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PubMed2002

High heat flux cooling by microbubble emission boiling.

In subcooled flow boiling of water in a horizontal rectangular channel, microbubble emission boiling occurred at higher subcooling of liquid in transition boiling, and the heat flux increased more than the critical heat flux. The maximum heat flux reached 10 MW/m(2) for a channel with 12 mm x 14mm cross-section at 40K liquid subcooling and 0.5 m/sec liquid velocity. For smaller rectangular channels with 14 mm x 5mm, 14mm x 3mm, and 14mm x 1mm cross-sections, the maximum heat flux was 7 MW/m(2)-more than 20 times the cooling limit of a present day CPU. Microbubble emission boiling is expected to realize high heat flux cooling for electronic devices. In convection boiling with subcooled water jet, the same boiling regime and heat flux were obtained for a downward heating surface and an upward heating surface. In subcooled flow boiling with strong convection, the hydrodynamic force is predominant for vapor-liquid exchange. Accordingly, microbubble emission boiling is expected for high heat flux cooling or high heat flux heat transfer in microgravity.

Journal Article↗

PubMed2003

The ultrasonic weak short-pulse responses of microbubbles based on a two-frequency approximation.

The ultrasonic short-pulse responses of microbubbles are of interest in cavitation, transient responses, and contrast imaging. We extend the two-frequency analytic solutions of Newhouse and Shankar [J. Acoust. Soc. Am. 75, 1473-1477 (1984)] to approximate the short-pulse responses of microbubbles in a low-amplitude field. Based on their results, there is an expected component near dc in the spectrum of bubble echoes excited by a short pulse. Here this component is named the low-frequency response, and its theoretical properties are verified experimentally. Including the fundamental and second-harmonic components, the weak short-pulse responses of microbubbles include three types of response. Our work has determined the constraint conditions under which this approximated solution can be used to analyze these short-pulse responses. This paper also provides the amplitude and spectral properties of these responses. The low-frequency response has a special bandwidth-dependent property and has potential applications in imaging and bubble sizing.

Journal Article↗

PubMed1996

Effect of static pressure on acoustic transmittance of Albunex microbubble suspensions.

Albunex (ALX), an albumin-stabilized microbubble echo contrast agent, is sensitive to pressures similar to those produced by the heart. The tested hypothesis was that the acoustic transmittance of ALX suspensions will increase with increasing hydrostatic pressure (Ps). The test involved an acoustic setup analogous to a spectrophotometer. The acoustic transmittance of microbubble suspensions was strongly Ps dependent. Transmittance at 1 MHz was essentially zero at ambient pressure, increasing to approximately 50%, approximately 63%, and nearly 100% at Ps of 80, 120, and 400 mm Hg, respectively. The ultrasound pulses used to interrogate samples were without measurable effect on the acoustic transmittance of suspensions maintained at ambient pressure during experimental measurements. The data indicate that many of the microbubbles are destroyed at Ps comparable to those produced by the heart.

Acoustics↗

PubMed1999

Shock wave-inertial microbubble interaction: methodology, physical characterization, and bioeffect study.

A method of generating in situ shock wave-inertial microbubble interaction by a modified electrohydraulic shock wave lithotripter is proposed and tested in vitro. An annular brass ellipsoidal reflector (thickness = 28 mm) that can be mounted on the aperture rim of a Dornier XL-1 lithotripter was designed and fabricated. This ring reflector shares the same foci with the XL-1 reflector, but is 15 mm short in major axis. Thus, a small portion of the spherical shock wave, generated by a spark discharge at the first focus (F1) of the reflector, is reflected and diffracted by the ring reflector, producing a weak shock wave approximately 8.5 microseconds in front of the lithotripter pulse. Based on the configuration of the ring reflector (different combinations of six identical segments), the peak negative pressure of the preceding weak shock wave at the second focus (F2) can be adjusted from -0.96 to -1.91 MPa, at an output voltage of 25 kV. The preceding shock wave induces inertial microbubbles, most of which expand to a maximum size of 100-200 microns, with a few expanding up to 400 microns before being collapsed in situ by the ensuing lithotripter pulse. Physical characterizations utilizing polyvinylidene difluoride (PVDF) membrane hydrophone, high-speed shadowgraph imaging, and passive cavitation detection have shown strong secondary shock wave emission immediately following the propagating lithotripter shock front, and microjet formation along the wave propagation direction. Using the modified reflector, injury to mouse lymphoid cells is significantly increased at high exposure (up to 50% with shock number > 100). With optimal pulse combination, the maximum efficiency of shock wave-induced membrane permeabilization can be enhanced substantially (up to 91%), achieved at a low exposure of 50 shocks. These results suggest that shock wave-inertial microbubble interaction may be used selectively to either enhance the efficiency of shock wave-mediated macromolecule delivery at low exposure or tissue destruction at high exposure.

