ultrasound contrast agents (UCAs). After taking into account the insonifying pulse characteristics and size distribution of the population of UCAs, a good comparison between simulated results and previously measured experimental data is obtained by determining a threshold maximum radial expansion (Rmax) to indicate the onset of postexcitation. This threshold Rmax is found to range from 3.4 to 8.0 times the initial bubble radius, R0, depending on insonification frequency. These values are well above the typical free bubble inertial cavitation threshold commonly chosen at 2R0. The close agreement between the experiment and models suggests that lipid-shelled UCAs behave as unshelled bubbles during most of a large amplitude cavitation cycle, as proposed in the Marmottant equation.

Algal cell disruption using microbubbles to localize ultrasonic energy.

Microbubbles were added to an algal solution with the goal of improving cell disruption efficiency and the net energy balance for algal biofuel production. Experimental results showed that disruption increases with increasing peak rarefaction ultrasound pressure over the range studied: 1.90 to 3.07 MPa. Additionally, ultrasound cell disruption increased by up to 58% by adding microbubbles, with peak disruption occurring in the range of 10(8)microbubbles/ml. The localization of energy in space and time provided by the bubbles improve efficiency: energy requirements for such a process were estimated to be one-fourth of the available heat of combustion of algal biomass and one-fifth of currently used cell disruption methods. This increase in energy efficiency could make microbubble enhanced ultrasound viable for bioenergy applications and is expected to integrate well with current cell harvesting methods based upon dissolved air flotation.

Encapsulated contrast microbubble radial oscillation associated with postexcitation pressure peaks

This work combines modeling and experiment to assess encapsulated microbubble oscillations associated with broadband pressure peaks detected after microbubble excitation (postexcitation signals). Data were acquired from albumin-shelled and phospholipid-shelled microbubbles using a passive cavitation detector consisting of a confocally aligned 2.8-MHz transmitter and 13-MHz receiver. Microbubbles in weak solutions were insonified with a 5-cycle pulse at a peak rarefactional pressure of 2.0+/-0.2 MPa. For each microbubble type, at least 100 received signals were identified as individual-microbubble responses. The average broadband noise from signals with postexcitation response was 4.2-7.2 dB higher than from signals without postexcitation. Pressure-time responses for each microbubble type were simulated using the model by Marmottant et al. [J. Acoust. Soc. Am. 118, 3499-3505 (2005)], with insonification conditions matching the experiment. Increased broadband noise predicted for microbubbles with postexcitation response was consistent with that observed experimentally (4.0-8.9 dB). The model predicted that postexcitation signals occur only when the radial oscillation exceeds both the shell break-up threshold and twice the initial radius (free bubble inertial cavitation threshold).

Influence of microbubble size on postexcitation collapse thresholds for single ultrasound contrast agents using double passive cavitation detection - [Letters]

For the first time, and using an acoustical method, it has been shown experimentally that the inertial cavitation threshold pressure of an albumin-shelled microbubble is significantly correlated with its initial size.

Evaluation of the Temporal Stability of Definity Using Double Passive Cavitation Detection

To the best of our knowledge, no studies have been reported that evaluated the stability of ultrasound contrast agents (UCAs) over time once the vial was opened. Indeed, air injected into the vial via a syringe might interact with the UCAs and degrade them, potentially modifying their physical characteristics. In a clinical context, for example, for diagnosis, therapy, or bioeffect studies, the stability of UCAs once the vial is opened might become critical using either infusion or bolus injection. In particular, for bioeffects studies when the same vial yields UCAs over time, the UCAs’ physical characteristics must remain stable during the experimental period to avoid misinterpretation of experimental results. Analysis of the temporal stability of Definity (Lantheus Medical Imaging, Inc, North Billerica, MA), a second-generation UCA made of microbubbles filled with octafluoropropane (C3F8) gas and stabilized by a lipid shell,1 was performed using double passive cavitation detection, which has been fully described previously.2 This method is based on determining the presence or absence of a postexcitation signal occurring a few microseconds after the principle excitation of the UCA; it is assumed that postexcitation signals are emitted by gas bubbles formed after the collapse of the UCA. Double passive cavitation detection experiments give access to the postexcitation curve from which the 50% collapse threshold is extracted and further analyzed2; the temporal stability of the UCA’s physical characteristics was assessed by evaluating the 50% collapse threshold over a 2-week period. In addition, to analyze the initial size of the UCA samples, microscope images were acquired (BX51; Olympus Optical Co, Ltd, Tokyo, Japan) and processed using a circle detection routine based on the Hough transform. This study was performed using 1 vial of Definity (lot 4576U). The vial was reactivated before each set of experiments. Six time points (from day 0 to day 15) were evaluated over a 2-week period. For each time point, 3 parameters were analyzed: the size distribution of the UCA population, the bubble diameter of 100 randomly selected UCAs, and the 50% collapse thresholds based on an average of 1085 double passive cavitation detection response estimates. The 95% confidence intervals (CIs) were estimated for the last 2 parameters. Figure 1 shows the 6 UCA size distributions. The UCA sizes were compared using a χ2 test with the Yates correction; no significant difference was detected between the 6 populations (P = .19). Figure 2 shows that there was no significant difference between the 6 time points for both the bubble size and the 50% collapse threshold, as all the 95% CIs are overlapping. Figure 1 Size distributions of the UCAs for the 6 groups over the 2-week period. D indicates day. Figure 2 Mean UCA diameters (A) and 50% collapse thresholds (B) with their 95% CIs. The gray rectangles represent the overlapping of the 95% CIs between the 6 groups. D indicates day. The results suggest that the physical characteristics of Definity are stable at least over 2 weeks and following 6 reactivations.

