Contrast-enhanced ultrasound

Contrast-enhanced ultrasound (CEUS) is the application of ultrasound contrast medium to traditional medical sonography. Ultrasound contrast agents rely on the different ways in which sound waves are reflected from interfaces between substances. This may be the surface of a small air bubble or a more complex structure. Commercially available contrast media are gas-filled microbubbles that are administered intravenously to the systemic circulation. Microbubbles have a high degree of echogenicity (the ability of an object to reflect ultrasound waves). There is a great difference in echogenicity between the gas in the microbubbles and the soft tissue surroundings of the body. Thus, ultrasonic imaging using microbubble contrast agents enhances the ultrasound backscatter, (reflection) of the ultrasound waves, to produce a sonogram with increased contrast due to the high echogenicity difference. Contrast-enhanced ultrasound can be used to image blood perfusion in organs, measure blood flow rate in the heart and other organs, and for other applications.
Targeting ligands that bind to receptors characteristic of intravascular diseases can be conjugated to microbubbles, enabling the microbubble complex to accumulate selectively in areas of interest, such as diseased or abnormal tissues. This form of molecular imaging, known as targeted contrast-enhanced ultrasound, will only generate a strong ultrasound signal if targeted microbubbles bind in the area of interest. Targeted contrast-enhanced ultrasound may have many applications in both medical diagnostics and medical therapeutics. However, the targeted technique has not yet been approved by the FDA for clinical use in the United States.
Contrast-enhanced ultrasound is regarded as safe in adults, comparable to the safety of MRI contrast agents, and better than radiocontrast agents used in contrast CT scans. The more limited safety data in children suggests that such use is as safe as in the adult population.
Bubble echocardiogram.
An echocardiogram is a study of the heart using ultrasound. A bubble echocardiogram is an extension of this that uses simple air bubbles as a contrast medium during this study and often has to be requested specifically.
Although colour Doppler can be used to detect abnormal flows between the chambers of the heart (e.g., persistent (patent) foramen ovale), it has a limited sensitivity. When specifically looking for a defect such as this, small air bubbles can be used as a contrast medium and injected intravenously, where they travel to the right side of the heart. The test would be positive for an abnormal communication if the bubbles are seen passing into the left side of the heart. (Normally, they would exit the heart through the pulmonary artery and be stopped by the lungs.) This form of bubble contrast medium is generated on an "ad hoc" basis by the testing clinician by agitating normal saline (e.g., by rapidly and repeatedly transferring the saline between two connected syringes) immediately prior to injection.
Microbubble contrast agents.
General features.
There are a variety of microbubble contrast agents. Microbubbles differ in their shell makeup, gas core makeup, and whether or not they are targeted.
Regardless of the shell or gas core composition, microbubble size is fairly uniform. They lie within a range of 1–4 micrometres in diameter. That makes them smaller than red blood cells, which allows them to flow easily through the circulation as well as the microcirculation.
Targeted microbubbles.
Targeted microbubbles are under preclinical development. They retain the same general features as untargeted microbubbles, but they are outfitted with ligands that bind specific receptors expressed by cell types of interest, such as inflamed cells or cancer cells. Current microbubbles in development are composed of a lipid monolayer shell with a perfluorocarbon gas core. The lipid shell is also covered with a polyethylene glycol (PEG) layer. PEG prevents microbubble aggregation and makes the microbubble more non-reactive. It temporarily “hides” the microbubble from the immune system uptake, increasing the amount of circulation time, and hence, imaging time. In addition to the PEG layer, the shell is modified with molecules that allow for the attachment of ligands that bind certain receptors. These ligands are attached to the microbubbles using carbodiimide, maleimide, or biotin-streptavidin coupling. Biotin-streptavidin is the most popular coupling strategy because biotin's affinity for streptavidin is very strong and it is easy to label the ligands with biotin. Currently, these ligands are monoclonal antibodies produced from animal cell cultures that bind specifically to receptors and molecules expressed by the target cell type. Since the antibodies are not humanized, they will elicit an immune response when used in human therapy. Humanizing antibodies is an expensive and time-intensive process, so it would be ideal to find an alternative source of ligands, such as synthetically manufactured targeting peptides that perform the same function, but without the immune issues.
Types.
There are two forms of contrast-enhanced ultrasound, untargeted (used in the clinic today) and targeted (under preclinical development). The two methods slightly differ from each other.
Untargeted CEUS.
Untargeted microbubbles, such as the aforementioned SonoVue, Optison, or Levovist, are injected intravenously into the systemic circulation in a small bolus. The microbubbles will remain in the systemic circulation for a certain period of time. During that time, ultrasound waves are directed on the area of interest. When microbubbles in the blood flow past the imaging window, the microbubbles’ compressible gas cores oscillate in response to the high frequency sonic energy field, as described in the ultrasound article. The microbubbles reflect a unique echo that stands in stark contrast to the surrounding tissue due to the orders of magnitude mismatch between microbubble and tissue echogenicity. The ultrasound system converts the strong echogenicity into a contrast-enhanced image of the area of interest. In this way, the bloodstream's echo is enhanced, thus allowing the clinician to distinguish blood from surrounding tissues.
Targeted CEUS.
Targeted contrast-enhanced ultrasound works in a similar fashion, with a few alterations. Microbubbles targeted with ligands that bind certain molecular markers that are expressed by the area of imaging interest are still injected systemically in a small bolus. Microbubbles theoretically travel through the circulatory system, eventually finding their respective targets and binding specifically. Ultrasound waves can then be directed on the area of interest. If a sufficient number of microbubbles have bound in the area, their compressible gas cores oscillate in response to the high frequency sonic energy field, as described in the ultrasound article. The targeted microbubbles also reflect a unique echo that stands in stark contrast to the surrounding tissue due to the orders of magnitude mismatch between microbubble and tissue echogenicity. The ultrasound system converts the strong echogenicity into a contrast-enhanced image of the area of interest, revealing the location of the bound microbubbles. Detection of bound microbubbles may then show that the area of interest is expressing that particular molecular marker, which can be indicative of a certain disease state, or identify particular cells in the area of interest.
Applications.
Untargeted contrast-enhanced ultrasound is currently applied in echocardiography and radiology. Targeted contrast-enhanced ultrasound is being developed for a variety of medical applications.
Untargeted CEUS.
Untargeted microbubbles like Optison and Levovist are currently used in echocardiography. In addition, SonoVue ultrasound contrast agent is used in radiology for lesion characterization. 
Advantages.
On top of the strengths mentioned in the medical sonography entry, contrast-enhanced ultrasound adds these additional advantages:
Disadvantages.
In addition to the weaknesses mentioned in the medical sonography entry, contrast-enhanced ultrasound suffers from the following disadvantages: