Training the Next Generation of Researchers in the Organ-on-Chip Field

Round 1

Reviewer 1 Report

This paper explains

Organ-on-chip (OoC) technology bridges the principles of biology and engineering to create a new generation of in vitro models and involves highly interdisciplinary collaboration across STEM disciplines. Training the next generation of scientists, technicians and policy makers is a challenge that requires a tailored effort. To promote the qualification, usability, uptake and long-term development of OoC technology, we designed a questionnaire to evaluate the key aspects for training, identify the major stakeholders to be trained, their professional level and specific skillset. The 151 respondents unanimously agreed on the need to train the next generation of OoC researchers and that the training should be provided early, in interdisciplinary subjects and throughout the researchers’ career. We identified two key training priorities: (i) training scientists with a biology background in microfabrication and microfluidics principles and (ii) training OoC developers in pharmacology/toxicology. This makes training in OoC a transdisciplinary challenge rather than an interdisciplinary one. The data acquired and analyzed here serves to guide training initiatives for preparing competent and transdisciplinary researchers, capable of assuring the successful development and application of OoC technologies in academic research, pharmaceutical/chemical/cosmetic industries, personalized medicine and clinical trials on chip.

Overall paper is looking good however the following concerns need to be addressed properly

1.      The paper is looking very short and needs to add more data

2.      Supplementary files are missing I could not find them on the submission page and also on the link provided in the supplementary materials

 

 

 

Author Response

Point 1: The paper is looking very short and needs to add more data

 

Response 1: We present a manuscript with 6 Figures and 16 pages in the final format. Due to the lack of specifc suggestions, we evaluated the answers to the review form and addresed the following “must be improved” items:

 

Are all the cited references relevant to the research?/ Is the article adequately referenced?

References were included following Reviewer 2 and Reviewer 3 comments:

19. Choi, B.C.K.; Pak, A.W.P. Multidisciplinarity, Interdisciplinarity and Transdisciplinarity in Health Research, Services, Education and Policy: 1. Definitions, Objectives, and Evidence of Effectiveness. Clin Invest Med 2006, 29, 351–364.
20. Velez, A.-L.; Hall, R.P.; Lewis, S.N. Designing Transdisciplinarity: Exploring Institutional Drivers and Barriers to Collaborative Transdisciplinary Teaching. Journal of Public Affairs Education 2022, 28, 138–155, doi:10.1080/15236803.2021.1992196.
21. Rogal, J.; Schlünder, K.; Loskill, P. Developer’s Guide to an Organ-on-Chip Model. ACS Biomater. Sci. Eng. 2022, 8, 4643–4647, doi:10.1021/acsbiomaterials.1c01536.
22. Fuchs, S.; Johansson, S.; Tjell, A.Ø.; Werr, G.; Mayr, T.; Tenje, M. In-Line Analysis of Organ-on-Chip Systems with Sensors: Integration, Fabrication, Challenges, and Potential. ACS Biomater Sci Eng 2021, 7, 2926–2948, doi:10.1021/acsbiomaterials.0c01110.
23. Zhou, L.; Liu, L.; Chang, M.A.; Ma, C.; Chen, W.; Chen, P. Spatiotemporal Dissection of Tumor Microenvironment via In-Situ Sensing and Monitoring in Tumor-on-a-Chip. Biosensors and Bioelectronics 2023, 115064, doi:10.1016/j.bios.2023.115064.

Are the arguments and discussion of findings coherent, balanced and compelling?

The discussion was improved following Reviewer 2 comments, Points 5 and 6.

For empirical research, are the results clearly presented?

Figure 1 was changed and the text of the results section as edited following Reviewer 2 comments, Points 2, 3 and 4.

Are the conclusions thoroughly supported by the results presented in the article or referenced in secondary literature?

The discussion was improved following Reviewer 2 comments to highlight the study limitations and possible implication of the low number of respondents on the conclusions, see Point 5.

 

Point 2: Supplementary files are missing I could not find them on the submission page and also on the link provided in the supplementary materials

 

Response 2: We contacted the editorial office that assure to make the Supplementary material available for the reviewers.

Reviewer 2 Report

The article "Training the next generation of researchers in the Organ-on-Chip field"  with the educational specialities and needs within this highly multidisciplinary field. The manuscript uses data from a survey to identify key aspects that need special attention when educating young researchers in the field of Organ-on-a-Chip. Albeit this relative young discipline is on the way of beeing firmly established in academia, industry and the work of regulatory institutions, there are only few initiatives that try provide tailored education to researchers. Here, the presented manuscript tries to fill knowledge gaps in terms of identifying educational needs. I therefore regard the content of this paper of high relevance and want to advocate its publication after minor revision.  

