Fabrication of Chemofluidic Integrated Circuits by Multi-Material Printing

Round 1

Reviewer 1 Report

This paper discusses the challenges and inefficiencies associated with traditional mask-based fabrication procedures for manufacturing microfluidic components and integrated circuits using active polymers in laboratory settings. To address these issues, the authors introduce an alternative manufacturing process that utilizes multi-material 3D printing to efficiently print active polymers into microfluidic structures, such as microvalves, on large-area substrates with a single device. The authors explore two types of chemofluidic valves, hydrogel-based closing valves, and PEG-based opening valves, and discuss their respective printing procedures, influencing variables, special features, properties, and tolerances. They also demonstrate the effectiveness of this concept with a chemofluidic chip that automates a typical clinical chemistry and laboratory medicine analysis procedure.

 

While the authors provide a thorough exploration of the hydrogel-based closing valves and PEG-based opening valves, it would be beneficial to mention other types of valves, such as cantilever, membrane, and ball valves, and cite some papers, such as the micro vertically-allocated SU-8 check valve and its characteristics or the study on the fabrication of an SU-8 cantilever vertically-allocated in a closed fluidic microchannel. Additionally, the authors should further investigate the diodcity of the hydrogel valves to fully understand their features. In Figure 12, the authors show a logic microfluidic, and it would be helpful to include a logic schematic for this part.

 

Overall, this paper is highly instructive for researchers in the field of microfluidics and provides valuable insights into an alternative manufacturing process that utilizes multi-material 3D printing for producing precise active-material devices on chip substrates with tolerances comparable to photolithography, but at significantly faster speeds and with increased flexibility.

Author Response

Reviewer 1

We thank the reviewers for their comments, which help us to improve the quality of the manuscript. The changed passages are marked in red in the manuscript.

Reviewer 1: While the authors provide a thorough exploration of the hydrogel based closing valves and PEG-based opening valves, it would be beneficial to mention other types of valves, such as cantilever, membrane, and ball valves, and cite some papers, such as the micro vertically-allocated SU-8 check valve and its characteristics or the study on the fabrication of an SU-8 cantilever vertically allocated in a closed fluidic microchannel.

 

Answer: We have now explicitly referred to the possibility of manufacturing check valves in Line 503 and integrated three literature references.

 

Reviewer 1: Additionally, the authors should further investigate the diodicity of the hydrogel valves to fully understand their features.

 

Answer: Our valves are symmetrically designed and have valve closing as a central functionality. We have investigated these properties on the basis of pressure resistance and now describe them in the manuscript from line 367. Diodicity plays no role with these valves. Due to their symmetrical design, it can be assumed that they should also exhibit the same pressure behaviour in reverse flow tests. We have described hydrogel-based check valves in [33].

 

Reviewer 1: In Figure 12, the authors show a logic microfluidic, and it would be helpful to include a logic schematic for this part.

 

Answer: We have now integrated a schematic of the application chip (Figure 6).

 

Author Response File: Author Response.pdf

Reviewer 2 Report

According to the authors, micro-fluidic devices with integrated circuits have been fabricated previously using active polymers (Line 46-51). In this manuscript, the authors introduce a new additive manufacturing system capable of printing active polymers, which can be used to realise micro-fluidic devices with integrated circuits. As an alternative to photolithography-based methods, their system is suitable for rapid prototyping purposes. The authors showcase the capabilities of their system by systematically designing, fabricating, and characterising a proof-of-concept micro-fluidic device based on two different active polymers.

 

From a manufacturing perspective, this work is technologically meaningful and should be considered for publication. These are a few comments that may help improving the quality of the manuscript:

 

Line 13: The authors mention that 3D printing may be more efficient on a lab scale than photolithography. However, it is unclear what it means. From a practical perspective, labs with common access to cleanroom facilities may find it more "efficient" to employ standard photolithography-based processes than to setup and operate their own 3D printer along with additional requirements, such as a glovebox. From a technical perspective, semiconductor manufacturing techniques are suitable for batch processing. Therefore, if high resolution, reproducibility, and low cost per device are more important than rapid prototyping, then photolithography-based methods may be a more efficient approach than 3D printing, even on a “lab scale”. 

 

Line 22-23: Commercial steppers (i.e., ArF steppers) are capable of achieving an alignment accuracy smaller than 100 nm, significantly more precise than what is reported in this manuscript. The authors should avoid making general assumptions without proper context

 

Line 52: The authors should clarify why photolithography for chemofluidic LoC is especially challenging on a "lab scale”

 

The authors should avoid subjective and unclear expressions, such as "very efficiently" (Line 16), ”very precise" (Line 22), and "quite successful" (Line 36), which can be misinterpreted. There are other occurrences throughout the text.

 

Line 66: The authors mention that their technique can be used for multi-material printing, but only two types of polymers were considered in this manuscript. it is reasonable to assume that other materials would also work, but it should be clearly mentioned that only two materials were tested whenever multi-material capabilities are mentioned.

