Numerical simulation study on opening blood-brain barrier by ultrasonic cavitation

Abstract

Experimental studies have shown that ultrasonic cavitation can reversibly open the blood-brain barrier (BBB) to assist drug delivery. Nevertheless, the majority of the present study focused on experimental aspects of BBB opening. In this study, we developed a three-bubble-liquid-solid model to investigate the dynamic behavior of multiple bubbles within the blood vessels, and elucidate the physical mechanism of drug molecules through endothelial cells under ultrasonic cavitation excitation. The results showed that the large bubbles have a significant inhibitory effect on the movement of small bubbles, and the vibration morphology of intravascular microbubbles was affected by the acoustic parameters, microbubble size, and the distance between the microbubbles. The ultrasonic cavitation can significantly enhance the unidirectional flux of drug molecules, and the unidirectional flux growth rate of the wall can reach more than 5 %. Microjets and shock waves emitted from microbubbles generate different stress distribution patterns on the vascular wall, which in turn affects the pore size of the vessel wall and the permeability of drug molecules. The vibration morphology of microbubbles is related to the concentration, arrangement and scale of microbubbles, and the drug permeation impact can be enhanced by optimizing bubble size and acoustic parameters. The results offer an extensive depiction of the factors influencing the blood-brain barrier opening through ultrasonic cavitation, and the model may provide a potential technique to actively regulate the penetration capacity of drugs through endothelial layer of the neurovascular system by regulating BBB opening.

Keywords: Blood–brain barrier; Drug delivery; Finite element method (FEM); Multiple bubbles.

Fig. 1

A schematic diagram of a bubble–bubble–bubble–blood–vessel system (xy plane).

Fig. 2

Bubble radius-time curves under different calculation conditions (Fig. 2(a) is taken from reference and Fig. 2(b) shows the results of this paper).

Fig. 3

Drug molecule distribution and trajectory in blood. The values in the figure represent the Darcy velocity (m $\bullet$ s⁻¹) of the particles.

Fig. 4

Intravascular blood distribution. The values in the figure represent the blood velocity (m $\bullet$ s⁻¹).

Fig. 5

Drug molecule distribution and trajectory in blood. The values in the figure represent the blood velocity (m $\bullet$ s⁻¹).

Fig. 6

The curve of radius and secondary Bjerknes force with time.

Fig. 7

The displacement-position curve of upper and lower vascular wall.

Fig. 8

The shear stress-position curve of upper and lower vascular wall.

Fig. 9

The permeability-position curve of upper and lower vascular wall.

Fig. 10

The unidirectional flux of the model at different times under ultrasonic excitation. The values in the figure represent the unidirectional flux (mol $\bullet$ s⁻¹).

Fig. 11

The stress distribution of the model at different times under ultrasonic excitation. The values in the figure represent the wall stress (N/m²).

Fig. 12

The effect of different ultrasound frequencies on model results under ultrasonic excitation.

Fig. 13

The effect of different number of cycles on model results under ultrasonic excitation.

Fig. 14

The effect of different bubble–bubble distances on model results under ultrasonic excitation.

Fig. 15

The stress distribution of the model at different ultrasonic amplitudes under ultrasonic excitation. The values in the figure represent the wall stress (N/m²).

Fig. 16

The effect of different ultrasonic amplitudes on wall shear stress and unidirectional flux under ultrasonic excitation.

Fig. 17

The maximum total displacement at three different initial radius (R₁₀ = R₂₀ = R₃₀, f = 1.0 MHz, N = 5, R_L = 8 μm).

Fig. 18

The stress distribution of the model at different $R_{30}$ under ultrasonic excitation. The values in the figure represent the wall stress (N/m²).

Fig. 19

With the ultrasonic excitation, the stress distribution of the model at different $R_{30}$.

Fig. 20.T

He stress distribution of the model at different times under ultrasonic excitation. The values in the figure represent the wall stress (N/m²).

Fig. 21

The effect of different viscosity coefficients on model results under ultrasonic excitation.

Fig. 22

The influence of bubble arrangement on the model results (Bubbles are evenly distributed in the cavity).

Fig. 23

The stress distribution of the model at different times under ultrasonic excitation. The values in the figure represent the wall stress (N/m²).