Atelocollagen exhibits superior performance compared to growth factors in upregulating proteins associated with tendon healing

Sung-Jin Park; Jong Pil Yoon; Kyung-Soo Oh; Seok Won Chung

doi:10.1371/journal.pone.0323156

Peer Review History

Original SubmissionApril 3, 2025
16 May 2025 Decision Letter - Carlos Alberto Antunes Viegas, Editor Dear Dr. Chung, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jun 30 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. 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Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. If data are owned by a third party, please indicate how others may request data access. Additional Editor Comments : Dear authors, Please review and respond to the reviewers' recommendations, not forgetting to respond to the requests from reviewer 2, within the scope of the report provided by ScreenIT. Kind regards [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** Reviewer #1: Manuscript ID: PONE-D-25-17647 Title: Atelocollagen exhibits superior performance compared to growth factors in upregulating proteins associated with tendon healing This manuscript presents an in vitro study evaluating the efficacy of atelocollagen (AC) compared to several individual growth factors (BMP-2, TGF-β1, IGF-1, and VEGF) on molecular markers associated with tendon healing. The experimental design, including Western blotting, MTT assay, and immunofluorescence, is generally robust. The manuscript is well-written and contributes novel insights into the potential of AC as a biological augmentation strategy. However, there are minor areas that require clarification and revision before acceptance. 1. Introduction The introduction clearly outlines the clinical need for enhanced tendon-to-bone interface healing and the limitations of current biological augmentation strategies. The rationale for using growth factors such as BMP-2, TGF-β1, IGF-1, and VEGF is well described, and the transition to discussing Atelocollagen as an alternative is logical. However, to better emphasize the novelty of this study, the authors should more clearly highlight the limitations of previous literature. In particular, the authors are encouraged to underscore that, to date, no published studies have directly examined or compared the effects of atelocollagen on molecular markers relevant to tendon healing—especially in the context of rotator cuff tears—making the current investigation uniquely valuable. The hypothesis is clearly stated 2. Materials and Methods Lines 90-91: Please justify the use of C2C12 cells instead of tenocytes or tendon-derived stem cells. This point should also be addressed in the discussion. Line 145–150: There is a typographical error in the section header "Statical analysis" → should be corrected to "Statistical analysis" 3. Results Lines 170–176: Only IGF-1 group showed a statistically lower ratio compared to AC on col I/III ratio. Consider discussing the biological relevance of this change more in the Results or Discussion. 4. Discussion It would also strengthen the manuscript if the authors could cite additional references supporting the beneficial effects of atelocollagen in rotator cuff repair, to provide a broader context for the clinical relevance of their findings. Moreover, discussing the limitations of those previous studies would help clarify how the present study addresses existing gaps in the literature. Line 274: Please remove or revise Line 274, unless supporting angiogenesis data are provided. 5. Conclusion The conclusion is consistent with the results and maintains a modest tone. 6. Figures and Table Please spell out all abbreviations in the figure legends or provide explanatory footnotes to ensure clarity for the reader. 7. References Reference formatting and selection are appropriate. Reviewer #2: This is an automated report for PONE-D-25-17647. This report was solicited by the PLOS One editorial team and provided by ScreenIT. ScreenIT is an independent group of scientists developing automated tools that analyze academic papers. A set of automated tools screened your submitted manuscript and provided the report below. Each tool was created by your academic colleagues with the goal of helping authors. The tools look for factors that are important for transparency, rigor and reproducibility, and we hope that the report might help you to improve reporting in your manuscript. Within the report you will find links to more information about the items that the tools check. These links include helpful papers, websites, or videos that explain why the item is important. While our screening tools aim to improve and maintain quality standards they may, on occasion, miss nuances specific to your study type or flag something incorrectly. Each tool has limitations that are described on the ScreenIT website. The tools screen the main file for the paper; they are not able to screen supplements stored in separate files. Please note that the Academic Editor had access to these comments while making a decision on your manuscript. The Academic Editor may ask that issues flagged in this report be addressed. If you would like to provide feedback on the ScreenIT tool, please email the team at ScreenIt@bih-charite.de. If you have questions or concerns about the review process, please contact the PLOS One office at plosone@plos.org. Reviewer #3: As the development is a gradual and progressive process, assessment of tendon development in one point (only day 5) is not reasonable and sufficient. So, it is strongly recommend to perform the analysis and asses the gene expression in different time points (such as 3, 7, 14 and 21 days after culture) and longer time for the special genes (genes express in earlier or final development stage) in each phase. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #2: No Reviewer #3: Yes: Abbas Parham ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. Attachments Attachment Submitted filename: report_10.1101+2025.04.06.647440.pdf https://doi.org/10.1371/journal.pone.0323156.r001
