An In Vitro Study of the Thermal Effect of Holmium Laser Lithotripsy of Ureteral Stones

An In Vitro Study of the Thermal Effect of Holmium Laser Lithotripsy of Ureteral Stones | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article An In Vitro Study of the Thermal Effect of Holmium Laser Lithotripsy of Ureteral Stones Li Taixun, Shao Guangjing, Li Huijuan, Guo Suqin, Wang Wei, Li Hongzhou, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2085574/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To observe the local thermal effect of holmium laser in ureteral models. Methods This study was conducted in July-August 2022 using a 3D printed kidney model (ureteral diameter: approximately 6 mm; length: approximately 20 cm). A clinically collected calcium oxalate monohydrate stone was polished into a 5 mm diameter sphere, placed under the ureteropelvic junction, and ligated with silk wire above the stone. The kidney model was placed in a water bath, and the temperature of the water bath was maintained at approximately 37°C to simulate the constant temperature of the human body. A fifth generation EMS pulse width tunable holmium laser was selected as the laser device. The laser fiber diameter was 200 μm. The thermometer was a multi-channel real-time thermometer with two temperature probes placed in the ureter. The distance between the probe and the fiber tip was maintained at 5 mm. Perfusion fluid: saline, temperature around 24°C; perfusion rate: 0, 10, 20, 30, 50 ml/min. We used a flexible ureteroscope with holmium laser fiber. The lithotripsy was performed by a physician. The holmium laser was continuously excited for 120 s. The temperature was measured and recorded once per second by an electronic thermometer. Each set of experiments was repeated three times. Results The operating graph of the temperature around the holmium laser fiber versus the time was recorded for different operating modes, and the change in temperature around the fiber was recorded at each time point in the absence of perfusion. The temperature of 43°C was reached around the fiber after an average of 9.2±3.0 s of laser excitation; the higher the power, the shorter the time to reach 43°C. The operating curve of the temperature around the laser fiber versus the time was recorded at the perfusion rate of 20 ml/min for each time period, and it was found that the temperature around the fiber was ≤43°C at ≤20 W of fragmentation power. At a perfusion flow rate of 50 ml/min, the holmium laser began to excite and reached a plateau between approximately 20 and 30 s. The plateau temperature powdered group > fragmentation group ( p < 0.01). Conclusion During ureteroscopic holmium laser lithotripsy, holmium laser excitation will produce a local thermal effect. Keeping the lithotripsy power ≤ 20 W within the perfusion flow rate ≥ 20 ml/min can reduce the local high temperatures caused by the thermal effect of the holmium laser and reduce any thermal damage, while the local thermal effect of low-energy high-frequency powdering mode is the highest and the local thermal effect of high-energy low-frequency powdering mode is the lowest. holmium laser thermal effect perfusion rate power Figures Figure 1 Introduction The human urinary tract is a narrow tube containing a small amount of fluid. The holmium laser is one of the most commonly used lasers for endoscopic lithotripsy of the urinary tract. Its lithotripsy mechanism includes photothermal and hotomechanical effects.[1, 2] Alongside the development of laser technology, the lithotripsy power of he laser has gradually increased, effectively improving its efficiency.[3] However, the complications that follow holmium laser lithotripsy, such as ureteral stenosis, have become problematic. Different lithotripsy protocols can be established by setting the output energy and frequency of the laser. The common clinical lithotripsy modes can be divided into the high-energy low-frequency “fragmenting” mode and the low-energy high-frequency “dusting” mode.[4] The thermal effects of these two modes in the urological tract and how to perfuse to reduce the risk of holmium laser thermal damage are still inconclusive. Based on this, we explored the thermal effects of a holmium laser in July–August 2022 by simulating the ureteral stone environment in in vitro experiments to explore the thermal effects of holmium lasers under different modes of operation and perfusion with continuous excitation. Materials And Methods MATERIALS: ureteral stone model: We used a 3D printed kidney model (ureteral diameter, approximately 6 mm; length, approximately 20 cm). We polished a clinically collected calcium oxalate monohydrate stone into a 5 mm diameter sphere, placed it under the ureteropelvic junction, and ligated it with silk wire above the stone. We then placed the 3D printed kidney model into a water bath. The holmium laser thermal effect model was constructed in vitro by maintaining the water bath temperature at 37°C to simulate a constant human temperature. The laser equipment selected was a fifth generation EMS pulse width tunable holmium laser device. The laser fiber diameter was 200 μm. The thermometer was a multi-channel real-time thermometer (Guangzhou Rayman Instrument Technology Co., Ltd., Guangzhou, China), with two thermometric probes placed in the ureter. The distance between the probe and the fiber tip was kept at 