Acoustics↗

PubMed2002

Mechanism of parenchymal enhancement of the liver with a microbubble-based US contrast medium: an intravital microscopy study in rats.

PURPOSE: To investigate the mechanism of prolonged contrast material enhancement of the liver observed with the lipid-shell ultrasonographic (US) contrast agent AF0150, with use of intravital microscopy. MATERIALS AND METHODS: Eight Sprague-Dawley rats were used. Six received fluorescent microspheres to label the Kupffer cells; two were used as controls. The edge of the middle lobe of the liver was transilluminated with white light. Fluorescent microspheres were observed under fluorescence light. After injection of AF0150, behavior of microbubbles was observed for 6 minutes while viewing a single high-power field. Multiple other fields were then assessed for stationary bubbles and their relation to Kupffer cells. The number of bubbles in motion, aggregated, stationary, and associated with labeled cells were counted. RESULTS: Of 590 bubbles, 34 (5.8%) became stationary and 556 (94.2%) kept moving. Of the 34 stationary microbubbles, 21 dislodged within 30 seconds. Microbubbles were homogeneously distributed throughout the lobule, in contrast to the dominant periportal distribution of the labeled Kupffer cells. Among 83 stationary bubbles observed from all fields of view, only 14 (17%) were associated with fluorescent-labeled cells. CONCLUSION: The late parenchymal liver enhancement effect of AF0150 is likely not related to Kupffer-cell uptake, but rather to a mechanical slowdown within the sinusoids.

Animals↗

PubMed2000

Harmonic hepatic US with microbubble contrast agent: initial experience showing improved characterization of hemangioma, hepatocellular carcinoma, and metastasis.

PURPOSE: To characterize blood flow in focal hepatic lesions with harmonic ultrasonographic (US) imaging and a microbubble contrast agent. MATERIALS AND METHODS: Thirty patients with known hepatic masses were examined after injection of a perfluorocarbon microbubble agent. Tumor vascularity was assessed with continuous, harmonic gray-scale imaging with a low mechanical index (MI). Tumor vascular volume was assessed with brief, high-MI insonation called interval-delay imaging, which caused microbubble destruction. As the total contrast agent volume in the liver reflects the total vascular volume, quantitation of lesion enhancement relative to normal hepatic enhancement helped determine the vascular volume of the tumor relative to that of normal parenchyma. RESULTS: Low-MI continuous harmonic imaging showed lesional vessels in hepatocellular carcinomas, minimal or no vessels in hemangiomas, and variable vascularization in metastases. High-MI interval-delay imaging showed greater enhancement in hepatocellular carcinomas than in normal liver (P <.02) and showed less enhancement in hemangiomas than in normal liver (P <.02). Enhancement in metastases was greater in the margins than in the center; as a result, the lesions appeared smaller (P <.03) and less well defined on the interval-delay images. CONCLUSION: Contrast-enhanced harmonic imaging appears superior to conventional Doppler US for hepatic mass characterization. Low-MI continuous and high-MI interval-delay imaging can help assess tumor vascular pattern and microvascular volume.

Adult↗

PubMed2000

Hepatocellular carcinoma treated with percutaneous radio-frequency ablation: usefulness of power Doppler US with a microbubble contrast agent in evaluating therapeutic response-preliminary results.

PURPOSE: To evaluate the usefulness of power Doppler ultrasonography (US) with a microbubble contrast agent in assessing the therapeutic response of hepatocellular carcinomas (HCCs) treated with percutaneous radio-frequency (RF) ablation. MATERIALS AND METHODS: Forty patients with 45 nodular HCC lesions 1.0-3.8 cm in diameter underwent power Doppler US before and after intravenous injection of a microbubble contrast agent. The same procedures were repeated after US-guided percutaneous RF ablation. The results of these studies were compared with those of three-phase helical computed tomography (CT) performed immediately after RF ablation. RESULTS: Before RF ablation, nonenhanced power Doppler US demonstrated flow signals within tumor in 33 of 45 HCCs. After contrast agent administration, flow signals increased or newly appeared in all cases. After RF ablation, none of the ablated tumors showed intratumoral flow signals at nonenhanced power Doppler US, whereas six showed marginal intratumoral flow signals at contrast agent-enhanced power Doppler US. These six tumors were found to have small enhancing foci, suggestive of viable tumor, in corresponding areas at immediate follow-up CT. Additional RF ablation or transcatheter arterial chemoembolization was performed in these tumors. CONCLUSION: The results of power Doppler US with a microbubble contrast agent in HCCs treated with RF ablation correlated well with those of contrast-enhanced CT. Preliminary data suggest that contrast-enhanced power Doppler US can be a promising noninvasive technique for assessing therapeutic response.

