Nerve recovery from treatment with a vascularized nerve graft compared to an autologous non-vascularized nerve graft in animal models: A systematic review and meta-analysis

Berend O. Broeren; Liron S. Duraku; Caroline A. Hundepool; Erik T. Walbeehm; J. Michiel Zuidam; Carlijn R. Hooijmans; Tim De Jong

doi:10.1371/journal.pone.0252250

Peer Review History

Original SubmissionMay 10, 2021
23 Jun 2021 Decision Letter - Leila Harhaus, Editor PONE-D-21-15417 Nerve recovery from treatment with a vascularized nerve graft compared to an autologous non-vascularized nerve graft in animal models: a systematic review and meta-analysis PLOS ONE Dear Dr. Broeren, 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 Aug 07 2021 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: http://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, Leila Harhaus Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 3. Please include a separate caption for each figure in your manuscript. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information [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: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ****** 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: Nerve recovery from treatment with a vascularized nerve graft compared to an autologous non-vascularized nerve graft in animal models: a systematic review and meta-analysis This manuscript is a metanalysis comparing vascularized vs. no vascularized nerve graft. The article fits the scope of the journal. The title appropriately summarizes the article contents. The article is well-structured, the language is adequate. The references are uniform and according to the instructions for authors. The main concern is the heterogenous data with poor methodological details from the different manuscripts this paper is based on. Please consider the next suggestions/clarification to improve the manuscript: - Axonal account and diameter: were a uniform histological technique regarding the axonal account? Paper’s years of publication range from 1988 until 2016. Although these histological techniques are not novel, the sensitivity and specific of this technique has been improved during the last 30 years. Do the authors think it could exist a bias comparing these studies? - I have a similar concern regarding the three studies with neurophysiology. This technique needs an experience neurologist or neurophysiologist to get reliable data. I recommend the publication of the manuscript after the above comments are addressed. We thanks the authors the great effort needed for this study. Reviewer #2: Thank you for your work and efforts to do a meta analysis. What is the personal guidelines in your institution? Please add your guideline into this paper. The figures are in poor resolution, blurred and not clear. Kindly ask you improve the resolution. ****** 6. 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: No Reviewer #2: No [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.0252250.r001
Revision 1
2 Aug 2021 Author Response Rebuttal letter PONE-D-21-15417 “Nerve recovery from treatment with a vascularized nerve graft compared to an autologous non-vascularized nerve graft in animal models: a systematic review and meta-analysis” Berend O. Broeren1, Liron S. Duraku2, Caroline A. Hundepool2, Erik T. Walbeehm1, J. Michiel Zuidam2, Carlijn R. Hooijmans3,4, Tim De Jong1 PLOS ONE Leila Harhaus Academic Editor PLOS ONE Dear Ms Harhaus, We thank you and the reviewers for a careful reading and the constructive comments regarding our manuscript and for the opportunity to revise and resubmit. We have addressed all recommendations and suggestions to further improve the manuscript. On behalf of my co-authors, I thank you for considering this revised manuscript for publication. We appreciate your time and look forward to your response. Yours sincerely, Berend Broeren (corresponding author) berend.broeren@xs4all.nl Journal requirements: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. We have added our raw data using a supporting file and included a caption at the end of the manuscript. 3. Please include a separate caption for each figure in your manuscript. We have included a caption for each figure immediately following the paragraph in which the figure was first cited with a label, title and legend. 4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information We have included a caption for each supporting information file at the end of the manuscript with a label, title and legend. In-text citations were matched accordingly. 