An Update on the Correlation Between Neuroimmunomodulation, Photodynamic Therapy (PDT), and Wound Healing: The Role of Mast Cells

Round 1

Reviewer 1 Report (New Reviewer)

Comments and Suggestions for Authors

1. The abstract has a largely descriptive style and does not accurately address the objectives and conclusions drawn from the review. It should therefore be reorganised to address the clinical issue, the integrative emphasis on neuroimmunomodulation and PDT approaches, the strategic significance of mast cells, and the derived clinical implications.
2. The article is mostly descriptive, especially where it describes the phases of the healing of a wound as well as the molecular biomarkers, and could benefit from a critical analysis of the state of knowledge.
3. The underlying hypothesis that mast cells function as key neuroimmune messengers connecting PDT with wound healing is still too tacit. This underlying idea should be clearly stated and emphasized throughout the manuscript, ideally with a conceptual framework or summary table early on that weaves together PDT-induced ROS, activation of mast cells, neuropeptide release, modulation of the immune response, and outcomes with regard to wound healing.
4. The neuroimmunomodulation part concludes with a general introduction; nonetheless, it does not contain many details about the mechanism. There seems to be more importance on the signaling pathway (such as cholinergic and vagal).
5. The clinical evidence for PDT within chronic wounds is explored inadequately. The major limitation of light penetration into tissues, as well as the specificity of drug delivery for the photosensitizer, needs to be dealt with. Future potential combinations of treatments including a neuroimmune agent might be worth considering.
6. There is heterogeneity among mast cells, with the presence of variations between mucosal and connective tissue mast cells and between MCTC and MCT. The impact of PDT on specific subtypes of mast cells could be elaborated upon when discussing the mechanism.
7. The conclusion is repetitive and does not have a strong emphasize on new findings, whereas the "Prospective of research" part remains very general. The concerned part needs to move ahead by giving a hypothesis to the experiments, an experimental model, neuroimmune markers in PDT, and the possibilities of personalized light therapies.

Author Response

Ref. 1

 

The authors sincerely thank Ref. 1 for her/his thoughtful questions and attention to the manuscript.

 

Q1) The abstract has a largely descriptive style and does not accurately address the objectives and conclusions drawn from the review. It should therefore be reorganised to address the clinical issue, the integrative emphasis on neuroimmunomodulation and PDT approaches, the strategic significance of mast cells, and the derived clinical implications.

A1) The abstract has been revised and organized according to the Reviewer's suggestions (see page 1 lines 54-70).

Q2) The article is mostly descriptive, especially where it describes the phases of the healing of a wound as well as the molecular biomarkers, and could benefit from a critical analysis of the state of knowledge.

A2) A critical review of the question subject has been added (see page 6 lines 411-424)

Q3) The underlying hypothesis that mast cells function as key neuroimmune messengers connecting PDT with wound healing is still too tacit. This underlying idea should be clearly stated and emphasized throughout the manuscript, ideally with a conceptual framework or summary table early on that weaves together PDT-induced ROS, activation of mast cells, neuropeptide release, modulation of the immune response, and outcomes with regard to wound healing.

A3) The authors, taking into account the question, have revised the figure  by adding the influence of ROS in the mechanisms of cellular activation (see page 13 line 780) as well as adding a reflection on this topic (see page 12 lines 759-768).

Q4) The neuroimmunomodulation part concludes with a general introduction; nonetheless, it does not contain many details about the mechanism. There seems to be more importance on the signaling pathway (such as cholinergic and vagal).

A4) The authors, taking into account the question, have revised this part (See pages 6-7 lines 426-449)

Q5) The clinical evidence for PDT within chronic wounds is explored inadequately. The major limitation of light penetration into tissues, as well as the specificity of drug delivery for the photosensitizer, needs to be dealt with. Future potential combinations of treatments including a neuroimmune agent might be worth considering.

A5) We thank the reviewer for this important observation. In response, we have expanded our discussion on the clinical evidence supporting photodynamic therapy (PDT) for chronic wounds. While we acknowledge that limitations such as restricted light penetration and the challenge of targeted photosensitiser delivery remain critical issues, recent studies demonstrate that PDT represents a promising adjunctive therapy, particularly in the context of infected or poorly healing wounds such as diabetic foot ulcers and chronic leg ulcers.

To address these limitations, innovative strategies including nanocarrier systems, hydrogel-based delivery, and microneedle-assisted applications are under active investigation. Furthermore, combination therapies incorporating neuroimmune agents have shown potential to enhance healing outcomes by modulating the wound microenvironment and immune responses.

Accordingly, we have added a dedicated paragraph in the revised manuscript discussing these recent findings (see pages 13,14 lines 803-835) and have cited the relevant literature to substantiate our claims.

Q6) There is heterogeneity among mast cells, with the presence of variations between mucosal and connective tissue mast cells and between MCTC and MCT. The impact of PDT on specific subtypes of mast cells could be elaborated upon when discussing the mechanism.

A6) The authors, taking into account the question, have added this part (See page 11 lines 688-699)

Q7) The conclusion is repetitive and does not have a strong emphasize on new findings, whereas the "Prospective of research" part remains very general. The concerned part needs to move ahead by giving a hypothesis to the experiments, an experimental model, neuroimmune markers in PDT, and the possibilities of personalized light therapies.

