Perifascial areolar tissue graft promotes angiogenesis and wound healing in an exposed ischemic component rabbit model

Toru Miyanaga; Yasuo Yoshitomi; Aiko Miyanaga

doi:10.1371/journal.pone.0298971

Peer Review History

Original SubmissionSeptember 22, 2023
23 Oct 2023 Decision Letter - Alessandra Giuliani, Editor PONE-D-23-30878Perifascial areolar tissue graft promotes angiogenesis and wound healing in exposed ischemic component rabbit modelPLOS ONE Dear Dr. Miyanaga, 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. The study is interesting and the manuscript is well written; however, it requires minor revisions. Please answer all questions posed by reviewers. Please submit your revised manuscript by Dec 07 2023 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. 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Please ensure that each Supporting Information file has a legend listed in the manuscript after the references list. 6. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Dear Authors, In this study you demonstrated the effectiveness of PAT grafts and their therapeutic and potential impact on clinical practice. The study is interesting and the manuscript is well written. However, it requires minor revisions. Please answer all questions posed by reviewers. [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? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 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: The authors demonstrated in this study the efficacy of PAT grafts and its therapeutic and potential impact on clinical practice. The study is interesting and the manuscript is well written. Minor revisions: 1. Figure 2B: both in the figure and in the text (line 241) the magnification and scale bars lack 2. Line 287- line 291: P has to be connected with asterisks 3. please amplify the discussion pointing out the advantages of this methods (PAT) compared to the others Reviewer #2: In the name of God Dear Author Hello, I read your interesting manuscript. My questions, comments and questions are as follows: 1. I found a few grammatical errors. 2. Why perifascial areolar tissue (PAT) grafts is effective to promote granulation tissue formation that other tissues such as skin graft or pure fat doesn’t. 3. Did you consider PAT viability after grafting on an bare area? 4. What’s the mechanism of action of PAT for granulation tissue formation, it’s effect as a viable graft or it’s effect when necrosis occurs and intra cellular mediators such as growth factors release? If first hypothesis is correct please mention what’s the mechanism of PTA viability. 5. You stated: “The open wound area, as determined from photographs, was significantly larger in the PAT 345 group than in the control group on day 7 (P < 0.05) (Fig 4A)”. Does this mean wounds on both groups were not similar? 6. What’s the mechanism of viability of PAT graft. 7. You stated “The effectiveness of PAT grafts can be attributed to two primary factors, namely vascular bridging during graft survival and the provision of three essential elements that promote wound healing and angiogenesis: progenitor/stem cells, ECM molecules, and growth factors/cytokines. ”. My questions is why skin graft cannot do this? To best of our knowledge skin graft cannot cover or take on bare areas such as bone without periosteum but you concluded PAT can. Please clearly stat what’s the difference. 8. I think the manuscript is too long and includes parts that are unnecessary. Regards ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). 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Revision 1
15 Dec 2023 Author Response Response to the comments of the Reviewer Dear Editor, Thank you for evaluating our manuscript, your appreciation of our work, and your encouraging comments. We appreciate your comments and the reviewers’ guidance and thoughtful suggestions from which the manuscript has benefited. We have read the comments provided by you and the reviewers and have revised the manuscript accordingly. Please find our point-by-point responses to all comments below. Reviewer #1: 1. Figure 2B: both in the figure and in the text (line 241) the magnification and scale bars lack. (Response) Thank you for pointing this out. As such, the appropriate magnification levels and scale bars have been integrated into the Figure 2B. 2. Line 287- line 291: P has to be connected with asterisks (Response) We apologize for this oversight. The missing asterisks have been inserted. 