Potential advantages of using histotripsy to treat BPH include extracorporeal application of energy, feedback with real-time US, rapid tissue disintegration, and reduction of debris to a liquefied state passable via the urethra. To capitalize on these features, A stepwise research approach was followed, building on initial feasibility studies, to characterize the number of acoustic pulses needed to disrupt each of the tissues within the prostate (glandular, stromal, periurethral) and to assess safety. Specifically, studies were performed to characterize the lack of substantial bleeding with histotripsy treatment, to quantify pain and assess tolerability, and to understand the consequence of inadvertently applying histotripsy to critical structures adjacent to the prostate. In all of these studies, intact older male canines were used as the model that was anatomically most similar to the human prostate. Histotripsy was applied transabdominally in anesthetized supine canine subjects with a water bolus positioned over the suprapubic region. The histotripsy transducer was placed in the water bolus and its focal volume co-localized within the prostate (Fig. 23.2). High resolution US images of the prostate and bubble cloud were obtained from A 10 MHz TRUS probe. The bubble cloud was translocated through the treatment region either by following a prescribed pattern or manually with joystick controls to produce volume ablation.

The feasibility of prostate histotripsy was first established in acute studies [9]. Based on initial observations of variability in tissue disruption, additional studies were conducted demonstrating that glandular tissue was more easily disrupted than periurethral prostatic tissue (28,000 pulses/cm³ vs. 270,000 pulses/cm³) [15]. In cases where the prostatic urethra was not completely treated, the endoscopic appearance after histotripsy correlated with the probability of prostatic urethral disintegration by 14 days. This was a desired outcome in order to permit disintegrated material in the treatment cavity to drain via the urethra [17]. An alternative urethral-sparing treatment strategy was evaluated, where only a modest 1–2 cm³ volume of glandular tissue was disrupted and the periurethral tissue spared. This strategy resulted in pools of liquefied debris within the prostate that resorbed over an 8 week period. Residual treatment sites contained simple fluid and prostate volume decreased by 12% without evidence of abscess or increased chronic inflammation [18].

Limited hematuria and little hemorrhage were observed in previous studies. This prompted further exploration in nine canine subjects that were anticoagulated with warfarin (international normalized ratio ranged from 1.2 to 11.3) and then underwent large-volume histotripsy treatment of the prostate producing TURP-like defects [19]. Serial assessment of serum hemoglobin did not reveal a decrease and only mild hematuria without clots was noted in the first 48 h after treatment, before clearing. This suggested that histotripsy tissue treatment exhibits a hemostatic effect even in anticoagulated subjects.

In order to move towards human translation of this technology, it was important to characterize local and systemic effects of histotripsy. Eighteen canine subjects underwent histotripsy treatment to produce at least a 4 cm³ volume treatment cavity. Upon harvest (between 0 and 56 days after treatment) a vacuous treatment cavity was confirmed. Validated pain scoring revealed mild post-treatment discomfort that resolved with catheter removal. On several occasions, the treatment volume inadvertently included a portion of rectum, which resulted in a prostatorectal fistula in one case. In all other subjects, minimal hematuria and only transient abnormalities in blood tests were noted which resolved after several days [16]. The treatment cavity in each case exhibited only minimal residual debris and was covered with new urothelium 28 days after treatment (Fig. 23.3).

The prostate is surrounded by critical structures which must be spared of injury during prostate treatment. Although histotripsy is precise, targeting errors or patient motion may result in inadvertent treatment of these structures. It was apparent from earlier studies that damage thresholds from histotripsy vary based on tissue type [15, 20]. Studies were conducted to establish the damage thresholds of critical periprostatic structures by applying 1000, 10,000, or 100,000 histotripsy pulses directly on the urinary sphincter, neurovascular bundle, rectum, and 750,000 pulses to the bladder trigone, and ureteral orifices [21, 22]. After 10,000 pulses, the rectum exhibited moderate collagen disruption and focal mucosal disruption. The other structures however were more resilient. After 100,000 pulses the urinary sphincter was structurally intact and exhibited minimal histologic muscle fiber disruption. Arteries, veins, and nerves within the neurovascular bundles appeared intact, though extensive destruction of surrounding loose connective tissue was observed [21]. Cystoscopy, after histotripsy was applied to the bladder trigone, revealed moderate edema, though all ureteral orifices were preserved and patent [22].

