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PubMed1984

Microbubble dynamics visualized in the intact capillary circulation.

The potential for the use of contrast echocardiography to study myocardial perfusion has generated efforts to develop standardized echo contrast agents. The two methods used in this laboratory to generate microbubbles in solutions serving as contrast agents included the widely used hand-agitation method and the newer ultrasonic microcavitation (sonication) method. The latter has been demonstrated to generate smaller and more uniform microbubbles in an in vitro system. The present study was designed to observe, by direct microscopic examination of a cat mesentery preparation, the behavior and fate of the microbubbles in an in vivo system. The in vivo mesentery observations confirm the critical role of microbubble size in its unhindered passage through the capillary vasculature. The smaller and more uniform sonicated microbubbles passed rapidly through the microcirculation along with the red blood cells, whereas the larger microbubbles were observed to coalesce and interrupt the flow of blood and subsequently collapse or shrink.

Animals↗
PubMed1985

Generating precision microbubbles for use as an echocardiographic contrast agent.

To investigate whether precision microbubbles can be simply generated and used for quantitative contrast echocardiographic studies, precision microbubbles were fabricated in gelatin using a simple generator. The generator consisted of a fluid pump, a generating site containing a narrow bore tube and a bubble stream output port. Up to 5,000 microbubbles/s were generated with a controllable radius of 80 to 150 mu. No detectable interbubble size variation was observed under high power microscopy. To examine whether these bubbles could be used for quantitative contrast echocardiographic studies, they were then infused into a tube with a known flow of degassed water during ultrasonic imaging. The resulting ultrasonic contrast effect in the tube lumen at steady state was recorded and subsequently measured by videodensitometry. The precision microbubbles were visually and microscopically stable during the experimental run. Correlations between microbubble infusion rate and luminal videodensitometry on individual runs were r = 0.89, 0.83, 0.73 and 0.71. It is concluded that precision microbubbles can be generated in sufficient quantities on site to serve as an echocardiographic contrast agent for quantitative studies in vitro and at a very modest cost. These precision microbubbles are sufficiently stable to be collected and stored for short periods of time.

Air↗
PubMed1999

Microbubbles associated with mitral valve prostheses in pediatric patients.

OBJECTIVES: To assess whether microbubbles are associated with mitral valve prostheses in children and to investigate their relationship to exercise. BACKGROUND: Bright, highly mobile echoes are seen in left heart chambers of patients with mechanical mitral valve prostheses. The clinical importance of those microbubbles is not yet known but they survive long enough to reach the cerebral circulation. No such studies have been reported in children. METHODS: There were 20 male and 10 female patients with a mean age of 10.4 years (range 2-16 years). Transthoracic echocardiography with calculation of cardiac output and ejection fraction was performed at baseline and after exercise following mechanical mitral valve replacement. Studies were evaluated for the presence of microbubbles. The mean time from operation to time of study was 18 months (range 0.2-89 months). RESULTS: Of the 30 children evaluated, 28 (93%) had evidence of microbubbles. Exercise increased the number of microbubbles in 15 of the 26 children. This was positively associated with an increase in cardiac output. CONCLUSIONS: (1) Microbubbles are commonly observed in children with mechanical mitral prostheses and are augmented by exercise. (2) This phenomenon is of a special concern in children due to their expected longevity with the prosthesis.

Adolescent↗
PubMed2003

Measurement of radial artery contrast intensity to assess cardiac microbubble behavior.

OBJECTIVES: We sought to determine whether analysis of the contrast signal from the radial artery is better able to reflect changes in left ventricular (LV) microbubble dynamics than the signal from the LV itself. BACKGROUND: Assessment of microbubble behavior from images of the LV may be affected by attenuation from overlying microbubbles and nonuniform background signal intensities. The signal intensity from contrast in a peripheral artery is not affected by these artifacts and may, thus, be more accurate. METHODS: After injection of a contrast bolus into a peripheral vein, signal intensity was followed simultaneously in the LV and radial artery. The measurements were repeated using continuous, triggered, low and high mechanical index harmonic imaging of the LV. RESULTS: Peak and integrated signal intensities ranged from 25 dB and 1550 dB/s, respectively, with radial artery imaging to 5.6 dB and 471 dB/s with ventricular imaging. Although differences in microbubble behavior during the different imaging protocols could be determined from both the LV and radial artery curves, analysis of the radial artery curves yielded more consistent and robust differences. CONCLUSIONS: The signal from microbubbles in the radial artery is not affected by shadowing and is, thus, a more accurate reflection of microbubble behavior in the LV than the signal from the LV itself. This may have important implications for the measurement of myocardial perfusion by contrast echocardiography.

