(CAP) Contrast agent particles are filled with gas and coated by a shell. The reflectivity of a particle increases with the diameter. The used particles are too large to cross the endothelium, so that there is no interstitial phase of enhancement. They are essentially markers for the blood pool and their distribution is similar to those of tagged red cells. In addition, any body cavity that can be accessed can be injected with vascular contrast.

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From Acusphere Inc
AI-700 (trade name Imagify™) is an US contrast agent, usable for myocardial perfusion undergoing regulatory FDA approval. The synthetic polymers used in AI-700 (perflubutane polymer microspheres) do not break during the ultrasound imaging procedure. The used perfluorocarbon filling gas is less soluble in water and therefore has the propensity to stay inside the contrast agent particles. As a result, a higher concentration of gas is delivered to the myocardium over a longer period of time, thereby enabling AI-700 to target the broader application of myocardial perfusion assessment.
Imagify is a dry powder consisting of small, porous microparticles filled with perfluoropropane. These microparticles are made of a synthetic biodegradable polymer, called poly (D, L-lactide co-glycolide), or PLGA, that has been used in other drug delivery systems approved by the FDA.
The composition and structure of the phospholipid containing microparticles and the properties of the perfluorocarbon gas slow the rate at which the gas dissolves and prevent the microparticles from being quickly broken down. The powder is to suspend in sterile water and injected by a single intravenous injection prior to ultrasound imaging.

In 2009, Acusphere Inc received feedback from the Food and Drug Administration (FDA) to their New Drug Application (NDA) stating that another clinical trial would be required for U.S. approval, this one demonstrating that Imagify with ultrasound is superior to ultrasound without Imagify.
In June 2004, Acusphere entered into a Collaboration, License and Supply Agreement with Nycomed Danmark APS for the European development and marketing rights to Acusphere's lead product candidate AI-700.
Acusphere's focus will be on preparing the Marketing Authorization Application (MAA) for filing in Q4 2010, building upon the work that the previous partner, Nycomed, had done, in concert with the NDA.


In 2008 the FDA panel rejected the regulatory application for AI-700 (Imagify™) because of safety concerns.

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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.

Ultrasound enhancement is the increase in reflection amplitude from objects that lie behind a weakly attenuating structure. Contrast agent particles enhance the reflectivity of blood.
The enhancement artifact may occur in structures below a cyst.

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.