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PubMed2001

The effects of streptokinase and hydroxyethyl starch on in vitro clot disruption by ultrasound.

BACKGROUND: In vitro studies showed that low-frequency ultrasound (US) causes blood clot dissolution. This effect is augmented with thrombolytics, microbubbles and microparticles. However, in animal models of transcutaneous delivery, US alone is not effective, probably due to attenuation of US energy by overlying skin. When combined with thrombolytics or microbubbles, transcutaneous US is highly effective. PURPOSE: To assess the synergistic effect of low-intensity low-frequency US and saline, hydroxyethyl starch (HAES) (a non-gas filled microparticle containing solution), streptokinase (STK), and their combination on blood clot disruption. METHODS: Human blood clots from 4 healthy donors, 2-4 hours old, were immersed for 0, 15, or 30 min in 37 degrees C in 10 ml of the above-mentioned solutions, and then were randomized to 10 sec of 20 kHz US or no US. The % difference in weight was calculated. RESULTS: Immersion for 30 min without US resulted in 13.8 +/- 1.2% clot lysis in saline, and 22.0 +/- 1.3%, 21.7 +/- 2.1%, and 23.2 +/- 1.9% in STK, HAES, and STK + HAES, respectively (p = 0.002). US augmented clot lysis in all groups and at all time points. With low-intensity US, HAES was not better than saline. However, the combination of HAES + STK with US resulted in larger clot disruption at 15 sec incubation time (46.7 +/- 3.2%) than with saline (29.6 +/- 2.1%), HAES (29.6 +/- 2.5%), and STK (32.8 +/- 3.6%) (p < 0.001). CONCLUSION: low-frequency, low-intensity US combined with HAES and STK resulted in greater clot disruption at short incubation times. This combination may assist in achieving faster reperfusion in in vivo models.

Blood↗

PubMed2002

Identification of angiogenesis in primary breast carcinoma according to the image analysis.

Tumor angiogenesis may be an independent prognostic factor for breast cancer survival. However, we can get the angiogenic property of the breast cancer only after the removal of breast tissue. To get this information before surgical resection of the tumor, we evaluated 29 breast carcinoma patients with Tc-99m MIBI scintimammography and power Doppler ultrasound (US) with a microbubble contrast agent preoperatively and compare their results with intratumoral microvessel density (IMD) and reverse transcriptase-polymerase chain reaction (RT-PCR) of VEGF mRNA. IMD was well correlated with VEGF121 (r = 0.220, P = 0.024) and VEGF165 (r = 0.419, P = 0.046) mRNA level of the tumor. Power Doppler US grading of the tumor is well correlated with IMD (r = 0.552, P = 0.033). However, early uptake and washout index calculated from Tc-99m MIBI scintimammography showed no correlation with IMD or VEGF mRNA level, while washout index was inversely correlated with power Doppler US grading (r = -0.945, P = 0.001). In conclusion, the preoperative evaluation of breast cancer with power Doppler US with a microbubble contrast agent could predict tumor angiogenesis. Tc-99m MIBI scintimammography needs further study to use it as an image analysis for angiogenesis.

Adult↗

PubMed2000

Ultrasound for the visualization and quantification of tumor microcirculation.

Advances in ultrasound based methods for the non-invasive assessment of the tumor microcirculation are described. Two new ultrasound approaches are highlighted. The first method relies on commercially available ultrasound contrast agents in combination with specialized nonlinear imaging sequences. Nonlinear scattering by microbubble contrast agents provides a unique intravascular signature that can be distinguished from the echoes caused by surrounding tissues. Through destruction-reperfusion experiments it is possible to use microbubble contrast agents as a tracer revealing the kinetics of tumor blood flow. The second ultrasound method for examining the microcirculation involves the use of much higher frequencies. At frequencies on the order of 50 MHz, Doppler processing allows the direct assessment of flow dynamics in realtime in arterioles as small as 15 microm. Three dimensional Doppler maps of flow patterning are presented. The strengths and weaknesses of these new methods are discussed and the potential for their use in preclinical animal drug studies, clinical drug trials, and prognostic studies is described.

