From micro-total-analysis-system (MTAS) to neurons-on-chip – the application range is broad and has given major new insights into the spread of the disease on a patient level as well as on a molecular scale. Most important findings were, that the size of the protein aggregates found in patients and in in-vitro assays is related to their toxicity. Especially the larger aggregated protein assemblies (oligomers) are considered as the damage causing species as described in an interview with the biotech company Fluidic Analytics¹.

This fact is the main driver in the research field for the development of protein sizing technologies of higher precision and specificity. In particular – since a single misfolded protein can corrupt others and spread the disease – we, therefore, seek methods to detect these specimens on a single-molecule level. Microfluidics has provided powerful tools for protein misfolding disease research: Microdroplet devices, diffusional sizing devices and electrophoresis-on-chip have proven invaluable for the study of protein aggregates (See Fig.1 A-C). However, to truly reach MTAS and analyze protein solutions on the single-molecule level, the nanofluidic regime opens up a totally new set of applications which are challenging to achieve or not possible at all with conventional microfluidics.

Fig. 1: Illustration of micro-, and nanofluidic chip designs used in protein misfolding disease research (A) Microdroplet generators are used to separate single cells (FACS) or confine protein into independent experiments in micron-sized droplets; (B) Diffusional-sizing devices use the spread of a sample injected in the centre of a microfluidics channel and its developing diffusion profile to estimate its hydrodynamic radius; (C) Electrophoresis on chip allows to measure the charge of molecules flowing through a perpendicular applied electric field; (A*) Smaller channel cross-sections allow the generation of nanodroplets; (B*) Diffusional sizing can be facilitated by observing single molecules diffusing in nanochannels between two reservoirs. If channels widths reach the size of proteins also filtration becomes possible; (C*) Electrophoretic trapping in nanofunnels can be used to concentrate and capture charged molecules in solution (e.g. DNA);

The new chip designs that arise from smaller channel widths are similar to microfluidic chip layouts but allow to significantly decrease the needed sample concentrations to the femtomolar range and the usage of new physics by reaching the nanoscale (See Fig.1 (A*)-(C*)). Nanodroplet maker chips (A*) produce even smaller independent nanoreactors for massive parallelization of drug testing or drug encapsulation. Nanochannels (B*) in between two microfluidic reservoirs can be used to measure single proteins in solution as they propagate from one reservoir to the other. This allows to measure the sizes of protein monomers (approx. 0.5 nm) up to macromolecular assemblies such as oligomers (2-10 nm), exosomes (40-100 nm) or viruses (80-120 nm) in solution, without permanent surface immobilization and a relatively simple chip design. Nanofunnels (C*) concentrate charged proteins and short stranded DNA (e.g. µDNA) in solution by application of an electric field, which facilitates an easier detection of these with optical setups. Especially for the analysis of protein solutions, nanochannels have the major advantage of eased experimental setup and conduction of experiments. Microfluidic diffusional sizing devices need external machinery such as multiple-precision syringe pumps, optical microscopes, high-voltage power supplies and standardized flow measurement protocols to allow for reliable protein sizing measurements. With a nanochannel device, a single 50 µl injection manually pipetted into a chip mounted on top of a commercial microscope can be used to evaluate e.g. antibody binding events with the highest precision at femtomolar concentrations. This decreases the total sample consumption by orders of magnitude, increases throughput and eases the training of staff for conduction of single-molecule experiments drastically. However, the availability of nanofluidic devices is currently limited to research laboratories and companies² with expensive clean-room facilities or researchers with expertise in nanofabrication³– where high prototyping costs put additional constraints.

A way to circumvent this matter is soft lithography⁴, which allows a cost-effective fabrication of disposable nanofluidic devices from a single master wafer. Recently, we demonstrated the scalable integration of nanofluidic functionalities into existing microfluidic designs using two-photon lithography as an effective alternative fabrication method in comparison to conventional electron beam lithography⁵. Commercial 2-photon lithography systems (e.g. Nanoscribe’s Quantum X and Photonic Professional GT2) are available and provide a sophisticated way to produce nanofluidic master wafers, but open-source systems can also be found in the community, and provide an even more cost-effective nanolithography solution for master fabrication and soft lithographic chip imprinting without cleanroom facilities.

