Light-Emitting Diodes: Advances, Challenges and Applications in Musculoskeletal Pain

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Comments on photonics -4346661

Minor revision

This manuscript was prepared as a focused narrative review of the literature addressing LED-based PBM for musculoskeletal pain, including both low-level laser therapy and LED-based approaches. It’s well written and can be accepted in the current form, but it should be revised following the comments given below.

 

1. In Table 1, the detailed information of the reference should be deleted and modified as [ref. 22] or other concise form. Because the words in Main finding are crowded. If the authors modify the Study Reference part, the table (especially Main finding) would be more readable.
2. In Table 1, Some sentences in Protocol summary (Study Reference 27) “Out-comes included pain intensity by VAS and mandibular range of motion by digital calipers, assessed before treatment, immediately after the first session, and after six sessions.” should be deleted for redundant reason.
3. The abbreviation should be adapted in this article for concise reason. For example, in 4.2.3, low back pain should appear at the first time, then (LBP) would be better when it appears again. So does photobiomodulation when it appears again, it would be better to use PBM.
4. The light of laser is also scattering (including reflection and refraction) in the tissue, not likely a beam in Figure 2. Please redraw it. If you are interested in the behavior of laser light in the tissue (under 1 centimeter of the mouth), you can refer the published paper “Su, C.T., Chiu, F.C., Ma, S.H. and Wu, J.H. (2022) 'Optimization of Photobiomodulation Dose in Biological Tissue by Adjusting the Focal Point of Lens', Photonics.

 

 

Author Response

Reviewer 1

Comments and Suggestions for Authors

Comments on photonics -4346661

Minor revision

This manuscript was prepared as a focused narrative review of the literature addressing LED-based PBM for musculoskeletal pain, including both low-level laser therapy and LED-based approaches. It’s well written and can be accepted in the current form, but it should be revised following the comments given below.

 

1. In Table 1, the detailed information of the reference should be deleted and modified as [ref. 22] or other concise form. Because the words in Main finding are crowded. If the authors modify the Study Reference part, the table (especially Main finding) would be more readable.

YES, thank you very much!

We have modified the Table according to your recommendations.

Thank you very much!

 

1. In Table 1, Some sentences in Protocol summary (Study Reference 27) “Out-comes included pain intensity by VAS and mandibular range of motion by digital calipers, assessed before treatment, immediately after the first session, and after six sessions.” should be deleted for redundant reason.

YES, thank you for this comment. We agree that the sentence in the Protocol summary for Study Reference 27 is redundant. Accordingly, the sentence “Outcomes included pain intensity by VAS and mandibular range of motion by digital calipers, assessed before treatment, immediately after the first session, and after six sessions” has been deleted from Table 1

1. The abbreviation should be adapted in this article for concise reason. For example, in 4.2.3, low back pain should appear at the first time, then (LBP) would be better when it appears again. So does photobiomodulation when it appears again, it would be better to use PBM.

1. The light of laser is also scattering (including reflection and refraction) in the tissue, not likely a beam in Figure 2. Please redraw it. If you are interested in the behavior of laser light in the tissue (under 1 centimeter of the mouth), you can refer the published paper “Su, C.T., Chiu, F.C., Ma, S.H. and Wu, J.H. (2022) 'Optimization of Photobiomodulation Dose in Biological Tissue by Adjusting the Focal Point of Lens', Photonics.

Thank you for this valuable comment. We agree that laser light does not remain as a narrow, unscattered beam once it enters biological tissue. Due to tissue optical properties, laser light undergoes scattering, reflection, and refraction, especially within superficial and subsurface tissue layers.

Accordingly, we have redrawn Figure 2 to better represent the behavior of laser light in tissue. In the revised figure, the laser light is shown as a collimated incident beam before reaching the tissue surface, followed by scattering and diffusion within the tissue, rather than as a beam maintaining its shape throughout the tissue.

We appreciate the reviewer’s suggestion and have considered the recommended paper by Su et al. (2022), “Optimization of Photobiomodulation Dose in Biological Tissue by Adjusting the Focal Point of Lens,” published in Photonics, when revising the schematic representation, and added also the reference no. 73, by Su et al. (2022). Thank you very much!

 

 Submission Date

13 May 2026

Date of this review

27 May 2026 17:26:17

Thank you very much for your work and for paying special attention to the revision of our manuscript.

Your extremely valuable and objective recommendations were helpful in refining our review.

Thank you very much!

