Effects of tight junctions on biomechanical response of blood-brain barrier under stable cavitation

The rising prevalence of central nervous system (CNS) diseases has imposed substantial social and economic burdens on healthcare systems. The blood-brain barrier (BBB), a highly selective physiological barrier in the CNS, severely restricts the delivery of most therapeutic agents to the brain, thereby limiting treatment efficacy. Stable cavitation of microbubbles induced by focused ultrasound (FUS) offers a promising strategy for transiently and non-invasively opening the BBB, holding significant clinical potential. However, the underlying biophysical mechanisms remain challenging for understanding, particularly the disruption of tight junctions (TJs) during stable cavitation and the mechanical responses of the BBB under long-term loading. In this study, a three-dimensional (3D) finite element simulation is conducted to model the mechanical behavior of endothelial cells and TJs using the Yeoh hyperelastic model and a modified standard linear solid (MSLS) model, respectively. This framework enables simulation of coupled interactions among oscillating bubbles, surrounding fluid, and the BBB. Numerical results reveal that stable cavitation induces pronounced periodic deformation of the BBB, with localized stress concentrations prominently occurring in TJ regions during bubble expansion. The occurrence of the flow recirculation is correlated to the stress imposing on the BBB. Compared to a linear elastic model, the present nonlinear material formulation demonstrates enhanced deformation and effectively suppressed peak shear stresses of the BBB. We find the fluid stress exerted on the BBB obtained is not large enough to lead to rupture of the TJs. Furthermore, our results indicate a typical fatigue-like feature in TJs under cyclic loading, wherein the von Mises stress is characterized by an initial softening followed by hardening. This suggests that fatigue-like behavior under long-term loading might be the dominant mechanism for the failure of TJs under stable cavitation. These findings contribute to the understanding of the biomechanical mechanisms underlying FUS-microbubble-mediated BBB opening (FUS-BBB) and provide a theoretical foundation for its application in CNS drug delivery and brain disease treatment.