PONE-D-20-31353

Gastric examination using a novel three-dimensional magnetically assisted capsule endoscopy with a hand-held magnetic controller: A porcine model.

PLOS ONE

Dear Dr. LIM,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Edoardo Sinibaldi

Academic Editor

PLOS ONE

Additional Editor Comments:

Dear Authors,

you are kindly encouraged to improve the manuscript by leveraging the points raised by the Reviewers, in particular by Reviewer #1.

You are also kindly invited to declare any potential conflicts of interest.

Best regards

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3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"This research was supported by T2B Infrastructure Center for Digestive Disorders"

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

" This experiment was supported by a grant from the Korean Health Technology R&D project through the Korean Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI19C0665)."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

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"The authors have declared that no competing interests exist."

We note that one or more of the authors are employed by a commercial company: Intromedic CO., LTD.

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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: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: N/A

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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: No

Reviewer #2: Yes

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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: No

Reviewer #2: Yes

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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: Dear Authors,

Thank you for reporting this interesting piece of work reporting the gastric examination of a porcine model using a 3D magnetically assisted capsule endoscopy system. Please find below my comments and questions concerning the various sections of your manuscript.

- INTRODUCTION -

1. Please quantify or provide a range in frames-per-sec on what the 'high' in

"development of high frame rate of CE camera" refer to.

- METHODS -

1. This first paragraph describes that "Laboratory animal breeding and experiment were carried out in strict accordance with ethical guidelines and carried out at KNOTUS Co. Ltd (Incheon, Korea), a certified facility." What are the ethical guidelines of KNOTUS? Please attach the guidelines as supplementary information or link it to a publically available URL.

2. Why was the study restricted to just one subject? Considering that the MACE was not able to pass the pylorus and travel through the small and large intestines because of the presence of the lesion, isn't this pre-clinical study preliminary and perhaps even incomplete to determine the efficacy of this 3D MACE and new magnetic controller?

3. Fig 1A, B, and C are generally of very low quality and appear not in focus. Please replace these images with higher quality images.

(a) - Please use a scale bar and mark the dimensions of the capsule in Fig1A.

(b) - The pictures of the capsule in Fig1A do not clearly show the 2 camera system that is important detail in this novel capsule. Please replace it with a macro-photograph that showcases the camera and imaging system on the capsule clearly.

(c) Fig C is also of very low quality. None of the text on display nor the label on the product is legible.

4. The functionality of the real-time receiver and sensor belt has to be described. What sensors are used in the belt? What kind of receivers on the real-time receiver. Please include a schematic of the whole 3D capsular endoscopy system.

5.

(a) In Section 2. Devices, Subsection (2) Hand-held magnetic controller, it is not clear what a conventional controller is? Is it an existing Intromedic product? What are its dimensions? How dos the new magnetic controller compare to other research-stage or other commercial handheld controllers? Please provide refernces to other controllers as well. What would be most appropriate is if controllers and their magnet configurations can be compared in a figure.

(b) It is mentioned that "the magnetic force is equal between the two"? How has this been calculated or estimated. The other sections of the paper do not provide satisfactory explanation to this.

- RESULTS -

1. In Fig 4C, its very hard to visually distinguish a remarkable difference between conventional MACE and 3D MACE. Could another image of a different region be provided that shows a marked difference?

2. In the section on Safety,

(a) I note that the MACE was released from the pig only after 7 days post the experiment. Is the delay primarily due to the fact that the presence of the lesion did not allow the capsule to enter the dudenum?

(b) How does the capsule staying within the pig for 7 days, affect the subject? Is there some part of the ethical guidelines of KNOTUS facility which deals with such a situation?

- DISCUSSIONS -

1. Is the difference between MC4000 and MC4000-M, only the presence of the magnetic controller, or is there something else?

2. Regarding the hammer-shaped magnetic controller, pleas refer to my questions in the Methods section about comparing existing magnetic controllers. Ideally please include a comparative imagery of existing handheld magnetic controllers w.r.t to the new dsign?

3. "Therefore, the calculated magnetic forces of the two controllers are similar". The explanations given to explain the force equivalent is unsatisfactory, if dimensions are not provided of conventional controller nor analytical or magnetostatic simulations regarding this.

4. As I mentioned earlier, I do not believe one of the concluding statements "This preclinical trial provides a basis for further clinical studies on 3D MACE." since the submitted manuscript has not detailed a complete GI tract examination and the present study seems to be incomplete and needs further preclinical trials on multiple subjects before becoming a basis for clinical studies.

Reviewer #2: This is an interesting porcine study; there are many typos or mistakes in you submission- please revise.

Furthermore, I would prefer a title like: Gastric examination using a novel three-dimensional (3D) magnetically assisted capsule endoscope and a hand-held magnetic controller: A porcine model study.

Although the majority of the images are useful and of high quality, I believe that the main set up of the experiment, that is (if not a real image) please consider adding an infographic showing the set up of the experiment.

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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.

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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.]

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PONE-D-20-31353R1

Gastric examination using a novel three-dimensional (3D) magnetically assisted capsule endoscope and a hand-held magnetic controller: A porcine model study

PLOS ONE

Dear Dr. LIM,

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 Sep 04 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,

Edoardo Sinibaldi

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.

Additional Editor Comments (if provided):

Dear Authors,

although the manuscript was improved, a few further revisions are needed for providing a scientifically sound contribution. In particular, quantitative lesion estimation seems to remain a relatively major point (for which the Reviewer suggests some additional test-bench characterization, also in view of the systematic quest for reduced additional experimental work during the pandemics). Even the supplementary video could provide added value (also based on the overall comments set). Additional points could be tackled through manageable efforts.

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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: All comments have been addressed

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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: N/A

**********

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

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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:

- Methods 2. Devices (2) Hand-held magnetic controller -

1. Please specify the effective operation distance (in cm) between the controller and the 3D MACE.

2. The authors only mentioned the magnetic flux density (in Gauss) 10 cm away, but not the corresponding magnetic force (in Newton) with respect to the MACE. Please complement this information.

3. If during the operation, the hand-held controller is accidentally moved beyond the effective range with the MACE, would it lost the pose control of MACE? If this is the case, how to re-localize MACE and restore control of MACE? Please comment.

- Methods 3. Porcine gastric examination... -

Please add a picture or a general schematic of the experiment setup, including the test subject (i.e. the mini-pig) together with the arrangement of all the devices.

- Results 2. Verification of images of the gastric... -

The result in terms of lesion size estimation is not quantitatively sound. Eventually only one set of data was reported and assessed. It would be recommended to perform additional test-bench characterization to quantitatively assess the accuracy of the lesion size estimation.

- Supplementary material -

In S2 Fig, different orientations of MACE were shown, however, it would be really interesting to see a supplementary video of the pose (position and orientation) control of MACE under the guidance of the hand-held controller.

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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.

Gastric examination using a novel three-dimensional magnetically assisted capsule endoscope and a hand-held magnetic controller: A porcine model study.

PONE-D-20-31353R2

Dear Dr. LIM,

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.

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Kind regards,

Edoardo Sinibaldi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

The manuscript was improved by leveraging the raised comments.

Reviewers' comments: