Changes in Cell Biology under the Influence of Low-Level Laser Therapy

Round 1

Reviewer 1 Report

The nomenclature has to be consistent. LLLT, low level, low energy etc. should no longer be used. However, with the current confusion in nomenclature issues, a few initial lines about the choice of nomenclature can be used, Or be addressed in the editorial preface on the issue.

References seem to be copied and pasted. Please use consistent style or the selected style of the jounal.

"Energy" is not J/cm2

PBM includes the use of non-coherenct devices. If the authors want to limit their review to coherent light sources, this should be discussed.

The role of CCO in cell stimulation has been questioned

"Irradiation" suggested (like illumination) rather than radiation  (cancer treatment)

Historical references to Mester and Maiman are these days  superfluous and common knowledge

I suggest an initial discussion about the importance of the parameters (Arndt-Schultz etc.) and the fact that effects seen in various studies may not be seen if parameters were changed.

Author Response

Reviewer #1:

 

We would like to thank the Reviewer for an in-depth analysis of the manuscript and for pivotal comments provided, which have resulted in a significant improvement of this manuscript.

 

Ad 1,  3 and 6  We believe that the Reviewer touched upon an imported problem of current confusion in nomenclature, therefore in the whole manuscript we unified all acronyms (particular LLLT) moreover, we tried to be scrupulous and not to use different definitions interchangeably additionally we added a short comment in the introduction section

Ad 2. Another valid point mentioned by the Reviewer is a remark regarding references style and formating – we are pleased to inform you that after potential acceptance of the manuscript all references will be formatted with the cooperation of the editorial office and in accordance with the journal recommendations. Additionally, we are pleased to inform you that we updated the references data set.

Ad 5  We realize that the works of Master and Maiman are mainly of historical importance, but given their pioneering nature and contribution to the development of this field of science, we believe they should be mentioned in this review.

 

Ad 4. and 7   We would like to thank the Reviewer for the remark regarding PBM, different radiation parameters, and light sources. Followed by the Reviewers suggestion we add short comments regarding this topic in the introduction section “ What needs to be emphasized, photobiomodulation (PBM) is a broader concept referring to different kinds of light sources, not only to coherence lasers light (e.g. visible, near-infrared (NIR), infrared (IR). The North American Association for Laser Therapy (NAALT) and World Association for Laser Therapy (WALT) defines [3] PBM as " the therapeutic use of light absorbed by endogenous chromophores, triggering non-thermal, non-cytotoxic, biological reactions through photochemical or photophysical events, leading to physiological changes”.

Interpretation of published studies is difficult and often can be confusing. This fact is inextricably linked with methodological issues. Available studies refer to various light sources with different radiation parameters, including coherence, wavelength, polarization, power, energy density, etc. Additionally, the biological effect of light therapy is often heterogeneous and strongly depends on the light parameters set and specific cell response.

Two main LLLT features seem to have the strongest impact on cell biology. First is the wavelength - 600–1,070 nm has the greatest impact on the promotion of cell proliferation. This phenomenon is probably related to absorption or interference of light beyond this range. Light with shorter wavelengths is strongly absorbed by hemoglobin, while those with longer wavelengths are absorbed by water [4]. The second important factor is energy density in general, lower energy densities energy density (0.05 J/cm² – 10 J/cm²). promote cell proliferation and greater enhanced cell apoptosis energy density (above 50 J/cm²). The mutual transition of both phenomena has got a continuous nature. This biphasic response is also known as the "Arndt-Schulz law".

Additionally few other parameters of LLLT seem to have an impact on the therapeutic effect of LLLT, yet full discussion regarding this issue seems to be beyond scope of this manuscript. As a short example, we can use laser operating mode -although the continuous-wave (CW) irradiation has been a gold standard in LLLT however, few studies suggested that pulse wave (PW) [5] may be superior to CW, particularly in regenerative applications however no strong evidence supporting this thesis [5], therefore, future studies focused on this topic are necessary to form unequivocal statements in this particular issue. Other more specific effects on cell life processes have been discussed in the next part of the manuscript 

Reviewer 2 Report

The manuscript ID photonics-1815275 mainly presents a review related to particular studies about cell biology functions assisted by low-level laser irradiation therapy. Please see below a list of comments to the authors:

1.   A roadmap about the use of low-level laser therapy in cell biology would be welcome.

2.   The incorporation of a graphical scheme to point out the advantages of laser therapy on cell biology could be useful for the presentation of this work.

