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PubMed2002

In vitro transfer of antisense oligodeoxynucleotides into coronary endothelial cells by ultrasound.

Since antisense oligodeoxynucleotides (AS-ODNs) have been recognized as a new generation of putative therapeutic agents, we established a delivery technique that could transfect AS-ODNs, which are designed for endothelin type B receptor (ETB), into cultured human coronary endothelial cells (HCECs) by exposure to ultrasound in the presence of echo contrast microbubbles. Ultrasound offers several advantages such as being nontoxic, nonantigenic and providing rapid gene transfer. We standardized the optimal conditions, which consisted of 2 x 10(6) cells suspended in phosphate buffer with 900nM ODN, 50 microl of echo contrast microbubbles (Optison), and ultrasound exposure (1.0 W/cm(2), 10% duty cycle, and 10s duration). The percentage of transfected cells was 25.2+/-2.0% after ultrasound treatment. This is the first demonstration of the use of the ultrasound exposure technique in conjunction with microbubbles in HCECs.

Base Sequence↗

PubMed2002

The dependence of ultrasound contrast agents backscatter on acoustic pressure: theory versus experiment.

Experimental investigations have not fully explored the interaction between ultrasound beams and microbubble contrast agents. Moreover theoretical investigations have not solved the problem of the microbubble oscillation. A simple in-vitro system based on a commercial scanner (ATL UM9) was used to insonate (3 MHz transmission) diluted contrast suspensions of Definity and Quantison at different acoustic pressures (0.27-1.52 MPa). The experimental data were referred to a blood mimicking fluid in order to extract an estimate of their scattering cross-section. The results were compared with the solutions of the three main bubble oscillatidn models, Rayleigh-Plesset, Herring and Gilmore. Non-linear solutions of the above models were produced numerically using the Mathematica Package Software. The experiments showed that both agents provided a linear increase in scattering cross-section with increasing acoustic pressure. The thick shelled Quantison provided an increasing number of scatterers with increasing acoustic pressure, which proved that free bubbles leaked out of the shell. At high acoustic pressures both Quantison and Definity scattering cross-sections were almost identical, and were probably that of a free bubble. The Rayleigh-Plesset model provided a scattering cross-section almost independent of acoustic pressure. On the contrary the scattering cross-sections calculated by the Herring and Gilmore models solutions displayed a definite dependence on acoustic pressure of an order higher than one, which is slightly higher than the order of dependence exhibited by the experimental data. However, the increase of the experimentally measured scattering cross-section with acoustic pressure was sharper than the calculated one by the above two models. This is most probably due to the fact that the models simulated damped and not free bubble oscillations. In conclusion the Rayleigh-Plesset model was inadequate in describing the bubble oscillations even at small diagnostic acoustic pressures. The Herring and Gilmore models could simulate the dependence of the scattering cross-section of encapsulated microbubbles on acoustic pressure. However the contribution of free bubble oscillations has still to be modelled.

Journal Article↗

PubMed1999

Targeted delivery of gas-filled microspheres, contrast agents for ultrasound imaging.

Gas-filled microbubbles, with the size of several micrometres, are strong scatterers of ultrasound waves used in diagnostic imaging. Application of these microbubbles as ultrasound contrast materials is discussed, in view of the design of materials capable of selectively targeting the diseased tissues/organs. Methods of preparation, mechanisms of action, biodistribution and stability in vitro and in vivo are reviewed. Targeted microbubbles with various ligands (antibodies, peptides) attached to the shells have been prepared and tested in vitro and in vivo. Examples of specific application in diagnostic imaging and possible therapeutic use are discussed.

Journal Article↗

PubMed2001

Feasibility of the flash-replenishment concept in renal tissue: which parameters affect the assessment of the contrast replenishment?

