Novel measurement tool and model for aberrant urinary stream in 3D printed urethras derived from human tissue

Andrew J. Cohen; German Patino; Mehran Mirramezani; Sudarshan Srirangapatanam; Anas Tresh; Bhagat Cheema; Jenny Tai; Dylan Romero; Anthony Enriquez; Laurence S. Baskin; Shawn C. Shadden; Benjamin N. Breyer

doi:10.1371/journal.pone.0241507

Peer Review History

Original SubmissionJune 2, 2020
28 Jul 2020 Decision Letter - Peter F.W.M. Rosier, Editor PONE-D-20-16734 Novel measurement tool and model for aberrant urinary stream in 3D printed urethras derived from human tissue PLOS ONE Dear Dr. Enriquez, 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. ACADEMIC EDITOR: In addition to the reviewers comments I ask you to consider to rephrase "altered the shape of the urethra' in the patient summary. Furthermore: because meatal stenosis (shape -size variation) is very much different from pelvic muscle and or prostatic outflow obstruction a short discussion about flow -rate (which uroflowmetry measures) and or flow velocity (which the 'nozzle' (meatus) affects) might help the reader to understand the fundamental limitations of urodlowmetry for -diagnosis of- meatal abnormalities. Please ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact. Please submit your revised manuscript by Sep 11 2020 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 We look forward to receiving your revised manuscript. Kind regards, Peter F.W.M. Rosier, M.D. PhD 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. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. 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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: This paper is well written, easy to understand and thorough in its description and discussion. The only significant matters requiring attention are I think: - p.3 Intro 1st para: you claim there is no instrument, but ref 6 does describe something of this sort. You also neglect to mention the drop spectrometer (doi: 10.1109/tbme.1976.324642), an acknowledgement of which might be appropriate. - The difference in flow rates between cadaver and model is clearly significant. You should in this context discuss the difference in elasticity between tissue and polymer, which is likely to be a cause. Otherwise, this difference will seem to invalidate the model - the outlet of the model will clearly be a major factor for spraying. I think some reference to any rounding / shaping (or not) of this that you did will help understand. - the CFD modeling does not really fit with this paper, and would easily make a separate publication if you chose to do so. Other smaller errors to attend to: - unit of flow is correctly ml/s in Table 1, but is not consistent through the paper - ref 10 on p4 seems to be too late in the sentence - p5 references to equipment should normally include manufacturer and location - p6: 'rectangular' should be 'rectangle'? - p11, 1st para: 'recapitulated' = ? - p12 2nd para: 'vertical' = 'vortical'? - Fig 2a: 'calibration over catheter' = ? - Fig 3: 'Alternations' 'sprauy' Reviewer #2: Summary: The authors forced a certain flow rate (4 discrete values) through 4 human cadaveric urethral specimens and 3D printed models of these. The tip of the urethras was altered in 8 different ways (degrees of obstruction). The effects on the flow rate and the spray of the urine was studied as well as the similarity between the specimens and the 3D models. Finally, computational fluid dynamics was applied to study intra-urethral pressure and fluid vorticity. The authors describe 5 objectives of their study. The main aim was to provide models for studying the best surgical approach to correct anatomical abnormalities of the meatus. Major comments: 1. It is doubtful whether the cadaveric urethra is a good model for the living urethra because of the absence of muscle tone. This is not discussed. In addition, there appear to be large differences in Qmax values and spray areas between the cadaveric urethras and the 3D models (Table 1), raising the same question. 2. I found it sometimes difficult to follow what the authors exactly did and I suppose this is partly due to the presentation of data. Why not, for instance, is Appendix 2 incorporated in Table 1. Also, presentation in a graph might be more explaining than presentation in a table. 3. In spite of 1 and 2, I can agree with the authors that 3D models could be used to study the clinical effect of different surgical approaches of a given urethral abnormality before application in patients. Minor comments: 1. Abstract, Results and Limitations, last sentence: 2x was. 2. There is a discrepancy between the text in Results and Table 1: 3D printed models had …: 10.6 ml/sec should be 11.6 ml/sec (Table 1). ****** 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: Yes: Andrew Gammie Reviewer #2: Yes: Jan Groen [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.0241507.r001
Revision 1
