Contrast-enhanced ultrasound

Contrast-enhanced ultrasound (CEUS) is the application of

There are a variety of microbubble contrast agents. Microbubbles differ in their shell makeup, gas core makeup, and whether or not they are targeted.^[citation needed]

• Microbubble shell: selection of shell material determines how easily the microbubble is taken up by the
  Hydrophobic particles have also been applied to stabilize microbubble shells.^[5]
• Microbubble gas core: The gas core is primary part of the ultrasound contrast microbubble that determines its echogenicity. Gas bubbles that are subjected to ultrasound pulsate and scatter a characteristic signal. This signal manifests itself as a high-amplitude entity in a contrast-enhanced sonogram. Gas cores can be composed of
  perfluorocarbon, or nitrogen.^[4] Heavy gases are less water-soluble so they are less likely to leak out from the microbubble leading to microbubble dissolution.^[3] As a result, microbubbles with heavy gas cores last longer in circulation. To increase harmonic pulsation behavior, liquid and solid cores have been added to the gas contents.^[6]

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.

Specific agents

• Perflutren lipid microspheres (brand names Definity, Luminity) are
  lipid shell.^[7][8]
• Octafluoropropane gas core with an albumin shell (Optison) is another
  GE Healthcare
  ).
• Sulphur hexafluoride microbubbles (SonoVue Bracco (company)). It is mainly used to characterize liver lesions that cannot be properly identified using conventional (b-mode) ultrasound. It remains visible in the blood for 3 to 8 minutes, and is expired by the lungs.^[9]
• Air within a lipid/galactose shell (formerly Levovist, an FDA-approved microbubble that was made by Schering).^[4]
• Perflexane lipid microspheres (formerly Imagent or Imavist) was an injectable suspension developed by Alliance Pharmaceutical approved by the FDA (in June 2002) for improving visualization of the left ventricular chamber of the heart, the delineation of the endocardial borders in patients with suboptimal echocardiograms. Beside its use to assess cardiac function and perfusion it is also used as an enhancer of the images of prostate, liver, kidney and other organs.^[10]

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

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.^[12] 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.^{[citation needed]}

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^[13] ultrasound contrast agent is used in radiology for lesion characterization.

• Organ Edge Delineation: microbubbles can enhance the contrast at the interface between the tissue and blood. A clearer picture of this interface gives the clinician a better picture of the structure of an organ. Tissue structure is crucial in echocardiograms, where a thinning, thickening, or irregularity in the heart wall indicates a serious heart condition that requires either monitoring or treatment.
• Blood Volume and Perfusion: contrast-enhanced ultrasound holds the promise for (1) evaluating the degree of blood perfusion in an organ or area of interest and (2) evaluating the blood volume in an organ or area of interest. When used in conjunction with
  Doppler ultrasound, microbubbles can measure myocardial flow rate to diagnose valve problems. And the relative intensity of the microbubble echoes^[14]
  can also provide a quantitative estimate on blood volume.
• Lesion Characterization: contrast-enhanced ultrasound plays a role in the differentiation between benign and malignant focal liver lesions. This differentiation relies on the observation[15] or processing^[16][17] of the dynamic vascular pattern in a lesion with respect to its surrounding tissue parenchyma.

Targeted CEUS

• leukocytes
  :
  • The inflamed blood vessels specifically express certain receptors, functioning as
    cell adhesion molecules, like VCAM-1, ICAM-1, E-selectin. If microbubbles are targeted with ligands that bind these molecules, they can be used in contrast echocardiography to detect the onset of inflammation. Early detection allows the design of better treatments. Attempts have been made to outfit microbubbles with monoclonal antibodies that bind P-selectin, ICAM-1, and VCAM-1,^[4] but the adhesion to the molecular target was poor and a large fraction of microbubbles that bound to the target rapidly detached, especially at high shear stresses of physiological relevance.^[18]
  • biomimicry of the leukocyte's selectin-integrin cell arrest system,^[22]
    having shown an increased adhesion efficiency, but yet not efficient enough to allow clinical use of targeted contrast-enhanced ultrasound for inflammation.
• Microbubbles can be conjugated to a recombinant single-chain variable fragment specific for activated glycoprotein IIb/IIIa (GPIIb/IIIa), which is the most abundant platelet surface receptor. Despite the high shear stress at the thrombus area, the GPIIb/IIIa-targeted microbubbles will specifically bind to activated platelets and allow real-time molecular imaging of thrombosis, such as in myocardial infarction, as well as monitoring success or failure of pharmacological thrombolysis.^[23]
• Cancer: cancer cells also express a specific set of receptors, mainly receptors that encourage angiogenesis, or the growth of new blood vessels. If microbubbles are targeted with ligands that bind receptors like VEGF or activated glycoprotein IIb/IIIa, they can non-invasively and specifically identify areas of cancers.^[24]
• VCAM-1) have been employed to deliver miR126 in a preclinical setting to stop the development of AAA in vivo.^[25]
• Drug Delivery: drugs can be incorporated into the microbubble's lipid shell. The microbubble's large size relative to other drug delivery vehicles like
  liposomes may allow a greater amount of drug to be delivered per vehicle. By targeted the drug-loaded microbubble with ligands that bind to a specific cell type, microbubble will not only deliver the drug specifically, but can also provide verification that the drug is delivered if the area is imaged using ultrasound.^[26] Ultrasound-guided drug delivery has been successfully applied in the treatment of pancreatic cancer.^[27][28]