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PubMed2007

Interaction of transthoracic ultrasound and intravenous microbubbles with cardiac mechanoreceptors.

The purpose of this study was to examine the effect of transthoracic ultrasound (TTU) and intravenous microbubbles (MB) on cardiac mechanoreceptors. In 16 rabbits (eight normal and eight chronic heart failure), renal sympathetic nerve activity (RSNA), heart rate and mean arterial pressure were examined before, during and after 1 MHz TTU at different peak negative pressures (0.12 to 0.43 MPa) and duty cycles in the presence and absence of perfluorocarbon MB. TTU applications were for 10 s, and the overall duration of MB infusion was approximately 60 s for each setting. TTU without MB had no effect on any parameter. During the microbubble infusion, however, TTU at higher peak negative pressures (> or =0.27 MPa) and 100% duty cycle resulted in a consistent decrease in RSNA(-41 +/- 41% p < 0.001). This was accompanied by brief reflex reductions in mean arterial pressure and heart rate. The changes in RSNA induced by TTU and MB in all rabbits were abolished by vagotomy. TTU, in the presence of MB, stimulates mechanoreceptors in the heart reflexively to reduce RSNA.

Animals↗

PubMed2007

Phagocytosis of ultrasound contrast agent microbubbles by Kupffer cells.

Delayed parenchymal phase images of the liver more than 5 min after IV injection of ultrasound contrast agents are thought to be related to the phagocytosis of contrast agent microbubbles by macrophages. In this study, we examined whether liver-specific macrophages, Kupffer cells, phagocytosed the microbubbles and whether their elimination affected the delayed parenchymal images of the liver. Phase-contrast microscope observations showed that Kupffer cells phagocytosed various contrast agents in vitro. Among the contrast agents used, 99% of Sonazoid and Optison, and 47% of Levovist were phagocytosed, whereas only 7.3% of SonoVue and 0% of Imavist were phagocytosed. Elimination of Kupffer cells in vivo by gadolinium chloride (GdCl(3)) resulted in decreased intensity of the delayed parenchymal images with Sonazoid and Levovist, while SonoVue showed no changes compared with control. Our findings suggested that Kupffer cells phagocytosed contrast agents and they were responsible for the delayed images of contrast ultrasound in the liver.

Albumins↗

PubMed2003

Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents.

Ultrasonography (US) is the first choice for screening patients with suspected liver lesions. However, due to a lack of contrast agents, US used to be less sensitive and specific compared with computed tomography (CT) and magnet resonance imaging (MRI). The advent of microbubble contrast agents increased both sensitivity and specificity dramatically. Rapid developments of the contrast agents as well as of special imaging techniques were made in recent years. Today numerous different US imaging methods exist which based either on Doppler or on harmonic imaging. They are using the particular behaviour of microbubbles in a sound field which varies depending on the energy of insonation (low/high mechanical index, MI) as well as on the properties of the agent themselves. Apart from just blood pool enhancement some agents have a hepatosplenic specific late phase. US imaging during this late phase using relatively high MI in phase inversion mode (harmonic imaging) or stimulated acoustic emission (SAE; Doppler method) markedly improves the detection of focal liver lesions and is also very helpful for lesion characterisation. With regards to detection, contrast enhanced US performs similarly to CT as shown by recent studies. Early results of studies using low MI imaging and the newer perfluor agents are also showing promising results for lesion detection. Low MI imaging with these agents has the advantage of real time imaging and is particularly helpful for characterisation of focal lesions based on their dynamic contrast behaviour. Apart from the techniques which based on the morphology of liver lesions there were some attempts for the detection of occult metastases or micrometastases by means of liver blood flow changes. Also in this field the use of US contrast agents appears to have advantages over formerly used non contrast-enhanced methods although no conclusive results are available yet.

Carcinoma, Hepatocellular↗

PubMedDate not supplied

Systemic targeted delivery of antisense with perflourobutane gas microbubble carrier reduced neointimal formation in the porcine coronary restenosis model.

