Zinc in Dermatology: Exploring Its Emerging Role in Enhancing Botulinum Toxin Formulations and Clinical Efficacy
, Iulianna C. Taritsa 1, Dominika Gavlasova 4, Theodore C. Lee 5, Gavin J. Lin 6, Umar Choudry 2 and Samuel J. Lin 1,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Authors,
This is an interesting review article about zinc (preferably Zn complexes as used in pharmaceutical products and cosmetics) and mentioning a possible incorporation of Zn in botulinum toxin formulations for aesthetic procedures. I suggest some aspects, which could enhance the quality of the manuscript:
Please rewrite the Title of the manuscript to be more suggestive!
Abstract:
Beginning with the Abstract section and the entire manuscript, please do not use the term „therapeutic” regarding nuraceuticals/nutricosmetics/supplements and/or cosmetics/cosmeceuticals/dermatocosmetic products– according to current EU legislation supplements and/or cosmetics can improve skin conditions, but unfortunately they do not possess any pharmacological effect.
Please make a clear distinction between aesthetic medicine/dermatological products vs. cosmetic preparations.
Please make Keywords more specific!
Introduction:
Lines 34: What do authors mean by “repair”? – eventually skin regeneration.
It is recommended, that references must be numbered in order of appearance in the text (including tables and legends reference) and listed at the end of the manuscript according to CIMB instructions for authors!
Authors are kindly asked to use the manuscript template according to the instructions for authors of the journal - chapter/subchapter/justify, text editing, figure and table title/references, etc..
Please consider that in cosmetics according to the INCI denomination, zinc possesses antioxidant properties, while other INCI containing zinc (namely Zn complexes) have other functions (for e.g. ZnO is an UV filter, etc.). Also, Zn compounds/ingredients according to Regulation 1223/2009 have restrictions mentioned in Annexes (ZINC SALICYLATE - III/24; Zinc oxide (nano) - VI / 30a, etc.), which I recommend to discuss in this review, being an essential legislative aspect.
Figure 1: Please make the Figure more clear and intelligible! Please consider Zn/Zn complexes effects in mentioned product categories (like mentioned for e.g. for ZnO in sunscreens). Perhaps CosIng/CIR databases could be useful (https://ec.europa.eu/growth/tools-databases/cosing/; https://cir-reports.cir-safety.org/) to specify the correct effect as discussed in the manuscript.
The authors should emphasize beginning with the Abstract and in the Introduction section about the originality of their study.
Table 1 and entire manuscript - please make a clear distinction of product type - OTC (like sunscreens eventually in USA), topical creams is very generic - cosmetics/pharmaceutical products? Nanoparticles should be considered as active/cosmetic ingredient/API, not necessarily as a finished product. What do authors mean by “hybrid gels” as classification in Table 1?
Line 110: “… adhesion enhancers…” – in cosmetics (like mentioned for face powders, which indeed is included in the cosmetics category) according to it’s INCI name, Zn possesses ANTICAKING, OPACIFYING, VISCOSITY CONTROLLING properties!
Line 123: “Z-Cote” - if a registered ingredient of BASF, please give complete details of ingredient manufacturer - city, country). Please consider this aspect for all ingredients/products mentioned in the manuscript (including commercially available ingredients/products, for e.g. Botox).
Lines 148-153: Please add reference(s), it is not a personal finding evidenced by clinical evaluation(s) of the claimed effect!
Lines 187-197: Like suggested before, please make a clear distinction between cosmetic/cosmeceutical formulation, nutraceuticals/nutricosmetics and pharmaceutical products. Please consider that animal testing for cosmetics is banned within Regulation CE 1223/2009 (not even literature data after the implementation of Regulation 1223/2009 can be used to sustain safety or efficacy of cosmetics/cosmeceuticals)! Regulation 1223/2009 bans ingredient and cosmetic product animal testing!
Line 257: What do authors mean by “cosmetic patients”?
Please detail subchapter “8. Registered patents on zinc in Botulinum Neurotoxin-A formulations”, not only mentioning the two patents.
Lines 323-332: Please mention referents of the described study, if it is not a personal finding! Is it ref. 45?
Please carefully check English grammar, syntax and word spacing!
Kind regards!
Comments on the Quality of English LanguageMinor editing of English language are required.
