Developments in ultrasound contrast media

Ultrasound microbubble contrast agents are effective and safe echo enhancers. An ingenious array of methods are employed to achieve stability and provide a clinically useful enhancement period. Microbubbles enhance ultrasound signals by up to 25 dB (greater than 300-fold increase) due to resonant behaviour. This is used to rescue failed Doppler studies and may be extended to image the microcirculation of tumours and the myocardium using non-linear modes. Functional studies open up a whole range of applications by using a variety of active and passive quantitation techniques to derive indices from the transit of contrast through a tissue of interest. This has been especially successful in the detection of liver metastases and cirrhosis and shows great promise as a clinical tool. It also has great potential in measuring microcirculatory flow velocity. The demonstration that some microbubbles are not just pure blood pool agents but have a hepatosplenic specific phase has extended the versatility of ultrasound. Imaging of this stationary phase with non-linear modes such as phase inversion and stimulated acoustic emission, has improved the sensitivity and specificity of ultrasound in the detection and characterisation of focal liver lesions to rival that of CT and MR. Received: 23 June 2000 Revised: 18 July 2000 Accepted: 24 July 2000     

Value of US imaging of metacarpophalangeal joints in patients with early rheumatoid arthritis

Technological advances in the field of ultrasound imaging may have, especially in metacarpophalangeal joints, an impact on decision making in patients with early rheumatoid arthritis. First, the normal anatomy of the metacarpophalangeal joints is briefly reviewed. Then, the authors describe the main ultrasound imaging findings of early RA. The role of ultrasound imaging in the assessment of therapeutic response as well as the benefit of microbubble ultrasound contrast agents are considered.     

Microbubble contrast agents: targeted ultrasound imaging and ultrasound-assisted drug-delivery applications

The use of microbubble contrast agents for general tissue delineation and perfusion enjoys steady interest in ultrasound imaging. Microbubbles as contrast materials require a small dosage and show excellent detection sensitivity. Targeting ligands on the surface of microbubbles permit the selective accumulation of these particles in the areas of interest, which show an up-regulated level of receptor molecules on vascular endothelium. Selective contrast imaging of inflammation, ischemia-reperfusion injury, angiogenesis, and thrombosis has been achieved in animal models. Ultrasound-assisted drug delivery and activation, performed by combining microbubble agent containing drug substances or coadministered with pharmaceutical agents (including plasmid DNA for transfection), has been achieved in multiple model systems in vitro and in vivo. Ultrasound and microbubbles-based targeted acceleration of the thrombolytic enzyme action already have reached clinical trials. Overall, microbubble targeting and ultrasound-assisted microbubble-based drug-delivery systems will offer a step toward the application of targeted personalized diagnostics and therapy.     

Detection of individual microbubbles of ultrasound contrast agents: imaging of free-floating and targeted bubbles

RATIONALE AND OBJECTIVES: During echo examinations with microbubble contrast, individual "dots" of ultrasound reflection can be visualized. To address the question whether these signals represent individual microbubbles, very dilute suspensions of ultrasound contrast agents or individual microbubbles attached to Petri dishes were prepared and studied by ultrasound imaging. METHODS: Microbubble suspensions were diluted in saline and evaluated by a clinical ultrasound imaging system. Microbubble concentration was verified by Coulter counter. Single microbubble preparation on a Petri dish was established by streptavidin-biotin interaction under microscopy control and subjected to ultrasound imaging. RESULTS: Ultrasound of dilute microbubble dispersions demonstrated distinct white foci; concentration of these sites was consistent with signals from individual microbubbles as determined by Coulter. Individual microbubbles immobilized on polystyrene were also visualized by ultrasound. CONCLUSION: Ultrasound medical systems can resolve backscatter signals from individual microbubbles of ultrasound contrast, both in solution and in the targeted immobilized state, implying picogram sensitivity.     

