{"paper_id":"ff64895c-e7d9-44f7-b497-001499498aa8","body_text":"ORIGINAL ARTICLE\nEvaluation of a novel deep tissue transvaginal near-infrared laser\nand applicator in an ovine model\nRalph Zipper1 & Brian Pryor2\nReceived: 1 December 2020 / Accepted: 2 April 2021\n# The Author(s) 2021\nAbstract\nPhotobiomodulation therapy (PBMT) is an effective means of treating muscle spasm and pain. A novel near-infrared laser system\nhas been commercialized for the treatment of myofascial pelvic pain in women (SoLá Therapy, UroShape, LLC). This study was\nundertaken to determine if this device is capable of delivering therapeutic levels of irradiance to the pelvic muscles and to identify\nthe surface irradiance required to achieve this goal. This novel class IV near-infrared laser and transvaginal applicator were used\nto deliver near-infrared light energy through the vaginal mucosa of an adult Suffolk/Dorset Ewe. Irradiance was measured on the\nsurface of the levator ani muscle, inside the levator ani muscle, and inside the bladder. Measurements were taken at powers of\n5 W and 0.5 W. 3.0% of vaginal surface irradiance was measured inside of the levator ani muscle. 4.4% of vaginal surface\nirradiance was measured inside the bladder. At 5 W, the novel laser system provided a surface irradiance of 738 mW/cm2.A t0 . 5\nW, the system provided a surface irradiance of 74 mW/cm 2. A novel class IV near-infrared laser and transvaginal applicator\ndelivered therapeutic irradiance to the levator ani muscle and bladder of an anesthetized ewe at a power setting of 5 W. A power\nsetting of 0.5 W failed to deliver therapeutic energy into either the levator ani muscle or bladder. Clinical applications targeting\ndeeper tissues such as the pelvic muscles and or bladder should consider power settings that exceed 0.5 W and or irradiance of≥\n75 mW/cm2.\nKeywords Photobiomodulation . Pelvis . Pain . Irradiance . Therapy\nIntroduction\nThousands of published laboratory studies and hundreds of\npublished randomized controlled trials have described and\ndefined the beneficial effects of near-infrared (NIR) light en-\nergy on living tissue, photobiomodulation [1]. The benefits of\nNIR energy have been demonstrated on conditions including\nsprain and strains, post-surgical pain, whiplash, muscular back\npain, radiculopathy, tendinitis, and chronic conditions such as\nosteoarthritis rheumatoid arthritis, neck and back pain,\nepicondylitis, carpal tunnel syndrome, tendinopathy, fibromy-\nalgia, plantar fasciitis, and chronic regional pain syndrome, as\nwell as neuropathic pain conditions such as postherpetic\nneuralgia, trigeminal neuralgia, and diabetic neuropathy [ 1].\nCotler et al., in their review of the scientific and medical liter-\nature, including nearly 100 publications, noted that“The long-\nterm effects of low-level laser therapy (NIR) occur within a\nweek or two and can last for months and sometimes years as a\nresult of improved tissue healing. ” [1]. These authors also\npointed out that there are four targets of NIR energy, trigger\npoints to reduce tenderness and relax contracted muscle fibers,\nnerves to induce analgesia, the site of injury to promote\nhealing, remodeling, and reduce inflammation, and lymph\nnodes to reduce edema and inflammation.\nIt is estimated that approximately 14% of adult women\nsuffer from chronic pelvic pain (CPP) [ 2]. A recent study of\nalmost 50,000 female US veterans found a 30% incidence of\nCPP and a 16.8% incidence of opioid use amongst sufferers\n[3]. The incidence of opioid use amongst CPP patients in the\ngeneral population is consistent with the military cohort [ 4].\nThe majority of CPP sufferers share a treatable pathology,\nhypertonicity, and tenderness of the pelvic muscles, levator\nmyalgia (myofascial pelvic pain). It is estimated that 60 to\n85% of women with CPP have levator myalgia [ 4, 5].