Chirp-Coded Subharmonic Imaging With Volterra Filtering: Histotripsy Bubble Cloud Assessment In Vitro and Ex Vivo.

Histotripsy is a noninvasive focused ultrasound therapy that liquifies tissue via bubble activity. Conventional ultrasound imaging is used in current clinical practice to monitor histotripsy. Developing surrogate imaging metrics for successful treatment outcomes remains an unmet clinical need. The goal of this work was twofold. First, we investigated whether histotripsy bubble clouds detected with nonlinear imaging (chirp-coded subharmonic imaging with and without Volterra filtering) could be used to assess the ablation zone in vitro. Second, we evaluated the feasibility of improving bubble cloud contrast with this approach in ex vivo porcine kidney. Histotripsy bubble clouds were generated in red blood cell-doped agarose phantoms and imaged with a curvilinear ultrasound probe. The ablation zone was assessed based on images collected with a digital camera. The relationship between the bubble cloud area and the ablation area was assessed using receiver operating characteristic (ROC) analysis, F1 score, accuracy, and Matthews correlation coefficient. Histotripsy bubble clouds were also generated in ex vivo porcine tissue and the ability to improve bubble cloud contrast to tissue was evaluated. Implementing chirp-coded subharmonic imaging with the third-order Volterra filter enhanced contrast-to-tissue ratio (CTR) by up to $40.06~\pm ~0.70$ dB relative to standard imaging in vitro. Furthermore, subharmonic imaging combined with Volterra filtering estimated bubble cloud areas that best matched the ablation zone area based on the analysis metrics. Furthermore, ex vivo studies showed CTR improvement of up to $26.95~\pm ~6.49$ dB. Taken together, these findings advance image guidance and monitoring approaches for histotripsy.