Author Response
Reviewer #1:
We would like to extend our sincere gratitude to the reviewer for their valuable time and feedback. We have addressed all the suggestions as detailed below and have incorporated the changes into the revised manuscript.
Comment 1: Please rewrite the Title of the manuscript to be more suggestive!
Response 1: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 2: Beginning with the Abstract section and the entire manuscript, please do not use the term „therapeutic” regarding nuraceuticals/nutricosmetics/supplements and/or cosmetics/cosmeceuticals/dermatocosmetic products– according to current EU legislation supplements and/or cosmetics can improve skin conditions, but unfortunately they do not possess any pharmacological effect.
Response 2:
Comment 3: Please make a clear distinction between aesthetic medicine/dermatological products vs. cosmetic preparations.
Response 3: Thank you for highlighting this. We have updated the title of the manuscript. Comment 4: Please make Keywords more specific!
Response 4: Thank you for highlighting this. We have updated the title of the manuscript. Comment 5: Lines 34: What do authors mean by “repair”? – eventually skin regeneration.
Response 5:
Comment 6: It is recommended, that references must be numbered in order of appearance in the text (including tables and legends reference) and listed at the end of the manuscript according to CIMB instructions for authors! Authors are kindly asked to use the manuscript template according to the instructions for authors of the journal - chapter/subchapter/justify, text editing, figure and table title/references, etc..
Response 6: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 7: Please consider that in cosmetics according to the INCI denomination, zinc possesses antioxidant properties, while other INCI containing zinc (namely Zn complexes) have other functions (for e.g. ZnO is an UV filter, etc.). Also, Zn compounds/ingredients according to Regulation 1223/2009 have restrictions mentioned in Annexes (ZINC SALICYLATE - III/24; Zinc oxide (nano) - VI / 30a, etc.), which I recommend to discuss in this review, being an essential legislative aspect.
Response 7: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 8: Figure 1: Please make the Figure more clear and intelligible! Please consider Zn/Zn complexes effects in mentioned product categories (like mentioned for e.g. for ZnO in sunscreens). Perhaps CosIng/CIR databases could be useful (https://ec.europa.eu/growth/tools-databases/cosing/; https://cir-reports.cir-safety.org/) to specify the correct effect as discussed in the manuscript.
Response 8: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 9: The authors should emphasize beginning with the Abstract and in the Introduction section about the originality of their study.
Response 9: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 10: Table 1 and entire manuscript - please make a clear distinction of product type - OTC (like sunscreens eventually in USA), topical creams is very generic - cosmetics/pharmaceutical products? Nanoparticles should be considered as active/cosmetic ingredient/API, not necessarily as a finished product. What do authors mean by “hybrid gels” as classification in Table 1?
Response 10: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 11: Line 110: “… adhesion enhancers…” – in cosmetics (like mentioned for face powders, which indeed is included in the cosmetics category) according to it’s INCI name, Zn possesses ANTICAKING, OPACIFYING, VISCOSITY CONTROLLING properties!
Response 11: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 12: Line 123: “Z-Cote” - if a registered ingredient of BASF, please give complete details of ingredient manufacturer - city, country). Please consider this aspect for all ingredients/products mentioned in the manuscript (including commercially available ingredients/products, for e.g. Botox).
Response 12: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 13: Lines 148-153: Please add reference(s), it is not a personal finding evidenced by clinical evaluation(s) of the claimed effect!
Response 13: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 14: Lines 187-197: Like suggested before, please make a clear distinction between cosmetic/cosmeceutical formulation, nutraceuticals/nutricosmetics and pharmaceutical products. Please consider that animal testing for cosmetics is banned within Regulation CE 1223/2009 (not even literature data after the implementation of Regulation 1223/2009 can be used to sustain safety or efficacy of cosmetics/cosmeceuticals)! Regulation 1223/2009 bans ingredient and cosmetic product animal testing!
Response 14: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 15: Line 257: What do authors mean by “cosmetic patients”?
Response 15: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 16: Please detail subchapter “8. Registered patents on zinc in Botulinum Neurotoxin-A formulations”, not only mentioning the two patents.
Response 16: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 17: Lines 323-332: Please mention referents of the described study, if it is not a personal finding! Is it ref. 45?
Response 17: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 18: Please carefully check English grammar, syntax and word spacing!
