Ultrasonically imageable bubbles have now been generated in excised canine bladders under conditions which acoustically mimic the in vivo state of the urine. Based on anticipated in vivo bubble generation and a theoretical model for enhanced bubble growth, new approaches to the production and control of bubbles in vivo will be studied to determine methods for controlled generation and detection of bubbles for use as contrast agents and potentially for therapy. Initial studies will be directed toward rapid bubble generation and size assessment in water, with control of cavitation nuclei and gas saturation. We have recently described new techniques utilizing frequency-modulated ultrasound pulses, that should, at relatively low intensities, cause rapid growth of small, resonant bubbles to facilitate their detection at small concentrations within stronger reflections from blood and surrounding tissues. Creation, growth and maintenance of bubbles will be evaluated extensively in water and growth of a short bolus of encapsulated microbubbles will also be investigated. Promising techniques will be tried in urine, contained in freshly-excised organs to maintain in vivo properties. Strategically interwoven with the generation and growth studies will be development of methods for detecting and analyzing the bubble generation and growth, while minimizing the chance of bubble collapse. Most detection methods will be specific for echoes from bubbles. Experimental apparatus developed initially will be modified for limited demonstrations of controlled generation of bubbles in vivo. Bubbles will be generated in the collecting system, ureter, and in the urinary bladder (a relatively easy site suitable for evaluation of reflux and as part of a possible diagnostic test for interstitial cystitis). Current medical marketing estimates are that ultrasound equipment sales in dollars and numbers of procedures will exceed those of any other imaging modality in the early to mid 1990's. Short boluses of bubbles produced at will, or regrown from orally-introduced or intravenously injected cavitation nuclei, should comprise a relatively low cost, but very diverse and powerful new tool for medical care. There should be indirect benefits as well in terms of increased knowledge of methods to suppress undesired cavitation in routine and other enhanced ultrasound diagnostic procedures. While selective generation and tracking of bubbles throughout the urinary and vascular systems, as a hopefully noninvasive, dynamic, ultrasound contrast agent, is an impressive goal, the list of potential applications from this project is even broader than might be expected.