5 mm. METHODS: The effects of different power and energy modes (10, 12, 15, 18, 20 W) and perfusion rates (perfusion fluid: saline; temperature: around 24°C; perfusion rate: 0, 10, 20, 30, 50 ml/min) on the holmium laser thermal effect were studied in an in vitro model of the holmium laser thermal effect in an operating room. Under room temperature conditions (temperature 22°C, humidity 60%), a flexible ureteroscope with holmium laser fiber was used, and the lithotripsy was performed by a physician. The holmium laser was continuously excited for 120 s. The temperature was measured and recorded once per second using an electronic thermometer. Each set of experiments was repeated three times. Statistical methods: SPSS 25.0 statistical software was used to process the data. The measurement data all followed a normal distribution and are expressed as mean±SD. The paired t-test was used for comparison between two groups, and the non-parametric rank sum test for multiple groups was used for comparison between multiple samples. Differences were considered statistically significant at p < 0.05. Results The operating curves of the temperature around the holmium laser fiber versus time were recorded for different operating modes, and the variation of the temperature around the fiber was recorded at each time point without perfusion (Table 1). The laser excitation reached 43°C around the fiber at an average of 9.2±3.0 s. The higher the power, the shorter the time to reach 43°C. The operating curve of temperature around the laser fiber versus time was recorded for each time period at a perfusion rate of 20 ml/min. The temperature around the fiber was found to be ≤43°C at ≤20 W of lithotripsy power (Figure 1). At a perfusion flow rate of 50 ml/min, for example, the plateau period was reached between approximately 20 and 30 s after the holmium laser excitation started, and the plateau temperature powdered group > fragmentation group ( p < 0.01, Table 2). Table 1 Excitation times at 43°C for different powers of holmium laser without perfusion Times 10 W 12 W 15 W 18 W 20 W Average value (Mean±SD) 43°C time 13 11 9 8 5 9.2±3.0 Table 2 Plateau temperature of holmium laser thermal effect at 50 ml/min perfusion rate with different power and different operating modes 50 ml/min groups Platform period temperature t-value P-value Fragmentation model Powdered model 10 W 23.88±0.34 24.48±0.25 -14.529 <0.01 12 W 24.24±0.37 25.43±0.35 -23.378 <0.01 15 W 25.77±0.29 26.21±0.34 -9.013 <0.01 18 W 26.49±0.33 27.21±0.08 -16.316 <0.01 20 W 27.03±0.46 28.04±0.18 -18.347 <0.01 Discussion A holmium laser is a high-energy pulsed laser with a wavelength of 2100 nm. Its lithotripsy mechanism includes photothermal and photomechanical effects. [1] The photothermal effect is the absorption of laser energy by water to form a vapor bubble cavity. Then, the laser energy reaches the stone surface through the vapor bubble cavity channel, and the resulting micro-vapor bubbles break the stone during expansion or fragmentation. [5] The photothermal mechanism is that the temperature of the stone rises rapidly after the laser energy is absorbed, and the high temperature causes the stone to decompose; while the laser energy is absorbed by the water and the resulting vacuole expands to form a micro-vapor bubble, which in turn can cause the stone to break down. [6] As the laser energy is absorbed by water in the liquid environment, a thermal effect phenomenon is generated. Whether this phenomenon causes local high tissue temperatures and burns local tissue is an important indicator for evaluating its efficacy. [7] Research shows that body temperature > 43 ℃ will cause substantial damage to cells; local tissue temperature > 45 ℃ will cause tissue damage, and at temperature > 60 ℃, tissue protein thermal coagulation denaturation results and irreversible damage occurs. [8, 9] The holmium laser has a penetration depth of approximately 0.3 mm and has good precision cutting ability, which is ideal for endoscopic treatment. Theoretically, it does not cause direct thermal damage as long as the laser fiber is >0.3 mm away from human tissue. [10] In the human urinary tract there is only a small amount of fluid. To avoid complications such as stone regression or intrapelvic hypertension, the operator will be able to reduce the irrigation flow during the procedure, which may cause thermal damage to the tissue due to insufficient local irrigation and heat accumulation beyond the safe tissue temperature. [11] The literature suggests that the thermal effect of holmium lasers has become a major cause of intraoperative urological tract injury. Through in vitro experiments, we found that the laser was continuously excited for 9.2 ± 3.0 s in the absence of perfusion, and the temperature of each group exceeded 43°C. Considering that the perfusion fluid we used during surgery was generally approximately 22-25°C at room temperature, which was consistent with the temperature of the perfusion fluid used in our experiments, this suggests that in clinical surgery, with an output power ≥ 10 W and no or poor perfusion, continuous laser excitation should not exceed 9 s, and the intermittent excitation mode should be adopted for lithotripsy. By observing the process of continuous laser excitation to the plateau temperature, we found that under the same conditions, the dusting mode produced the greatest thermal effect and the highest plateau temperature; while the fragmenting mode produced the least thermal effect and the lowest plateau temperature. This suggested that in the case of ureteral stone obstruction, the fragmenting mode could be used preferentially to break up the stone, release the obstruction, and protect kidney function, while the laser work time is short and a postoperative stone residual rate is lower [4] . Compared with Chinese scholars’ studies on the thermal effects of holmium lasers, [12, 13] their models lacked perfusion and did not correspond to actual clinical practice. Some foreign scholars have also conducted similar studies. [9] Therefore, based on the recommendations of other scholars, we used a 3D printed kidney model to simulate a real human ureter, a 37°C thermostatic water bath to simulate a human thermostatic environment, and a bilateral thermometry probe for temperature measurement to make the holmium laser thermal effect study model more realistic and the measurement results more accurate. During the experiment, we found that the temperature of the plateau period gradually decreased with the gradual increase of the perfusion volume and that when the perfusion volume was above 20 ml/min, the temperature around the fiber dropped to below 43°C. Maxwell et al., [14] in an in vitro model, found an intra-ureteral holmium laser temperature of 42°C at a perfusion volume of 15 ml/min, while Aldoukhi et al. [15] found a local temperature of approximately 43.1°C in the in vitro model when using a 20 W power powdered lithotripsy mode, maintaining a perfusion volume of approximately 10 ml. The safe perfusion volume varied between models with a large variability in the distance between the temperature probe and the head end of the fiber, but maintaining a perfusion volume above 20 ml/min was safe for all. As the perfusion volume decreases, the plateau temperature exceeds 43°C when 10 ml/min, which indicates that the heat that can be taken away by the perfused liquid is much less than the heat released by the laser, and the perfusion volume needs to be increased to remove the excess heat to keep the plateau temperature at 43°C. In conclusion, under the experimental conditions of this study, the infused fluid can maintain a safe local temperature by effective heat convection and diffusion when the infusion volume is ≥20 ml/min. This study could not fully model the real scenario of in vivo lithotripsy because it was an in vitro model of lithotripsy, and there were some limitations. However, the preliminary findings provide a valuable reference for in vivo testing and clinical application, and subsequent in vivo testing on animals is needed to further validate the findings. In summary, a local thermal effect caused by holmium laser excitation will occur during ureteroscopic holmium laser lithotripsy. Locally high temperatures caused by the thermal effect and the thermal damage can be reduced using a lithotripsy power ≤20 W with a perfusion flow rate ≥20 ml/min. The high-energy low-frequency fragmenting mode has the lowest local thermal effect, whereas the low-energy high-frequency dusting mode has the largest. The datasets generated and/or analysed during the current study are not publicly available due the mechine is not appear on the market, all the data are should be privated, but are available from the corresponding author on reasonable request References Sofer M, Watterson JD, Wollin TA, et al. Holmium:YAG laser lithotripsy for upper urinary tract calculi in 598 patients. J Urol. 2002;167(1):31-4. Lv T, Xiao Q, Li ZJ. Analysis of Ablation Efficiency of Holmium Laser Pulses for Urinary Calculus Under Various Environments. Analysis of Ablation Efficiency of Holmium Laser Pulses for Urinary Calculus Under Various Environments. 2010;30(s1):100414. Liao W B, Yang S X, Song C, et al. Management of ureteral strictures after ureteroscopic holmium laser lithotripsy: a 5-year single-center retrospective study. Chinese Journal of Urology. 2021(12):910-4. Xiao B, Hu W, Zhang X, et al. Prognostic analysis of the "powder method" versus the "fragmentation method" for flexible ureteroscopic lithotripsy. Journal of Clinical Urology. 2018;33(07):520-2+36. Papatsoris AG, Skolarikos A, Buchholz N. Intracorporeal laser lithotripsy. Arab journal of urology. 2012;10(3):301-6. Teichman JM, Vassar GJ, Glickman RD, et al. Holmium:YAG lithotripsy: photothermal mechanism converts uric acid calculi to cyanide. j Urol. 1998;160(2) :320-4. Cinman NM, Andonian S, Smith AD. lasers in percutaneous renal procedures. world J Urol. 2010;28(2):135-42. Winship B, Wollin D, Carlos E, et al. The Rise and Fall of High Temperatures During Ureteroscopic Holmium Laser Lithotripsy. j Endourol. 2019;33(10):794 -9. Wollin DA, Carlos EC, Tom WR, et al. Effect of Laser Settings and Irrigation Rates on Ureteral Temperature During Holmium Laser Lithotripsy, an In Vitro Model. j Endourol. 2018;32(1):59-63. Yang G. S. Experience with multiple lasers in transurethral prostate surgery. Chinese Journal of Urology. 2020;41(06):405-7. Liu WC, Liu G, Tang JN, et al. Retrospective analysis of ureteral stenosis complicating holmium laser lithotripsy after ureteroscopy. Journal of Clinical Urology. 2014;29(07):573-4+80. Jiang S.K., Mo C.Q., Gui C.P., et al. Experimental study of the thermal effect of holmium laser in a urological cavity model. Chinese Journal of Urology. 