Response 18: Thank you for highlighting this. We have updated the title of the manuscript.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThis article outlines the many uses of zinc in dermatology, primarily for its potential addition to formulations of botulinum toxin. The authors did a good job of reviewing the current state of research and clinical practices regarding both the therapeutic properties and product stabilizers of zinc in dermatological products.
The article does not appear to be in journal format (eg citations). There are too many paragraphs left in the text - please merge them. I see no reason why individual section headers should be underlined. Please remove the underline.
The manuscript covers a wide range of zinc applications in the dermatology. Relevant tables and figure (the figure is half-hidden) have been included.
The review article looks more like information pulled from somewhere and simply inserted into the article. It lacks scientific critical analysis, which is a basic thing in this type of article. In its current form, the article looks more like an encyclopedia.
The conclusion is too vague, too long, and doesn't conclude anything of substance. The conclusion should briefly highlight what is presented in the article and a brief conclusion based on the critical analysis in the review article.
Submitted in this way, the article does not meet the requirements for publication in the journal.
For this reason, I would give the authors the opportunity to revise the article and resubmit it.
Author Response
Reviewer #2:
We would like to extend our sincere gratitude to the reviewer for their valuable time and feedback. We have addressed all the suggestions as detailed below and have incorporated the changes into the revised manuscript.
Comment 1: The article does not adhere to the journal format (e.g., citations). There are numerous paragraphs left in the text that need to be merged, and individual section headers are underlined, which should be removed.
Response 1: Thank you for highlighting these formatting issues. We have removed all underlines and consolidated the paragraphs as recommended. We do believe the citations are in proper journal format as we have followed the National Library of Medicine guidelines.
Comment 2: The manuscript covers a broad range of zinc applications in dermatology. However, the relevant tables and figures are not properly presented; specifically, one figure is partially obscured.
Response 2: We appreciate your observation. The figure has been revised to ensure it is fully visible and appropriately presented.
Comment 3: The review article appears to consist mainly of information assembled from various sources without sufficient scientific critical analysis. As it stands, the article resembles an encyclopedia rather than a critical review.
Response 3: Thank you for your insightful critique. We have revised the manuscript, with particular attention to the conclusion, to enhance the critical analysis and provide a more scholarly discussion.
Comment 4: The conclusion is overly vague and lengthy, lacking substantive synthesis. It should succinctly summarize the key findings and provide a brief conclusion based on the critical analysis of the review.
Response 4: We concur with your feedback. The conclusion has been refined to focus on the essential points derived from the critical analysis, rather than offering a broad overview of the article.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Authors,
even the manuscript contains some modifications according to reviewers suggestions, the Authors response document does not point any answers (all of them include as response following sentences "Thank you for highlighting this. We have updated the title of the manuscript."
Please correct references appearance in the text as mentioned in Instructions for authors, like also suggested before (in chronological order in the text and in brackets).
Please revise your manuscript according to previously comments and suggestions!
Comments on the Quality of English LanguageEnglish language is fine, but please check syntax and word spacing.
Author Response
Reviewer #1:
We would like to extend our sincere gratitude to the reviewer for their valuable time and feedback. We have addressed all the suggestions as detailed below and have incorporated the changes into the revised manuscript.
Comment 1: even the manuscript contains some modifications according to reviewers suggestions, the Authors response document does not point any answers (all of them include as response following sentences "Thank you for highlighting this. We have updated the title of the manuscript."
Response 3: We have changed the reponses to give more specific details.
Comment 2: Please correct references appearance in the text as mentioned in Instructions for authors, like also suggested before (in chronological order in the text and in brackets).
Response 2: All of the references are in chronological order in the text and in brackets.
Comment 3: Please revise your manuscript according to previously comments and suggestions!
Response 3: The previous comments and responses are amended and listed below.
ROUND 1 REVIEW:
Comment 1: Please rewrite the Title of the manuscript to be more suggestive!
Response 1: Thank you for highlighting this. We have updated the title of the manuscript to be more suggestive. The new title is “Zinc in Dermatology: Exploring It’s Emerging Role in Enhancing Botulinum Toxin Formulations and Clinical Efficacy”
Comment 2: Beginning with the Abstract section and the entire manuscript, please do not use the term „therapeutic” regarding nuraceuticals/nutricosmetics/supplements and/or cosmetics/cosmeceuticals/dermatocosmetic products– according to current EU legislation supplements and/or cosmetics can improve skin conditions, but unfortunately they do not possess any pharmacological effect.
