This is a revised proposal to develop and evaluate controlled generation of arterial microbubbles using intense, focused ultrasound pulses for possible diagnostic and therapeutic use. Since the previous submission, arterial microbubbles have been generated in flowing whole blood in vitro with 725 kHz ultrasound passing through canine tissues simulating human transcutaneous generation. Threshold intensities observed in blood were 2.3 times less than at the previous 1.8 MHz and temperature rise on realistically-placed vertebral bone was acceptable. Short boluses of ultrasonically imageable, less than 40 micron bubbles, generated in selected arteries, should be usable for diagnosis and monitoring of those vascular and perfusion abnormalities which currently are evaluated more slowly and expensively, and probably more invasively, with MRI or with angiography requiring arterial catheterization. Sparse distributions of 20 to 40 micron bubbles should be usable to refocus ultrasound beams for high resolution imaging through aberrating overlying tissues, even for imaging through the skull. The first and most certain medical use of bolus generation is expected to be identification of feeder arteries to therapeutic targets such as tumors and arterio-venous malformations. Coagulation of the feeder arteries, or thrombus generated by repeated, more extensive boluses, will occlude the target for safer, more effective ultrasound or chemical therapy or surgery. Knowledge of ultrasonic fields which produce vascular microbubbles of negligible damage up to vascular occlusion will help improve guidelines for safe diagnostic and therapeutic ultrasound. Bubbles will be produced and characterized under various conditions directed to the above goals. Studies will include bubble size distributions, constituents and longevity with and without contrast agent seeding and at two or more ultrasound frequencies, pulse amplitudes and durations and blood velocities. Current success at bolus production in exposed arteries with minimal arterial wall damage apparently is due to focusing within the vessel. Lower frequencies and other techniques will be utilized for desired bubble generation with lower thermal and cavitational damage, even, possibly, in smaller, deeper vessels where luminal containment of the focus is not possible. In vivo studies will be performed initially on the cerebral vasculature, as there is a good chance of success and the brain is the most sensitive and best studied major organ for arterial gas damage, albeit at volumes 750,000 times the minimum ultrasonically imageable volume. Neurologic diagnosis and treatment is in need of better techniques and, finally, transcutaneous arterial generation will be easiest in the carotid. Generation of the two types of diagnostic carotid boluses is planned in animal models for verification of thresholds, demonstration of intracranial imaging and initial evaluation of possible adverse effects demonstrable by optical histology, colored microspheres and autoradiography. Demonstration of feeder artery delineation for lesion treatment by vascular occlusion will be performed in the canine thyroid vasculature.
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