Wideband harmonic imaging: a novel contrast ultrasound imaging technique

A novel ultrasonic imaging method, wideband harmonic imaging, for nonlinear imaging of microbubble contrast agents is evaluated. In wideband harmonic mode, two pulses of alternate phase are send out. The image is then processed from the sum of both pulses, resulting in an image of nonlinear scatterers such as microbubbles. A prototype ultrasound system, Siemens Elegra, was evaluated with in vitro investigations and animal trials, using conventional, harmonic and wideband harmonic settings with the galactose based ultrasound contrast agent Levovist. Wideband harmonic imaging offers superior sensitivity for ultrasound contrast agents compared to conventional imaging and harmonic imaging. At low transmit power settings (MI 0. 1-0.5) the nonlinear response is already sufficient to generate a image of the blood pool distribution of Levovist in the rabbit kidney including the microvasculature, with clear delineation of vessels and perfused parenchyma. At high transmit amplitudes, nonlinear tissue response reduced the apparent image contrast between contrast agent and tissue. The results suggest that wideband harmonic imaging is currently the most sensitive contrast imaging technique, maintaining highest spatial resolution. This may add to image quality and offer new clinical potential for the use of ultrasound contrast agents such as Levovist.     

Impact of European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines on the use of contrast agents in liver ultrasound

The introduction of microbubble contrast agents and the development of contrast-specific techniques have opened new prospects in liver ultrasound. Over the past few years several reports have shown that contrast ultrasound can substantially improve detection and characterization of focal liver lesions with respect to baseline studies. The advent of second-generation agents and low mechanical index real-time scanning techniques has been instrumental in improving the easiness and the reproducibility of the examination. With the publication of the guidelines for the use of contrast agents in liver ultrasound by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB), contrast ultrasound enters into clinical practice. The guidelines define the indications and recommendations for the use of contrast ultrasound in focal liver lesion detection, characterization, and follow-up after tumor ablation procedures. We discuss the impact of EFSUMB guidelines on diagnostic protocols currently adopted in liver imaging.     

Molecular imaging of cardiovascular disease using ultrasound

Molecular imaging using probes that specifically home to function- or disease-specific targets is a promising tool for both basic research investigations as well as clinical diagnostics. Ultrasound-based molecular imaging utilizes acoustically active particles (contrast agents) bearing targeting ligands that specifically bind to a molecule of interest. In the presence of an ultrasound field, the bound particles are detectable as a persistent contrast effect during ultrasound imaging. Different types of targeted contrast agents have been reported, most of which share in common the presence of a gas encapsulated by a shell of varying chemical formulation. These agents, or “microbubbles,” are typically 2 to 4 μm in diameter, and have a natural resonance frequency that corresponds to the frequencies used in diagnostic echocardiography. This attribute makes it possible to induce microbubble resonance and non-linear oscillation at diagnostic ultrasound frequencies, leading to acoustic emissions from the microbubbles that can be detected as specific signals during two dimensional ultrasound imaging. Targeting ligands that have been attached to microbubbles include monoclonal antibodies, peptides, and the naturally occurring ligands for the receptor of interest, such as vascular endothelial growth factor. Because the contrast agents stay within the intravascular space, they are ideally suited for detection of endothelial epitopes, such as leukocyte adhesion molecules or angiogenesis receptors. Ultrasound molecular imaging with targeted contrast agents has been used to detect inflammation association with ischemia/reperfusion (ischemic memory), cardiac transplant rejection, early atherosclerosis, and angiogenesis. Application to tumor angiogenesis has also been reported using peptides that specifically bind to angiogenic tumor endothelium. Translation of ultrasound molecular imaging to the clinical arena will require optimization of contrast agent design to maximize specific binding, and customization of imaging systems to sensitively detect the binding events Dr Villanueva is supported in part by a grant (RO1HL077534) from the National Institutes of Health.     