Adult↗

PubMed1979

The lung as a filter for microbubbles.

A new ultrasonic Doppler device has been used noninvasively over the femoral artery of anesthetized dogs to prove that it can detect carefully calibrated microbubbles of 14--189 micrometers diam when these are infused directly into the aorta. The same evaluated technique has then been employed to detect any bubbles escaping into the arterial system when gas was infused into the venous system either as microbubbles or as a bolus. Results from 18 dogs showed that, under normal conditions, the lungs are a superb filter for bubbles and that any cutoff diameter is less than 22 micrometers. However, bubbles escaped entrapment when the lungs were severely overloaded with gas (20 ml) or were pretreated with a pulmonary vasodilator (aminophylline). The dog preparation and arterial Doppler device appear to be ideal for future studies to determine what other factors might compromise the capability of the lungs to filter microbubbles. Physiological parameters showed dramatic changes when bubbles were detected as escaping into the arterial system by comparison with their effect when retained within the lungs. Changes in respiration profile indicated that they may offer a useful index of the degree of venous embolization and, hence, a warning of impending overload leading to arterial embolization.

Air↗

PubMed1998

The stable microbubble test on tracheal aspirate samples from newborn babies for diagnosis of surfactant deficiency and/or surfactant malfunction.

For predicting the risk of respiratory distress syndrome (RDS), lung surfactant in amniotic fluid can be assessed by observation of stable microbubbles (< 15 microns diameter). It was investigated if the stable microbubble test (MT) developed on amniotic fluid could be applied on tracheal aspirate samples (TA) obtained from newborn infants. Forty-four TA from 29 newborn infants without pulmonary diseases (group 1) and 65 TA from 21 newborn infants with respiratory insufficiency (group 2) were analyzed by the MT for predicting surfactant deficiency and/or surfactant malfunction. Ten microbubbles/ mm2 was defined as cutoff value of the MT. A specificity of 90% and a sensitivity of 52% was obtained with this cutoff value. A much lower rate of false negative results (sensitivity 91%) was noted after surface tension measurement of TA. The sensitivity of the MT (52%) does not encourage the use of the MT on TA.

Cohort Studies↗

PubMed2003

Ultrasound-targeted microbubble destruction can repeatedly direct highly specific plasmid expression to the heart.

BACKGROUND: Noninvasive, tissue-specific delivery of therapeutic agents would be a valuable clinical tool. We have previously shown that ultrasound-targeted microbubble destruction can direct expression of an adenoviral reporter to the heart. The present study shows that this method can be applied to selectively deliver plasmid vectors to the heart. METHODS AND RESULTS: We used albumin and lipid microbubbles containing plasmids with a luciferase transgene to target the heart in rats. After 4 days, organs were harvested and analyzed for reporter gene expression. In a second set of experiments, the hearts of rats treated with plasmids were harvested at various time points during a 4-week period. Both luciferase activity and mRNA concentrations were measured. Luciferase transfection with plasmids showed highly specific gene expression in the heart, with hardly any activity in control organs. Time course evaluation showed high transgene expression in the first 4 days, with a rapid decline thereafter. Repeated treatment produced a second peak of transgene expression with similar decay. CONCLUSIONS: Ultrasound-mediated destruction of microbubbles directs plasmid transgene expression to the heart with much greater specificity than viral vectors and can be regulated by repeated treatments. This noninvasive technique is a promising method for cardiac gene therapy.

Animals↗

PubMed1998

Microbubbles targeted to intercellular adhesion molecule-1 bind to activated coronary artery endothelial cells.

