Complementary Metal Oxide Semiconductor-Based Optical Detection System for Fluidic Cellular Medium pH Quantification
, Gabriel M. Ferreira 1,2, Paulo J. Sousa 1,3, PatrÃcia C. Sousa 2, Susana O. Catarino 1,3 and Graça Minas 1,3,*
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsSummary
The manuscript presents a CMOS-based optical detection system for the quantification of pH levels in culture media for organ-on-a-chip (OoC) applications. The authors propose a setup comprising a CMOS photodiode and a PDMS based microchannel to quantify pH variations through optical transmittance at selected wavelengths. The system is suggested to be sensitive and potentially integrable into microfluidic platforms for continuous monitoring of cellular microenvironments.
General Comments
The manuscript addresses an area in organ-on-a-chip development, as monitoring pH is essential for cellular microenvironments and physiological responses. The CMOS-based photodiode integration demonstrates innovation, and the setup's scalability offers applications in real-time OoC monitoring. The experimental methods, however, require clarification in key areas, and the manuscript would benefit from some improvements in presentation. After a thorough review, I recommend a minor revision for this manuscript.
Minor Suggestions and Comments:
· The title should exclude "Organ-on-a-Chip" (OoC) as the system’s suitability for OoC has not been experimentally demonstrated. Instead, consider a more general title that emphasizes CMOS-based pH quantification in cellular media.
· The wavelength selection process should be better justified. Although the chosen wavelengths were experimentally identified, more discussion on their specific relevance to pH sensitivity would strengthen this section. Including a brief explanation of why alternative wavelengths (such as those associated with pH-sensitive dyes) were not considered could also be helpful.
· Authors should add details on how ambient light effects were minimised and how sample preparation was validated are essential for reproducibility.
· I highly suggest having a schematic figure as the first figure to show how the system works for the authors with less expertise in photonics. If the target audience is the researchers in the field of tissue engineering and OOC, the concept should be better shown in figure 1.
· Statistical analyses of the experimental data, including standard deviation or confidence intervals, should be added. This must be added to the figures such as Figure 2. This would validate the reliability and sensitivity of the proposed system.
· Figures are crucial for understanding the setup and results, yet the current quality makes interpretation difficult. All figures, particularly Figures 1 and 2, need higher resolution, clearer labeling, and improved contrast to ensure data and structural details are easily visible.
· The manuscript would benefit from a more detailed discussion of the limitations of the current system.
· The Conclusion could be expanded to include potential applications beyond OoC, as CMOS-based pH sensors may have broader applications in bioprocess monitoring and point-of-care diagnostics.
· There are several grammatical errors and instances of ambiguous phrasing. For example, ensure consistent tense throughout by using past tense (e.g., "This work proposed...") for completed experiments, while present tense can describe general conclusions or scientific principles. There are more sentences that requires improvements as follows:
o “It was achieved a resolution of 0.002 nA in the linear range of 30 pA to 3800 nA.”
o “It was observed that the transmittance varies according to the pH of the medium.” Switch to active voice where possible improves readability
o The CMOS process doping variations can be avoided with an initial calibration. (Awkward phrasing)
Comments on the Quality of English LanguagePlease refer to the report
Author Response
In the Answers to Reviewer1.pdf file
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThis work reported a miniaturized optical detection system by using optical transmittance principles. The proposed idea is novel, but there are some issues need to be addressed.
1. The section '2. Optical detection system design' and '3. Microsystem fabrication' should be merged as one section 'Materials and Methods'.
2. The Figure 4, Figure 5 and Figure 6 should be merged as one figure. The new figure will include older figure 4-6 as subfigures.
3. The authors claimed that '...showing potential to be integrated into an Organ-on-a-chip device'. However, the authors didn't show any results regarding to organ-on-a-chip models, such as vessel-on-a-chip and tumor-on-a-chip etc. In my view, it should present the adaptability of measuring pH in such real organ-on-a-chip models.
4. The conclusion seems redundant. Some contents should be discussed in Discussion section.
Author Response
In the Answers to Reviewer2.pdf file
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsAs the authors have stated, Organ-on-a-chip is an emerging biomedical engineering technology, and real-time monitoring of the culture medium's pH value is crucial. This article introduces a miniaturized optical detection system developed based on CMOS technology for quantifying the pH levels of endothelial cell culture medium. The innovative optical microsystem provides significant technical support for the application of organ-on-a-chip systems. I have some comments as followed, before considering this work for publishing.
1. There are some very basic spelling errors in the text that need to be corrected. For example, the "t" on line 61 should be "to", the phrase "shows the potential of miniturized system to detect and diferentiate the…" on line 316 contains two misspelled words, and the word "transmittaces" on line 322 should be changed to "transmittance". And there are also two spelling mistakes on line 174. Please carefully check if there are any more such simple errors in the text.
2. In page 4 line 149, “an current-to-frequency” or “a current-to-frequency”. In line 109, the abbreviation for Hydrochloric acid is HCl. In line 164, "VCap" as a proper noun for voltage does not require quotation marks. Please carefully check the text again for such basic errors.
3. I think that the neatness of the figures in the article are fundamental requirements, but the overall layout of the figures in this paper is too casual. For example, the two graphs in Figure 1 don’t have aligned axes, and the font sizes are inconsistent. Additionally, Figure 10 is unnecessarily split across different pages, Figure 12 is asymmetrical, and there are issues with most of the figures in the paper. Please make the necessary corrections to improve the article.
4. In section 2.1, would it be better to present a test schematic first, rather than starting directly with the data?
5. In section 3, since it is a microsystem, shouldn't you provide me with an overall connection or schematic diagram of the system, rather than individual unit images for me to comprehend?
6. More comparisons with existing optical sensors are helpful or necessary to prove the characteristics, advantages and novelty of the devices and systems in this work. For example but not limited to, Electronics 2024, 13(4), 691; Biosensors and Bioelectronics 237, 115477; Micromachines 2024, 15(11), 1320; Mater. Horiz., 1782-1789; Mater Today Bio. 2023, 22:100764; Sensors and Actuators B: Chemical 290, 2019, 285-292.
Author Response
In the Answers to Reviewer3.pdf file
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe current version seems good enough to be accepted.
Author Response
Dear Reviewer #2,
The current version seems good enough to be accepted. We thanks your positive comment. Best regards, Graça MinasReviewer 3 Report
Comments and Suggestions for AuthorsI am not sure the novelty or special merits of this work. The authors' comments on the potential and applications are based on review papers tens of years ago.
Author Response
Answers in Answer to Reviewer3-R2.pdf file
Author Response File: Author Response.pdf