Revision 1
9 Jun 2025 Author Response 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Manuscript ID: PONE-D-25-17647 Title: Atelocollagen exhibits superior performance compared to growth factors in upregulating proteins associated with tendon healing This manuscript presents an in vitro study evaluating the efficacy of atelocollagen (AC) compared to several individual growth factors (BMP-2, TGF-β1, IGF-1, and VEGF) on molecular markers associated with tendon healing. The experimental design, including Western blotting, MTT assay, and immunofluorescence, is generally robust. The manuscript is well-written and contributes novel insights into the potential of AC as a biological augmentation strategy. However, there are minor areas that require clarification and revision before acceptance. 1. Introduction The introduction clearly outlines the clinical need for enhanced tendon-to-bone interface healing and the limitations of current biological augmentation strategies. The rationale for using growth factors such as BMP-2, TGF-β1, IGF-1, and VEGF is well described, and the transition to discussing Atelocollagen as an alternative is logical. However, to better emphasize the novelty of this study, the authors should more clearly highlight the limitations of previous literature. In particular, the authors are encouraged to underscore that, to date, no published studies have directly examined or compared the effects of atelocollagen on molecular markers relevant to tendon healing—especially in the context of rotator cuff tears—making the current investigation uniquely valuable. Response: We thank the reviewer for this valuable comment. In response, we have revised the Introduction section to more clearly highlight the limitations of previous growth factor-based therapies, including their short half-life, rapid degradation, and challenges in controlled delivery. We have also underscored that, to date, no published studies have directly examined or compared the effects of atelocollagen on tendon healing-related molecular markers, particularly in the context of rotator cuff tears. These revisions aim to better highlight the novelty and significance of our work. The updated Introduction is included below for your review. Lines 66-74: “Among these, therapies based on exogenous growth factors such as bone morphogenetic protein-2 (BMP-2), transforming growth factor-beta 1 (TGF-β1), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF) have shown the potential to stimulate ECM remodeling, promote tendon cell proliferation, and enhance collagen synthesis [7-9] However, previous literature has highlighted critical limitations of these growth factor therapies, including their rapid degradation, short biological half-life, and difficulties in achieving sustained and localized delivery [8, 10, 11]. Consequently, despite promising experimental data, their clinical translation has been limited by the inability to maintain therapeutic concentrations at the repair site over time.” was added. Lines 75-83: The original sentences were deleted. Lines 84-93: “Given these challenges, alternative strategies that provide more sustained and controlled biological augmentation are urgently needed. Atelocollagen (AC), a highly purified collagen derivative, has emerged as a promising biomaterial for tendon repair due to its structural stability, biocompatibility, and inherent bioactivity [12]. Unlike exogenous growth factors, AC possesses a sustained bioactive profile and does not require additional carrier systems to maintain its therapeutic effects. Despite its promising biological properties, there is a paucity of data comparing the efficacy of AC with that of individual growth factors in regulating molecular markers critical for tendon healing [13]. In particular, no studies to date have directly examined or compared the effects of AC on key tendon healing-related molecular markers such as phosphorylated extracellular signal-regulated kinase (p-ERK), collagen type I (Col I), collagen type III (Col III), and tenascin C (TnC), especially within the context of rotator cuff tears.” was added. Lines 94-101: The original sentences were deleted. The hypothesis is clearly stated Response: We appreciate the reviewer’s comment. To ensure that the hypothesis is explicitly and clearly stated in the manuscript, we have refined the wording in the Introduction section. This revision ensures that the hypothesis is both clear and concise for the reader. Lines 103-106: The original sentences were deleted. Lines 106-109: “We hypothesize that AC would have comparable or superior effects to individual growth factors in upregulating p-ERK, Col I, Col III, and TnC, thus highlighting its potential as a robust biological augmentation strategy for TBI healing following surgical repair.” was added. 2. Materials and Methods Lines 90-91: Please justify the use of C2C12 cells instead of tenocytes or tendon-derived stem cells. This point should also be addressed in the discussion. Response: Thank you for your insightful comment. We acknowledge the concern regarding the choice of C2C12 myoblasts instead of tenocytes or tendon-derived stem cells (TDSCs). C2C12 cells, while not primary tenocytes, are a well-established myogenic cell line with robust proliferative and differentiation capacity. They exhibit myogenic-to-tenogenic trans differentiation potential when subjected to mechanical or biochemical stimuli, and are frequently used as a surrogate model in tendon research due to their consistent growth characteristics and reproducible responses.a,b) Furthermore, their use facilitates the standardization and reproducibility of experiments, which is crucial for elucidating the comparative molecular effects of AC and growth factors in an in vitro environment. We have added this justification to both the Materials and Methods and the Discussion sections (limitation section). a) Lautaoja JH, Pekkala S, Pasternack A, Laitinen M, Ritvos O, Hulmi JJ. Differentiation of Murine C2C12 Myoblasts Strongly Reduces the Effects of Myostatin on Intracellular Signaling. Biomolecules. 