Real-time feedback of histotripsy thrombolysis using bubble-induced color Doppler

Histotripsy thrombolysis is a non-invasive, drug-free, image-guided therapy that fractionates blood clots using well-controlled acoustic cavitation alone. Real-time quantitative feedback is highly desired during histotripsy thrombolysis treatment to monitor the progress of clot fractionation. Bubble-induced color Doppler (BCD) monitors the motion after cavitation generated by each histotripsy pulse, which has been found in gel and ex vivo liver tissue to be correlated with histotripsy fractionation. We investigated the potential of BCD to quantitatively monitor histotripsy thrombolysis in real time. To visualize clot fractionation, transparent three-layered fibrin clots were developed. Results indicated that a coherent motion follows the cavitation generated by each histotripsy pulse with a push and rebound pattern. The temporal profile of this motion expands and saturates as treatment progresses. A strong correlation exists between the degree of histotripsy clot fractionation and two metrics extracted from BCD: time of peak rebound velocity (tPRV) and focal mean velocity at a fixed delay (Vf,delay). The saturation of clot fractionation (i.e., treatment completion) matches well the saturations detected using tPRV and Vf,delay. The mean Pearson correlation coefficients between the progression of clot fractionation and the two BCD metrics were 93.1% and 92.6%, respectively. To validate BCD feedback in in vitro clots, debris volumes from histotripsy thrombolysis were obtained at different therapy doses and compared with Vf,delay. There is also good agreement between the increasing and saturation trends of debris volume and Vf,delay. Finally, a real-time BCD feedback algorithm to predict complete clot fractionation during histotripsy thrombolysis was developed and tested. This work illustrates the potential of BCD to monitor histotripsy thrombolysis treatment in real time.