HYPOTHESIS: The antisense phosphorodiamidate morpholino oligomer (PMO), AVI-4126, has been effective in reducing neointimal formation in animal models following delivery by pluronic gels, local delivery catheters and coated stents. Greater flexibility of repeated-dosage regimens and reduced procedure complexity may be provided by systemic injection of AVI-4126 bound to perfluorobutane gas microbubble carriers. The purpose of this study was to investigate the effects of perfluorocarbon gas microbubble carrier (PGMC)-based systemic delivery of AVI-4126 on expression of the c-myc in vascular tissue and restenosis after stent implantation. METHODS: Seven pigs underwent stent implantation (3 stents/animal). Five pigs received IV injection of PGMC and 2 mg of AVI-4126 (AVI BioPharma). Two served as control. Four hours postprocedure, 3 pigs were sacrificed and stented segments analyzed by high-performance liquid chromatography (HPLC) and Western blot. In chronic experiments, 4 pigs (12 stent sites) were sacrificed at 28 days. RESULTS: HPLC analysis of plasma samples of treated animals showed minimal presence of AVI-4126. HPLC of the treated arteries demonstrated easily detected concentrations of AVI-4126. Western blot analysis of the stented vessels demonstrated modest inhibition of c-myc. Morphometry showed that the neointimal area was significantly reduced in the AVI-4126/PGMC group compared with control (2.63+/-1.99 vs. 4.77+/-.1.71 mm2, respectively, P<.05). CONCLUSION: In the porcine coronary stent model, systemic targeted delivery of AVI-4126 using PGMC carrier significantly inhibited neointimal formation.

Animals↗

PubMed2006

Therapeutic use of ultrasound targeted microbubble destruction: a review of non-cardiac applications.

The development of second generation ultrasound contrast agents has extended the diagnostic scope of ultrasound imaging. Due to their physical characteristics, a therapeutic application of such microbubble based contrast agents has been promoted. Recently, several groups have demonstrated that ultrasound targeted microbubble destruction (UTMD) may deliver drugs or gene therapy vectors to organs accessible by ultrasound, thus providing a new technique for non-invasive, organ specific delivery of bioactive substances. Most applications in this field have been tested in cardiac models, but other organs can be treated as well. This article will give an overview of the background of UTMD and its non-cardiac applications.

Animals↗

PubMed2006

Efficient gene delivery to pancreatic islets with ultrasonic microbubble destruction technology.

This study describes a method of gene delivery to pancreatic islets of adult, living animals by ultrasound targeted microbubble destruction (UTMD). The technique involves incorporation of plasmids into the phospholipid shell of gas-filled microbubbles, which are then infused into rats and destroyed within the pancreatic microcirculation with ultrasound. Specific delivery of genes to islet beta cells by UTMD was achieved by using a plasmid containing a rat insulin 1 promoter (RIP), and reporter gene expression was regulated appropriately by glucose in animals that received a RIP-luciferase plasmid. To demonstrate biological efficacy, we used UTMD to deliver RIP-human insulin and RIP-hexokinase I plasmids to islets of adult rats. Delivery of the former plasmid resulted in clear increases in circulating human C-peptide and decreased blood glucose levels, whereas delivery of the latter plasmid resulted in a clear increase in hexokinase I protein expression in islets, increased insulin levels in blood, and decreased circulating glucose levels. We conclude that UTMD allows relatively noninvasive delivery of genes to pancreatic islets with an efficiency sufficient to modulate beta cell function in adult animals.

Animals↗

PubMed2005

Myocardial delivery of colloid nanoparticles using ultrasound-targeted microbubble destruction.