Commercialization potential in nanofluidics, therefore, lies within three sectors: Firstly, in the application of nanofluidic devices for biotechnological diagnostics and antibody development e.g. antibody testing to specific targets such as viruses, exosomes or protein complexes in solution at minimal sample consumption. Secondly, in the cost-effective fabrication and distribution of nanofluidic devices tailored to customer’s needs using fast and flexible fabrication techniques and thirdly in the key-knowledge transfer of chip architecture and physical effects happening on the nanoscale (similar to PCB design parameters known from the electronics industry) which can be exchanged by consulting services. However, for all of this to be economically relevant, the fabrication and prototyping need to be realized in a cheap and scalable manner without expensive cleanroom facility maintenance costs and at faster design-to-device delivery times than conventional chip industry allows. The combination of two-photon lithography with soft lithography, therefore, provides an effective integration of nanofluidics into existing microfluidic designs and paves the way for a broad implementation of nanofluidic chips for various applications related to neurodegenerative disease research and cancer diagnostics.

Neuron image photocredit: Oliver Vanderpoorten and Colin Hockings

References

<sup>1. Ruairi J MacKenzie, „Size Matters: Diffusion Technique Sorts Out Pathological Proteins”, NNR, https://www.technologynetworks.com/neuroscience/blog/size-matters-diffusion-technique-sorts-out-pathological-proteins-322669

2. Wunsch, B., Smith, J., Gifford, S. et al. Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm. Nature Nanotech 11, 936–940 (2016). https://doi.org/10.1038/nnano.2016.134

3. Levin, S., Fritzsche, J., Nilsson, S. et al. A nanofluidic device for parallel single nanoparticle catalysis in solution. Nat Commun 10, 4426 (2019). https://doi.org/10.1038/s41467-019-12458-1

4.Qin, D., Xia, Y. & Whitesides, G. Soft lithography for micro- and nanoscale patterning. Nat Protoc 5, 491–502 (2010). https://doi.org/10.1038/nprot.2009.234.

5. Vanderpoorten, O., Peter, Q., Challa, P.K. et al. Scalable integration of nano-, and microfluidics with hybrid two-photon lithography. Microsyst Nanoeng 5, 40 (2019). https://doi.org/10.1038/s41378-019-0080-3.</sup>

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Oliver Vanderpoorten

Oliver Vanderpoorten is part of the Centre for Misfolding Disease at the University of Cambridge where he conducts research on nanolithography and nanoscopy methods. He holds two master degrees in engineering subjects which give him an applied attitude towards biotechnological applications: He holds a Master in Electrical and Microsystems Engineering from OTH Regensburg (2015) and a second Master’s degree in Sensor Technologies from the University of Cambridge (2016). During his PhD in the EPSRC funded Sensor CDT he explored the landscape of nanofluidic chips for various applications related to life sciences and protein misfolding diseases and developed 2-photon lithography as fabrication method for nanofluidic devices. In his free time he’s interested in entrepreneurship, sailing, painting and spends his time with outreach to explain science to the public in an informal way (https://youtu.be/TPJPYvumErM?t=100).

The post Bridging the micro to the nanoscale – how to facilitate the transition to nanofluidic devices as new standard in life sciences appeared first on The MicroFluidic Circle.

Microfluidics advances have hovered on the horizon as a “new way” for some time. The creation and development of new drugs can cost millions, yet many end up being recalled for toxicity, or just plain not as effective in humans as they are in lab animals.

The authors of a 2019 statistical analysis, “Impact of organ-on-a-chip technology on pharmaceutical R&D costs,” describe how high drug prices are driven by the huge expense of creating new product. They report that 60-75 percent of new drugs that succeed in non-human phases fail in later phases. “Better predictive models are needed,” they concluded, in something of an understatement.

Better predictive models include microfluidic platforms called organs-on-a-chip. These platforms are engineered to improve on the prognostic capacity of animal or in vitro models — which too often inaccurately simulate human physiology. As controlled microenvironments with vasculature perfusion that mimic the structure and function of human tissue, organ-a-chip technology has the potential to decrease the conventional roadblock of extensive development time frames, and their choking costs.

Although actual expenditures of private pharmaceutical companies are not made public, the statistical analysts estimate the potential of microfluidics to reduce R&D costs at 10-25 percent. The authors granularly analyzed some development costs by phase. They concluded that organ-on-a-chip technology could significantly reduce R&D costs by reducing the length of the early-stage research process.

