Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Microbubbles”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed1991

Microbubble-induced serotonin secretion in human platelets.

The effect of nitrogen (N2) microbubbles on platelets resembles that of common platelet agonists with respect to aggregation (Thorsen T et al., Undersea Biomed Res 1986; 13: 289-303). In the present study we examined the effect of microbubbles on platelet secretion of preloaded 14C-serotonin. We demonstrate that stirring of platelet-rich plasma with N2-microbubbles causes a loss of single platelets that is associated with secretion. However, secretion did not increase above baseline values until after 20 min of microbubble exposure, when platelet aggregation had reached 40%. After that time the secretion rate increased. There was no correlation between secreted serotonin and the degree of platelet aggregation. Although no 14C-serotonin secretion occurred in presence of acetylsalicyclic acid (ASA), microbubble-induced platelet aggregation was only marginally reduced. Epinephrine alone caused significant platelet aggregation but no 14C-serotonin secretion and it enhanced N2-microbubble-induced platelet aggregation and secretion; ASA completely prevented secretion under these circumstances but failed to abolish the enhancement of aggregation compared with microbubbles alone. Earlier studies have shown that platelets adhere to the bubble surfaces (Thorsen T et al., Undersea Biomed Res 1987; 14: 45-59). The results in the present study indicate that non-adhering platelets in the bulk phase are not activated by means of autocrine stimulation through dense granule material.

Blood Platelets↗
PubMed2005

Microbubble-enhanced ultrasound exposure promotes uptake of methotrexate into synovial cells and enhanced antiinflammatory effects in the knees of rabbits with antigen-induced arthritis.

OBJECTIVE: To evaluate whether microbubble-enhanced ultrasound (US) treatment promotes the delivery of methotrexate (MTX) into synovial cells and the enhanced antiinflammatory effects of intraarticular MTX therapy in a rabbit arthritis model. METHODS: Arthritis was induced in both knees of 53 rabbits by immunization with ovalbumin. MTX including a microbubble agent was then injected into the left and right knee joints, and the right knees were exposed to US (MTX+/US+ group), while the left knees were not (MTX+/US- group). The knee joints were evaluated histologically in 7 rabbits at 5 time points up to day 56. Quantitative gene expression of interleukin-1beta (IL-1beta) in synovial tissue was measured on days 7 and 28. Eight rabbits were used for the measurement of MTX concentration in synovial tissue 12 hours after treatment. To evaluate the effect of microbubble-enhanced US treatment in the absence of MTX, only the microbubble agent was injected into the left and right knee joints of 10 rabbits with or without US exposure, and these animals were evaluated histologically on days 7 and 28. RESULTS: The MTX concentration in synovial tissue was significantly higher in the MTX+/US+ group than in the MTX+/US- group. Synovial inflammation was less prominent in the MTX+/US+ group compared with the MTX+/US- group, judging from the results of the histologic evaluation and the gene expression levels of IL-1beta in synovial tissue. It also appeared that microbubble-enhanced US exposure itself did not affect inflammation. CONCLUSION: Microbubble-enhanced US exposure promoted the uptake of MTX into synovial cells, which resulted in enhancement of the antiinflammatory effects of the intraarticular MTX injection. These results suggest that application of this technique may have clinical benefit.

Animals↗
PubMed2006

Vibrating microbubbles poking individual cells: drug transfer into cells via sonoporation.

Ultrasound contrast microbubbles have the ability to enhance endothelial cell permeability and thus may be used as a new way to deliver drugs. It facilitates the transfer of extracellular molecules into cells activated through ultrasound driven microbubbles. The present study is designed to correlate the relationship between microbubble induced cell deformation and enhanced cell membrane permeability. Propidium iodide (PI) was used as a membrane integrity probe. Using high-speed imaging of vibrating microbubbles against endothelial cells and imaging transport of PI into these cells showed a direct correlation between cell deformation and resulting cell membrane permeability. The membrane permeabilization lasted for a short period without affecting endothelial cells viability. We identified that microbubbles are crucial to enhance transient cell membrane permeability. Thus, permeability of individual cells is increased. The roles of ultrasound contrast microbubbles as the trigger for improved drug efficacy are discussed.

