The primary finding from this study is that increasing FSD shifts the distribution of stone fragments toward smaller sizes with Ho:YAG laser lithotripsy when employing MD mode with fragmentation settings (0.8 J x 10 Hz). Interestingly, this relationship was not seen in trials where SP mode was used and invites further exploration of laser (and pulse mode) stone interactions and the process by which stones comminute. From a clinical perspective, these results suggest that FSD is a parameter that could be utilized with MOSES™ distance mode to control the distribution of fragment sizes produced during laser lithotripsy. Discovery of this new relationship between FSD and fragment size may motivate technological developments to measure (and better manage) FSD during laser lithotripsy.

Success of stone fragment aspiration during ureteroscopy is directly related to the fragment size produced from laser lithotripsy and the size of the outflow channel. Several experimental studies have characterized fragment sizes suitable for effective aspiration with different commercially available DISS and FANS devices [1,2,3,4, 22, 23]. Fragments up to 0.25 mm were cleared with FANS:ureteroscope combinations as tight as 11/13 Fr FANS:9.5 Fr ureteroscopes [3, 4] and DISS devices with 3.6 Fr working channels [22, 23]. Fragments up to 0.5 mm were cleared with 11/13 Fr FANS:7.5 Fr ureteroscopes [3, 4] and DISS devices with a 5.1 Fr working channels [2, 22]. Fragments up to 1.0 mm were cleared with 11/13 Fr FANS:6.3 Fr ureteroscopes [3, 4]. Fragments up to 2.0 mm were cleared with 12/14 FANS:6.3 Fr ureteroscopes [4]. Thus, fragment size thresholds of 0.25, 0.5, 1.0, and 2.0 mm can all be considered relevant thresholds based on the variety of ureteroscopic equipment currently available.

The results of this current study demonstrate a statistically significant inverse relationship between FSD and the size distribution of fragments produced when using Ho:YAG laser with fragmentation settings in MD mode. As FSD increased, the distribution shifted towards smaller sized stone fragments: as FSD decreased, the distribution shifted towards larger sized stone fragments. This point is most easily understood from Fig. 5, where the risk of creating a fragment > 1 mm with FSD of 0 mm is approximately 4, 7, 27, and 27 times greater than at FSD of 0.5, 1.0, 1.5, and 2.0 mm respectively when using MD mode. Interestingly, the relationship between increasing FSD and a shift towards smaller fragment sizes with MD mode was not seen with SP mode. In fact, with SP mode there was no statistical difference in fragment size distribution for any FSD tested.

While this study is the first to our knowledge to examine the relationship between FSD and fragment size, previous publications have examined the relationship between laser pulse modes and fragment size with Ho:YAG laser lithotripsy. Tominaga et al. evaluated pop-dusting parameters (0.5 J x 80 Hz) and found MOSES™ contact (MC) mode produced a greater mass of fragments < 0.5 mm than MD or long pulse (LP) [24]. Black et al. using a fixed 2 mm FSD found that for fragmentation settings (1 J x 20 Hz), MD produced a greater percentage of stone mass < 0.25 mm and lower percentage of fragments > 2 mm compared to SP mode [25].

Data from this current study also supports a benefit to using MD mode compared to SP mode with respect to fragment size. At every FSD, a greater percentage of the ablated stone mass was in the form of fragments < 0.25 mm for MD mode compared to SP. Similarly, the percentage of ablated stone mass composed of fragments > 0.25, > 0.5, > 1.0, and > 2.0 mm was less for MD mode compared to SP mode at every FSD distance. For example, considering FSD of 1.0 mm the mass percentage of fragments > 0.25 was 19% vs. 27%, > 0.5 mm was 9% vs. 17%, > 1.0 mm was 0% vs. 7%, and > 2.0 mm was 0% vs. 1% for MD and SP mode respectively (Table 1).

One factor that may contribute to this difference between MD and SP mode is pulse length. Full-width-half-max pulse length measurements of the 0.8 J laser pulses used in this study were 342 µs for MD and 61 µs for SP (Online Resource 1), demonstrating a similar pattern to previous measurement of 1 J pulses [17, 26]. In the study by King et al., peak pressures from 1 J pulses were measured to be 62 bars for SP and 11 bar for MD mode [26]. These values can serve as approximate benchmarks for peak pressures in the current study. The higher pressure transients that occur on the surface of a stone with shorter laser pulse lengths, induce photoacoustic effects that over multiple pulses may propagate fractures in stones, which could in turn produce larger fragments [26].

The potential benefits of using larger FSD with MD mode to shift the fragment distribution toward smaller sizes, must be considered in the context of decreased ablation rate. For example, ablation rate at 2 mm FSD was 5 and 6 times lower than at 0 mm FSD for MD and SP respectively. These ablation rate findings are consistent with results from previous studies [14, 17] and are likely a consequence of greater energy absorption in the longer fluid path between the laser fiber and the stone with larger FSDs. As a result, less energy from each laser pulse reaches the stone. Lower ablation rates at larger FSDs translate into longer lasing time and greater energy use, but overall treatment time may be shorter if clogging and the associated time to clear clogs is reduced by producing smaller fragments. Optimization of treatment in the future will need to balance the speed of stone ablation against the risk of clogging and account for the size of the outflow channel being used. Effective use of FSD as a tool to control fragment size is predicated on development of effective technologies to measure FSD in real-time and perhaps even to regulate laser energy delivery within a defined FSD range. Several approaches based on reflectance and fluorescence for determination of appropriate FSD have demonstrated promising preclinical results [27, 28].

This study was focused only on Ho:YAG laser lithotripsy. We acknowledge that thulium fiber laser (TFL) and Tm:YAG lasers are also used frequently, and many authors have reported that TFL produces more dust and fewer larger fragments than Ho:YAG [12, 29]. However, in certain scenarios with TFL treatment of human stones, larger fragments can still occur [12]. It is unclear with TFL and Tm:YAG lasers if a similar relationship between FSD and fragment size might also exist. It is expected though, that stone ablation mass and ablation rate would decrease as FSD increases [30], similar to the Ho:YAG data in this study.

This current study was designed to test the scientific hypothesis that FSD is inversely related to production of larger stone fragments. While this hypothesis was confirmed and opens up a number of exciting possibilities for laser lithotripsy and aspiration of stone fragments, it is not broadly clinically applicable at this point. First, only one setting (0.8 J x 10 Hz) was tested using two pulse modes (MD, SP) in this study. While this was sufficient to demonstrate that an FSD/fragment size relationship exists for MD mode, the mechanism on which it is based and the role that different modulated and unmodulated pulse modes play, needs further exploration. Second, brushite crystalline aggregate model stones rather than human stones were used in this study. This was partially necessitated by the need to have uniform stone samples and flat stone surfaces across all experimental trials. This stone model exhibits a comminution behavior more similar to human stones than BegoStone [19] but even so, studies to validate the FSD/fragment size relationship are needed with human stones. Third, the model stones were fixed to a petri dish to prevent movement during ablation. This approach allows for consistent delivery of laser energy and precise control of FSD during trials needed to test the proposed hypothesis. This degree of stone fixation though, is not typical clinically and applicability of the findings to mobile stones will also need to be explored.