The analysts note that, “Experts believed that the technology will help to make quicker and more precise decisions” during initial stages of research. One analyst said that if organ-on-chip was capable of identifying appropriate biomarkers, it would become the “Holy Grail” of biotechnology.

The authors do not pretend change arrives astride a fast horse. “The extent to which organ-on-a-chip can evolve in terms of predictability and applicability to the human biophysiology is yet to be seen,” they write. “Challenges of automation, parallelization, standardization and ease of use remain.”

Concerns driving the current conversation among experts focus on the magnitude of transformation. The tradition of utilizing in vitro and animal models is deeply ingrained and rooted, to state one obvious funding barrier. Results anticipated by innovators and early adopters can “take much longer to materialize when meeting the skepticism of the late majority and laggards.”

Not only are microfluidic devices pushing for legitimacy in the minds of some, but the very methods used to create them are often never-before-seen tools butting up against history as well. 3D bioprinting comes to mind.

There are pre-publication reports concerning vascularized micro-tissues for many major organs. For example, micro-tissued pancreatic islets have potential for insulin regulation and insulinomas. Liver buds are being researched. There has been progress in bioprinting vascularized thyroid glands.

In addition, genome engineering techniques may create genetic disease models using microfluidic platforms. Personalized medicine applications may include drug screening for patient-specific tumors.

In their study titled “Long-term Expanding Human Airway Organoids for Disease Modeling,” lung specialists wrote that “human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.”

The world certainly does have an “infectious pulmonary disease” on board.

Can regulatory shibboleths and personal proclivities accommodate the pace of innovation? Despite the complexity of research, the degree of potential is climbing. According to a recent Research and Markets report, microfluidics technology is replicating many functions of traditional healthcare, including clinical diagnostics, point-of-care diagnostics and drug delivery: “The global microfluidics market size is projected to reach USD 44.0 billion by 2025 from USD 15.7 billion in 2020.”

One research team recently described why “frontier technological tools by which infections are studied and new drugs and vaccines are tested” include “microfluidic chambers for the culture of organoids.” Given they are Milan, Italy-based, this team comprises COVID-19 experts.

The pandemic-weary world awaits “frontier tools.”

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Kathy Jean Schultz

Kathy Jean Schultz is a freelance medical science writer who focuses on medical innovations. She earned a Master’s Degree in Research Methodology from Hofstra University, and a Master’s Degree in Psychology from Long Island University. She is a member of the National Association of Science Writers, and the Association of Health Care Journalists. Her articles about organoids include "Would you trust a 3-D printed mini organ to test your drugs?" and "Stem cells not only slow disease, they come with their own safety test".

• http://kathyjeanschultz.pressfolios.com/

The post Microfluidics and Approval Bottlenecks in a Pandemic appeared first on The MicroFluidic Circle.

Financial potential is being matched medical potential, as microenvironments play a role in new findings about stem cell treatment that may speed patients’ recovery from chemotherapy and radiation. And microfluidics advances have also led to a new tool for diabetes research.

Bone marrow stem cells produce the body’s blood and immune cells, but chemotherapy and radiation suppress that production, and it can take weeks or months for the blood and immune systems to recover. Results of a recent study by UCLA Broad Stem Cell Research Center scientists showed how a newly developed drug compound might hasten the blood system’s recovery after radiation and chemotherapy in mice. Some of the heretofore unknown capacity of microenvironments were critical to this type of investigation.

“The potency of this compound in animal models was very high,” said study co-author Dr. John Chute. “It accelerated the recovery of blood stem cells, white blood cells and other components of the blood system necessary for survival. If found to be safe in humans, it could lessen infections and allow people to be discharged from the hospital earlier.”

Looking at both mouse — and human stem cells (in dishes) — growth factors were observed to promote the recruitment of stem cells from degraded bone marrow, which fueled proliferation and reconstitution. “We’re very excited about the potential medical applications of these findings,” said Chute.

The new compound enabled the blood system to recover sooner from cancer treatments in mice because it was able to stop the molecular process that slows blood stem cell regeneration. “The new compound lifts molecular ‘brakes’ that normally slow the regeneration of blood stem cells,” according to the team.