June 01, 2026

Reviewer 2 Report

Comments and Suggestions for Authors

1. The literature search strategy and PRISMA flowchart are missing. As a "focused narrative review", the article does not describe the systematic literature search strategy (database, search terms, time range, inclusion and exclusion criteria), nor does it provide a PRISMA flowchart or similar literature screening process. Although the author claims to use a narrative review method, Table 1 cites literature from 2021-2026 but does not explain how these literature were identified and screened.
2. Confusion between LED specific evidence and laser evidence. The author has repeatedly emphasized the specificity of "LED based PBM", but Section 4.2 extensively cites research on laser (LLLT) and high-intensity laser (HILT) to support the clinical application of LED (such as Dundar et al. using Ga Al As laser [39], Yousefi Nooraie's review on LLLT [42]). Although the author discussed the differences between laser and LED in Section 5, the boundary between LED specific evidence and laser evidence is blurred in the clinical evidence section.
3. The presentation of dosimetric data lacks standardization, and the dosimetric parameter reports in Table 1 are incomplete and inconsistent. For example:
The study [26] reported a total radiated power of 126 mW; energy of 75.6 J per point, but did not report radiation (mW/cm ²) or radiation exposure (J/cm ²). It is recommended that Table 1 should standardize the reporting of key dosimetric parameters (wavelength, power, irradiation area, radiation, flux, irradiation time, total energy), and missing items should be labeled as "NR" (not reported). At the same time, a column should be added to indicate whether it complies with the WALT dosage recommendations.
4. Figures 1 and 2 were created using AI, and some information in the figures is inaccurate. Please verify and make necessary modifications
5. The author has repeatedly emphasized the specificity of "LED based PBM", but Section 4.2 extensively cites research on laser (LLLT) and high-intensity laser (HILT) to support the clinical application of LED (such as Dundar et al. using Ga Al As laser [39], Yousefi Nooraie's review on LLLT [42]). Although the author discussed the differences between laser and LED in Section 5, the boundary between LED specific evidence and laser evidence is blurred in the clinical evidence section.

Comments on the Quality of English Language

Author Response

Reviewer 2

Comments and Suggestions for Authors

1. The literature search strategy and PRISMA flowchart are missing. As a "focused narrative review", the article does not describe the systematic literature search strategy (database, search terms, time range, inclusion and exclusion criteria), nor does it provide a PRISMA flowchart or similar literature screening process. Although the author claims to use a narrative review method, Table 1 cites literature from 2021-2026 but does not explain how these literature were identified and screened.

 

Thank you for this important comment. We agree that the literature identification and screening process should be described more clearly, particularly because Table 1 includes recent studies published between 2021 and 2026.

Accordingly, we have revised the Materials and Methods section by adding a dedicated subsection entitled “Literature search strategy and studies selection.” In this subsection, we now specify the databases consulted, the search terms used, the time range considered, and the main inclusion and exclusion criteria applied during study selection. We also clarified that the review focused primarily on recent clinical and translational evidence published between 2021 and 2026, while earlier publications were considered only when they provided relevant mechanistic, methodological, or dosimetric context.

 

We did not include a PRISMA flowchart because the manuscript was designed as a focused narrative review rather than a formal systematic review or meta-analysis. Therefore, the literature search was not intended to follow a formal PRISMA-based process involving exhaustive database retrieval, duplicate removal, independent screening, full-text eligibility assessment, and quantitative reporting of excluded records. Instead, the revised Methods section now provides a transparent and reproducible description of how the literature was identified, screened, and selected for narrative synthesis, while preserving the focused narrative and interpretive nature of the review.

2. 
   Confusion between LED specific evidence and laser evidence. The author has repeatedly emphasized the specificity of "LED based PBM", but Section 4.2 extensively cites research on laser (LLLT) and high-intensity laser (HILT) to support the clinical application of LED (such as Dundar et al. using Ga Al As laser [39], Yousefi Nooraie's review on LLLT [42]). Although the author discussed the differences between laser and LED in Section 5, the boundary between LED specific evidence and laser evidence is blurred in the clinical evidence section.

 

 

Thank you for this important comment. We agree that the boundary between LED-specific evidence and evidence derived from laser-based photobiomodulation was not sufficiently clear in the clinical evidence section.

Accordingly, we have revised Section 4.2 to distinguish more explicitly between: (i) studies using LED-based PBM devices, (ii) studies using combined laser–LED devices, (iii) low-level laser therapy studies used only as contextual or mechanistic support, and (iv) high-intensity laser therapy studies discussed only for comparative purposes. We have also modified the wording throughout the section to avoid implying that laser or HILT evidence provides direct clinical evidence for LED-based PBM.

In the revised version, LED-specific studies are presented as the primary clinical evidence for LED-based PBM. Laser and HILT studies are now clearly identified as indirect evidence and are discussed only when they help clarify photobiological principles, dose-response considerations, target depth, treatment geometry, or methodological issues relevant to PBM research. We have also added cautionary statements emphasizing that direct equivalence between LED, LLLT, and HILT cannot be assumed without adequate reporting of wavelength, irradiance, radiant exposure, treatment area, tissue contact, and anatomical target depth.

We believe these revisions clarify the evidentiary hierarchy of the review and address your concern regarding the blurred boundary between LED-specific clinical evidence and laser-based phototherapy evidence.