AIMS: Ultrasound (US)-targeted microbubble destruction (UTMD) is a promising method for delivering genetic material to the heart. The aim of this study was: (i) to test whether colloid nanoparticles can be delivered to the rat myocardium using UTMD; and (ii) to determine whether tissue damage and contractile dysfunction occurs in hearts exposed to UTMD in vivo. METHODS AND RESULTS: Hearts from anaesthetized rats were exposed to perfluorocarbon-enhanced sonicated dextrose albumin (PESDA) (at two different microbubble concentrations) and US at peak pressures of 0.6, 1.2, or 1.8 MPa for 1, 3, or 9 min. During US, pairs of 30 and 100 nm fluorescent nanospheres were infused intravenously. Left ventricular function was assessed before and immediately after US, as well as at 24 h and 7 days. At the end of the experiments, the number of ruptured microvessels and the amount of nanospheres deposited were quantified. Rats exposed to PESDA alone or US alone showed no functional abnormalities, no capillary ruptures, and no nanosphere delivery. In contrast, rats exposed to both PESDA and US exhibited microvascular ruptures and nanosphere deposits. They also showed transient contractile dysfunction and premature ventricular contractions. All these changes were time-, US peak pressure-, and PESDA concentration-dependent. CONCLUSION: UTMD allows colloid nanoparticles to be delivered to the rat myocardium through microvessel rupture sites. The efficacy of delivery depends on the peak pressure applied, the duration of US exposure, and contrast concentration. UTMD also causes time- and peak pressure-dependent contractile dysfunction, and tissue alterations that are spontaneously reversible over time.

Animals↗

PubMed2005

In vivo pressure estimation using subharmonic contrast microbubble signals: proof of concept.

Changes in ambient pressure affects the reflectivity of ultrasound contrast microbubbles leading to an excellent correlation between subharmonic signals and hydrostatic pressure. The aortas of two dogs were scanned with an experimental pulse-echo system to validate in vivo pressure estimation based on subharmonic microbubble signals. Results matched well with instantaneous pressure measurements (from 20-60 mmHg) obtained simultaneously with a pressure catheter (root mean square errors <27%).

Algorithms↗

PubMed2005

Signal intensity of the liver parenchyma in microbubble contrast agent in the late liver phase reflects advanced fibrosis of the liver.

BACKGROUND: Microbubble of Levovist accumulates in liver parenchyma, and the phenomenon has been reported as late liver-specific parenchymal. The aim of the present study was to compare the parenchymal enhancement effect of Levovist with the degree of liver dysfunction. PATIENTS AND METHODS: Sixty consecutive patients who consented to be treated were enrolled in this study. Pulse-inversion ultrasonography (US) in the liver parenchymal phase of enhancement with Levovist was performed in a preoperative examination. The mechanical index of pulse-inversion US was set at 1.3. The gray-scale intensity of the non-tumor area of the liver parenchyma at the level of the focal zone was measured. The hepatic fibrosis index was measured in each liver by morphometric analysis. The correlation between the gray-scale intensity of the non-tumor area of the liver parenchyma and the hepatic fibrosis index was assessed. RESULTS: There was a significant inverse correlation between the gray scale of the liver parenchyma and the hepatic fibrosis index (r = -0.809, P < 0.01). The average signal intensity of the liver parenchyma was 144.5 in a normal liver, 133.6 in chronic hepatitis, and 102.6 in liver cirrhosis, demonstrating a significant difference between a normal and cirrhotic liver (P < 0.01). CONCLUSIONS: The signal intensity of a microbubble disruption of the liver parenchyma in the late phase of enhancement with Levovist was considered to reflect the degree of hepatic fibrosis.

Adult↗

PubMedDate not supplied

Cell disintegration by laser-induced transient microbubbles and its simultaneous monitoring by interferometry.

Selective retina treatment (SRT) is a novel short pulsed laser therapy of several retinal diseases associated with a decreased metabolism at the retinal pigment epithelium (RPE). The range of laser pulse energies is small, in which the desired selective RPE disintegration is achieved without adverse effects to the neural retina. Thus, a real-time dosimetry control is required. We investigated a noninvasive interferometric technique able to monitor microbubble formation around the intracellular melanin granula, which is the origin of the desired RPE damage. A porcine ex vivo RPE model was irradiated by single pulses (350 ns1.7 mus) of a neodymium: yttrium lithium fluoride laser (527 nm). The specimen was simultaneously probed by a Michelson interferometer (helium neon-laser: 633 nm) and by a hydrophone. Cell viability assays (Calcein-AM) were performed after irradiation. At threshold radiant exposure for cell death (ED(50)=129+/-5 mJ cm2 for 350 ns; ED50=180+/-5 mJ cm2 for 1.7 mus), the interferometric transients changed due to microbubble formation. No major differences in the bubble dynamics were observed between both pulse durations. An algorithm to determine cell death from the interferometric transients showed less than 10% false positive or false negative results for the applied laser expositions compared to the viability assay. Interferometry is a reliable noncontact technique to monitor RPE disintegration and may serve as real-time dosimetry control during SRT.

