SEARCH · Search PubMed
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.
Because ultrasound microbubbles lower the threshold for cavitation by ultrasound energy, they may be used as cavitation nuclei for drug and gene delivery. By tailoring the physical properties of microbubbles and coating materials, drugs and genetic drugs can be incorporated into ultrasound contrast agents. As the microbubbles enter the region of insonation, the microbubbles cavitate, locally releasing the therapeutic agents.
The combination of ultrasound (US) exposure and ultrasound contrast agent (UCA) further increases the amount of drug-mediated thrombolysis. The aim of this study was to examine the efficacy of the combination of US and UCA on tissue plasminogen activator (tPA) thrombolysis, and the dependence on the microbubble structure. A catheter-type transducer capable of US emission (10 MHz, spatial peak temporal average intensity = 1.02 W/cm2 and peak negative pressure = 0.33 MPa) in the continuous-wave mode was employed. In 28 artificial white thrombi, serial changes in acoustic properties monitored by echography and histopathology during the tPA-mediated thrombolysis were analyzed. The thrombi were assorted to 4 groups; UCA nontreated (Control), sonicated albumin (A)-, SH-U508A (SH)- and dodecafluoropentane emulsion (DDFP)-treated groups. Persistence of microbubble opacification and thrombus weight were also measured. After the sample was suspended in a beaker with tPA (8000U) and 100 mL of saline, the UCA was administered and the mixture exposed to US for 10 min. Weight reduction of the thrombus was greatest in the DDFP Group (-49 +/- 8%), and that in the A Group (-8 +/- 5%) was not significantly different from that in the Control Group (-5 +/- 1%). The persistence of the microbubbles expressed as the decay of the time-intensity curve, was longest in the DDFP Group. The echo intensity of the superficial layer of the thrombus exposed to US was high and weight loss was marked. Multiple cavity formation was observed histopathologically. The stability of the microbubbles was an important factor of the US and UCA enhancement effect on tPA-mediated thrombolysis. This combination therapy has potential for clinical application in patients with thrombotic arterial and venous occlusion and left arterial thrombus.
Microbubbles, currently used as contrast agents have potential therapeutic applications. Microbubbles, upon insonation of sufficiently intense ultrasound will cavitate. Cavitation with microbubbles can be used to dissolve blood clots or deliver drugs. Targeting ligands and drugs can be incorporated into microbubbles to make highly specific diagnostic and therapeutic agents for activation with ultrasound. In this paper I will review some of these potential applications and experimental results using such agents for thrombolysis, drug and gene delivery.
OBJECTIVES: This study sought to determine the basis of detection of stenosis by myocardial contrast echocardiography using venous administration of microbubbles and to define the relative merits of bolus injection versus continuous infusion. BACKGROUND: The degree of video intensity (VI) disparity in myocardial beds supplied by stenosed and normal coronary arteries can be used to quantify stenosis severity after venous administration of microbubbles. However, the comparative merits of administering microbubbles as a bolus injection or continuous infusion has not been studied. METHODS: Coronary stenoses of varying severity were created in either the left anterior descending or the left circumflex coronary artery in 18 dogs. Imagent US (AF0150) was given as a bolus injection in 10 dogs (Group I) and as both a bolus injection and a continuous infusion in 8 dogs (Group II). For bolus injections, peak VI was derived from time-intensity plots. During continuous infusion, microbubble velocity and microvascular cross-sectional area were derived from pulsing interval versus VI plots. Myocardial blood flow (MBF) was determined using radiolabeled microspheres. RESULTS: During hyperemia, VI ratios from the stenosed versus normal beds correlated with radiolabeled microsphere-derived MBF ratios from those beds for both bolus injections (r = 0.81) and continuous infusion (r = 0.79). The basis for detection of stenosis common to both techniques was the decrease in myocardial blood volume distal to the stenosis during hyperemia. The advantage of continuous infusion over bolus injection was the abolition of posterior wall attenuation and the ability to quantify MBF. CONCLUSIONS: Both bolus injection and continuous infusion provide quantitative assessment of relative stenosis severity. Compared with bolus injection, continuous infusion also allows quantification of MBF and data acquisition without attenuation of any myocardial bed.