The purpose of the study was to evaluate whether power pulse inversion (PPI) and pulse inversion (PI) techniques allow the measurement of indices of microcirculatory flow in real-time at low emission power using contrast microbubbles. PPI and PI imaging were performed in a kidney perfusion model during continuous infusion of Definity (0.12 mL/min). At steady state of tissue enhancement, contrast was destroyed by emission of echo bursts at high emission power (MI = 1.3). Consecutively, contrast replenishment was assessed at low emission power (MI = 0.09) in real-time imaging modes (PPI: 12 Hz; PI: 25 Hz). Regions-of-interest (ROI) of variable sizes were placed in the renal cortex and bigger arteries to compare replenishment of macro- and microcirculation. Nonlinear curve fitting was performed using the mathematical model y=s+A(1-e(-betat)), with A as the parameter describing blood volume and beta as a parameter describing the speed of microbubble contrast replenishment. Replenishment curves could be visually appreciated and quantitatively analyzed in all renal segments. A was significantly higher in bigger arteries compared to renal cortex (p < 0.001). beta was found to be significantly higher in the arteries as compared to the cortex (p < 0.001). The SD of beta diminishes with increasing size of the ROI. The acquisition of replenishment curves following ultrasound (US)-induced destruction of contrast microbubbles is feasible at low power using PPI and PI. Assessment of replenishment kinetics allows the differentiation between macro- and microcirculation. Size and position of the ROI have an important impact on the generation of replenishment curves in both imaging modalities, which has to be taken into account.

Animals↗

PubMed2001

Evaluation of blood flow in the cerebral microcirculation: analysis of the refill kinetics during ultrasound contrast agent infusion.

By means of harmonic imaging, it is possible to display brain perfusion qualitatively using ultrasound (US) contrast agent (UCA) bolus injection. With UCA continuous infusion reaching a steady state, mean microbubble velocity can be measured, analyzing the reappearance rate after microbubble destruction by US (refill kinetics). We performed an animal pilot study to investigate this new method for the assessment of brain perfusion. Using harmonic grey-scale imaging, five sedated male beagle dogs were investigated through the intact skull with increasing pulsing intervals (250 to 8000 ms) and three UCA infusion rates (0.5, 1.0 and 1.5 mL/min of Optison). Cerebral blood flow was increased by acetazolamide (30 mg/kg BW). Intensity vs. pulsing interval curves were analyzed using an exponential curve fit [I(t) = A(1-e(-beta t))] and parameters of the curve were compared. We found that increasing the pulsing interval above 4000 ms led to no further increase of echo enhancement for infusion rates. Mean beta values were not influenced by infusion rate (p = 0.25 and p = 0.55). Mean F values increased nonsignificantly with rising infusion rate (p = 0.25 and p = 0.86). Acetazolamide led to an increase of mean beta and F values (p = 0.18 and p = 0.025, respectively). It is possible to evaluate changes in brain perfusion through the intact skull by analyzing the UCA refill kinetics after US-induced microbubble destruction.

Albumins↗

PubMed2002

Endothelial cell injury in venule and capillary induced by contrast ultrasonography.

The aim of the present study was to test the hypothesis that microvascular endothelial cells (EC) are subject to the bioeffects induced by contrast ultrasound (US) because of their proximity to the circulating microbubbles. We examined EC injury in each microvessel section (arteriole, capillary or venule) in rat mesenteries among the following five groups: three controls (sham operation, microbubble injection alone, US exposure with saline injection), and two contrast-US groups (US exposure at a 1-Hz or 30-Hz frame rate with microbubble injection). Propidium iodide (PI), a fluorescent indicator of cell injury, was employed to visualize impaired EC. PI-positive nuclei were equally few among the three controls. Contrast-US increased PI-positive cells in capillaries (1-Hz frame rate, 2.4 +/- 2.2 cells per 0.1-mm vessel length, p = 0.09; 30-Hz frame rate, 4.3 +/- 1.8 cells, p < 0.01) and in venules (1-Hz frame rate, 4.1 +/- 2.5 cells, p < 0.05; 30-Hz frame rate, 13.8 +/- 3.6 cells, p < 0.01) compared with sham operation (0.10 +/- 0.22 cells). The finding indicates that diagnostic contrast US potentially causes EC injury, particularly in venules and capillaries.

Analysis of Variance↗

PubMed1999

Analysis of flash echo from contrast agent for designing optimal ultrasound diagnostic systems.

Microbubble-based contrast agents can enhance echoes in areas of low blood flow, but the bubbles are extremely sensitive and collapse easily when exposed to ultrasound (US) irradiation. An experimental study of bubble collapse was carried out to design new functions for US diagnostic systems to detect echoes from microbubbles more efficiently. For contrast agent (Levovist) solution, a high-intensity, but momentary, echo (flash echo), was observed in the first frame image after a several-second suspension of transmission, but was not seen in the second frame image. These "flash echo" signals were analyzed and categorized based on microscopic observation, and the results showed that the longevity of the microbubbles was reduced by conditions such as B-mode imaging. Next, a numerical simulation of the bubbles in liquid was performed under the same conditions as in the in vitro experiment. The results showed that even bubbles less than 1 microm in diameter expand and collapse within one pulse drive, which would generate flash echoes. The flash echo imaging system described here permits flexible intermittent scanning with variable intervals, with a variable number of frames at the trigger, and with simultaneous monitoring at low power output. Animal experiments were also conducted to evaluate the system. As the interval between frames was increased, the flash echoes gradually increased, and perfusion in the parenchyma was clearly observed with an interval of 4 s.