Albumins↗
PubMed1990

Lipid-coated ultrastable microbubbles as a contrast agent in neurosonography.

Lipid-coated microbubbles can be synthesized from selected lipid monolayer systems for use as ultrasonic contrast. These microbubbles have the property of longevity of weeks in vitro (ultrastability) and longevity of hours in vivo. The bubbles can be manufactured with a mean diameter of approximately 2 microns in a tight diameter distribution; all are less than 6 microns and 99% are smaller than 4.5 microns. The current study compared the in vivo survival characteristics of these lipid-coated microbubbles with microbubbles produced by saline. The comparison was made in the rat brain using direct intraparenchymal injections and injections into a previously created cyst/coagulum. The echogenic enhancement by the lipid-coated microbubbles persisted in vivo for over 24 hours in both the intraparenchymal environment and in the cyst/coagulum. The saline bubble echos were not detectable by 3 hours in a cyst/coagulum, and not detectable in the parenchyma after 2 hours. The sonographic characteristics and longevity of lipid-coated microbubbles make this agent a potentially useful clinical contrast material for neurosonography.

Animals↗
PubMed2003

Volume scattering of distributed microbubbles and its influence on blood flow estimation.

In recent years, microbubble contrast agents have become a potential adjunct in Doppler ultrasound diagnosis. In this paper, we show that volume scattering makes the effective band in Doppler spectrum shift downward after injection of microbubbles. Because the insonified volume comprises a collection of distributed microbubbles, the statistical properties such as the autocorrelation function and ensemble average power spectrum of the echoes from a collection of distributed microbubbles were derived first. It can be observed that, beyond a critical frequency, the theoretical volume backscattering cross section derived from the ensemble average power spectrum of microbubbles decreases with frequency. On the contrary, the volume backscattering cross section of red cells increases with frequency. Using two-dimensional (2-D) Fourier transform, the variation in Doppler spectrum caused by different volume backscattering cross section can be demonstrated, and the consequential downward shifts of the estimated Doppler parameters (e.g., the mean and maximum Doppler shifts, and the variance of Doppler power spectrum) after microbubble injection are shown. In addition, it can be observed that the variation gets larger as the transmitted bandwidth increases. And, the variations in Doppler parameters estimated with experimental data are presented to verify the theoretical deviations.

Blood Flow Velocity↗
PubMed1997

Differences in Myocardial Contrast Produced with Transient Response Imaging When Using Intravenous Microbubbles Containing Gases of Different Molecular Weight.

The purpose of this study was to determine the effect of different microbubble gases on the amount of myocardial contrast (MC) produced from intravenously (IV) injected dextrose albuinin microbubbles when using a new imaging modality termed transient response imaging (TRI). In 6 dogs (4 closed chest, 2 open chest) the peak anterior myocardial videointensity (PMVI) and visual degree of MC were determined following IV injections of equivalent doses of perfluorocarbon exposed sonicated dextrose albumin (PESDA), sulfur hexafluoride-exposed sonicated dextrose albumin (SHESDA), and room air exposed sonicated dextrose albumin (RASDA) microbubbles. TRI was performed by triggering ultrasound impulses to 1 point every one to two cardiac cycles. The PMVI produced with TRI was compared to conventional 30 Hz frame rate imaging (CI) for each gas. Visual anterior and posterior MC was evident with TRI in all six dogs using PESDA, but not in any dog with CI. Although RASDA and SHESDA did not produce MC with CI, visually evident anterior MC was seen after 7 of 8 SHESDA and 4 of 9 RASDA injections when using TRI with both gases. PESDA produced the highest peak PMVI of all three microbubbles when using TRI, while SHESDA produced a significantly higher PMVI than RASDA. We conclude that although MC can be produced with TRI using microbubble gases of lower molecular weight, the brightest and most consistent contrast is produced with fluorocarbon containing microbubbles.

Journal Article↗
PubMed1994

In vivo myocardial kinetics of air-filled albumin microbubbles during myocardial contrast echocardiography. Comparison with radiolabeled red blood cells.

