Ultrasound Contrast Enhancement Research Articles

Coating microbubbles with nanoparticles for medical imaging and drug delivery.

Coating microbubbles with nanoparticles for medical imaging and drug delivery.

Structural regulation of self-assembled iron oxide/polymer microbubbles towards performance-tunable magnetic resonance/ultrasonic dual imaging agents

Fe3O4/polymer hybrid microcapsules were prepared via a template-free route which is based on polyamine-salt aggregates (PSAs) self-assembly approach. The measurements of transmission electron microscopy (TEM) indicated that the diameter and shell thickness of the microcapsules could be tuned by varying the experimental conditions, such as the concentration of reactants and evolution time employed during the PSA assembly. The results of vibrating sample magnetometer (VSM) demonstrated that the magnetic nanoparticles content of the synthesized microcapsules was tunable and all samples exhibited superparamagnetic behavior. After filling appropriate perfluorocarbon into the inner cavities of the microcapsules, the biomedical applications of the resultant microbubbles, including ultrasonic imaging (USI) and magnetic resonance imaging (MRI), were studied in vitro. It showed that the synthesized magnetic microbubbles possessed both strong ultrasound contrast enhancement capability and high relaxation rate. The excellent acoustic and magnetic properties of these self-assembled microbubbles ensure that the Fe3O4/polymer hybrid microbubbles have great potential as MRI/USI dual-modality contrast agents.

Nanosized Ultrasound Enhanced-Contrast Agent for in Vivo Tumor Imaging via Intravenous Injection.

To enhance the detection limit of ultrasound (US) imaging, ultrasound enhanced-contrast agents (UECAs) that can go preferentially to the target tissue such as a tumor and amplify the US signal have been developed. However, nanosized UECAs among various UECAs developed are very limited to clearly demonstrate proper ability for selective tumor detection by US imaging upon their intravenous injection. In this study, we prepared CaCO3 nanoparticles that were formed inside a flexible and biocompatible pluronic-based nanocarrier. This nanosized UECA was stable in serum-containing media and generated CO2, more preferentially at low pH; thus, it could be detected by US imaging. After intravenous injection into tumor-bearing mice, this nanosized UECA showed a significant US contrast enhancement at the tumor site in 1 h, in contrast to no change in the liver, followed by a rapid clearance from the body in 24 h. Therefore, the present nanosized UECA could be applied as an effective diagnostic modality for in vivo tumor imaging by ultrasonography.

Rol actual de la ecografía en el diagnóstico del cáncer de mama

En los últimos años, la ecografía de mama, gracias al avance tecnológico de transductores de alta resolución lateral, imágenes armónicas, Doppler color, vistas panorámicas, uso de ecorrealzadores, tridimensionales, ha llegado a ser el examen de imágenes más importante en la evaluación complementaria a la mamografía de las lesiones mamarias y en muchos casos (mujeres con mamas densas, en menores de 35 años y en gestantes) es el examen de primera línea, con mayor sensibilidad y especificidad. Se realiza una revisión de las características ecográficas de las lesiones benignas, malignas y cáncer de mama; la clasificación ecográfica según la terminología bi-rads (breast imaging reporting and data system); Do-ppler del cáncer de mama, tridimensional (3D), metástasis ganglionar; ecografía como método de descarte y biopsia de lesiones de mama mediante guía ecográfica.

Clinical value of contrast-enhanced ultrasound to identify cirrhosis combined with small lesions in the liver

Objective To study the value of contrast enhanced ultrasound in identifying cirrhosis combined with small lesions in the liver. Methods A retrospective analysis of patients with small lesions in liver cirrhosis were 72 cases,including 82 lesions.All patients were routine ultrasound and angiography. Results 49 cases of liver cirrhosis with benign lesions for the performance of ultrasound contrast enhancement phase were synchronized with the liver parenchyma,33 cases of liver cirrhosis with malignant lesions in the arterial phase showed a rapid and uniform enhancement.Benign lesions and malignant lesions were no significant differences in the timing of the beginning of growth(t= 0.812,P> 0.05).The peak time,enhance time before they eliminate time aspects of malignant lesion group were less benign lesion group(t= 2.836,3.771,7.062,P< 0.05,P< 0.01).The sensitivity,specificity and accuracy through conventional ultrasound were 46.9%,76.2%,68.3%.The sensitivity,specificity,and accuracy through contrast enhanced ultrasound were 97.1%,97.8%,97.6%.Ultrasound contrast sensitivity,specificity,accuracy were higher(χ2 = 5.36,7.22,8.04,all P< 0.05). Conclusion Contrast enhanced ultrasound can more accurately identify nature of small lesions of liver cirrhosis. Key words: Liver oirrhosis; Liver neoplasms; Ultrasonography

In vivo imaging of microfluidic-produced microbubbles.