Animals↗

PubMedDate not supplied

Intravenous perfluoropropane-exposed sonicated dextrose albumin produces myocardial ultrasound contrast that correlates with coronary blood flow.

If microbubble gas blood solubility and diffusivity are reduced, the persistence (and hence ultrasound reflectivity) of the microbubble in blood is prolonged. Recently we have sonicated a multifold dilution of human albumin with 5% dextrose while exposed to gases of low blood solubility and diffusivity and produced microbubbles that consistently opacify the myocardium after intravenous injection. The objective of this study was to test the hypothesis that a gas with very low diffusivity, perfluoropropane, when introduced into dextrose albumin during sonication, would produce visually evident myocardial ultrasound contrast after intravenous injection compared to sonicating with gases that have more rapid diffusivity. Second, we sought to determine whether the degree of contrast (peak myocardial videointensity) achieved with this agent would correlate with coronary blood flow. In eight open-chest dogs, intravenous injections of dextrose albumin sonicated with either room air, sulfur hexafluoride, or perfluoropropane (PESDA) were given under baseline conditions. PESDA injections were repeated when coronary flow was increased during low-dose dobutamine infusion. Left anterior descending coronary blood flow was monitored with transit-time flow probe. Background-subtracted anterior myocardial peak videointensity was measured after each injection. Visible myocardial opacification was seen in 100% of the 0.04 to 0.08 ml/kg intravenous injections of PESDA. No significant myocardial contrast was observed with the same doses of intravenous room air- or sulfur hexafluoride-exposed sonicated dextrose albumin. There was a strong correlation between left anterior descending coronary artery flow (range 17 to 96 ml/min) and myocardial peak videointensity (r = 0.75; p < 0.0001) in all dogs. We conclude that intravenous injections of PESDA can safely produce consistent myocardial ultrasound contrast. the peak videointensity produced correlates with changes in coronary blood flow. Therefore this agent could be used to quantify coronary blood flow noninvasively.

Air↗

PubMed2005

Effect of microstructure on molecular oxygen permeation through condensed phospholipid monolayers.

A method is presented that allows novel measurement of the effect of microstructure on the oxygen permeability of highly condensed, polycrystalline phospholipid monolayers. Oxygen permeability of the polycrystalline shell coating a stationary microbubble is measured directly using an apposing microelectrode in the induced transfer mode and modeling oxygen flux through the shell and intervening aqueous medium. Varying cooling rate through the phospholipid main phase transition permits control of shell microstructure by manipulation of crystalline domain size and shape. Domain boundary density, defined as the ratio of the mean domain perimeter to the mean domain area, of the microbubble shell is determined by fluorescence microscopy. Oxygen permeability was shown to increase linearly with domain boundary density at a constant phospholipid acyl chain length and, accordingly, was shown to decrease exponentially with increasing chain length at a constant domain boundary density. Modification of the energy barrier theory to account for microstructural effects, in terms of the domain boundary density, provides a general equation to model passive transport through polycrystalline monolayer films. Results from this method show promise in determining the gas transport kinetics of medical microbubbles and the gas exchange characteristics of biological monolayers.

Cell Membrane Permeability↗

PubMed2002

Instrumentation for contrast echocardiography.

A number of new imaging methods have been developed specifically for use with ultrasound contrast agents. These methods rely on the peculiar behavior of microbubbles in an ultrasound field. At low incident acoustic pressures (reflected by the mechanical index, MI) microbubbles emit harmonics. These can be detected using harmonic or pulse inversion imaging. At higher MI, bubbles are disrupted, emitting a strong, nonlinear echo. Harmonic power Doppler methods are able to detect this echo, offering the most sensitive method for the detection of microbubble at the perfusion level. Although the first images of myocardial perfusion were made using this disruption method, it requires intermittent imaging with interframe intervals of up to 6 heart beats. Pulse inversion Doppler imaging is a newer method that is able to detect the nonlinear component of bubble echoes at a very low MI, thereby making possible real-time myocardial perfusion imaging. An understanding of the behavior of bubbles during an imaging examination is an essential prerequisite to its success in clinical practice.