27 Aug 2020 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: This paper is well written, easy to understand and thorough in its description and discussion. The only significant matters requiring attention are I think: - p.3 Intro 1st para: you claim there is no instrument, but ref 6 does describe something of this sort. You also neglect to mention the drop spectrometer (doi: 10.1109/tbme.1976.324642), an acknowledgement of which might be appropriate. Thank you for your comments and suggestion. We appreciate the historic, research significance of the drop spectrometer. We have added references for this series of work in multiple points throughout the present work. - The difference in flow rates between cadaver and model is clearly significant. You should in this context discuss the difference in elasticity between tissue and polymer, which is likely to be a cause. Otherwise, this difference will seem to invalidate the model Thank you. You astutely identify the major limitation of this work. The polymer used in this experiment had no elasticity, and essentially was a rigid pipe. The cadaveric tissue, while pliable, likely does not recapitulate live human urethral elasticity given lack of muscle tone. We hypothesis this is why the flow rates between cadaver and models were significantly different. We experimentally determined the cadaveric urethral mucosa deformed by 2-3 mm during dynamic testing by observation with ultrasound. The material for the 3D models, in contrast, was non-pliable. Moreover, for simplicity the CFD model simulation assumed a non-pliable urethra. The elasticity of normal human urethral tissue at the tip of the penis is unknown. Histologic analysis confirms the presence of elastic fibers. Detailed biomechanical analysis of animals, such as horse urethra may or may not be translatable to human models. Therefore, incorporation of elasticity in any model remains a challenge, partly due to lack of basic knowledge in this arena. Means to measure human urethral elasticity may be possible via elastography. This has been performed on the prostatic urethra with quite heterogeneous results. Given the lack of gold-standard references, it is hard to incorporate such data here. While complex deformable polymers are now possible with 3D printing, cost limitations remain a concern. Furthermore, urethral elasticity likely is not uniform across the urethral length and how to incorporate dynamic elasticity to fully model human tissue may only be possible via simulation. These ideas are summarized for the reader on page 12 in a new paragraph. “The discrepancy in flow rates between cadaveric and 3D printed tissues likely was in part due to their material properties. The polymer used in this experiment had no elasticity, and essentially was a rigid pipe. The degree to which tissue elasticity impacts flow is unknown but certainly mechanical properties suggest distal urethral obstruction could be directly related to lack of tissue dispensability at high fluid flow rates.(6) The 3D printed model had no dispensability, which may explain the consistently worse flow rates observed. Of note, the cadaveric tissue, while certainly pliable, likely did not recapitulate live human urethral elasticity either. Means to measure human urethral elasticity may be possible via elastography; early work in this area reveals heterogeneous results.(20) Furthermore, urethral elasticity likely is not uniform across urethral length. (21) Even if measured reliably, the limitations of 3D printing may require incorporation of dynamic elasticity be reserved for computational fluid modeling.” Outside of the scope of the article but of interest to the reviewer may be the ongoing research in measuring ‘stiffness’ in arteries. Shear wave elastography has been proposed as a method to study arterial wall elasticity. To our knowledge this has never been applied to the human urinary tract, but could be a modality to gain enough information to incorporate in the future. Bastos AL, Silva EA, Silva Costa W, et al. The concentration of elastic fibres in the male urethra during human fetal development. BJU International 2004;94:620–623. doi:10.1111/j.1464-410X.2004.05012.x. Messas E, Pernot M, Couade M. Arterial wall elasticity: State of the art and future prospects. Diagnostic and Interventional Imaging 2013;94:561–569. doi:10.1016/j.diii.2013.01.025. Natali AN, Carniel EL, Frigo A, et al. Experimental investigation of the biomechanics of urethral tissues and structures: Biomechanics of urethral tissues and structures. Exp Physiol 2016;101:641–656. doi:10.1113/EP085476. Kwon JK, Kim DK, Lee JY, et al. Relationship between Lower Urinary Tract Symptoms and Prostatic Urethral Stiffness Using Strain Elastography: Initial Experiences. JCM 2019;8:1929. doi:10.3390/jcm8111929. - the outlet of the model will clearly be a major factor for spraying. I think some reference to any rounding / shaping (or not) of this that you did will help understand. We have edited the methods section to further aid in understanding of the varied shape confirmations that we enacted. Furthermore the Fig x has been granted additional explanation to