Modeling the synergistic enhancement of drug permeation by a dual-microbubble system under ultrasonic excitation.

Abstract

The high selectivity of the vascular endothelium, exemplified by the blood-brain barrier (BBB), provides critical protection to tissues against harmful substances; however, it also severely restricts the targeted delivery of therapeutic agents, particularly large molecule drugs. Ultrasound-mediated microbubble cavitation has emerged as a promising strategy for enhancing drug delivery. However, conventional single-microbubble systems suffer from limitations, including uneven energy distribution and suboptimal permeabilization efficacy. Moreover, the synergistic mechanisms underlying dual-microbubble interactions within the microvasculature remain poorly understood. In this study, we developed a coupled two-microbubble fluid-solid system (TMFSS) model utilizing the finite element method to simulate the dynamic behavior of dual microbubbles within blood vessels under ultrasonic excitation. Our investigation focused on key parameters-including microbubble spacing, acoustic pressure amplitude, microbubble size, and shear-thinning blood rheology-and their effects on microbubble oscillation, microstreaming, vascular wall stress, and endothelial permeability. The results demonstrate that, compared with single-microbubble systems, the ultrasound-assisted TMFSS significantly enhances drug permeability. This synergistic permeabilization effect strongly depends on the acoustic parameters, blood viscosity, microbubble size, and spatial distribution. Our study quantitatively elucidates the structure‒activity relationship between TMFSS dynamics and drug penetration efficiency and presents a parameter optimization strategy for the precise modulation of vascular endothelial permeability.