Left: Part of a microfluidic system in an academic lab, Right: A commercial prototype of the same system. (Image courtesy of CBio and Arizona State University)

In the noncommercial lab, no matter how final your design is, you always deal with prototypes: Made in very small numbers, subject to changes at any time, and often not a polished product. During commercialization, there are prototypes and commercial products. Most of what we discuss will apply to both, but the commercial product is the end goal, and the bar is higher for it than for the prototype.

A few new considerations pop up during commercialization:

1. Requirements in production quality will be much more strict.
2. Production volumes will go up.
3. Cost restrictions will increase.

Quality:

In academia, I have heard this comment more than once: “Our fabrication is very reliable, we have about 90% success rate,” meaning 10% of their production was off-spec, but this was still a success. I have worked with wafers (PDMS casting molds) with four copies of a design where one was damaged, but I used it. My yield was just 75% of what it could have been. This is passable in academia because people fabricate for their own use, and don’t necessarily answer to an end user. Also, when only a few copies of a device are being fabricated, it may not be justified to fix all fabrication issues. With my wafer example above, if I anticipate a redesign, I wouldn’t remake a wafer since additional PDMS castings would be quicker and cheaper than a new wafer.

Obviously, you cannot tell your customer, “Don’t use channels 3 and 7, they are bad.” You also cannot afford to throw away 10% of your production run. The quality of the commercial product has to be the same as any other item you would buy for your lab commercially. Every device has to work, every time.

Volume:

Startups are not in the business of inventing great tech. They are just in business. Success will now be measured by how many instruments are sold. Most instruments are expected to sell in the hundreds to thousands of units, and any disposable parts are expected to sell a similar number for each unit of instrument sold. Fabrication methods available to an academic lab –or any research lab- are very inadequate. For example, making a batch of microfluidic chips in a cleanroom takes half a day to two days, and yields at best ~20 chips. Your startup may have 3D printing or CNC machining capabilities, but they will likely be limited to small batches of prototypes.

Most startups will likely need to contract a manufacturing company for their fabrication needs very early on.

Cost:

Money was scarce in the university lab, and it will be scarce in the startup. Money is always scarce, and the cost is always a big factor. In a startup, there is a new pressure that is seldom felt in academia. Being able to afford fabrication is no longer enough. Your cost has to be low enough that you can add a large margin on it and still sell at an acceptable price. I have recently used photolithography and wet chemistry techniques to produce a batch of microfluidic chip prototypes. They cost $357 per chip (and two days for a batch of 12). These chips were part of a disposable cartridge, and to be sold at my company’s target price, they needed to cost $1 or less! You may want to throw away money like this for your prototypes for testing your design, supplying your first customers, or other considerations.

Startups need fabrication methods that are more consistent, cheaper, and larger volume, which produce higher quality parts. That sounds unattainable, like the well-known triangle below, but industrial partners can make it happen.

Startups have two ways of having it all: Investors provide the financial muscle to contract the first large production runs, and sales to customers pay for subsequent ones.

What to do?

If your startup is part of an accelerator or an incubator, chances are some fabrication facilities will be available. Many university incubators focusing on tech companies provide access to the university’s cleanrooms at reduced rates. Others may have 3D printing or CNC cores, or even access to other fabrication technologies like roll-to-roll manufacturing. These facilities will be invaluable for prototypes, and not just for cost reasons. If your company has access to these, you have direct access to the staff, and your company’s personnel can go and fabricate your devices. More importantly, your turnaround times will not be tied to the schedule of an outside company, which usually take several weeks to fulfill orders.

Sooner or even sooner, you will need to outsource your fabrication. The key factors in choosing a vendor are:

• Cost (Depends on method and order size)
• Turnaround time (Typically several weeks)
• Type of fabrication method
• Smallest feature sizes, tolerances, cleanliness
• Range of services provided

Suppliers can provide services other than just making your part. They may take care of assembly, packaging, and testing as well. It’s also advantageous to source all parts of a subassembly from a single supplier. Parts from different suppliers are not guaranteed to fit together well, no matter how meticulous your CAD drawings.

When thinking about specs like smallest feature sizes, don’t forget about cleanliness, especially for machined parts. For example, when holes are drilled in glass parts with bits or lasers, debris (several microns in diameter) from the drilling falls on the part, which is a concern for narrow microfluidic channels. Conversely, when selecting glass or silicon substrates, wafer tolerances are seldom an issue because microelectronic and optic applications already have very strict tolerance requirements.

Injection molding: By far the most popular manufacturing method in the world, injection molding is best suited for large volumes –staples like syringes can have millions/month volumes. Injection molders will have larger minimum order sizes, likely at least 1,000. Small volumes are prohibited by the cost of the mold. The mold can cost anywhere from $5,000 to over $100k, but this cost is spread out over thousands of units. However, the slightest design change necessitates making a new mold, so this technique is better once designs are finalized. Injection molding typically has minimum feature sizes of ~20 microns, but companies such as Stratec and TechniColor have injection molding capabilities with submicron feature sizes; however, channel walls are significantly sloped in these cases. Injection molding is the most likely eventual route to large scale fabrication if it is suitable for your parts.

Machining: Various machining techniques allow parts to be made subtractively in a wide variety of ways. These techniques also have their setup costs which can be spread out over a large number of units. The complexity of design is a huge factor in the cost of machined parts. Unlike techniques like photolithography or wet etch, each individual feature in a machined part is formed separately. The number and complexity of features directly impacts fabrication time, and cost. A coverslip with a large number of inlet and outlet ports can be shockingly expensive because manufacturers have to charge machine time for each hole. “Organic” shapes and features that are not at the right angle to surfaces often cost extra. Your parts should be designed to be as efficient and cost saving as possible, and the best practices vary between techniques. The ability of a supplier to guide you in this regard should be a big indicator of their suitability for you¹.

3D printing: 3D printing has become more popular and sophisticated in the past several years, and high volume production is now a reality. While a 3D printer sitting on your desk is a great way to prototype devices, note that these commonly available printers produce parts with textured surfaces, which may be unacceptable for your microfluidic devices.  However, nanometer scale roughness can be achieved with commercially available 3D printing technology². Setup costs are virtually nonexistent in 3D printing, which makes them cost-effective for very small production volumes, and also make it more amenable to design changes. 3D printing is also the most suited option for organic, irregular shapes. It should be considered strongly for prototype stages. Elveflow has an online guide for 3D printing technologies for microfluidics³.

Lithography and etching: These are likely to be very familiar methods to a microfluidics startup team, and your first prototypes are very likely to be made with these techniques. Outside suppliers can fabricate parts with these techniques at some volume, but these techniques tend to be expensive –they come into their own in the scales found in the electronics industry. However, all features are fabricated at once (e.g. all channels are etched simultaneously), so they can be an attractive alternative to machining, depending on the design⁴.

Note: Aytug Gencoglu has no conflict of interest regarding other companies mentioned or cited in this blog post. This blog post is not an endorsement of any companies or services.

<sup>1. Vaidya, N., Solgaard, O., 3D printed optics with nanometer scale surface roughness. Microsystems and Nanoengineering, 2018. v.4, article number: 18. DOI 10.1038/s41378-018-0015-4.

2. Elveflow, How to Choose a Microfluidic 3D Printer?. URL: https://www.elveflow.com/microfluidic-tutorials/soft-lithography-reviews-and-tutorials/how-to-choose-your-soft-lithography-instruments/microfluidic-3d-printer/
Last accessed: 03/01/2019.

3. Hudak, A., How to Cut CNC Machining Costs. Fictiv Hardware Guide, 2016. URL: https://www.fictiv.com/hwg/fabricate/how-to-cut-cnc-machining-costs Last accessed: 03/01/2019.

4. Gale, B. K., Jafek, A. R., Lambert, C. J., Goenner, B. L., Moghimifam, H., Nze, U. C., Kamarapu, S. K., A Review of Current Methods in Microfluidic Device Fabrication and Future Commercialization Prospects. Inventions, 2018. v.3(3) 60. DOI: 10.3390/inventions3030060.</sup>

For further reading:
^{5. Silverio, V., de Freitas, S. C., Microfabrication Techniques for Microfluidic Devices. Complex Fluid-Flows in Microfluidics, 1st ed., Chapter: 2, Publisher: Springer International Publishing AG, Editors: Francisco José Galindo-Rosales, pp.25-51. DOI: 10.1007/978-3-319-59593-1}

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Aytug Gencoglu

Aytug Gencoglu has a decade of microfluidics experience, primarily in academic labs. He has previously published articles on electrode deterioration, pH changes in microfluidic channels, and dielectrophoresis, and developed microfluidics components for dielectrophoretic cell characterization.

• aytuggencoglu@outlook.com

The post Fabrication Challenges in Early Stage Startups appeared first on The MicroFluidic Circle.

In one sense, organ on a chip devices are becoming more complex, as evidenced by the March 2018 announcement of an organ on a chip device that can model up to 10 organs and their interactions for a continuous 1 month run². In another sense, organ on a chip models are still very simplistic, as they don’t yet feature the multi-tissue structure that defines an organ. Most organ on a chip applications feature a channel or chamber in which cells are cultured, and interact with various factors, such as a liquid phase flowing adjacent to the cells, which simulates blood flow around the tissue³. However, the name “organ on a chip” paints a very different picture. A lay person who hears this term would never picture the relatively simple devices which are used today. This is where it may be worth examining organ on a chip as a PR case study for scientists.