Intramuscular injection of naked plasmid DNA is a safe approach to the systemic delivery of therapeutic gene products, but with limited efficiency. We have investigated the use of microbubble ultrasound to augment naked plasmid DNA delivery by direct injection into mouse skeletal muscle in vivo, in both young (4 weeks) and older (6 months) mice. We observed that the albumin-coated microbubble, Optison (licensed for echocardiography in patients), significantly improves the transfection efficiency even in the absence of ultrasound. The increase in transgene expression is age related as Optison improves transgene expression less efficiently in older mice than in younger mice. More importantly, Optison markedly reduces muscle damage associated with naked plasmid DNA and the presence of cationic polymer PEI 25000. Ultrasound at moderate power (3 W/cm2 1 MHz, 60 s exposure, duty cycle 20%), combined with Optison, increases transfection efficiency in older, but not in young, mice. The safe clinical use of microbubbles and therapeutic ultrasound and, particularly, the protective effect of the microbubbles against tissue damage provide a highly promising approach for gene delivery in muscle in vivo.
Clusters of microbubbles, represent probable sites of newly initiated DNA synthesis, were identified in nuclear DNA from Physarum polycephalum by using the electron microscope. Their presence is associated specifically with S-phase. Each microbubble corresponds in size to a replicating segment of DNA about 100-5000 nucleotide residues in length. The DNA structures containing microbubbles are metastable, and revert to native DNA in the presence of moderate concentrations of formamide used to prepare samples for electron microscopy. It is suggested that each cluster of microbubbles may correspond to a unit of replication (a replicon) in Physarum DNA.
BACKGROUND: With the advent of second harmonic imaging in echocardiography, microbubbles have been observed during opening and closure of mechanical prosthetic valves. The single phenomenon of cavitation, an extremely short event described in the literature, cannot explain the persistence of microbubbles during several hundred milliseconds. Therefore, in vitro we reproduced two distinct phenomena created by a local depression occurring during the closure and/or opening of prosthetic valves: Cavitation and degassing. METHODS: We used a water circuit system enriched with CO(2) that passes through a Venturi tube in order to create variable pressure gradients. Three types of observations were performed: (1). the dimensions of the bubbles as a function of pressure, (2). calibration of the echocardiograph, and (3). comparison and illustrations of the difference between bubble formation by cavitation (vaporization) and degassing (liberation of CO(2)). RESULTS: According to the different pressures exerted, the dimensions of the bubbles only vary by several microns, not measurable in practice. Second, the calibration of the echocardiograph reveals that the dimensions of the bubbles measured by ultrasound are greater by a factor of 1.75. Finally, the observed cavitation is a short phenomenon (several milliseconds) and happens under a great local pressure gradient. The degassing produces microbubbles lasting up to as long as > 1 second under much lower pressure. CONCLUSION: This in vitro study suggests that microbubbles observed during several hundred milliseconds after the opening of prosthetic cardiac valves are the result of degassing of CO(2) in blood rather than a cavitation phenomenon as suggested in the literature.
AIM: To determine the role of microbubble-enhanced colour Doppler ultrasound (CDUS) in assessing portal venous patency prior to liver transplantation. MATERIALS AND METHODS: Over a 2-year period, all patients with chronic liver disease undergoing routine pre-transplant CDUS examination in whom the portal venous system was inadequately demonstrated were recruited to the study. CDUS was performed in 368 patients and 33 patients (9%) were recruited. A repeat CDUS examination following an intravenous bolus injection of the microbubble contrast agent Levovist (Schering Healthcare AG, Berlin, Germany) was performed. Diagnostic confidence was recorded on a free linear analogue scale for both examinations. Findings were compared with indirect portography and surgery. RESULTS: Of the 33 patients with sub-optimal baseline examinations, improvement in portal vein visualization was achieved in 31 patients (94%). Median diagnostic confidence increased from 50% (interquartile range 30-60) to 90% (interquartile range 75-98) (P < 0.001) following administration of Levovist. Overall accuracy of portal vein assessment using microbubble-enhanced CDUS in 15 patients in whom a definitive diagnosis was made within 2 months was 87%. CONCLUSION: Microbubble-enhanced CDUS is a simple, inexpensive adjunct to standard pre liver transplant screening of the portal vein. It is particularly helpful in patients with end-stage cirrhosis who are at high risk of portal vein thrombosis and in whom the conventional examination is sub-optimal.
