Therapeutic ultrasound strategies that harness the mechanical activity of cavitation nuclei for beneficial tissue bio-effects are actively under development. The mechanical oscillations of circulating microbubbles, the most widely investigated cavitation nuclei, which may also encapsulate or shield a therapeutic agent in the bloodstream, trigger and promote localized uptake. Oscillating microbubbles can create stresses either on nearby tissue or in surrounding fluid to enhance drug penetration and efficacy in the brain, spinal cord, vasculature, immune system, biofilm or tumors. This review summarizes recent investigations that have elucidated interactions of ultrasound and cavitation nuclei with cells, the treatment of tumors, immunotherapy, the bloodÀbrain and bloodÀspinal cord barriers, sonothrombolysis, cardiovascular drug delivery and sonobactericide. In particular, an overview of salient ultrasound features, drug delivery vehicles, therapeutic transport routes and pre-clinical and clinical studies is provided. Successful implementation of ultrasound and cavitation nuclei-mediated drug delivery has the potential to change the way drugs are administered systemically, resulting in more effective therapeutics and less-invasive treatments.

Acoustically sensitive emulsion droplets composed of a liquid perfluorocarbon have the potential to be a highly efficient system for local drug delivery, embolotherapy, or for tumor imaging. The physical mechanisms underlying the acoustic activation of these phase-change emulsions into a bubbly dispersion, termed acoustic droplet vaporization, have not been well understood. The droplets have a very high activation threshold; its frequency dependence does not comply with homogeneous nucleation theory and localized nucleation spots have been observed. Here we show that acoustic droplet vaporization is initiated by a combination of two phenomena: highly nonlinear distortion of the acoustic wave before it hits the droplet and focusing of the distorted wave by the droplet itself. At high excitation pressures, nonlinear distortion causes significant superharmonics with wavelengths of the order of the droplet size. These superharmonics strongly contribute to the focusing effect; therefore, the proposed mechanism also explains the observed pressure thresholding effect. Our interpretation is validated with experimental data captured with an ultrahigh-speed camera on the positions of the nucleation spots, where we find excellent agreement with the theoretical prediction. Moreover, the presented mechanism explains the hitherto counterintuitive dependence of the nucleation threshold on the ultrasound frequency. The physical insight allows for the optimization of acoustic droplet vaporization for therapeutic applications, in particular with respect to the acoustic pressures required for activation, thereby minimizing the negative bioeffects associated with the use of high-intensity ultrasound.

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