Horses for courses (or something much smaller!): The design, development and acoustic testing of sub-micron cavitation nucleation agents for biomedical applications

Abstract

Lipid and protein-shelled microbubbles have been the mainstay of cavitation nucleation strategies for therapeutic applications for several decades. However, a growing number of therapeutic ultrasound applications require nuclei that (i) are significantly smaller in size, in order to overcome a particular biological barrier such as the leaky vasculature of tumours or the stratum corneum; (ii) offer greatly increased cavitation persistence, both during a single extended ultrasound pulse and in terms of extended circulation following intravenous administration; and (iii) have better resilience to sudden ambient pressure changes in order to enable direct injection without nuclei destruction into tissue targets via a needle and syringe. We will review a range of novel cavitation agents currently under development, including sub-micron gas-stabilizing solid particles and nanodroplets, and provide an overview of their known characteristics in terms of acoustic emissions, activation and cavitation thresholds, cavitation persistence, and circulation. Where possible, the relevant performance of these cavitation nucleation agents will be compared to microbubbles for applications ranging from drug delivery to nucleated tissue fractionation.