Microfluidics-based production of stable microbubbles for ultrasound contrast enhancement or drug/gene delivery allows for precise control over microbubble diameter but at the cost of a low production rate. In situ microfluidic production of microbubbles directly in the vasculature may eliminate the necessity for high microbubble production rates, long stability, or small diameters. Towards this goal, we investigated whether microfluidic-produced microbubbles directly administered into a mouse tail vein could provide sufficient ultrasound contrast. Microbubbles composed of nitrogen gas and stabilized with 3 % bovine serum albumin and 10 % dextrose were injected for 10 seconds into wild type C57BL/6 mice, via a tail-vein catheter. Short-axis images of the right and left ventricle were acquired at 12.5 MHz and image intensity over time was analyzed. Microbubbles were produced on the order of 10(5) microbubbles/s and were observed in both the right and left ventricles. The median rise time, duration, and decay time within the right ventricle were 2.9, 21.3, and 14.3 s, respectively. All mice survived the procedure with no observable respiratory or heart rate distress despite microbubble diameters as large as 19 μm.

Non-invasive Ultrasound to Identify Eosinophil Granule Proteins in Eosinophilic Esophagitis

Although traditional microbubble contrast agents are bright, the high contrast of gas bubbles and air–water interfaces in the upper gastrointestinal tract renders these agents less useful for diagnosing diseases such as eosinophilic esophagitis, a disease characterized by patchy infiltration of eosinophils into the esophagus. Here we report a first-in-class ultrasound contrast enhancement agent composed of echogenic insulin particles, which are labeled with molecular recognition elements to diagnose eosinophil-associated diseases. We prepared solid echogenic insulin particles, tethered antibodies to eosinophil granule major basic protein 1 (MBP-1) to their surfaces and experimentally evaluated binding of these agents to MBP-1 on ex vivo non-human primate esophagi. We found that insulin particles can be readily observed by ultrasound and bind to MBP-1-coated esophagi within minutes. Our results suggest the potential of this new class of solid contrast agents to image, diagnose and improve management of eosinophilic esophagitis.

Ultrasound modulated optical tomography contrast enhancement with non-linear oscillation of microbubbles.

Ultrasound modulated optical tomography (USMOT) is an imaging technique used to provide optical functional information inside highly scattering biological tissue. One of the challenges facing this technique is the low image contrast. A contrast enhancement imaging technique based on the non-linear oscillation of microbubbles is demonstrated to improve image contrast. The ultrasound modulated signal was detected using a laser pulse based speckle contrast detection system. Better understanding of the effects of microbubbles on the optical signals was achieved through simultaneous measurement of the ultrasound scattered by the microbubbles. The length of the laser pulse was found to affect the system response of the speckle contrast method with shorter pulses suppressing the fundamental ultrasound modulated optical signal. Using this property, image contrast can be enhanced by detection of the higher harmonic ultrasound modulated optical signals due to nonlinear oscillation and destruction of the microbubbles. Experimental investigations were carried out to demonstrate a doubling in contrast by imaging a scattering phantom containing an embedded silicone tube with microbubbles flowing through it. The contrast enhancement in USMOT resulting from the use of ultrasound microbubbles has been demonstrated. Destruction of the microbubbles was shown to be the dominant effect leading to contrast improvement as shown by simultaneously detecting the ultrasound and speckle contrast signals. Line scans of a microbubble filled silicone tube embedded in a scattering phantom demonstrated experimentally the significant image contrast improvement that can be achieved using microbubbles and demonstrates the potential as a future clinical imaging tool.