The following aspects should be adressed for revision

- the first paragraph (line 22- 45) in the introduction feels a bit redundant here and there; for example: the potential role of OoCs in 3Rs is mentioned twice (line 30/31 and line 45), the paragraph might be shortened to line out the specifics of the OoC field in a more precise and clear manner without redundancies

 - the circle Diagram in Figure 1a should be replaced by a bar-diagram, similar to the other data presented

- data is sometimes presented in absolute numbers (x/y) or percentages (x%), this seems to be a bit confusing and makes it hard to compare findings, the authors might decide for one way to present their data instead of using both possibilities, alternatively data might be presented in a stringent way in the text and then also summarized in both, absolute numbers and percentages, in a table for better transparancy

- the academic background and familiarity with different disciplines of the survey participants is provided rather late in the text (Figure 5 and 6), yet the participants themselves provide part of the context for the evaluation of the answers given in the survey (as stated by the authors themselves in line 340-341), I would therefore recommend to start with the data on the participants and then present their answers. Or to use an analogy: I would start with the patient data before presenting the data of the clinical survey

- the discussion should clearly adress the study limitations in a brief paragraph (realtively low nr. of participants, recruitment, possible bias by different number of participants from academics and NAI) and discuss the meaning of the presented data in light of these

- the terms multidisciplinarity, transdisciplinarity and interdisciplinarity are used quite frequently, especially to adress special educational needs of OoC research, therefore the underlying concepts seem to be important for understanding the manuscript and its core statements, yet these terms are not defined/explained within in the manuscript only a reference is given, I would like to recommend to precisly define each term for the reader to allow for complete recapitulation of the surveys' implications

- in line 489: the sentence seems to be a missing bullet point!?!

 

Author Response

Point 1: the first paragraph (line 22- 45) in the introduction feels a bit redundant here and there; for example: the potential role of OoCs in 3Rs is mentioned twice (line 30/31 and line 45), the paragraph might be shortened to line out the specifics of the OoC field in a more precise and clear manner without redundancies

Response 1: We thank the reviewer comment. We removed the refence to 3Rs in line 45 and edited the text in lines 39-40 of the revised manuscript as follows:

The technology promises great potential for human-based translational [2] and personalized medicine [3] for the reduction of pharmaceutical R&D costs [4,5] and, through the generation of mechanistic knowledge, can be a game-changer towards the 3Rs and the transition to non-animal science [6,7]

 

Point 2: the circle Diagram in Figure 1a should be replaced by a bar-diagram, similar to the other data presented

Response 2: The diagram was transformed as suggested.

 

Point 3: data is sometimes presented in absolute numbers (x/y) or percentages (x%), this seems to be a bit confusing and makes it hard to compare findings, the authors might decide for one way to present their data instead of using both possibilities, alternatively data might be presented in a stringent way in the text and then also summarized in both, absolute numbers and percentages, in a table for better transparancy

 

Response 3: For transparency, we present all data in absolute and relative values in the supplementary materials. In the figures, we only present absolute numbers and always include the number of respondents of each subgroup in both methods section and respective figure. We agree with this point and edited the 1st and 2nd paragraphs of results subsection 3.2 and the 2nd paragraph of results subsection 3.3, by presenting “%” instead of (x/y) proportion of responses/respondents in the text, refering to the data of Figure 2, now Figure 4 as well as Figure 4b, now Figure 6b. We did not change the third paragraph refering to Figure 3, now Figure 5, because we consider it important to show the cut-off values in the same scale as in the figure, i.e., 1-5 instead of %.

 

Point 4: the academic background and familiarity with different disciplines of the survey participants is provided rather late in the text (Figure 5 and 6), yet the participants themselves provide part of the context for the evaluation of the answers given in the survey (as stated by the authors themselves in line 340-341), I would therefore recommend to start with the data on the participants and then present their answers. Or to use an analogy: I would start with the patient data before presenting the data of the clinical survey

 

Response 4: We moved the text refering to figures 5 and 6 to the end of the first results subsection. Accordingly, Figure 5 is now 2, Figure 6 is Figure 3, Figure 3 is now Figure 5, and Figure 4 is now 6.