Animals↗

PubMed2003

Controlled vesicle deformation and lysis by single oscillating bubbles.

The ability of collapsing (cavitating) bubbles to focus and concentrate energy, forces and stresses is at the root of phenomena such as cavitation damage, sonochemistry or sonoluminescence. In a biomedical context, ultrasound-driven microbubbles have been used to enhance contrast in ultrasonic images. The observation of bubble-enhanced sonoporation--acoustically induced rupture of membranes--has also opened up intriguing possibilities for the therapeutic application of sonoporation as an alternative to cell-wall permeation techniques such as electroporation and particle guns. However, these pioneering experiments have not been able to pinpoint the mechanism by which the violently collapsing bubble opens pores or larger holes in membranes. Here we present an experiment in which gentle (linear) bubble oscillations are sufficient to achieve rupture of lipid membranes. In this regime, the bubble dynamics and the ensuing sonoporation can be accurately controlled. The use of microbubbles as focusing agents makes acoustics on the micrometre scale (microacoustics) a viable tool, with possible applications in cell manipulation and cell-wall permeation as well as in microfluidic devices.

Acoustics↗

PubMed2006

Multiphoton imaging of ultrasound/Optison mediated cerebrovascular effects in vivo.

Ultrasound (US) enhanced with microbubble contrast agents may transiently disrupt the blood-brain barrier (BBB) with minimal damage, providing a technique for noninvasive, localized drug-delivery deep within the brain. The mechanism and temporal profile of disruption are not understood, owing to the limitations of imaging modalities used previously. In this study, we monitored US-induced BBB disruption with multiphoton microscopy, providing high-resolution temporal and spatial information about the permeabilization mechanism and immediate effects of US exposure. Anesthetized C57 mice were prepared with a craniotomy and injected intravenously with fluorescent dyes to permit visualization of the vasculature and BBB integrity. The animals were imaged through a cranial window while exposed to low-intensity US (f=1.029 MHz, power=0.2 W) with a coincident intravenous injection of Optison (a microbubble contrast agent). We observed arteriolar vasoconstriction on US exposure that disrupted blood flow and lasted up to 5 mins; BBB disruption occurred via two characteristically distinct processes-perivascular fluorescence gradually increased (over minutes) along the length of the affected vessel without apparent rupture of the vessel wall or rapidly (seconds) increased in select, focal regions. These data corroborated previous studies suggesting increased endothelial transcytosis and breached tight junctions and demonstrated vasoconstriction, which might alter BBB permeability by modifying cerebral blood flow.

Albumins↗

PubMed2001

Computerized contrast angiosonography: a new diagnostic tool for the urologist?

OBJECTIVES: To evaluate the diagnostic potential of echo-enhanced ultrasonography (US) for depicting the vascularization pattern of renal cell carcinoma (RCC), and calculating the first-pass effect using harmonic imaging, against that obtained by triphasic helical computed tomography (CT). PATIENTS AND METHODS: Sixty patients with surgically confirmed RCC underwent US using B-mode and power Doppler methods with or without an intravenous microbubble echo-enhancing agent. After depicting and defining the tumour extent by B-mode US, the first-pass effect/enhancement by the echo-enhancing agent within the lesion, and that of a reference area of unaffected renal cortex, were recorded on-line by calculating the mean pixel intensity. Time-intensity curves, i.e. the rise time and gradient of both the suspected tumour and reference areas, were constructed. RESULTS: Using B-mode US, the extent of all tumours was delineated (mean tumour size 3.8 cm, SD 0.6). After applying the microbubble agent all tumours were enhanced, whereas the perfusion was decreased (in 48%), increased (in 16%) or similar (in 36%) compared with the cortical reference area. Using the Hounsfield classification, these results correlated well with the hypo/hypervascularity shown on CT. CONCLUSION: Ultrasonography has considerable potential in diagnosing RCC, if combined with echo-enhancing methods, harmonic imaging and computer-based calculation of tumour vascularization. Dynamic US studies should provide a diagnostic yield similar to that of CT.

