Microbubble-Mediated Sonoporation
Ultrasound-driven microbubbles are emerging as powerful tools for delivering drugs across biological barriers, including the blood–brain barrier. Our research reveals the physical mechanism by which these bubbles enable drug uptake, combining ultra-high-speed imaging and theoretical modelling to uncover the role of cyclic microjetting in targeted therapies.
Contributors: Marco Cattaneo, Giulia Guerriero
Ultrasound-responsive microbubbles are promising agents for non-invasive and localised drug delivery, with clinical trials already demonstrating potential for treating neurological disorders, cancers, and cardiovascular diseases. However, the precise mechanism enabling drugs to cross cell membranes has remained unclear, until now.
Using a custom-built side-view ultra-high-speed microscopy setup capturing up to 10 million frames per second, we directly visualise the interaction between individual phospholipid-coated microbubbles and human endothelial cells. We discover that, under mild ultrasound pressures (below 100 kPa), bubbles become unstable via the Faraday instability, developing three-dimensional shape oscillations that we characterised experimentally for the first time. As these shapes evolve, the bubble surface folds inward and ejects stable, cyclic microjets that repeatedly hammer the cell membrane, opening nanoscale pores and enabling drug uptake, a process known as sonoporation.
We establish a threshold in bubble radial expansion (~1 μm) beyond which microjets form and drug delivery becomes effective. Unlike classical inertial jets, which require violent bubble collapses, cyclic jetting operates under stable cavitation conditions, minimising cellular damage while maintaining efficacy. Our modelling confirms that microjet-induced stresses exceed those from other proposed mechanisms, such as oscillatory shear or acoustic streaming, by at least an order of magnitude.
These insights not only resolve a long-standing debate about the origin of sonoporation but also provide clear criteria for optimising ultrasound protocols. By carefully selecting bubble size and ultrasound parameters, we can achieve efficient, safe, and repeatable drug transport, even across restrictive barriers like the blood–brain barrier. For more details see e.g. our external page journal publication.
