A Novel, Low-Cost, 3D-Printed Motorized Injector for Retinal Sheet Transplantation

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article by Lim and colleagues, entitled “A Novel Motorized Injector for Subretinal Transplantation,” introduces a motorized retinal sheet injector that enhances stability and placement accuracy compared to manual methods for subretinal cell or tissue delivery. The concept and design of this instrument are not only innovative but also represent an important advancement with potential applications in human subretinal injection procedures. Therefore, the work demonstrates high overall merit and is likely to be of significant interest to readers; however, there are some issues that are mentioned below. 

Major notes

Title is clear but could emphasize the novelty and cost-efficiency: e.g., “Low-Cost, 3D-Printed Motorized Injector for Retinal Sheet Transplantation”.

Abstract is well written but slightly long; consider shortening sentences for clarity and impact. Also, it is not necessary to detail statistical and background information here, only in the results.

Add a sentence on potential clinical implications in the abstract.

In the Intro, provide a brief comparison of existing manual injectors vs robotic systems earlier in the introduction.

Clarify why 3D printing and Arduino were chosen (cost, accessibility).

Ensure all figures have high resolution and a consistent font size. Some of the figure captions are barely visible, including: Fig2D, 6A,B.

Add scale bars where it is needed in Figures 2–4, 7

Figure captions should be more self-explanatory (currently, some rely on text).

In  Methods, include details on calibration of actuator speeds, sizes (image vs. track), and if safety limits were presented.

Specify the statistical software used for ANOVA and F-tests, and generally add more details about statistical validation and significance levels.

Clarify and justify sample sizes, also put them where they are needed in the figures. A side-by-side comparison is basically not possible based on Fig.6 A -B due to track visibility issues. 

In results, add confidence intervals for the accuracy percentages.

Include sample and effect sizes for ANOVA results.

In the discussion, expand on limitations: e.g., lack of in vivo validation, learning curve for surgeons.

It may be a valuable future insight to suggest integrating robotic platforms or utilizing AI-assisted positioning.

In References, check consistency in formatting (some references lack DOI spacing).

Ensure all cited patents and devices are properly referenced to avoid future problems.

Corrections & Minor Edits

Abstract

“three discrete actuator positions (‘min’, ‘mid’, ‘max’)” → capitalize consistently: Min, Mid, Max.

“p<10⁻¹¹” → use standard format: p < 1 × 10⁻¹¹.

Introduction

“retinitis pigmentosa—results” → replace em dash with comma: retinitis pigmentosa, results.

Remove the stray period after “Figure 1.”

Methods

“dimensions of the assembly is shown” → are shown.

“heat-shrinkable fluorinated ethylene propylene (FEP) nozzle is loosely fitted over the nozzle” → clarify: FEP tubing loosely fitted over the mandrel.

Results

“manual trials recorded 0% accuracy” → consider rephrasing: Some manual trials resulted in complete misplacement (0% overlap).

Discussion

“nears the limit of human physiological tremor” → approaches the limit.

“Our device will not eliminate tremor entirely but aims to reduce unnecessary movements” → While tremor cannot be fully eliminated, the device significantly reduces unintended movements.

Tables & Abbreviations, Other

“Linear dichroismh” → typo: should be Linear dichroism or remove if irrelevant.

 

Use SI units with spaces (e.g., 0.7 × 1.2 mm, not 0.7x1.2mm).

Author Response

Comments 1: Title is clear but could emphasize the novelty and cost-efficiency: e.g., “Low-Cost, 3D-Printed Motorized Injector for Retinal Sheet Transplantation”. 

Response 1: Thank you for this suggestion. We agree that the proposed title is a better descriptor of our device, and we have updated the title as such. 

 

Comments 2: Add a sentence on potential clinical implications in the abstract. 

Response 2 : Thank you for this note. We have included a sentence at the end of the abstract indicating the potential clinical impact of our injector. 

 

Comments 3: Abstract is well written but slightly long; consider shortening sentences for clarity and impact. Also, it is not necessary to detail statistical and background information here, only in the results. 

Response 3:Thank you for this suggestion. We have removed the statistical and background information and have made the abstract more concise. 

 

Comments 4: In the Intro, provide a brief comparison of existing manual injectors vs robotic systems earlier in the introduction. 