improve the readability and understanding of the methods. Ultimately, the alterations were based on mucosa to mucosa apposition. Hence the original organic shape of the meatus would remain, simply with smaller aperture. - the CFD modeling does not really fit with this paper, and would easily make a separate publication if you chose to do so. We appreciate that the CFD modeling is a complex topic potentially worthy of its own focused manuscript. In constructing the 3D printed models, the 3D representation of the urethral lumen was created. Moreover, the CFD models recapitulate the findings of 3D printed urethral experiments and offer tantalizing clues to the internal flow within the lumen. In presenting this compendium of methodologies together, we feel the reader can best critically appraise how these inter-connected methods may lead to broadened clinical understanding and application. Other smaller errors to attend to: - unit of flow is correctly ml/s in Table 1, but is not consistent through the paper Thank you. We have corrected such unit omissions through the manuscript for consistency and scientific vigor. - ref 10 on p4 seems to be too late in the sentence This has been corrected - p5 references to equipment should normally include manufacturer and location This oversight has been corrected - p6: 'rectangular' should be 'rectangle'? Corrected - p11, 1st para: 'recapitulated' = ? Corrected - p12 2nd para: 'vertical' = 'vortical'? Corrected - Fig 2a: 'calibration over catheter' = ? This has been further explained in the methods and the fig legend. - Fig 3: 'Alternations' 'sprauy' This has been corrected Reviewer #2: Summary: The authors forced a certain flow rate (4 discrete values) through 4 human cadaveric urethral specimens and 3D printed models of these. The tip of the urethras was altered in 8 different ways (degrees of obstruction). The effects on the flow rate and the spray of the urine was studied as well as the similarity between the specimens and the 3D models. Finally, computational fluid dynamics was applied to study intra-urethral pressure and fluid vorticity. The authors describe 5 objectives of their study. The main aim was to provide models for studying the best surgical approach to correct anatomical abnormalities of the meatus. We very much appreciate you reading the manuscript and found your comments extremely helpful. Major comments: 1. It is doubtful whether the cadaveric urethra is a good model for the living urethra because of the absence of muscle tone. This is not discussed. In addition, there appear to be large differences in Qmax values and spray areas between the cadaveric urethras and the 3D models (Table 1), raising the same question. We appreciate this concern; together with the reviewer’s 1’s similar reservations about the elasticity of the model we have added a discussion paragraph (page 12) to directly address this issue. We agree a major limitation is the fact the polymer used in this experiment had no elasticity, and essentially was a rigid pipe. The cadaveric tissue likely does not fully recapitulate live human urethral elasticity. 2. I found it sometimes difficult to follow what the authors exactly did and I suppose this is partly due to the presentation of data. Why not, for instance, is Appendix 2 incorporated in Table 1. Also, presentation in a graph might be more explaining than presentation in a table. We tested multiple presentation of data strategies with a wide audience of experts, clinicians, and scientists given the complexity of the tip alterations and the data generated. After circulating several draft graphics and tables it was the consensus opinion to use the current hybrid approach. Hence, we have broken up the data into Table 1 and Figure 3 to illustrate our points. Nonetheless, we are very open to merging Table 1 and Appendix 2 to aid in understanding. As such a new Table 1 has been uploaded and appendix 2 eliminated. 3. In spite of 1 and 2, I can agree with the authors that 3D models could be used to study the clinical effect of different surgical approaches of a given urethral abnormality before application in patients. Minor comments: 1. Abstract, Results and Limitations, last sentence: 2x was. Thank you for pointing out this error, it his has been corrected 2. There is a discrepancy between the text in Results and Table 1: 3D printed models had …: 10.6 ml/sec should be 11.6 ml/sec (Table 1). We appreciate you finding this mis-type and it has been corrected. Attachments Attachment Submitted filename: PLOS Response to Reviewersbnb.docx https://doi.org/10.1371/journal.pone.0241507.r002
