Real-Time Transcranial Histotripsy Treatment Localization and Mapping Using Acoustic Cavitation Emission Feedback.

Cavitation events generated during histotripsy therapy generate large acoustic cavitation emission (ACE) signals that can be detected through the skull. This article investigates the feasibility of using these ACE signals, acquired using the elements of a 500-kHz, 256-element hemispherical histotripsy transducer as receivers, to localize and map the cavitation activity in real time through the human skullcap during transcranial histotripsy therapy. The locations of the generated cavitation events predicted using the ACE feedback signals in this study were found to be accurate to within <1.5 mm of the centers of masses detected by optical imaging and found to lie to within the measured volumes of the generated cavitation events in >~80 % of cases. Localization results were observed to be biased in the prefocal direction of the histotripsy array and toward its transverse origin but were only weakly affected by focal steering location. The choice of skullcap and treatment pulse repetition frequency (PRF) were both observed to affect the accuracy of the localization results in the low PRF regime (1-10 Hz), but the localization accuracy was seen to stabilize at higher PRFs (≥10 Hz). Tests of the localization algorithm in vitro, for treatment delivered to a bovine brain sample mounted within the skullcap, revealed good agreement between the ACE feedback-generated treatment map and the morphological characteristics of the treated volume of the brain sample. Localization during experiments was achieved in real time for pulses delivered at rates up to 70 Hz, but benchmark tests indicate that the localization algorithm is scalable, indicating that higher rates are possible with more powerful hardware. The results of this article demonstrate the feasibility of using ACE feedback signals to localize and map transcranially generated cavitation events during histotripsy. Such capability has the potential to greatly simplify transcranial histotripsy treatments, as it may provide a non-MRI-based method for monitoring and localizing transcranial histotripsy treatments in real time.

Soft-Tissue Aberration Correction for Histotripsy.

Acoustic aberrations caused by natural heterogeneities of biological soft tissue are a substantial problem for histotripsy, a therapeutic ultrasound technique that uses acoustic cavitation to mechanically fractionate and destroy unwanted target tissue without damaging surrounding tissue. These aberrations, primarily caused by sound speed variations, result in severe defocusing of histotripsy pulses, thereby decreasing treatment efficacy. The gold standard for aberration correction (AC) is to place a hydrophone at the desired focal location to directly measure phase aberrations, which is a method that is infeasible in vivo. We hypothesized that the acoustic cavitation emission (ACE) shockwaves from the initial expansion of inertially cavitating microbubbles generated by histotripsy can be used as a point source for AC. In this study, a 500-kHz, 112-element histotripsy phased array capable of transmitting and receiving ultrasound on all channels was used to acquire ACE shockwaves. These shockwaves were first characterized optically and acoustically. It was found that the shockwave pressure increases significantly as the source changes from a single bubble to a dense cavitation cloud. The first arrival of the shockwave received by the histotripsy array was from the outer-most cavitation bubbles located closest to the histotripsy array. Hydrophone and ACE AC methods were then tested on ex vivo porcine abdominal tissue samples. Without AC, the focal pressure is reduced by 49.7% through the abdominal tissue. The hydrophone AC approach recovered 55.5% of the lost pressure. Using the ACE AC method, over 20% of the lost pressure was recovered, and the array power required to induce cavitation was reduced by approximately 31.5% compared to without AC. These results supported our hypothesis that the ACE shockwaves coupled with a histotripsy array with transmit and receive capability can be used for AC for histotripsy through soft tissue.

Bubble-Induced Color Doppler Feedback Correlates with Histotripsy-Induced Destruction of Structural Components in Liver Tissue.

Bubble-induced color Doppler (BCD) is a histotripsy-therapy monitoring technique that uses Doppler ultrasound to track the motion of residual cavitation nuclei that persist after the collapse of the histotripsy bubble cloud. In this study, BCD is used to monitor tissue fractionation during histotripsy tissue therapy, and the BCD signal is correlated with the destruction of structural and non-structural components identified histologically to further understand how BCD monitors the extent of treatment. A 500-kHz, 112-element phased histotripsy array is used to generate approximately 6- × 6- × 7-mm lesions within ex vivo bovine liver tissue by scanning more than 219 locations with 30-1000 pulses per location. A 128-element L7-4 imaging probe is used to acquire BCD signals during all treatments. The BCD signal is then quantitatively analyzed using the time-to-peak rebound velocity (tprv) metric. Using the Pearson correlation coefficient, the tprv is compared with histologic analytics of lesions generated by various numbers of pulses using a significance level of 0.001. Histologic analytics in this study include viable cell count, reticulin-stained type III collagen area and trichrome-stained type I collagen area. It is found that the tprv metric has a statistically significant correlation with the change in reticulin-stained type III collagen area with a Pearson correlation coefficient of -0.94 (p <0.001), indicating that changes in BCD are more likely because of destruction of the structural components of tissue.

Non-Invasive Thrombolysis Using Microtripsy in a Porcine Deep Vein Thrombosis Model.

Histotripsy is a non-invasive therapeutic technique that uses ultrasound generated from outside the body to create controlled cavitation in targeted tissue, and fractionates it into acellular debris. We have developed a new histotripsy approach, termed microtripsy, to improve targeting accuracy and to avoid collateral tissue damage. This in vivo study evaluates the safety and efficacy of microtripsy for non-invasive thrombolysis in a porcine deep vein thrombosis model. Acute thrombi were formed in left femoral veins of pigs (∼35 kg) by occluding the vessel using two balloon catheters and infusing with thrombin. Guided by real-time ultrasound imaging, microtripsy thrombolysis treatment was conducted in 14 pigs; 10 pigs were euthanized on the same day (acute) and 4 at 2 wk (subacute). To evaluate vessel damage, 30-min free-flow treatment in the right femoral vein (no thrombus) was also conducted in 8 acute pigs. Blood flow was successfully restored or significantly increased after treatment in 13 of the 14 pigs. The flow channels re-opened by microtripsy had a diameter up to 64% of the vessel diameter (∼6 mm). The average treatment time was 16 min per centimeter-long thrombus. Only mild intravascular hemolysis was induced during microtripsy thrombolysis. No damage was observed on vessel walls after 2 wk of recovery, venous valves were preserved, and there was no sign of pulmonary embolism. The results of this study indicate that microtripsy has the potential to be a safe and effective treatment for deep vein thrombosis in a porcine model.