Histotripsy-induced cavitation cloud initiation thresholds in tissues of different mechanical properties

Abstract

Histotripsy is an ultrasound ablation method that depends on the initiation and maintenance of a cavitation bubble cloud to fractionate soft tissue. This paper studies how tissue properties impact the pressure threshold to initiate the cavitation bubble cloud. Our previous study showed that shock scattering off one or more initial bubbles, expanded to sufficient size in the focus, plays an important role in initiating a dense cavitation cloud. In this process, the shock scattering causes the positive pressure phase to be inverted, resulting in a scattered wave that has the opposite polarity of the incident shock. The inverted shock is superimposed on the incident negative pressure phase to form extremely high negative pressures, resulting in a dense cavitation cloud growing toward the transducer. We hypothesize that increased tissue stiffness impedes the expansion of initial bubbles, reducing the scattered tensile pressure, and thus requiring higher initial intensities for cloud initiation. To test this hypothesis, 5-cycle histotripsy pulses at pulse repetition frequencies (PRFs) of 10, 100, or 1000 Hz were applied by a 1-MHz transducer focused inside mechanically tunable tissue-mimicking agarose phantoms and various ex vivo porcine tissues covering a range of Young's moduli. The threshold to initiate a cavitation cloud and resulting bubble expansion were recorded using acoustic backscatter detection and optical imaging. In both phantoms and ex vivo tissue, results demonstrated a higher cavitation cloud initiation threshold for tissues of higher Young's modulus. Results also demonstrated a decrease in bubble expansion in phantoms of higher Young's modulus. These results support our hypothesis, improve our understanding of the effect of histotripsy in tissues with different mechanical properties, and provide a rational basis to tailor acoustic parameters for fractionation of specific tissues.

Fig. 1

Schematic of bubble cloud formation by shock scattering. (1) During the initial cycles of a histotripsy pulse, individual bubbles are expanded in the focus in response to incident negative pressure. (2) The shockwaves from subsequent cycles are scattered off initially expanded bubbles, (3) which inverts the shock and constructively interferes with the negative phase of the next incident wave. (a) Previous work has demonstrated a histotripsy bubble cloud is only formed when initial bubbles expand to a large enough size for shock scattering to result in sufficiently large reflected negative pressures. (b) If expansion of initial bubbles is of insufficient size to cause significant scattering, the negative pressures produced will be insufficient to initiate a histotripsy bubble cloud.

Fig. 2

Experimental setup. A 1-MHz therapy transducer focus was aligned inside samples for cavitation initiation experiments. Bubble cloud formation was monitored using a low-frequency marine hydrophone and verified with high-speed optical imaging.

Fig. 3

Example histotripsy pressure waveform.

Fig. 4

Example waveforms collected by marine hydrophone with corresponding optical images of bubble cloud. Results show a significant increase in the amplitude of the waveform collected by the marine hydrophone when a cavitation cloud has been initiated compared with uninitiated cases. Examples shown are of 2.5% agarose tissue phantoms treated at 10 Hz right below and above the cavitation cloud threshold with peak negative pressures of (a) 24.2 MPa and (b) 25.1 MPa. The threshold for cloud initiation was determined to be the lowest pressure at which a bubble cloud was initiated within ten pulses and maintained for the duration of the treatment for all six samples.

Fig. 5

Cavitation cloud initiation threshold in phantoms with varied agarose concentration. Threshold results show significant increase in the peak negative pressure required to initiate cavitation inside higher concentration tissue phantoms. All increases in threshold between gel concentrations were considered significant (p-values < 0.05).

Fig. 6

The initiation threshold of cavitation clouds induced by histotripsy in ex vivo porcine tissues plotted as a function of tissue Young’s modulus.

Fig. 7

Simulation of initial bubble expansion in tissues of varied Young’s modulus. Plot shows the history of the bubble radius for a 10-nm initial bubble subjected to the first cycle of a histotripsy pulse at a peak negative pressure of 15 MPa with Young’s moduli varied from 1 kPa to 10 MPa.

Fig. 8

Bubble expansion in agarose tissue phantoms of varied concentration. Results show the maximum bubble expansion and the bubble collapse time for bubbles produced by histotripsy in agarose tissue phantoms. Results show a significant decrease in (a) maximum bubble expansion and (b) bubble collapse time with increasing agarose concentration. All decreases in bubble diameter and collapse time between gel concentrations were considered significant (p-values < 0.05).