Noninvasive thrombolysis using histotripsy beyond the intrinsic threshold (microtripsy)

Abstract

Histotripsy has been investigated as a non-invasive, drug-free, image-guided thrombolysis method that fractionates blood clots using acoustic cavitation alone. In previous histotripsy-mediated thrombolysis studies, cavitation clouds were generated using multi-cycle pulses and tended to form on vessel wall. To avoid potential cavitational damage to vessel wall, a new histotripsy approach, termed Microtripsy, has been recently discovered where cavitation is generated via an intrinsic-threshold mechanism using single-cycle pulses. We hypothesize that microtripsy can generate and confine cavitation in vessel lumen without contacting vessel wall, which results in recanalization within clot and potentially eliminating vessel damage. To test our hypothesis, microtripsy was investigated for clot recanalization in an in vitro flow model. Clots were formed inside a vessel phantom (6.5 mm inner diameter) in line with a flow system. Microtripsy was applied by a 1-MHz transducer at a pulse repetition frequency of 50 Hz with a peak negative pressure (P-) of 30 MPa or 36 MPa. To create a flow channel through a clot, the cavitation focus was scanned through the clot at an interval of 0.3 or 0.7 mm. The treated clots were 3D-scanned by a 20-MHz ultrasound probe to quantify the channels. Restored flow rates were measured and clot debris particles generated from the treatments were analyzed. In all treatments, cavitation cloud was consistently generated in the center of the vessel lumen without contacting the vessel wall. After each treatment, a flow channel was successfully generated through and completely confined inside the clot. The channels had a diameter up to 60 % of the vessel diameter with restored flow up to 500 mL/min. The debris particles were small with over 99.9% < 10 μm and the largest at 153 um. Each clot (2 cm long) was recanalized within 7 min. The size of the flow channels increased by using higher P- and was significantly larger by using the 0.3 mm scan interval than those using 0.7 mm. The results in this study show the potential of this new microtripsy thrombolysis method for fast, precise, and effective clot recanalization, minimizing risks of vessel damage and embolism.

Enhancement of High-Intensity Focused Ultrasound Heating by Short-Pulse Generated Cavitation

“…In another study, a threshold of −33 MPa was observed in water by a focused acoustic pulse, and it was considered that cavitation bubbles were originated from nanometer-sized nuclei [42]. In histotripsy, cavitation bubbles are induced by extremely high-intensity pulses with a peak-negative pressure exceeding the threshold range and a soft tissue is eroded by the collapse of the bubbles [43][44][45]. Although the intrinsic threshold is extremely high, an acoustic pulse with a longer duration can generate clouds of bubbles even at a lower intensity because of the mechanism called "shock scattering" [46].…”

“…The typical duration of the trigger pulse was 10-100 µs. The duration time was set longer than the pulse duration of several µs in histotripsy studies [40,41,[43][44][45]. Since a peak negative pressure of a typical trigger pulse did not exceed the intrinsic threshold, typically around −30 MPa, the relatively longer duration time was necessary to form bubble clouds through a shock scattering mechanism.…”

Noninvasive thrombolysis using microtripsy: a parameter study

“…In addition, ultrasound combined with microbubble contrast agents has been demonstrated to successfully augment clot dissolution in the presence or absence of thrombolytic drugs [18–20]. Ultrasound has also been investigated as an independent thrombolysis method under approaches utilizing acoustic cavitation [21–26]. …”

“…Using the shock scattering approach, the cavitation cloud is less-confined and tends to be generated in contact with vessel wall where the weak nuclei reside, resulting in potential vessel damage from histotripsy treatment. A new histotripsy approach, termed microtripsy, has been recently investigated for thrombolysis application to improve treatment precision and avoid potential vessel damage [26]. Microtripsy uses an intrinsic threshold mechanism where a cavitation cloud is initiated via a single ultrasound pulse with only one high negative pressure phase.…”

“…The location and size of the cavitation cloud generated using the intrinsic threshold mechanism is more reproducible and predictable than the shock scattering mechanism. Our microtripsy thrombolysis study showed that, cavitation can be precisely generated and confined in the vessel lumen without contacting vessel wall, allowing for a precise flow channel to be created within the clot while minimizing the risk of vessel damage [26]. …”