Please, see the following lines: 320-344 and 585-588.

Thank you very much!

 

 

3. 
   The presentation of dosimetric data lacks standardization, and the dosimetric parameter reports in Table 1 are incomplete and inconsistent. For example:
   The study [26] reported a total radiated power of 126 mW; energy of 75.6 J per point, but did not report radiation (mW/cm²) or radiation exposure (J/cm²). It is recommended that Table 1 should standardize the reporting of key dosimetric parameters (wavelength, power, irradiation area, radiation, flux, irradiation time, total energy), and missing items should be labeled as "NR" (not reported). At the same time, a column should be added to indicate whether it complies with the WALT dosage recommendations.

 

 

Thank you for this important comment. We agree that the original version of Table 1 did not present dosimetric parameters in a sufficiently standardized manner. Because PBM outcomes are strongly influenced by wavelength, optical power, irradiation area, irradiance, radiant exposure, exposure time, and total delivered energy, inconsistent reporting may limit reproducibility and may also lead to inappropriate comparisons between studies.

Accordingly, we have revised Table 1 by adding standardized columns for wavelength, device/emitter type, optical power, irradiation area, irradiance, radiant exposure/fluence, irradiation time, energy per point or treatment field, number of sessions/treatment schedule, and WALT dosage compliance. When a parameter was not reported in the original publication or could not be reliably derived from the available information, it was labeled as “NR” (not reported).

We also added a column indicating whether the available information allowed assessment of compliance with WALT dosage recommendations. When the dosimetric information was insufficient to judge compliance, this was indicated as “Unclear/NR.” For protocols, registry records, and systematic reviews, this item was classified as “Not applicable.” These revisions were made to improve transparency, reproducibility, and comparability across studies, while avoiding unsupported assumptions when key dosimetric parameters were missing.

 

4. 
   Figures 1 and 2 were created using AI, and some information in the figures is inaccurate. Please verify and make necessary modifications.

 

We have revised and redesigned Figures 1 and 2, at your suggestion, and scientifically verified them. Please, see the new Figures 1 and 2. Thank you very much!

5. 
   The author has repeatedly emphasized the specificity of "LED based PBM", but Section 4.2 extensively cites research on laser (LLLT) and high-intensity laser (HILT) to support the clinical application of LED (such as Dundar et al. using Ga Al As laser [39], Yousefi Nooraie's review on LLLT [42]). Although the author discussed the differences between laser and LED in Section 5, the boundary between LED specific evidence and laser evidence is blurred in the clinical evidence section.

 

We thank you for this important comment. We agree that the distinction between LED-specific evidence and laser-based photobiomodulation evidence required clarification.

Accordingly, we have revised Section 4.2 to more clearly differentiate studies using LED-based PBM devices from those using combined laser–LED systems, low-level laser therapy, or high-intensity laser therapy. LED-specific studies are now presented as the primary clinical evidence, whereas laser and HILT studies are explicitly identified as indirect or comparative evidence only.

We have also revised the wording to avoid implying direct equivalence between LED-based PBM, LLLT, and HILT, and added cautionary statements emphasizing that such modalities cannot be considered interchangeable without adequate reporting of key dosimetric and methodological parameters, including wavelength, irradiance, radiant exposure, treatment area, tissue contact, and target depth.

We believe these revisions clarify the evidentiary hierarchy and address the concern regarding the previously blurred boundary between LED-specific and laser-based evidence.

 

Thank you very much!

 

Comments on the Quality of English Language

 

We thank you for this helpful comment. We have thoroughly revised the entire manuscript to improve the clarity, readability, and overall quality of the English language. We paid particular attention to grammar, sentence structure, terminology, and the precise expression of the research aims, methods, results, and conclusions. We believe that the revised version now communicates the scientific content more clearly and effectively.

 

Submission Date

13 May 2026

Date of this review

26 May 2026 08:27:12

 

Thank you very much for your work and for paying special attention to the revision of our manuscript.

Your extremely valuable and objective recommendations were helpful in refining our review.

Thank you very much!

June 02, 2026

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript is devoted to the current topic of LED photobiomodulation, focusing on musculoskeletal pain. The manuscript describes in detail the use of LEDs for the treatment or rehabilitation of various conditions. Furthermore, the manuscript thoroughly describes the methodological shortcomings of the articles in this area and outlines requirements for such studies to allow for a comprehensive comparison. The work is detailed and well-structured. However, there are some shortcomings that require correction:

1. In its current form, the review focuses primarily on clinical experience but weakly addresses the physical aspects of photobiomodulation (specific laser irradiation parameters). I propose adding a separate section where the authors would detail the parameters they highlighted as important.

2. Although the authors point out that one of the shortcomings of articles on this topic is the incompleteness of technical information, this review omits critical information regarding the radiation power/power density. This information appears in only two studies in Table 1. However, the authors frequently indicate that power selection is an important parameter for photobiomodulation. At least approximate value ranges should be provided.