OBJECTIVE: To compare transfection efficiency and safety for antisense oligodeoxynucleotides (AS-ODNs) between two type of phospholipids-based vectors. METHODS: An AS-ODNs sequence HA824 combined with luciferase reporter plasmid was used. Under low intensity ultrasound (US), a breast cancer cell line SK-BR-3 was exposed to different concentration of microbubbles and liposomes. Transfection efficiency was detected by fluorescence microscopy. Cell viability was verified by propidium iodide assay. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the inhibitory effect of HA824 on HER-2 expression at mRNA level. Atomic force microscopy (AFM) scanning techniques was employed to observe the change of membrane pore size. RESULTS: AS-ODNs transfection efficiency showed an increasing tend with microbubble concentration, but not with liposome concentration. Maximum transfection efficiency with minimum cell viability was achieved under 2% microbubble concentration. Too strong sonoporation activity would enlarge membrane pores significantly and cause low cell viability. CONCLUSION: US-mediated AS-ODNs transfection enhanced by phospholipids-based microbubbles represents an effective and safe avenue.
Despite over ten years of in vitro investigations of ultrasound contrast agents, the level of understanding of their behaviour in ultrasound fields is limited. Several problems associated with these investigations, particular to the nature of contrast agents, are discussed. Using a commercial scanner the RF normalized backscatter of two different contrast agents (Definity and Quantison) was measured at different suspension concentrations and acoustic pressures. Both contrast agents scattered ultrasound nonlinearly and the backscatter showed a dependence on acoustic pressure. In order to assess the average behaviour of the agents across the range of acoustic pressures and microbubble concentrations the experimental data were fitted to a theoretically acceptable model using nonlinear regression analysis. The analysis showed that both the backscatter and the attenuation of the Quantison suspensions displayed a higher order of dependence on acoustic pressure than the Definity suspensions. It was also discovered that Quantison microbubbles did not demonstrate uniform behaviour across the acoustic pressure range. At lower acoustic pressures the behaviour could not follow a model similar to that which predicted the behaviour at higher acoustic pressures, which was mainly due to the fact that free bubbles were released in a fashion dependent on acoustic pressure. The fact that two different populations of scatterers exist in the same suspensions makes the assessment of the behaviour of the particular agent impossible with the high concentrations that are commonly used. Very low concentration suspensions whereby single scattering events can be monitored should be more useful. In conclusion, the approach of using high microbubble concentrations in order to investigate the properties of ultrasonic contrast agents is limited in that the results of such studies cannot be used to understand the behaviour of single microbubbles.
Microbubbles are currently used as ultrasound contrast agents. Their potential therapeutic applications are also under investigation. This work is designed to provide some insight into the mechanisms of energy absorption and deposition by a preformed gas bubble in the microvasculature to optimize its efficacy. In the linear regime, the most favourable condition for the transfer of energy from an ultrasonic field to a gas bubble occurs when the centre frequency of the ultrasonic field equals the resonance frequency of the bubble. The resonance frequency of gas microbubbles has been investigated up to now mainly in unbounded liquids; however when bubbles are confined in small regions, their resonance frequency is strongly affected by the surrounding boundaries. A parametric study on how the resonance frequency of microbubbles in blood vessels is affected by the bubble radius, vessel radius and the bubble position in the vessel is presented. The resonance frequency decreases below its free value with decreasing vessel radius for vessels smaller than 200-300 microm depending on the bubble size. This model suggests the possibility of using ultrasound in a range of frequencies that are, in general, lower than the ones used now for therapeutic and diagnostic applications of ultrasound (a few MHz). When microbubbles oscillate at their resonance frequency they absorb and therefore emit more energy. This energy may allow specific blood vessels to be targeted for both diagnostic and therapeutic applications of ultrasound.