\n* Ralph Zipper\nralph.zipper@uroshape.com\n1 UroShape, LLC, 200 S. Harbor City Blvd, Suite 401,\nMelbourne, FL 32901, USA\n2 Litecure, LLC, 101 Lukens Dr, STE A, New Castle, DE 19720, USA\nhttps://doi.org/10.1007/s10103-021-03315-z\n/ Published online: 14 April 2021\nLasers in Medical Science (2022) 37:639–643\n\nAlleviation of this tender pelvic muscle hypertonicity is the\nmainstay of CPP treatment. Unfortunately, randomized con-\ntrolled trials have failed to identify an effective stand-alone\ntreatment. Although many patients benefit from skilled man-\nual therapy (PT) as part of a multimodality treatment regimen,\naccess is limited [6]. Additionally, results of physical therapy\nare less than optimal, with recent studies finding less than 40%\npain reduction [7, 8]. Factors including the length of physical\ntherapy treatments and or discomfort may contribute to low\npatient compliance [ 9]. The delivery of therapeutic doses of\nNIR energy to the pelvic muscles may represent a much-\nneeded alternative treatment for those suffering from CPP.\nAs with medications, the correct dose of NIR energy must\nbe delivered over the correct amount of time to achieve the\ndesired outcome. Numerous investigators have reported opti-\nmal irradiance and fluence. Bolton et al. noted that although\n810 nm irradiance of 800 mW/cm\n2 at a fluence of 2.4 J/cm 2\nproduced greater cell proliferation than irradiance of 400 mW/\ncm2, the higher irradiance lost effect at 7.2 J/cm 2 [10].\nHowever, at 400 mW/cm 2 and 7.2 J/cm 2, proliferation\nremained significantly increased. More recently, Anders\net al. found optimal effects at irradiances between 10 mW/\ncm\n2 and 50 mW/cm 2 delivered to a fluence of 200 mJ/cm 2\n[11, 12]. Although an underreporting of irradiance by inves-\ntigators in the field has hastened the development of a precise-\nly defined dosing regimen, ideal irradiance most likely exists\nin the range of 10 mW/cm\n2 to 400 mW/cm2, and ideal fluence\nmost likely exists in the range of 0.075 to 8.0 J/cm 2. This\ndosing must occur at the level of the target tissue and not the\noverlying skin or mucous membrane. Only a small fraction of\nthe energy applied to the skin or mucous membrane of an\norganism will reach the target tissue. Hence, the ideal power\nsettings of a laser can only be determined by knowing both the\nirradiance at the level of the skin and the percentage of the\nirradiance that will reach the target tissue. Although there may\nbe a consistent pattern of energy decay per millimeter of var-\nious tissue types traversed en route to a target tissue, an esti-\nmate of such decay is best made for each specific target. The\npathway to each unique target tissue represents pathways\nthrough unique chromophores. The primary objective of this\nstudy is to determine the irradiance needed at the surface of the\nvaginal mucosa to achieve therapeutic irradiance at the levels\nof the levator ani muscle and bladder. A secondary endpoint\nof this study is to determine if this novel transvaginal infrared\nlaser system is capable of delivering such irradiance. As it is\ncritical to incorporate the absorption of water and blood in\ndetermining the depth of penetration, a cadaveric study would\nbe insufficient. This study utilizes a live ovine model.\nThe vaginal structure of sheep is considered similar in\nstructure to humans and provides a sufficiently analogous sys-\ntem for conducting gynecological procedures. Recent histo-\nlogical evaluation of the ovine mucosa and surgical anatomic\ndissection has validated this analogy [ 13, 14]. Compared to\nsmaller species, the size of the ovine model also allows for\nconvenient testing of an index device as designed for use in\nhumans. Considering these factors in conjunction with the\navailability of the ovine model makes this the preferred model\nfor testing a transvaginal treatment device. This research study\nwas conducted in compliance with the requirements of the\nAnimal Welfare Act and amendments and standards in the\nGuide for the Care and the Use of Laboratory Animals,\nILAR, National Academy Press, latest edition as well as\nGLP, guidelines for nonclinical laboratory studies as de-\nscribed in the Code of Federal Regulations, 21 Part 58, and\nwith any applicable amendments. The study was performed in\nan Association for the Assessment and Accreditation of\nLaboratory Animal Care, International (AAALAC) accredited\nfacility and approved by the Institutional Animal Care and\nUse Committee (IACUC).