Noninvasive Thrombolysis using Microtripsy

Abstract

Thrombosis refers to blood clot formation and when pathological, is the cause of many vascular diseases. For example, deep vein thrombosis (DVT), which affects three million Americans per year, is the formation of clots in the deep veins of the legs. Current clinical treatments include thrombolytic drugs and catheter-based surgical procedures. Both methods have significant drawbacks, such as excessive bleeding, invasiveness, and long treatment time. Ultrasound has been combined with thrombolytic drugs and/or microbubbles to enhance drug delivery. However, these methods are still quite slow and share the drawbacks of thrombolytic drugs.

Histotripsy is a tissue ablation method that mechanically fractionates soft tissue via well-controlled acoustic cavitation generated by microsecond-long, high-pressure ultrasound pulses. The initial feasibility and safety of using histotripsy as a noninvasive, drug-free, and image-guided thrombolysis technique has been demonstrated both in vitro and in vivo.

The overriding goal of this dissertation is clinical translation of histotripsy thrombolysis. First, an integrated image-guided histotripsy thrombolysis system suitable for clinical DVT treatment are designed and constructed. Second, the recently discovered technical innovations, microtripsy and bubble-induced color Doppler (BCD), are investigated for histotripsy thrombolysis application to further improve treatment efficacy. Microtripsy is a new histotripsy approach and uses an intrinsic threshold mechanism to generate more reproducible and predictable cavitation via a single ultrasound pulse, which can minimize vessel damage by confining cavitation within vessel lumen and eliminate cavitation on vessel wall. BCD is developed to monitor tissue motion induced by histotripsy pulses and investigated as a real-time quantitative feedback for histotripsy thrombolysis. Finally, a comprehensive pre-clinical study in a large animal DVT model is conducted to validate the safety and efficacy of this clinically designed system incorporating these technical innovations. It is our hope that this dissertation work will establish a foundation for the translation of this noninvasive thrombolysis technology into relevant clinical applications.