Contrast Media↗

PubMed2002

Advances in ultrasound.

Ultrasound (US) has undergone dramatic changes since its inception three decades ago; the original cumbersome B-mode gantry system has evolved into a high resolution real-time imaging system. This review describes both recent advances in ultrasound and contrast media and likely future developments. Technological advances in electronics and computing have revolutionized ultrasound practice with ever expanding applications. Developments in transducer materials and array designs have resulted in greater bandwidths with improvements in spatial and contrast resolution. Developments in digital signal processing have produced innovations in beam forming, image display and archiving. Technological advances have resulted in novel imaging modes which exploit the non-linear behaviour of tissue and microbubble contrast agents. Microbubble contrast agents have dramatically extended the clinical and research applications of ultrasound. Not only can Doppler studies be enhanced but also novel non-linear modes allow vessels down to the level of the microcirculation to be imaged. Functional and quantitative studies allow interrogation of a wide spectrum of tissue beds. The advent of tissue-specific agents promises to improve the sensitivity and specificity of ultrasound in the detection and characterization of focal liver lesions to rival that of computed tomography (CT) and magnetic resonance imaging (MRI). Ultrasound has recently moved into therapeutic applications with high intensity focused ultrasound (HIFU) and microbubble assisted delivery of drugs and genes showing great promise.

Humans↗

PubMed2000

Imaging techniques for the myocardial contrast echocardiography.

Myocardial contrast echocardiography (MCE) has seen a significant evolution of its clinical application with the advent of newer microbubbles suitable for intravenous administration and development of ultrasound imaging technologies. These new technologies, which are specifically aimed to improve our ability to visualize these microbubbles in the myocardial circulation, require the user to have an understanding of the basis for optimal use in the clinical setting. The discussion below aims to provide a summary of these new microbubble technologies.

Contrast Media↗

PubMed2002

Coronary microcirculation in essential hypertension: a quantitative myocardial contrast echocardiographic approach.

AIMS: The aims of the present study were: (a) to demonstrate whether quantitative myocardial contrast echocardiography can detect the increase in coronary flow induced by dipyridamole infusion vasodilation through the myocardial opacification due to the transit of microbubbles, both at rest and after dipyridamole induced vasodilation; (b) to explore the coronary microcirculatory function before and after dipyridamole in two different models: asymptomatic and relatively young hypertensive patients with a mild degree of left ventricular hypertrophy, and healthy controls. METHODS AND RESULTS: Two groups of strictly age-matched males were studied (case-control study): 10, relatively young and asymptomatic essential hypertensive patients with a mild degree of left ventricular hypertrophy with a normal left ventricular function, and 10 healthy controls. The main findings were: the microbubbles' appearance area was significantly lower in hypertensive patients than in controls (P<0.05) because of a significantly lower time to peak. The peak intensity at rest was higher in hypertensives than in controls (P<0.05); but the per cent increase after vasodilatory stimulus was significantly higher in controls (+71% in controls vs +31% in hypertensives; P<0.05). The microbubbles' disappearance area was comparable in both groups at rest; the per cent increase of this parameter after dipyridamole was significantly higher in controls (+124%) than in hypertensives (+90%) (P<0.05). The results achieved in this study documented that the coronary microcirculation in hypertensive patients presenting a mild degree of left ventricular hypertrophy, explored with quantitative myocardial contrast echocardiography, showed a different behaviour in comparison with controls, in the vasodilatory response to dipyridamole. CONCLUSION: The coronary microcirculation in hypertensives showed a reduced vasodilation capacity of the resistance arterioles under dipyridamole induced vasodilatation, and a possible impairment of the endothelium dependent vasodilation. This happened despite an increase in the left ventricular mass, where the relation between capillary bed distribution and hypertrophied myocardium (rarefaction phenomenon) is not completely respected.

Adult↗

PubMedDate not supplied

Myocardial contrast echocardiography: basic principles.

Myocardial contrast echocardiography (MCE) is a new technique that can be used to examine the myocardial microcirculation. It uses gas-filled microbubbles that behave similarly to red blood cells in the microcirculation. This report describes the parts of the coronary microcirculation visualized by MCE. It also describes the types of microbubbles currently available for research. The properties of microbubbles and their interaction with ultrasound are also described as well as different imaging techniques. This information is necessary to understand the basics of MCE.