The new compound speeded up the regeneration of both mouse and human blood stem cells after exposure to radiation. The bloodstream’s own regenerative capacity seemed to power up healing. Angiogenesis, the formation of new blood cells, is controlled by chemical signals, yet many of the mechanisms by which blood cell regeneration uses bone marrow have been unknown. The study highlights the process by which growth factors recruit stem cells from the bone marrow microenvironment. Advances detailing bone marrow’s microenvironments are a significant contribution.

Microfluidic devices can be monitored and imaged using fluorescent markers for tracking, and microenvironments needed to be precisely controlled for this investigation.

Among the mice that received high doses of radiation, almost all that were given the compound survived; more than half of those that did not receive the compound died. Mice that received chemotherapy but no compound had low levels of white blood cells and neutrophils — which fight bacteria — after two weeks; in mice that were treated, white blood cell counts recovered to normal levels within two weeks. The researchers are now refining the process, in preparation for human trials.

Microfluidics research also has another new arrow in its quiver, in the form of a new tool for diabetes research, developed by a team based at the Harvard Stem Cell Institute. The device improves aspects of studying diabetes, including upgrading the screening process prior to transplantation of insulin-producing cells into a patient.

The team noted that although microfluidic devices have been used to address research limitations in the past, previous adoption has been hampered by “incompatibility of most device materials with large-scale manufacturing. We designed and built a thermoplastic, microfluidic-based Islet-on-a-Chip compatible with commercial fabrication methods, that automates islet loading, stimulation, and insulin sensing.”

The design of their “Islet-on-a-Chip” is based on the human pancreas, where islets process non-stop, incoming information about glucose levels, and adjust insulin production accordingly. The new, automated, miniature device gives results in real-time, which can speed up clinical decision-making.

In addition to diabetes research, the device may prove useful in other areas. Its core technology can be modified to sense an array of microfluidic systems. Because it can detect cell secretions continuously, it can be employed to investigate how cells communicate using protein signals, throughout the body.

“It was exciting to see our lab’s method for measuring islet function taken forward from individual cells to much bigger groups of cells, and incorporated into a device that can be used widely in the community,” said co-author Dr. Michael Roper. “Now, we have a device that integrates glucose delivery, islet positioning and capture, reagent mixing, and insulin detection, and requires far fewer reagents. So labs can use it to do more experiments at the same cost, using a much shorter and easier process.”

Scalable, easier, shorter, and cost-contained. That says it all.

Enjoyed this article? Don’t forget to share.

Kathy Jean Schultz

Kathy Jean Schultz is a freelance medical science writer who focuses on medical innovations. She earned a Master’s Degree in Research Methodology from Hofstra University, and a Master’s Degree in Psychology from Long Island University. She is a member of the National Association of Science Writers, and the Association of Health Care Journalists. Her articles about organoids include "Would you trust a 3-D printed mini organ to test your drugs?" and "Stem cells not only slow disease, they come with their own safety test".

• http://kathyjeanschultz.pressfolios.com/

The post Industry Predictions of Microfluidics Commercialization are Buoyed by Recent Advances in Diabetes and Cancer Research appeared first on The MicroFluidic Circle.

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.

Fig. 1. Global microfluidics market. Estimates of global market shares of microfluidics by economic region were estimated from GranViewResearch⁵.

In this global market, the In-Vitro diagnostics represent the largest portion of the microfluidic applications. Furthermore, the large North American market will continue to expand due to the increasing demand for Point-of-Care (POC) devices, many of which may be categorized as medical devices that can be covered by insurance companies. This can slowly be realized by quicker return on investments, the decline of manufacturing costs and further miniaturization of devices³. From these three advantages, miniaturization is key for the potential of microfluidics to become wearable POCs. For instance, microfluidic chips in laboratories are small devices that required large setups that include multiple pumps and syringes; thus, hindering their application as wearable devices. However, wearable devices will be based on non-continuous flow chips that do not need to be plugged to pumps. For example, pocket-size devices already exist to continuously monitor glucose in patients suffering from diabetes helping determine the correct time for insulin injections. The features of these type of devices can be extended to local monitoring/analysis and responsive drug administration. The type of processes that these devices can regulate is enzymatic reactions, detection of antibodies, cells or molecules⁶. Indeed, the prosperous future of microfluidics has attracted large corporations such as Roche, Becton Dickinson and Company and Abbott that are now leaders in Point-of-Care & Clinical and Veterinary diagnostics, with other major vendors such as Fluidigm Corp., Agilent Technologies Inc., Illumina, Inc., and Shimadzu³. Microfluidics also show potential in the cosmetic industry, for example, L’Oréal has recently released the first wearable microfluidics sensor capable of measuring pH for applications in aiding eczema and atopic dermatitis. The invention of microfluidic products starts from accomplishing proof-of-concept device which is later on an integration of different elements. Unquestionably, a steady increase in both scientific publications and patents have been seen filed proving that a genuine interest in developing new technologies exists (Fig. 2).