Animals↗
PubMed2006

Microbubble-enhanced ultrasound to deliver an antisense oligodeoxynucleotide targeting the human androgen receptor into prostate tumours.

We have shown recently that downregulation of the androgen receptor (AR), one of the key players in prostate tumor cells, with short antisense oligodeoxynucleotides (ODNs) results in inhibition of prostate tumor growth. Particularly with regard to an application of these antisense drugs in vivo, we now investigated the usefulness of microbubble-enhanced ultrasound to deliver these ODNs into prostate cancer cells. Our short antisense AR ODNs were loaded onto the lipid surface of cationic gas-filled microbubbles by ion charge binding, and delivered into the cells by bursting the loaded microbubbles with ultrasound. In vitro experiments were initially performed to show that this kind of delivery system works in principle. In fact, transfection of prostate tumor cells with antisense AR ODNs using microbubble-enhanced ultrasound resulted in 49% transfected cells, associated with a decrease in AR expression compared to untreated controls. In vivo, uptake of a digoxigenin-labelled ODN was found in prostate tumour xenografts in nude mice following intratumoral or intravenous injection of loaded microbubbles and subsequent exposure of the tumour to ultrasound, respectively. Our results show that ultrasound seems to be the driving force of this delivery system. Uptake of the ODN was also observed in tumors after treatment with ultrasound alone, with only minor differences compared to the combined use of microbubbles and ultrasound.

Androgen Receptor Antagonists↗
PubMed2004

Micromanipulation of endothelial cells: ultrasound-microbubble-cell interaction.

Ultrasound (US) in combination with contrast microbubbles has been shown to alter the permeability of cell membranes without affecting cell viability. This permeabilisation feature is used to design new drug delivery systems using US and contrast agents. The underlying mechanisms are still unknown. One hypothesis is that oscillating microbubbles cause cell deformation resulting in enhanced cell membrane permeability. This technical note reveals the interaction between oscillating microbubbles and endothelial cells under a microscope recorded with a fast framing camera at 10 million frames per second. A microbubble expansion of 100% resulted a 2.3-mum displacement of the cell membrane. During the insonification, changes of approximately 15% in the cross-sectional distance of the endothelial cells were observed due to microbubble vibrations. In conclusion, the use of such a camera makes it possible to reveal the mechanisms of interactions between ultrasound, microbubbles and cells.

Animals↗
PubMed2005

Delivery of oligodeoxynucleotides into human saphenous veins and the adjunct effect of ultrasound and microbubbles.

Therapy with naked oligodeoxynucleotides (ODNs, molecular weight: 3000 to 7500) provides an elegant means of modulating gene expression without the problems associated with conventional gene therapy, but the relatively low transfer efficiency on intravascular administration is a limitation to clinical application. Ultrasound, which can be potentiated by microbubbles, shows promise as a method of delivering macromolecules such as plasmid DNA and other transgenes into cells. Since uptake of molecules into cells depends on their molecular weight, it might be expected that the delivery of ODNs, which are relatively small, will be facilitated by ultrasound and microbubbles. In the present study, we delivered ODNs into veins using ultrasound and microbubbles. First, we quantified the uptake of fluorescent-labeled ODNs into intact ex vivo human saphenous veins and isolated smooth muscle cells from the veins, evaluating the effect of ultrasound and microbubbles on uptake. Ultrasound potentiated the delivery of ODN in cells, except at high concentrations. When intact veins were studied, we achieved nuclear localization of fluorescent-labeled ODNs in cells. This increased with increasing concentration and incubation time and was not potentiated by ultrasound, even when microbubbles were used. We then applied a therapeutic ODN (antisense to intercellular adhesion molecule 1, ICAM-1) to vein samples and documented a functional inhibition of gene expression in a sequence-specific manner at the protein level with immunohistochemistry and western blot analysis. Again, no significant difference was seen with adjunct ultrasound. These observations suggest high diffusion of ODNs into human saphenous veins in this ex vivo model, indicating potential applications to inhibition of vascular bypass graft occlusion and other vasculopathies. Although microbubble-ultrasound was of value with cells in culture, it was not beneficial with intact veins.

