BACKGROUND:Nerve guidance conduits (NGCs) are a clinically approved option for peripheral nerve repair but remain ineffective compared with autograft "gold standard" treatment options. A combinatorial approach to conduit-based peripheral nerve repair could improve repair outcomes. Photobiomodulation therapy (PBMT) has shown potential to enhance axonal regeneration, but its efficacy in combination with NGCs requires further evaluation. OBJECTIVE:This pilot study investigated the therapeutic potential of a novel 3D-printed, collagen-based NGC combined with PBMT for peripheral nerve regeneration in a 10 mm rat sciatic nerve injury model. MATERIALS AND METHODS:A total of 36 male, 3-month-old, Sprague-Dawley rats were used in a pre-clinical rat model of peripheral neurotmesis and randomly assigned to one of three groups (N = 12 each): Autograft (control), NGC-PBMT (experimental), and NGC + PBMT (experimental). All groups were further subdivided (N = 6) by recovery period (3 or 6 weeks). Collagen-based NGCs were fabricated via DLP 3D printing and implanted into rats with 10 mm sciatic nerve transections. PBMT treatment was applied transcutaneously every other day at 980 nm for 30 s at 1 W. Gross examination, immunohistochemistry, and immunofluorescence were used to assess biocompatibility, vascularization, and nerve regeneration at 3- and 6-weeks post-surgery. RESULTS:Gross examination revealed no sign of inflammation or immune rejection, with significant neovascularization observed throughout the NGCs. Immunostaining demonstrated nerve regeneration in all groups, with progressive axonal growth from week 3 to 6 in the NGC-PBMT group. However, neither experimental group achieved regeneration comparable to the autograft control. PBMT did not yield significant improvement in regenerative outcomes under the tested parameters. CONCLUSIONS:Altogether, this study provides encouraging preliminary evidence that these novel, 3D-printed NGCs are biocompatible and promote early nerve regeneration after peripheral neurotmesis. While PBMT did not enhance outcomes in this study, further work is needed to optimize light delivery parameters and improve conduit design for enhanced neuroregeneration.

In this chapter, the evolution of the terms “photobiomodulation” (PBM) and “photobiomodulation therapy” (PBMT) and of the other terminology used in the field of photonic medicine are discussed. An overview of the role of photoacceptors in PBM, the effects of absorbed light on mitochondrial function, the generation of cell-signaling molecules, and the promotion of gene expression is provided. Clinically important effects of PBMT at the cellular and system levels are also explored.

Objective: Photobiomodulation at higher irradiances has great potential as a pain-alleviating method that selectively inhibits small diameter nerve fibers and corresponding sensory experiences, such as nociception and heat sensation. The longevity and magnitude of these effects as a function of laser irradiation parameters at the nerve was explored. Methods: In a rodent chronic pain model (spared nerve injury-SNI), light was applied directly at the sural nerve with four delivery schemes: two irradiance levels (7.64 and 2.55 W/cm(2) ) for two durations each, corresponding to either 4.8 or 14.4 J total energy, and the effect on sensory hypersensitivities was evaluated. Results: At emitter irradiances of 7.64 W/cm(2) (for 240 s), 2.55 W/cm(2) (for 720 s), and 7.64 W/cm(2) (for 80 s) the heat hypersensitivity was relieved the day following photobiomodulation (PBM) treatment by 37 +/- 8.1% (statistically significant, p < 0.001), 26% +/- 6% (p = 0.072), and 28 +/- 6.1% (statistically significant, p = 0.032), respectively, and all three treatments reduced the hypersensitivity over the course of the experiment (13 days) at a statistically significant level (mixed-design analysis of variance, p < 0.05). The increases in tissue temperature (5.3 +/- 1.0 and 1.3 +/- 0.4 degrees C from 33.3 degrees C for the higher and lower power densities, respectively) at the neural target were well below those typically associated with permanent action potential disruption. Conclusions: The data from this study support the use of direct PBM on nerves of interest to reduce sensitivities associated with small-diameter fiber activity.