BACKGROUND: Preclinical atherosclerosis is associated with increased endothelial cell (EC) expression of leukocyte adhesion molecules (LAMs), which mediate monocyte adhesion during atherogenesis. Identification of cell-surface LAMs may uniquely allow assessment of endothelial function, but there are no in vivo methods for detecting LAMs. We tested a new microbubble designed to bind to and allow specific ultrasound detection of intercellular adhesion molecule-1 (ICAM-1). METHODS AND RESULTS: A perfluorobutane gas-filled lipid-derived microsphere with monoclonal antibody to ICAM-1 covalently bound to the bubble shell was synthesized. Bubbles with either nonspecific IgG or no protein on the shell were synthesized as controls. Coverslips of cultured human coronary artery ECs were placed in a parallel-plate perfusion chamber and exposed to 1 of the 3 microbubble species, followed by perfusion with culture medium. Experiments were performed with either normal or interleukin-1beta-activated ECs overexpressing ICAM-1, and bubble adherence was quantified with epifluorescent videomicroscopy. There was limited adherence of control bubbles to normal or activated ECs, whereas a 40-fold increase in adhesion occurred when anti-ICAM-1-conjugated bubbles were exposed to activated ECs compared with normal ECs (8.1+/-3.5 versus 0.21+/-0.09 bubbles per cell, respectively, P<0.001). Although diminished, this difference persisted even after perfusion at higher wall shear rates. CONCLUSIONS: A gas-filled microbubble with anti-ICAM-1 antibody on its shell specifically binds to activated ECs overexpressing ICAM-1. Diagnostic ultrasound in conjunction with targeted contrast agents has the unique potential to characterize cell phenotype in vivo.

Antibodies, Monoclonal↗

PubMed1998

Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound.

BACKGROUND: We have previously shown that the application of ultrasound to thin-shelled microbubbles flowing through small microvessels (<7 microm in diameter) produces vessel wall ruptures in vivo. Because many intravascular drug- and gene-delivery vehicles are limited by the endothelial barrier, we hypothesized that this phenomenon could be used to deliver drug-bearing vehicles to tissue. METHODS AND RESULTS: An exteriorized rat spinotrapezius muscle preparation was used. Intravascular fluorescent red blood cells and polymer microspheres (PM) (205 and 503 nm in diameter) were delivered to the interstitium of rat skeletal muscle through microvessel ruptures created by insonifying microbubbles in vivo. On intravital microscopy, mean dispersion areas per rupture for red blood cells, 503-nm PM, and 205-nm PM were 14.5x10(3) microm2, 24. 2x10(3) microm2, and 27.2x10(3) microm2, respectively. PM dispersion areas were significantly larger than the mean dispersion area for red blood cells (P<0.05). CONCLUSIONS: Microvessel ruptures caused by insonification of microbubbles in vivo may provide a minimally invasive means for delivering colloidal particles and engineered red blood cells across the endothelial lining of a targeted tissue region.

Animals↗

PubMed1998

Direct in vivo visualization of intravascular destruction of microbubbles by ultrasound and its local effects on tissue.

BACKGROUND: Our aim was to observe ultrasound-induced intravascular microbubble destruction in vivo and to characterize any resultant bioeffects. METHODS AND RESULTS: Intravital microscopy was used to visualize the spinotrapezius muscle in 15 rats during ultrasound delivery. Microbubble destruction during ultrasound exposure caused rupture of < or = 7-microm microvessels (mostly capillaries) and the production of nonviable cells in adjacent tissue. The number of microvessels ruptured and cells damaged correlated linearly (P<0.001) with the amount of ultrasound energy delivered. CONCLUSIONS: Microbubbles can be destroyed by ultrasound, resulting in a bioeffect that could be used for local drug delivery, angiogenesis, and vascular remodeling, or for tumor destruction.

Air↗

PubMed1999

Subharmonic imaging with microbubble contrast agents: initial results.

The subharmonic emission from insonified contrast microbubbles was used to create a new imaging modality called Subharmonic Imaging. The subharmonic response of contrast microbubbles to ultrasound pulses was first investigated for determining adequate acoustic transmit parameters. Subharmonic A-lines and gray scale images were then obtained using a laboratory pulse-echo system in vitro and a modified ultrasound scanner in vivo. Excellent suppression of all backscattered signals other than from contrast microbubbles was achieved for subharmonic A-lines in vitro while further optimization is required for in vivo gray scale subharmonic images.

Animals↗

PubMed2003

The dynamic bubble trap reduces microbubbles in extracorporeal circulation and high intensity transient signals in the middle cerebral artery: a case report.

Microemboli during extracorporeal circulation (ECC) might be a reason for postoperative neuropsychological dysfunction. This case report shows that reduction of microbubbles in the arterial line, as well as high intensity transient signals (HITS) in the middle cerebral artery (MCA), could be accomplished by use of a dynamic bubble trap (DBT) during routine coronary artery bypass graft (CABG) surgery in a 63-year-old male. The DBT was placed after the arterial filter, an ultrasound Doppler device was used for detection of microemboli before and after the DBT. HITS were measured by a transcranial ultrasound Doppler in both MCAs. For first 32 min of ECC, the DBTwas excluded; 54 916 microbubbles and 507 HITS were counted. In the next 30 min, blood flow was directed through the DBT. This led to a significant reduction of microbubbles from 55 888 to 18 237; accordingly, only 120 HITS were registered. A DBT, integrated in ECC for routine CABG, effectively reduces air bubbles, thus protecting the cerebrovascular system from microembolization, as demonstrated by lower HITS counts.