Animals↗

PubMed2005

Characterization of ultrasound contrast microbubbles using in vitro experiments and viscous and viscoelastic interface models for encapsulation.

Zero-thickness interface models are developed to describe the encapsulation of microbubble contrast agents. Two different rheological models of the interface, Newtonian (viscous) and viscoelastic, with rheological parameters such as surface tension, surface dilatational viscosity, and surface dilatational elasticity are presented to characterize the encapsulation. The models are applied to characterize a widely used microbubble based ultrasound contrast agent. Attenuation of ultrasound passing through a solution of contrast agent is measured. The model parameters for the contrast agent are determined by matching the linearized model dynamics with measured attenuation data. The models are investigated for its ability to match with other experiments. Specifically, model predictions are compared with scattered fundamental and subharmonic responses. Experiments and model prediction results are discussed along with those obtained using an existing model [Church, J. Acoust. Soc. Am. 97, 1510 (1995) and Hoff et al., J. Acoust. Soc. Am. 107, 2272 (2000)] of contrast agents.

Capsules↗

PubMed2005

Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C.

BACKGROUND AND AIMS: A reliable non-invasive assessment of the severity of diffuse liver disease is much needed. We investigated the utility of hepatic vein transit times (HVTT) for grading and staging diffuse liver disease in a cohort of patients with hepatitis C virus (HCV) infection using an ultrasound microbubble contrast agent as a tracer. MATERIALS AND METHODS: Eighty five untreated patients with biopsy proven HCV induced liver disease were studied prospectively. All were HCV RNA positive on polymerase chain reaction testing. Based on their histological fibrosis (F) and necroinflammatory (NI) scores, untreated patients were divided into mild hepatitis (F < or =2/6, NI < or =3/18), moderate/severe hepatitis (3 < or =F <6 or NI > or =4), and cirrhosis (F=6/6) groups. In addition, 20 age matched healthy volunteers were studied. After an overnight fast, a bolus of contrast agent (Levovist) was injected into an antecubital vein and spectral Doppler signals were recorded from both the right and middle hepatic veins for analysis. HVTTs were calculated as the time from injection to a sustained rise in Doppler signal >10% above baseline. The Doppler signals from the carotid artery were also measured in 60 patients and carotid delay times (CDT) calculated as the difference between carotid and hepatic vein arrival times. The earliest HVTT in each patient was used for analysis. RESULTS: Mean (SEM) HVTT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis groups showed a monotonic decrease of 38.1 (2.8), 38.8 (2.4), 26.0 (2.4), and 15.8 (0.8) seconds, respectively. Mean (SEM) CDT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis patients again showed progressive shortening of 30.3 (2.6), 25.9 (2.6), 14.8 (2.1), and 5.6 (1.2) seconds, respectively. There were significant differences between the groups for HVTT (ANOVA, p<0.001) and CDT (ANOVA, p<0.001). There was 100% sensitivity and 80% specificity for diagnosing cirrhosis and 95% sensitivity and 86% specificity for differentiating mild hepatitis from more severe liver disease. CONCLUSION: We have shown, for the first time, that HVTT using an ultrasound microbubble contrast agent can assess HCV related liver disease with clear differentiation between mild hepatitis and cirrhosis. There were significant differences between these two groups and the moderate/severe hepatitis group. CDT offers no additional benefit or greater differentiation than HVTT and can be omitted, thus simplifying this technique. HVTT may complement liver biopsy and may also be a useful alternative for assessment of liver disease in patients who have contraindications to biopsy.

Adult↗

PubMed2004

Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride-filled microbubble contrast agent: diagnostic performance and confidence.

