DIAGNOSITIC ULTRASOUND CONTRAST AGENTS--DEVELOPMENT AND EVALUATION

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Diagnostic ultrasound offers many advantages over other diagnostic techniques, specifically safety, portability, acquisition of real time images, and relatively low cost. Despite great advances, primarily improvements in signal processing techniques such as gray scale imaging and color Doppler, there remain areas where improved image contrast would be of great benefit. These include differentiation of soft tissue in metastases in organs such as the liver, kidney and breast, imaging of cavities such as blood vessels and the heart, and tissue perfusion. The long term objective of this work is to develop diagnostic ultrasound contrast agents that will fulfill the needs of the medical community by improving the contrast of ultrasound images. In addition we hope to introduce contrast agent targeting and to facilitate implementation and use of the second harmonic. Development of an agent demonstrating a strong second harmonic would be highly advantageous in this new imaging area. Specifically, the work will continue to evolve in two complementary, parallel directions which are: Further characterization and improvement of a dual surfactant-stabilized micro-bubble system, and development and characterization of an new agent based on the bioerodible polymer, poly-L- lactide-co-glycolide (PLGA), which was started in the first granting period. Both areas will include in vitro and in vivo investigations. Specific aim 1: Identification of the molecular forces which are acting to stabilize the surfactant-stabilized agent and development of a model for the molecular arrangement of the surfactants around the gas bubble. Experimental design will include infra red analysis of Langmuir-Blodgett films of the dual surfactant mixtures and gas chromatographic analysis of agent to determine whether the sonication step used in the fabrication of the agent causes any chemical changes. The results from these studies will be used to identify new surfactants. Specific aim 2: Extensive characterization of the polymer-based agent. This will include studying the effects of fabrication parameters on the microcapsule mean size, size distribution, and wall thickness using Coulter analysis and scanning electron microscopy. Specific aim 3: In vitro acoustic characterization of both agents to optimize the acoustic properties. measured parameters will include back- scatter and attenuation and second harmonic analysis. Specific aim 4: In vivo characterization of both agents including dose response, attenuation back-scatter and Doppler enhancement and a study of second harmonic imaging in rabbit, and cardiac imaging in dog.