3. I suggest specifying the adequacy of the blinding method in the studies reviewed, given that light exposure (even if non-therapeutic) may induce patient expectations of the effect.

4. In the manuscript, the authors frequently emphasize the importance of beam geometry (shape), but in fact, they mean beam radius. If they are specifically referring to beam shape, I suggest adding information on the use of non-traditional laser beam shapes (e.g., Bessel beam), as it has unique properties that distinguish it from Gaussian beams, such as tissue propagation.

5. Information should be added regarding whether modern LED arrays are truly capable of completely replacing high-intensity laser systems in conditions requiring high power density for deep penetration.

6. A small note: line 98 states "These wavelength bands are widely used... although penetration depth is strongly affected by wavelength..." and repeats "wavelength" twice. This should be corrected.

7. Figure 2 compares laser and LED, but not in the context of musculoskeletal pain, but rather medical applications in general. It is necessary to clarify which specific areas of musculoskeletal pain would benefit from laser and LED therapy.

Author Response

Reviewer 3

Comments and Suggestions for Authors

The manuscript is devoted to the current topic of LED photobiomodulation, focusing on musculoskeletal pain. The manuscript describes in detail the use of LEDs for the treatment or rehabilitation of various conditions. Furthermore, the manuscript thoroughly describes the methodological shortcomings of the articles in this area and outlines requirements for such studies to allow for a comprehensive comparison. The work is detailed and well-structured. However, there are some shortcomings that require correction:

1. In its current form, the review focuses primarily on clinical experience but weakly addresses the physical aspects of photobiomodulation (specific laser irradiation parameters). I propose adding a separate section where the authors would detail the parameters they highlighted as important.

Response to Reviewer:

Thank you for this valuable suggestion. We agree that the physical and dosimetric aspects of photobiomodulation should be more clearly emphasized. To address this point, we have modified Table 1, by inserting two new columns and added a separate section before the Limitations section, entitled “Key Irradiation Parameters in LED-Based Photobiomodulation.” This new section summarizes the main irradiation parameters considered essential for interpretation and reproducibility, including wavelength, optical power, irradiance, radiant exposure/fluence, total delivered energy, exposure time, treatment area, number of irradiation sites, treatment frequency, total number of sessions, application mode, and anatomical target depth. We believe that this addition strengthens the physical framework of the review and improves the clarity and translational value of the manuscript.

 

1. Although the authors point out that one of the shortcomings of articles on this topic is the incompleteness of technical information, this review omits critical information regarding the radiation power/power density. This information appears in only two studies in Table 1. However, the authors frequently indicate that power selection is an important parameter for photobiomodulation. At least approximate value ranges should be provided.

Response to Reviewer:

Thank you for this important and constructive observation. We agree that radiation power and power density/irradiance are essential physical parameters for interpreting photobiomodulation protocols and that their incomplete reporting limits reproducibility and cross-study comparison. To address this concern, we revised the manuscript by modifying Table 1, inserting two new columns, i.e., “Key dosimetric parameters (wavelength (nm), total radiated power (mW/cm²), irradiation area (cm²), fluence (J/cm²), irradiation time (s), total energy (J)” and “WALT dosage compliance”.

In addition, we expanded a new section focused on dosimetry, placed before the Limitations section, and introduced new Table 4 as relevant in this regard.

We believe that this revision directly addresses the reviewer’s concern and strengthens the physical and dosimetric framework of the review.

 

1. I suggest specifying the adequacy of the blinding method in the studies reviewed, given that light exposure (even if non-therapeutic) may induce patient expectations of the effect.

Response to Reviewer:

Thank you for this relevant methodological suggestion. We agree that the adequacy of blinding is an important issue in photobiomodulation studies, particularly because visible or perceived light exposure, warmth, device appearance, treatment duration, and interaction with the operator may influence patient expectations and placebo responses.

To address this point, we revised the manuscript to specify, where available, the blinding approach used in the reviewed studies, including sham devices, placebo light exposure, inactive emitters, visually identical devices, participant blinding, assessor blinding, and double- or triple-blind designs. We also added a brief methodological comment emphasizing that sham irradiation should reproduce the appearance, sound, duration, and handling of active PBM as closely as possible, while avoiding therapeutic irradiance or radiant exposure.

Where the original studies did not provide sufficient information to judge the adequacy of blinding, this has now been explicitly indicated as incompletely reported. We also clarified that inadequate or poorly described blinding may overestimate treatment effects, especially in pain outcomes, which are particularly sensitive to expectation and contextual effects. Please, see new subsection 9.1. Blinding and expectation effects.

 

1. In the manuscript, the authors frequently emphasize the importance of beam geometry (shape), but in fact, they mean beam radius. If they are specifically referring to beam shape, I suggest adding information on the use of non-traditional laser beam shapes (e.g., Bessel beam), as it has unique properties that distinguish it from Gaussian beams, such as tissue propagation.