Influence of microbubble size distribution on postexcitation thresholds for single ultrasound contrast agent using double passive cavitation detection

A recent study has shown that double passive cavitation detection (DPCD) is a valid method for determining cavitation characteristics including collapse thresholds of isolated microbubbles based on the detection of postexcitation signal (PES) occurring 1 to 5 μs after the principle excitation of the bubble. The hypothesis is that PES is associated with the collapse of a free gas bubble released from the ultrasound contrast agent (UCA) after the rupture of its shell. It has been shown that responses of UCAs depend on several parameters such as the shell and gas core as well as the size of the microbubble. However, a detailed study of the influence of size distribution only on single microbubble collapse thresholds is still not available. The aim of this study was to determine whether there was a significant correlation between microbubble size distribution and collapse thresholds. Experiments were performed using serum albumin and dextrose microbubbles. Four size distributions were obtained and we determined microbubble collapse thresholds for each distribution using the DPCD method (3 cycle tone bursts at the central frequency of 4.6 MHz). Statistical analysis was based on comparing the means of collapse threshold for the four size distributions using an analysis of variance. The microbubble collapse threshold was found to be significantly (p<;0.05) correlated to the microbubble size distribution: the DPCD experiments demonstrated that, in the configuration of the experiments, PES thresholds were higher for microbubbles exhibiting smaller size distribution.

An axisymmetric model of ultrasound contrast agent collapse following shell rupture

Widely used spherically symmetric models of ultrasound contrast agents (UCA) are unable to capture complicated collapse behaviors when the UCA shell ruptures. Observations from acoustic passive cavitation detection analysis of collapsing UCAs as well as images from high speed videos of UCA destruction suggest that including spatial asymmetry in the shell interface conditions of models may be useful for studying collapse, onset of fragmentation, and initiation of postexcitation rebound. The concept of lipid shell rupture is incorporated into an axisymmetric boundary element method formulation as a circular hole developing during the growth phase of an initially spherical bubble. The different material interfaces are represented by a spatially varying surface tension due to different pressure discontinuity conditions from the inner gas region to the outer fluid region. Results from the simplified geometrical model simulations demonstrate that shell fragments may influence the evolution of collapsing UCA and...

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...

Comparing the Marmottant model for ultrasound contrast agents with experimental postexcitation signals.

When insonified with sufficiently large rarefactional pressures, single unconstrained ultrasound contrast agents undergo inertial collapse with postexcitation emissions. Experimental measurements of postexcitation signal data for Definity microbubbles are compared with the Marmottant theoretical model for large amplitude oscillations of ultrasound contrast agents (UCAs). After taking into account the insonifying pulse characteristics, microbubble properties, and size distribution of the population of UCAs, a good comparison between simulated results and experimental data is obtained by determining a threshold maximum radial expansion (Rmax) to indicate the onset of postexcitation activity. Though this threshold Rmax is found to vary depending on insonification frequency, the values obtained are well above the typical free bubble inertial cavitation threshold commonly chosen at 2R0. The close agreement between the experiment and models suggests that lipid shelled UCAs behave as unshelled bubbles during mos...