Aged↗
PubMed2006

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.

Computer Simulation↗
PubMed2005

Influence of fluid shear and microbubbles on bacterial detachment from a surface.

Prevention of microbial adhesion and detachment of adhering microorganisms from surfaces is important in many environmental, industrial, and medical applications. Fluid shear is an obvious parameter for stimulating microbial detachment from surfaces, but recently it has been pointed out that a passing air-liquid interface also has potential in stimulating microbial detachment. In the present study, the ability of microbubbles to stimulate detachment of bacterial strains from a glass surface is compared with the effects of fluid flow. Adhesion and detachment of Actinomyces naeslundii T14V-J1, Streptococcus oralis J22, and their coadhering aggregates were studied on glass, mounted in a parallel plate flow chamber. High fluid wall shear rates (11,000 to 16,000 s(-1)) were established in a laminar flow regime in the absence and presence of microbubbles. Wall shear rates stimulated detachment ranging from 70% to 30% for S. oralis and A. naeslundii, respectively. Coadhering aggregates were detached up to 54%. The presence of microbubbles in the flow increased the detachment of A. naeslundii within 2 min of flow from 40% in the absence of microbubbles to 98%, while detachment of neither S. oralis nor coadhering aggregates was affected by the presence of microbubbles. In summary, extremely high fluid flows can be effective in stimulating microbial detachment, depending on the strain involved. The addition of microbubbles to the flow allows the detachment of tenaciously adhering bacteria not detached by flow alone, but not of adhering coaggregates.

Actinomyces↗
PubMed2006

Microbubble contrast agent with focused ultrasound to create brain lesions at low power levels: MR imaging and histologic study in rabbits.

PURPOSE: To evaluate magnetic resonance (MR) imaging-based thermometry for predicting the onset and spatial extent of lesions produced by focused ultrasound combined with a microbubble contrast agent (Optison; GE Healthcare, Milwaukee, Wis) and to compare the resulting induced temperature increase and threshold for damage with those in studies performed without the agent. MATERIALS AND METHODS: The experiments were approved by the animal care committee. Fifty-three locations in the brains of 15 rabbits were sonicated with various exposure parameters by using a 1.5-MHz focused ultrasound transducer. MR imaging was used to map the temperature rise and, along with light microscopy, to examine the lesions. Diameters of isotherms created from thermometry were compared with the resulting lesions by using Bland-Altman analysis and linear regression. The minimum acoustic power necessary for lesion creation was determined, and the apparent temperature threshold for damage was calculated with probit analysis. These thresholds were compared with prior work performed without the contrast agent. The heating induced with the microbubbles was compared with that in sonications performed without them by using a t test. RESULTS: The MR imaging-mapped temperature distributions matched the shape of the lesions. The diameters of isotherms correlated well with diameters measured at contrast material-enhanced MR imaging (mean difference between measurements, 0.0 mm +/- 0.5; R = 0.93). The temperature increase with microbubbles was statistically larger (P < .01) than for sonications performed without microbubbles. In some locations (mostly continuous wave exposures), damage was observed along the ultrasound beam path. The time-averaged acoustic power damage threshold was reduced by 91% for 10-second exposures when compared with earlier studies performed without microbubbles. The probability of producing lesions was 50% at a temperature increase of 5.9 degrees C, 5.5 degrees C lower than was observed earlier without the agent. CONCLUSION: MR imaging-based temperature measurements appeared to correlate with focused ultrasound-induced lesions in the brain when microbubbles were present, even though the temperature appeared to be below the threshold for thermal damage.