3. Please amplify the discussion pointing out the advantages of this methods (PAT) compared to the others (Response) We appreciate your insightful recommendation. We have expanded our discussion to emphasize the benefits of the PAT method over alternative approaches. Under the new subheading “Comparative efficacy of PAT grafting versus other treatments” in section 4.8, we provide a comprehensive analysis, comparing PAT grafts with other clinically employed treatments for ischemic tissue-exposed wounds. Reviewer #2: There are some concerns: 1. I found a few grammatical errors. (Response) We have submitted the manuscript for an additional round of revision with Editage to ensure that all grammatical errors are corrected. 2. Why perifascial areolar tissue (PAT) grafts is effective to promote granulation tissue formation that other tissues such as skin graft or pure fat doesn't. (Response) We appreciate your query. We have now incorporated a detailed comparison with skin grafting, as suggested. Current understanding acknowledges that full-thickness skin grafts have the potential for integration with ischemic tissues. However, the specific mechanisms facilitating this process remain inadequately elucidated. Furthermore, the consensus is that such grafts are typically not indicated for application on ischemic tissues. We have reviewed in detail the reports on the methodology of skin grafting and incorporated them into our discussion, particularly emphasizing this in the “Vascular bridging” subheading in Section 4.2. It should be noted that our discussion does not encompass fat grafting, as this technique is predominantly applied to intact tissue rather than to open wounds. 3. Did you consider PAT viability after grafting on a bare area? (Response) We appreciate your invaluable suggestion. Our observations revealed that at 7 days post-application, vascular bridging was grossly visible in two of the six cases and four of the six cases on histological analysis. By day 14, granulation tissue had nearly enveloped all exposed cartilage areas, obscuring the gross observation of vascular bridging, though vascular formation was present in all cases on tissue sections. Unlike skin grafts, the PAT grafts did not allow for a clear demarcation between viable and necrotic tissue on the dates of gross observation. Histological analysis also indicated areas of cellular attrition, yet a membranous structure persisted. Consequently, the precise determination of graft survival rates was challenging. Notably, granulation tissue formation was significantly accelerated by day 14, suggesting that even in the absence of vascular bridging, the grafts likely contributed to wound healing through their biomaterial properties, including stem content. The aforementioned explanation has been incorporated into the manuscript in sections 3.3 “PAT graft survival,” 3.4.1 “Granulation tissue growth,” and 4.8.2 'Comparative Analysis with Other Treatment Modalities.” 4. What's the mechanism of action of PAT for granulation tissue formation, it's effect as a viable graft or it's effect when necrosis occurs and intra cellular mediators such as growth factors release? If first hypothesis is correct please mention what's the mechanism of PTA viability. (Response) We are grateful for your guidance. To address this, we have introduced a new subheading, 4.7 “Mechanisms underlying PAT graft viability.” This section is dedicated to elucidating the inferred biological mechanisms that contribute to the viability of PAT grafts. 5. You stated: "The open wound area, as determined from photographs, was significantly larger in the PAT 345 group than in the control group on day 7 (P < 0.05) (Fig 4A)". Does this mean wounds on both groups were not similar?. (Response) We apologize for the confusion and thank you for highlighting the ambiguity in this part. Wound healing principally involves two mechanisms: wound contraction and re-epithelialization. Given that wound contraction can lead to hypertrophic scarring, optimal treatment strategies aim to minimize this process, particularly in humans, without impeding overall wound closure. In our study, the PAT group exhibited a transient delay in wound closure due to reduced contraction by day 7, and yet demonstrated an expedited re-epithelialization by day 14. Consequently, the total time to wound closure in the PAT group was found to be comparable to that of the control group by the 14th day. This suggests that the observed process in the PAT group may represent an ideal paradigm for wound healing. For easier understanding, we have added explanations in sections 3.4.3 “Wound contraction evaluation” and 4.6 “Wound contraction control with PAT graft.” 6. What's the mechanism of viability of PAT graft. (Response) We have added a section, 4.7, “Mechanisms underlying PAT graft viability,” accordingly. This new section provides a comprehensive summary of the currently understood biological processes contributing to the efficacy of PAT grafts. 