Cavitation at the cellular scale - or microcavitation - has been implicated as a potential biological risk to the patient, analogous to low level ionizing radiation. Cavitation can be caused by acoustic waves of relatively low energy density which can create a small, but very high concentration of energy in the form of a collapsing bubble. The energy of a single bubble collapse has been estimated to be, in the units of ionizing radiation, on the order of 300 million electron volts, deposited in a region the size of the cell nucleus. Theoretical estimates of the acoustic conditions to produce such bubbles fall in the range of some diagnostic ultrasound equipment, yet clinical confirmation of this possibility has been absent, either because experimental methods have been too insensitive to cellular activity on a spatial scale of one micron and on a temporal scale of a microsecond, or because the theoretical estimates include assumptions that do not obtain in vivo. The work outlined in this proposal continues our earlier experimental and theoretical work, extending it to a) more sensitive systems of cavitation detection, b) more clinically relevant fluids (e.g. blood, amniotic fluid, aqueous and vitreous humor - which have a range of viscosities), c) more comprehensive theoretical models for bubble inception and action, d) a closer look at the interaction of ultrasound with biological membranes - in the presence and absence of free radical scavengers, and e) to high pulse amplitude systems (such as in Extracorporal Shock Wave Lithotripters) that can induce cavitation in vivo. Our quantitative results with active and passive cavitation detection reveal a new and valuable perspective with regard to the likelihood of deleterious effects from cavitation induced by diagnostic ultrasound: In particular, the preoccupation with the question of whether cavitation occurs is replaced with the more realistic questions of how often it occurs and with what consequences. Moreover, the size of cavitation nuclei appears to be of relatively small importance compared to the number and concentration of nuclei, which appears to be an extremely small fraction of the """"""""particles"""""""" that are exposed to the diagnostic ultrasound beam. Whereas gas saturation effects also appear of relatively small importance, the visco-elastic characteristics of the biological environment play a much greater role in determining the potential location, inception, and violence of cavitation. The extension of this work to biological fluids and clinical instrumentation should provide definitive evidence on these questions and thus provide a basis on which to assess quantitatively the risk from diagnostic ultrasound.
