Collagen-Inducing Compounds from Chihuahuan Desert Plants for Potential Skin Bioink 3D Printing Applications: A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript lacks substantial content and fails to present any relatively novel insights. Overall, it does not meet the fundamental requirements of a review article, and in my opinion, the current version is unacceptable. Specific points are as follows:

(1) While this paper is intended as a review, its writing style does not conform to the basic standards of a review article;

(2) The authors' discussion on material modification, preparation methods, and applications is noticeably insufficient;

(3) This review resembles a report rather than an academic contribution, and the authors should provide more in-depth analysis and synthesis;

(4) For a review paper, it is unreasonable to include only two figures and one table throughout the entire text.

Author Response

General Evaluation:
The reviewer noted insufficient depth, limited novelty, and a lack of structural and analytical components expected in a scientific review. We greatly appreciate these observations, which guided a comprehensive restructuring of the manuscript.

1. Comment: “Writing style does not conform to the basic standards of a review article.”

Response:
We thank the reviewer for highlighting this issue. We have completely revised the manuscript to conform to the expectations of a systematic and biomaterials-focused review. The study was enriched by incorporating newly eligible publications, reorganizing sections for improved flow, and adding clearer thematic synthesis. We strengthened the narrative to explicitly highlight how Chihuahuan Desert plants constitute a rational foundation for the design of enhanced dermal bioinks. Key species examined now include: Allium cepa, Aloe vera, Carya illinoinensis, Larrea tridentata, Matricaria chamomilla L., Mimosa tenuiflora, Simmondsia chinensis, and Opuntia spp., alongside secondary species with fewer published studies.

2. Comment: “Discussion on material modification, methods, and applications is insufficient.”

Response:
We agree. In the revised version, we substantially expanded the Results, Discussion, and Conclusions. We incorporated new datasets and analyses from recently screened studies related to biomaterial modification, natural compound integration, rheological implications, and post-print biological performance. These additions significantly deepen the technical discussion.

3. Comment: “The review resembles a report rather than an academic contribution.”

Response:
We addressed this by performing a full analytical expansion new references were incorporated, including detailed botanical descriptions, molecular descriptions, mechanistic propositions, sustainability considerations, and a dedicated analysis of biopolymer phytochemical interaction. We added a bioethical framework and a section proposing how selected metabolites may strengthen rheology and regenerative properties within 3D bioprinting. These additions collectively transform the manuscript into an academically robust review.

4. Comment: “Only two figures and one table are insufficient.”

Response:
We fully agree and have addressed this by adding significatively new figures. These include botanical visualizations, molecular representations, summary schemes of mechanisms, and conceptual diagrams showing integration of phytochemicals into bioink strategies. Tables were reformulated for clarity and scientific precision.

Reviewer 2 Report

Comments and Suggestions for Authors

Many improvements are needed to reach the publication level, which I believe can be achieved, but only after addressing the following suggestions:

1. The sources presented in this review are not relevant to the title “Natural Collagen-Promoting Agents from Chihuahua Flora for Dermal 3D Bioprinting: A Systematic Review” and some of them are not properly cited.
2. The authors cited in Table 1 are not listed in the References section, except for A. Salazar-Gómez & A.J. Alonso-Castro, but the article was published in MDPI, not Frontiers as listed in Table 1 (Salazar-Gómez A, Alonso-Castro AJ. Medicinal Plants from Latin America with Wound Healing Activity: Ethnomedicine, Phytochemistry, Preclinical and Clinical Studies—A Review. Pharmaceuticals. 2022; 15(9):1095. https://doi.org/10.3390/ph15091095).
3. The articles found for the authors Laura A. de la Rosa & Emilio Álvarez-Parrilla (2011, 2018), mentioned in Table 1, are not focused on dermal scaffold research as it should be – “Table.1 Timeline: Recent Phytochemicals Mexican research with bioactivity and applied in dermal scaffold research” – (de la Rosa LA, Alvarez-Parrilla E, Shahidi F. Phenolic compounds and antioxidant activity of kernels and shells of Mexican pecan (Carya illinoinensis). J Agric Food Chem. 2011 Jan 12;59(1):152-62. doi: 10.1021/jf1034306; Vazquez-Flores, Alma & Núñez-Gastélum, José Alberto & Alvarez-Parrilla, Emilio & Wall, Abraham & Rodrigo-Garcia, Joaquin & Ayala-Zavala, J. Fernando & Aguilar, Gustavo & De la Rosa, Laura. (2018). By-Products of the Nut and Peanut Agro-Industry as Sources of Phytochemicals Suitable for the Nutraceutical and Food Industries. 10.1201/b22352-8); Moreover, Table 1 seems to be made by AI. Please rewrite Table 1.
4. In Tabel 2 are presented “Plant-Derived Wound-Healing Agents....”, but many cited articles don’t describe these plants extracts. For example, ref 18 doesn’t describe about “Larrea tridentata (NDGA, Ellagic Acid & Extracts)”; ref 34 doesn’t describe about “Aloe Species (Aloe vera & Aloe saponaria)”, ref 44 doesn’t describe about “Jojoba (Simmond-sia chinensis)” plants, etc. Please write in Table 2 only relevant sources.
5. Also, in section 3.1 Biopolymers and Plant-Derived Wound-Healing Agents, the author should have written about the effect of “Plant-Derived Wound-Healing Agents” from Chihuahua Flora. For example, in both studies of Chelu et al. (cited in this section) isn’t mentioned that “aloe compounds” are from that area.
6. Overall, this review does not focus on the topic mentioned in the title, most of the research mentioned does not specifically refer to "Natural Collagen-Promoting Agents from Chihuahua Flora for Dermal 3D Bioprinting". So, in order to be published, this manuscript should be carefully rewritten being centered on the topic of this manuscript.

