Precise Manipulation of Bubble Cavitation and Blood-Brain Barrier Modulation using Temporal Interference Ultrasound.

Authors

Jie Jin, Zhenxiang Ji, Zhetao Shangguan, Tianyi Yan, Shengyou Qian, Dingjie Suo

Published in

BME frontiers. Volume 7. Pages 0323. Epub Oct 14, 2026.

Abstract

Objective: To determine whether temporal interference (TI) ultrasound can enhance microbubble (MB) cavitation and provide transient modulation of blood-brain barrier (BBB) permeability. Impact Statement: By integrating a time-dependent multiphysics MB-vessel model with in vivo validation, this study links TI-enhanced cavitation dynamics to vessel-wall mechanical responses and a transient BBB permeability window, providing a mechanistic basis for pressure-efficient ultrasound-mediated brain delivery. Introduction: Focused ultrasound combined with MBs can transiently increase BBB permeability, but reliable control of cavitation intensity and post-sonication barrier recovery remains a key challenge for safe and effective brain delivery. Methods: A fluid-solid coupled MB-vessel model was used to evaluate MB dynamics, vessel-wall normal and shear stresses, porosity, acoustic-pressure dependence, and the influence of non-Newtonian blood rheology under 1.0 MHz single-frequency and 1.0 + 0.8 MHz TI excitation. In vivo Evans blue experiments in mice were then used to compare BBB opening across pressure levels and to characterize the recovery profile from 0.5 to 12 h after 0.3-MPa TI sonication. Results: Ultrasound-driven MB oscillation and collapse increased vessel-wall stress and modeled porosity. Compared with single-frequency ultrasound, TI excitation promoted earlier MB instability and collapse and produced stronger vessel-wall mechanical responses under energy-equivalent acoustic exposure conditions. In vivo, Evans blue extravasation increased with the reference pressure amplitude and showed higher mean values following TI ultrasound, with a significant between-mode difference at 0.5 MPa. After 0.3-MPa TI sonication, extravasation progressively decreased from 0.5 to 12 h, consistent with a transient BBB permeability increase. Non-Newtonian rheology altered the local shear environment but had limited effects on peak normal stress and porosity within the simulated time window. Conclusion: TI ultrasound enhances MB-mediated BBB opening under energy-normalized acoustic exposure conditions while producing a time-limited increase in permeability, supporting its further development for temporally controlled brain delivery.

PMID:
42876864
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

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