PURPOSE: To assess whether characterization of solid focal liver lesions could be improved by using ultrasonographic (US) contrast-specific modes after sulfur hexafluoride-filled microbubble contrast agent injection, as compared with lesion characterization achieved with preliminary baseline US. MATERIALS AND METHODS: Four hundred fifty-two solid focal hepatic lesions that were considered indeterminate at baseline gray-scale and color Doppler US were examined after microbubble contrast agent injection performed by using low-acoustic-power contrast-specific modes during the arterial (10-40 seconds after injection), portal venous (50-90 seconds after injection), and late (100-300 seconds after injection) phases. Two readers independently and retrospectively reviewed baseline and contrast material-enhanced US scans and classified each depicted lesion as malignant or benign according to standard diagnostic criteria. Sensitivity, specificity, accuracy, and positive and negative predictive values and areas under the receiver operating characteristic curve (Az) were calculated by considering histologic analysis (317 patients) or contrast-enhanced helical computed tomography followed by serial US 3-6 months apart (135 patients) as the reference standards. RESULTS: Different contrast enhancement patterns were observed according to lesion characteristics. During the late phase, benign lesions were predominantly hyper- or isoechoic relative to the adjacent liver parenchyma, whereas malignant lesions were predominantly hypoechoic. Review of the contrast-enhanced US scans after baseline image review yielded significantly improved diagnostic performance (P <.05). Overall diagnostic accuracy was 49% before versus 85% after review of the contrast-enhanced scan for reader 1 and 51% before versus 88% after review of the contrast-enhanced scan for reader 2. Diagnostic confidence-that is, the Az-was 0.820 before versus 0.968 after review of the contrast-enhanced scan for reader 1 and 0.831 before versus 0.978 after review of the contrast-enhanced scan for reader 2. CONCLUSION: The use of contrast-specific modes with a sulfur hexafluoride contrast agent led to improved characterization of solid focal liver lesions.

Adenoma, Liver Cell↗

PubMed2004

Ultrasonic analysis of peptide- and antibody-targeted microbubble contrast agents for molecular imaging of alphavbeta3-expressing cells.

The goal of targeted ultrasound contrast agents is to significantly and selectively enhance the detection of a targeted vascular site. In this manuscript, three distinct contrast agents targeted to the alphavbeta3 integrin are examined. The alphavbeta3 integrin has been shown to be highly expressed on metastatic tumors and endothelial cells during neovascularization, and its expression has been shown to correlate with tumor grade. Specific adhesion of these contrast agents to alphavbeta3-expressing cell monolayers is demonstrated in vitro, and compared with that of nontargeted agents. Acoustic studies illustrate a backscatter amplitude increase from monolayers exposed to the targeted contrast agents of up to 13-fold (22 dB) relative to enhancement due to control bubbles. A linear dependence between the echo amplitude and bubble concentration was observed for bound agents. The decorrelation of the echo from adherent targeted agents is observed over successive pulses as a function of acoustic pressure and bubble density. Frequency-domain analysis demonstrates that adherent targeted bubbles exhibit high-amplitude narrowband echo components, in contrast to the primarily wideband response from free microbubbles. Results suggest that adherent targeted contrast agents are differentiable from free-floating microbubbles, that targeted contrast agents provide higher sensitivity in the detection of angiogenesis, and that conventional ultrasound imaging techniques such as signal subtraction or decorrelation detection can be used to detect integrin-expressing vasculature with sufficient signal-to-noise.

Antibodies↗

PubMed2006

Selective surfactant prophylaxis in preterm infants born at < or =31 weeks' gestation using the stable microbubble test in gastric aspirates.

OBJECTIVE: To evaluate the stable microbubble test (SMT) ability to select candidates for surfactant prophylaxis for respiratory distress syndrome (RDS). STUDY DESIGN: We followed patients treated according to a new routine for surfactant prophylaxis based on the SMT to determine timing of the initial dose of surfactant, proportion of infants using surfactant, and the predictive value of the SMT. Gastric secretions were collected after birth. Newborns with < 25 microbubbles (MB)/mm(2) received prophylactic surfactant. Surfactant was given only after confirmation of RDS (rescue therapy) to newborns with > or =25 MB/mm(2). RESULTS: Fifty-four (55%) had a low MB count and received prophylactic surfactant. Three out of 44 infants with a high MB count required rescue therapy (negative predictive value 93%; CI:81.3-98.6%). The median interval and interquartile range between surfactant administration and birth in the prophylaxis group was 20 (17-27) minutes. Surfactant was used in 23 of 28 (82%) infants born at < 28 weeks of gestation and in 34 of 70 (49%) infants between 28 and 31 weeks. CONCLUSIONS: The SMT may be useful to determine surfactant prophylaxis (< 30 min after birth). This approach may reduce costs and the number of unnecessary interventions.

