Progress in Sonothrombolysis for the Treatment of Stroke

Abstract

In 1974, Sobbe et al1 applied 26.5-kHz ultrasound (US) to recanalize thrombosed iliofemoral arteries in dogs with minimal complications. These pioneer efforts were followed by studies showing that catheter-based or transcutaneous US can enhance the effect of fibrinolytic agents in recanalizing thrombosed arteries,2–8 thus paving the way for first clinical studies evaluating the adjunct effect of US in treating patients with ischemic stroke. ### Mechanisms #### US Thrombolysis Despite numerous studies documenting a thrombolytic effect of US, the mechanisms remain poorly understood. Inertial cavitation (ie, the formation and violent collapse of gas-filled bubbles in a fluid exposed to US) gave rise to transient microjets that disintegrate thrombus mechanically.9 Stable cavitation (ie, sustainable nonlinear periodic contraction or expansion of a gas body or bubble) may be more effective than inertial cavitation in clot lysis.10 US also facilitates penetration of fibrinolytic drugs into the thrombus and binding to fibrin.11 This is because US promotes the motion of fluids around the clot surface through a process called microstreaming. Moreover, pressure waves may increase the permeation of tissue-type plasminogen activator (tPA) into the interior of the fibrin network.12 Heating is uniformly present in tissue exposed to US but has been deemed too mild to explain thrombolytic effects. #### Microbubble-Enhanced Thrombolysis With tPA Significant amplification of lysis occurs with the addition of microbubbles to the combination of thrombolytic drug and US.13–15 Microbubbles, composed of lipid, albumin, or galactose shells and ranging in size from 0.5 to 5 μm, lower the threshold for thrombolysis by providing a pre-existing bubble that easily can be made to cavitate by US. Stable cavitation can produce microstreaming in the area and dramatically enlarge the bubble momentarily. This will cause localized mechanical stress on the adjacent clot. The surface of the clot will erode, and even penetration and numerous microscopic …