2021;42(03):220-5. Gong, Chunyu, Qu, R., Deng, Huizhuo, et al. Preliminary study on the thermal effect of the common power of holmium laser surgery. China Health Industry. 2017;14(08):55-6. Maxwell AD, MacConaghy B, Harper JD, et al. Simulation of Laser Lithotripsy-Induced Heating in the Urinary Tract. J Endourol. 2019;33(2):113-9. Aldoukhi AH, Ghani KR, Hall TL, et al. Thermal Response to High-Power Holmium Laser Lithotripsy. j Endourol. 2017;31(12):1308-12. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2085574","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":143169142,"identity":"d51386a6-db10-467e-bc14-399afb51d47b","order_by":0,"name":"Li Taixun","email":"","orcid":"","institution":"Heze Municipal Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Taixun","suffix":""},{"id":143169143,"identity":"37d95d4f-64d4-4240-bfe8-041cbb4f3a10","order_by":1,"name":"Shao Guangjing","email":"","orcid":"","institution":"Heze Municipal Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shao","middleName":"","lastName":"Guangjing","suffix":""},{"id":143169144,"identity":"c9569baa-0536-4a89-bfff-48c0cbdb9d9d","order_by":2,"name":"Li Huijuan","email":"","orcid":"","institution":"Heze Municipal Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Huijuan","suffix":""},{"id":143169145,"identity":"30a5690b-5621-4f7e-9b23-e68ad34473ba","order_by":3,"name":"Guo Suqin","email":"","orcid":"","institution":"Heze Municipal Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Guo","middleName":"","lastName":"Suqin","suffix":""},{"id":143169146,"identity":"25c4f519-7c8a-41b6-b3e4-71f6faadd700","order_by":4,"name":"Wang Wei","email":"","orcid":"","institution":"Heze Municipal Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wang","middleName":"","lastName":"Wei","suffix":""},{"id":143169147,"identity":"18587ae3-a963-40a4-8f9e-31ad3c5fcb0f","order_by":5,"name":"Li Hongzhou","email":"","orcid":"","institution":"Heze Municipal Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Hongzhou","suffix":""},{"id":143169148,"identity":"968783b3-cea0-4b48-b292-cf9699f47769","order_by":6,"name":"Sun Mingchong.","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYBACfvb+jw8+GNjUs7E3EKlFsueAseGMirQEfp4DRGoxuJFgJs1z5nCC5IwEYl12IyFBcmYbc57BzccbbzDU2EQT1MHY8+CAwcc2tmKD22nFFgzH0nIbCGlhZk9sSJzZxsO44XaOmQRjw2HCWtgYkhkO87ZJMG64eYZILTwcaYzNPGcMEmfO4CFSiwTPGWbGGRUJxvw8QL8kEOMX++M97D8+GPyXY2M/vPHGhxobwlqQgYFEAinKIVpI1TEKRsEoGAUjAwAAlA9DDuu0nkUAAAAASUVORK5CYII=","orcid":"","institution":"Heze Municipal Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Sun","middleName":"","lastName":"Mingchong.","suffix":""}],"badges":[],"createdAt":"2022-09-20 15:14:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2085574/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2085574/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":27796507,"identity":"e459ade2-7808-4c93-8577-d1cf73570e20","added_by":"auto","created_at":"2022-10-14 19:14:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":40528,"visible":true,"origin":"","legend":"\u003cp\u003ePlateau temperature of the thermal effect of holmium laser with different power at 20 ml/min perfusion rate\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2085574/v1/283b4095b791c5bf80d16c95.png"},{"id":30007850,"identity":"ee2c58b3-7928-408f-8fb1-820099006155","added_by":"auto","created_at":"2022-12-07 12:29:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":193544,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2085574/v1/056645bb-a640-4a09-8945-7d82f2313839.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"An In Vitro Study of the Thermal Effect of Holmium Laser Lithotripsy of Ureteral Stones","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe human urinary tract is a narrow tube containing a small amount of fluid. The holmium laser is one of the most commonly used lasers for endoscopic lithotripsy of the urinary tract. Its lithotripsy mechanism includes photothermal and hotomechanical effects.[1, 2] Alongside the development of laser technology, the lithotripsy power of he laser has gradually increased, effectively improving its efficiency.[3] However, the complications that follow holmium laser lithotripsy, such as ureteral stenosis, have become problematic. Different lithotripsy protocols can be established by setting the output energy and frequency of the laser. The common clinical lithotripsy modes can be divided into the high-energy low-frequency \u0026ldquo;fragmenting\u0026rdquo; mode and the low-energy high-frequency \u0026ldquo;dusting\u0026rdquo; mode.[4] The thermal effects of these two modes in the urological tract and how to perfuse to reduce the risk of holmium laser thermal damage are still inconclusive. Based on this, we explored the thermal effects of a holmium laser in July\u0026ndash;August 2022 by simulating the ureteral stone environment in in vitro experiments to explore the thermal effects of holmium lasers under different modes of operation and perfusion with continuous excitation.