The precision and reliability of the stable microbubble test as a predictor of respiratory distress syndrome (RDS) were studied. In blind experiments, the stable microbubble test was performed by three analysts in quadruplicate on six different amniotic fluid samples obtained from pregnant women whose babies developed RDS and on three samples prepared from mature controls. Three-way analysis of variance revealed that there were statistically significant differential effects of the analyst, observer, and sampling on the stable microbubble values, and also that there were statistically significant interactions between the analyst and observer as well as between the analyst and sampling. However, the magnitude of these effects was not large enough to modify the interpretation of the test results. We conclude that the rapidity, simplicity and reliability of the stable microbubble test allow for its use as a bedside procedure in identifying infants who are likely to develop RDS.
The Gilmore formulation for bubble dynamics coupled with zeroth-order gas diffusion were used to investigate theoretically the cavitation activity produced by a modified XL-1 lithotripter [J. Acoust. Soc. Am. 105, 1997-2009 (1999)]. The model calculation confirms many of the basic features in bubble dynamics observed experimentally, in particular the strong secondary shock wave emission generated by in situ lithotripter shock wave-inertial microbubble interaction. In addition, shock wave-inertial microbubble interaction produced by a Dornier HM-3, the most commonly used clinical lithotripter, was evaluated. It was shown that the forced collapse of inertial microbubbles with strong secondary shock wave emission could be produced consistently, provided that an appropriate preceding shock wave and interpulse delay were used. Further, it was demonstrated that truncation of the tensile stress of the lithotripter shock wave could significantly reduce the large expansion of the bubble following shock wave-inertial microbubble interaction, which may alleviate the risk for vascular injury during shock wave exposure.
PURPOSE: To evaluate the effects of a new microbubble contrast agent for ultrasound (US) on breast masses. MATERIALS AND METHODS: Thirty-four patients underwent color Doppler US before and after intravenous injection of a "contrast agent" containing microbubbles. The authors subjectively evaluated the increase in intensity of the Doppler signals, the changes in the vascular patterns, and the timing of the transit of the microbubble bolus. The diagnostic confidence was assessed before and after administration of contrast material. RESULTS: After contrast material injection, there was greater and longer signal enhancement in the cancers than in the benign lesions. The cancers displayed characteristic vascular morphologic features, with more additional vessels visualized in relation to the lesion and a greater increase in vascular tortuousity. Shunts between vessels were demonstrated in all cancers but were not seen in any benign lesion. The diagnostic confidence increased with use of the contrast agent. The appearance at contrast-enhanced US led to a change in the US diagnosis in four patients. This increased both sensitivity and specificity to 100%. CONCLUSION: Injection of a microbubble agent enabled accurate differentiation of benign masses from carcinomas.
PURPOSE: To evaluate objectively the effects of a microbubble contrast agent on the color Doppler ultrasound (US) examination of breast lesions. MATERIALS AND METHODS: Forty-seven patients aged 23-71 years underwent color Doppler US before and after intravenous injection of a microbubble contrast agent. A 3-minute computer-assisted assessment of the color pixel density (CPD) was used to evaluate objectively the increase in the number of color Doppler US signals, the transit time of the microbubble bolus, and the potential additional differential diagnostic information. RESULTS: Peak CPD at contrast agent-enhanced color Doppler US was 14.3% +/- 8.1 (mean +/- 1 standard deviation) for carcinomas and 9.3% +/- 4.9 for benign lesions (P = .04). The time to peak enhancement was shorter in carcinomas (38 seconds +/- 20) than in benign tumors (71 seconds +/- 48, P = .02). Final CPD was close or equal to baseline values. With the median of 13% for peak CPD as a threshold, the sensitivity for this parameter was 55%, the specificity was 79%, and the accuracy was 62% (P = .04). For a median time to peak of 50 seconds, the sensitivity was 84%, the specificity was 57%, and the accuracy was 76%. CONCLUSION: After microbubble contrast agent injection, carcinomas and benign lesions behave differently in degree, onset, and duration of Doppler US enhancement. High interindividual variability and temporal variations in the Doppler US signal still limit the value of these criteria for prospective diagnosis.