Carcinoma, Renal Cell↗

PubMed2002

Vascular angiographic asymmetry on three-dimensional transrectal power Doppler ultrasonography in patients with organ-confined prostate cancer.

OBJECTIVE: To assess whether organ-confined prostate cancer not detected on routine transrectal ultrasonography (TRUS) can be detected using three-dimensional (3-D) power Doppler methods. PATIENTS AND METHODS: A preliminary trial of the use of TRUS with 3-D power Doppler image reconstruction was conducted in 116 patients being evaluated for lower urinary tract symptoms. Using a microbubble enhancing agent, an adequate horizontal plane allowed the simultaneous visualization and assessment of the symmetry of echogenicity and vascularization of the peripheral area of both prostate lobes, which is not possible in standard TRUS. The peripheral zone vascular asymmetry in the horizontal plane was also assessed retrospectively in those patients with pT2a,b prostate carcinoma. RESULTS: Stage pT2a,b prostate carcinoma was confirmed in 26 patients; in this group, two independent investigators confirmed the vascular asymmetry between the left and right peripheral zone, in the horizontal plane, in 22 patients, giving a sensitivity of 85%. CONCLUSIONS: Vascular asymmetry allows guided biopsy in lesions that are invisible using standard TRUS. Microbubble agents are an effective method of increasing the acoustic signals from small vessels of the prostate.

Adult↗

PubMed2001

Therapeutic ultrasound for gene delivery.

In vitro and in vivo studies using perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles to enhance gene delivery are reviewed. In vitro studies show PESDA binds to oligonucleotides and that ultrasound can be used to deposit these nucleotides. In addition, in vitro studies show that drug release from microspheres is dependent on ultrasound transmission frequency as well as pulsed or continuous application. Early in vivo studies confirm that ultrasound in combination with microbubbles can be used to facilitate gene deposition. However, the role of ultrasound targeting gene delivery remains to be determined.

Animals↗

PubMed2003

A method of detecting and quantifying severity of myocardial perfusion defects with intravenous ultrasound contrast and breath holding during stress echocardiography.

Although breath holding is commonly used to improve and maintain image quality during stress echocardiography, its effects on the qualitative and quantitative analysis of myocardial contrast enhancement (MCE) following intravenously injected microbubbles is unknown. The purpose of this study was to determine how breath holding affects MCE following either an intravenous bolus or continuous infusion of perfluorocarbon containing microbubbles. In 48 patients, intravenous Optison was given at peak dobutamine stress to assess myocardial perfusion. The degree of myocardial opacification was assessed immediately following a breath hold in inspiration (BH(ini)), at the end of a breath hold (BH(term)), and following expiration and a subsequent second breath hold (BH(reinsp)). Pulmonary venous time velocity integrals were recorded during these different phases as well. Eleven patients had quantitative coronary angiography. Mean duration of the breath hold was 7 +/- 1 seconds. Pulmonary venous return fell by 29% +/- 18% at BH(term) (P < 0.001). There was complete disappearance of MCE at BH(term) in 27 of 35 bolus injection patients at peak stress, and no return of MCE following flash destruction during breath holding in 11 of 13 patients receiving continuous infusions. BH(reinsp) resulted in a boluslike return of contrast, with a transient, bright MCE in 44 of 48 patients, and a time intensity plot that resembled a gamma variate function. Perfusion defects were visualized in 25 patients during BH(ini) and 28 patients during BH(reinsp). Coronary artery territory agreement between perfusion assessed during BH(ini) and BH(reinsp) and quantitative coronary angiography was 76% and 81%, respectively.

