Micro-Particle Image Velocimetry Investigation of Flow Fields of SonoVue Microbubbles Mediated by Ultrasound and Their Relationship With Delivery

Penglin Zou,Ziqi Wang,Yan Pang,Mengqi Li,Lianfang Du,Yourong Duan,Qiusheng Shi,Zhaomiao Liu,Guoxiu Zhang,Lifang Jin

doi:10.3389/fphar.2019.01651

Abstract

The flow fields generated by the acoustic behavior of microbubbles can significantly increase cell permeability. This facilitates the cellular uptake of external molecules in a process known as ultrasound-mediated drug delivery. To promote its clinical translation, this study investigated the relationships among the ultrasound parameters, acoustic behavior of microbubbles, flow fields, and delivery results. SonoVue microbubbles were activated by 1 MHz pulsed ultrasound with 100 Hz pulse repetition frequency, 1:5 duty cycle, and 0.20/0.35/0.70 MPa peak rarefactional pressure. Micro-particle image velocimetry was used to detect the microbubble behavior and the resulting flow fields. Then HeLa human cervical cancer cells were treated with the same conditions for 2, 4, 10, 30, and 60 s, respectively. Fluorescein isothiocyanate and propidium iodide were used to quantitate the rates of sonoporated cells with a flow cytometer. The results indicate that (1) microbubbles exhibited different behavior in ultrasound fields of different peak rarefactional pressures. At peak rarefactional pressures of 0.20 and 0.35 MPa, the dispersed microbubbles clumped together into clusters, and the clusters showed no apparent movement. At a peak rarefactional pressure of 0.70 MPa, the microbubbles were partially broken, and the remainders underwent clustering and coalescence to form bubble clusters that exhibited translational oscillation. (2) The flow fields were unsteady before the unification of the microbubbles. After that, the flow fields showed a clear pattern. (3)The delivery efficiency improved with the shear stress of the flow fields increased. Before the formation of the microbubble/bubble cluster, the maximum shear stresses of the 0.20, 0.35, and 0.70 MPa groups were 56.0, 87.5 and 406.4 mPa, respectively, and the rates of the reversibly sonoporated cells were 2.4% ± 0.4%, 5.5% ± 1.3%, and 16.6% ± 0.2%. After the cluster formation, the maximum shear stresses of the three groups were 9.1, 8.7, and 71.7 mPa, respectively. The former two could not mediate sonoporation, whereas the last one could. These findings demonstrate the critical role of flow fields in ultrasound-mediated drug delivery and contribute to its clinical applications.

Highlights

IntroductionA microbubble population driven by ultrasound can enhance the delivery of external molecules through a process called ultrasound-mediated drug delivery (UMDD) (Tang et al, 2017)
To promote its clinical translation, this study investigated the relationships among the ultrasound parameters, acoustic behavior of microbubbles, flow fields, and delivery results
These findings demonstrate the critical role of flow fields in ultrasoundmediated drug delivery and contribute to its clinical applications

Summary

Introduction

A microbubble population driven by ultrasound can enhance the delivery of external molecules through a process called ultrasound-mediated drug delivery (UMDD) (Tang et al, 2017). Numerous preclinical studies have proven the feasibility of UMDD and its advantages of safety, efficiency, and convenience (Shi et al, 2014; Xing et al, 2016; Lin et al, 2018). Through further research and development, UMDD has entered the clinical trial stage. Good therapeutic effect and no significant adverse effects have been observed (Carpentier et al, 2016; Dimcevski et al, 2016), which indicates that UMDD has great clinical potential. Many obstacles still need to be overcome before clinical application can be achieved. One of the most important obstacles is that the exact mechanism has not been elucidated (Helfield et al, 2016b)

Methods

Results

Conclusion