Animals↗
PubMed2006

Transient permeabilization of cell membranes by ultrasound-exposed microbubbles is related to formation of hydrogen peroxide.

In the present study, we addressed the interactions among ultrasound, microbubbles, and living cells as well as consequent arising bioeffects. We specifically investigated whether hydrogen peroxide (H(2)O(2)) is involved in transient permeabilization of cell membranes in vitro after ultrasound exposure at low diagnostic power, in the presence of stable oscillating microbubbles, by measuring the generation of H(2)O(2) and Ca(2+) influx. Ultrasound, in the absence or presence of SonoVue microbubbles, was applied to H9c2 cells at 1.8 MHz with a mechanical index (MI) of 0.1 or 0.5 during 10 s. This was repeated every minute, for a total of five times. The production of H(2)O(2) was measured intracellularly with CM-H(2)DCFDA. Cell membrane permeability was assessed by measuring real-time changes in intracellular Ca(2+) concentration with fluo-4 using live-cell fluorescence microscopy. Ultrasound, in the presence of microbubbles, caused a significant increase in intracellular H(2)O(2) at MI 0.1 of 50% and MI 0.5 of 110% compared with control (P < 0.001). Furthermore, we found increases in intracellular Ca(2+) levels at both MI 0.1 and MI 0.5 in the presence of microbubbles, which was not detected in the absence of extracellular Ca(2+). In addition, in the presence of catalase, Ca(2+) influx immediately following ultrasound exposure was completely blocked at MI 0.1 (P < 0.01) and reduced by 50% at MI 0.5 (P < 0.001). Finally, cell viability was not significantly affected, not even 24 h later. These results implicate a role for H(2)O(2) in transient permeabilization of cell membranes induced by ultrasound-exposed microbubbles.

Animals↗
PubMed2005

Microbubbles: pathophysiology and clinical implications.

Gas embolism is a known complication of various invasive procedures, and its management is well established. The consequence of gas microemboli, microbubbles, is underrecognized and usually overlooked in daily practice. We present the current data regarding the pathophysiology of microemboli and their clinical consequences. Microbubbles originate mainly in extracorporeal lines and devices, such as cardiopulmonary bypass and dialysis machines, but may be endogenous in cases of decompression sickness or mechanical heart valves. Circulating in the blood stream, microbubbles lodge in the capillary bed of various organs, mainly the lungs. The microbubble obstructs blood flow in the capillary, thus causing tissue ischemia, followed by inflammatory response and complement activation. Aggregation of platelets and clot formation occurs as well, leading to further obstruction of microcirculation and tissue damage. In this review, we present evidence of the biological and clinical detrimental effects of microbubbles as demonstrated by studies in animal models and humans, and discuss management of the microbubble problem with regard to detection, prevention, and treatment.

Blood Coagulation↗
PubMed2006

Treatment of deeply located acute intravascular thrombi with therapeutic ultrasound guided by diagnostic ultrasound and intravenous microbubbles.

OBJECTIVE: We sought to determine the added value of simultaneous imaging of intravenously infused microbubbles that are being used to dissolve an intravascular thrombus with therapeutic ultrasound (TUS). METHODS: In a chronic canine arteriovenous graft occluded by a thrombus, TUS (1 MHz) was applied through a 6-cm-thick tissue-mimicking phantom (measured mean +/- SD peak negative pressure through the phantom, 958 +/- 104 kPa) during an intravenous infusion of either saline (n = 6 occlusions) or lipid-encapsulated microbubbles (ImaRx Therapeutics, Inc, Tucson, AZ). Therapeutic ultrasound was intermittently applied during the microbubble infusion either at set time intervals (n = 6 occlusions) or when simultaneous diagnostic ultrasound (DUS) indicated a sustained presence of microbubbles (n = 12 occlusions). Success was defined as return of rapid flow within the graft (grade 3 flow). RESULTS: Diagnostic ultrasound showed microbubbles moving through small channels within the thrombus before angiographic evidence of flow in the graft. This guided the timing of TUS application better than using set time intervals. Angiographic clearance of the thrombus and restoration of grade 3 flow at 45 minutes of treatment were seen in 33% of deeply located thrombosed grafts treated with TUS at set time intervals and 92% of grafts treated with TUS guided by DUS (P < .001 compared with set time intervals). CONCLUSIONS: The use of TUS with intravenous microbubbles has a high success rate in recanalizing deeply located thrombosed arteriovenous grafts when performed with DUS guidance.

