Ultrasonic Imaging and Therapy Using Microbubbles for Deep Vein Thrombosis

Author: ORCID icon orcid.org/0000-0002-9517-6265
Xie, Yanjun, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia
Hossack, John, EN-Biomed Engr Dept, University of Virginia

Sonothrombolysis is a therapeutic technique that combines ultrasound, thrombolytic agents and microbubbles to facilitate the dissolution of thrombi. In exposure to ultrasound, microbubbles exhibit therapeutic functions as a result of cavitation or drug delivery. Sonothrombolysis is being explored as an alternative therapy for deep vein thrombosis (DVT), as it can induce bio-effects and lower the risk of bleeding. Microfluidics techniques can generate microbubbles of adjustable diameter and stability. Transiently stable microbubbles have been examined for their ability of recanalization. In this dissertation, sonothrombolysis for DVT using microfluidically produced microbubbles is evaluated in terms of safety and effectiveness. Additionally, ultrasound imaging techniques are applied for the assessment of DVT.
For real-time monitoring of microbubbles to avoid failure cases, a closed-loop feedback control system was implemented in a flow-focusing microfluidic device with integrated on-chip electrodes. The diameter of microbubbles and the production rate were derived from the impedance variations caused by the passage of microbubbles. This measurement method was consistent with the optical diameter benchmark (R^2=0.98). A proportional-integral controller regulated the diameter of microbubbles in the range of 14-24 µm.
In experiments involving a murine model of DVT, a 3D ultrasound imaging approach was developed to quantify the volume of a thrombus. The volumes of fabricated blood clots were correlated with their weight in a flow system, with an R^2 of 0.89. A mouse model of DVT in the inferior vena cava was imaged using 3D ultrasound, followed by macroscopic observation. The proposed approach was evaluated against macroscopic measurement, showing an R^2 of 0.91, and it was applicable to efficacy experiments.
Mice diagnosed with DVT were randomly divided into experimental and control groups. During therapy, microfluidically produced microbubbles of 18 µm diameter and recombinant tissue plasminogen activator were administered through a tail vein catheter for 30 minutes, while ultrasound was applied to the abdominal region of the mice in the sonothrombolysis group. The sonothrombolysis therapy significantly reduced the residual volume of thrombi to 20%, versus 52% without therapy (p = 0.012 < 0.05). The results suggest that large microbubbles produced using microfluidic techniques are effective therapeutic agents in sonothrombolysis.
The stiffness of a thrombus indicates its age and compositions. Ultrasound-based shear wave elastography offers an estimate of tissue stiffness through analysis of the propagation of shear waves. A Fourier feature network-based algorithm was designed to denoise displacement data and improve elasticity reconstruction in shear wave elastography. It was validated in phantom and ex vivo studies and shown to outperform a reference filtering method. After enhancement using this algorithm, the root mean square error and the structural similarity index of the reconstruction were 1.76 kPa and 0.949 compared to the ground truth, respectively.

PHD (Doctor of Philosophy)
ultrasound, therapeutic ultrasound, deep vein thrombosis, 3D ultrasound imaging, contrast agent, thrombolytic agent, microfluidics, shear wave elastography, physics-informed model
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