Organs-on-Chips: Revolutionizing Biomedical Research

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a timely and relevant review of the emerging field of merging AI and OOC technology in a very concise fashion. The manuscript in its present form could improve in significance and organization in parts of the manuscript as highlighted below:

Page 2, paragraph on "Organ-on-Chip technology" suggests that OOC devices "significantly reduces time and cost associated with traditional trial- and error methods"; this statement is too general and dismissed the systematic approach applied to animal models and other in vitro tests next to OOC. Please reflect accordingly or explain specifically what is meant with "trial and error" in this context.

Page 3 (top) states in the paragraph on "3D Modelling..."  "cells on the silicon processor; please add context and the appropriate reference to what type of silicon processors is meant. Or simply state "a silicon processor" instead of "the silicon processor". In the same paragraph there is a general statement made about "personalized medicine" in general but in the conclusion this opportunity of following via OOC technology a personalized approach is reduced to "cancer medicine/research". Please make sure that the approach of personalized medicine is well introduced, explained and cited throughout all the discussed models as well as concluded in the Conclusion section in a fashion that reflects on such opportunity in more general terms rather than limiting it to "cancer".

Same page, section on  "Integrating AI with OOC Technology": The sentence "Through AI-powered image analysis, the impact of drugs on cells can be measured with greater precision, ...." all statements of this sentence needs appropriate references to be cited. Furthermore, please explain for the statement on "AI can reduce the number of physical tests, cutting down expenses and time" in more detail how this is achieved specifically since AI models also require investment etc. Ideally, this statement is supported by a better understanding on cost drivers. And also align the final statement on page 3 with additional explanations after reviewing the state-of-the-art in developing AI for OOCs for personalized medicine.

Page 4- top: Authors refer to "require specialized skills" and "data privacy and security": please add information on the type of skills including appropriate citation and with regard to privacy and security please add also the concern on "predictability" as it is yet highly uncertain how testing with OOC (even when AI is utilized for data analysis and interpretation) adds to predictability of drug efficacy (and safety). 

Also on page 4 the authors start at the bottom of the page reviewing Organ-on-Chip models. It is noticed that not all examples are given with clear visuals. Some Figures appear randomly selected like on page 5, Fig. 2 does not demonstrate "connectivity of heart with other organs", for example; hence, this is somewhat misleading. The Figures 2-5 show only a certain type of OOC, the ones with top and bottom microfluidic channels being separated by a membrane, whereas this is one specific OOC technology, the manuscript title and Abstract/Introduction does not reveal to be concerned only with this specific design. Please check carefully what is the rationale of the review and either provide more varied OOC examples as visuals in the Figures or change the title and introduction text accordingly; as also Table 1 on page 8 seems to acknowledge only OOCs as devices being separated by a membrane; which is somehow misleading as OOC technology can have many other geometric arrangements, too.

In terms of organization, the reader may also wonder why only providing visuals for some of the OOC models but not all of the ones discussed? Maybe one Figure with a several panels providing and overview of examples of devices would be more appropriate to showcase what is all possible.

Page 8: Figure 6 does not related to "Skin-on-Chip"; why it is positioned there?Please check, what your intentions of showing Fig. 6 are and reposition where appropriate to align with the main text.

Same page (P. 8), Table 1: with regard to "History", why does it state: "Emulate Organ-Chips"; do authors mean that the "publications relate to emulating organs on a chip"? What does "They" in "and they are used by" refers to in the same line on "History; check context, please. Now, it reads like that "the publications are used by leading pharmaceutical companies,... "

As already mentioned above, the "how it works" in Table 1 seems to relate only to the microfluidics that applies a membrane in between the channels. Also, what do the authors mean with "cyclic fluid flow"? Also non-cyclic flow can provide shear to cells; and not all devices apply "cyclic" flows. Please balance this statement accordingly,

Finally, the table shows "disadvantages"; what is meant by the authors with "longevity" in this context of using OOCs? Please clarify, as obviously, cultured OOCs could run for a long time, too.

Page 9, paragraph on Commercialization and Challenges: Please correct the sentence where it is referred to Table 1. The table does not include information on "assessment".

Further on the same page (P.9) the authors keep adding new information to the Conclusions not yet discussed in the main text, like: "nanotherapeutics", "enabling precise monitoring of cellular responses" or different types of tissues without references. Please introduce "additional organs like adipose, retina and placenta (and potential others) in a appropriate discussion or in the main text in the appropriate context of the models introduced in this review and provide the appropriate references or remove these statements from the conclusions.

 

 

 

Author Response

Reviewer 1 Comments and Authors' Response

1. On "trial-and-error methods" (Page 2):

Reviewer Comment: The phrase "significantly reduces time and cost associated with traditional trial-and-error methods" is too general.

Response: Revised to clarify that while traditional methods like animal models and in vitro tests are systematic, they often require multiple cycles due to species-specific variations. OoCs reduce this by enabling early human-relevant data collection (Page 2, Introduction).

 

2. On "the silicon processor" in 3D Modelling section (Page 3):

Reviewer Comment: The term “the silicon processor” lacks context; suggestion to add clarity or revise.

Response: Revised to “chips constructed on a silicon processor, a broad term that denotes microfabricated substrates constructed out of silicon or other materials” for clarity and supported with citation (Page 3).

 

3. On limiting personalized medicine to cancer in Conclusion:

Reviewer Comment: Generalized personalized medicine must be discussed throughout, not limited to cancer.