Fig. 2. Scientific publications and patents over time. A number of publications and filed patents were calculated from Google Scholar including the word “Microfluidics”.

Unfortunately, the number of microfluidics-based products remains truncated despite a large number of proof-of-concept research and patents. The fact that these are not turned into products fast enough can be attributed to several factors. In academia, microfluidics is still not widely known across scientific fields and their apparent complexity shadowing the advantages prevents other scientists from using them. Additionally, the costs of devices often exceed the benefits of a lab-on-chip. In industry, the initial high capital investments and costly reagents and materials are obvious bottlenecks. As of today, there are no microfluidic systems employed for large scale manufacturing or pharmaceutical products from such systems⁷. Microfluidic technology must be cost-effective and integrable within larger machines to be feasible before reaching industrial applications⁸. Therefore, the areas of opportunity are to foster plug-and-play devices with well-defined standards in which interfacing individual chips are straightforward. On one hand, microfluidic technology needs to integrate into larger and powerful platforms based on the application and the technical aspects required. On the other hand, wearable devices need to be further miniaturized and suitable application niches need to be identified. It is unmistakable that by handling small liquid samples, microfluidics offers an evident potential to lower cost and increase high-throughput applications across industries. In conclusion, the market forecasts of microfluidics are optimistic despite the seemingly slow introduction of new microfluidic products.

<sup>1. Whitesides, G. M. The Origins and the Future of Microfluidics. Nature 2006, 442 (7101), 368–373. doi.org/10.1038/nature05058.

2. Yetisen, A. K.; Volpatti, L. R. Patent Protection and Licensing in Microfluidics. Lab Chip 2014, 14 (13), 2217–2225. doi.org/10.1039/c4lc00399c.

3. Microfluidics Market – By Material (Ceramics, Polymers), By Components (Microfluidic Chips, Pumps, Needles), By Application (In-Vitro Diagnostics, Pharmaceutical Research, Drug Delivery) – World Forecasts to 2022; 2018.

4. Microfluidics Market by Application (Genomics, Proteomics, Capillary Electrophoresis, IVD (POC, Clinical Diagnostics), Drug Delivery, Microreactor, Lab Tests), Component (Chips, Pump, Needle), Material (Polymer, Glass, Silicon) – Global Forecast to 2023; 2018.

5. Microfluidics Market Size, Share & Trends Analysis Report By Application (Pharmaceutical, In Vitro Diagnostics, By Material, By Region, And Segment Forecasts, 2018 – 2024; 2018.

6. Bohr, A.; Colombo, S.; Jensen, H. Future of Microfluidics in Research and in the Market. Microfluid. Pharm. Appl.2019, 425–465. doi.org/10.1016/B978-0-12-812659-2.00016-8.

7. Bohr, A.; Colombo, S.; Jensen, H. Future of Microfluidics in Research and in the Market. In Microfluidics for Pharmaceutical Applications; William Andrew Publishing, 2019; pp 425–465. doi.org/10.1016/B978-0-12-812659-2.00016-8.

8. Zambrano, A. Why Hasn’t Microfluidics Reached Consumer Market despite a Huge Number of Academic Inventions and Publications during the Past 15 Years? Microfluidic Circle 2018, No. October.</sup>

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Adrian Zambrano

Adrian Zambrano is a scientist at the Max Planck Institute of Molecular Cell Biology and Genetics in Germany where he synthesizes protein/polymer scaffolds for micro-droplets and utilizes microfluidics for the encapsulation of enzymatic DNA replicators and other DNA-based assays. He holds a Ph.D. in physics from the University of Paris-Saclay/CNRS and B.Sc. in chemical engineering from the University of Nevada, Reno. His personal interests lie in the commercialization and development of high-throughput assays based on microfluidic technology.

