Enhancement of sonodynamic tissue damage production by second-harmonic superimposition: theoretical analysis of its mechanism

Among the nonthermal effects of ultrasound, acoustic cavitation may have the highest potential for therapeutic applications if it can be somehow controlled. Recent in vitro and in vivo experiments have demonstrated that sonochemically active cavitation can be enhanced an order of magnitude by superimposing the second harmonic onto the fundamental in insonation. Moreover, they have shown that sonochemically active cavitation can be controlled with relative ease, thereby even in a progressive wave field. The effect of second-harmonic superimposition on the rectified diffusion through the gas-liquid interface of cavitated microbubbles is estimated theoretically. The theoretical rectified diffusion rate explained an asymmetric behavior of the threshold for producing sonodynamic tissue damage as a function of the fundamental and the second-harmonic amplitudes. The tissue damage was produced with a focused progressive wave in a liver lobe of a mouse administered with a sonodynamically active agent. The result suggests that the acceleration of the rectified diffusion is a primary mechanism of the enhancement of sonodynamically effective cavitation by second-harmonic superimposition.