Myocardial contrast echocardiography (MCE) is a new technique for assessing myocardial perfusion that uses intracoronary injections of microbubbles of air. Because these microbubbles have a mean diameter of 4.3 +/- 0.3 microns and an intravascular rheology similar to that of red blood cells (RBCs), we hypothesized that their mean myocardial transit rates recorded on echocardiography would provide an estimation of regional myocardial blood flow in the in vivo beating heart. Accordingly, blood flow to the left anterior descending coronary artery (LAD) of 12 open-chest anesthetized dogs (group I) was adjusted to 4 to 6 flows (total of 60 flows), and microbubbles and radiolabeled RBCs were injected into the LAD in a random order at each stage. The mean myocardial RBC transit rates were measured by fitting a gamma-variate function to time-activity plots generated by placing a miniature CsI2 probe over the anterior surface of the heart, and the mean myocardial microbubble transit rates were measured from time-intensity plots derived from off-line analysis of MCE images obtained during the injection of microbubbles. An excellent correlation was noted between flow (measured with an extracorporeal electromagnetic flow probe) and mean myocardial RBC transit rate (y = 2.83 x 10(-3)x + 0.01, r = .96, SEE = 0.02, P < .001). A close correlation was also noted between mean RBC and microbubble myocardial transit rates (y = 1.01x + 0.01, r = .89, SEE = 0.02, P < .001). Despite its theoretical advantages, a lagged normal density function did not provide a better fit to the MCE data than the gamma-variate function.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed2004

[Ultrasound microbubbles promote thrombolysis of rabbit femoral artery thrombus].

OBJECTIVE: To evaluate the efficacy of intravenous ultrasound microbubbles for thrombolysis of arterial thrombus without using thrombolytic drugs. METHODS: Twelve rabbit models of acute bilateral femoral artery thrombosis were established and 6 of them received transcutaneous ultrasound and intravenous albumin microbubble treatment for thrombosis on one side while only microbubble treatment for the other side. The other 6 rabbits received ultrasound treatment on one side but no treatment on the other to serve as the control group. RESULTS: None of the 6 arteries treated with microbubbles alone and only 2 arteries treated with ultrasound alone in the 6 control rabbits were recanalized. All the 6 femoral arteries treated with microbubbles together with ultrasound were recanalized (P=0.014), with significantly shorter patent time and smaller residual thrombus cross-sectional area than those of the arteries with only ultrasound treatment (P=0.004 and P=0.003, respectively). CONCLUSION: Treatment with intravenous microbubbles assisted by transcutaneous ultrasound effectively promotes arterial thrombolysis in vivo, and this technique can be of significance in clinical treatment of acute thrombotic occlusions.

Animals↗
PubMed2004

Microbubbles and ultrasound: from diagnosis to therapy.

The development of ultrasound contrast agents, containing encapsulated microbubbles, has increased the possibilities for diagnostic imaging. Ultrasound contrast agents are currently used to enhance left ventricular opacification, increase Doppler signal intensity, and in myocardial perfusion imaging. Diagnostic imaging with contrast agents is performed with low acoustic pressure using non-linear reflection of ultrasound waves by microbubbles. Ultrasound causes bubble destruction, which lowers the threshold for cavitation, resulting in microstreaming and increased permeability of cell membranes. Interestingly, this mechanism can be used for delivery of drugs or genes into tissue. Microbubbles have been shown to be capable of carrying drugs and genes, and destruction of the bubbles will result in local release of their contents. Recent studies demonstrated the potential of microbubbles and ultrasound in thrombolysis. In this article, we will review the recent advances of microbubbles as a vehicle for delivery of drugs and genes, and discuss possible therapeutic applications in thrombolysis.

Contrast Media↗
PubMed2006

Preparation of microbubble suspensions by co-axial electrohydrodynamic atomization.

In this paper we report a novel method, based on co-axial electrohydrodynamic jetting, for the preparation of microbubble suspensions containing bubbles <10 microm in size and having a narrow size distribution. No selective filtration is necessary and the suspensions are produced directly by the process. To demonstrate the method, glycerol was used as the liquid medium, flowing in the outer needle of the co-axial twin needle arrangement and undergoing electrohydrodynamic atomization in the stable cone-jet mode while air flowed through the inner needle at the same time. At zero applied voltage a hollow stream of liquid flowed from the outer needle. When the applied voltage was increased, eventually the hollow stream became a stable cone-jet and emitted a microthread of bubbles, which were collected in a container of glycerol to obtain microbubble suspensions. The size of the microbubbles was measured via optical microscopy and laser diffractometry. Several microbubble suspensions were prepared and characterised and the size distribution was found to be critically dependent on the ratio (n) of flow rates of liquid/air and, in particular the flow rate of the air. At n=1.5, with the flow rate of air set at approximately 1.7 microl/s, a microbubble suspension containing bubbles in the size range 2-8 microm was obtained.