Albumins↗

PubMed2000

Contrast echocardiography for myocardial perfusion imaging using intravenous agents: progress and promises.

AIMS: This article is a convenient overview to assist the interested echocardiographist towards acquiring his own experience in the field of myocardial perfusion imaging using intravenous contrast agents. This goal is now pursued in many centres, since contrast echo holds the advantages of cardiac ultrasound (non-invasiveness, high spatial and temporal resolution, wide availability, use of non-ionizing radiation), and because a variety of transpulmonary agents-together with a spectrum of imaging modalities-are becoming available. METHODS AND RESULTS: Many technical considerations need to be addressed for optimal myocardial perfusion imaging: characteristics of the contrast medium (air-filled or perfluorocarbon filled and/or encapsulated agents), modality of administration (bolus injection or continuous infusion) and interaction between microbubbles and ultrasound (dependency on power output). Moreover, intermittent harmonic imaging, intermittent harmonic power Doppler, pulse inversion and amplitude modulation imaging have all been developed to enhance microbubble detection over myocardial tissue. These new acquisition modalities also yield specific artifacts impacting on myocardial perfusion assessment. Finally, acute myocardial infarction and chronic ischaemic heart disease (at baseline and during stress) are the most studied clinical models for perfusion imaging with contrast echo, and are reviewed in this article. CONCLUSION: Perfusion imaging with intravenous contrast agents has never been as close to widespread clinical use as it is today, but many methodological issues remain unsettled before the wish of the contrast echocardiographist comes true: that is, a cheap, user-friendly and widely available technology that would disclose new information in echocardiography.

Artifacts↗

PubMed2002

Localization of a coronary artery fistula using contrast transesophageal echocardiography.

With the increasing use of transesophageal and other cardiac imaging, coronary fistulas are being discovered more often. The clinical significance of these communications is unclear. Microbubble echo-contrast has been used to enhance endocardial definition, myocardial perfusion, and augment Doppler signals. This case describes the use of microbubbles to enhance the color Doppler signals to better define location and extent of a coronary artery fistula communicating with the left ventricle.

Aged↗

PubMed2003

Quantification of myocardial blood flow and assessment of its transmural distribution with real-time power modulation myocardial contrast echocardiography.

BACKGROUND: The purpose of this study was to examine the ability of real-time myocardial contrast echocardiography (MCE) with power modulation to quantitate myocardial blood flow (MBF) and to assess its transmural distribution in open-chest dogs undergoing partial or total coronary stenoses. METHODS AND RESULTS: MBF was measured in 12 dogs instrumented with a cuff occluder around the left anterior descending coronary artery at rest, during partial coronary stenosis (during infusion of adenosine), and during coronary occlusion. The MCE-derived rate of microbubble velocity, beta, and myocardial blood volume, A, were obtained by curve fitting of videointensity versus time plots, after the transient destruction of microbubbles by high-energy ultrasound. The data were compared with MBF measured with radiolabeled microspheres. Significant correlations were found between radiolabeled microsphere-derived MBF and both beta (r = 0.93) and the product of A x beta (r = 0.91). MCE beta reserve also correlated well with microsphere-derived flow reserve. Comparing endocardial/epicardial MCE ratios and microsphere-derived MBF ratios, significant correlation was also found between endomicropsheres/epimicrospheres MBF ratio and both endo/epi beta (r = 0.90) and endo/epi A x beta (r = 0.88). CONCLUSIONS: Real-time power modulation MCE allows for an accurate quantification of MBF and of its transmural distribution in open-chest dogs undergoing partial or total coronary stenoses.

Animals↗

PubMed2007

A trap-and-release integrated microfluidic system for dynamic microarray applications.