7. You stated "The effectiveness of PAT grafts can be attributed to two primary factors, namely vascular bridging during graft survival and the provision of three essential elements that promote wound healing and angiogenesis: progenitor/stem cells, ECM molecules, and growth factors/cytokines.". My questions is why skin graft cannot do this? To best of our knowledge skin graft cannot cover or take on bare areas such as bone without periosteum but you concluded PAT can. Please clearly stat what's the difference. (Response) Thank you for highlighting the missing explanation. There has long been a theory that full-thickness skin grafts exhibit a “bridging” capability, enabling them to extend over ischemic tissue. However, as you correctly note, the current consensus now holds that such wounds are generally not amenable to grafting. After a detailed review of the literature, we have discussed the mechanism underlying this phenomenon, integrating our findings into section 4.2, “Vascular bridging.” Furthermore, we have expanded on the distinctions and advantages of PAT grafting in comparison to traditional skin grafting. This comparative analysis, particularly focusing on the unique aspects of PAT grafting, is presented in section 4.8.1, “Distinctive aspects relative to skin grafting.” 8. I think the manuscript is too long and includes parts that are unnecessary. (Response) We've tried to cut down on unnecessary parts, but the manuscript has still become longer due to some added sentences. If you still think the manuscript includes parts that are unnecessary, could you please specify which parts you think are not needed? Attachments Attachment Submitted filename: Response to the comments of the Reviewer.docx https://doi.org/10.1371/journal.pone.0298971.r002
2 Jan 2024 Decision Letter - Alessandra Giuliani, Editor PONE-D-23-30878R1Perifascial Areolar Tissue Graft Promotes Angiogenesis and Wound Healing in an Exposed Ischemic Component Rabbit ModelPLOS ONE Dear Dr. Miyanaga, 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 Feb 16 2024 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. Please include the following items when submitting your revised manuscript: 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'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Alessandra Giuliani Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: No ****** 6. 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: (No Response) Reviewer #2: Dear Author Hello, I read revised manuscript. The desired corrections have been made, but the writing style of the article is confusing for the reader. This is due to the lengthy and repetitive sentences, which make it tiresome to read and difficult to understand the main concept of the article. ****** 7. PLOS authors have the option to publish the peer review history of their article (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: Yes: Agarbati Silvia Reviewer #2: Yes: Mehdi Ayaz ******** [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. https://doi.org/10.1371/journal.pone.0298971.r003
Revision 2
30 Jan 2024 Author Response Response to the Reviewer’s comments Dear Editor; Thank you for evaluating our manuscript and for your encouraging comments and appreciation of our work. Our manuscript has benefited from your comments and the reviewers’ guidance and thoughtful suggestions. We have read the comments provided by you and the reviewers and revised the manuscript accordingly. Please find our point-by-point responses to all the comments below. Reviewer #2: I read revised manuscript. The desired corrections have been made, but the writing style of the article is confusing for the reader. This is due to the lengthy and repetitive sentences, which make it tiresome to read and difficult to understand the main concept of the article. (Response) Thank you for pointing out this issue. We agree that the sentences were long and difficult to understand because of repetitive text. We modified the text to avoid repetition and improved understandability. Consequently, the word count has been reduced from 6340 to 5407 words. Thank you again. Attachments Attachment Submitted filename: renamed_1cfa0.docx https://doi.org/10.1371/journal.pone.0298971.r004
2 Feb 2024 Decision Letter - Alessandra Giuliani, Editor Perifascial Areolar Tissue Graft Promotes Angiogenesis and Wound Healing in an Exposed Ischemic Component Rabbit Model PONE-D-23-30878R2 Dear Dr. Miyanaga, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Alessandra Giuliani Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0298971.r005
Formally Accepted
8 Feb 2024 Acceptance Letter - Alessandra Giuliani, Editor PONE-D-23-30878R2 PLOS ONE Dear Dr. Miyanaga, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Alessandra Giuliani Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0298971.r006

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