# Background Plantar fasciitis (PF) results in pain-related disability and excessive healthcare costs. Photobiomodulation therapy (PBMT) has shown promise for decreasing both pain and disability related to PF. # Purpose The purpose was to assess the clinical impact of PBMT on pain and function in people with PF. # Study Design Prospective, randomized controlled clinical trial # Methods A convenience sample of adults with PF were randomly assigned to one of three groups: (1) usual care, (2) usual care plus nine doses of PBMT with 25W output power over three weeks, or (3) usual care plus nine doses of PBMT with 10W output power over three weeks. Both 10W and 25W PBMT participants received the same total dose (10J/cm^2^) by utilizing a simple area equation. Pain (with Defense and Veterans Pain Rating Scale) and function (by Foot and Ankle Ability Measure) were measured at baseline, weeks 3, and 6 for all groups, and at 13 and 26 weeks for PBMT groups. # Results PBMT groups experienced a reduction in pain over the first three weeks (from an average of 4.5 to 2.8) after which their pain levels remained mostly constant, while the UC group experienced a smaller reduction in pain (from an average of 4 to 3.8). The effects on pain were not different between PBMT groups. PBMT in both treatment groups also improved function more than the UC group, again with the improvement occurring within the first three weeks. # Conclusions Pain and function improved during the three weeks of PBMT plus UC and remained stable over the following three weeks. Improvements sustained through six months in the PBMT plus UC groups. # Level of Evidence Level II- RCT or Prospective Comparative Study

Background: Peripheral nerve injuries pose a significant clinical issue for patients, especially in the most severe cases wherein complete transection (neurotmesis) results in total loss of sensory/motor function. Nerve guidance conduits (NGCs) are a common treatment option that protects and guides regenerating axons during recovery. However, treatment outcomes remain limited and often fail to achieve full reinnervation, especially in critically sized defects (>3 cm) where a lack of vascularization leads to neural necrosis. Conclusions: A multitreatment approach is, therefore, necessary to improve the efficacy of NGCs. Stimulating angiogenesis within NGCs can help alleviate oxygen deficiency through rapid inosculation with the host vasculature, whereas photobiomodulation therapy (PBMT) has demonstrated beneficial therapeutic effects on regenerating nerve cells and neovascularization. In this review, we discuss the current trends of NGCs, vascularization, and PBMT as treatments for peripheral nerve neurotmesis and highlight the need for a combinatorial approach to improve functional and clinical outcomes.

Objectives Pharmacologic pain treatments lack specific targeting and often produce unwanted side effects (eg, addiction, additional hyperalgesia). We previously established that the direct application of laser irradiation (direct photobiomodulation [PBM]) of the sural nerve reduces thermal hypersensitivity in a rodent model of chronic pain, but not mechanical hypersensitivity. These observations were consistent with a selective reduction in the small-diameter fiber contribution to electrophysiologically measured evoked response after direct PBM of a sensory nerve (saphenous). However, to our knowledge, direct application of laser irradiation has never been performed in an animal model of acute nociceptive pain or on a mixed nerve in which sensory and motor outcomes can be observed. Materials and Methods In this study, we describe the effects of direct application of laser irradiation (808 nm, 60 mW, 4 minutes) on a mixed nerve (sciatic nerve) in an acute nociceptive pain model (intradermal capsaicin injection) in rats over the course of two weeks. To investigate whether laser irradiation of a mixed nerve alters motor function, in separate experiments, we applied laser irradiation to the sciatic nerve (using the same parameters as in the chronic pain experiments), and force generation of the gastrocnemius was measured. Results Capsaicin-induced hypersensitivities to mechanical (pin prick) and thermal (Hargreaves) noxious stimuli, associated with Aδ- and C-fibers, showed a maximal reduction of 70% and 56.2%, respectively, by direct PBM, when compared with a control group (vehicle injection, no PBM) on the same day. This reduction was determined to be significant using a mixed-design analysis of variance with a p value < 0.05. Force generation remained unchanged for up to 120 minutes after laser irradiation. In summary, direct PBM selectively inhibits C- and Aδ-fiber transmission while leaving Aɑ-, Aβ-, and motor-fiber activity intact. Conclusions These results, in conjunction with our previous analyses of laser irradiation effects on the sural nerve in a chronic spared nerve injury pain model, suggest that direct PBM is a promising candidate for treating pain induced by small-diameter fiber activity.

