How do microbubbles and ultrasound interact? Basic physical, dynamic and engineering principles

Ultrasound contrast agents consisting of gas microbubbles stabilised by a polymer or surfactant coating have been in clinical use for several decades. Research into the biomedical uses of microbubbles, however, remains a highly active and growing field. This is largely due to their considerable versatility and the wide range of applications for which they have demonstrated potential benefits. In addition to contrast enhancement, diagnostic applications include: perfusion mapping and quantification and molecular imaging. In drug and gene therapy microbubbles can be used as vehicles which are inherently traceable in vivo and can provide both targeted and controlled release. In addition, the dynamic behaviour of the microbubbles in response to ultrasound excitation contributes to the therapeutic process. At low intensities microbubbles have been shown to mediate reversible enhancement of cell and endothelial permeability, including temporary opening of the blood brain barrier. At higher intensities they have been used as means of increasing the efficiency of thrombolysis, high-intensity focused ultrasound (HIFU) surgery and lithotripsy. The aim of this review is to describe the key physical principles which determine how microbubbles and ultrasound interact and the implications for their design, preparation and exploitation in diagnostic and therapeutic applications.