In vitro evidence

In vitro experiments on the effectiveness of BWL across multiple studies demonstrate its potential as a noninvasive, effective, and controlled method for fragmenting urinary stones of various compositions, including calcium oxalate monohydrate (COM), struvite, uric acid, and cystine, with high comminution rates.

Dose settings and size of stone fragments

Maxwell et al. highlighted that higher ultrasound frequencies (800 kHz) produced smaller fragments (< 1 mm), while lower frequencies (170 kHz) resulted in larger fragments (3–4 mm), allowing for controlled fragmentation tailored to clinical needs [6]. Simulations demonstrate that increasing pressure amplitude (up to 6.5 MPa) and ultrasound frequency (up to 800 kHz), improved stone fragmentation while minimizing tissue damage, potentially making it safer and more effective than shock wave lithotripsy (SWL). Moghimnezhad et al. [11] which was similarly shown by Bailey et al. [12] especially effective for small stones (1–3 mm), achieving 87% mass reduction to submillimeter dust within 10 min. Larger stones (3–5 mm) fragmented effectively at both low (390 kHz) and high frequencies, implying that a mixed-frequency approach show potential benefits. Ramesh et al. [13] confirmed BWL’s broad applicability by fragmenting 89% of human urinary stones within 30 min and validated the use of ultrasonic propulsion [14] for real-time assessment of fragmentation.

Physical mechanisms of burst wave

Sapozhnikov et al. [15] developed a theoretical model indicating that stress amplification within stones depends on ultrasound frequency and stone geometry and identified optimal frequency ranges (ka ≈ 2–5) for different stone compositions, supporting a sequential fragmentation strategy using low and high frequencies. Maxwell et al. [16, 17] further investigated the physical mechanisms of BWL, using photoelastic imaging to confirm that elastic waves (shear and longitudinal) propagate within the stone, forming standing waves that create localized stress points and initiate fractures. The results demonstrated that lower frequencies produced larger fragments, whereas higher frequencies generated smaller, passable fragments.

What we learned from pre-clinical experimentsStone comminution

Wang et al. evaluated the effectiveness and safety of BWL, using three porcine models implanted with 6–7 mm human COM kidney stones [18]. Stones were targeted and treated transcutaneously using a BWL and an ultrasound imaging probe for guidance with an exposure time of three 10-minute intervals per stone. Findings showed at least 50% of each stone was reduced to < 2 mm fragments and 100% of four stones were reduced to < 4 mm fragments. Yet, in three out of five treatments, stones were completely disintegrated.

Maxwell et al. [19] developed a BWL system tailored for treating obstructing ureteric stones in pet cats using 35 natural COM stones. The system could effectively fragment stones into pieces smaller than 1 mm—with an average reduction of stone mass by 73–97% within 30 to 50 min of treatment. Overall, the study supports the potential of this adapted BWL system as it holds the promise of effective stone fragmentation and minimal associated tissue damage.

Holmes et al. [20] applied BWL combined with ultrasonic propulsion to treat urolithiasis in a bottlenose dolphin and a harbor seal. In the dolphin, two BWL treatments fragmented ureteral stones, and the ultrasonic propulsion helped reposition the fragments, demonstrating that BWL and ultrasonic propulsion combined can effectively address urinary stones in animals with challenging anatomies.

Tissue injury

Regarding safety, Wang et al. showed no skin or intervening tissue damage, a minimal injury to the functional renal volume on magnetic resonance imaging (MRI) and minor petechial hemorrhages in the urothelium near the stone fragments with no significant renal parenchymal injury on histological assessment [18, 21]. Connors et al. [22] investigated for immediate functional or morphological kidney damage in 12 female pigs split into two groups: one group received BWL treatment (18,000 pulses delivered at 10 pulses per second with 20 cycles per pulse, using specific pressure settings of 12 MPa positive and − 7 MPa negative), while the other served as sham controls. The results showed no significant changes in renal function, nor did it produce measurable hemorrhagic lesions compared to sham-treated kidneys. The authors suggest that the lower pressure and reduced cavitation associated with BWL may account for its tissue-sparing effects.

Shelton et al. [23] evaluated if BWL causes renal hemorrhage in a therapeutically anticoagulated state using a porcine model with unilateral heparinized kidney and contralateral kidney as control. Urine analyses revealed only minimal microscopic hematuria in both groups, with no significant differences. MRI-based lesion analysis showed that the hemorrhagic injury in BWL-treated kidneys was not different from controls. This suggests that BWL can safely fragment kidney stones without inducing significant bleeding, even in an anticoagulated state, offering a promising alternative for patients who require continuous anticoagulation.

May et al. [24] investigated whether BWL induces detectable renal injury by real time monitoring of porcine kidneys using custom BWL transducers at 170 kHz and 335 kHz. Most lesions induced by BWL, especially those generated using the 335 kHz transducer, were very small and insignificant but larger injuries were observed at 170 kHz. Histologically, the injuries were like those seen with SWL, characterized by focal tubular damage and intraparenchymal hemorrhage. These results suggest that real-time ultrasound monitoring, combined with MRI-based quantification, offers an effective framework for preclinical safety evaluation of BWL, potentially allowing clinicians to adjust treatment parameters in real time to minimize renal injury.

What we learned from human studies

To date, clinical studies have demonstrated BWL effectiveness in stone comminution and stone displacement by combining with ultrasonic propulsion, as well as safety and tolerability in awake patients within a short ten minutes treatment.

