Blood Brain Barrier Disruption by Focused Ultrasound and Microbubbles: A Numerical Study on Mechanical Effects

Introduction: Microbubbles are widely used as contrast agent in diagnostic ultrasound. Recently they have shown good potential for applications in the therapeutic field such as drug delivery to the brain. Recent studies have shown focused ultrasound in conjunction with injected micro-bubbles could temporarily disrupt blood-brain barrier and let therapeutic agents transport into the brain tissue. The main aim of current study was to investigate, the interactions between ultrasonic acoustic field and microbubbles and the resultant mechanical effects on microvessels. Materials and Methods: In this study, we have used numerical approach to simulate microbubble confined in a microvessel filled with viscose fluid as blood. In the main stream of our study two crucial equations have been solved: equation of bubble oscillation on the bubble surface in an ultrasonic acoustic field (R-P equation), and equations of mass conservation and continuity (Navier Stokes) in fluid domain. Microbubble radius change, subjected to ultrasonic wave, and the force-fluid coupling which cause high velocity gradient and subsequent exertion of shear stress on interior vessel wall have been calculated. In this study microvessel considered as a viscoelastic solid. Acoustic pressure amplitude has been varied between 1.5P0 and 5P0 (P0 is hydrostatic pressure in fluid, P0~ 104.6kPa) with a constant frequency (f=1MHz). Then at a constant pressure of 2.5P0 acoustic frequency has been changed between 1 and 6MHz. Shear stress and transmural pressure, two important metrics for mechanical effects and vessel damage, have been calculated for each case. Results: The results obtained from the preliminary analysis of simulation study demonstrate that by increasing acoustic pressure both shear stress and transmural pressure increase linearly between 4-20 and 300-650kPa respectively. When the acoustic pressure reached the value 5P0 vessel ruptured and at this point, our simulation was stopped. This study has shown that by increasing acoustic frequency, relative difference of bubble radius, increase to%66 and then decrease to %12. In this case, shear stress and transmural pressure reached almost to a maximum of 10 and 450kPa respectively. Conclusion:  The present study has gone some way towards enhancing our understanding of interaction between the acoustic field and micro bubbles. Mechanical effects on vessel wall are pressure and frequency dependant and it’s important to find a threshold for acoustic pressure that below it vessel damages won’t occur. This study has identified threshold for acoustic pressure is about 0.45P0. Also, it is very important to consider microbubbles resonance frequency at which maximum amplitude of oscillation and mechanical effects occur.