• adrianzamphd@gmail.com
• https://sites.google.com/view/adrianzambrano/

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Buzzwords aside, this microfluidic technology’s potential is very real. So real, in fact, that the United States Food & Drug Administration (FDA) launched a partnership with an organ-on-a-chip company in 2017. Understandably, increased success and commercialization makes organs-on-chips more accessible to scientists studying critical medical challenges. But it also encourages the oft-overlooked providers of elective health treatments to entice consumers with unchecked experiments and claims. This elective consumer space is less regulated and more vulnerable to abuse—especially when providers can deceive consumers with buzzwords teeming with scientific credibility. Organ-on-a-chip technology is a boon for novel experiments in labs, but only peer review and regulation can prevent its abuse by pseudoscientists.

Lessons from past malpractice

Without effective peer review, it’s easy to imagine dietary supplement manufacturers, for example, marketing the next snake oil based on staged microfluidics studies. In the United States, so long as the manufacturer does not explicitly claim its products cure disease, FDA regulation is not much of a barrier. This could practically pave the way for misleading advertisements: “Do you get TIRED at night? Our HUMAN-ON-A-CHIP studies PROVE this supplement is RIGHT FOR YOU!” The only thing protecting the consumer from deception, in this case, is peer review.

FDA White Oak Campus. Credit: Flickr

Unfortunately, deceptive marketing is not just a malevolent step-child of promising research, it is indelibly bound at the hip. Look no further than “stem cells” for proof. Stem cells can be pluripotent, meaning they can give rise to nearly any type of cell in the body. Their discovery has had a monumental impact on the future of regenerative medicine. But even before scientists devised a method to make pluripotent stem cells more ethical and accessible, this buzzword carried connotations of “miracle cells.”

Fast-forward to 2018, and the FDA has had to crack down on so-called “stem cell clinics” that endanger patients with elective stem cell injections for various ailments. Aside from being risky, these cell-therapy procedures are unproven—the cells used are often extracted from the patient’s fat and are not even pluripotent. This business model works well enough to warrant FDA involvement, but not well enough to prevent patient harm. These clinics ride the coattails of legitimate stem cell research and profit from the power of a buzzword. Unfortunately, consumer and patient exploitation are inevitably tied to commercialization, and it is fair to say that no accessible technologies—especially groundbreaking ones—are immune.

Organ-on-a-chip technology has become drastically more accessible. Two years ago, I had zero experience with microfluidic or biological research. Today, I spend the majority of my time designing organ-on-a-chip devices and experiments. The barrier for entry is low—I could plan a simple experiment and successfully grow human cells on a chip. But without the scientific expertise and integrity of the women and men around me, drawing worthwhile and reproducible conclusions that hold up against peer review would be infeasible. The danger with buzzwords is that they can only be policed by public caution and skepticism. As this technology becomes more popular, the scientific community should emphasize peer review and regulation in all of its applications.

Some room for optimism

All of this is not to say that organ-on-a-chip commercialization is anything short of revolutionary and, well…good. Patients stand to benefit tremendously from new treatments and fundamental knowledge. Hesperos and Emulate, two commercial pioneers of the field have numerous collaborations in the healthcare industry. Hesperos provides a platform to accelerate drug development, and Emulate hopes to break new ground in personalized medicine with their “patient-on-a-chip” initiative. Organ-on-a-chip technology has also played a role in advancing novel treatment methods. Recently, researchers at Harvard’s Wyss Institute developed a chip that allowed accurate modeling of a portion of the human kidney using pluripotent stem cells. This work opens doors for repairing damaged kidneys—offering a legitimate stem cell therapy.

Because these are cases of medical and pharmaceutical research, peer review and regulation (in the form of double-blind studies) will have the ultimate say. The elective consumer space is more of a gray area. Fortunately, we have an opportunity to treat it with comparable scientific rigor. The FDA could one day choose to mandate using organ-on-a-chip devices for safety testing of dietary supplements. Microfluidic experiments are significantly cheaper than animal or human trials, and this may make evidenced-based policy more feasible. We could also one day request the use of organ-on-a-chip platforms to validate risky cell-therapy procedures before experimenting on live patients. If we don’t lose sight of peer review and regulation as governors of science, we can validate market claims to benefit the consumer. Reliable public scientific data, in a space where not much exists, allows us to address the credibility of lofty claims rather than to leave them unchecked.