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: Partly 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A 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: Nerve recovery from treatment with a vascularized nerve graft compared to an autologous non-vascularized nerve graft in animal models: a systematic review and meta-analysis This manuscript is a metanalysis comparing vascularized vs. no vascularized nerve graft. The article fits the scope of the journal. The title appropriately summarizes the article contents. The article is well-structured, the language is adequate. The references are uniform and according to the instructions for authors. The main concern is the heterogenous data with poor methodological details from the different manuscripts this paper is based on. Please consider the next suggestions/clarification to improve the manuscript: - Axonal account and diameter: were a uniform histological technique regarding the axonal account? Paper’s years of publication range from 1988 until 2016. Although these histological techniques are not novel, the sensitivity and specific of this technique has been improved during the last 30 years. Do the authors think it could exist a bias comparing these studies? We appreciate the positive comments of Reviewer #1 and share the concerns regarding the heterogenous data and the poor methodological details from the different manuscripts this paper is based on. Therefore, it was extensively described in the section ‘limitations of this study” and the recommendation to use the Gold Standard Publication Checklist or ARRIVE guidelines for future animal studies to improve the reporting and methodological quality of animal studies in our conclusion was made. As to the uniformity of histological technique to measure axonal count, we added a section in the “limitations of this study” section. Different techniques were used by the studies in this review. To compensate for these differences, we used a standardized mean difference for our meta-analysis. The statement made by Reviewer #1 that these techniques have evolved is true and the sensitivity and specific of this technique may have been improved during the last 30 years. Over the years methods have evolved from manually calculating axonal count from a light microscopic photograph to a computer calculated estimate. Searching the publication databases, we found little evidence on which one is the best or on a clear sensitivity or specificity for these methods. Kim et al. concluded that semi-automated method for counting axons in transmission electron microscopic images were strongly correlated with those of conventional counting methods and showed excellent reproducibility. Nevertheless, the techniques for histomorphometry will always be an estimation and therefore prone to bias. - I have a similar concern regarding the three studies with neurophysiology. This technique needs an experience neurologist or neurophysiologist to get reliable data. The studies where neurophysiology was one of the outcome measurements did not mention the skillset of the person who assessed the outcomes. The data could possibly be biased but this cannot be established with the information at hand. I recommend the publication of the manuscript after the above comments are addressed. We thanks the authors the great effort needed for this study. Reviewer #2: What is the personal guidelines in your institution? Please add your guideline into this paper. Although we don’t have a clinical guideline for peripheral nerve gaps, we have added information of the clinical practice of our institution in the introduction of the manuscript. The use of vascularized nerve grafts is debated in our medical centers because of the lack of clinical evidence indicating the superiority of a vascularized nerve graft, the concern of a more significant donor site morbidity compared to conventional nerve autografts and the complexity of the surgery. The figures are in poor resolution, blurred and not clear. Kindly ask you improve the resolution. All figures have been improved using the PACE digital diagnostic tool to make sure the resolution improved and the PLOS requirements were met. Attachments Attachment Submitted filename: Respons to Reviewers .docx* https://doi.org/10.1371/journal.pone.0252250.r002
22 Oct 2021 Decision Letter - Leila Harhaus, Editor PONE-D-21-15417R1Nerve recovery from treatment with a vascularized nerve graft compared to an autologous non-vascularized nerve graft in animal models: a systematic review and meta-analysisPLOS ONE Dear Dr. Broeren, 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 Dec 06 2021 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, Leila Harhaus 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 #3: (No Response) ******** 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 #3: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes ****** 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 #3: 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 #3: Yes ****** 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 #3: The study provided an interesting overview of the field of vascularized nerve grafts, indicating that vascularized nerve grafts can achieve superior results in terms of axon count, axon diameter, and nerve conduction velocity when compared to non-vascularized nerve grafts. However, the manuscript needs some major and minor revision before publication. Major Points The introduction should include a more detailed explanation of the technique and rationale behind these techniques. The author discussed the disadvantages of the vascularized nerve graft but did not discuss its advantages over the conventional ANT. Interestingly, the author emphasizes the critical nature of functional recovery but includes no data in the