Noninvasive diagnosis of liver lesions is usually performed with contrast material-enhanced computed tomography (CT) and magnetic resonance (MR) imaging and is based on enhancement features of the arterial and portal venous phases. Ultrasonography (US) is often limited in characterizing liver lesions because color and spectral Doppler US provide limited vascular information in large patients and in small or deep lesions. However, microbubble contrast agents, together with specialized US techniques, now allow diagnosis of liver lesions based on morphologic evaluation of lesion vascularity and visualization of specific enhancement features. Microbubble contrast agents are purely intravascular, easy to administer, and well tolerated and allow sensitive real-time evaluation of blood flow in hepatic lesions. During the portal venous phase, benign lesions (eg, hemangioma, focal nodular hyperplasia) typically enhance more than the liver, whereas malignant lesions (eg, hepatocellular carcinoma, metastases) enhance less. Microbubble-enhanced US allows characterization of very small lesions that may not be accurately characterized with CT or MR imaging. Findings from initial studies suggest that microbubble-enhanced US of the liver provides enhancement information comparable to that provided by contrast-enhanced CT and MR imaging, along with real-time morphologic evaluation of lesion vascularity.
Platelet aggregation induced by N2 microbubbles (simulating microbubbles developed during deep diving) was measured in seven volunteers before and after intake of ethyl-eicosapentaenoate (-EPA, 3.5 g/day) and ethyl-docosahexaenoate (-DHA, 2.5 g/day) for 2 wk. The relative content of arachidonic acid (AA) decreased in platelets from all individuals, whereas the content of EPA and DHA increased. The decrease of AA was almost identical with the increase of EPA plus DHA. In plasma the AA content was unchanged, while EPA and DHA increased. The N2 microbubble-induced aggregation showed a significant negative correlation with the DHA content both in platelets and in plasma. Less aggregation was also observed with high EPA content in platelets or plasma. A significant correlation between AA content in platelets and aggregation was seen. Intake of marine oils may be beneficial to divers under deep diving and to patients during extracorporeal circulation, because this may reduce the microbubble-induced aggregation.
BACKGROUND: The application of ultrasound to microbubbles in skeletal muscle creates capillary ruptures. We tested the hypothesis that this bioeffect could be used to stimulate the growth and remodeling of new arterioles via natural repair processes, resulting in an increase in skeletal muscle nutrient blood flow. METHODS AND RESULTS: Pulsed ultrasound (1 MHz) was applied to exposed rat gracilis muscle after intravenous microbubble injection. Capillary rupturing was visually verified by the presence of red blood cells in the muscle, and animals were allowed to recover. Ultrasound-microbubble-treated and contralateral sham-treated muscles were harvested 3, 7, 14, and 28 days later. Arterioles were assessed by smooth muscle alpha-actin staining, and skeletal muscle blood flow was measured with 15- micro m fluorescent microspheres. An approximately 65% increase in arterioles per muscle fiber was noted in treated muscles compared with paired sham-treated control muscles at 7 and 14 days after treatment. This increase in arterioles occurred across all studied diameter ranges at both 7 and 14 days after treatment. Arterioles per muscle fiber in sham-treated and untreated control muscles were comparable, indicating that the surgical intervention itself had no significant effect. Hyperemia nutrient blood flow in treated muscles was increased 57% over that in paired sham-treated control muscles. CONCLUSIONS: Capillary rupturing via microbubble destruction with ultrasound enhances arterioles per muscle fiber, arteriole diameters, and maximum nutrient blood flow in skeletal muscle. This method has the potential to become a clinical tool for stimulating blood flow to organs affected by occlusive vascular disease.