Controlling microbubble dynamics in ultrasound therapy

Abstract

Microbubble-mediated focused ultrasound therapies such as blood-brain barrier opening, sonothrombolysis, and sonoporation can non-invasively deliver drugs to a targeted region. Despite the potential impact this technology could have in the clinic, there are currently concerns regarding its efficacy, uniformity and safety. These challenges ultimately stem from a limited ability to control the microbubble dynamics during ultrasound exposure. In the current thesis, we sought to design ultrasound exposure sequences and develop monitoring techniques that promote the desired acoustic cavitation activity and suppress unwanted stimuli that do not produce a safe therapeutic bioeffect. For example, violent cavitation activity could cause irreversible damage within the treatment area. The behaviour of microbubble populations exposed to low-power therapeutic ultrasound was first qualitatively studied using high-speed microscopy. Microbubbles were found to form large clusters within milliseconds of exposure and collectively coalesce into larger bubbles. Based on these observations and findings in the literature, new therapeutic sequences were designed and tested. Rapid short-pulse sonication consisted of μs-long pulses separated by short off-times. When compared to conventional ultrasound sequences, this pulse sequence enhanced the lifetime and mobility of cavitation nuclei and resulted in more uniform acoustic activity distributions. To better monitor ultrasound treatment as it evolves, we developed a method that passively measures microbubble velocities via the Doppler effect emerging in the microbubble acoustic emissions. Using standard passive cavitation detection techniques in one and two dimensions, we estimated microbubble velocities on the order of m s-1 during ultrasound exposure. Finally, we tested our new therapeutic design in a mouse model in order to improve the safety of blood-brain barrier opening. We achieved drug delivery with a similar magnitude but with a better uniformity compared to conventional sequences, thus demonstrating evidence of favourable microbubble dynamics within the targeted region. Taken together, our contribution in ultrasonic stimulation using new sequences and monitoring using passive acoustic detection techniques improves our control of microbubble dynamics in ultrasound therapy and has the potential to promote treatment efficacy and suppress unwanted damage.