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eMATERIALS: ureteral stone model: We used a 3D printed kidney model (ureteral diameter, approximately 6 mm; length, approximately 20 cm). We polished a clinically collected calcium oxalate monohydrate stone into a 5 mm diameter sphere, placed it under the ureteropelvic junction, and ligated it with silk wire above the stone. We then placed the 3D printed kidney model into a water bath. The holmium laser thermal effect model was constructed in vitro by maintaining the water bath temperature at 37\u0026deg;C to simulate a constant human temperature. The laser equipment selected was a fifth generation EMS pulse width tunable holmium laser device. The laser fiber diameter was 200 \u0026mu;m. The thermometer was a multi-channel real-time thermometer (Guangzhou Rayman Instrument Technology Co., Ltd., Guangzhou, China), with two thermometric probes placed in the ureter. The distance between the probe and the fiber tip was kept at 5 mm.\u003c/p\u003e\n\u003cp\u003eMETHODS: The effects of different power and energy modes (10, 12, 15, 18, 20 W) and perfusion rates (perfusion fluid: saline; temperature: around 24\u0026deg;C; perfusion rate: 0, 10, 20, 30, 50 ml/min) on the holmium laser thermal effect were studied in an in vitro model of the holmium laser thermal effect in an operating room. Under room temperature conditions (temperature 22\u0026deg;C, humidity 60%), a flexible ureteroscope with holmium laser fiber was used, and the lithotripsy was performed by a physician. The holmium laser was continuously excited for 120 s. The temperature was measured and recorded once per second using an electronic thermometer. Each set of experiments was repeated three times.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistical methods: SPSS 25.0 statistical software was used to process the data. The measurement data all followed a normal distribution and are expressed as mean\u0026plusmn;SD. The paired t-test was used for comparison between two groups, and the non-parametric rank sum test for multiple groups was used for comparison between multiple samples. Differences were considered statistically significant at \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe operating curves of the temperature around the holmium laser fiber versus time were recorded for different operating modes, and the variation of the temperature around the fiber was recorded at each time point without perfusion (Table 1). The laser excitation reached 43\u0026deg;C around the fiber at an average of 9.2\u0026plusmn;3.0 s. The higher the power, the shorter the time to reach 43\u0026deg;C. The operating curve of temperature around the laser fiber versus time was recorded for each time period at a perfusion rate of 20 ml/min. The temperature around the fiber was found to be \u0026le;43\u0026deg;C at \u0026le;20 W of lithotripsy power (Figure 1). At a perfusion flow rate of 50 ml/min, for example, the plateau period was reached between approximately 20 and 30 s after the holmium laser excitation started, and the plateau temperature powdered group \u0026gt; fragmentation group (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.01, Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003eExcitation times at 43\u0026deg;C for different powers of holmium laser without perfusion\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003eTimes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.344887348353552%\"\u003e\n \u003cp\u003e10 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.518197573656845%\"\u003e\n \u003cp\u003e12 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.518197573656845%\"\u003e\n \u003cp\u003e15 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.518197573656845%\"\u003e\n \u003cp\u003e18 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.17157712305026%\"\u003e\n \u003cp\u003e20 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.54419410745234%\"\u003e\n \u003cp\u003eAverage value\u003c/p\u003e\n \u003cp\u003e(Mean\u0026plusmn;SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"14.38474870017331%\"\u003e\n \u003cp\u003e43\u0026deg;C time\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.344887348353552%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.518197573656845%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.518197573656845%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.518197573656845%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.17157712305026%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.54419410745234%\"\u003e\n \u003cp\u003e9.2\u0026plusmn;3.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;\u003c/strong\u003ePlateau temperature of holmium laser thermal effect at 50 ml/min perfusion rate with different power and different operating modes\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"605\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" width=\"16.859504132231404%\"\u003e\n \u003cp\u003e50 ml/min\u003c/p\u003e\n \u003cp\u003egroups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" width=\"46.94214876033058%\"\u003e\n \u003cp\u003ePlatform period temperature\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"19.669421487603305%\"\u003e\n \u003cp\u003e\u003cem\u003et-value\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" width=\"16.52892561983471%\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;P-value\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"48.59154929577465%\"\u003e\n \u003cp\u003eFragmentation model\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"51.40845070422535%\"\u003e\n \u003cp\u003ePowdered model\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.859504132231404%\"\u003e\n \u003cp\u003e10 