Response: Expanded personalized medicine discussion in both the main body (cardiology, neurology, respiratory, metabolic disease examples) and Conclusion to reflect broader applicability (Page 4 & Conclusion section).

 

4. On AI statement lacking citations and detail (Page 3):

Reviewer Comment: Claims like “AI reduces number of physical tests…” need detail and citation.

Response: Added detailed explanation on in silico modeling, predictive simulations, cost breakdown, and specific AI models (CNNs), supported by relevant citations (Page 4).

 

5. On specialized skills and data privacy (Page 4):

Reviewer Comment: Please specify skills and discuss predictability as an additional concern.

Response: Expanded section to specify skills (biomedical engineering, microfabrication, AI programming) and included “predictability” concerns with validation challenges of OoC results (Page 6).

 

6. On Figures and Table 1 clarity (Pages 5–8):

Reviewer Comment: Figures misleadingly represent only one OoC format; visuals should be more varied or revise title/scope.

Response: Revised figure captions for clarity and added explanatory text. Addressed diversity of OoC models within the text (e.g., cardiac, bone marrow, BBB, gut) to balance perspective (Pages 5–8). Table 1 language also revised for clarity (“cyclic flow,” “longevity,” and “Emulate Organ-Chips”) (Page 8).

 

7. On Figure 6 misplacement (Page 8):

Reviewer Comment: Figure 6 does not relate to “Skin-on-Chip.”

Response: Figure has been repositioned appropriately and caption aligned with the skin-on-chip section (Page 8).

 

8. On unclear language in Table 1 - “Emulate Organ-Chips” and “they are used by…”

Reviewer Comment: Unclear subject in “History” row.

Response: Reworded to: “Organ-Chip technology has been advanced by companies such as Emulate Inc., and their chips are now used by major pharmaceutical companies...” for clarity (Table 1).

 

9. On Conclusion introducing new ideas (Page 9):

Reviewer Comment: Avoid introducing terms like “nanotherapeutics,” “retina,” “placenta” without support.

Response: These terms are now discussed earlier in the text with context, appropriate examples, and citations (e.g., retina, adipose, placenta organs mentioned in future direction section and backed with references) (Conclusion).

Reviewer 2 Report

Comments and Suggestions for Authors

Manuscript ID: biophysica-3723899 

Title: Organs-on-Chips: Revolutionizing Biomedical Research

Comment: Reject

Organs-on-Chips (OoC) technology has begun to be considered a pragmatic tool for drug evaluation, offering researchers an opportunity to move beyond the less physiologically relevant animal models. This article focuses on the current state and future significance of OoC technology, the integration of OoC with AI, and biomedical research advancements and applications of OoC models. There are some problems in this review. Each part was not deeply reviewed, just a superficial list of the contents. The manuscript should be rejected.

Other details are as follows:

1. Abstract does not summarize the contents of this review, there is an excessive description of the combination of OoC and AI, while the advancements and applications in biomedical researchof  OoC and other related contents of this article are not mentioned.
2. “Integrating AI with Organ-on-a-Chip Technology”lacks specific application and corresponding comments.
3. “Organ-on-a-Chip Models: Advancements and Applications in Biomedical Research”merely lists each type of OoC, but fails to provide detailed description of their application in biomedical research.
4. “Commercialization and Challenges of Organ-on-a-Chip Technology”dose not introduce the application examples of commercially available OoC.
5. The references are not enough and more related papers on this topic should be added to enrich this manuscript. 

Comments on the Quality of English Language

In its current state, the level of English throughout the manuscript does not meet the journal’s required standard. The authors may wish to ask a native speaker to check the whole manuscript for grammar, style and syntax

Author Response

Reviewer 2 Comments and Authors' Response

1. General Recommendation: Reject due to superficial review and weak organization.

Response: Major restructuring and expansion have been implemented:

• Each section now includes detailed applications of OoC in biomedical research.
• AI-OoC integration is described with specific mechanisms and citations.
• Commercially available OoC examples (e.g., Emulate, Mimetas) are added.

 

2. On Abstract lacking complete summary and overemphasizing AI:

Response: Abstract has been revised to balance focus between OoC, AI, and applications. Biomedical research applications, limitations, and commercialization aspects now explicitly mentioned.

 

3. On “Integrating AI…” lacking applications:

Response: Section now includes examples of CNNs for image analysis, real-time feedback control, predictive modeling of cell response, and multi-omics integration (Page 4–5).

 

4. On superficial listing in “OoC Models…” section:

Response: Each model (Heart, Liver, Gut, Lung, etc.) now includes detailed functions, mechanisms, and specific biomedical applications with citations (Pages 5–7).

 

5. On missing discussion of commercial OoCs in “Commercialization…”

Response: Section now includes companies like Emulate, InSphero, Mimetas with funding details and use cases (Page 8).

 

6. On insufficient references:

Response: Reference list expanded significantly (now includes over 40 references), with sources from Nature, Frontiers, MDPI, etc., supporting all key claims throughout the manuscript.

 

7. English Language Concerns:

Response: The manuscript has been carefully revised for clarity, grammar, and fluency by multiple authors and further checked using language editing tools to meet publication standards.

 

The Authors thank the Reviewers for their valuable time and reviews of our Article Submission. We sincerely hope that our revised submission is of satisfaction to the esteemed reviewer’s.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript has been revised according to the comments of the referees. In my opinion, this manuscript can be published in its present form.

Comments on the Quality of English Language

The manuscript has been revised according to the comments of the referees. In my opinion, this manuscript can be published in its present form.