Assessment of tissue perfusion by contrast-enhanced ultrasound

Contrast-enhanced ultrasound (CEUS) with microbubble contrast agents is a new imaging technique for quantifying tissue perfusion. CEUS presents several advantages over other imaging techniques in assessing tissue perfusion, including the use of microbubbles as blood-pool agents, portability, availability and absence of exposure to radiation or nuclear tracers. Dedicated software packages are necessary to quantify the echo-signal intensity and allow the calculation of the degree of tissue contrast enhancement based on the accurate distinction between microbubble backscatter signals and native tissue background. The measurement of organ transit time after microbubble injection and the analysis of tissue reperfusion kinetics represent the two fundamental methods for the assessment of tissue perfusion by CEUS. Transit time measurement has been shown to be feasible and has started to become accepted as a clinical tool, especially in the liver. The loudness of audio signals from spectral Doppler analysis is used to generate time-intensity curves to follow the wash-in and wash-out of the microbubble bolus. Tissue perfusion may be quantified also by analysing the replenishment kinetics of the volume of microbubbles after their destruction in the imaged slice. This allows to obtain semiquantitative parameters related to local tissue perfusion, especially in the heart, brain, and kidneys.     

Tissue harmonic and contrast-specific imaging: back to gray scale in ultrasound

The development of new US techniques that produce images based on nonlinear acoustic effects of US interaction with matter or microbubble contrast agents has opened new prospects for gray-scale US in native tissue and contrast imaging. Tissue harmonic imaging uses higher frequencies generated on propagation of the US beam through matter to improve image quality and resolve small anatomic structures and details, and is becoming a routine approach in US examination of many abdominal districts. Contrast-specific imaging techniques display enhancement of US agents in gray-scale with optimal contrast and spatial resolution, and offer high sensitivity either to microbubble movement or to microbubble destruction in dependence of the level of the applied acoustic peak pressure. Owing to the ability to exploit the microcirculation, contrast-specific techniques have enabled the evolution of contrast US from vascular imaging to the imaging of perfused tissues. Several studies have shown that these methods can substantially improve US detection and characterization of focal liver lesions, and promising results have been reported in other areas of investigation. This article reviews physical principles, technical issues, and clinical applications of tissue harmonic and contrast-specific imaging. It is foreseen that the new gray-scale US techniques will rapidly become a tool in numerous clinical scenarios.     

Ultrasound of focal liver lesions

This paper gives a comprehensive overview of ultrasound of focal liver lesions. Technical aspects such as examination technique and the use of Doppler modes as well as recent developments such as tissue harmonic imaging and microbubble contrast agents are discussed. The clinical significance and sonographic features of various liver lesions such as haemangioma, focal nodular hyperplasia, adenoma, regenerative nodule, metastasis, hepatocellular carcinoma and various types of focal infections are described. With the exception of cysts and typical haemangiomas, definitive characterisation of a liver lesion is often not possible on conventional ultrasound. This situation has changed with the recent advent of ultrasound contrast agents, which permit definitive diagnosis of most lesions. Contrast-enhanced sonography using recently developed contrast-specific imaging modes dramatically extends the role of liver ultrasound by improving its specificity in the detection and characterisation of focal lesions to rival CT and MRI.     

Technische Grundlagen der Kontrastsonographie im ��berblick und Ausblick in die Zukunft

Ultrasound contrast agents have considerably expanded the range of ultrasound diagnostics. Up to date ultrasound machines with contrast-specific software allow the selective demonstration and quantification of contrast agents in real-time based on the specific signal signature of oscillating contrast agent microbubbles. After intravenous injection the microbubbles are transported with the bloodstream and distributed purely intravascularly. This allows an artefact-free representation of the vascular architecture and delineation of the vascular lumen, independent of blood flow velocity and with high spatial resolution. Traumatic lesions and active bleeding can be detected with high sensitivity. Blood volume in vessels and organs can be assessed qualitatively and quantitatively. The possibility of short-term destruction of microbubbles within the ultrasound field allows the measurement of blood flow velocity during replenishment and based on that the assessment of perfusion in parenchymal tissue. Target-specific microbubbles for imaging of molecular surface structures as well as drug-loaded microbubbles for local ultrasound-mediated therapy are under development.     