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.8099173553719%\"\u003e\n \u003cp\u003e23.88\u0026plusmn;0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.132231404958677%\"\u003e\n \u003cp\u003e24.48\u0026plusmn;0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.669421487603305%\"\u003e\n \u003cp\u003e-14.529\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.52892561983471%\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.859504132231404%\"\u003e\n \u003cp\u003e12 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.8099173553719%\"\u003e\n \u003cp\u003e24.24\u0026plusmn;0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.132231404958677%\"\u003e\n \u003cp\u003e25.43\u0026plusmn;0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.669421487603305%\"\u003e\n \u003cp\u003e-23.378\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.52892561983471%\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.859504132231404%\"\u003e\n \u003cp\u003e15 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.8099173553719%\"\u003e\n \u003cp\u003e25.77\u0026plusmn;0.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.132231404958677%\"\u003e\n \u003cp\u003e26.21\u0026plusmn;0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.669421487603305%\"\u003e\n \u003cp\u003e-9.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.52892561983471%\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.859504132231404%\"\u003e\n \u003cp\u003e18 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.8099173553719%\"\u003e\n \u003cp\u003e26.49\u0026plusmn;0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.132231404958677%\"\u003e\n \u003cp\u003e27.21\u0026plusmn;0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.669421487603305%\"\u003e\n \u003cp\u003e-16.316\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.52892561983471%\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.859504132231404%\"\u003e\n \u003cp\u003e20 W\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.8099173553719%\"\u003e\n \u003cp\u003e27.03\u0026plusmn;0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.132231404958677%\"\u003e\n \u003cp\u003e28.04\u0026plusmn;0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.669421487603305%\"\u003e\n \u003cp\u003e-18.347\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.52892561983471%\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eA holmium laser is a high-energy pulsed laser with a wavelength of 2100 nm. Its lithotripsy mechanism includes photothermal and photomechanical effects.\u003csup\u003e[1]\u003c/sup\u003e The photothermal effect is the absorption of laser energy by water to form a vapor bubble cavity. Then, the laser energy reaches the stone surface through the vapor bubble cavity channel, and the resulting micro-vapor bubbles break the stone during expansion or fragmentation.\u003csup\u003e[5]\u003c/sup\u003e The photothermal mechanism is that the temperature of the stone rises rapidly after the laser energy is absorbed, and the high temperature causes the stone to decompose; while the laser energy is absorbed by the water and the resulting vacuole expands to form a micro-vapor bubble, which in turn can cause the stone to break down.\u003csup\u003e[6]\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003eAs the laser energy is absorbed by water in the liquid environment, a thermal effect phenomenon is generated. Whether this phenomenon causes local high tissue temperatures and burns local tissue is an important indicator for evaluating its efficacy.\u003csup\u003e[7]\u003c/sup\u003e Research shows that body temperature \u0026gt; 43 ℃ will cause substantial damage to cells; local tissue temperature \u0026gt; 45 ℃ will cause tissue damage, and at temperature \u0026gt; 60 ℃, tissue protein thermal coagulation denaturation results and irreversible damage occurs.\u003csup\u003e[8, 9]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe holmium laser has a penetration depth of\u0026nbsp;approximately\u0026nbsp;0.3 mm and has good precision cutting ability, which is ideal for endoscopic treatment. Theoretically, it does not cause direct thermal damage as long as the laser fiber is \u0026gt;0.3 mm away from human tissue.\u003csup\u003e[10]\u003c/sup\u003e In the human urinary tract there is only a small amount of fluid. To avoid complications such as stone regression or intrapelvic hypertension, the operator will be able to reduce the irrigation flow during the procedure, which may cause thermal damage to the tissue due to insufficient local irrigation and heat accumulation beyond the safe tissue temperature.