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.

The company is a member of the Bracco Group, a highly innovative health care group and world leader in global integrated solutions for the diagnostic imaging field. The Bracco Group is headquartered in Milan, Italy. Its North American operations consist of Bracco Diagnostics and Bracco Research USA, both located in Princeton, New Jersey. Bracco Diagnostics is one of the fastest growing developers and marketers of diagnostic pharmaceuticals in North America, with products for various imaging applications, including Isovue® (iopamidol) X-ray contrast agent, ProHance®, (gadoteridol), MRI contrast agent, and nuclear medicine products.
Gadoteridol has been available in Europe and the USA for several years. Holder of the Marketing Authorization: Bracco International B.V. - Strawinskylaan 3051 - 1077 ZX Amsterdam The Netherlands. (Contact: Kirk Deeter, Phone: +NL-303-838-8708)

The Bracco Group is the world's leading provider of global diagnostic imaging solutions, with net sales of more than 1 billion euro, of which more than 64% from international sales; it has operations in 115 countries and about 3,500 employees, of whom more than 600 work in R&D. Bracco invests around 15% of its turnover in R&D and has a portfolio of 1,500 patents worldwide. The Bracco Group deploys an integrated approach to diagnostic imaging, with an offer that encompasses contrast media, its core business where it is one of the world's top players, biomedical equipment from Esaote, one of the world's primary producers of magnetic resonance and ultrasonographic medical equipment, contrast media delivery systems from Acist Medical Systems, a top US company in advanced contrast media injection systems, and medical application software from EBIT-AET and Singapore's Volume Interactions, the leading developer of advanced medical software. Bracco has formed a high-level international research network, whose three centers in Milan, Geneva and Princeton study and develop products for the latest-generation diagnostic techniques, from X-rays and computerized axial tomography to magnetic resonance and echo contrast.

Ultrasound Contrast Agents:

EchoGen® is a fluorocarbon-based (dodecafluoropentane) third generation USCA. EchoGen® consists of microbubbles stabilized with surfactants in a phase shift colloid emulsion (perflenapent). EchoGen® requires no preparation, reconstitution, or refrigeration.
Perflenapent emulsion would represent a significant advance in contrast echocardiography caused by effective and long lasting opacification of the left ventricle and enhanced endocardial border delineation.
The persistence of the contrast effect permits interrogation in multiple echocardiographic views, as well as the visualization and localization of myocardial perfusion deficits at rest by producing a negative contrast effect.
October 12, 2000
Sonus Pharmaceuticals, Inc. announced a strategic decision to refocus the Company on the development of its drug delivery and blood substitute products. At the same time, Sonus has withdrawn the NDA (New Drug Application) and discontinued clinical activity for its ultrasound contrast product, EchoGen®.
August 06, 2001
Sonus Pharmaceuticals, Inc. announced that it has entered into an agreement to sell its ultrasound contrast assets for $6.5 million to Amersham plc. As part of the agreement, Sonus has also assigned to Nycomed its interest in the ultrasound contrast patent license agreement entered into with Chugai Pharmaceutical Co. Ltd. and Molecular Biosystems Inc in January 2001.