Correlation of structure and echogenicity of nanoscaled ultrasound contrast agents in vitro

Ultrasound is a common tool for clinical diagnosis due to its safety and economic. Especially the addition of ultrasound contrast agents leads to a high diagnostic reliability. In recent years ultrasound has been used as a trigger for directed drug delivery or to enhance thrombolysis. We developed a nanoscaled ultrasound contrast agent (NUSCA) to improve these applications. In the future drugs can be incorporated into this contrast agent to achieve a combination of ultrasound diagnosis and therapy. The aim of the present study is to elucidate the structure of the nanoscaled lipid formulations and a potential dependence of the ultrasound contrast enhancement on this structure. Our NUSCA is based on the phospholipids 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and the single-chained polyethylene glycol (40) stearate (PEG40S). In this study the effect of increasing concentrations of the single chained PEG40S on the structure of the lipid formulations was characterised using Dynamic Light Scattering, cryo-Transmission Electron Microscopy, Nuclear Magnetic Resonance spectroscopy, lipid monolayer studies and epifluorescence measurements. In addition, the ultrasound contrast enhancement for the formulations was determined in vitro. Dependence between structure and ultrasound contrast was found. All PEG40S concentrations lead to a mixture of liposomes and discoid micelles. With increasing PEG40S content the amount of micelles increased. Certain PEG40S concentrations lead to an ultrasound contrast superior to the contrast of the commercially available ultrasound contrast agent SonoVue®.

L’échographie avec contraste peut montrer des lésions carotidiennes symptomatiques non visualisées en angio-RM

We report the cases of two patients who presented symptoms focused on a wall of the common carotid: carotidodynia in one patient and a transient ischemic attack in the other. The B-mode ultrasound showed an enlarged thickened medio-adventitial echostructure with a slightly heterogeneous and iso or hypoechoic appearance. There was no narrowing. Injection of ultrasound contrast led to significant enhancement in the wall reflecting neovascularization secondary to inflammation. Other imaging methods (MR and CT angiography) found no abnormality. At the 3-month follow-up visit, the surface area of the lesions was greatly decreased and the ultrasound contrast enhancement had disappeared. These two cases illustrate how focal lesions of the carotid wall missed on MR and CT angiography can be detected and visualized with B-mode ultrasound contrast enhancement. Contrast enhanced ultrasound leads to the concept of "active lesions" resulting from inflammatory processes that can be readily monitored without radiation.

The expression and clinical significance of MPO in patients with chronic ischemic cerebrovascular disease

Objective To investigate the expression and clinical significance of myeloperoxidase (MPO) in patients with chronic ischemic cerebrovascular disease.Methods 70 carotid atherosclerotic plaques patients with plasma MPO level in our hospital were measured and taken ultrasound examination at the same time.Results There was no significant difference for those with contrast-enhanced imaging and without increase in the general information (P ＞0.05).The enhanced infarct rate was 80.5％ (33/41).The non-enhanced infarct was 44.8％ (13/29).The carotid plaque ultrasound contrast enhancement in patients with cerebral infarction group was significantly higher than non-enhanced group(P ＜ 0.01 ).In the plasma levels of MPO detection,contrast-enhanced carotid ultrasound group was significantly higher than non-enhanced group( P ＜ 0.01 ).The cerebral infarction patients was significantly higher than non-cerebral infarction group (P ＜ 0.01 ).Conclusion The atherosclerotic plaque instability in patients with high expression level of MPO was significantly higher,which indicated high level expression of MPO in the diagnosis of chronic cerebrovascular disease had a very important role.Supplemented by the results of ultrasound imaging may had a clear diagnosis. Key words: Brain ischemia; Peroxidase ; Ultrasonography; Carotid artery diseases

Biomedical photoacoustics beyond thermal expansion using triggered nanodroplet vaporization for contrast-enhanced imaging

Since being discovered by Alexander Bell, photoacoustics may again be seeing major resurgence in biomedical imaging. Photoacoustics is a non-ionizing, functional imaging modality capable of high contrast images of optical absorption at depths significantly greater than traditional optical imaging techniques. Optical contrast agents have been used to extend photoacoustics to molecular imaging. Here we introduce an exogenous contrast agent that utilizes vaporization for photoacoustic signal generation, providing significantly higher signal amplitude than that from the traditionally used mechanism, thermal expansion. Our agent consists of liquid perfluorocarbon nanodroplets with encapsulated plasmonic nanoparticles, entitled photoacoustic nanodroplets. Upon pulsed laser irradiation, liquid perfluorocarbon undergoes a liquid-to-gas phase transition generating giant photoacoustic transients from these dwarf nanoparticles. Once triggered, the gaseous phase provides ultrasound contrast enhancement. We demonstrate in phantom and animal studies that photoacoustic nanodroplets act as dual-contrast agents for both photoacoustic and ultrasound imaging through optically triggered vaporization.

Facile one-pot synthesis of polymer–phospholipid composite microbubbles with enhanced drug loading capacity for ultrasound-triggered therapy

This paper reports the one-pot synthesis of perfluorocarbon microbubbles with crosslinked shells of poly(acrylic acid) and phospholipid that boast excellent ultrasound contrast enhancement, enhanced loading capacity, and the ability to retain or release their contents through variation in the level of ultrasound exposure.