Cerebrovascular Circulation↗

PubMed1986

Microbubbles as a contrast agent for neurosonography and ultrasound-guided catheter manipulation: in vitro studies.

Tissue-equivalent ultrasound phantoms, including models of the ventricular system and cyst phantoms, may be useful for developing expertise in both biopsy procedures and shunt catheter placement that use ultrasound guidance. These phantoms have been constructed (1) to assess the ability to position biopsy needles and manipulate shunt catheters with conventional angiographic guidewires and (2) to evaluate the usefulness of microbubbles as an ultrasound contrast agent. Optimal catheter and needle position and catheter patency are demonstrated with microbubbles generated by hand injection of small volumes of saline, a safe ultrasound contrast agent that, to our knowledge, has not been previously exploited in neurosonography. Microbubbles can define biopsy needle location without direct imaging of the biopsy needle; they can also define the extent of communication or separation of fluid-filled or loculated spaces.

Air↗

PubMed1997

Inflammatory pancreatic masses: differentiation from ductal carcinomas with contrast-enhanced sonography using carbon dioxide microbubbles.

OBJECTIVE: The aim of this study was to evaluate the clinical efficacy of contrast-enhanced sonography using carbon dioxide microbubbles to differentiate inflammatory pancreatic masses from ductal carcinomas of the pancreas. SUBJECTS AND METHODS: Fifty-five patients, including 35 patients with ductal carcinomas and 20 with inflammatory pancreatic masses, underwent contrast-enhanced sonography, CT, and digital subtraction angiography (DSA). Carbon dioxide microbubbles were prepared by mixing 10 ml of carbon dioxide and the same amount of 25% soybean oil vigorously. Carbon dioxide microbubbles were injected through an angiographic catheter that was placed in the celiac axis. Vascularity of the tumors as determined by those three techniques was interpreted by three physicians who had no knowledge of the pathologic results. RESULTS: Contrast-enhanced sonography was best at revealing tumor vascularity among the three techniques. On contrast-enhanced sonography, 19 (95%) of the 20 inflammatory pancreatic masses were isovascular and 32 (91%) of the 35 ductal carcinomas were hypovascular. In contrast, the isovascularity of inflammatory masses was five (25%) on CT, and two (10%) on DSA, respectively. The sensitivity and accuracy rate of differentiating both diseases on contrast-enhanced sonography were 98% and 95%, respectively; on CT, they were both 73%; and on DSA they were both 67%. From our results, an isovascular mass is probably an inflammatory mass, whereas a hypovascular mass is most likely a ductal carcinoma on contrast-enhanced sonography. CONCLUSION: Contrast-enhanced sonography can help differentiate an inflammatory pancreatic mass from a ductal carcinoma.

Adenocarcinoma↗

PubMed2002

[Assessment of myocardial ischemia and infarction by intravenous myocardial contrast echocardiography with perfluorocarbon microbubbles]

OBJECTIVE: To assess the value of myocardial contrast echocardiography (MCE) with intermittent second harmonic technique and perfluorocarbon microbubbles in identifying myocardial ischemia and infarction. METHODS: Open-chest dogs were performed by intravenous MCE with perfluorocarbon microbubbles after 3 h of left anterior descending coronary artery (LAD) occlusion. The parameters of time-intensity curve were measured and compared between the normal and ischemic myocardial area at short-axis view of left ventricule midpapillary muscle level. The infarct size assessed by MCE was compared with the gross pathologic specimen stained with triphenyltetrazolium chloride (TTC). RESULTS: The peak intensity (PI), T1/2, and area under curve (AUC) in the ischemic area were significantly different versus the normal area 13.5+/-1.9 compared with 22.5+/-2.4; 16.6+/-0.9 compared with 9.7+/-0.5; 231.6+/-14.9 compared with 405.6+/-12.3 P<0.02). The percents of the no flow area determined by MCE had correlation with those by TTC stain(r=0.89, P=0.01). CONCLUSION: Intermittent second harmonic MCE using intravenous injection of perfluorocarbon microbubbles could assess myocardial perfusion, diagnose ischemia, and define myocardial infarct size.

Journal Article↗