There is an undeniable magnetism inherent to buzzwords. They attract media attention and research funding, but also opportunists, hucksters, and charlatans. To this point, we have had to take the bad with the good.  Fortunately, we can learn from ongoing malpractice and arm ourselves with the most impenetrable shield in a scientifically literate society: skepticism.

Featured image credit: NCATS

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Max Levy

Max Levy is a Ph.D. student at the University of Colorado Boulder studying chemical and biological engineering. His research focuses on the intersection of nanotechnology and drug development. He also serves as a science writer, and as a senior editor for the "Science Buffs" blog.

The post How Organ-on-a-Chip Technology Might Be Used (and Abused) in the Elective Consumer Space appeared first on The MicroFluidic Circle.

The rising prevalence of lifestyle-related & infectious diseases and an increasing preference for self-testing are driving the global point-of-care diagnostics market. In addition, growing private investments and the availability of venture funding for the development of new products, coupled with government support for improving the adoption of POC devices, are further supporting the growth of the POC diagnostics market. The rising incidence and prevalence of various diseases, coupled with product miniaturization and the decentralization of healthcare, are the major factors that are expected to offer significant growth opportunities to players operating in the POC diagnostics market.

According to the National Cancer Institute, the cost of cancer treatment in the US was USD 125 billion in 2010; this is expected to reach USD 158 billion by 2020. According to the World Cancer Research Fund International (WCRFI), in 2012, there were an estimated 14.1 million new cancer cases worldwide; this figure increased to 17.5 million in 2015 and is expected to reach 24 million by 2035. The rising incidence of cancer is expected to increase the uptake of cancer-related diagnostic technologies. Similarly, the increasing incidence of other major chronic and infectious diseases, coupled with advancements in coagulation tests, blood gas electrolytes, hematology, urine chemistry, and cardiac markers, are creating new avenues for the growth of the POC diagnostics market. This, in turn, is expected to support the growth of the microfluidics market, as POC testing is the largest segment of the microfluidics market for in vitro diagnostics.

Significant return on investment

Microfluidics is proving an economical solution for screening samples against reagents when testing for toxicity or in research on biomarkers. Microfluidics significantly reduces the cost per test by reducing overall reagent consumption. Nine out of the top fifteen pharmaceutical firms, including Merck, Novartis, GSK, Pfizer, and Sanofi-Aventis, have adopted microfluidic-based micro-reactors to control parameters in chemical reactions and better understand and enhance the quality of production. While the initial investment in microfluidic devices is usually higher than that for their conventional counterparts, reductions in reagent consumption down the line make these devices highly economical in the long run.

Using microfluidics-based devices can accelerate drug discovery as these devices assist in finding new and promising drug targets. This decreases the cost of drug discovery and development. Currently, the majority of pharmaceutical companies and governments across developed and developing countries are focusing on cost-cutting measures. This has further encouraged the usage of microfluidics-based devices.

Entry of new players and the launch of new and advanced products

The ecosystem in the microfluidics market is changing rapidly with the launch of new products, entry of new players, rapidly growing IP base, and acquisitions. Over the last few years, the market has witnessed the emergence of several new small players and spinoffs focusing majorly on technology and product development. Several established players in the diagnostics and life sciences markets are focusing on acquiring these promising small players with a focus on adding and integrating new technologies to their portfolios. This also proves beneficial for smaller companies by expanding their marketing and distribution capabilities. This, in turn, allows them to achieve maximum potential sales for their products.

On the other hand, the complex and time-consuming approval process is hampering the introduction of new products in the market. For example, in the US, the FDA approval process for medical devices has become lengthy over the years. The average approval time for a 510(K) application increased to 151 days during 2011–2015, as opposed to 96 days in 2001–2005. This is expected to have a major impact on the drug delivery, pharmaceutical, and IVD industries. Furthermore, during the approval process, it is not certain whether the product will receive approval, or whether the terms of the approval may have a negative impact on the profitability of the product. Any enforcement action by governments also results in negative publicity, which impacts the market adversely.

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Mayur Jain

Mayur is working in MnM as a research analyst in the healthcare domain for three years. He has worked on syndicated market research reports including lateral flow assay market, and immunohistochemistry market among others. At MnM, Mayur has been enriching his knowledge in market sizing & forecasting, competitive intelligence mapping, data mining, primary/secondary research, market assessment, industry analysis, among others. Mayur completed his Bachelors in Pharmaceutical Sciences from Pune University (India) and Post-Graduation Diploma in Management (IB) from Indira Schools of Business Studies, Pune (India).