 

Point 5: the discussion should clearly adress the study limitations in a brief paragraph (realtively low nr. of participants, recruitment, possible bias by different number of participants from academics and NAI) and discuss the meaning of the presented data in light of these

 

Response 5: The followig paragraph was included in lines 505-520 of the discssion

This work allowed to identify the training priorities, key skill sets and adequate types of training from the perspective of each stakeholder. However, its limitations included the low participant number, primarily caused by the still small number of researchers in this emerging field, and the discrepancy between the number of respondents be-tween some groups, e.g., academia and NAI. Recruiting consisted in social media publications, direct contacting of experts based on their scientific publication record and in the EUROOCs annual meetings in 2019 and 2020 (online). The field is still relatively small, and the number of stakeholders in academia outnumbers the other groups. For this reason, the analysis of the importance of OoC aspects and respective aspects of training in OoC technology to be provided for the various stakeholders is presented based on group specific responses (Figure 3, 4 and 5). The overall stakeholder opinion on the educational level, the amount and the type of courses in which OoC topics should be integrated was selected to better guide the design of future training programs. In this analysis, there is a possible bias towards the opinions of the academic group due to its high representation. Future studies should target more specific training strategies towards the application of OoC technologies in a more mature, diverse and numerous community.

 

Point 6: the terms multidisciplinarity, transdisciplinarity and interdisciplinarity are used quite frequently, especially to adress special educational needs of OoC research, therefore the underlying concepts seem to be important for understanding the manuscript and its core statements, yet these terms are not defined/explained within in the manuscript only a reference is given, I would like to recommend to precisly define each term for the reader to allow for complete recapitulation of the surveys' implications

 

Response 6: We included the definitions in the introduction, now lines 65-69 and as follows:

Choi and Pak, 2006, defined multidisciplinarity by drawing knowledge from different disciplines while staying within each discipline boundaries; interdisciplinarity by linking disciplines; and transdisciplinarity by the integration of disciplines transcending their traditional boundaries [19].

We also reviewed the use of the terms in the whole manuscript and edited the following:

From multi to interdisciplinary:

While most respondents held a bachelor’s degree in basic sciences, such as biochemistry/biology (38%) or engineering (21%), we observed a shift towards interdisciplinary fields for postgraduate studies (Figure 2)

 

And include the following sentence in the discussion (lines 446-452):

This term was however not used or defined in our survey. It would have been in-teresting to further explore the understanding and opinion of the respondents to the importance of integrative transdisciplinary training. Indeed, transdisciplinary training requires innovative approaches, namely, creativity and problem-based learning, for which there is no reference in the literature on OoC specifically and is still a growing approach facing implementation challenges in STEM fields in general [32].

 

Point 7: in line 489: the sentence seems to be a missing bullet point!?!  

 

Response 7: The typo was corrected.

Reviewer 3 Report

The authors present a well though off paper and research, specially by identifying an unmet need for such growing field. 

The authors describe the analyzed results of a targeted questionnaire aimed to experts/ users/ and developers on the OoC field. With conclusions highlighting the need for targeted training in cell/molecular biology and/or microfabrication; depending on the background of the responder. 

The main suggestion that we would like to be discussed on the paper is the concept of "monitoring and analyzing", as this topic on itself cover a range of fields outside of the concluded biological and fabrication training. The authors state that scientists as end-users find it a key aspect that needs training or reinforcement. These references could help with the discussion (https://doi.org/10.1016/j.bios.2023.115064 https://doi.org/10.1016/j.bios.2022.115057) as the filed itself has been looking into several attempts on how to monitor OoC technology. And the technology being developed for it comes more from and electronical and chemical background training. As such we would like to see a further discussion or breakdown of the topic based on the collected data. 

Three minor suggestions, first the aesthetics for the graphs on figure 5 and 6. Figure 5 could be simplified to represent only the most relevant results. And the remaining results be put as a part of the supplementary and reference it there. On figure 6 the same thing could be done, and in addition some of the labeling seems "off" or out of the field they represent. For example, in figure 6a for "Not familiar with any" the number 5 is out of the aqua frame. 

Second, with still focus on figure 6. There is really little discussion about the "biological system" the participants reported. We will either like to read a further discussion on this, especially with focus between academic and NAI respondents. Or for the topic to be discussed as a narrow down of the type of biological training every stakeholder should focus on. 

Third, the authors state the term "transdisciplinary" in the abstract, yet there is only mention of the topic on the discussion with a single reference (Takeuchi 2020). We strongly believe the authors do not need to focus on emphasis on this term, as the presented data and discussion clearly states that the field is interdisciplinary at all the stages. And so, we highly encourage the topic of interdisciplinary to be the main take home message, with a focus on bioengineering as the pilar of training. As this field is one of the few that really reflects such concept.        