Colloids↗
PubMed2005

Laser Doppler anemometry measurements of the shear stresses on ultrasonic contrast agent microbubbles attached to agar.

Ultrasonic contrast agents are currently being developed to target and bind to specific areas of interest such as atheromous plaque. A microbubble has been developed in-house which can be targeted to attach to specific cell-lines. To assess the feasibility of using the microbubble in vivo, the shear stresses which the bound microbubbles can withstand need to be known. A flow chamber was developed for use with intravascular ultrasound (IVUS) and laser Doppler anemometry (LDA). Biotin was incorporated into the microbubble shells and streptavidin was used to attach them to agar. IVUS at 40 MHz was then used to image the attached microbubbles under steady flow at a range of flow rates from 75 to 480 mL min(-1) through a flow area of 9 mm(2). LDA was employed to find high resolution velocity profiles of the flow in the chamber at a selection of these flow rates and the shear stresses on the bubbles were calculated. The bubbles were found to remain attached to the agar for shear stresses of up to 3.4 Pa. This compares with mean physiological arterial shear stresses of less than 1.5 Pa for pulsatile flow.

Agar↗
PubMed2005

Preparation, characterization and in vivo observation of phospholipid-based gas-filled microbubbles containing hirudin.

The objective of this work was to prepare echogenic phospholipid-based gas-filled microbubbles (PGM) and investigate their physical characteristics, echogenicity and loading ability of hirudin under various NaCl concentrations. PGM were prepared by a sonication-lyophilization method. Hirudin was used as a model drug to evaluate the drug encapsulation efficiency of the PGM. PGM loaded with hirudin were prepared by dissolving lyophilized powder with hirudin solution. The morphology, particle size and microbubble concentration of PGM were measured. The hirudin encapsulation efficiency as a function of NaCl concentration was determined. The mean particle size and microbubble concentration of PGM were unchanged by the presence of hirudin for at least 60 min after preparation. Hirudin encapsulation quantity was proportional to the hirudin concentration until saturation occurred at high concentration, and the encapsulation efficiency had an inverse relationship. Hirudin encapsulation efficiency was affected by NaCl concentration. When NaCl concentration was increased from 10 mg mL(-1) to 20 mg mL(-1) in PGM solution, hirudin encapsulation efficiency decreased from 35.8 to 26.7%, and microbubble concentration decreased from 2.7 x 10(8) to 1.7 x 10(8) microbubbles per mL. The PGM were shown easily to be visible in in vivo rabbit liver. There was no difference in echogenicity between the loaded and unloaded bubbles. PGM prepared by the sonication-lyophilization method exhibited satisfactory physical characteristics and loading ability and are suitable for use in imaging and ultrasound-triggered delivery.

Animals↗
PubMed2005

Time and pressure dependence of acoustic signals radiated from microbubbles.

Encapsulated microbubbles are considered to be microsensors for in vivo blood pressure measurements in the cardiovascular system. To study the potential of this method, we developed a simulation and an experimental set-up that relate various characteristics of radiated acoustic signals from the microbubbles to the varying ambient pressure. Both the simulation and the experiment show that the radiated pressure from microbubbles generates a significant subharmonic component, which is modulated by changes in the ambient pressure. A time-dependent decrease of the steady-state radii within a population of microbubbles causes a phase reversal phenomenon, which explains the observed time delay in the build-up of the subharmonic modulation response. Additionally, we identify a frequency-capturing effect that indicates the termination of the nonlinear behavior of the microbubbles. Our research suggests that these subharmonic signals can be used for in vivo blood pressure measurements and highlights some of the considerations that need to be addressed in developing such techniques.

Albumins↗
PubMed2003

Microbubble responses to a similar mechanical index with different real-time perfusion imaging techniques.

The purpose of this study was to determine differences in contrast enhancement and microbubble destruction rates with current commercially available low-mechanical index (MI) real-time perfusion imaging modalities. A tissue-mimicking phantom was developed that had vessels at 3 cm (near field) and 9 cm (far field) from a real-time transducer. Perfluorocarbon-exposed sonicated dextrose albumin microbubbles (PESDA) were injected proximal to a mixing chamber, and then passed through these vessels while the region was insonified with either pulses of alternating polarity with pulse inversion Doppler (PID) or pulses of alternating amplitude by power modulation (PM) at MIs of 0.1, 0.2 and 0.3. Effluent microbubble concentration, contrast intensity and the slope of digital contrast intensity vs. time were measured. Our results demonstrated that microbubble destruction already occurs with PID at an MI of 0.1. Contrast intensity seen with PID was less than with PM. Therefore, differences in contrast enhancement and microbubble destruction rates occur at a similar MI setting when using different real-time pulse sequence schemes.