28 Sep 2020 Decision Letter - Peter F.W.M. Rosier, Editor PONE-D-20-16734R1 Novel measurement tool and model for aberrant urinary stream in 3D printed urethras derived from human tissue PLOS ONE Dear Dr. Enriquez, 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. ACADEMIC EDITOR: The reviewer suggests a fes changes in wording. I agree with these, can you adapt the 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 We look forward to receiving your revised manuscript. Kind regards, Peter F.W.M. Rosier, M.D. PhD Academic Editor PLOS ONE [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: (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 #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 #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: 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 #1: Thank you for carefully considering and addressing the comments made. There are just some small remaining issues to sort: You use 'dispensability' twice now on p.12, whereas I think you mean 'distensibility'. In the new text on p.12, you use 'recapitulate' which may be a valid technical term in modelling, but it does not communicate well here. I suggest 'did not reproduce live human tissue' is clearer, as you have done in the abstract. Your comment on shear wave elastography is interesting, and you may be interested to check out J Urol 2017; 198:422-429. I agree that this method may well be worth future investigation. In Tables 1 and 2, the addition of horizontal and vertical lines may assist understanding. I found it not immediately obvious which figures the p-values corresponded with, and also where the division between specimens lay. Reviewer #2: Discussion, first paragraph: intrauthreal should be corrected. In the Discussion, more attention is paid now to the differences between living tissue, cadaveric urethras and 3D models, that is, to the limitations of the study. There are large differences between results obtained in the cadaveric urethras and the 3D models. Nevertheless, this study seems a good onset of a series of experiments and observations on the value of 3D models in clinical practice. ****** 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: Andrew Gammie Reviewer #2: Yes:** Jan Groen [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.0241507.r003
Revision 2
6 Oct 2020 Author Response 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: Thank you for carefully considering and addressing the comments made. There are just some small remaining issues to sort: You use 'dispensability' twice now on p.12, whereas I think you mean 'distensibility'. In the new text on p.12, you use 'recapitulate' which may be a valid technical term in modelling, but it does not communicate well here. I suggest 'did not reproduce live human tissue' is clearer, as you have done in the abstract. Thank you again for your helpful comments and keen eye for errors. We have made these corrections on page 12 . Your comment on shear wave elastography is interesting, and you may be interested to check out J Urol 2017; 198:422-429. I agree that this method may well be worth future investigation. In Tables 1 and 2, the addition of horizontal and vertical lines may assist understanding. I found it not immediately obvious which figures the p-values corresponded with, and also where the division between specimens lay. We have added some vertical and horizontal lines to aid in drawing the readers eye. We are open to any and all table formatting suggestions to bring the paper in line with PLOSone formatting standards without reservation. Reviewer #2: Discussion, first paragraph: intrauthreal should be corrected. Thank you, this spelling error corrected. In the Discussion, more attention is paid now to the differences between living tissue, cadaveric urethras and 3D models, that is, to the limitations of the study. There are large differences between results obtained in the cadaveric urethras and the 3D models. Nevertheless, this study seems a good onset of a series of experiments and observations on the value of 3D models in clinical practice. Attachments Attachment Submitted filename: PLOS response2.docx https://doi.org/10.1371/journal.pone.0241507.r004
16 Oct 2020 Decision Letter - Peter F.W.M. Rosier, Editor Novel measurement tool and model for aberrant urinary stream in 3D printed urethras derived from human tissue PONE-D-20-16734R2 Dear Dr. Enriquez, 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, Peter F.W.M. Rosier, M.D. PhD Academic Editor PLOS ONE Additional Editor Comments (optional): 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 ******** 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: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) ****** 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: (No Response) ****** 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: (No Response) ****** 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) ****** 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:** Andrew Gammie https://doi.org/10.1371/journal.pone.0241507.r005
Formally Accepted
30 Oct 2020 Acceptance Letter - Peter F.W.M. Rosier, Editor PONE-D-20-16734R2 Novel Measurement Tool and Model for Aberrant Urinary Stream in 3D Printed Urethras derived from Human Tissue Dear Dr. Enriquez: 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 Dr. Peter F.W.M. Rosier Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0241507.r006

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