A7) The conclusion has been revised and organized according to the Reviewer's suggestions (see page 14 lines 837-857)

 

 

 

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

This manuscript brings together valuable information for healthcare professionals regarding noninvasive therapies to accelerate wound healing

To provide a useful overview for healthcare professionals, I recommend a schematic representation of the wound healing process, including all the stages that are part of the healing process

Specify exactly what are the sources (produced by the body or taken from the diet) of the metalloproteins that are directly involved in the healing process

Would calcium deficiency in the body slow down the wound healing process? Or does it act indirectly?

Would supplementation with antioxidants, both topically and systemically, be beneficial?

Present the advantages and disadvantages of photodynamic therapy compared to the classical 

Author Response

The authors sincerely thank Ref. 2 for his thoughtful questions and attention to the manuscript.

Q1) This manuscript brings together valuable information for healthcare professionals regarding noninvasive therapies to accelerate wound healing.

A1) The authors sincerely thank Ref.2 for her/his comment!

Q2) To provide a useful overview for healthcare professionals, I recommend a schematic representation of the wound healing process, including all the stages that are part of the healing process.

A2) The authors took into account the author's suggestion and the part relating to wound healing was considered in the review! (See pages 2-3 lines 63-117)

Q3) Specify exactly what are the sources (produced by the body or taken from the diet) of the metalloproteins that are directly involved in the healing process.

A3) This suggestion was incorporated in the review (see page 3 lines 107-108)

Q4) Would calcium deficiency in the body slow down the wound healing process? Or does it act indirectly?

A4) This suggestion was incorporated in the review (see pages 3-4 lines 148-165)

Q5) Would supplementation with antioxidants, both topically and systemically, be beneficial?

A5) We appreciate the reviewer’s insightful question regarding the potential role of antioxidant supplementation, both topical and systemic, in the context of chronic wound management. Indeed, emerging preclinical and early clinical evidence supports the therapeutic potential of various antioxidant compounds—including vitamin E, curcumin, polyphenols, chitosan, N-acetylcysteine (NAC), and quercetin—through mechanisms such as redox modulation, attenuation of oxidative stress, regulation of inflammation, and enhancement of tissue repair.Topical formulations may offer direct modulation of local oxidative stress, while systemic administration could be beneficial in addressing systemic contributors, particularly in patients with relevant comorbidities. Nonetheless, as highlighted in the literature, further well-designed clinical trials are required to establish optimal dosing regimens, delivery strategies, and long-term safety profiles.

While we acknowledge the relevance of this approach, we have opted not to incorporate additional content on antioxidant therapies in the current manuscript, as this falls outside the primary scope of our review. We do, however, consider this an important area for future investigation and appreciate the reviewer’s thoughtful suggestion.

Q6) Present the advantages and disadvantages of photodynamic therapy compared to the classical 

A6) We thank the reviewer for this valuable suggestion. In response, we have included a paragraph in the revised manuscript outlining the key advantages and limitations of photodynamic therapy (PDT) in comparison with conventional treatments for chronic wounds. The discussion highlights PDT’s broad-spectrum antimicrobial activity, reduced risk of resistance, and potential for improved healing outcomes, alongside its limitations such as restricted tissue penetration and the need for precise delivery systems. These additions aim to provide a balanced perspective on the clinical applicability of PDT. (see pages 13,14 lines 803-835). The new content has been clearly marked in the manuscript for ease of reference.

Round 2

Reviewer 1 Report (New Reviewer)

Comments and Suggestions for Authors

I have carefully reviewed the revised version of the manuscript titled " An update on the correlation between neuroimmunomodula-tion, photodynamic treatment, and wound healing. Role of mast cells." The authors have adequately addressed all the comments and concerns raised during the review process. The necessary revisions have improved the clarity, scientific rigor, and overall quality of the manuscript.

Based on the satisfactory revisions and the scientific merit of the work, I recommend the acceptance of this manuscript for publication.

Author Response

C1) I have carefully reviewed the revised version of the manuscript titled " An update on the correlation between neuroimmunomodulation, photodynamic treatment, and wound healing. Role of mast cells." The authors have adequately addressed all the comments and concerns raised during the review process. The necessary revisions have improved the clarity, scientific rigor, and overall quality of the manuscript.

Based on the satisfactory revisions and the scientific merit of the work, I recommend the acceptance of this manuscript for publication.

A1) The authors sincerely thank Ref. 1 for her/ his suggestions that improved the quality of the manuscript.

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

For clarity and transparency, authors may consider including a schematic diagram illustrating the process of identifying and selecting the relevant literature.

 

Author Response

Ref. 2

 

The authors sincerely thank Ref. 2 for her/his thoughtful questions and attention to the manuscript.

 

Q1) For clarity and transparency, authors may consider including a schematic diagram illustrating the process of identifying and selecting the relevant literature.

A1) We have added a schematic diagram illustrating the process of identifying and selecting the relevant lecterature (see pages 1-2)

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The current manuscript presents some basic knowledge on neuroimmunomodulation, photodynamic therapy, and wound healing. While these are relevant and clinically interesting topics, the review primarily compiles elementary information without offering in-depth mechanistic discussion or critical synthesis that would benefit readers already familiar with the field. As a result, the manuscript does not provide substantial new insight or conceptual advancement. Furthermore, the novelty and scientific contribution of the work are not clearly defined. Based on the current content, the review does not address any innovative aspect that would meaningfully advance the existing literature. In addition, 50% of the text was found to overlap with previously published material, indicating a high level of textual similarity. This raises serious concerns regarding originality and academic integrity.