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Vascular Ultrasound Contrast Agents
Vascular ultrasound contrast agents are gas microbubbles with a diameter less than 10 μm (2 to 5 μm on average for most of the newer agents) to pass through the lung capillaries and enter into the systemic circulation. Air bubbles in that size persist in solution for only a short time; too short for systemic vascular use in medical ultrasound imaging. So the gas bubbles have to be stabilized to persist long enough and survive pressure changes in the heart.
Most vascular contrast media are stabilized against dissolution and coalescence by the presence of additional materials at the gas-liquid interface. In some cases, this material is an elastic solid shell that enhances stability by supporting a strain to counter the effect of surface tension. In other cases, the material is a surfactant, or a combination of two or more surfactants.
Typically the effective duration of vascular enhancement is a few minutes, after which the microbubbles dissipate. This rather short duration of vascular enhancement makes it easy to perform repeated dynamic studies. Intravenous vascular contrast agents will be used in imaging malignant tumors in the liver, kidney, ovary, pancreas, prostate, and breast. Tumor neovascularization can be a marker for angiogenesis, and Doppler signals from small tumor vessels may be detectable after contrast injection. Contrast agents are useful for evaluating vessels in a variety of organs, including those involved in renal, hepatic, and pancreatic transplants. If an area of ischemia or a stenosis is detected after contrast administration, the use of other more expensive imaging modalities, including CT and MRI, can often be avoided.

See also Acoustically Active Lipospheres.
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History of Ultrasound
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.
In 1880 the Curie brothers discovered the piezoelectric effect in quartz. Converse piezoelectricity was mathematically deduced from fundamental thermodynamic principles by Lippmann in 1881.
In 1917, Paul Langevin (France) and his coworkers developed an underwater sonar system (called hydrophone) that uses the piezoelectric effect to detect submarines through echo location.
In 1935, the first RADAR system was produced by the British physicist Robert Watson-Wat. Also about 1935, developments began with the objective to use ultrasonic power therapeutically, utilizing its heating and disruptive effects on living tissues. In 1936, Siemens markets the first ultrasonic therapeutic machine, the Sonostat.
Shortly after the World War II, researchers began to explore medical diagnostic capabilities of ultrasound. Karl Theo Dussik (Austria) attempted to locate the cerebral ventricles by measuring the transmission of ultrasound beam through the skull. Other researchers try to use ultrasound to detect gallstones, breast masses, and tumors. These first investigations were performed with A-mode.
Shortly after the World War II, researchers in Europe, the United States and Japan began to explore medical diagnostic capabilities of ultrasound. Karl Theo Dussik (Austria) attempted to locate the cerebral ventricles by measuring the transmission of ultrasound beam through the skull. Other researchers, e.g. George Ludwig (United States) tried to use ultrasound to detect gallstones, breast masses, and tumors. This first experimentally investigations were performed with A-mode. Ultrasound pioneers contributed innovations and important discoveries, for example the velocity of sound transmission in animal soft tissues with a mean value of 1540 m/sec (still in use today), and determined values of the optimal scanning frequency of the ultrasound transducer.
In the early 50`s the first B-mode images were obtained. Images were static, without gray-scale information in simple black and white and compound technique. Carl Hellmuth Hertz and Inge Edler (Sweden) made in 1953 the first scan of heart activity. Ian Donald and Colleagues (Scotland) were specialized on obstetric and gynecologic ultrasound research. By continuous development it was possible to study pregnancy and diagnose possible complications.
After about 1960 two-dimensional compound procedures were developed. The applications in obstetric and gynecologic ultrasound boomed worldwide from the mid 60's with both, A-scan and B-scan equipment. In the late 60's B-mode ultrasonography replaced A-mode in wide parts.
In the 70's gray scale imaging became available and with progress of computer technique ultrasonic imaging gets better and faster.
After continuous work, in the 80's fast realtime B-mode gray-scale imaging was developed. Electronic focusing and duplex flow measurements became popular. A wider range of applications were possible.
In the 90's, high resolution scanners with digital beamforming, high transducer frequencies, multi-channel focus and broad-band transducer technology became state of the art. Optimized tissue contrast and improved diagnostic accuracy lead to an important role in breast imaging and cancer detection. Color Doppler and Duplex became available and sensitivity for low flow was continuously improved.
Actually, machines with advanced ultrasound system performance are equipped with realtime compound imaging, tissue harmonic imaging, contrast harmonic imaging, vascular assessment, matrix array transducers, pulse inversion imaging, 3D and 4D ultrasound with panoramic view.

History of Ultrasound Contrast Agents
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:
first generation USCA = non-transpulmonary vascular;;
second generation USCA = transpulmonary vascular, with short half-life (less than 5 min);
third generation USCA = transpulmonary vascular, with longer half-life (greater than 5 min).

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.
Transesophageal Echocardiography
(TEE) Transesophageal echocardiography provides a superior view of cardiac anatomy compared with transthoracic echocardiography. TEE is performed by the introduction of a probe attached to a fiberoptic endoscope into the esophagus. Caused by the position close to the heart e.g., clot finding and the view of the mitral valve are improved.

Indications:
aortic atherosclerotic disease;
aortic dissection;
artificial mitral valves;
clots inside the left atrium;
cardiac infections;
masses or clots in the heart.

The piezoelectric crystal creating the acoustic power is mounted on the gastroscope that must be swallowed by the patient. This endoscopic transducer is miniaturized to approximately the size of a fingernail. Usually the probe is in place for an average of 15 minutes, to numb the surface a topical anesthetic is sprayed into the throat, in addition a conscious sedation is recommended.

See also Myocardial Contrast Echocardiography, Stress Echocardiogram, M-Mode Echocardiography, Contrast Enhanced Ultrasound and Vascular Ultrasound Contrast Agents.
Acoustically Active Lipospheres
(AALs) Acoustically active lipospheres and ultrasound are under development to deliver bioactive molecules to the vascular endothelium. The AALs are similar to both ultrasound contrast agents and drug-delivering liposomes. They can carry bioactive substances using biologically inert shells and deliver those substances when disrupted by ultrasound.
The lipospheres consist of a small gas microbubble surrounded by a thick oil shell and are enclosed by an outermost lipid layer. The gas bubble contained in these vehicles makes them acoustically active, similar to ultrasound contrast agents. Acoustically active lipospheres can be nondestructively deflected using ultrasound radiation force, and fragmented with high intensity ultrasound pulses. Their lipid-oil complex can carry bioactive substances at high concentrations. An optimized sequence of ultrasound pulses can deflect the AALs toward a vessel wall then disrupt them, painting their contents across the vascular endothelium.

See also Filling Gas, and MRX 115.
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