Animals↗

PubMed1983

[Contrast echocardiography--limits and possibilities in cardiologic diagnosis].

After injection of biocompatible fluids, contrast echocardiograms are obtained by ultrasound reflection from microbubbles in the streaming blood, which is thus opacified analogous to angiocardiography. As the microbubbles cannot pass the pulmonary capillaries, left heart contrasts are usually not seen after peripheral venous injection. Especially intracardiac shunts and valvular deficiencies may be recognized by this technique, which became an important diagnostic tool in the diagnosis of congenital heart disease and in critically ill patients. The blurred border between the opacified cavity and the myocardium may be abolished by digital image enhancement techniques, applied to contrast echocardiograms, thus making these pictures more suitable for volume determination and ventricular function analysis than non-contrast echocardiograms. Newer contrast agents such as mini-microbubbles are able to pass the pulmonary vascular bed after venous injection. Furthermore, myocardial perfusion studies are being conducted in animals by opacification of the myocardium with echo contrast agents in order to detect ischaemic areas.

Cardiac Output↗

PubMed2005

Asymmetric oscillation of adherent targeted ultrasound contrast agents.

With a lipid shell containing biotin, micron-sized bubbles bound to avidin on a porous and flexible cellulose boundary were insonified by ultrasound. The oscillation of these targeted microbubbles was observed by high-speed photography and compared to the oscillation of free-floating microbubbles. Adherent microbubbles were observed to oscillate asymmetrically in the plane normal to the boundary, and nearly symmetrically in the plane parallel to the boundary, with a significantly smaller maximum expansion in each dimension for bound than free bubbles. With sufficient transmitted pressure, a jet was produced traveling toward the boundary.

Journal Article↗

PubMed2001

Ultraharmonic myocardial contrast imaging: in vivo experimental and clinical data from a novel technique.

Myocardial contrast echocardiography (MCE) with high-mechanical-index (MI), triggered harmonic imaging is the best-established technique to date for the assessment of myocardial perfusion. A high signal-to-noise ratio, which is significantly influenced by precontrast tissue signals, is an important prerequisite. Our goal was to evaluate the efficacy of ultraharmonic MCE, a technique that rejects tissue signals by receiving signals beyond the second but below the third harmonic. Imaging was performed in 6 closed-chest dogs and in 15 healthy volunteers (11 of whom also had dipyridamole stress). Analyses of videointensity (VI) confirmed uniformly low precontrast tissue VI, a significant increase of postcontrast VI (before and after dipyridamole), and a significant decrease in VI after microbubble destruction. We conclude that ultraharmonic MCE produces low precontrast tissue signals, thus optimizing postcontrast myocardial opacification, and exhibits efficient microbubble destruction with use of multiple-frame triggering. Thus this new technique opens up a new possibility of further optimizing coronary microcirculation imaging with microbubbles.

Adult↗

PubMed2003

Renal perfusion abnormality. Coded harmonic angio US with contrast agent.

PURPOSE: Coded harmonic angio (CHA) US is a recently developed technique that can depict the effects of contrast agents. The purpose of this study was to determine the role of this technique in depicting the enhancement patterns of various renal perfusion abnormalities compared with dynamic CT. MATERIAL AND METHODS: During a 6-month period, various renal lesions including renal cell carcinoma (n=12), transitional cell carcinoma (n=5), acute pyelonephritis (n=5), and renal trauma (n=2) were evaluated with CHA US using a microbubble contrast agent. US images were obtained before contrast administration and with a bolus injection of 4 g of microbubble contrast agent (300 mg/ml) every 10 s for 1 min and every minute for 5 min. The contrast enhancement patterns of various renal masses were compared with dynamic CT. RESULTS: Of 12 renal cell carcinomas, 9 (75%) showed heterogeneous enhancement and the remaining 3 (25%) showed homogeneous enhancement. Enhancement of more than adjacent renal parenchyma was seen 16-252 s after injection. The duration of enhancement was 13-208 s (mean, 80 s). All transitional cell carcinomas showed peripheral enhancement. Enhancement was seen 22-270 s after injection. The duration of enhancement was 191-238 s (mean, 291 s). Five patients with acute pyelonephritis and 2 with renal trauma showed focal perfusion defects not shown on the pre-contrast examinations. CONCLUSION: CHA US with microbubble contrast agent is an effective US technique for the evaluation of both tumor vascularity and renal perfusion abnormality.

Adult↗