2020;10(5):695. b) Uemura K, Hayashi M, Itsubo T, Oishi A, Iwakawa H, Komatsu M, Uchiyama S, Kato H. Myostatin promotes tenogenic differentiation of C2C12 myoblast cells through Smad3. FEBS Open Bio. 2017 Feb 20;7(4):522-532. Lines 117-119: “Although they are not primary tendon cells, they have been extensively validated as a surrogate model for tenogenic signaling and differentiation under tendon-specific stimuli, ensuring high reproducibility, standardized cell expansion, and reliable molecular response quantification.” was added. Lines 344-347: “First, although C2C12 myoblasts are a well-established and reproducible in vitro model for investigating tendon-specific signaling and tenogenic differentiation under biochemical or mechanical stimuli, they do not fully recapitulate the cellular and extracellular matrix interactions of primary tenocytes or tendon-derived stem cells.” Line 145–150: There is a typographical error in the section header "Statical analysis" → should be corrected to "Statistical analysis" Response: We have corrected the typographical error from "Statical analysis" to "Statistical analysis." 3. Results Lines 170–176: Only IGF-1 group showed a statistically lower ratio compared to AC on col I/III ratio. Consider discussing the biological relevance of this change more in the Results or Discussion. Response: Thank you for your valuable comment. We appreciate the opportunity to clarify the biological relevance of the finding that only the IGF group showed a statistically lower Col I/III ratio compared to the AC group. This result suggests that while IGF may support some aspects of tendon healing, it does not effectively promote the ECM reorganization toward a more biomechanically robust state, as indicated by the lower Col I/III ratio. In contrast, the significant enhancement of this ratio in the AC-treated group underscores AC’s superior ability to foster a more mature and load-bearing collagen matrix. This difference is crucial because a higher Col I/III ratio is associated with improved tendon mechanical strength and long-term functional recovery. We have integrated this interpretation into the revised Discussion section to highlight the unique advantage of AC over IGF in this context. Lines 280-285: The original sentences were deleted. Lines 286-297: “Notably, our results demonstrated that only the IGF group showed a statistically lower Col I/III ratio compared to the AC group, while no significant differences were found between AC and the other growth factors. This selective enhancement suggests that AC may overcome IGF’s limitations in promoting biomechanical matrix integrity. A lower Col I/III ratio, as seen with IGF treatment, is associated with less organized and weaker ECM, potentially compromising tendon mechanical strength. In contrast, the significant increase in the Col I/III ratio in the AC-treated group indicates a shift toward a more mature, load-bearing collagen composition that supports improved tendon function. These findings collectively underscore that AC not only promotes ECM remodeling but also uniquely enhances the formation of a biomechanically robust tendon matrix compared to IGF alone. Given that clinical studies have linked a higher Col I/III ratio to improved mechanical properties and reduced retear rates, this highlights AC’s potential as an effective biological augmentation strategy for tendon healing.” was added. 4. Discussion It would also strengthen the manuscript if the authors could cite additional references supporting the beneficial effects of atelocollagen in rotator cuff repair, to provide a broader context for the clinical relevance of their findings. Moreover, discussing the limitations of those previous studies would help clarify how the present study addresses existing gaps in the literature. Response: Thank you for your valuable comment. In response, we have added additional references supporting the beneficial effects of atelocollagen in rotator cuff repair to provide a broader clinical context. Furthermore, we have included a brief discussion of the limitations of these previous studies to highlight how the present study addresses existing gaps in the literature. These additions strengthen the overall clinical relevance of our findings and underscore the translational potential of atelocollagen as a biological augmentation strategy. Lines 326-336: “Atelocollagen has garnered considerable attention as a promising biomaterial in the context of rotator cuff repair, with preclinical evidence suggesting its ability to enhance TBI healing and improve biomechanical properties [12, 13]. Importantly, Suh et al., reported that atelocollagen scaffolds significantly augmented structural stability and biocompatibility in TBI healing models [37]. Nevertheless, these investigations have largely been confined to short-term evaluations and have not directly compared AC with alternative biological augmentation strategies, thereby limiting the broader applicability of their findings. In contrast, the present study seeks to address these limitations by examining key molecular markers of tendon healing while directly comparing AC to growth factor-based therapies. This approach offers valuable insights into the capacity of AC to foster tendon-specific cellular responses and orchestrate matrix remodeling, highlighting its potential as a refined strategy for biological augmentation in tendon repair.” was added. Line 274: Please remove or revise Line 274, unless supporting angiogenesis data are provided. Response: Thank you for your helpful comment. In response, we have removed the mention of neovascularization (angiogenesis) from the discussion of atelocollagen’s effects to focus exclusively on the primary molecular mechanisms examined in this study, including ERK activation, TnC upregulation, and improved Col I/III ratio. Line 338: “VEGF-mediated neovascularization” was deleted. 