Author Response

1. Comment: “Sources are not relevant to the title; some are not properly cited.”

Response:
We thank the reviewer for this important observation. In response, and aligned with Reviewer 3’s suggestion, we restructured the title to:
“Collagen-Inducing Compounds from Chihuahuan Desert Plants for Potential Skin Bio-Ink 3D Printing Applications: Review.”
The revised title now accurately reflects the central scope of the manuscript. All citations have been corrected, updated, and validated.

2. Comment: “Authors in Table 1 are missing in the References section.”

Response:
Table 1 was completely rewritten and corrected. All corresponding references are now properly included and verified according to their accurate publication sources. The previously misattributed MDPI article has been corrected.

3. Comment: “Some references (e.g., De la Rosa & Alvarez-Parrilla) do not relate to dermal scaffolds.”

Response:
We acknowledge the reviewer’s concern. The revised table now contextualizes these works appropriately. Their contributions appear only when relevant to phytochemical characterization, antioxidant mechanisms, or molecular candidates with potential applicability to bioink enhancement. Ambiguous or non-relevant content has been removed or rewritten with explicit clarification.

4. Comment: “Table 2 includes agents not described in the cited articles.”

Response:
We agree and have corrected this. Table 2 was restructured and repurposed within the Discussion to ensure only directly supported and traceable associations remain. Irrelevant citations were removed.

5. Comment: “Section 3.1 should focus on Chihuahua Flora agents.”

Response:
We updated the section to clarify that while some metabolites are found globally, the Chihuahuan Desert hosts the same species or chemotypes, which justifies their examination. We explicitly describe the relevance of these compounds as naturally occurring in the region, aligning with the manuscript’s core objective.

6. Comment: “The review does not focus on the topic.”

Response:
Following this essential critique, we rewrote major sections and realigned the manuscript’s analytical depth directly to collagen-inducing mechanisms, biomaterial compatibility, and 3D bioprinting relevance. The title was adjusted, and content was tightly refocused.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript (JFB (ISSN 2079-4983),addresses an interesting and timely question—whether Chihuahuan plants contain small molecules or extracts capable of inducing collagen synthesis for use in dermal 3-D bioprinting. Unfortunately, in its present form the paper reads more like a narrative literature summary than the systematic review advertised in the title. Major restructuring, additional analyses and full transparency of the search strategy are required before the work can meet Journal of Functional Biomaterials’ standards for a systematic or scoping review. 1- The manuscript should undergo a native-speaker edit if the journal does not provide copy-editing. Numerous errors in commas, spacing, and abbreviations. 2- Title: replace “Natural Collagen-Promoting Agents from Chihuahua Flora” with “Systematic Review of Collagen-Inducing Compounds from Chihuahuan Desert Plants for Potential Skin Bio-Ink Applications” to improve discoverability. 3- The Introduction and Discussion promise relevance for “dermal 3-D bioprinting”, yet none of the included papers actually embed Chihuahuan extracts in a bio-ink or evaluate printability, rheology, cross-linking or post-print cell viability. Either: (i) re-title the paper to reflect “collagen-stimulating potential of Chihuahuan plants for skin regeneration”, OR (ii) add a dedicated section that critically maps which extracts/compounds are compatible with common skin bio-inks (GelMA, collagen, fibrin, alginate, hyaluronic acid, starch, cellulose, chitosan, gelatin, and pectin) and discuss photoinitiator compatibility, temperature stability, and regulatory status with the FDA/EMA. 4- No Figures of Chihuahuan Desert Plants: The authors should add the most botanical photographs and provide chemical structures of the top three most active compounds. 5- Add a paragraph on how geographically restricted sourcing (endemic Chihuahuan species) aligns with Nagoya Protocol and CBD regulations. Address sustainable cultivation, seasonal variation, and Good Agricultural/Collection Practice (GACP) to convince biomaterials readership that supply chains are realistic. 6- A systematic review must be prospectively registered (PROSPERO, Open Science Framework, INPLASY, etc.). No registration number is supplied. 7- The search strings are only briefly mentioned; just one major biomaterials-oriented database (Scopus) is mentioned, while Embase and Compendex are missing, and it would increase the databases in this study. 8- Current eligibility is too vague (“any study that mentioned collagen and Chihuahua plants”). This invites selection bias. 9- Collagen-promoting activity is meaningless if the extract composition is unknown. Table 2 should summarise the analytical methods used (HPLC-MS, GC-MS, NMR) and the major secondary metabolites identified in each study. 10- In lines 468-471, the authors mention in the Strengths and Limitations section," However, the heterogeneity in extract preparation methods, amount, and animal models limited direct comparisons and precluded meta-analysis. Additionally, many of the studies were preclinical and with limited clinical trials available, restricting generali-zability to human patients. "Knowing that if meta-analysis is impossible, present a structured narrative synthesis following ENTREQ or SWiM guidance, with harvest plots that visually rank efficacy. 11- A validated tool must be used (SYRCLE for animal studies, ROBINS-I for non-randomised in vitro work, or a custom but transparent scale). Simply stating “quality was evaluated” is insufficient. Provide an Excel table with domain ratings and justify the downgrade.

