Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Review for:

Jellybush honey extract: a solution for enhanced wound healing and scar reduction across diverse skin phototypes

Dear Authors, I am writing some observations and suggestions for your paper.

In Materials and Methods, chapter 2, instead of underline titles (lines 94, 100, 110) it is better to give them numbers, 2.1., 2.2., 2.3. and so on

Please explain all abbreviations (for example, in line 106, explain NHDF, DMEM, line 112, please explain IL-1 α, and so on, each time there is a new abbreviation )

Line 136, please explain the MTS method.

Line 152, please explain, RNALater.

Figure 1., charts are to small and barely visible. Is it possible to enlarge ?

Figure 3, also, please improve quality of charts .

Figure 5, please explain are these individuals part of your study, or from another study?

Is there an explanation of academic backgrounds of authors, because we can see their employment , but not their academic background ?

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

A manuscript titled “Jellybush honey extract: a solution for enhanced wound healing and scar reduction across diverse skin phototypes”. Australian Jellybush honey extract being studied as a natural element to enhance wound healing and reduce scarring in various skin types. The extract reduced inflammation, increased antioxidant activity, and somewhat increased pro-collagen I production. Gene expression research on damaged human skin explants treated with the extract for 6 days showed precisely tailored wound healing gene regulation. A double-blind clinical trial found that cream with 2% extract improved skin homogeneity, scar surface area, and hypertrophic and atrophic scar look compared to placebo. The work is well-written and well-organized. However, there are a few problems that need to be addressed.

Please provide the HPLC chromatograms for standard leptosperin, the honey extract, and the cream formulation.

Kindly provide the year and month of collection for the honey sample.

Kindly disclose further specifics on the extraction and filtering techniques employed in honey extraction.

Kindly specify the quantity of glycerin included into the honey extract.

The formulation must specify the quantity of leptosperin.

Figure 1 requires enlargement.

The first and second paragraphs of the findings should be relocated to the discussion section.

 

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript explores an aqueous Jellybush (Leptospermum polygalifolium) honey as a cosmetic active for modulating wound-healing biology and improving acne-scar appearance. This study followed a clear path from in vitro tests to a small clinical trial, suggesting that aqueous Jellybush honey may help calm early inflammation, support barrier repair, and modestly improve acne-scar texture and color over eight weeks. The translational storyline and the choice of practical, image-based clinical endpoints are appreciated. Please kindly find the following comments/suggestions/questions for improvement:

1. In my humble opinion, the term ‘extraction’, as written in the Methodology section as well as with regard to the use of the term "honey extract" in the article, might seem inaccurate for a process that consists in diluting honey in water and heating it (95 °C/10 min). Please clarify whether this is an aqueous dilution/solubilization and report the exact solid:liquid ratio, filtration/centrifugation steps, and pH/osmolality. I'd suggest the authors to write the sample as "Jellybush honey" instead of "Jellybush honey extract".
2. The authors also cited ~21 ppm leptosperin in the sample. How could this compound be considered as the main bioactive? On what analytical and functional evidence is that claim based? How about the other bioactive compounds? This part may be worth a deeper explanation in teh Discussion section.
3. The Methodology section consisted in using several cell lines, including Normal Human Epidermal Keratinocytes (NHEK), Normal Human Dermal Fibroblasts (NHDF), and Human follicle dermal papilla cells (Promocell, Heidelberg, Germany, C-12071). However, it seems that only NHDF appeared in the Figure legends. Please clarify and correct accordingly. In addition, please justify the use of different cell lines for different tests. Why not using the same cell lines in all tests for objectivity?
4. Formulations: The active phase in the sample is “Glycerin (AND) Water (AND) Honey extract) 2%,” while the placebo contains 1.10% glycerin separately. Confirm that total glycerin and osmolality/humectancy are matched between arms to avoid performance bias; otherwise, adjust the placebo or explicitly justify. In addition, would it be possible for the authors to reveal the proportion between glycerin, water, and honey in the sample?
5. Questions for Discussion enrichment: (a) Given the modest average 3% scar-area reduction, what would be the expected time-to-benefit beyond 8 weeks? (b) Have the authors benchmarked Jellybush honey against standard cosmetic actives or silicone-based comparators or other studied ingredients with similar effects?
6. Minor editing: Correct taxon and typos (e.g., Western not “Weatern,” Masson’s trichrome not “trichome,” Differentiation not “Diffrentiation,” area not “aera,”, etc.). Gene/protein notation: standardize (IL-1A vs IL1A; MMP-1 vs MMP1). Please italicize all scientific names in Latin as well as gene names.

Thank you.

Author Response

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Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

The authors of submitted manuscript entitled “Jellybush honey extract: a solution for enhanced wound healing and scar reduction across diverse skin phototypes” characterized wound healing potential of water extract and its clinical efficacy in double blind clinical trial.

Overall, study is interesting and I appreciate that the authors performed the clinical trial based on positive outcomes from in vitro experiments. I have several comments to the design of study:

1. It is not clear how extract of jellybush honey was prepared. The authors mentioned that honey was extracted in water at 95°C. Honey is completely dissolved in water. What was the extract? What are the major compositions? More details about the extract need to be added to the manuscript.
2. Toxicological data (or cytotoxicity) of the honey extract was not shown. The authors should elaborate more about the toxicological data.
3. Ethical issue. Clinical study involving humans needs to be approved by the Ethical committee (Number of approval). The authors provided only informed consent of participants which is not satisfactory.
4. References should be removed from the Results section. Same parts in Results section including lines 226-233 should be moved to Discussion section.
5. Abstract needs to be re-written. I suggest showing the exact values in cases when the authors mentioned simulation, increasing the activity. Furthermore, honey extract should be defined in the abstract (water based extract,…)

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Acceptable MS

Reviewer 3 Report

Comments and Suggestions for Authors

The revised manuscript has taken into account and answered all previously given comments and suggestions. Therefore, I think this manuscript can be accepted for publication.

Reviewer 4 Report

Comments and Suggestions for Authors

The authors addressed all my issues and comments. Congratulations. The revised ms has been improved.