Overview of experimental studies of biological effects of medical ultrasound caused by gas body activation and inertial cavitation

Ultrasound exposure can induce bioeffects in mammalian tissue by the nonthermal mechanism of gas body activation. Pre-existing bodies of gas may be activated even at low-pressure amplitudes. At higher-pressure amplitudes, violent cavitation activity with inertial collapse of microbubbles can be generated from latent nucleation sites or from the destabilization of gas bodies. Mechanical perturbation at the activation sites leads to biological effects on nearby cells and structures. Shockwave lithotripsy was the first medical ultrasound application for which significant cavitational bioeffects were demonstrated in mammalian tissues, including hemorrhage and injury in the kidney. Lithotripter shockwaves can also cause hemorrhage in lung and intestine by activation of pre-existing gas bodies in these tissues. Modern diagnostic ultrasound equipment develops pressure amplitudes sufficient for inertial cavitation, but the living body normally lacks suitable cavitation nuclei. Ultrasound contrast agents (UCAs) are suspensions of microscopic gas bodies created to enhance the echogenicity of blood. Ultrasound contrast agent gas bodies also provide nuclei for inertial cavitation. Bioeffects from contrast-aided diagnostic ultrasound depend on pressure amplitude, UCA dose, dosage delivery method and image timing parameters. Microvascular leakage, capillary rupture, cardiomyocyte killing, inflammatory cell infiltration, and premature ventricular contractions have been reported for myocardial contrast echocardiography with clinical ultrasound machines and clinically relevant agent doses in laboratory animals. Similar bioeffects have been reported in intestine, skeletal muscle, fat, lymph nodes and kidney. These microscale bioeffects could be induced unknowingly in diagnostic examinations; however, the medical significance of bioeffects of diagnostic ultrasound with contrast agents is not yet fully understood in relation to the clinical setting.