Introduction: Photobiomodulation (PBM) has been studied since the 1960s as a clinical tool. More recently, PBM has been observed to reduce compound action potential components and hypersensitivities associated with neuropathic pains. However, no definitive description of efficacious light parameters has been determined. Some reasons may be that previous meta-analyses and reviews have focused on emitter output rather than the light at the target tissue and have included data sets that are large but with notable variability (e.g., combining data from various disease etiologies, and data from PBM at various wavelengths). This fact has made it difficult to successfully define the range of effective parameters. Methods: In this study, photon propagation software was used to estimate irradiance at a target nerve using several published data sets chosen for their narrow criteria to minimize variability. Utilizing these estimates, effective and ineffective light irradiances at the nerve of interest for wavelengths of 633 nm or 808-830 nm were examined and estimated. These estimates are focused on the amount of light required to achieve a reduction in pain or a surrogate measure via a hypothesized nerve block mechanism. Results: Accounting for irradiance at the target nerve yielded a clear separation of PBM doses that achieved small- fiber nerve block from those that did not. For both the 633 nm group and the 808-830 group, the irradiance separation threshold followed a nonlinear path with respect to PBM application duration, where shorter durations required higher irradiances, and longer durations required lower irradiances. Using the same modeling methods, irradiance was estimated as a function of depth from a transcutaneous source (distance from skin surface) for emitter output power using small or large emitter sizes. Conclusion: Taken together, the results of this study can be used to estimate effective PBM dosing schemes to achieve small-fiber inhibition for various anatomical scenarios.

Photobiomodulation, Photomedicine, and Laser SurgeryVol. 37, No. 2 Guest EditorialLight-Emitting Diode Therapy and Low-Level Light Therapy Are Photobiomodulation TherapyJuanita J. Anders, Praveen R. Arany, G. David Baxter, and Raymond J. LanzafameJuanita J. AndersAddress correspondence to: Juanita J. Anders, BA, MS, PhD, Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20854 E-mail Address: juanita.anders@usuhs.eduDepartment of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland.Search for more papers by this author, Praveen R. AranyDepartment of Oral Biology and Biomedical Engineering, School of Dental Medicine, Engineering and Applied Sciences, University at Buffalo, Buffalo, New York.Search for more papers by this author, G. David BaxterCentre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, Dunedin, New Zealand.Search for more papers by this author, and Raymond J. LanzafameExecutive Editor, Photobiomodulation, Photomedicine, and Laser Surgery, Rochester, New York.Search for more papers by this authorPublished Online:8 Feb 2019https://doi.org/10.1089/photob.2018.4600AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byUse of low-level laser therapy for patients with chronic rhinosinusitis: a single-blind, sham-controlled clinical trial20 December 2022 | Lasers in Medical Science, Vol. 38, No. 1A long‐term follow‐up of early breast cancer patients treated with photobiomodulation during conventional fractionation radiotherapy in the prevention of acute radiation dermatitis2 October 2022 | Lasers in Surgery and Medicine, Vol. 54, No. 10Near-infrared light reduces β-amyloid-stimulated microglial toxicity and enhances survival of neurons: mechanisms of 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Background: Breast cancer-related lymphedema (BCRL) is a prevalent long-term condition secondary to cancer treatment. BCRL impacts physical function, psychological health, and quality of life for patients who have survived breast cancer.Objectives: This study will assess the feasibility of a fully-powered randomized controlled trial investigating the effectiveness of low level laser therapy (LLLT), also known as photobiomodulation (PBM) therapy, as an adjunct treatment for managing BCRL.Methods: This study will be a pragmatic two-armed randomized controlled feasibility trial. Twenty female participants being treated for BCRL at the Dunedin Hospital, New Zealand, will be recruited over a 6-month window. Subject to informed consent, participants will be offered LLLT (PBM) in addition to their regular treatment for BCRL. Twelve treatments with laser therapy will continue for 6 weeks (twice weekly). Feasibility outcomes (recruitment rate, randomization rate, participant's adherence to the LLLT (PBM) treatment protocol, and participant retention rates) will be collected during the recruitment and intervention period. Participant satisfaction will be collected on completion of treatment intervention. Safety outcomes of LLLT (PBM) will be collected at each treatment visit. Clinical outcome measures (limb circumference, participant's perceived symptoms, psychological impacts, and activity disability) will be assessed at baseline, 6 and 12 weeks post-randomization.Conclusions: Results of this feasibility trial will inform the design and implementation of a future definitive randomized controlled trial, which will investigate the effectiveness of LLLT (PBM) for women with BCRL.