manuscript, implying that vascularized nerve grafts may have an effect on functional recovery. While we are well aware of the heterogeneity associated with assessing functional recovery following peripheral nerve injury, these issues should also be discussed in the manuscript. This manuscript provided compelling evidence that a peripheral nerve surgeon should place a greater emphasis on the vascularized nerve graft. The author, however, did not discuss the findings under "Discussion." What is the author's opinion about the superior axon count and diameter? Why do you see the effects even for the nerve conduction velocity and not for the muscle weight? Justifies the advantages of an enlarged donor site the disadvantages? Can the findings of an animal study be applied to humans? Therefore the Discussion section should be appropriately revised. Minor Points Abstract Line 54: What does this sentence mean? Three out of four measurements. In which measurements is a vascularized nerve graft superior? Introduction: The author should give a short overview of the technique of the vascularized nerve graft and explain its rationality further - Line 63: When is it necessary to bridge the gap – when a tensionless coaptation is not possible – this should be added Line 67: please rephrase the sentence – the meaning is clear – but the expression has to be improved Line 80: what did these studies show – please elaborate on the findings of the previous research Line 88: why do you use them and not nerve tubes? When you mean Axogen, then due to the results of the ranger study – these should be added. Line 117: what about functional regeneration? Did the studies give no information focusing on the functional regeneration compared to a "conventional" ANT Material and Methods: Figure 1: Can you please clarify why you exclude the 175 manuscripts to classify the arguments. Would you please adjust the figure? Results: Line 205; the meaning of the sentence is not clear – please rephrase Line 210: please add the level of significance Line 235: why here SEM and not SMD? Discussion: This is a critical point in line 319 – 329. However, no data on functional recovery were provided, even with a small number of studies – despite the fact that this is the most important "test" for peripheral nerve injury recovery due to its clinical relevance. Line 371: Because histomorphometry is crucial to this review, the author should explain how the axonal count was obtained. Counting axons using random field of interest methods and counting the entire diameter have varying degrees of validity for the data. ****** 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 #3: No [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.0252250.r003
Revision 2
12 Nov 2021 Author Response 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 #3: (No Response) 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 #3: Partly 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes 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 #3: 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 #3: Yes 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 #3: The study provided an interesting overview of the field of vascularized nerve grafts, indicating that vascularized nerve grafts can achieve superior results in terms of axon count, axon diameter, and nerve conduction velocity when compared to non-vascularized nerve grafts. However, the manuscript needs some major and minor revision before publication. Major Points The introduction should include a more detailed explanation of the technique and rationale behind these techniques. The author discussed the disadvantages of the vascularized nerve graft but did not discuss its advantages over the conventional ANT. We have added information on the technique and rationale behind the technique in the introduction of the manuscript. Page 4 line 72-74 and 76-80 Interestingly, the author emphasizes the critical nature of functional recovery but includes no data in the manuscript, implying that vascularized nerve grafts may have an effect on functional recovery. While we are well aware of the heterogeneity associated with assessing functional recovery following peripheral nerve injury, these issues should also be discussed in the manuscript. We have added information on the rationale behind the choice of our outcome measurements and discuss the relevance of functional outcomes. Page 16 line 350, 351 This manuscript provided compelling evidence that a peripheral nerve surgeon should place a greater emphasis on the vascularized nerve graft. The author, however, did not discuss the findings under "Discussion." The findings were indeed discussed in the “Discussion”. This review suggests that a vascularized nerve graft does result in a significantly better nerve recovery compared to non-vascularized nerve autografts in animal models regarding the outcome measurements nerve fiber diameter, nerve conduction velocity and axonal count. Page 15 line 326-328 Treating a nerve gap with a vascularized graft results in superior nerve recovery compared to non-vascularized autografts nerve grafts in three out of four outcome measurements. Page 19 line 414, 415 