Microbubbles in ultrasound-triggered drug and gene delivery

Not all bubbles in the bloodstream are detrimental. During the past decade, contrast-enhanced ultrasound has evolved from a purely investigational tool to a routine diagnostic technique. This transformation has been facilitated by advances in the microbubble contrast agents and contrast-specific ultrasound imaging techniques. The ability to non-invasively image molecular events with targeted microbubbles is likely to be important for characterizing pathophysiology and for developing new therapeutic strategies in the treatment of cardiovascular and neoplastic diseases.

Microbubbles in medical imaging: current applications and future directions.

During the past 25 years, many attempts have been made to establish effective ultrasound contrast agents for both cardiac and noncardiac applications. The ideal ultrasound contrast agent would be: (a) nontoxic; (b) injectable intravenously; (c) capable of passing through the pulmonary, cardiac and capillary circulations; and (d) stable for recirculation. A variety of potential ultrasound contrast agents have been or are now under development. Present and future ultrasound contrast agents should provide for increased diagnostic capabilities in a variety of normal and abnormal vessels and organs throughout the body. These agents will enhance tumor vascularity, delineate areas of ischemia, as well as improve visualization of vascular stenosis. Future developments with modification of ultrasound equipment should increase the capabilities of these agents to improve imaging as well as Doppler sensitivity.

Ultrasound contrast agents: A review

A model for the oscillation of gas bubbles encapsulated in a thin shell has been developed. The model depends on viscous and elastic properties of the shell, described by thickness, shear modulus, and shear viscosity. This theory was used to describe an experimental ultrasound contrast agent from Nycomed, composed of air bubbles encapsulated in a polymer shell. Theoretical calculations were compared with measurements of acoustic attenuation at amplitudes where bubble oscillations are linear. A good fit between measured and calculated results was obtained. The results were used to estimate the viscoelastic properties of the shell material. The shell shear modulus was estimated to between 10.6 and 12.9 MPa, the shell viscosity was estimated to between 0.39 and 0.49 Pas. The shell thickness was 5% of the particle radius. These results imply that the particles are around 20 times more rigid than free air bubbles, and that the oscillations are heavily damped, corresponding to Q-values around 1. We conclude that the shell strongly alters the acoustic behavior of the bubbles: The stiffness and viscosity of the particles are mainly determined by the encapsulating shell, not by the air inside.

Oscillations of polymeric microbubbles: Effect of the encapsulating shell

Background In this work, we report a novel targetable ultrasonic contrast agent with the potential to noninvasively define and localize myriad pathological tissues for diagnosis or therapy. The agent is a biotinylated, lipid-coated, perfluorocarbon emulsion that has low inherent echogenicity unless bound to a surface or itself. Methods and Results In study 1, emulsions with and without biotin were suspended in buffered saline and imaged with a 7.5-MHz linear-array transducer. Neither emulsion manifested significant ultrasonic backscatter until avidin was added. Avidin-induced aggregation produced a marked enhancement in backscatter from the biotinylated but not from the control emulsion. In study 2, porcine fibrin clots in vitro were pretargeted with biotinylated antifibrin monoclonal antibodies and then exposed to avidin and then to biotinylated or control perfluorocarbon emulsions. The basal acoustic reflectivity of clots imaged with a 7.5-MHz linear-array transducer was uniformly low and was increased ...

A Novel Site-Targeted Ultrasonic Contrast Agent With Broad Biomedical Application

Absorption and scatter of encapsulated gas filled microspheres: Theoretical considerations and some measurements

Albunex (Molecular Biosystems Inc (MBI), San Diego, USA and Nycomed Imaging AS, Oslo, Norway) is the first ultrasound contrast agent that is stable enough to show transpulmonary passage. This implies that the contrast agent can be injected intravenously and still give contrast in the left side of the heart. Albunex is made by sonication of a 5% solution of human albumin. This process generates air bubbles encapsulated by a shell of aggregated albumin. The air-filled microspheres have characteristics similar to those of air bubbles in water, with respect to both backscatter and attenuation of the ultrasound signal. Clinical studies have shown that Albunex is a safe product. We have documented the diagnostic efficacy of Albunex for the study of the anatomy and function of the heart, but more research needs to be done to document its diagnostic efficacy for the study of myocardial perfusion and Doppler enhancement. Acoustical properties of Albunex are discussed.

T. Skotland

Papers

Absorption and scatter of encapsulated gas filled microspheres: Theoretical considerations and some measurements

Albunex-a new ultrasound contrast agent