ObjectivesThis study aimed to determine the feasibility of conducting a full scale randomized controlled trial investigating the effectiveness of low level laser therapy (LLLT), also known as photobiomodulation (PBM) therapy, used in addition to conventional therapy, for managing breast cancer related lymphedema (BCRL).Materials and MethodsPatients with BCRL were recruited from the Southern District Health Board (New Zealand) via lymphedema therapists’ referrals, and randomly allocated into either the laser group, which received BCRL conventional therapy (e.g., wearing compression garments, massage therapy, and/or exercise) plus a 6‐week LLLT (PBM) intervention program (wavelength: 980/810 nm (80:20 ratio); output power: 500 mW beam spot size: 5 cm2; irradiance: 100 mW/cm2; treatment time per area: 1 minute dosage per area treated: 30J (6J/cm2); 10 points of treatment from axilla to wrist total LLLT (PBM) treatment time: 10 minutes total dosage delivered: 300 J), or the control group, which received BCRL conventional therapy alone. Feasibility was determined by recruitment and randomization rates, retention of participants and treatment protocol adherence, and was assessed during the recruiting and intervention periods. Data on participant satisfaction and adverse reactions of LLLT (PBM) were collected on completion of this study. Clinical outcomes (i.e., limb circumference, participant's perceived symptoms, psychological impacts, and activity disability) were assessed at baseline, and 6 and 12 weeks post‐randomization.ResultsOver a 6‐month recruitment window, 17 participants with BCRL were recruited in the study, and randomized into the two groups (recruitment rate of 81%, and randomization rate of 100%). Treatment adherence was high in the laser group (88.9% of participants completed all treatments). Retention rates were 88.9% for the laser group and 100% for the control group at both 6 and 12 weeks post‐randomization. All participants who completed LLLT (PBM) treatment indicated that they were satisfied with the treatment. No serious adverse reactions were reported in this study. Clinical outcomes failed to show additional benefits of LLLT (PBM) intervention.ConclusionThis study demonstrated that it is feasible to conduct a fully powered RCT to definitively test the effectiveness of the additional use of LLLT (PBM) in the management of BCRL. For such a trial, 114 participants will be needed at baseline. Lasers Surg. Med. 50:924–932, 2018. © 2018 Wiley Periodicals, Inc.