Response to Reviewer:

Thank you for this precise and helpful comment. We agree that the term “beam geometry” was used too broadly in several parts of the manuscript. In many instances, our intention was to refer mainly to beam/spot size, beam radius, irradiated area, divergence, and spatial distribution of energy at the tissue surface, rather than to beam shape in the strict optical sense.

To avoid ambiguity, we have revised the terminology throughout the manuscript. Where appropriate, “beam geometry” has been replaced or specified as “spot size,” “beam radius,” “irradiated area,” “beam divergence,” or “spatial energy distribution.” We also added a short clarification noting that non-traditional laser beam profiles, such as Bessel beams, may have distinctive propagation properties compared with conventional Gaussian beams, including reduced diffraction and different axial intensity distribution. Please, see lines 816-824. However, because the present review focuses mainly on LED-based PBM and clinically used LED/laser PBM protocols in musculoskeletal pain, a detailed discussion of advanced structured laser beams was considered beyond the scope of this review.

We believe that this revision improves the physical accuracy of the manuscript while maintaining its clinical and translational focus.

 

1. Information should be added regarding whether modern LED arrays are truly capable of completely replacing high-intensity laser systems in conditions requiring high power density for deep penetration.

Response to Reviewer:

Thank you for this helpful comment. Please, see new text added at your suggestion. Please, see lines 896-903. Thank you very much!

 

1. A small note: line 98 states "These wavelength bands are widely used... although penetration depth is strongly affected by wavelength..." and repeats "wavelength" twice. This should be corrected.

Response to Reviewer:

Thank you for this helpful comment. The text was modified following your recommendation. Please, see lines 189-191.

Thank you very much!

 

1. Figure 2 compares laser and LED, but not in the context of musculoskeletal pain, but rather medical applications in general. It is necessary to clarify which specific areas of musculoskeletal pain would benefit from laser and LED therapy.

Response to Reviewer:

Thank you for this useful comment. We agree that the previous version of Figure 2 presented the comparison between laser and LED PBM in a relatively general medical context and did not sufficiently specify its relevance to musculoskeletal pain. To address this concern, we revised Figure 2 and its accompanying text to focus specifically on musculoskeletal pain applications.

The revised figure now clarifies that LED-based PBM may be particularly suitable for broad-field, superficial, or moderately deep musculoskeletal targets, such as cervical myofascial pain, temporomandibular disorders involving masticatory muscles, fibromyalgia-related widespread pain, plantar fascia disorders, superficial tendinopathies, periarticular knee osteoarthritis pain, and selected rehabilitation settings where large-area coverage is useful. In contrast, laser-based PBM may be more appropriate when precise point irradiation, higher spatial targeting, or deeper localized delivery is required, such as trigger points, tendon insertions, entheses, joint-line applications, carpal tunnel syndrome, and selected deeper periarticular structures.

We also clarified that the choice between laser and LED should not be based only on emitter type, but on wavelength, irradiance, radiant exposure, beam/spot size, treatment area, anatomical depth, and the intended biological target. This revision better aligns the figure with the scope of the review and with the clinical interpretation of PBM in musculoskeletal pain.

Submission Date

13 May 2026

Date of this review

24 May 2026 18:27:37

Thank you very much for your work and for paying special attention to the revision of our manuscript.

Your extremely valuable and objective recommendations were helpful in refining our review.

Thank you very much!

June 03, 2026

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

1. The article provides a detailed description of the system retrieval strategy (database, search terms, time range), but does not follow the PRISMA or any systematic evaluation process (such as not providing a screening flowchart, not specifying the specific execution method of inclusion/exclusion criteria, and not conducting quality assessment). This "semi systematic" expression makes it difficult for readers to judge the objectivity and completeness of literature selection.
In the study of fibromyalgia, it was reported that the total emission power was 967 W, the total area was 34544 cm ², and the total energy per segment was approximately 1160400 J. These values are exceptionally large in physics, and the article does not specify whether these values are the total electrical power of the equipment or the optical output power, nor does it discuss the thermal safety at such high energy levels. The author should verify or explain these parameters.
3. The article repeatedly emphasizes that coherence is rapidly lost in tissues, so the difference in efficacy between laser and LED should be attributed to dose rather than coherence. This argument is theoretically reasonable, but the author did not cite any direct head to head clinical studies comparing laser and LED under the same wavelength, dose, and irradiation area. Without such evidence, the persuasiveness of the conclusion is limited.
Figure 1 describes LED-PBM as a linear pathway from "photon absorption" to "clinical analgesia", involving multiple molecular events (NF - κ B, Nrf2, IL-6/STAT3, etc.). However, the temporal dynamics, dose dependence, and tissue specificity of these pathways in the context of musculoskeletal pain have not been systematically validated in the human body. Illustrations may give readers an excessive hint that the mechanism has been fully elucidated.
5. The conclusion section proposes that LED-PBM should be used as an auxiliary tool for multimodal rehabilitation, but does not provide any specific parameter selection guidance (such as which wavelength, irradiance, and irradiation time should be selected for target tissues at different depths). For readers who wish to use LED-PBM in clinical settings, the 'actionable information' provided in this article is limited.

