Probing the pressure dependence of sound speed and attenuation in bubbly media: Experimental observations, a theoretical model and numerical calculations

Ultrasound causes high-energy chemistry. It does so through the process of acoustic cavitation: the formation, growth and implosive collapse of bubbles in a liquid. During cavitational collapse, intense heating of the bubbles occurs. These localized hot spots have temperatures of roughly 5000 degrees C, pressures of about 500 atmospheres, and lifetimes of a few microseconds. Shock waves from cavitation in liquid-solid slurries produce high-velocity interparticle collisions, the impact of which is sufficient to melt most metals. Applications to chemical reactions exist in both homogeneous liquids and in liquid-solid systems. Of special synthetic use is the ability of ultrasound to create clean, highly reactive surfaces on metals. Ultrasound has also found important uses for initiation or enhancement of catalytic reactions, in both homogeneous and heterogeneous cases.

The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.