Response 2: We have removed the term therapeutic from the entire manuscript.
Comment 3: Please make a clear distinction between aesthetic medicine/dermatological products vs. cosmetic preparations.
Response 3: Thank you for highlighting this. We have included lines 24-27: “Although zinc has historically been used in topical dermatological products and systemic health interventions, its potential in cosmetic preparations, such as anti-aging therapies or non-invasive aesthetic treatments, remains under-researched. “ Lines 29-33: While current studies on oral zinc supplementation present mixed results concerning its ability to prolong botulinum toxin effects, this underscores the need for more rigorous investigation in the realm of aesthetic medicine. Zinc's well-established role in stabilizing dermatological products, such as sunscreens, and its applications in wound healing and skin regeneration, further highlight its potential for broader therapeutic uses beyond cosmetic applications.
Comment 4: Please make Keywords more specific!
Response 4: Thank you for highlighting this. We have updated the keywords to: zinc; botulinum toxin; dermatology; cosmetic science; aesthetic injectables; formulation stability to better specify the topics covered in the manuscript.
Comment 5: Lines 34: What do authors mean by “repair”? – eventually skin regeneration.
Response 5: We have updated “repair” to “regeneration” in this line per your suggestion. The updated sentence is: Zinc is crucial for skin health, participating in skin morphogenesis, regeneration, and maintenance, providing protection and defense.
Comment 6: It is recommended, that references must be numbered in order of appearance in the text (including tables and legends reference) and listed at the end of the manuscript according to CIMB instructions for authors! Authors are kindly asked to use the manuscript template according to the instructions for authors of the journal - chapter/subchapter/justify, text editing, figure and table title/references, etc..
Response 6: Thank you for highlighting this. We have updated the references to be in chronological order and in brackets.
Comment 7: Please consider that in cosmetics according to the INCI denomination, zinc possesses antioxidant properties, while other INCI containing zinc (namely Zn complexes) have other functions (for e.g. ZnO is an UV filter, etc.). Also, Zn compounds/ingredients according to Regulation 1223/2009 have restrictions mentioned in Annexes (ZINC SALICYLATE - III/24; Zinc oxide (nano) - VI / 30a, etc.), which I recommend to discuss in this review, being an essential legislative aspect.
Response 7: Thank you for highlighting this. We have updated the title of the manuscript.
Comment 8: Figure 1: Please make the Figure more clear and intelligible! Please consider Zn/Zn complexes effects in mentioned product categories (like mentioned for e.g. for ZnO in sunscreens). Perhaps CosIng/CIR databases could be useful (https://ec.europa.eu/growth/tools-databases/cosing/; https://cir-reports.cir-safety.org/) to specify the correct effect as discussed in the manuscript.
Response 8: Thank you for highlighting this. We have made the figure more clear and legible as previously half of it was cut off.
Comment 9: The authors should emphasize beginning with the Abstract and in the Introduction section about the originality of their study.
Response 9: Thank you for highlighting this. We have written in lines 33-36 in the abstract: This review identifies a critical gap in the literature and calls for future research to optimize zinc concentrations and delivery methods specifically for aesthetic medical procedures, offering new insights into improving dermatological treatments beyond the scope of traditional cosmetic preparations. We have also written lines 63-66 in the introduction: By examining current research and clinical practices, this article offers an original perspective on the multifaceted role of zinc in enhancing dermatological treatments and product formulations, shedding light on areas that have been largely overlooked in existing literature. Top of Form
Comment 10: Table 1 and entire manuscript - please make a clear distinction of product type - OTC (like sunscreens eventually in USA), topical creams is very generic - cosmetics/pharmaceutical products? Nanoparticles should be considered as active/cosmetic ingredient/API, not necessarily as a finished product. What do authors mean by “hybrid gels” as classification in Table 1?
Response 10: Thank you for highlighting this. We have updated “hybrid gels” in Table 1 to be more specific. The updated term is Composite Gels (ZnO nanoparticles with a chitosan hydrogel). We have updated “nanoparticles” to Antibacterial Wound Dressings or Gels.