After 5 years of successful research funded by National Institutes of Health and several foundations, our research group realized that additional resources would be needed to move further along the translational pathway towards human application. After evaluation of the options, it became clear that we needed to create a start-up company. HistoSonics, Inc. was formed in December 2009 and financed by a consortium of venture capital firms. HistoSonics was subsequently successful at creating a human prototype device (VortxR_X™) for treatment of BPH and in May 2013 the US Food and Drug Administration approved an investigational device exemption to conduct a human pilot trial. Results from this 25 patient first-in-man trial demonstrated an excellent safety profile and improvement in lower urinary tract symptoms, however TURP-like tissue destruction as seen in the canine model has not yet been achieved [23]. The histotripsy system will need to be refined in order to enhance the acoustic pressures needed for more effective cavitation and tissue disruption.

Histotripsy has been applied in a canine ACE-1 cancer model with metastatic potential to explore histotripsy effects on malignant tissue [24]. In seven canine subjects, histotripsy was applied to prostate tumor implants [25]. Tumor disruption was apparent in all acute subjects while histology from chronic subjects revealed necrosis and hemorrhage. Metastases were apparent in all three tumor implanted controls, while none of the histotripsy treated chronic subjects exhibited metastases [25].

A similar study in rabbits with subcapsular renal implants of VX-2 tumor demonstrated pools of homogenized tumor, while kidneys harvested at 24 h after treatment also exhibited an acute inflammatory response [26]. This study confirmed malignant tissue in the kidney could be homogenized with histotripsy and led to a subsequent study to measure the metastatic burden after histotripsy [27]. Thirteen days after tumor implantation in the kidney, histotripsy was applied, followed by nephrectomy 1 day later and necropsy 7 days later. There was no statistical difference in total lung metastases or density of metastases when comparing histotripsy treated and control rabbits [27]. Similar results have been reported in a murine model treated with mechanical HIFU, a focused ultrasound therapy that combines cavitational and thermal effects [28]. These studies, though not definitive, do suggest that histotripsy may have a direct or indirect effect that impedes tumor metastases. Further studies are needed to verify these findings.

Induction and control of cavitation is the fundamental concept that underlies histotripsy. SWL treatment of urinary stones is also, at least partially, dependent on cavitation. Histotripsy was used to erode Ultracal-30 model stones and produced particles no larger than 100 μm [29, 30]. While SWL breaks down stone by progressive subdivision, histotripsy uses cavitation to produce surface erosion. Understanding this mechanistic difference led to the hypothesis that SWL and histotripsy could be used synergistically to improve treatment of urinary stones. When both histotripsy and SWL acoustic pulses were applied to model stones, stone comminution was more efficient and the distribution of stone fragments was shifted to smaller sizes than seen with SWL alone [31].

Additional urologic applications for histotripsy include non-invasive fenestration of ureteroceles which has been tested in an ex-vivo tissue model [32] and in-vitro histotripsy treatment of urinary stents and catheters to destroy Escherichia Coli biofilms [33]. Histotripsy has application for non-urologic diseases as well. Transcutaneous liver ablation is feasible in an in-vivo porcine model and could be applied as treatment for hepatocellular carcinoma and liver metastases [34]. Histotripsy has been used to puncture the intracardiac ventricular septum in porcine models. This has utility for temporizing newborns with sever cardiac defects [35]. Intrauterine histotripsy for potential fetal intervention was successful in ablating liver and renal tissue in a sheep model [36]. Deep venous thrombi can also be disintegrated with non-invasive histotripsy to re-establish venous flow as demonstrated in porcine models [37]. In phantom blood vessel models it has been possible to create an acoustic embolus trap to prevent larger particles from escaping during histotripsy thrombolysis [38].