What is the author's opinion about the superior axon count and diameter? Why do you see the effects even for the nerve conduction velocity and not for the muscle weight? We have added information on how the authors think about the superior axon count and diameter and the lacking effect in muscle weight. See page 16 line 334-339 Justifies the advantages of an enlarged donor site the disadvantages? We have added information on how the authors think about the question if the advantages of a vascularized nerve graft justify the disadvantages of an enlarged donor site. Page 17 line 366-370 Can the findings of an animal study be applied to humans? We think this is a fair question. However, we also think this cannot be said with certainty. Animal research comes closed to clinical research and is therefore the most appropriate alternative if clinical research is not available. Of course, something can be said for the fact that research in primates comes closer to humans than, say, the rat. In particular when it comes to nerve grafts because of the length and diameter of the nerve graft. Therefore, we recommended future studies to be performed under conditions more closely resembling human circumstances and to use long nerve grafts. Therefore the Discussion section should be appropriately revised. Minor Points Abstract Line 54: What does this sentence mean? Three out of four measurements. In which measurements is a vascularized nerve graft superior? This sentence was changed to clarify it. See page 3 line 54, 55 Introduction: The author should give a short overview of the technique of the vascularized nerve graft and explain its rationality further – Changed, page 4 line 72-74 and 76-80 Line 63: When is it necessary to bridge the gap – when a tensionless coaptation is not possible – this should be added This had been added see page 3 line 64, 65 Line 67: please rephrase the sentence – the meaning is clear – but the expression has to be improved This sentence has been rephrased see page 3 line 66-69 Line 80: what did these studies show – please elaborate on the findings of the previous research Information has been added see page 4 line 82, 83 Line 88: why do you use them and not nerve tubes? When you mean Axogen, then due to the results of the ranger study – these should be added. Did you mean line 98? Why we use autografts in most cases and not allografts? Autografts give a better outcome, with the down side of donor site morbidity which is minimal for most used nerve grafts. If not enough length of autografts is present, we use axogen. We added references. See page 5 line 98, 99 Line 117: what about functional regeneration? Did the studies give no information focusing on the functional regeneration compared to a "conventional" ANT No functional outcomes were described in more than one of the included articles. Only one described grasping strength and another one the sciatic function index. Material and Methods: Figure 1: Can you please clarify why you exclude the 175 manuscripts to classify the arguments. Would you please adjust the figure? Figure was adjusted accordingly. Results: Line 205; the meaning of the sentence is not clear – please rephrase Rephrased see page 10 line 215 Line 210: please add the level of significance The significance was added, see page 11 line 226 Line 235: why here SEM and not SMD? Changed to SMD, see page 12 line 250, 251 Discussion: This is a critical point in line 319 – 329. However, no data on functional recovery were provided, even with a small number of studies – despite the fact that this is the most important "test" for peripheral nerve injury recovery due to its clinical relevance. We rephrased this sentence. See page 16 line 350, 351 Line 371: Because histomorphometry is crucial to this review, the author should explain how the axonal count was obtained. Counting axons using random field of interest methods and counting the entire diameter have varying degrees of validity for the data. We have added information on how axonal count was obtained in the Results of the manuscript. See page 11 line 220-224 Attachments Attachment Submitted filename: Respons to reviewers.docx https://doi.org/10.1371/journal.pone.0252250.r004
18 Nov 2021 Decision Letter - Leila Harhaus, Editor Nerve recovery from treatment with a vascularized nerve graft compared to an autologous non-vascularized nerve graft in animal models: a systematic review and meta-analysis PONE-D-21-15417R2 Dear Dr. Broeren, 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, Leila Harhaus Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0252250.r005
Formally Accepted
22 Nov 2021 Acceptance Letter - Leila Harhaus, Editor PONE-D-21-15417R2 Nerve recovery from treatment with a vascularized nerve graft compared to an autologous non-vascularized nerve graft in animal models: a systematic review and meta-analysis Dear Dr. Broeren: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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 plosone@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 Prof. Dr. med. Leila Harhaus Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0252250.r006

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