Comments on the Quality of English Language

The manuscript should undergo a native-speaker edit if the journal does not provide copy-editing. Numerous errors in commas, spacing, and abbreviations.

Author Response

We thank Reviewer 3 for an exceptionally detailed and rigorous assessment. Their insights were pivotal in transforming the manuscript into a coherent systematic review aligned with biomaterials standards.

1. Comment: “Manuscript requires native-level English editing.”

Response:
We performed a complete language revision. The manuscript was internally re-edited and reviewed by English-fluent colleagues. If further refinement is recommended after resubmission, we are prepared to proceed with professional editing.

2. Comment: “Title should be revised for discoverability.”

Response:
We implemented the exact recommended title structure, ensuring accurate representation and search-indexing relevance.

3. Comment: “Introduction and Discussion promise relevance for bioprinting, but no included papers embed extracts in bioinks.”

Response:
We appreciate this critical point. While the literature does not yet include direct incorporation of most Chihuahuan extracts into biotinks, we now clearly frame the manuscript as a systematic evaluation of collagen-inducing potential and a scientific proposal for translational integration into bioinks.
We added a dedicated section mapping:

• compound compatibility with GelMA, collagen, fibrin, alginate, HA, cellulose, gelatin, pectin;
• photoinitiator considerations (e.g., LAP, Irgacure);
• thermal stability;
• FDA/EMA regulatory context.
  This fully addresses the reviewer’s directive.

4. Comment: “Include botanical photographs and chemical structures.”

Response:
Completed. Botanical photographs, edited with clear labels, and chemical structures of the top active compounds (e.g., NDGA, ellagic acid, acemannan) were added.

5. Comment: “Add paragraph on Nagoya Protocol, CBD, sustainability, and GACP.”

Response:
We added a bioethical and sustainability subsection addressing restricted sourcing, ecological implications, cultivation feasibility, and international compliance.

6. Comment: “Systematic review must be prospectively registered.”

Response:
The review was registered in OSF:
DOI: https://doi.org/10.17605/OSF.IO/KYSTV

7–10. Comments on search strategy, eligibility criteria, analytical characterization, and methodological transparency

Response:
All methodological sections were rewritten.
We:

• expanded database coverage,
• defined inclusion/exclusion criteria with precision,
• clarified search strings,
• improved risk-of-bias evaluation using accepted frameworks,
• incorporated compound identification methods (HPLC-MS, GC-MS, NMR) where applicable.

11–12. Comments on synthesis method and quality assessment

Response:
We followed the reviewer’s guidance by strengthening the narrative synthesis structure and refining the conceptual ranking of efficacy. Although meta-analysis remains infeasible, our revised approach now follows principles from ENTREQ/SWiM for transparency.
Biological study quality assessment was acknowledged, and while in-depth toxicological evaluation exceeds the present scope, the manuscript clearly defines its position as material-focused and translational.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have addressed all the raised issues properly. The manuscript is now publishable as it is.

Author Response

General Evaluation:
1) comment: The authors have addressed all the issues raised properly. The manuscript is now publishable as it is.

2) comment: Figures and tables must be improved

Response:

• Thank you for your feed back
• Thank you for your feedback. Unnecessary spaces have been removed from the tables, and the added images have been compressed. However, higher-quality images are also included in a separate zip file.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Thanks, you have processed all the comments  

Comments on the Quality of English Language

The manuscript should undergo a native-speaker edit if the journal does not provide copy-editing. Numerous errors in commas, spacing, and abbreviations.

Author Response

General evaluation:

• Comment: The manuscript should undergo a native-speaker edit if the journal does not provide copy-editing. Numerous errors in commas, spacing, and abbreviations.
• Comment: the English could be improved to more clearly express the research.
• Comment: Figures and tables must be improved

 

Response:

• Thank you for your feedback; a detailed review of the English has been conducted to improve it.
• That point is noted in the previous section
• Thank you for your feedback. Unnecessary spaces have been removed from the tables, and the added images have been compressed. However, higher-quality images are also included in a separate zip file.

Author Response File: Author Response.pdf