Noninvasive Thrombolysis Using Histotripsy Pulsed Ultrasound Cavitation Therapy.

Abstract

Histotripsy is a noninvasive ultrasound therapy that utilizes short, high-amplitude, focused ultrasound pulses to mechanically reduce targeted tissue structures to liquid debris by acoustic cavitation. In this work, the physical mechanisms of histotripsy and its application as a method of thrombolysis were investigated. Cavitation activity which causes tissue breakdown during histotripsy was studied by high-speed photography. It was found that cavitation clouds form due to scattering of shock waves in a focused ultrasound pulse from individual inertial cavitation bubbles. The scattered shock is a large tensile wave which expands clusters of cavitation bubbles when the tensile pressure is greater than a measured threshold of approximately 30 MPa. The interaction of this cavitation with tissue and cells was explored with a phantom containing agarose and red blood cells to measure cavitation-based mechanical damage. The observations indicated that cell lysis may be achieved by bubble-induced tensile strain upon expansion, causing membrane rupture. Based on these studies, focused histotripsy therapy transducers were designed to controllably generate cavitation clouds in the vasculature for performing thrombolysis. Transducers were integrated with ultrasound imagers to provide feedback for targeting and monitoring progress of treatment. Rapid thrombolysis was observed when histotripsy was applied to clots in-vitro, and the resulting debris was mainly subcellular and unlikely to cause embolism. Additionally, it was observed that histotripsy can attract, trap, and destroy free clot fragments in a vessel phantom. Based on these observations, a noninvasive embolus trap (NET) was developed, acting as a filter to prevent embolism during the thrombolysis procedure. An in-vivo porcine model of deep-vein thrombosis was used to evaluate the safety and efficacy of the histotripsy thrombolysis technique. These experiments demonstrated the feasibility of the treatment and suggest histotripsy can achieve rapid clot breakdown in a controlled manner.