Response 4: We would like to thank the reviewers for this suggestion. We would like to keep the comparison in the discussion rather than the introduction, as we believe that it may lead the reader to expect a head-to-head study on these existing systems, but we do not have access to them. 

 

Comments 5: Clarify why 3D printing and Arduino were chosen (cost, accessibility). 

Response 5: Thank you for this point. We have inserted a statement at the end of the introduction indicating our justification for using 3D printing and Arduino. 

 

Comments 6: Ensure all figures have high resolution and a consistent font size. Some of the figure captions are barely visible, including: Fig2D, 6A,B. 

Response 6: Thank you for this note. We have worked on improving the quality of all of our figures, and have made inserted figure captions with more consistent sizing. 

 

Comments 7: Add scale bars where it is needed in Figures 2–4, 7 

Response 7: Thank you for this note. Scale bars have been added in the figures as appropriate. 

 

Comments 8: Figure captions should be more self-explanatory (currently, some rely on text). 

Response 8: Thank you for this point. We have edited the figure captions to be more clear and self-explanatory. 

 

Comments 9: In Methods, include details on calibration of actuator speeds, sizes (image vs. track), and if safety limits were presented. 

Response 9: Thank you for this note. We agree with this change and have included a paragraph in the methods section including the details of the actuator. 

 

Comments 10: Specify the statistical software used for ANOVA and F-tests, and generally add more details about statistical validation and significance levels. 

Response 10: Thank you for this note. We have used Microsoft Excel to perform our statistical analyses and have included a statement reflecting this. 

 

Comments 11: Clarify and justify sample sizes, also put them where they are needed in the figures. A side-by-side comparison is basically not possible based on Fig.6 A -B due to track visibility issues. 

Response 11: Thank you for this point. We have adjusted the figures as appropriate, and in particular, have color coded Fig. 6 A and B to be color coded to better show the tracks. 

 

Comments 12: In results, add confidence intervals for the accuracy percentages. 

Response 12: Thank you for this point. We have added the 95th percent confidence intervals for the accuracy percentages. 

 

Comments 13: Include sample and effect sizes for ANOVA results. 

Response 13: Thank you for this point. We have calculated and included the sample size, eta squared, and Cohen’s d values for our ANOVA test. 

 

Comments 14: In the discussion, expand on limitations: e.g., lack of in vivo validation, learning curve for surgeons. 

Response 14: Thank you for this point. We have a paragraph dedicated to the limitations at the end of the discussion: 

 

“Despite these promising results, there are several limitations. The study was conducted with only four participants, and the in vitro model may not fully replicate in vivo conditions. Additionally, operator variability and learning effects were not comprehensively addressed, and the clinical relevance of the measured parameters requires further validation in animal models. While the device is currently designed for rodent transplantation, its modular construction with swappable parts allows for future scaling to human application. 

 

Comments 15: It may be a valuable future insight to suggest integrating robotic platforms or utilizing AI-assisted positioning. 

Response 15: Thank you for this point; we agree that integration with AI and robotic platforms would be valuable in future iterations of our device. We have included a statement on this in the conclusion. 

 

Comments 16: In References, check consistency in formatting (some references lack DOI spacing). 

Response 16: Thank you for this note. We have checked the references section to ensure consistent formatting throughout. 

 

Comments 17:Ensure all cited patents and devices are properly referenced to avoid future problems. 

Response 17: Thank you for this note. We have ensured that the patented Aramant and Seiler injector is referenced appropriately in the manuscript. 

 

Comments 18: 

Abstract 

“three discrete actuator positions (‘min’, ‘mid’, ‘max’)” → capitalize consistently: Min, Mid, Max. 

“p<10⁻¹¹” → use standard format: p < 1 × 10⁻¹¹. 

 

Introduction 

“retinitis pigmentosa—results” → replace em dash with comma: retinitis pigmentosa, results. 

Remove the stray period after “Figure 1.” 

Methods 

“dimensions of the assembly is shown” → are shown. 

“heat-shrinkable fluorinated ethylene propylene (FEP) nozzle is loosely fitted over the nozzle” → clarify: FEP tubing loosely fitted over the mandrel. 

Results 

“manual trials recorded 0% accuracy” → consider rephrasing: Some manual trials resulted in complete misplacement (0% overlap). 

Discussion 

“nears the limit of human physiological tremor” → approaches the limit. 

“Our device will not eliminate tremor entirely but aims to reduce unnecessary movements” → While tremor cannot be fully eliminated, the device significantly reduces unintended movements. 