\nMaterials and methods\nOne healthy, non-pregnant sheep of reproductive maturity\nwas enrolled. Prior to enrollment in the procedure, the animal\nwas housed separately from the opposite sex. Administration\nof vaginal ointments and medications was avoided for 1 week\nprior to the procedure. The animal received intravenous seda-\ntion followed by the induction of general endotracheal anes-\nthesia. Following induction of anesthesia, the animal was\nplaced in the dorsal lithotomy position. Examination of the\nvagina demonstrated a normal-appearing mucosa without ev-\nidence of trauma or infection. The vaginal length was mea-\nsured at 11 cm.\nThe laser calibration was confirmed within 40 h of the\nstudy and again on the morning of the study. Irradiance mea-\nsurements were made utilizing the BK Precision 2712 Digital\nMultimeter and the B&W Tek NIR Power Probe (Fig. 1).\nHigh sensitivity sensors (1 μW/cm\n2)a n dal o w\nsensitivity sensors (500 mW/cm 2)w e r eu t i l i z e d .\nThis meter had been calibrated within 7 days of the study\nby the factory engineers. The Probes were bench tested with\nthe calibrated laser and a control laser (LTS 1500, LiteCure,\nLLC) for accuracy on the day of the study.\nMucosal surface irradiance was measured by placing the\ntransmitting section of the delivery device (vaginal probe)\ndirectly over a Power Probe. Measurements were made at\npowers of 0.5 and 5.0 W. Next, a 3-cm incision was created\nin the perineal skin. An American Board of Obstetrician and\nGynecologist –certified pelvic reconstructive surgeon per-\nformed a transperineal dissection down to the levator ani mus-\ncle directly beneath the mid vaginal vault. A 3 × 2 × 1.5 mm\nPower Probe was placed on the surface of the levator ani\nmuscles. The distance from the perineum to the Power Probe\nwas measured (6 cm). The measurement was used to facilitate\nvaginal placement of the energy delivery device directly over\n640 Lasers Med Sci (2022) 37:639–643\n\nthe Power Probe. A second Power Probe was placed through a\ntunnel into the belly of the muscle. This probe was placed\n1 cm proximal and 1 cm to the right of the more superficial\nPower Probe. The energy delivery device was placed in the\nvagina over the superficial (surface) levator ani Power Probe.\nIrradiance measurements were made at 5.0 W and then 0.5 W.\nAfter 5 min, the measurements were repeated in reverse order\n(0.5 W first). The energy device was next placed over the\ndeeper Power Probe, and irradiance measurements were made\nat 0.5 W and then 5.0 W. After 5 min, the measurements were\nrepeated in reverse order (5.0 W first). Power Probe was next\nplaced through the urethra and into the bladder. The energy\ndevice was next placed in the vagina under the bladder Power\nProbe. Irradiance measurements were made at 5.0 W and 0.5\nW. After 5 min, the measurements were repeated in reverse\norder (0.5 W first). The bladder was next catheterized of 50 cc\nof urine. Following euthanasia, the posterior vaginal wall,\nrectum, and levator ani were excised in-block, and depth mea-\nsurements were taken (see Table 1).\nResults\nApproximately 12.5% of the irradiance at the vaginal mucosa\nreached the surface of the levator ani muscle. Approximately\n3% of the initial irradiance reached the center of the levator ani\nmuscle. At a power of 5 W, approximately 4.5% of the irra-\ndiance reached the bladder. At 0.5 W, the irradiance reaching\nthe bladder was too low to be detected by the Power Probe\n(Table 1). Postmortem measurements were made of the har-\nvested posterior pelvic tissues. The distance from the vaginal\nmucosal surface to the levator ani was 7 mm. The distance to\nthe mid-levator ani muscle belly was 10 mm. The levator ani\nthickness was 4 mm.