Dynamic microarrays hold great promise for advancing research in proteomics, diagnostics and drug discovery. However, this potential has yet to be fully realized due to the lack of reliable multifunctional platforms to transport and immobilize particles, infuse reagents, observe the reaction, and retrieve selected particles. We achieved all these functions in a single integrated device through the combination of hydrodynamic and optical approaches. Hydrodynamic forces allow simultaneous transportation and immobilization of large number of particles, whereas optical-based microbubble technique for bead retrieval gives dexterity in handling individual particles without complicated circuitry. Based on the criterion derived in this paper, the device was designed, and fabricated using standard photolithography and soft lithography methods. We examined the dynamics of bubble formation and dissipation in the device, and parametric studies revealed that higher power settings at short intervals were more efficient than low power settings at longer intervals for bead retrieval. We also demonstrated the capabilities of our device and its potential as a tool for screening methods such as the "one-bead-one-compound" (OBOC) combinatorial library method. Although both approaches, hydrodynamic confinement and optical-based microbubbles, are presented in one device, they can also be separately used for other applications in microchip devices.

Journal Article↗

PubMed1979

Size classes of replication units in DNA from sea urchin embryos.

Sea urchin DNA containing replication structures was isolated from two to four cell stage and blastula stage embryos, and examined by electron microscopy. In addition to the expected eye forms, we also observed molecules with large internal single-stranded gaps. Such structures were not present in DNA devoid of replicating molecules such as that isolated from sea urchin sperm. When the size of eye forms and interbubble distances between the two stages were compared, there was no detectable difference. In both stages, we observed two distinct size classes of bubbles and of interbubble distances. In the case of bubble sizes, the smaller size class was comprised of clustered microbubbles that ranged from 200 base pairs to 1 Kilobase (kb) with a mean of 432 base pairs. The large eye forms measured 1--35 kb with a mean of 6.8 kb. Interbubble distances also yielded two distinct populations, with the smaller class ranging from 400 base pairs to 2.3 kb (mean = 1.1 kb) and the larger population ranging from 2.8 to 36 kb (mean = 10.9 kb). Although other possibilities cannot be entirely excluded, the data support the contention that a substantial fraction of the larger eye-form population arises from the fusion of the clustered microbubbles.

Animals↗

PubMed1999

Subharmonic generation from ultrasonic contrast agents.

Ultrasonic contrast agents are used to enhance backscatter from blood and thus aid in delineating blood from surrounding tissue. However, behaviour of contrast agents in an acoustic field is nonlinear and leads to harmonic components in the backscattered signal. Various research groups have investigated second-harmonic emissions. In this work, the subharmonic emission from contrast agents is investigated with a view towards potential use in imaging. It is shown that the microbubbles with various surface properties, such as contrast agents, generate significant subharmonics under various insonating conditions. Theoretical results as well as experimental results using Optison indicate the generation of strong subharmonics with burst insonation at twice the resonant frequency of the microbubble. It is suggested that subharmonic imaging may provide a better modality than second-harmonic imaging to delineate blood from tissue and will be of significant importance for imaging deep vessels, such as in echocardiography and vascular diseases, due to the high signal-to-clutter ratio of the subharmonic imaging.

Albumins↗

PubMed2001

New developments in ultrasonography for the detection of prostate cancer.

The introduction of contrast agents has changed the diagnostic role of ultrasonography dramatically. Advanced ultrasound techniques, although currently largely unexplored, especially for prostate applications, were introduced to improve, for example, differential diagnosis. Also, new technologies became available using the interaction of the angioemboli with the transmitted ultrasound waves, and sensitive methods to detect microbubbles were developed. As the traveling of microbubbles through the vascular system is a dynamic process, new information becomes available: when the concentration of the contrast agent can be determined as a function of time, a measure for the actual blood flow can be obtained that provides quantitative information. Initially developed to enhance the ultrasound examinations in cardiac applications, contrast agents can currently be found in radiologic applications as well. The first reports of enhanced Doppler examinations of prostatic blood flow have been published, and the results indicate that contrast agents are a promising addition to the conventional ultrasound examination. In this paper, we present a short overview of the status of transrectal ultrasound imaging in prostate cancer, background information on contrast agents and imaging modalities, and early results of enhanced Doppler studies of the prostate to identify cancer. The early results suggest the feasibility of using angioemboli to enhance ultrasound imaging of prostate diseases, and although many issues remain to be solved, angioemboli in combination with a dedicated imaging modality have the potential to improve the diagnostic application of ultrasound in evaluating the prostate for disease.