Harper et al. reported the first account of in-human BWL trial on kidney and ureteral stone in 2021 [25]. Effectiveness and safety of in-human BWL were demonstrated by the complete comminution of a 7 mm renal stone into < 2 mm fragments on endoscopic view within 10 min (8.5 min at 7 MPa peak negative pressure and 10 Hz repetition rate, and 30 s at 6 MPa and 17 Hz) in the first patient under anaesthesia. The BWL pulses were triggered by the operator during phases of the breathing cycle when the stone falls within the target zone on real-time ultrasound. Tolerability of in-human BWL was demonstrated by the first awake patient with 7.5 mm symptomatic ureterovesical stone reporting no added discomfort from BWL treatment. The ability to control breathing in an awake patient might improve the treatment outcomes.

Hall et al. evaluated the efficacy and usage of ultrasonic propulsion alone or with BWL bursts in 24 unanaesthetised patients with ureteral stones prospectively [26]. The primary outcome of stone displacement occurred in 66%; whilst secondary outcome was a 86% distal ureteral stone passage rate. The pain scores were significantly lowered during the procedure from 2.1±2.3 to 1.6±2.0 (p = 0.03). The study pointed out room for finetuning of transducer engineering when 6 out of 26 patients failed screening due to a large skin to stone distance.

Harper et al. looked into the effectiveness of stone fragmentation in 19 patients with BWL in ten minutes [7], where they reported a median stone comminution of 90% stone volume in 91% targeted stones, of which 39% targeted stones were completely fragmented (defined as all fragments = < 2 mm). The study examined for any tissue injury by independent blinded visual scoring of ureteroscopic video, where only mild petechiae and small blood clots were noted with no reported adverse events, confirming its safety.

Chew et al. [8] reported the first in-human multi-center prospective trial of BWL on urinary tract stones with therapy dose levels between 4.5 and 8 MPa of acoustic negative pressure (NCT03811171). BWL successfully fragmented stones in 88% of cases, with 51% achieving residual fragments of less than or equal to 2 mm on non-contrast CT scan at 10 ±2 weeks. 86% of trial patients underwent BWL without sedation in a clinic setting over 30 min. The procedure was well-tolerated, with only Clavien-Dindo Grade 1 adverse events, most commonly transient hematuria (93.2%) followed by renal colic treated with analgesics (56.8%). Despite being able to treat stones across depths ranging from 4 cm to 14 cm with three different treatment probes, limitations exist including challenges in treating certain stone locations due to ultrasound constraints. As BWL is an ultrasound based technology, stone located at proximal, mid ureter and some upper pole calyceal stones are not amenable to BWL if not identified by ultrasound, particularly if obscured by air or overlying bone.

Ongoing trials of BWL

Ongoing trials of BWL focus on two main themes, namely consolidation of the efficacy and safety of BWL, and improving stone-free rates by combining BWL with other technologies.

There are currently two ongoing studies registered in the ClinicalTrials.gov. Chew et al. showed the feasibility of BWL in 44 patients with upper urinary tract stones [8], paving ground work for the pivotal trial. SonoMotion (San Mateo, California) designed a trial to include patients to further evaluate the efficacy and safety of BWL (NCT05701098): SOUND Pivotal Trial– Sonomotion stOne comminUtion resoNance ultrasounD. This prospective, open-label multicenter, single-arm study, plans to include up to 116 patients with upper urinary tract stones of 4–10 mm. The primary outcome is to investigate the safety (in terms of adverse events, unplanned emergency department or clinic visits, and the need for further intervention) and effectiveness (size of fragment at 10 weeks after treatment) of BWL. This study is currently recruiting at 10 study locations, all located in North America.

The other clinical trial registered is to study the combination of BWL with ultrasound propulsion. The previous study published by Hall et al. in 2022 only included 13 patients who used both technologies, and the primary outcome was stone motion [26]. The registered trial by the University of Washington is titled Ultrasound to Facilitate Stone Passage (NCT04796792, or Propulse2 [27]). It is a prospective, open-label, multicenter study to determine whether the combination of breaking and repositioning of stones with ultrasound under no anesthesia can result in better stone passage. The trial has three phases: phase 1 is to include 20 subjects that tests for the feasibility; phase 2a is a randomized control trial which aims to include a total of 100 subjects, in a 1:1 ratio; phase 2b is a feasibility study of BWL by 20 subjects with spinal cord injury. Phase 2 of this study will be conducted concurrently after phase 1 results are reviewed by the FDA and approved to proceed to phase 2. This study is not yet recruiting.

Take home messages and future directions

Animal studies, reinforced by experimental evidence and substantial provisional findings replicated in human trials, demonstrate BWL as a promising non-invasive alternative to SWL. BWL offers controllable stone fragmentation and the capability to generate dust by modulating shock wave frequency. This coupled with minimal tissue damage and nephron injury is a significant leap forward from SWL. Furthermore, BWL’s stone propulsion feature may enhance treatment efficacy for lower pole and ureteric stones. When combined with its portable design, these benefits position BWL as a potential candidate for portable office-based or even home-based lithotripsy, marking a transformative step in urological care. Although BWL still faces the same challenges as SWL regarding ultrasound constraints with acoustic window and skin-to-stone distance, these limitations will hopefully be resolved in the future as technology advances. Finally, BWL’s safety profile in anticoagulated patients without the need of anesthesia could establish it as a groundbreaking advancement in urolithiasis management. The potential of BWL is yet unrealized. Its utility as an alternative to SWL or as an adjunct to ureteroscopy in relocation and/or fragment disintegration can be defined once it is commercially available. Its portability best suits stones and patients amenable for ambulatory procedures.