With the increasing scientific use and commercialization of lab on a chip devices in general, it is likely that in a few years the terms “lab on a chip” and “organ on a chip” will become familiar to the general public. At that point, the name “organ on a chip” will present a problem because “organ on a chip” paints a vivid picture, but that picture is very inaccurate, and a little alarming. Many may think that these devices include full organs that are connected to some sort of chip, maybe an electronic one. Currently, the only people who have heard of this technology have read something about it. Once “organ on a chip” is a household term, it must be expected that there will be a portion of the public who have heard of the term but have no idea what it looks like, or what it does.

In that case, organ on a chip technology may face unnecessary opposition from the public, who do not want lab experiments that use human or animal organs. The myth that artificial organs are grown on chips may come about. Artificially making organs is a controversial idea that has faced ethical or religious objections, with 23% of Americans reported to oppose bioengineered organs for medical use in a 2015 report⁴. Of course, these objections have nothing to do with the actual organ on a chip technology, but it is possible that Organ on a chip researchers face them anyway from a public who is misled by the evocative name of the technology.

Cloning and stem cell technologies have faced similar problems before. Some of the objections to these technologies have come from myths about them, such as cloning technology being used to fully replicate an adult⁵. Could organ on a chip also face public opposition based on a misunderstanding of what it really is?

It is possible. First, organ on a chip would have to become a commonly recognized term. This is likely to happen as exciting breakthroughs continue to get news coverage. At that point, some people will likely associate the term with artificial organs and could oppose the idea. Whether such opposition would get any momentum may not be so much up to the scientific community. For example, if an influential TV personality started to denounce it, organ on a chip could be a hot topic. Unfortunately, some technologies are criticized or opposed based on perceived issues that are not in line with reality.

What about legislation and politics? In the US, stem cell research has been restricted or banned in many states, and federal funding for it has been restricted in the past. GMOs are heavily regulated around the world as well. However, major political resistance against organ on a chip devices are not likely, even if the public perceives the same problems with organ on a chip devices. This is because stem cell research and GMOs are very clearly defined in terms of the techniques involved. Stem cell legislation has usually defined its scope specifically based on whether embryos are involved, and how they are obtained⁶. In the case of an organ on a chip, there is not a specific technique or process step that could be targeted by legislation. It is simply a new configuration for in vitro models and microfluidic devices. This points to another reason serious opposition may never happen –would be leaders of activism against organ on a chip would first find out more about organs on a chip, and learning more about the technology could dissuade most from opposing it.

Where would this leave a potential controversy? There may or may not be a short time of 1-2 years where organs on a chip become well known, and then become a hotly debated technique. The vicissitudes of politics and media would be a big, unpredictable factor there. A lasting stigma is not likely; organs on a chip would be just another technology that some people really misunderstand. However, there is a takeaway for the scientific community. There is a lesson on managing the message and the image here, and the importance of names is obvious. By picking this very evocative, but misleading name, have we invited trouble? Will we later have to correct myths, be opposed by the public and spend our time answering nonsensical questions?

Should we have purposefully picked a different name? Should we look for an alternative now? Probably not, but it is good to think about the subject. What we should do in the future is to think from this marketing perspective every now and then, especially when coining a new term, or announcing a breakthrough. Scientists have the most control over the message when they are reporting their work – until they announce it, the world does not know about it. We should take advantage of that moment.

<sup>1. Funk, C., 2017. “Real Numbers: Mixed Messages about Public Trust in Science.” Issues in Science and Technology, 34(1), 86-88.

2. Hamzelou, J., 2018. “Miniature organs mimic human body.” New Scientist 27(3170), 1025-1031.

3. Bhatia, S. N., Ingber, D. E., 2014. “Microfluidic organs-on-chips.” Nature Biotechnology 32(8), 760-772.

4. Funk, C., Raine, L., Page, D., 2015. “Americans, politics and science issues.” Pew Research Center.

5. Miller, R. G., 2006. “Cloning: A critical analysis of myths and media.” Science Scope, 29(6), 70-74.

6. Pew Research Center, 2001. “Human Cloning: Religious Perspectives.” http://www.pewforum.org/2001/05/03/human-cloning-religious-perspectives/ (See Mr. Wasinger’s comments)</sup>

Enjoyed this article? Don’t forget to share.

Aytug Gencoglu

Aytug Gencoglu has a decade of microfluidics experience, primarily in academic labs. He has previously published articles on electrode deterioration, pH changes in microfluidic channels, and dielectrophoresis, and developed microfluidics components for dielectrophoretic cell characterization.

• aytuggencoglu@outlook.com

The post Scientists Should Think Like Marketers: The Organ on a Chip Case appeared first on The MicroFluidic Circle.