Development and characterization of new nanoscaled ultrasound active lipid dispersions as contrast agents

Ultrasound contrast agents are widely used in clinical diagnosis. In recent years, the use of ultrasound contrast agents as therapeutic agents has gained a lot of attention. Of special interest are ultrasound-enhanced gene delivery in various tissues (e.g. cardiac, vascular, skeletal muscle and tumor tissue), ultrasound-enhanced protein delivery (e.g. insulin delivery) and ultrasound-enhanced delivery of small chemicals (e.g. doxorubicin, vancomycin). Commercially available ultrasound contrast agents such as SonoVue® or Optison® are ranged in a size of 2–8μm. These micronscaled agents show a good ultrasound contrast enhancement and thus they are used for diagnostic imaging. But they are not suitable for targeted drug delivery to tumor tissues or blood clots because for these applications particles smaller than 700nm are needed. In the present study, we developed new nanoscaled ultrasound contrast agents with a size between 70 and 300nm. The lipid formulations show excellent contrast intensities using diagnostic ultrasound of about 1.4MHz. The negatively charged colloidal dispersions are long-time stable under physiological conditions without loss of ultrasound reflectivity. The adjustable supramolecular organization of the carriers depends on the composition and varies from micellar to liposomal structures. The small size and the circulation stability of these systems make them promising for novel diagnostics and controlled drug release applications.

Intra‐operative contrast‐enhanced ultrasound improves image enhancement in the evaluation of liver tumors

Intra-operative hepatic tumor ultrasound assessment can be difficult in patients with abnormal hepatic parenchyma because of the inability to enhance echogenic differences. Prospective pilot study of intra-operative ultrasound contrast enhancement in the evaluation of liver tumors to establish safety, dosing, and increased image enhancement with ultrasound contrast evaluation. A single bolus of perfluten lipid microspheres was then injected and ultrasound images were then re-recorded and saved. Twenty consecutive patients underwent contrast-enhanced ultrasound evaluation during the operative procedure. All patients received at least one bolus dose of microspheres (median 2 dose, range 1-3), without change in heart rate, blood pressure, end tidal CO(2), oxygen saturation, and sedation monitoring at the time of dosing and until 4 hr post-bolus doses. Two blinded independent readers found the contrasted images to have a statistically greater degree of enhancement (median improvement of 4, P = 0.01) and greater degree of size/border characteristics in the contrasted images (median improvement of 5, P = 0.01) for all histologies. In five patients, the extent of hepatic resection was altered from partial to complete lobectomy in order to obtain acceptable oncologic margin. Contrast-enhanced ultrasound is safe and effective in pre-resection and pre-ablation treatment planning.

CMR2009: 1.05: Microbubble size affects intensity and duration of ultrasound contrast enhancement in mice

CMR2009: 1.05: Microbubble size affects intensity and duration of ultrasound contrast enhancement in mice

Ultrasound-induced apoptosis in the presence of Sonazoid and associated alterations in gene expression levels: A possible therapeutic application

Ultrasound (US) has been shown to induce apoptosis and cell lysis in cancer cells. In this study, we report on the potential of using Sonazoid, a new echo-contrast agent, that is chemically more stable and US-resistant in combination with US in cancer therapy. The biological effects and their mechanisms in the presence or absence of ultrasonic exposure in vitro were investigated. In addition, the impact of the agent on the expression levels of genes responsive to US was studied using global-scale microarrays and computational gene expression analysis tools. Our results show that the combination led to enhanced cell killing in the presence of 1 MHz acoustic field. The apoptosis induction was shown to be mediated by the mitochondrial pathway. The occurrence of US-induced DNA damage was also observed. Despite these findings, the agent at concentrations similar to those clinically used can be considered as well tolerated. Furthermore, Sonazoid enhanced expression of genes that related to apoptosis and are responsive to US, although it alone had almost no effect. These results indicate the potential of Sonazoid for US contrast enhancement as well as the possibility of its use in US-aided therapies.