Comments on the Quality of English Language

Author Response

Reviewer 2

Round 2, June 04 2026

1. The article provides a detailed description of the system retrieval strategy (database, search terms, time range), but does not follow the PRISMA or any systematic evaluation process (such as not providing a screening flowchart, not specifying the specific execution method of inclusion/exclusion criteria, and not conducting quality assessment). This "semi systematic" expression makes it difficult for readers to judge the objectivity and completeness of literature selection.

 

Response to Reviewer 2:

We thank you for this important and constructive comment. We agree that the previous wording could have created ambiguity regarding the methodological nature of the manuscript. Our aim was not to present the article as a PRISMA-based systematic review or meta-analysis, but as a focused narrative review supported by a structured literature search and a transparent qualitative synthesis.

To avoid misunderstanding, we have removed the ambiguous expression “semi-systematic” and now consistently describe the manuscript as a focused narrative review. We have also revised Section 2.1, “Literature Search Strategy and Study Selection,” to provide a clearer description of the screening and study-selection process. The revised text now explains how records were screened for relevance, how potentially eligible full texts were assessed, how duplicate or overlapping reports were handled, and how the final literature was organized according to clinical condition, device type, wavelength, irradiation protocol, comparator, outcome measures, and main findings.

In addition, we have made the inclusion and exclusion criteria more explicit. The revised Methods section now clarifies that studies were included when they addressed PBM or low-level light-based therapy in musculoskeletal or orofacial pain conditions; evaluated LED-based, laser-based, or combined PBM devices; reported clinical, functional, inflammatory, mechanistic, or dosimetric outcomes relevant to pain modulation and tissue recovery; or provided methodological or translational information relevant to PBM interpretation. We also clarified that studies were excluded when they were unrelated to musculoskeletal or orofacial pain, did not involve PBM or low-level light-based therapy, focused exclusively on unrelated dermatological or cosmetic indications, lacked sufficient methodological or contextual information for interpretation, were non-English publications, or were conference abstracts without adequate methodological detail.

We also explicitly state that no PRISMA flowchart was included because the manuscript was not designed as a formal systematic review. Likewise, no pooled quantitative synthesis or formal risk-of-bias assessment was performed. Instead, the evidence was appraised narratively using criteria relevant to PBM research, including study design, adequacy of comparator or sham control, blinding, sample size, follow-up duration, completeness of dosimetric reporting, wavelength and irradiance reporting, treatment geometry, outcome relevance, and methodological or translational robustness.

Finally, we have strengthened the Limitations section to acknowledge that the absence of a predefined protocol, PRISMA-based screening pathway, and formal risk-of-bias framework limits the ability to judge the completeness of the evidence base in the same way as in a systematic review. We believe these revisions improve methodological transparency, clarify the scope of the article, and help readers better assess the objectivity and completeness of the literature selection within the intended framework of a focused narrative review.

Changes made in the manuscript:

Section 2.1 has been revised to expand and clarify the screening/study-selection process and the practical application of inclusion and exclusion criteria. The terminology has been corrected to avoid implying a formal systematic review, and the Limitations section has been strengthened to explicitly acknowledge the absence of PRISMA methodology, protocol registration, and formal risk-of-bias assessment.

 

2. In the study of fibromyalgia, it was reported that the total emission power was 967 W, the total area was 34544 cm ², and the total energy per segment was approximately 1160400 J. These values are exceptionally large in physics, and the article does not specify whether these values are the total electrical power of the equipment or the optical output power, nor does it discuss the thermal safety at such high energy levels. The author should verify or explain these parameters.

 

Response to Reviewer 2:

We thank you for this important observation. We agree that the initially reported values may appear exceptionally large if interpreted as focal optical delivery or as electrical power applied to the patient. We have therefore revised the manuscript to clarify that these values refer to the total optical output of a whole-body LED PBM system, distributed over a very large emitting surface, and not to a concentrated point-source exposure. Please, see the Table 1 NovoTHOR parameters in Reference [29].

Specifically, the reported value of 967 W represents the estimated total emitted optical/radiant power of the whole-body red/NIR LED system, calculated from the reported irradiance and total emitting surface:

28 mW/cm² × 34,544 cm² ≈ 967 W.