Contrast Media↗

PubMed2000

Identification of microemboli during haemodialysis using Doppler ultrasound.

BACKGROUND: Doppler ultrasound methods were used during haemodialysis sessions for the detection of microemboli and determination of their origin. METHODS: A 2-MHz ultrasound probe (Multidop X(4) DWL((TM))) was used to assess the number of microembolic signals (MES) in the subclavian vein downstream from the arteriovenous fistula before the dialysis session and over two periods of 15 min at the beginning and end of haemodialysis sessions in 25 patients without previous cardiovascular disease. A similar probe was used during in vitro studies to detect MES at different sites in the dialysis machine (before and downstream from the blood pump, and before and downstream from the air trap). RESULTS: No MES were detected during in vivo studies before haemodialysis sessions. MES were registered in all patients (100%) at the beginning and end of the haemodialysis procedure at an average of 12.7+/-9 and 16. 7+/-11.5 signals/min respectively. The average intensity of MES was 19.2+/-5.0 dB and 19.4+/-3.9 dB respectively. No MES were detected on the arterial line during in vitro studies. In contrast, 19+/-6 MES/min were detected after the blood pump, 13+/-4.2 before the air trap, and 16.5+/-5.5 thereafter. CONCLUSIONS: In all patients, MES were recorded during haemodialysis sessions in the drainage vein from arteriovenous fistulae. The results of in vitro studies indicate that MES are formed by the blood pump of the haemodialysis machine. The intensity of the MES suggests that they correspond to synthetic particles or microbubbles, which are not detected by the air trap. The final destination of these microbubbles will be assessed in further studies.

Adult↗

PubMed2001

Contrast-enhanced ultrasound voiding cystography as a screening examination for vesicoureteral reflux in the follow-up of renal transplant recipients: a new approach.

BACKGROUND: The aim of the study was to evaluate a new diagnostic procedure, ultrasound contrast-enhanced voiding cystography (USVC), for vesicoureteral reflux (VUR) in renal transplant recipients and to compare it with radionuclide voiding cystography (RVC). METHODS: Twenty-three renal transplant recipients with recurrent urinary tract infection were investigated simultaneously by RVC and USVC. After catheterization, the empty bladder was filled with normal saline (mean 250+/-30 ml) and 30-45 mBq of (99m)Tc-labelled colloid. At the end of filling the bladder, 19.5 ml of galactose-based, microbubble-containing echo-enhancing agent, at a concentration of 200 mg/ml, was instilled. During the filling and voiding phases the movement of the radiotracer was recorded by a gamma camera and the presence of microbubbles in the urinary tract by ultrasound. RVC was used to detect and grade the degree of VUR. RESULTS: Nuclear studies identified VUR in 16 (69.6%) of 23 recipients with recurrent urinary tract infection: VUR grade I in three (13%) recipients, grade II in eight (34.8%) and grade III in five (21.7%) using a simplified grading system. USVC with contrast-enhancement detected VUR in 14 (60.9%) recipients. Overall sensitivity and specificity of contrast-enhanced USVC was 75 and 71%, respectively. Statistical analysis showed that the accuracy of this procedure increased with higher grades of VUR and its sensitivity reached 100% for detection of VUR grade III. CONCLUSION: In our preliminary study, contrast-enhanced USVC has proved to be an effective examination, with the same accuracy rate as RVC in detecting grade III VUR episodes with low diagnostic accuracy for low reflux grades.

Adult↗