A Study on Targeted-Ultrasound Assisted Thrombolysis

Ischemic stroke, myocardial infarction and deep vein thrombosis are common diseases which are related to thrombosis. Systemic thrombolytic therapy is one of the most widely used treatments for recanalization of the occluded vessel. However, the administration of thrombolytic agents has a major disadvantage of inducing comprehensive hemorrhage and may cause death. Therefore, there is a clinical need for treatment methods to increase the effectiveness of complete reperfusion without increasing the probability of bleeding. Several studies have shown that low-frequency ultrasound (20 kHz~2 MHz) enhances enzymatic thrombolysis by increasing the transport of thrombolytic agents into clots through cavitation-related mechanisms. Besides, there were some studies shown a thrombolytic potential of ultrasound in combination with ultrasound contrast agent even without the presence of thrombolytic agents. Thus, the use of ultrasound to enhance and accelerate the thrombolysis of occluded vessels is an area of active investigation. The purpose of this study was to develop two approaches for improving the efficiency and safety of ultrasound-assisted thrombolysis which were base upon the therapeutic frequency we chosen and the use of targeted contrast agents：(1). Targeted ultrasound contrast agent：Ultrasound contrast agents, mainly microbubbles, are good nuclei for reducing the threshold for cavitation induction. By the virtue of the rapid discovery of novel biomarkers and affinity ligands, targeted ultrasound contrast agents are developed to recognize thrombi and thereby increasing the local concentration of microbubbles. One hypothesis of the present study was that a targeted ultrasound contrast agent can enhance both the thrombolytic efficacy and safety in transcutaneous (noninvasive) ultrasound for the same reason. (2). The ultrasound frequency： For clinical need, we were trying to develop a high-frequency ultrasound system with high-resolution for imaging and a possible combined diagnostic and therapeutic in vivo application using the same transducer. Thus, one component of this study is the investigation of the feasibility of sonothrombolysis by using intravascular ultrasound (IVUS, > 20 MHz). Here we used the dual high-frequency method to induce cavitation and estimate its intensity by measuring differential ICD, acoustic intensity of the low frequency component. According to the experimental results, we conclude that：1. Our thrombus-targeted ultrasound contrast agent was capable of targeting specific sites and has the potential for inducing localized cavitation thus avoiding the possible endothelial damage in the clinical application. 2. The magnitude of acoustic intensity plays a major rule in the cavitation induction using high-frequency ultrasound. Besides, due to the limitation of high-frequency ultrasound aperture size, sonothrombolysis using intravascular ultrasound may not be feasible.