The corresponding total radiant energy per session is therefore:

967 W × 1200 s ≈ 1,160,400 J.

However, this total energy should not be interpreted as energy delivered to a small anatomical point or segment. It is distributed over the whole-body treatment area, by whole-body PBM treatment using a NovoTHOR_ whole-body light bed. Please, see Table 1 NovoTHOR parameters in Reference [29]. The clinically relevant local exposure is the irradiance/fluence at the treatment surface, namely 28 mW/cm² and 25.2 J/cm² over 20 min. These values are within the non-thermal range commonly reported for PBM protocols and are fundamentally different from a high-power focal thermal exposure.

We have also clarified that this whole-body LED PBM protocol cannot be directly classified according to WALT point-dose recommendations, because WALT tables are primarily designed for localized point-based PBM/LLLT applications, whereas the cited fibromyalgia studies used large-field whole-body irradiation. We have added text emphasizing that total device output, irradiance, illuminated area, exposure time, and total energy must be interpreted together, particularly for broad-field LED arrays.

To address the thermal-safety concern, we have added an explicit statement that the relevant safety parameter is the distributed irradiance rather than total device power alone. At 28 mW/cm², the exposure is intended for photobiomodulatory, non-thermal action. We also note that the cited fibromyalgia studies using this whole-body LED PBM approach reported no clinically significant thermal adverse effects. The manuscript has been revised to make this distinction clearer and to avoid any possible misinterpretation of the reported values as focal or electrical energy delivered to tissue.

 

3. The article repeatedly emphasizes that coherence is rapidly lost in tissues, so the difference in efficacy between laser and LED should be attributed to dose rather than coherence. This argument is theoretically reasonable, but the author did not cite any direct head to head clinical studies comparing laser and LED under the same wavelength, dose, and irradiation area. Without such evidence, the persuasiveness of the conclusion is limited.

 

 

Response to Reviewer 2:

 

We thank you for this important and constructive comment. We agree that the statement regarding coherence should not be interpreted as definitive clinical proof that laser and LED devices have equivalent efficacy when all other parameters are matched. Our intention was to emphasize a mechanistic and dosimetric interpretation of PBM, namely that coherence is rapidly degraded in biological tissue and that wavelength, irradiance, beam geometry, treatment area, exposure time, and delivered dose are likely to be major determinants of biological response. However, we agree that the available clinical evidence does not yet include enough direct head-to-head trials comparing laser and LED devices under rigorously matched conditions of wavelength, dose, irradiation area, treatment geometry, and target depth.

We have therefore revised the manuscript to make this limitation explicit. The relevant conclusion has been softened to state that the loss of coherence in tissue supports a plausible rationale for focusing on dosimetry rather than coherence alone, but does not by itself establish clinical equivalence between laser and LED PBM. We have also clarified that laser and LED studies should not be pooled or compared indiscriminately unless dosimetric equivalence is clearly documented.

In response to the Reviewer’s suggestion, we have added a specific statement identifying the need for direct comparative clinical trials in which laser and LED interventions are matched as closely as possible for wavelength, irradiance, fluence/radiant exposure, beam area, exposure time, number of sessions, and anatomical target. Such studies would be required to determine whether coherence contributes independently to clinical efficacy after controlling for dose delivery and treatment geometry.

Accordingly, the revised manuscript now presents the laser-versus-LED discussion as a hypothesis-generating, dosimetry-oriented framework rather than as a definitive clinical conclusion.

 

4. Figure 1 describes LED-PBM as a linear pathway from "photon absorption" to "clinical analgesia", involving multiple molecular events (NF - κ B, Nrf2, IL-6/STAT3, etc.). However, the temporal dynamics, dose dependence, and tissue specificity of these pathways in the context of musculoskeletal pain have not been systematically validated in the human body. Illustrations may give readers an excessive hint that the mechanism has been fully elucidated.

 

Response to Reviewer 2:

We thank you for this valuable comment. We agree that Figure 1, in its original form, may have appeared too linear and could have unintentionally suggested that the molecular pathway from photon absorption to clinical analgesia has been fully established in humans. This was not our intention.

We have revised the figure legend and the corresponding explanatory text to clarify that Figure 1 represents a conceptual and hypothesis-generating framework, not a fully validated causal sequence. The molecular events shown in Figure1, including NF-κB, Nrf2/HO-1, nitric oxide signaling, ROS modulation, and mitochondrial responses, are presented as mechanisms reported or proposed mainly from experimental, preclinical, translational, and selected clinical biomarker studies. We now explicitly state that their temporal dynamics, dose-response behavior, tissue specificity, and relative contribution to analgesia in human musculoskeletal pain remain incompletely characterized.

We have also modified the wording in the manuscript to avoid implying a simple linear progression from photon absorption to clinical pain relief. Instead, the revised text emphasizes that PBM responses are likely network-based, dose-dependent, tissue-dependent, and phenotype-dependent, and that different pathways may predominate according to wavelength, irradiance, radiant exposure, anatomical target, inflammatory status, tissue depth, and timing of assessment.