5. Conclusion The conclusion is consistent with the results and maintains a modest tone. Response: Thank you for your positive feedback and for acknowledging the clarity and modest tone of our conclusions. 6. Figures and Table Please spell out all abbreviations in the figure legends or provide explanatory footnotes to ensure clarity for the reader. Response: Thank you for your suggestion. We have revised the figure legends and table footnotes to spell out all abbreviations, ensuring that readers can easily understand the figures and data presented. Lines 638-639: “p-ERK, phosphorylated extracellular signal-regulated kinase; AC, atelocollagen; BMP-2, bone morphogenetic protein-2; IGF-1, insulin-like growth factor, SD; standard deviation.” was added. Lines 643-646: “AC, atelocollagen; BMP-2, bone morphogenetic protein-2; IGF-1, insulin-like growth factor-1; VEGF, vascular endothelial growth factor; TGF-β1, transforming growth factor-beta 1; TnC, tenascin C; SD, standard deviation.” was added. Lines 650-651: “AC, atelocollagen; IGF-1, insulin-like growth factor-1; Col I/III, collagen type I/III; ECM, extracellular matrix; SD, standard deviation” was added. Lines 656-657: “AC, atelocollagen; VEGF, vascular endothelial growth factor; TGF-β1, transforming growth factor-beta 1” was added. Lines 664-666: “AC, atelocollagen; VEGF, vascular endothelial growth factor; TGF-β1, transforming growth factor-beta 1; F-actin, filamentous actin.” was added. Lines 668-669: “. AC, atelocollagen; VEGF, vascular endothelial growth factor; TGF-β1, transforming growth factor-beta 1; SD, standard deviation.” 7. References Reference formatting and selection are appropriate. Response: Thank you for your positive feedback and for acknowledging the appropriateness of the reference formatting and selection. Reviewer #2: This is an automated report for PONE-D-25-17647. This report was solicited by the PLOS One editorial team and provided by ScreenIT. ScreenIT is an independent group of scientists developing automated tools that analyze academic papers. A set of automated tools screened your submitted manuscript and provided the report below. Each tool was created by your academic colleagues with the goal of helping authors. The tools look for factors that are important for transparency, rigor and reproducibility, and we hope that the report might help you to improve reporting in your manuscript. Within the report you will find links to more information about the items that the tools check. These links include helpful papers, websites, or videos that explain why the item is important. While our screening tools aim to improve and maintain quality standards they may, on occasion, miss nuances specific to your study type or flag something incorrectly. Each tool has limitations that are described on the ScreenIT website. The tools screen the main file for the paper; they are not able to screen supplements stored in separate files. Please note that the Academic Editor had access to these comments while making a decision on your manuscript. The Academic Editor may ask that issues flagged in this report be addressed. If you would like to provide feedback on the ScreenIT tool, please email the team at ScreenIt@bih-charite.de. If you have questions or concerns about the review process, please contact the PLOS One office at plosone@plos.org. Reviewer #3: As the development is a gradual and progressive process, assessment of tendon development in one point (only day 5) is not reasonable and sufficient. So, it is strongly recommend to perform the analysis and asses the gene expression in different time points (such as 3, 7, 14 and 21 days after culture) and longer time for the special genes (genes express in earlier or final development stage) in each phase. Response: Thank you for your constructive feedback regarding the temporal aspects of tendon development assessment. We agree that tendon healing and regeneration involve Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0323156.r002
13 Aug 2025 Decision Letter - Carlos Alberto Antunes Viegas, Editor Atelocollagen exhibits superior performance compared to growth factors in upregulating proteins associated with tendon healing PONE-D-25-17647R1 Dear Dr. Seok Won Chung, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Carlos Alberto Antunes Viegas, DVM; MSc; PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author Reviewer #1: All comments have been addressed Reviewer #3: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions??> Reviewer #1: Yes Reviewer #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: Yes Reviewer #3: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available??> The PLOS Data policy Reviewer #1: Yes Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #3: Yes ****** Reviewer #1: The authors have made appropriate and thoughtful revisions in response to the reviewer comments. It is evident that they carefully considered each point raised and have incorporated the necessary changes to improve the clarity, rigor, and overall quality of the manuscript. The revised version reflects a clear effort to address the concerns and suggestions in a constructive and thorough manner. I find the current version of the manuscript to be satisfactory, and I believe that no additional modifications are required at this time. Therefore, I have no further comments or suggestions for the authors. Reviewer #3: In the revised version of paper entitled"Atelocollagen exhibits superior performance compared to growth factors in upregulating proteins associated with tendon healing", All comments have been correctly addressed. ****** what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy Reviewer #1: No Reviewer #3: No ******** https://doi.org/10.1371/journal.pone.0323156.r003
Formally Accepted
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