3.   One major criticism is the absence of a clear discussion involving the different parameters of the laser irradiation (like wavelength) over cell mechanisms studied.

4.   Fractional descriptions of energy transfer have been reported for low and high photoenergy irradiation. The authors are invited to see for instance: https://doi.org/10.1016/j.ijthermalsci.2022.107734, and discuss within the text about potential implications and perspectives in advanced laser therapy.

5.   The authors should clearly state in their report what this review adds beyond previous reviews in comparative topics of research. You can see for instance: doi: 10.3389/fonc.2020.01255

6.   What levels of intensity are considered useful for the cell biology functions analyzed?

7.   How is the influence of the incident polarization over the changes in cell biology applications discussed?

8.   Pulsed vs continuous-wave irradiation present different results in cell biology functions for low laser therapy? Please comment.

9.   It is suggested to split the collective citations in order to better justify each reference selected for this review with individual expressions.

10.               Only one reference corresponds to 2022, please update the list.

Author Response

 

Reviewer #2:

 

              We would like to thank the Reviewer for an in-depth analysis of the manuscript and for pivotal comments provided, which have resulted in a significant improvement of this manuscript.

 

Ad 1 and 2 . As the Reviewer suggested, we provided additional Figures to the body of the manuscript to improve the clarity of the paper and achieve proper illustration to the readers' LLLT clinical applications.

Ad 3,6,7,8 As the Reviewer suggested, we added a short discussion regarding the impact of the different parameters of the laser irradiation on cell biology “..Interpretation of published studies is difficult and often can be confusing. This fact is inextricably linked with methodological issues. Available studies refer to various light sources with different radiation parameters, including coherence, wavelength, polarization, power, energy density, etc. Additionally, the biological effect of light therapy is often heterogeneous and strongly depends on the light parameters set and specific cell response.

Two main LLLT features seem to have the strongest impact on cell biology. First is the wavelength - 600–1,070 nm has the greatest impact on the promotion of cell proliferation. This phenomenon is probably related to absorption or interference of light beyond this range. Light with shorter wavelengths is strongly absorbed by hemoglobin, while those with longer wavelengths are absorbed by water [4]. The second important factor is energy density in general, lower energy densities energy density (0.05 J/cm² – 10 J/cm²). promote cell proliferation and greater enhanced cell apoptosis energy density (above 50 J/cm²). The mutual transition of both phenomena has got a continuous nature. This biphasic response is also known as the "Arndt-Schulz law".

Additionally few other parameters of LLLT seem to have an impact on the therapeutic effect of LLLT, yet full discussion regarding this issue seems to be beyond scope of this manuscript. As a short example, we can use laser operating mode -although the continuous-wave (CW) irradiation has been a gold standard in LLLT however, few studies suggested that pulse wave (PW) [5] may be superior to CW, particularly in regenerative applications however no strong evidence supporting this thesis [5], therefore, future studies focused on this topic are necessary to form unequivocal statements in this particular issue. Other more specific effects on cell life processes have been discussed in the next part of the manuscript

 

Ad 4 As the Reviewer suggested we discussed the potential impact of  fractional descriptions of energy implications and perspectives in advanced laser therapy “…which in combination with the recently described [118] effective use of fractional descriptions of energy transfer as a tool dedicated to the modification of cell biological functions, can open a completely new field of precise LLLT selected for specific medical indications.”

 

Ad 5. As the Reviewer suggested we added a statement regarding the aims of our manuscript along with special determinants of our manuscript “.. This paper aims to review the impact of LLLT on the basic intracellular process and additionally discusses the effect of LLLT on individual intracellular information transmission pathways”

 

Ad 9,10  Another valid point mentioned by the Reviewer is a remark regarding updating and rebuilding the references list used. We revised the manuscript references database.

Round 2

Reviewer 1 Report

The authors are advised to consult the journal editor for a consistent style of writing the references. The list is impressing, though.

The nomenclature is now better defined

The English in the new parts is difficult, with very long sentences.

A few observations from reading the revision:

1)    NAALT is now North American Association for Photobiomodulation therapy

2)    Page 1/43: coherent lasers

3)    3/60  promote cell proliferation and greater enhanced cell apoptosis energy density (above 50 60 J/cm²) EDIT THIS SENTENCE

4)    Additionally few other parameters of LLLT seem to have an impact on the therapeu- 63 tic effect of LLLT, yet full discussion regarding this issue seems to be beyond scope of this 64 manuscript.