\u003csup\u003e[11]\u003c/sup\u003e The literature suggests that the thermal effect of holmium lasers has become a major cause of intraoperative urological tract injury. Through in vitro experiments, we found that the laser was continuously excited for\u0026nbsp;9.2 \u0026plusmn; 3.0\u0026nbsp;s in the absence of perfusion, and the temperature of each group exceeded 43\u0026deg;C. Considering that the perfusion fluid we used during surgery was generally\u0026nbsp;approximately\u0026nbsp;22-25\u0026deg;C at room temperature, which was consistent with the temperature of the perfusion fluid used in our experiments, this suggests that in clinical surgery, with an output power \u0026ge; 10 W and no or poor perfusion, continuous laser excitation should not exceed 9 s, and the intermittent excitation mode should be adopted for lithotripsy. By observing the process of continuous laser excitation to the plateau temperature, we found that under the same conditions, the dusting mode produced the greatest thermal effect and the highest plateau temperature; while the fragmenting mode produced the least thermal effect and the lowest plateau temperature. This suggested that in the case of ureteral stone obstruction, the fragmenting mode could be used preferentially to break up the stone, release the obstruction, and protect kidney function, while the laser work time is short and a postoperative stone residual rate is lower\u003csup\u003e[4]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eCompared with Chinese scholars\u0026rsquo; studies on the thermal effects of holmium lasers,\u0026nbsp;\u003csup\u003e[12, 13]\u003c/sup\u003e their models lacked perfusion and did not correspond to actual clinical practice. Some foreign scholars have also conducted similar studies.\u003csup\u003e[9]\u003c/sup\u003e Therefore, based on the recommendations of other scholars, we used a 3D printed kidney model to simulate a real human ureter, a 37\u0026deg;C thermostatic water bath to simulate a human thermostatic environment, and a bilateral thermometry probe for temperature measurement to make the holmium laser thermal effect study model more realistic and the measurement results more accurate. During the experiment, we found that the temperature of the plateau period gradually decreased with the gradual increase of the perfusion volume and that when the perfusion volume was above 20 ml/min, the temperature around the fiber dropped to below 43\u0026deg;C. Maxwell et al.,\u003csup\u003e[14]\u003c/sup\u003e in an in vitro model, found an intra-ureteral holmium laser temperature of 42\u0026deg;C at a perfusion volume of 15 ml/min, while Aldoukhi et al.\u003csup\u003e[15]\u003c/sup\u003e found a local temperature of approximately 43.1\u0026deg;C in the in vitro model when using a 20 W power powdered lithotripsy mode, maintaining a perfusion volume of\u0026nbsp;approximately\u0026nbsp;10 ml. The safe perfusion volume varied between models with a large variability in the distance between the temperature probe and the head end of the fiber, but maintaining a perfusion volume above 20 ml/min was safe for all. As the perfusion volume decreases, the plateau temperature exceeds 43\u0026deg;C when 10 ml/min, which indicates that the heat that can be taken away by the perfused liquid is much less than the heat released by the laser, and the perfusion volume needs to be increased to remove the excess heat to keep the plateau temperature at 43\u0026deg;C. In conclusion, under the experimental conditions of this study, the infused fluid can maintain a safe local temperature by effective heat convection and diffusion when the infusion volume is \u0026ge;20 ml/min.\u003c/p\u003e\n\u003cp\u003eThis study could not fully model the real scenario of in vivo lithotripsy because it was an in vitro model of lithotripsy, and there were some limitations. However, the preliminary findings provide a valuable reference for in vivo testing and clinical application, and subsequent in vivo testing on animals is needed to further validate the findings.\u003c/p\u003e\n\u003cp\u003eIn summary, a local thermal effect caused by holmium laser excitation will occur during ureteroscopic holmium laser lithotripsy. Locally high temperatures caused by the thermal effect and the thermal damage can be reduced using a lithotripsy power \u0026le;20 W with a perfusion flow rate \u0026ge;20 ml/min. The high-energy low-frequency fragmenting \u0026nbsp;mode has the lowest local thermal effect, whereas the low-energy high-frequency dusting mode has the largest.\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due the mechine is not appear on the market, all the data are should be privated, \u0026nbsp;but are available from the corresponding author on reasonable request\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSofer M, Watterson JD, Wollin TA, et al. Holmium:YAG laser lithotripsy for upper urinary tract calculi in 598 patients. J Urol. 2002;167(1):31-4.\u003c/li\u003e\n \u003cli\u003eLv T, Xiao Q, Li ZJ. Analysis of Ablation Efficiency of Holmium Laser Pulses for Urinary Calculus Under Various Environments. Analysis of Ablation Efficiency of Holmium Laser Pulses for Urinary Calculus Under Various Environments. 2010;30(s1):100414.\u003c/li\u003e\n \u003cli\u003eLiao W B, Yang S X, Song C, et al. Management of ureteral strictures after ureteroscopic holmium laser lithotripsy: a 5-year single-center retrospective study. Chinese Journal of Urology. 2021(12):910-4.\u003c/li\u003e\n \u003cli\u003eXiao B, Hu W, Zhang X, et al. Prognostic analysis of the \u0026quot;powder method\u0026quot; versus the \u0026quot;fragmentation method\u0026quot; for flexible ureteroscopic lithotripsy. Journal of Clinical Urology. 2018;33(07):520-2+36.\u003c/li\u003e\n \u003cli\u003ePapatsoris AG, Skolarikos A, Buchholz N. Intracorporeal laser lithotripsy. Arab journal of urology. 2012;10(3):301-6.\u003c/li\u003e\n \u003cli\u003eTeichman JM, Vassar GJ, Glickman RD, et al. Holmium:YAG lithotripsy: photothermal mechanism converts uric acid calculi to cyanide. j Urol. 1998;160(2) :320-4.\u003c/li\u003e\n \u003cli\u003eCinman NM, Andonian S, Smith AD. lasers in percutaneous renal procedures. world J Urol. 2010;28(2):135-42.