Dynamic behavior of microbubbles according to the flow velocity in an artificial capillary for theranostic applications

Abstract

Microbubbles are composed of a functional gas encapsulated into a biocompatible shell layer in a liquid. They play a critical role in ultrasonic medical applications of diagnosis, therapy, and theranostics. Although a few studies show the potentials of ultrasound-mediated drug delivery with those functional materials, the interacting mechanism between microbubbles and ultrasound in vivo has not been fully understood. Therefore, in this study, we proposed an artificial capillary model in order to investigate the dynamic behavior of microbubbles under several ultrasonic conditions with the fluidic flow. The artificial multi-branch microfluidic chip resembles tumor vessels, which observe the different flows in the separated branches. The microfluidic chip has a uniform 150μm height, and the width becomes smaller as it expands into branches. The main branch has 400μm; the middle branch has 300μm wide; the smallest size is 200μm. To apply the ultrasound into the microfluidic channel, a custom-built pulser system a commercial ultrasonic phased array was used with the acoustic parameters such as the operating frequency of 2MHz, applied voltage of 60Vpp, pulse length of 16μsec and 1kHz pulse repetition frequency. A high-speed camera captured the interaction of microbubbles and ultrasound in each branch. The frame rate was set to be 50,000 of frame per second (fps) in 512х512 pixels. The microbubbles were injected in the channels with a flow rate of 0.1mL/min, which is based on the human cardiac blood flows. We successfully obtained the velocity dependence of the microbubbles and ultrasound in the artificial capillary model. Figure 1 shows that the velocity of the microbubbles increased as they were in the center of the microfluidic channel, where the drag force from the channel wall was minimum. We explored the serial high-speed camera image data to quantify the microbubble speed in each location, as shown in Figure 1. The acoustic radiation force slowed down all the microbubbles under a velocity of 7mm/sec (Figure 2). The acoustic field created a resistive force to capture the microbubbles with slow velocity; however, the microbubbles where located near the center of the channel passed without any interaction of the ultrasonic force. Since the blood flow velocity varies depending on the vessel type, hence, it is apparent that drug delivery with ultrasound-mediated microbubble in the capillaries and principle veins is more capable instead of drug delivery in the major arteries. We are modifying our fluidic system with the circadian rhythmic fluidic flow condition to devise an efficient verification system by making a similar in vivo environment.