\nDiscussion\nNumerous investigators have reported on the dose-response\neffect associated with the application of NIR light to living\ntissue. Although this effect is sometimes referred to as the\n“biphasic dose-response” effect of light therapy, there is noth-\ning novel about this effect. This effect has been well under-\nstood in the pharmaceutical industry for over a century. In the\nsimplest of terms, too small of a dose does nothing. A slightly\nlarger dose may have an effect. A bit more gets the desired\neffect, and a bit more starts to harm. Take the correct dose over\nTable 1 Irradiance at target tissue. Irradiance at target tissue provides\nthe laser power in watts (W), a description of each sensor’sp o s i t i o ni nt h e\nsubject, the depth of this position from the vaginal mucosa in millimeters,\nthe irradiance at this depth in milliwatts per centimeter squared, and the\nirradiance at the surface in milliwatts per centimeter squared. The\npercentage of power lost at depth is described as “irradiance reaching\ndepth”\nPower setting (W) Sensor depth (mm) Mean irradiance at\nvaginal mucosa (mW/cm\n2)\nMean irradiance\nat depth (mW/cm2)\nSensor position Irradiance\nreaching depth\n5 7.5 738 92 Surface of levator ani—\nbeneath mid vaginal vault\n12.47%\n0.5 7.5 74 9.5* Surface of levator ani—\nbeneath mid vaginal vault\n12.84%*\n5 10 738 22 Mid levator ani muscle—\nbeneath mid vaginal vault\n2.98%\n0.5 10 74 0** Mid levator ani muscle—\nbeneath mid vaginal vault\n0**\n5 N/A 738 33 Floating in bladder w/ 50 cc urine 4.47%\n0.5 N/A 74 0.02 Floating in bladder w/ 50 cc urine 0.03%\nThree measurements were made at each location. Variation was ≤0.5 mW. *Sensor error is ±0.0005 W. **The Power Probe sensors fractured in the\ntissue tunnel. A measurement was not available\nFig. 1 The SoLá Pelvic Therapy Laser System and its transvaginal\ndelivery system. The delivery system consists of a reusable handpiece\nand proprietary laser fiber that radiates energy perpendicular to the fiber.\nThe distal handpiece is covered by a single-use, sterile, wand with a\nbulbous tip. Inset is the BK 2712 Precision Multimeter with a custom\nB&W Tek near-infrared Power sensor. These sensors were implanted in\nthe subject\n641Lasers Med Sci (2022) 37:639–643\n\ntoo long of a time interval, and there may be little or no effect,\nbut take that same dose all at once, and you may be harmed. In\nsummary, the correct amount of NIR energy per unit area must\nbe delivered over the correct amount of time. In the dosing of\nlaser energy, these two variables are described by irradiance\n(power density) and fluence (irradiance × time).\nAlthough both a pilot study and clinical experience have\ndemonstrated the safety and efficacy of this novel transvaginal\ninfrared laser system, this is the first study to document irra-\ndiance at the level of target pelvic tissues. This study demon-\nstrates that a novel class IV NIR laser with a novel\ntransvaginal delivery system is capable of delivering therapeu-\ntic doses of NIR energy to at least 10 mm below the vaginal\nmucosa. This depth is sufficient to reach into the human leva-\ntor ani muscles and bladder, which are found at depths and\nthicknesses similar to that of the studied animal [ 15].\nThe irradiance loss identified in our study is similar to the\nirradiance loss reported by Anders et al. Ander found that\napproximately 3% of NIR light transmitted through rabbit\nepithelium reached the targeted perineal nerve (12 mm deep)\n[11, 12]. This was nearly identical to our finding at 10 mm.\nAlthough each area of the body represents a potential new\nchallenge secondary to varying tissue thickness and chromo-\nphores, this variation may represent less of a challenge to class\nIV NIR lasers. Our study validates the finding of Anders. A\nlow-power laser in the milliwatt range is unlikely to deliver\ntherapeutic dosing to deeper tissues.\nAlthough the loss of irradiance per unit depth appears to be\nsimilar across different powers, there was an unexpectedly\nlarge drop at 500 mW when measured inside the bladder.\nLower irradiances may be more vulnerable to the refraction\nencountered in urine. Based on the loss of irradiance docu-\nmented at 5 W, 500 mW should result in irradiance of 2.2 and\n3.3 mW/cm\n2 in the levator muscle and bladder. One must\nremember that the surface irradiance of most class IIIB\n(milliwatt) lasers is confined to small spot sizes. Small spot\nsizes impair penetration and will unlikely be able to achieve\nthe 3 –4.5% irradiance at the target depths achieved by the\nstudied system herein. Even if such transmission could be\nachieved, the small spot size would require treatment times\nthat could be prohibitive.