\u003c/li\u003e\n \u003cli\u003eWinship B, Wollin D, Carlos E, et al. The Rise and Fall of High Temperatures During Ureteroscopic Holmium Laser Lithotripsy. j Endourol. 2019;33(10):794 -9.\u003c/li\u003e\n \u003cli\u003eWollin DA, Carlos EC, Tom WR, et al. Effect of Laser Settings and Irrigation Rates on Ureteral Temperature During Holmium Laser Lithotripsy, an In Vitro Model. j Endourol. 2018;32(1):59-63.\u003c/li\u003e\n \u003cli\u003eYang G. S. Experience with multiple lasers in transurethral prostate surgery. Chinese Journal of Urology. 2020;41(06):405-7.\u003c/li\u003e\n \u003cli\u003eLiu WC, Liu G, Tang JN, et al. Retrospective analysis of ureteral stenosis complicating holmium laser lithotripsy after ureteroscopy. Journal of Clinical Urology. 2014;29(07):573-4+80.\u003c/li\u003e\n \u003cli\u003eJiang S.K., Mo C.Q., Gui C.P., et al. Experimental study of the thermal effect of holmium laser in a urological cavity model. Chinese Journal of Urology. 2021;42(03):220-5.\u003c/li\u003e\n \u003cli\u003eGong, Chunyu, Qu, R., Deng, Huizhuo, et al. Preliminary study on the thermal effect of the common power of holmium laser surgery. China Health Industry. 2017;14(08):55-6.\u003c/li\u003e\n \u003cli\u003eMaxwell AD, MacConaghy B, Harper JD, et al. Simulation of Laser Lithotripsy-Induced Heating in the Urinary Tract. J Endourol. 2019;33(2):113-9.\u003c/li\u003e\n \u003cli\u003eAldoukhi AH, Ghani KR, Hall TL, et al. Thermal Response to High-Power Holmium Laser Lithotripsy. j Endourol. 2017;31(12):1308-12.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"holmium laser, thermal effect, perfusion rate, power","lastPublishedDoi":"10.21203/rs.3.rs-2085574/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2085574/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective \u003c/strong\u003eTo\u003cstrong\u003e \u003c/strong\u003eobserve the local thermal effect of holmium laser in ureteral models.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eThis study was conducted in July-August 2022 using a 3D printed kidney model (ureteral diameter: approximately 6 mm; length: approximately 20 cm). A clinically collected calcium oxalate monohydrate stone was polished into a 5 mm diameter sphere, placed under the ureteropelvic junction, and ligated with silk wire above the stone. The kidney model was placed in a water bath, and the temperature of the water bath was maintained at approximately 37°C to simulate the constant temperature of the human body. A fifth generation EMS pulse width tunable holmium laser was selected as the laser device. The laser fiber diameter was 200 μm. The thermometer was a multi-channel real-time thermometer with two temperature probes placed in the ureter. The distance between the probe and the fiber tip was maintained at 5 mm. Perfusion fluid: saline, temperature around 24°C; perfusion rate: 0, 10, 20, 30, 50 ml/min. We used a flexible ureteroscope with holmium laser fiber. The lithotripsy was performed by a physician. The holmium laser was continuously excited for 120 s. The temperature was measured and recorded once per second by an electronic thermometer. Each set of experiments was repeated three times.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eThe operating graph of the temperature around the holmium laser fiber versus the time was recorded for different operating modes, and the change in temperature around the fiber was recorded at each time point in the absence of perfusion. The temperature of 43°C was reached around the fiber after an average of 9.2±3.0 s of laser excitation; the higher the power, the shorter the time to reach 43°C. The operating curve of the temperature around the laser fiber versus the time was recorded at the perfusion rate of 20 ml/min for each time period, and it was found that the temperature around the fiber was ≤43°C at ≤20 W of fragmentation power. At a perfusion flow rate of 50 ml/min, the holmium laser began to excite and reached a plateau between approximately 20 and 30 s. The plateau temperature powdered group \u0026gt; fragmentation group (\u003cem\u003ep \u003c/em\u003e\u0026lt; 0.01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eDuring ureteroscopic holmium laser lithotripsy, holmium laser excitation will produce a local thermal effect. Keeping the lithotripsy power ≤ 20 W within the perfusion flow rate ≥ 20 ml/min can reduce the local high temperatures caused by the thermal effect of the holmium laser and reduce any thermal damage, while the local thermal effect of low-energy high-frequency powdering mode is the highest and the local thermal effect of high-energy low-frequency powdering mode is the lowest.\u003c/p\u003e","manuscriptTitle":"An In Vitro Study of the Thermal Effect of Holmium Laser Lithotripsy of Ureteral Stones","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-10-14 19:14:07","doi":"10.21203/rs.3.rs-2085574/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4dfba5e8-8eae-473a-a327-75741b74a2b5","owner":[],"postedDate":"October 14th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-12-07T12:29:39+00:00","versionOfRecord":[],"versionCreatedAt":"2022-10-14 19:14:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2085574","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2085574","identity":"rs-2085574","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}