Perfluorooctyl Bromide Polymeric Capsules as Dual Contrast Agents for Ultrasonography and Magnetic Resonance Imaging

AbstractPolymeric capsules with a thick shell made of biodegradable and biocompatible polymer and a liquid core of perfluorooctyl bromide (PFOB) were evaluated for stability as well as for ultrasound and magnetic resonance imaging (MRI) contrast enhancement. The method of preparation allows the mean capsule diameter to be regulated between 70 nm and 25 µm and the capsule thickness‐to‐radius ratio from 0.25 to 0.54. Capsule diameter remains stable at 37 °C in phosphate buffer for at least 4 and 6 h for nanocapsules and microcapsules, respectively. The in vitro ultrasound signal‐to‐noise ratio (SNR) was measured from 40 to 60 MHz for 6 µm and 150 nm capsules: the SNR increases with capsule concentration up to 20–25 mg mL−1, and then reaches a plateau that depends on capsule diameter (13.5 ± 1.5 dB for 6 µm and 6 ± 2 dB for the 150 nm capsules). The ultrasound SNR is stable for up to 20 min for microcapsules and for several hours for nanocapsules. For nanocapsules, the thinner the shell, the larger the SNR and the more compressible the capsules. Nanocapsule suspensions imaged in vitro with a commercial ultrasound imaging system (normal and tissue harmonic imaging modes, 7–14 MHz probe) were detected down to concentrations of 12.5 mg mL−1. Injections of nanocapsules (200 µg ml−1) in mice in vivo reveal that the initial bolus passage presents significant ultrasound enhancement of the blood pool during hepatic imaging (7–14 MHz probe, tissue harmonic imaging mode). 19F‐MRI images were obtained in vitro at 9.4T using spin‐echo and gradient echo sequences and allow detecting nanocapsules in suspension (50 mg mL−1). In conclusion, these results show initial feasibility for development of these capsules toward a dual‐modality contrast agent.

Use of ultrasound guidance and contrast enhancement: a study of continuous infraclavicular brachial plexus approach*

We describe our experience of combining the use of ultrasound (US) guidance with contrast enhancement and peripheral nerve stimulation for the insertion of infraclavicular brachial plexus catheters. Thirty patients scheduled to have upper limb surgery under regional block were studied. Under US guidance and peripheral nerve stimulation assistance, continuous peripheral nerve block needle and stimulating catheter were placed in the infraclavicular area. Needle and catheter tip location was confirmed with agitated 5% dextrose and seen under colour Doppler with US before injecting local anaesthetic (LA). Patients were evaluated in terms of onset times and efficacy of block. Post-operatively, on block recession a catheter was stimulated and visualization of spread of LA during injection through the catheter was done. Secondary block (subsequent to re-injection of LA) was assessed. Patients were followed-up for a week. Mean time to onset of block was 19.7 (+/- 4.9) min. There were no incomplete blocks and all components of the plexus were blocked completely. Post-operatively, in 95.7% of patients, the spread of hand-agitated LA via the catheter could be seen by color Doppler with ultrasonography. All patients had excellent post-operative analgesia and high degree of satisfaction. There were no complications. Contrast enhancement with US guidance during infraclavicular brachial plexus block enables direct visualization of needle and catheter tip location. Our early experience suggests that this leads to successful initial and subsequent post-operative block. Further controlled studies are needed to compare this technique with more prevalent and conventional techniques of catheter insertion.

Contrast-enhanced ultrasound to evaluate the severity of chronic hepatitis C

Background Non-invasive techniques are being developed to assess the severity of liver disease. Haemodynamic changes in the hepatic circulation during the development of liver disease can be evaluated with contrast-enhanced ultrasound. Aim To evaluate the possible correlation between ultrasound contrast-agent transit times and different stages of chronic hepatitis C. Patients Sixteen patients with clinically evident hepatitis C virus-related cirrhosis, 22 non-cirrhotic patients with chronic hepatitis C and 14 controls with no clinical evidence of liver disease were studied. Methods Contrast-enhanced hepatic ultrasonography was performed with a sulphur hexafluoride-filled microbubble contrast agent, and time curves of hepatic vein signal intensity were analysed to determine the time of enhancement onset (hepatic vein arrival time) and peak enhancement (hepatic vein peak enhancement). Results Hepatic vein arrival time in cirrhotic patients was significantly shorter ( p < 0.001) than in non-cirrhotic patients and controls. Within the group with chronic hepatitis C, METAVIR scores of fibrosis and necro-inflammatory changes had no significant effect on hepatic vein arrival times. Conclusion Analysis of the time of onset of ultrasound contrast enhancement of the hepatic vein appears to be a simple, non-invasive method for reliably excluding cirrhosis with signs of portal hypertension, but not for assessing the severity of either chronic hepatitis C or cirrhosis.