BACKGROUND:Breast cancer related lymphedema (BCRL) is a prevalent complication secondary to cancer treatments which significantly impacts the physical and psychological health of breast cancer survivors. Previous research shows increasing use of low level laser therapy (LLLT), now commonly referred to as photobiomodulation (PBM) therapy, for BCRL. This systematic review evaluated the effectiveness of LLLT (PBM) in the management of BCRL. METHODS:Clinical trials were searched in PubMed, AMED, Web of Science, and China National Knowledge Infrastructure up to November 2016. Two reviewers independently assessed the methodological quality and adequacy of LLLT (PBM) in these clinical trials. Primary outcome measures were limb circumference/volume, and secondary outcomes included pain intensity and range of motion. Because data were clinically heterogeneous, best evidence synthesis was performed. RESULTS:Eleven clinical trials were identified, of which seven randomized controlled trials (RCTs) were chosen for analysis. Overall, the methodological quality of included RCTs was high, whereas the reporting of treatment parameters was poor. Results indicated that there is strong evidence (three high quality trials) showing LLLT (PBM) was more effective than sham treatment for limb circumference/volume reduction at a short-term follow-up. There is moderate evidence (one high quality trial) indicating that LLLT (PBM) was more effective than sham laser for short-term pain relief, and limited evidence (one low quality trial) that LLLT (PBM) was more effective than no treatment for decreasing limb swelling at short-term follow-up. CONCLUSIONS:Based upon the current systematic review, LLLT (PBM) may be considered an effective treatment approach for women with BCRL. Due to the limited numbers of published trials available, there is a clear need for well-designed high-quality trials in this area. The optimal treatment parameters for clinical application have yet to be elucidated.

Background and Objective Various irradiances have been reported to be beneficial for the treatment of neuropathic pain with near infrared light. However, the mechanistic basis for the beneficial outcomes may vary based on the level of irradiance or fluence rate used. Using in vivo and in vitro experimental models, this study determined the mechanistic basis of photobiomodulation therapy (PBMT) for the treatment of neuropathic pain using a high irradiance.Study Design/Materials and Methods ln vitro experiments: Cultured, rat DRG were randomly assigned to control or laser treatment (L T) groups with different irradiation times (2, 5, 30, 60 or 120s). The laser parameters were: output power = 960 mW, irradiance = 300mW/cm2, 808 nm wavelength and spot size = 3cm diameter/ area = 7.07cm2, with different fluences according to irradiation times. Mitochondrial metabolic activity was measured with the MTS assay. The DRG neurons were immunostained using a primary antibody to β-Tubulin III. ln vivo experiments: spared nerve injury surgery (SNI), an animal model of persistent peripheral neuropathic pain, was used. The injured rats were randomly divided into three groups (n = 5). 1) Control: SNI without LT, 2) Short term: SNI with LT on day 7 and euthanized on day 7, 3) Long term: SNI with LT on day 7 and euthanized on day 22. An 808 nm wavelength laser was used for all treatment groups. Treatment was performed once on Day 7 post-surgery. The transcutaneous treatment parameters were: output power: 10 W, fluence rate: 270 mW/cm2, treatment time: 120s. The laser probe was moved along the course of the sciatic/sural nerve during the treatment. Within 1 hour of irradiation, behavior tests were performed to assess its immediate effect on sensory allodynia and hyperalgesia caused by SNI.Results ln vitro experiments: Mitochondrial metabolism was significantly lower compared with controls for all LT groups. Varicosities and undulations formed in neurites of DRG neurons with a cell body diameter 30µm or less. ln neurites of DRG neurons with a cell body diameter of greater than 30µm, varicosities formed only in the 120s group. ln vivo experiments: For heat hyperalgesia, there was a statistically significant reduction in sensitivity to the heat stimulus compared with the measurements done on day 7 prior to LT. A decrease in the sensitivity to the heat stimulus was found in the LT groups compared with the control group on day 15 and 21. For cold allodynia and mechanical hyperalgesia, a significant decrease in sensitivity to cold and pin prick was found within 1 hour after L T. Sensitivity to these stimuli returned to the control levels after 5 days post-L T. No significant difference was found in mechanical allodynia between control and L T groups for all time points examined.Conclusion These in vitro and in vivo studies indicate that treatment with an irradiance/fluence rate at 270 m W/cm2 or higher at the level of the nerve can rapidly block pain transmission. A combination therapy is proposed to treat neuropathic pain with initial high irradiance/fluence rates for fast pain relief, followed by low irradiance/fluence rates for prolonged pain relief by altering chronic inflammation.