To prevent overinterpretation, we have added a cautionary sentence indicating that Figure 1 should be interpreted as a simplified visual synthesis of plausible mechanisms rather than as evidence that these pathways have been systematically validated in vivo in humans for each musculoskeletal pain condition. We agree with the Reviewer that this distinction is important for maintaining scientific accuracy and avoiding excessive mechanistic certainty.

 

5. The conclusion section proposes that LED-PBM should be used as an auxiliary tool for multimodal rehabilitation, but does not provide any specific parameter selection guidance (such as which wavelength, irradiance, and irradiation time should be selected for target tissues at different depths). For readers who wish to use LED-PBM in clinical settings, the 'actionable information' provided in this article is limited.

 

Response to Reviewer 2

 

We thank you for this useful comment. We agree that the recommendation that LED-PBM may be used as an adjunctive tool in multimodal rehabilitation would be more clinically useful if accompanied by clearer practical guidance on parameter selection. Our original intention was not to prescribe fixed clinical protocols, because the available evidence remains heterogeneous and does not yet support universal dose recommendations across all musculoskeletal conditions. However, we agree that the manuscript should provide readers with a more actionable framework for selecting and reporting LED-PBM parameters.

In response, we have added a new dedicated subsection before the final section of the manuscript, entitled “Practical Parameter-Selection Considerations for Clinical LED-PBM” This new subsection summarizes general translational guidance according to target depth and tissue type. Specifically, we clarify that red wavelengths, particularly around 630–660 nm, are generally more appropriate for superficial targets such as skin-adjacent trigger points, superficial myofascial pain, and shallow periarticular tissues, whereas near-infrared wavelengths, commonly around 780–980 nm and especially 810–850 nm in many LED systems, may be more suitable for moderately deeper targets such as tendons, joint capsules, periarticular tissues, and peripheral nerves. We also emphasize that wavelength selection must be interpreted together with irradiance, radiant exposure, treatment area, contact geometry, tissue thickness, skin pigmentation, vascularity, and anatomical depth.

We have added that irradiance and exposure time should not be selected independently. Instead, clinicians and researchers should report and interpret irradiance, radiant exposure, treatment duration, illuminated area, total energy, number of sessions, and anatomical target together. We further clarify that low-to-moderate irradiance is generally preferred for non-thermal PBM, while excessive irradiance or radiant exposure may fall outside the biphasic therapeutic window.

To avoid overstatement, we present these recommendations as practical translational guidance rather than as definitive clinical prescriptions. We also explicitly state that condition-specific protocols should follow the parameters used in controlled trials whenever available, and that deeper or anatomically complex targets may require depth-aware dosimetry, optical modeling, or device calibration rather than simple extrapolation from surface dose.

This addition improves the clinical applicability of the review while preserving appropriate caution regarding the current limitations of LED-PBM evidence.

 

Comments on the Quality of English Language

We thank you for this helpful comment. The manuscript has been carefully revised throughout to improve the quality, clarity, and readability of the English language. We have corrected grammar and syntax, refined sentence structure, improved the flow of the text, and ensured more precise use of scientific terminology. Particular attention was given to sections describing the research rationale, methodology, PBM mechanisms, dosimetric parameters, clinical evidence, limitations, and translational implications. We believe that these revisions have substantially improved the manuscript and now allow the research content to be communicated more clearly and effectively to an international readership.

Thank you very much for your careful work and for the attention you have given to the second revision of our manuscript (Round 2). Your objective and highly valuable recommendations have been very helpful in further refining and strengthening our review.

We sincerely appreciate your time, expertise, and constructive feedback.

June 04, 2026

 

Submission Date

13 May 2026

Date of this review

04 Jun 2026 03:25:41

 

Author Response File: Author Response.pdf

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

1.Suggest adding a literature search strategy diagram.

Comments on the Quality of English Language

Author Response

Reviewer 2

Round 3

1. Suggest adding a literature search strategy diagram.

Response: Thank you for the suggestion. We have added a literature search strategy and study selection diagram to the Materials and Methods section to improve transparency. The new figure summarizes the electronic databases searched, manual reference screening, record screening, full-text eligibility assessment, exclusion criteria, and final selection of studies included in the qualitative narrative synthesis. Since the article is a focused narrative review rather than a systematic review or meta-analysis, the figure is presented as a structured literature search and study selection diagram rather than a formal PRISMA flowchart.

Please, see: Figure 1. Literature Search Strategy and Study Selection Flow Diagram.

Thank you very much.

 

2. Quality of English Language

Response: We have also thoroughly revised the entire manuscript to improve clarity, readability, and the overall quality of the English language. Particular attention was paid to grammar, sentence structure, terminology, and the precise expression of the research objectives, methods, findings, and conclusions. We believe that the revised version now communicates the scientific content more clearly and effectively.

Thank you very much.

June 11, 2026

Author Response File: Author Response.pdf