Acoustics↗
PubMed2003

Differences in definity and optison microbubble destruction rates at a similar mechanical index with different real-time perfusion systems.

The purpose of this study was to determine microbubble responses to different pulse sequence schemes that exist on low mechanical index (MI) real-time perfusion imaging systems using either intravenous albumin-coated (Optison) or lipid-encapsulated (Definity) microbubbles. A tissue-mimicking phantom was created that permitted insonation of microbubbles at 3 cm (near field) and 9 cm (far field) from the diagnostic transducer face. Differences in effluent microbubble concentration were measured after they passed through vessels being insonified with pulse sequence schemes that transmitted alternating polarity (pulse inversion Doppler), alternating amplitude (power modulation), or both (contrast pulse sequencing) at a similar MI, frame rate, and transmit frequency. Normalized contrast signal intensity within a recirculating chamber was also measured in the near and far field. Pulse inversion Doppler produced less initial normalized contrast signal intensity and greater destruction rates than amplitude varying pulse sequence schemes like power modulation or contrast pulse sequencing at both the 0.1- and 0.2-MI settings. These differences indicate that the same MI setting on different real-time perfusion imaging techniques will produce different microbubble responses.

Albumins↗
PubMed2003

Microbubble potentiated ultrasound as a method of stroke therapy in a pig model: preliminary findings.

PURPOSE: Low-frequency ultrasound (LFUS) with intraarterial or intravenous microbubbles can recanalize thrombosed dialysis grafts and arteries. A similar method for declotting intracranial arteries in an animal model has been developed. MATERIALS AND METHODS: Swine underwent selective cerebral angiography, and 1 mL of 2-6 hour old clot was placed in one ascending pharyngeal artery and rete mirabile. This occluded the primary brain blood supply from the rete mirabile in the base of the skull. Human albumin octafluoropropane microbubbles were injected through the same catheter in 0.5-1.0-mL doses for a total of 4.5 mL in 21 minutes. Transcutaneous pulsed-wave 1-MHz ultrasound was administered through a temporal approach using 2.2 W/cm(2). Repeated angiography was performed through 24 minutes. Saline controls underwent an identical process on the opposite side. Declotting was graded on a scale of 0-4, and flow used the 0-3 thrombolysis in myocardial infarction (TIMI) scale. Success was defined as declotting of grade >/= 3 (>70% clearing) with flow of >/= 2. RESULTS: Seven pigs received 14 declotting sequences. Average clot age was 217 minutes. Average declotting score was 3.1, and flow was 2.1 for microbubbles and 1.4 and 0.1 for saline controls, P =.016 in each. Success occurred with microbubbles in six of seven attempts and in controls in zero of seven attempts, P =.031. CONCLUSIONS: LFUS with microbubble augmentation rapidly lyses intracranial clot and restores flow at ultrasound ranges similar to those required in humans. Further development of this possible acute stroke therapy is justified.

Animals↗
PubMed2003

Microbubble-enhanced cavitation for noninvasive ultrasound surgery.

Experiments were conducted to explore the potential of stabilized microbubbles for aiding tissue ablation during ultrasound therapy. Surgically exteriorized canine kidneys were irradiated in situ using single exposures of focused ultrasound. In each experiment, up to eight separate exposures were placed in the left kidney. The right kidney was then similarly exposed, but while an ultrasound contrast agent was continually infused. Kidneys were sectioned and examined for gross observable tissue damage. Tissue damage was produced more frequently, by lower intensity and shorter duration exposures, in kidneys irradiated with the contrast agent present. Using 250-ms exposures, the minimum intensity that produced damage was lower in kidneys with microbubbles than those without (controls) in 10 of 11 (91%) animals. In a separate study using approximately 3200 W/cm2 exposures, the minimum duration that produced damage was shorter after microbubbles were introduced in 11 of 12 (92%) animals. With microbubbles, gross observable tissue damage was produced with exposure intensity > or = approximately 800 W/cm2 and exposure duration > or = 10 micros. The overall intensity and duration tissue damage thresholds were reduced by approximately 2x and approximately 100x, respectively. Results indicate that acoustic cavitation is a primary damage mechanism. Lowering in vivo tissue damage thresholds with stabilized microbubbles acting as cavitation nuclei may make acoustic cavitation a more predictable, and thus practical, mechanism for noninvasive ultrasound surgery.

Albumins↗