A boundary integral method with volume-changing objects for ultrasound-triggered margination of microbubbles

A variety of numerical methods exist for the study of deformable particles in dense suspensions. None of the standard tools, however, currently include volume-changing objects such as oscillating microbubbles in three-dimensional periodic domains. In the first part of this work, we develop a novel method to include such entities based on the boundary integral method. We show that the well-known boundary integral equation must be amended with two additional terms containing the volume flux through the bubble surface. We rigorously prove the existence and uniqueness of the solution. Our proof contains as a subset the simpler boundary integral equation without volume-changing objects (such as red blood cell or capsule suspensions) which is widely used but for which a formal proof in periodic domains has not been published to date. In the second part, we apply our method to study microbubbles for targeted drug delivery. The ideal drug delivery agent should stay away from the biochemically active vessel walls during circulation. However, upon reaching its target it should attain a near-wall position for efficient drug uptake. Though seemingly contradictory, we show that lipid-coated microbubbles in conjunction with a localized ultrasound pulse possess precisely these two properties. This ultrasound-triggered margination is due to hydrodynamic interactions between the red blood cells and the oscillating lipid-coated microbubbles which alternate between a soft and a stiff state. We find that the effect is very robust, existing even if the duration in the stiff state is more than three times lower than the opposing time in the soft state.