Microbubbles filled with air or inert gases are used as contrast agents in ultrasound imaging. Compression and rarefaction created by an ultrasound wave insonating a gas-filled microbubble along with the mechanical index of the ultrasonic beam lead to volume pulsations of the bubbles, and it is this change that results in the signal enhancement.
Microbubbles have diameters from 1 μm to 10 μm and a thin flexible or rigid shell composed of albumin, lipid, or polymer confining a gas such as nitrogen, or a perfluorocarbon. These microbubbles can cross the pulmonary capillaries and have a serum half-life of a few minutes. Microbubbles in the 1-10 μm range have their resonance at the frequencies used in diagnostic ultrasound (1−15MHz). Smaller bubbles resonate at higher frequencies. Caused by this coincidence, they are such effective reflectors.
The intrinsic compressibility of microbubbles is approximately 17,000 times more than water, and they are very strong scatterers of ultrasound. Under acoustic pressure the vibrating bubble radius may have a conventional linear response or a harmonic non-linear response. Microbubbles usually increase the Doppler signal amplitude by up to 30 dB.

(UCA / USCA) Ultrasonography is the most commonly performed diagnostic imaging procedure. The introduction of sonographic contrast media into routine practice modifies the use of ultrasound in a variety of clinical applications. USCAs consist of microbubbles filled with air or gases and can be classified according to their pharmacokinetics. Among the blood pool agents, transpulmonary ultrasound contrast agents offer higher diagnostic potential compared to agents that cannot pass the pulmonary capillary bed after a peripheral intravenous injection. In addition to their vascular phase, some USCAs can exhibit a tissue- or organ-specific phase.
The sonogram image quality is improved either by decreasing the reflectivity of the undesired interfaces or by increasing the backscattered echoes from the desired regions.

Different types of ultrasound contrast agents:
Ultrasound contrast agents act as echo-enhancers, because of the high different acoustic impedance at the interface between gas and blood. The enhanced echo intensity is proportional to the change in acoustical impedance as the sound beam crosses from the blood to the gas in the bubbles.

The ideal qualities of an ultrasound contrast agent:
A typical ultrasound contrast agent consists of a thin flexible or rigid shell composed of albumin, lipid, or polymer confining a gas such as nitrogen, or a perfluorocarbon. The choice of the microbubble shell and gas has an important influence on the properties of the agent.
Current generations of microbubbles have a diameter from 1 μm to 5 μm. The success of these agents is mostly dependent on the small size and on the stability of their shell, which allows passage of the microbubbles through the pulmonary circulation. Microbubbles must be made smaller than the diameter of capillaries or they would embolize and be ineffective and perhaps even dangerous.
The reflectivity of these microbubbles is proportional to the fourth power of a particle diameter but also directly proportional to the concentration of the contrast agent particles themselves.
Ultrasound contrast agents produce unique acoustic signatures that allow to separate their signal from tissue echoes and to depict whether they are moving or stationary. This enables the detection of capillary flow and of targeted microbubbles that are retained in tissues such as normal liver.
The new generation of contrast media is characterized by prolonged persistence in the vascular bed which provides consistent enhancement of the arterial Doppler signal. Contrast agents make it also possible to perform dynamic and perfusion studies. Targeted contrast imaging agents are for example taken up by the phagocytic cell systems and thus have liver/spleen specific effects.

See also Ultrasound Contrast Agent Safety, Adverse Reaction, Tissue-Specific Ultrasound Contrast Agent, and Bubble Specific Imaging.

Contrast microbubbles can be destroyed by intense ultrasound and the scattered signal level can increase abruptly for a short time during microbubble destruction, resulting in an acoustical flash (sudden increase in echogenicity).
Intermittent imaging with high acoustic output utilizes the properties of contrast microbubbles to improve blood-to-tissue image contrast by imaging intermittently at very low frame rates.
The frame rate is usually reduced to about one frame per second, or it is synchronized with cardiac cycles so that enough contrast microbubbles can flow into the imaging site where most microbubbles have been destroyed by the previous acoustic pulse. Because bubbles are destroyed by ultrasound, controlling the delay time between frames produces images whose contrast emphasizes regions with rapid blood flow rate or regions with high or low blood volume.

Standard scanners allow visualizing microbubbles on conventional gray scale imaging in large vascular spaces. In the periphery, more sensitive techniques such as Doppler or non-linear gray scale modes must be used because of the dilution of the microbubbles in the blood pool. Harmonic power Doppler (HPD) is one of the most sensitive techniques for detecting ultrasound contrast agents.
Commonly microbubbles are encapsulated or otherwise stabilized to prolong their lifetime after injection. These bubbles can be altered by exposure to ultrasound pulses. Depending on the contrast agent and the insonating pulse, the changes include deformation or breakage of the encapsulating or stabilizing material, generation of free gas bubbles, reshaping or resizing of gas volumes.
High acoustic pressure amplitudes and long pulses increase the changes. However, safety considerations limit the pressure amplitude and long pulses decrease spatial resolution. In addition, lowering the pulse frequency increases destruction of contrast bubbles. However, at low insonation power levels, contrast agent particles resist insonation without detectable changes. Newer agents are more reflective and will usually allow gray scale imaging to be used with the advantages of better spatial resolution, fewer artifacts and faster frame rates.

Feasible imaging methods with advantages in specific acoustic microbubble properties:
Resonating microbubbles emit harmonic signals at double their resonance frequency. If a scanner is modified to select only these harmonic signals, this non-linear mode produces a clear image or trace. The effect depends on the fact that it is easier to expand a bubble than to compress it so that it responds asymmetrically to a symmetrical ultrasound wave. A special array design allows to perform third or fourth harmonic imaging. This probe type is called a dual frequency phased array transducer.

See also Bubble Specific Imaging.

From Bracco Diagnostics, Inc.
SonoVue® was first launched in October 2001 and is now available in all European countries.
SonoVue is a second generation USCA, designed and optimized with regard to the resistance to pressure. SonoVue is an example of an important family of microbubbles whose membrane consists of phospholipids. SonoVue microbubbles are filled with sulfur hexafluoride (SF6), a gas which has a low solubility and diffuses slowly in blood for the gaseous phase of the microbubbles.
In particular, the SonoVue microbubbles, thanks to the high flexibility of their shell, are strongly echogenic in a wide range of frequencies and acoustic pressure and therefore can be used with both destructive and conservative contrast bubble specific imaging methods.

See also Coherent Contrast Imaging.