Author Response

Point 1: The main suggestion that we would like to be discussed on the paper is the concept of "monitoring and analyzing", as this topic on itself cover a range of fields outside of the concluded biological and fabrication training. The authors state that scientists as end-users find it a key aspect that needs training or reinforcement. These references could help with the discussion (https://doi.org/10.1016/j.bios.2023.115064 https://doi.org/10.1016/j.bios.2022.115057) as the filed itself has been looking into several attempts on how to monitor OoC technology. And the technology being developed for it comes more from and electronical and chemical background training. As such we would like to see a further discussion or breakdown of the topic based on the collected data. 

 

Response 1: We agree that “monitoring and analyzing” is a very broad topic, covering effluent analysis, live microscopy imaging, 3D imaging, sensors and post processing and all are in rapid development in OoC models. It is of utmost importance to consider this on OoC design stage, to assure that the methods are compatible with the properties of the system, e.g., optical transparency is essential for live microscopy monitoring, and some understanding of electronical and chemical fields is relevant and this point was not mentioned in the discussion. Sensor integration is a very good example on design and microfabrication constrains. We included the following paragraph in the discussion (lines 478-483 of the revised manuscript) on this topic towards chip design considerations and 3 relevant references:

Also, monitoring and analyzing, was particularly highlighted by respondents with interdisciplinary expertise and PhD candidates possibly reflecting the importance of considering the biological endpoints at the stage of OoC design and development as well as the diversity of skills required to analyze the data covering physics, chemistry, molecular biology expertise, among others [35–37].

 

Point 2: the aesthetics for the graphs on figure 5 and 6. Figure 5 could be simplified to represent only the most relevant results. And the remaining results be put as a part of the supplementary and reference it there. On figure 6 the same thing could be done, and in addition some of the labeling seems "off" or out of the field they represent. For example, in figure 6a for "Not familiar with any" the number 5 is out of the aqua frame. 

 

Response 2: Following Reviewer 2 comments figures 5 and 6 were moved now to Figures 2 and 3 as well as the corresponding text (See point 4, Reviewer 3). Reviewer 2 and we consider both figures important to show the characterization of the respondents and removing part of the data would leave the figures incomplete. Aesthetics were addressed in both figures.

 

Point 3: Second, with still focus on figure 6. There is really little discussion about the "biological system" the participants reported. We will either like to read a further discussion on this, especially with focus between academic and NAI respondents. Or for the topic to be discussed as a narrow down of the type of biological training every stakeholder should focus on. 

 

Response 3: Figure 6, now Figure 3, defines the expertise of the respondents in OoC modeling specific organs and questions Q2 and Q3 do not provide information on their opinions on training. We consider that moving this figure to early in the manuscript clarifies this. The key message of this figure is that scientists a biology background should be trained in microfabrication and microfluidics principles as discussed in point 2 of the discussion (line 496) and to observe that proportion of biology, engineering and interdisciplinary experts is even for most of the biological systems, there is no biological system specific bias. We added the following sentence in the results section (lines 223-225 of the revised manuscript).

Interestingly, there is no biological system specific bias between biology, engineering and interdisciplinary experts.

Regarding NAI and academic comparisons, NAI include respondents from companies that develop and sell OoC systems as well as end-users from the pharmaceutical industry, while academic respondents also include developers and end users. We consider that we don’t have data to narrow the discussion towards NAI and academic respondents, which is complemented by lines 362-365 of the discussion:

It would have been also of interest to stratify the respondents according to the OoC technologies development stage (platform development, OoC design, biological applications, or regulatory use) but that information was not available.

 

Point 4: Third, the authors state the term "transdisciplinary" in the abstract, yet there is only mention of the topic on the discussion with a single reference (Takeuchi 2020). We strongly believe the authors do not need to focus on emphasis on this term, as the presented data and discussion clearly states that the field is interdisciplinary at all the stages. And so, we highly encourage the topic of interdisciplinary to be the main take home message, with a focus on bioengineering as the pilar of training. As this field is one of the few that really reflects such concept.   

 

Response 4: A new reference was included (Choi and Pak, 2006) to present the definition of both terms (lines 65-69 of the revised manuscript) and a discussion of why this distintion is relevant but was not part of our survey (lines 446-452 of the revised manuscript) (see point 6 of reviewer 2 comments)

 

Round 2

Reviewer 1 Report

As the organ-on-a-chip technology is based on a microfluidics-based approach. On the micro level the microchannel is used and is definitely needed as a special kind of micromixer for making nanoparticles and drug preparation homogeneously, the following reference needs to be added with a small description in the paper.

Numerical analysis of non-aligned inputs M-type micromixers with different shaped obstacles for biomedical applications

 

 

Author Response

Thank you for your positive feedback