Focal liver lesions: role of contrast-enhanced ultrasound

The introduction of microbubble contrast agents and the development of contrast-specific techniques have opened new possibilities in liver imaging. Initially, only intermittent imaging with Doppler detection was available. Second-generation contrast agents and low mechanical index real-time scanning techniques are decisive advances that enable convenient liver examinations with high sensitivity and specificity. Hepatic lesions usually show typical perfusion and enhancement patterns through the various contrast phases, which help their characterization. Several published studies and the daily clinical routine show that, as opposed to conventional ultrasound (US), contrast-enhanced US can substantially improve detection and differentiation of focal liver lesions. Today, contrast-enhanced US is the dynamic imaging modality of choice for differentiation of focal liver lesions. Contrast uptake patterns of the most relevant liver lesions, as well as important clinical indications are presented and discussed.     

Molecular imaging with contrast ultrasound and targeted microbubbles

There is growing interest in the development of methods for imaging cellular and molecular mediators of cardiovascular diseases. Techniques for imaging molecular and cellular alterations have been explored for essentially all noninvasive cardiac imaging modalities. Molecular imaging with contrast-enhanced ultrasound relies on the detection of novel site-targeted microbubble contrast agents. These microbubbles are retained within regions of a specific disease process, thereby allowing phenotypic characterization of tissue. As microbubbles are pure intravascular tracers, the disease processes assessed must be characterized by antigens that are expressed within the vascular compartment. Accordingly, the pathologic states that have been targeted include inflammation, neoplasms, angiogenesis, and thrombus formation, all of which are mediated in part by molecular events within the vascular space. This review describes (1) different strategies that have been used to target microbubbles to regions of disease, (2) the unique challenges for imaging targeted ultrasound contrast agents, and (3) some of the early experience imaging molecular events in animal models of disease.     

Advances in ultrasound

Significant advances have been recently introduced into various fields of technology, taking advantage of the use of new piezoelectric materials and the large diffusion of broadband transducers. Various types of modulation may be applied to the pulse characteristics, using single pulse, multipulse or multiline techniques, and resulting in improved spatial resolution and better penetration. Non-linear imaging uses the harmonics component, which is generated by tissues or by contrast agents. Different modalities can be used to separate harmonics from fundamental bands from the received signal. New Doppler modes have been developed, whereas grey-scale flow imaging allows the simultaneous imaging of blood flow and tissues. Compounding techniques improve the contrast resolution of tissues and reduce artefacts. If 3D techniques are now currently available, real-time 4D imaging has been recently introduced. Elastographic imaging is still under evaluation, but promising clinical results have been shown. Recent release of the DICOM specification has made the full integration of ultrasound to the PACS systems easier. All these advances indicate that the contribution and potential of ultrasound in patient management is still growing.     

Ultrasound of the liver

This article summarizes the recent advances in ultrasound imaging of the liver, especially contrast-enhanced imaging. Contrast-enhanced ultrasound has dramatically changed the role of ultrasound in liver tumor characterization, detection, and other applications. Available ultrasound contrast agents, agents under development, contrast-specific imaging techniques, and its applications in liver imaging are discussed.     

Microbubbles as ultrasound contrast agents for molecular imaging: preparation and application

OBJECTIVE: The purpose of this review is to describe trends in microbubble application in molecular imaging. CONCLUSION: Microbubbles are used for contrast ultrasound imaging as blood-pool agents in cardiology and radiology. Their promise as targeted agents for molecular imaging is now being recognized. Microbubbles can be functionalized with ligand molecules that bind to molecular markers of disease. Potential clinical applications of molecular imaging with microbubble-based ultrasound contrast agents are in the monitoring of the biomarker status of vascular endothelium, visualizing tumor vasculature, and imaging inflammation and ischemia-reperfusion injury zones and thrombi.     