• mayur.jain@marketsandmarkets.com

The post Rising Demand for Point-of-Care Testing and Significant Return on Investment: Key Driving Factors of the Microfluidics Market appeared first on The MicroFluidic Circle.

From the economic perspective, the adoption of new technologies must be easily adaptable and cost-effective, unfortunately, these two requirements have not been properly met. Most publications regarding microfluidics are found mostly in engineering journals¹ or in patent form², thus limiting an immediate adoption due to their complexity. However, it’s not to say that microfluidics adoption is not on its way as applications range from chemical synthesis of organics, inorganics polymer particle as well as in emulsions, microencapsulation, steam reforming³ and biochemistry in high-throughput formats². Additionally, part of the easy adoption of microfluidics by industry is to address the technical problem of the complexity of scalability in which complex flow distribution and intricate reaction detection methods are required³,⁴. This latter issue mostly affects large-scale applications of microfluidic reaction technology.

As mentioned before, microfluidic technology must be cost-effective to be feasible, and this must be straightforwardly met when costly and delicate reagents are involved. The obvious advantages provided by microfluidics of small-volumes and precise liquid handling² can provide cost-effective high throughput biochemical assays and diagnostics³. However, to widely implement these technologies, portability, miniaturized and stand-alone lab-on-a-chip devices are still needed². Nevertheless, this remains a largely an unfulfilled vision of the microfluidics community.

Fig. 1. An analogy of the technological development to the modern computer. The blue colour indicates the current transition in technology progress.

To understand the current technological state of microfluidics, I can make an analogy to the history of the digital computer. In my opinion, we are seeing a transition in the technological development of microfluidics where advanced microfluidic chips are now being incorporated into laboratory equipment (Fig. 1). And as mentioned before, such applications are finding their niche in biochemical assays and diagnostics. Once, such device integration is widely adopted, we can expect a fast improvement of multifunctional and high-throughput microfluidics platforms.

Indeed, microfluidics has a large potential to be integrated into powerful platforms. However, the exact timeline of microfluidics fully reaching the consumer market is still hard to predict as it will depend on the demand of small volume handling, cost feasibility based on the application and the technical aspects of the scalability.

<sup>1. Caicedo, H. H.; Brady, S. T. Microfluidics: The Challenge Is to Bridge the Gap Instead of Looking for a ‘Killer App.’ Trends Biotechnol.2016, 34 (1), 1–3.

2. Chiu, D. T.; deMello, A. J.; Di Carlo, D.; Doyle, P. S.; Hansen, C.; Maceiczyk, R. M.; Wootton, R. C. R. Small but Perfectly Formed? Successes, Challenges, and Opportunities for Microfluidics in the Chemical and Biological Sciences. Chem2017, 2 (2), 201–223.

3. Elvira, K. S.; i Solvas, X. C.; Wootton, R. C. R.; deMello, A. J. The Past, Present and Potential for Microfluidic Reactor Technology in Chemical Synthesis. Nat. Chem.2013, 5 (11), 905–915.

4. Amador, C.; Gavriilidis, A.; Angeli, P. Flow Distribution in Different Microreactor Scale-out Geometries and the Effect of Manufacturing Tolerances and Channel Blockage. Chem. Eng. J.2004, 101 (1–3), 379–390.</sup>

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Adrian Zambrano

Adrian Zambrano is a scientist at the Max Planck Institute of Molecular Cell Biology and Genetics in Germany where he synthesizes protein/polymer scaffolds for micro-droplets and utilizes microfluidics for the encapsulation of enzymatic DNA replicators and other DNA-based assays. He holds a Ph.D. in physics from the University of Paris-Saclay/CNRS and B.Sc. in chemical engineering from the University of Nevada, Reno. His personal interests lie in the commercialization and development of high-throughput assays based on microfluidic technology.

• adrianzamphd@gmail.com
• https://sites.google.com/view/adrianzambrano/

The post Why Hasn’t Microfluidics Reached Consumer Market Despite a Huge Number of Academic Inventions and Publications During the Past 15 Years? appeared first on The MicroFluidic Circle.