 

Line 182: What do the authors mean by “diversity” of the active materials?

 

Could the system described in the manuscript be used in other research fields, such as soft robotics and electronic skins? If so, it would be useful to mention it in the text.

 

To which extent can the resolution of the system be improved?

 

Are there constraints related to the substrate (i.e., material, curvature, roughness, etc.)?

 

Figure 2: The absence of an arrow between (d) and (e) is confusing. Please, consider editing the figure.

Figure 7: Each point represents 15 hydrogels. Please, add the corresponding error bars

Author Response

Reviewer 2

We thank the reviewers for their comments, which help us to improve the quality of the manuscript. The changed passages are marked in red in the manuscript.

Reviewer 2: Line 13: The authors mention that 3D printing may be more efficient on a lab scale than photolithography. However, it is unclear what it means. From a practical perspective, labs with common access to cleanroom facilities may find it more "efficient" to employ standard photolithography-based processes than to setup and operate their own 3D printer along with additional requirements, such as a glovebox. From a technical perspective, semiconductor manufacturing techniques are suitable for batch processing. Therefore, if high resolution, reproducibility, and low cost per device are more important than rapid prototyping, then photolithography-based methods may be a more efficient approach than 3D printing, even on a “lab scale”.

Line 22-23: Commercial steppers (i.e., ArF steppers) are capable of achieving an alignment accuracy smaller than 100 nm, significantly more precise than what is reported in this manuscript. The authors should avoid making general assumptions without proper context.

Line 52: The authors should clarify why photolithography for chemofluidic LoC is especially challenging on a "lab scale”

 

Answer: There are essentially three aspects that make the photolithographic structuring of active material layers challenging. First of all, standard photolithographic equipment such as steppers or mask aligners have to be modified to create an inert gas atmosphere and to expose chamber systems for the prepolymer solution to be exposed, or specially designed exposure systems have to be used. In addition, the prepolymer solutions are currently very thick, about 50µm in height, so that the good resolutions of steppers, for example, cannot be exploited technically. Secondly, quite extensive mask sets are required, because separate masks are needed for each active material layer, but also for components with different cross-linking or polymerisation parameters. Thirdly, chemofluidic ICs are currently large-area chips, and one can usually only process a single chip, so that the advantages of batch fabrication do not come into play.

We have now described this in lines 53 to 60.

 

Reviewer 2: The authors should avoid subjective and unclear expressions, such as "very efficiently" (Line 16), ”very precise" (Line 22), and "quite successful" (Line 36), which can be misinterpreted. There are other occurrences throughout the text.

 

Answer: We have clarified the points raised and found others, especially in chapter 4, and also improved them.

 

Reviewer 2: Line 66: The authors mention that their technique can be used for multi-material printing, but only two types of polymers were considered in this manuscript. it is reasonable to assume that other materials would also work, but it should be clearly mentioned that only two materials were tested whenever multi-material capabilities are mentioned.

Line 182: What do the authors mean by “diversity” of the active materials?

 

Answer: We have now pointed out in lines 72 and 73 that we are printing only two materials.

In lines 189 and 190 we replaced "diversity" by "difference between the two active materials (swelling hydrogels, soluble PEG)”.

 

Reviewer 2: Could the system described in the manuscript be used in other research fields, such as soft robotics and electronic skins? If so, it would be useful to mention it in the text.

 

Answer: We have referred to this in lines 503 and 504.

 

Reviewer 2: To which extent can the resolution of the system be improved?

 

Answer: We have not investigated the resolution limit, as we currently fabricate structures that are much larger. One drop of prepolymer solution required for our valves consists of approx. 400 individual drops. The manufacturer specifies a positioning accuracy of ± 2 µm for the pipettes. A resolution of 10 µm is certainly feasible, but cannot be named due to lack of corresponding investigations.

 

Reviewer 2: Are there constraints related to the substrate (i.e., material, curvature, roughness, etc.)?

 

Answer: We did not investigate this explicitly either, but used materials which we also use as standard for the photolithographic structuring of our components. However, it is known from literature (e.g. [33]) that the materials and their surface properties significantly influence the printing result.

 

Reviewer 2: Figure 2: The absence of an arrow between (d) and (e) is confusing. Please, consider editing the figure.

 

Answer: This is a misunderstanding. Process steps b-d and e-g describe two independent sub-processes that can run in parallel to each other. b-d illustrate the integration of the hydrogel valves into the corresponding layers, e-g show the production of PEG-based opening valves.

 

Reviewer 2: Figure 7: Each point represents 15 hydrogels. Please, add the corresponding error bars.

 

Answer: We have presented this in a misleading way. We replaced Figure 8 with Table 1 and better describe the facts in the table heading.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The authors carefully answered my questions.