Tables & Abbreviations, Other 

“Linear dichroismh” → typo: should be Linear dichroism or remove if irrelevant. 

Use SI units with spaces (e.g., 0.7 × 1.2 mm, not 0.7x1.2mm). 

Comments 18: Thank you for noting these grammatical errors. We agree with the recommendations and have made changes in the manuscript body as suggested 

Reviewer 2 Report

Comments and Suggestions for Authors

Overall, the development of an implantation device for RPE cell sheet transplantation is critically important, especially given the absence of commercially available instruments for this purpose. Currently, ongoing clinical trials rely on devices individually developed and patented by various research groups. This manuscript presents a modified implantation device that extends the innovations previously developed by Seiler's team. From a technical perspective, the described motorized injector represents a significant improvement over their earlier patented instrument, offering enhanced placement accuracy and operational stability.

However, it should be noted that all validation in this manuscript was performed in vitro, and further in vivo studies are necessary to establish the device’s clinical utility, particularly with a direct, head-to-head comparison to their previously developed instruments. In addition, while current implantation devices are designed for implants measuring at least 3 mm by 6 mm to sufficiently cover the macular region, the present device accommodates only 0.7 x 1.2 mm tissue, which may be inadequate for macular coverage. Furthermore, Figure 1 in the manuscript is not appropriate, as the information it presents has already been published previously.

Author Response

Comments 1: Overall, the development of an implantation device for RPE cell sheet transplantation is critically important, especially given the absence of commercially available instruments for this purpose. Currently, ongoing clinical trials rely on devices individually developed and patented by various research groups. This manuscript presents a modified implantation device that extends the innovations previously developed by Seiler's team. From a technical perspective, the described motorized injector represents a significant improvement over their earlier patented instrument, offering enhanced placement accuracy and operational stability. 

However, it should be noted that all validation in this manuscript was performed in vitro, and further in vivo studies are necessary to establish the device’s clinical utility, particularly with a direct, head-to-head comparison to their previously developed instruments. In addition, while current implantation devices are designed for implants measuring at least 3 mm by 6 mm to sufficiently cover the macular region, the present device accommodates only 0.7 x 1.2 mm tissue, which may be inadequate for macular coverage. Furthermore, Figure 1 in the manuscript is not appropriate, as the information it presents has already been published previously. 

 

Reponse 1: Thank you for this point. We agree that further in vivo studies are necessary to establish our device’s clinical utility. In addition, our current device does accommodate 0.7 x 1.2mm tissue, as early iterations of in vivo testing are to be conducted in rat models. However, because our device is modular, it can be easily adaepted to different sizes by redesigning and swapping injector tips to accommodate larger 3 x 6mm implants. Furthermore, we believe figure 1 serves as a crucial part of our manuscript, as it establishes the necessary background needed for comparing existing methods with our novel device. 

 

Reviewer 3 Report

Comments and Suggestions for Authors

This paper reported the novel motorized retinal sheet injector markedly improves stability and placement accuracy relative to manual methods, potentially reducing complications associated with subretinal delivery.  However, this paper can be accept after it needs the following revison.

1. The authors should show the process of making the motorized injector.
2. The accuracy of motorized injector should compare with reported injector for showing its advantages.
3. The quality of figures should be improved, such as Figure 6, Figure 7.
4.  The title of paper is missing.
5. The tense of this manuscript should be checked.

Author Response

Comments 1: The authors should show the process of making the motorized injector. 

Response 1: We thank you for this point. We do describe individual components, CAD design files, show exploded view and assembly components in Figures 2-4. If this is insufficient, can you please elaborate further? 

 

Comments 2: The accuracy of motorized injector should compare with reported injector for showing its advantages. 

Response 2: Thank you for this point. The two accuracy percentages presented in our paper compare motorized and manual methods, and current methods 

 

Comments 3: The quality of figures should be improved, such as Figure 6, Figure 7. 

Response 3: Thank you for this point. We have worked on improving the quality of all of our figures, especially figures 6 and 7 

 

Comments 4: The title of paper is missing. 

Response 4: Thank you for this point. We believe there may have been issues in the file formatting, but the title of the manuscript is now included. 

 

Comments 5: The tense of this manuscript should be checked. 

Response 5: Thank you for noting this, we have made grammatical changes throughout the manuscript.