\nThe studied class IV NIR laser is capable of achieving a\npower of 15 W. Its novel transvaginal delivery system dis-\nperses 810 nm and 980 nm light in a 360-degree array. This\nstudy demonstrates that this novel system is capable of\ndelivering therapeutic irradiances to and through the leva-\ntor ani muscle and into the bladder (Table 2). This finding\nfurther validates the encouraging therapeutic responses of\nCPP patients who have been treated with the system since\nJuly of 2019.\nOne weakness of this study is that the data was collected\nfrom a live ewe rather than a human. Although the tissues and\nanatomy are remarkably similar, variations in irradiance\ntransmission may exist. An additional limitation remains the\nsmall pool of NIR dose-response data available for the treat-\nment of pelvic muscle spasm and bladder symptoms.\nAlthough the data collected during the last year of commercial\nuse of this novel device suggest that the irradiance generated\nat 5 W is therapeutic and the irradiance generated at .5 W will\nnot be therapeutic in the transvaginal treatment of levator my-\nalgia (myofascial pelvic pain), future clinical studies should\ngather additional longitudinal data at power settings at, below,\nand above 5 W.\nAcknowledgements The authors would like to thank Mr. Kevin\nRichardson and Mr. Steven Bowers for their participation in the organi-\nzation and completion of the study.\nAuthor contribution Zipper: project development, data collection, man-\nagement of data analysis, manuscript writing\nPryor: project development, data collection, management of data anal-\nysis, manuscript writing\nFunding This study was paid for by UroShape, LLC, the manufacturers\nof the SoLá Pelvic Therapy Laser System. Dr. Zipper is the CEO of\nUroShape, LLC, and holds a financial interest in the company. Dr.\nPryor is the CEO of LiteCure, LLC, the supplier of the diode laser used\nin the manufacture of the SoLá Pelvic Laser System. Dr. Pryor has a\nfinancial interest in UroShape, LLC. Both Dr. Zipper and Dr. Pryor sit\non the Board of Directors of UroShape, LLC.\nAvailability of data and material Data available within the article or its\nsupplementary materials\nCode availability Not applicable\nDeclarations\nConflict of interest Ralph Zipper, MD, FPMRS, is the CEO of\nUroShape, LLC, the manufacturer of the deep tissue transvaginal near-\nTable 2 Irradiance at surface and inside levator ani muscle by power\nsetting. This table provides irradiance measurements in milliwatts per\ncentimeter squared at the surfac e of the vaginal mucosa, and the\nirradiance measurements in milliwatts per centimeter squared reaching\nthe middle portion (in depth) of the levator ani. These measurements\na r ep r o v i d e da tl a s e rp o w e rs e t t i n g so f1 ,2 ,3 ,4 ,5 ,a n d6W\nPower (W) Surface irradiance\n(mW/cm\n2)\nIrradiance inside\nlevator ani* (mW/cm2)\n1 166 4.95\n2 388 11.57\n3 522 15.56\n4 643 19.17\n5 738 22.00\n6 998 29.75\n*5 W irradiance measured. Other values calculated based on 5 W Power\nProbe measurement\n642 Lasers Med Sci (2022) 37:639–643\n\ninfrared laser and applicator. Dr. Zipper has a financial interest in\nUroShape, LLC.\nBrian Pryor, Ph.D., is the CEO of Litecure, LLC, the supplier of the\ndiode laser used in the manufacture of the UroShape laser system. Dr.\nPryor has a financial interest in UroShape, LLC.\nOpen Access This article is licensed under a Creative Commons\nAttribution 4.0 International License, which permits use, sharing, adap-\ntation, distribution and reproduction in any medium or format, as long as\nyou give appropriate credit to the original author(s) and the source, pro-\nvide a link to the Creative Commons licence, and indicate if changes were\nmade. The images or other third party material in this article are included\nin the article's Creative Commons licence, unless indicated otherwise in a\ncredit line to the material. If material is not included in the article's\nCreative Commons licence and your intended use is not permitted by\nstatutory regulation or exceeds the permitted use, you will need to obtain\npermission directly from the copyright holder. To view a copy of this\nlicence, visit http://creativecommons.org/licenses/by/4.0/.\nReferences\n1. 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