Gastric Juice↗

PubMed2006

An algorithm for the diagnosis of focal liver masses using microbubble contrast-enhanced pulse-inversion sonography.

OBJECTIVE: The objective of this study was to develop an algorithm for liver mass diagnosis using microbubble contrast-enhanced pulse-inversion sonography. SUBJECTS AND METHODS: Ninety-six lesions in 92 patients were evaluated with DMP 115 (Definity)-enhanced pulse-inversion sonography, comprising 44 malignancies (29 hepatocellular carcinomas, 12 metastases, two peripheral cholangiocarcinomas, and one hepatic lymphoma) and 52 benign lesions (26 hemangiomas, 20 focal nodular hyperplasias, and six others). All had continuous low-mechanical-index imaging through the arterial and portal venous phase. A three-person blind review evaluated single images at baseline, early and peak arterial phases, and through the extended portal phases with a movie showing arterial phase wash-in. Reviewers assessed lesional vascularity and enhancement blindly but did not make a diagnosis. Combinations of answers were compared with independently determined final diagnoses to develop an algorithm for liver mass diagnosis. RESULTS: Portal phase enhancement comprises the first step of the algorithm, with positive or sustained enhancement identifying 48 (92%) of 52 benign lesions and negative enhancement or washout present in 41 (93%) of 44 malignancies. Sustained portal phase enhancement with arterial phase peripheral nodularity and centripetal progression predicted 24 (92%) of 26 of the hemangiomas; diffuse arterial phase enhancement greater than the liver identified 19 (95%) of 20 of the focal nodular hyperplasias. With negative portal phase enhancement, arterial phase information was less effective at differentiating hepatocellular carcinoma (25 [86%] of 29 cases) from another hepatic malignancy (11 [73%] of 15 cases). CONCLUSION: A simple diagnostic algorithm for interpretation of microbubble-enhanced sonography provides sensitive and accurate diagnosis of commonly encountered liver masses.

Adolescent↗

PubMed2006

Role of microbubble ultrasound contrast agents in the non-invasive assessment of chronic hepatitis C-related liver disease.

Patients who are chronically infected with the hepatitis C virus often develop chronic liver disease and assessment of the severity of liver injury is required prior to considering viral eradication therapy. This article examines the various assessment methods currently available from gold standard liver biopsy to serological markers and imaging. Ultrasound is one of the most widely used imaging modalities in clinical practice and is already a first-line diagnostic tool for liver disease. Microbubble ultrasound contrast agents allow higher resolution images to be obtained and functional assessments of microvascular change to be carried out. The role of these agents in quantifying the state of hepatic injury is discussed as a viable method of determining the stage and grade of liver disease in patients with hepatitis C. Although currently confined to specialist centres, the availability of microbubble contrast-enhanced ultrasound will inevitably increase in the clinical setting.

Aged↗

PubMed2004

Investigation of the effects of microbubble shell disruption on population scattering and implications for modeling contrast agent behavior.

In a previous study, quantitative measurement of nonlinear scattering revealed some quantitative discrepancies with a model for ultrasound scattering by a population ensemble of microbubbles. This study is designed to investigate the effect of the shell on single-pulse scattering by a population of contrast microbubbles. Nonlinear scattering was measured shortly (15 micros) after exposure to a previous ultrasound pulse with variable intensity. The short time delay eliminated the influence of gas diffusion and focused the study on the consequence of ultrasound exposure. The results suggest that single-pulse scattering is dependent on the disruption properties of the bubble shell and confirm the significance of the shell properties.

Contrast Media↗