Histotripsy is a noninvasive focused ultrasound technology similar to HIFU [14-17]. However, the underlying mechanism of histotripsy is fundamentally different, relying instead on a mechanical effect at the cellular level to destroy tissue. The term ‘histotripsy’ was coined at the University of Michigan in 2004 [14]. In Greek, ‘Histo’ means ‘soft tissue’, and ‘tripsy’ refers to breakdown. In contrast to thermal HIFU which uses continuous or long bursts of ultrasound at moderately high intensity and high duty cycle (ultrasound on-time/total treatment time ≥10%) to heat tissue [18], histotripsy uses short ultrasound bursts (microseconds in length) with a low duty cycle (≤1%) to minimize heating [19], and higher peak pressure amplitudes to generate acoustic cavitation from endogenous gas in tissues. Acoustic cavitation is the generation, oscillation, and collapse of microbubbles activated by ultrasound [20]. Very high ultrasound pressure causes inertial expansion and collapse of cavitation bubbles that impart localized intense strain that can fracture cells [21] into an acellular debris [16]. Ultrasound imaging can be used to guide and monitor the histotripsy procedure in real-time. In contrast to many existing minimally-invasive techniques, histotripsy can noninvasively remove tissue. When histotripsy is applied to a tissue-fluid interface (e.g., blood clots or cardiac tissue), the tissue is eroded from the surface inwards creating perforations with sharp boundaries [14,17]. When targeting histotripsy inside a bulk tissue (e.g., a tumor), histotripsy liquifies the target tissue to an acellular homogenate, and the debris is absorbed over 1–2 months by the body, leaving small scars [22,23].
Prior to the invention of histotripsy, cavitation created during thermal HIFU was known to cause structural mechanical damage to tissue [24,25]. Soft tissue cavitation damage was also observed during lithotripsy, particularly when using high pulse repetition frequencies [26,27]. The effect was further explored as an intentional surgical technique termed ‘shock wave therapy’ targeting soft tissue and tumor cells [28-30]. Follow-up work developed a more controllable and likely more durable piezoelectric sound source [31,32]. Prior studies [27,29,32-36] show that shockwave therapy was able to intentionally produce mechanical tissue disruption in the kidney, liver, and thrombus in animal models, consistent with what later became known as histotripsy. The negative phase of the acoustic wave following the positive shock for these systems is much longer (several microseconds) than current histotripsy systems, creating a larger focal zone with more sparse cavitation sites, though complete liquefaction was possible with a sufficiently large number of pulses.
The ability to effectively remove tissue allows histotripsy to be used in applications that are not possible with thermal techniques. The non-thermal nature also enables histotripsy to overcome many of the limitations associated with thermal devices (e.g., heat sink effect, lack of precise margins, and predictability). Histotripsy has been investigated for many pre-clinical applications, including treatment for tumors in the liver [37-41], kidney [23,40,42,43], and prostate [44,45], neurological diseases [46,47], thrombosis [48-51], hematoma [52-54], neonatal and fetal congenital heart disease [17,55], valvular diseases [56,57], kidney stones [58], abscesses [59], tendons [60], and biofilms [61-63]. Phase I human trials have been undertaken for histotripsy treatment of benign prostatic hyperplasia [64], liver cancer, and calcified valve stenosis [65], with early results suggesting safety and feasibility in humans. This review provides a comprehensive overview of histotripsy, including the mechanism, bioeffects, parameters, instruments, preclinical and clinical studies, and advantages and limitations compared to related devices.