Angiography↗
PubMed1999

Targeting and ultrasound imaging of microbubble-based contrast agents.

Preparation and characterization of targeted microbubbles (ultrasound contrast agents) is described. Specific ligands were attached to the microbubble shell, and ligand-coated microbubbles were selectively attached to various targets, using either an avidin biotin model system or an antigen-antibody system for targeting to live activated endothelial cells. Firm attachment of microbubbles to the target was achieved. Forces necessary to detach microbubbles from the target were estimated to exceed dozens of pN. Microbubbles were bound to the target even in the rapidly moving stream of the aqueous medium. Down to 20 ng of the ultrasound contrast material on the target surface could be detected by the ultrasound imaging with a commercial medical imaging system. At high bubble density on the target surface, strong ultrasound image attenuation was observed.

Antigen-Antibody Reactions↗
PubMed1982

Intraoperative 2-dimensional echocardiography: ejection of microbubbles from the left ventricle after cardiac surgery.

Although the presence of entrapped air in the left ventricle at surgery has long been a concern, its prevalence and clinical significance are unknown. Two-dimensional echocardiography provides a unique means for observing intracardiac microbubbles intraoperatively. Accordingly, intraoperative 2-dimensional echocardiograms obtained in 79 patients immediately after cardiopulmonary bypass were examined for the presence of microbubbles. Left ventricular microbubbles were detected in 14% of coronary artery bypass operations (n = 22), 50% of multiple valve replacements (n = 8), 67% of single valve replacements (n = 58), and 100% of atrial septal defect closures (n = 4), left atrial myxoma resections (n = 2), and mitral commissurotomies (n = 2). Microbubbles were not observed in patients undergoing coronary artery bypass with valve replacement (n = 4) or with removal of left ventricular aneurysm (n = 1). Continuous ejection of microbubbles from the left ventricle was frequently noted for extended periods of time and, although no patient in this study showed evidence of gross neurologic dysfunction, the possibility of subclinical organ damage exists. We conclude that 2-dimensional echocardiography is useful for detection of intracardiac microbubbles and therefore may be instrumental in their elimination.

Cardiac Surgical Procedures↗
PubMed2004

Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow.

This study was performed to assess the binding kinetics of a targeted microbubble contrast agent exposed to shear stress. An ultrasound contrast targeted to P-selectin was designed by conjugating monoclonal antibodies against murine P-selectin (RB40.34) to the lipid monolayer shell of the microbubble using poly(ethylene glycol)-biotin-streptavidin. The attachment and detachment of targeted microbubbles to P-selectin immobilized on a culture dish were assessed in a parallel-plate flow chamber. Targeted microbubbles (5 x 10(6) particles/ml) drawn through the flow chamber coated with P-selectin (109 sites/microm(2)) at a shear stress of 0.3 dyn/cm(2) accumulated at a rate of 565 mm(-2) min(-1). Attachment rates increased at higher plate surface densities of P-selectin, and microbubble detachment was reduced. Accumulation rate first increased with shear stress, reached a maximum at approximately 0.6 dyn/cm(2) and then decreased. Control experiments on a plate that lacked P-selectin, or was blocked with mAb RB40.34, resulted in minimal bubble attachment. Microbubble detachment was tested by ramping up shear stress at 30-s intervals. Half-maximal detachment was reached at 34 dyn/cm(2). Overall, accumulation and retention of targeted ultrasound contrast agents is possible under physiologic flow conditions and is strongly influenced by shear stress and surface density of the target receptor.

