Submicron ultrasound contrast agents are gas-filled, double-walled microspheres with a diameter smaller than 1 μm that rupture when exposed to ultrasound energy at megahertz frequencies. These agents differ from traditional ultrasound contrast microbubbles in that the submicron bubbles may serve as extravascular agents. They are small enough to travel through the lymphatic system and to be extravasated from tumor neovasculature. The detection of these agents is limited by their hard shell, which requires high-pressure ultrasound insonation for shell rupture and excitation of the gas bubble. After shell rupture, the gas diffuses rapidly from submicron sized agents. The optimal processing of each echo is important.

The earliest introduction of vascular ultrasound contrast agents (USCA) was by Gramiak and Shah in 1968, when they injected agitated saline into the ascending aorta and cardiac chambers during echocardiographic to opacify the left heart chamber. Strong echoes were produced within the heart, due to the acoustic mismatch between free air microbubbles in the saline and the surrounding blood.
The disadvantage of this microbubbles produced by agitation, was that the air quickly leak from the thin bubble shell into the blood, where it dissolved. In addition, the small bubbles that were capable of traversing the capillary bed did not survive long enough for imaging because the air quickly dissipated into the blood. Aside from agitated saline, also hydrogen peroxide, indocyanine green dye, and iodinated contrast has been tested. The commercial development of contrast agents began in the 1980s with greatest effort to the stabilization of small microbubbles.

The development generations by now:
To pass through the lung capillaries and enter into the systemic circulation, microspheres should be less than 10 μm in diameter. Air bubbles in that size range persist in solution for only a short time; too short for systemic vascular use.
The first developed agent was Echovist (1982), which enabled the enhancement of the right heart. The second generation of echogenic agents, sonicated 5% human albumin-containing air bubbles (Albunex), were capable of transpulmonary passage but often failed to produce adequate imaging of the left heart. Both Albunex and Levovist utilize air as the gas component of the microbubble.
In the 1990s newer developed agents with fluorocarbon gases and albumin, surfactant, lipid, or polymer shells have an increased persistence of the microspheres. This smaller, more stable microbubble agents, and improvements in ultrasound technology, have resulted in a wider range of application including myocardial perfusion.

See also First Generation USCA, Second Generation USCA, and Third Generation USCA.

Tissue-specific ultrasound contrast agents improve the image contrast resolution through differential uptake. The concentration of microbubble contrast agents within the vasculature, reticulo-endothelial, or lymphatic systems produces an effective passive targeting of these areas. Other contrast media concepts include targeted drug delivery via contrast microbubbles.
Tissue-specific ultrasound contrast agents are injected intravenously and taken up by specific tissues or they adhere to specific targets such as venous thrombosis. These effects may require minutes to several hours to reach maximum effectiveness. By enhancing the acoustic differences between normal and diseased tissues, these tissue-specific agents improve the detectability of abnormalities.
Some microbubbles accumulate in normal hepatic tissue; some are phagocytosed by Kupffer cells in the reticuloendothelial system and others may stay in the sinusoids. Liver tumors without normal Kupffer cells can be identified by the lack of the typical mosaic color pattern of the induced acoustic emission. The hepatic parenchymal phase, which may last from less than an hour to several days, depending on the specific contrast medium used, may be imaged by bubble-specific modes such as stimulated acoustic emission (color Doppler using high MI) or pulse inversion imaging.

Targeted ultrasound contrast agents provide advantages compared with usual microbubble blood pool agents. The goal of targeted ultrasound contrast agents is to significantly and selectively enhance the detection of a targeted vascular site. Tissue-specific ultrasound contrast agents improve the image contrast resolution through differential uptake. Targeted drug delivery via contrast microbubbles is another contrast media concept and provides the potential for earlier detection and characterization of disease.
Targeted contrast imaging provides a higher sensitivity and specificity than obtained with a nontargeted contrast agent.
The detection of disease-indicative molecular signatures may allow early assessment of pathology on a molecular level.
Molecular imaging should be an efficient and less invasive technique to obtain three-dimensional localization of pathology.
Ultrasound agents typically remain within the vascular space, and therefore possible targets include molecular markers on thrombus, endothelial cells, and leukocytes. Targeted contrast agents permit noninvasive detection of thrombus, cancer, inflammation, or other sites where specific integrins or other adhesion molecules are expressed. Adhesion molecules such as monoclonal antibodies, peptides, asialoglycoproteins, or polysaccharides are incorporated into the shell of the microbubble or liposome. After injection into the bloodstream, the targeted agent accumulates via adhesion receptors at the affected site, enhancing detection with an ultrasound system.

See also Acoustically Active Lipospheres, and Tissue-Specific Ultrasound Contrast Agent.

(CEUS) Contrast agents increase the reflection of ultrasonic energy, improve the signal to noise ratio and caused by that the detection of abnormal microvascular and macrovascular disorders. Contrast enhanced ultrasound is used in abdominal ultrasound (liver sonography) as well as in cerebrovascular examinations e.g., for an accurate grading of carotid stenosis. The used contrast agents are safe and well tolerated.

The quality of the enhancement depends on:
The additional use of ultrasound contrast agents (USCAs) may overcome typical limitations like poor contrast of B-mode imaging or limited sensitivity of Doppler techniques. The development of new ultrasound applications (e.g., blood flow imaging, perfusion quantification) depends also from the development of pulse sequences for bubble specific imaging. In addition, contrast enhanced ultrasound improves the monitoring of ultrasound guided interventions like RF thermal ablation.

See also Contrast Enhanced Doppler Imaging, Contrast Harmonic Imaging, Contrast Imaging Techniques and Contrast Pulse Sequencing.