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.

[This entry is marked for removal.]

From POINT Biomedical Corp
BiSphere™ is a technology for drug delivery applications by ultrasound. BiSpheres™ consists of microparticles comprising a shell of an outer layer of a biologically compatible material and an inner layer of biodegradable polymer. The core of the microbubbles contains a filling gas, liquid, or solid for use in drug delivery or as a contrast agent for ultrasonic contrast imaging. The contrast agent particles are capable of passing through the capillary systems of a subject. The drug-loaded biSpheres™ would be administered intravenously and freely circulate throughout the body, while the drug encapsulated within would remain biologically unavailable. The drug would only be released when the biSpheres become flooded when passing through an externally directed ultrasound field.
The use of biSpheres™ to transport agents to specific sites within the body is expected to substantially increase local efficacy while decreasing systemic side effects or adverse reactions. The biSpheres™ may also serve to protect labile agents from metabolism or degradation. The noninvasive release of a protected, encapsulated agent can be controlled by ultrasound imaging to a depth of 20-30 cm from the skin surface.
The flexibility in size control in the biSphere™ technology has enabled the construction of submicron ultrasound contrast agents suitable for lymphatic imaging, with a diameter in the submicron range. This agent, while much smaller in size than CardioSphere®, is based on the BiSphere configuration: a shell within a shell enclosing a gas. The inner layer, made from a biodegradable polymer, provides the physical structure and controls the acoustic response. The outer layer functions as the biological interface. Each of these layers has been independently tailored to fulfill the specific requirements for lymphatic imaging.

From Bayer Schering Pharma AG:
Available in Europe since 1996 and in Japan since 1999. Currently, the marketing situation is unclear.
Levovist® is a first generation USCA consisting of galactose (milk sugar) ground into tiny crystals whose irregular surfaces act as nidation sites on which air pockets form when it is suspended in water, much as soda water bubbles form at small irregularities on the surface of the glass. A trace of palmitic acid is added as a surfactant to stabilize the resultant microbubbles. When Levovist® dissolves in blood, air trapped inside the galactose is released as free gas bubbles. These bubbles have a weak encapsulating shell and are easily destroyed by ultrasound.
Different contrast ultrasonography methods have been developed since the introduction of Levovist®. Initially, Levovist® was an echo contrast medium for improving sensitivity in color Doppler and Power Doppler examinations, but was found to suffer from significant blooming, making it difficult to observe small blood vessels. However, Levovist® improves the accuracy of echocardiographic examinations in such indications as assessment of left ventricular function.
In addition to their vascular phase, some ultrasound contrast agents (USCAs) can exhibit a tissue- or organ-specific phase. Levovist® can accumulate within the liver and the spleen for up to 20 min once it has disappeared from the blood pool and improves the detectability of focal liver lesions and allows more reliable control of interventional tumor treatments. Varied types of information can be obtained by applying contrast imaging at different times after the injection using Levovist® in both the arterial phase and the late organ-specific phase.
1 g Levovist® granules contain 999 mg D-galactose and 1 mg palmitic acid.
Brand names in other countries: Levovist/Levograf

(MI) The mechanical index is an estimate of the maximum amplitude of the pressure pulse in tissue. It is an indicator of the likelihood of mechanical bioeffects (streaming and cavitation). The mechanical index of the ultrasound beam is the amount of negative acoustic pressure within a ultrasonic field and is used to modulate the output signature of US contrast agents and to incite different microbubble responses.
The mechanical index is defined as the peak rarefactional pressure (negative pressure) divided by the square root of the ultrasound frequency.
The FDA ultrasound regulations allow a mechanical index of up to 1.9 to be used for all applications except ophthalmic (maximum 0.23). The used range varies from 0.05 to 1.9.
At low acoustic power, the acoustic response is considered as linear. At a low MI (less than 0.2), the microbubbles undergo oscillation with compression and rarefaction that are equal in amplitude and no special contrast enhanced signal is created. Microbubbles act as strong scattering objects due to the difference in impedance between air and liquid, and the acoustic response is optimized at the resonant frequency of a microbubble.
At higher acoustic power (MI between 0.2-0.5), nonlinear oscillation occurs preferentially with the bubbles undergoing rarefaction that is greater than compression. Ultrasound waves are created at harmonics of the delivered frequency. The harmonic response frequencies are different from that of the incident wave (fundamental frequency) with subharmonics (half of the fundamental frequency), harmonics (including the second harmonic response at twice the fundamental frequency), and ultra-harmonics obtained at 1.5 or 2.5 times the fundamental frequency. These contrast enhanced ultrasound signals are microbubble-specific.
At high acoustic power (MI greater than 0.5), microbubble destruction begins with emission of high intensity transient signals very rich in nonlinear components. Intermittent imaging becomes needed to allow the capillaries to be refilled with fresh microbubbles. Microbubble destruction occurs to some degree at all mechanical indices. A mechanical index from 0.8 to 1.9 creates high microbubble destruction. The output signal is unique to the contrast agent.

Any abnormal reaction of a patient to an examination or procedure, like for example side effects of contrast agents or claustrophobia. Claustrophobic attacks as can happen with MRI are unknown with ultrasound examinations. Adverse reactions with ultrasonic contrast agents are very infrequent. In general, adverse reactions increase with the quantity of contrast media and also with the osmolarity of the compound.
Most frequently encountered adverse reactions are: Heat sensation, dizziness, nausea, hypotension due to vasodilatation, which can progress to hypotensive shock and anaphylactic reactions.