Antibodies, Monoclonal↗
PubMed2000

Destruction of contrast microbubbles and the association with inertial cavitation.

The destruction of insonified Sonazoid microbubbles and its association with inertial cavitation in vitro utilizing an active acoustic detector was investigated. The experimental observation indicated that contrast microbubbles could be damaged at moderate acoustic pressures of 0.6-1.6 MPa (0.4-1.0 in mechanical index, MI). A damaged bubble could be dissolved into the medium on the order of 1 ms, implying that the destruction at moderate pressures is a relatively slow (relative to inertial bubble collapse), nonviolent dissolution process following the disruption of encapsulating surface materials. Inertial cavitation events in the presence of contrast microbubbles were observed using multiple highly intense ultrasound (US) pulses (>1.6 MPa). This observation suggested that intense US might disintegrate contrast microbubbles, and fragments of disintegrated microbubbles could be activated by an upcoming highly intense imaging pulse. The above results imply that inertial cavitation is unlikely to take place in the presence of Sonazoid contrast microbubbles when exposed to diagnostic US with an MI <1.

Contrast Media↗
PubMed2003

The behaviour of individual contrast agent microbubbles.

In recent years, our knowledge of the behaviour of ultrasonic microbubble contrast agents has improved substantially through in vitro experiments. However, there has been a tendency to use high concentrations of contrast agents in suspension, so that ultrasonic backscatter data are generated by a cloud of microbubbles. Such experiments involve a variety of assumptions with validity that is open to question. In addition, high concentrations of microbubbles cannot be used to understand the behaviour of individual microbubble scatterers. This paper proposes a technique that minimises the number of assumptions that need to be made to interpret in vitro experimental data. The basis of the technique is a dilute suspension of microbubbles that makes single scattering events distinguishable. A commercial scanner was used to collect radio frequency (RF) data from suspensions of two different contrast agents, Quantison and Definity. Backscatter data were collected over a range of acoustic pressures. It was found that Definity provided a constant number of scattering events per unit volume of suspension for almost all applied acoustic pressures. Quantison demonstrated an increasing number of scattering events per unit volume with increasing acoustic pressure. Below 0.6 MPa, Quantison scatterers were not individually detectable and provided levels of backscatter similar to those of a blood-mimicking fluid, which suggests that Quantison microbubbles had almost linear scattering behaviour. At acoustic pressures greater than 0.6 MPa, both agents appeared to provide echoes from free bubbles. The change in the number of scatterers per unit volume with acoustic pressure cannot be demonstrated using high concentrations of contrast agent.

Acoustics↗
PubMed1998

Dissolution of multicomponent microbubbles in the bloodstream: 2. Experiment.

The effect of the nature of the filling gas on the persistence of microbubbles in the bloodstream was studied. All the microbubbles were covered with the same shells. Various perfluorocarbons and perfluoropolyethers alone and as mixtures with nitrogen were used as the filling gases. The persistence time of microbubbles in the bloodstream tau increased with the molecular weight of the filling gas, from approximately 2 min for perfluorethane, to > 40 min for perfluorodiglyme, C6F14O3, and then decreased again to 8 min for C6F14O5. An acceptable ultrasound scattering efficacy was exhibited by the filling gases with intermediate molecular weights that possessed both a high saturated vapor pressure and a comparatively low water solubility (Ostwald coefficient). On the basis of the experimental data, it is concluded that the microbubble persistence tau is controlled primarily by the dissolution of microbubbles and not by the removal of the microbubbles by the reticular endothelial system. Although the qualitative experimental trends are in good agreement with the theoretical model developed previously, there are some quantitative differences. Possible reasons for these differences are discussed.

Air↗