Suggested: Additionally , even other parameters of LLLT seem to have an impact on the therapeu- 63 tic effect of LLLT. Yet, full discussion regarding this issue is beyond  the scope of this 64 manuscript.

As a short example, we can use laser operating mode -although the continu- 65 ous-wave (CW) irradiation has been a gold standard in LLLT however, few studies sug- 66 gested that pulse wave (PW) [5] may be superior to CW, particularly in regenerative ap- 67 plications however no strong evidence supporting this thesis [5], therefore, future studies 68 focused on this topic are necess

 

Suggested: .As a short example, we can use laser operating mode. Although the continu- 65 ous-wave (CW) irradiation has been a gold standard in LLLT, some studies sug- 66 gested that pulse wave (PW) [5] may be superior to CW, particularly in regenerative ap- 67 plications .However, no strong evidence support this theory [5] and therefore, future studies 68 focused on this topic are necess

 

5/151: Changes in cell signaling pathways and their clinical 151 impact ARE presented in figure 3.

 

9/301 including

This ambitious manuscript is much improved and will probably be accepted after a minor revision.

Author Response

We would like to thank the Reviewer for an in-depth analysis of the manuscript and for the pivotal comments provided, which have resulted in a significant improvement of this manuscript.

Ad 1 We would like to thank the Reviewer for the remark regarding of name of the North American Association for Photobiomodulation Therapy we corrected in the main text of the manuscript.

Ad 2, 5, 6 Due to the Reviewer`s recommendation we corrected a typo in the manuscript text.

Ad 3 Followed by the Reviewer’s suggestion we rephrased the misleading sentence.

Ad 4 We would like to thank the Reviewer for improving the mentioned sentence we corrected it in accordance with the Reviewers suggestion.

Additionally, we revised the English writing style in new parts of the manuscript.

Reviewer 2 Report

The authors have importantly improved the presentation of their work. The review is useful and it can be a base for future research. Then I can recommend this manuscript for publication in present form.

Author Response

We would like to thank the Reviewer for an in-depth analysis of the manuscript and for the pivotal comments provided, which have resulted in a significant improvement of this manuscript.

Round 3

Reviewer 1 Report

The manuscript is close to finishing but some idiomatic editing is still required. As the author stated, the list of references will be edited once the basic manuscript is approved. After the minor editing as suggested below, and with the edited list of references, I would be happy to read the final version before accepting.

1/20 signaling

3/58 1070, rather than 1, 070

…energy density. In general…

…has a continuous….

..is beyone THE scope…

However, no strong…

3/124 COX, not Cox

5/202 pathway by… (remove comma sign)

Laser irradiation

6/214 avoid ”laser therapy”

Edit the two references (underlined)

Author Response

We would like to thank the Reviewer for an in-depth analysis of the manuscript and for the pivotal comments provided, which have resulted in a significant improvement of this manuscript.

Ad 1,2,4,5,7.  We would like to thank the Reviewer for finding a typo in the manuscript text we corrected.

Ad 3.  Due to the Reviewer`s recommendation, we corrected indicated sentence

Ad 6. Followed by the Reviewer’s suggestion we corrected punctuation in the text.

Ad 8,9,10. We would like to thank the Reviewer for improving the mentioned sentence. We rephrased it by the Reviewers suggestion.

Ad 11. Followed by the Reviewers instructions we edited two highlighted references.

Round 4

Reviewer 1 Report

Dear authors,

The remaning issues are purely minor editing. Two notes:

5/166 irradiation

2/55 1070

Further to that, the list of references is still not edited into a consistent style.

After such editing, I will be happy to recommend this paper for publication

Author Response

We would like to thank the Reviewer for an in-depth analysis of the manuscript and for the pivotal comments provided, which have resulted in a significant improvement of this manuscript.

Ad 1,2.  We would like to thank the Reviewer for finding a typo in the manuscript text we corrected.

Ad 3  We are pleased to inform the Reviewer that all references will be edited to the necessary format by the Editors Office. We also strongly believe that any typos remaining in the manuscript will be captured by the editorial office and will be part of the editorial corrections. Below we attach a part of the email from the editorial office regarding the corrections of the references

 “We noticed that Reviewer 1 wrote "The authors are advised to consult the
journal editor for a consistent style of writing the references." We will
modify the references in your manuscript when finalizing your manuscript. “