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Stone comminution in shock wave lithotripsy (SWL) has been documented to result from mechanical stresses conferred directly to the stone, as well as the activity of cavitational microbubbles. Studies have demonstrated that the presence of this cavitation activity is crucial for stone subdivision; however, its exact role in the comminution process remains somewhat weakly defined, in part because it is difficult to isolate the cavitational component from the shock waves themselves. In this study, we further explored the importance of cavitation in SWL stone comminution through the use of histotripsy ultrasound therapy. Histotripsy was used to target model stones designed to mimic the mid-range tensile fracture strength of naturally occurring cystine calculi with controlled cavitation at strategic time points in the SWL comminution process. All SWL was applied at a peak positive pressure (p+) of 34 MPa and a peak negative pressure (p-) of 8 MPa; a shock rate of 1 Hz was used. Histotripsy pulses had a p- of 33 MPa and were applied at a pulse repetition frequency (PRF) of 100 Hz. Ten model stones were sonicated in vitro with each of five different treatment schemes: A) 10 min of SWL (600 shocks) with 0.7 s of histotripsy interleaved between successive shocks (totaling to 42 000 pulses); B) 10 min of SWL (600 shocks) followed by 10 min of histotripsy applied in 0.7-s bursts (1 burst per second, totaling to 42 000 pulses); C) 10 min of histotripsy applied in 0.7-s bursts (42 000 pulses) followed by 10 min of SWL (600 shocks); D) 10 min of SWL only (600 shocks); E) 10 min of histotripsy only, applied in 0.7-s bursts (42 000 pulses). Following sonication, debris was collected and sieved through 8-, 6-, 4-, and 2-mm filters. It was found that scheme D, SWL only, generated a broad range of fragment sizes, with an average of 14.9 ± 24.1% of the original stone mass remaining >; 8 mm. Scheme E, histotripsy only, eroded the surface of stones to tiny particulate debris- that was small enough to pass through the finest filter used in this study (<;2 mm), leaving behind a single primary stone piece (>;8 mm) with mass 85.1 ± 1.6% of the original following truncated sonication. The combination of SWL and histotripsy (schemes A, B, and C) resulted in a shift in the size distribution toward smaller fragments and complete elimination of debris >; 8 mm. When histotripsy-controlled cavitation was applied following SWL (B), the increase in exposed stone surface area afforded by shock wave stone subdivision led to enhanced cavitation erosion. When histotripsy-controlled cavitation was applied before SWL (C), it is likely that stone surface defects induced by cavitation erosion provided sites for crack nucleation and accelerated shock wave stone subdivision. Both of these effects are likely at play in the interleaved therapy (A), although shielding of shock waves by remnant histotripsy microbubble nuclei may have limited the efficacy of this scheme. Nevertheless, these results demonstrate the important role played by cavitation in the stone comminution process, and suggest that the application of controlled cavitation at strategic time points can provide an adjunct to traditional SWL therapy.