Comment 11: Line 110: “… adhesion enhancers…” – in cosmetics (like mentioned for face powders, which indeed is included in the cosmetics category) according to it’s INCI name, Zn possesses ANTICAKING, OPACIFYING, VISCOSITY CONTROLLING properties!
Response 11: Thank you for highlighting this. We have updated lines 110-113 to say “In addition, zinc stearate and zinc myristate are also used as adhesion enhancers in face powders with anticaking, opacifying and viscosity controlling properties”
Comment 12: Line 123: “Z-Cote” - if a registered ingredient of BASF, please give complete details of ingredient manufacturer - city, country). Please consider this aspect for all ingredients/products mentioned in the manuscript (including commercially available ingredients/products, for e.g. Botox).
Response 12: Thank you for highlighting this. We have updated line 123 to say Z-Cote, BASF Corporation, Antwerp, Belgium.
Comment 13: Lines 148-153: Please add reference(s), it is not a personal finding evidenced by clinical evaluation(s) of the claimed effect!
Response 13: Thank you for highlighting this. We have updated the reference after this finding.
Comment 14: Lines 187-197: Like suggested before, please make a clear distinction between cosmetic/cosmeceutical formulation, nutraceuticals/nutricosmetics and pharmaceutical products. Please consider that animal testing for cosmetics is banned within Regulation CE 1223/2009 (not even literature data after the implementation of Regulation 1223/2009 can be used to sustain safety or efficacy of cosmetics/cosmeceuticals)! Regulation 1223/2009 bans ingredient and cosmetic product animal testing!
Response 14: Thank you for highlighting this. We have updated this portion of the manuscript to state: “Both the zinc-hyaluronan gel and its combination with the silver foam dressing significantly reduced the non-epithelialized area compared to the pharmaceutical-grade silver-sulfadiazine cream. By the tenth day, the combined treatment showed superior re-epithelialization, and by day 22, it resulted in the formation of the thinnest scars. This research, conducted on a rat burn model for therapeutic purposes, concluded that the combined application of zinc-hyaluronan gel with a silver foam dressing was the most effective treatment for wound healing in this context.
In a clinical evaluation of the Zn-hyaluronan gel's potential as a pharmaceutical treatment for partial-thickness burns, a cohort of 60 patients, each with an average burn covering 3% of their Total Body Surface Area, was observed. The exudative phase lasted for three days, with no infections reported. It is important to note that these findings pertain to the therapeutic and pharmaceutical use of the gel for wound healing, not its application in cosmetics or cosmeceuticals. Additionally, animal testing for cosmetic products has been banned under Regulation CE 1223/2009, which strictly prohibits the use of animal data to support the safety or efficacy of cosmetic and cosmeceutical formulations.”
Comment 15: Line 257: What do authors mean by “cosmetic patients”?
Response 15: Thank you for highlighting this. We have updated this line to say “Studies of NAbs for non-cosmetic purposes lay the initial groundwork of this review, which have shown that antigenicity of Botulinum toxin preparations is a relevant problem in long-term neurologic treatments”
Comment 16: Please detail subchapter “8. Registered patents on zinc in Botulinum Neurotoxin-A formulations”, not only mentioning the two patents.
Response 16: Thank you for highlighting this. There are only 2 Botulinum Neurotoxin-A formulations with zinc. I have updated the title to say “Registered patents on zinc in Botulinum Neurotoxin-A formulations with Zinc”
Comment 17: Lines 323-332: Please mention referents of the described study, if it is not a personal finding! Is it ref. 45?
Response 17: Thank you for highlighting this. Yes, the described study is reference 45.
Comment 18: Please carefully check English grammar, syntax and word spacing!
Response 18: Thank you for highlighting this. We have carefully examined the manuscript for English grammar. Syntax and word spacing.
Reviewer 2 Report
Comments and Suggestions for AuthorsAfter taking into account my comments, your manuscript looks much better. Please try to unify the paragraphs, as you have so many.
Author Response
Comment 1: After taking into account my comments, your manuscript looks much better. Please try to unify the paragraphs, as you have so many.
Response 1: Thank you for this suggestion. We have unified many of the paragraphs to decrease the overall number of paragraphs per your suggestion!
Round 3
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Authors,
thank you for the revised manuscript.
Kind regards!