Nano/microparticles and ultrasound contrast agents

Microbubbles have been used for many years now in clinical practice as contrast agents in ultrasound imaging. Recently, their therapeutic applications have also attracted more attention. However, the short circulation time (minutes) and relatively large size (two to ten micrometers) of currently used commercial microbubbles do not allow effective extravasation into tumor tissue, preventing efficient tumor targeting. Fortunately, more multifunctional and theranostic nanoparticles with some special advantages over the traditional microbubbles have been widely investigated and explored for biomedical applications. The way to synthesize an ideal ultrasound contrast agent based on nanoparticles in order to achieve an expected effect on contrast imaging is a key technique. Currently a number of nanomaterials, including liposomes, polymers, micelles, dendrimers, emulsions, quantum dots, solid nanoparticles etc., have already been applied to pre or clinical trials. Multifunctional and theranostic nanoparticles with some special advantages, such as the tumor-targeted (passive or active), multi-mode contrast agents (magnetic resonance imaging, ultrasonography or fluorescence), carrier or enhancer of drug delivery, and combined chemo or thermal therapy etc., are rapidly gaining popularity and have shown a promising application in the field of cancer treatment. In this mini review, the trends and the advances of multifunctional and theranostic nanoparticles are briefly discussed.     

Seeking consensus: contrast ultrasound in radiology

This paper summarises the discussions from a meeting held on contrast ultrasound held on 21 October 2000 in Toronto, Canada. The aims of this meeting, supported by ATL/Philips Ultrasound, was to review the current clinical indications for contrast usage in the liver and kidney, arrive at recommendations for use of intravenous contrast agents, and speculate on the future uses. This paper is published to help understand this rapidly evolving field. Consensus points included a recommendation that Levovist in its post-vascular phase was of considerable value in detecting and excluding metastases in the liver, although unlikely realistically to replace CT or MR. Newer agents such as Sonovue, Definity and Sonazoid, suitable for low mechanical index (MI) imaging were also of great value and may have a further role for HCC detection. Equipment manufacturers should strive to keep improving low mechanical index modes for these agents. Promising applications for characterisation included further evaluation of lesions discovered on ultrasound and as a problem solver for CT or MR. To date no contrast agents have received approval from the FDA for radiological applications in the United States. The case for reimbursement for contrast agents was strongly supported by the panel.     

Microbubble ultrasound contrast agents: an update

Microbubble contrast agents for ultrasound (US) have gained increasing interest in recent years, and contrast-enhanced US (CEUS) is a rapidly evolving field with applications now extending far beyond the initial improvements achieved in Doppler US. This has been achieved as a result of the safe profile and the increased stability of microbubbles persisting in the bloodstream for several minutes, and also by the availability of specialized contrast-specific US techniques, which allow a definite improvement in the contrast resolution and suppression of signal from stationary tissues. CEUS with low transmit power allows real-time scanning with the possibility of prolonged organ insonation. Several reports have described the effectiveness of microbubble contrast agents in many clinical applications and particularly in the liver, spleen, and kidneys. CEUS allows the assessment of the macrovasculature and microvasculature in different parenchymas, the identification and characterization of hepatic and splenic lesions, the depiction of septal enhancement in cystic renal masses, and the quantification of organ perfusion by the quantitative analysis of the echo-signal intensity. Other fields of application include the assessment of abdominal organs after traumas and the assessment of vesico-ureteral reflux in children. Finally, tumor-targeted microbubbles make possible the depiction of specific biologic processes.     

Technical developments in MR angiography

CE MRA has evolved rapidly since the early studies by Prince et al [3]. Whereas many of the procedures in clinical use today rely heavily on the use of gadolinium contrast agents and standard. Fourier transform acquisition techniques, advances will have a significant impact on MRA by shortening the acquisition time, improving the reproducibility of the image-acquisition techniques, and improving spatial resolution or SNR. From a technical basis, shorter acquisition times associated with fast gradients are likely to improve spatial resolution and allow for acquisition of MR images over large FOVs. In addition, alternative k-space sampling techniques, such as parallel imaging and PR, are expected to further reduce acquisition time, while maintaining or improving spatial resolution. The approval and subsequent use of new contrast agents will also have a beneficial impact on the image quality of contrast-enhanced MRA applications. It is likely that these contrast agents will be coupled with advanced acquisition techniques to improve spatial resolution and technical success rates of MRA examinations.