Department of Biomedical Engineering, College of Engineering and Applied Sciences, University of Cincinnati, CVC 3921, 0586, 231 Albert Sabin Way, Cincinnati, OH, 45267-0586, USA.
Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Sci Rep. 2021 Feb 17;11(1):3987. doi: 10.1038/s41598-021-83442-3.
Adjuvant ultrasound at 2 MHz with or without an ultrasound contrast agent improves the rate of thrombus resolution by recombinant tissue plasminogen activator (rt-PA) in laboratory and clinical studies. A sub-megahertz approach can further expand this therapy to a subset of patients with an insufficient temporal bone window, improving efficacy in unselected patient populations. The aim of this study was to determine if a clinical ultrasound contrast agent (UCA), Definity, and 220 kHz pulsed ultrasound accelerated rt-PA thrombolysis in a preclinical animal model of vascular occlusion. The effect of Definity and ultrasound on thrombus clearance was first investigated in vitro and subsequently tested in a xenographic porcine cerebral thromboembolism model in vivo. Two different microcatheter designs (end-hole, multi-side-hole) were used to infuse rt-PA and Definity at the proximal edge or directly into clots, respectively. Sonothrombolysis with Definity increased clot mass loss relative to saline or rt-PA alone in vitro, only when rt-PA was administered directly into clots via a multi-side-hole microcatheter. Combined treatment with rt-PA, Definity, and ultrasound in vivo increased the rate of reperfusion up to 45 min faster than clots treated with rt-PA or saline. In this porcine cerebral thromboembolism model employing retracted human clots, 220 kHz ultrasound, in conjunction with Definity increased the probability of early successful reperfusion with rt-PA.
在实验室和临床研究中，2MHz 频率的辅助超声联合或不联合超声造影剂可提高重组组织型纤溶酶原激活剂（rt-PA）的溶栓率。亚兆赫兹方法可以将这种治疗方法进一步扩展到一部分颞骨窗不足的患者，从而提高未选择患者人群的疗效。本研究旨在确定临床超声造影剂（UCA）Definity 和 220kHz 脉冲超声是否能在血管阻塞的临床前动物模型中加速 rt-PA 溶栓。首先在体外研究了 Definity 和超声对血栓清除的影响，然后在异种猪脑血栓栓塞模型中进行了体内试验。两种不同的微导管设计（端孔、多孔侧孔）分别用于在近端边缘或直接注入血栓内输注 rt-PA 和 Definity。体外研究发现，与单独使用生理盐水或 rt-PA 相比，只有当 rt-PA 通过多孔侧孔微导管直接注入血栓时，Definity 增强了血栓质量的损失。体内联合使用 rt-PA、Definity 和超声治疗可使再灌注时间提前 45 分钟，比单独使用 rt-PA 或生理盐水治疗的血栓再灌注速度更快。在本研究中，使用缩回的人类血栓的猪脑血栓栓塞模型中，220kHz 超声联合 Definity 增加了 rt-PA 早期成功再灌注的可能性。
