Going with the (micro) flow: The world of microfluidics

01 November 2023
By Mark Wolverton
Photo credit: Courtesy of the Folch Lab

Even though you probably didn’t realize it at the time,  you probably used a microfluidic device sometime in the past three years. You swabbed the inside of your nose, or maybe spat into a tube, and then you waited for a small, disposable device to give you the verdict: Do you have Covid or not? In fact, you likely encountered microfluidics long before the world ever heard of Covid-19 if you’ve used an inkjet printer, taken a pregnancy test, tested your blood sugar, or mailed off your DNA to discover your personal genetic heritage.

Most of us are at least vaguely aware of the importance of microelectronics in our daily lives, especially since we spend so many hours staring at and using devices that depend on it, such as our phones, computers, TVs, even our cars. But while microelectronics is all about controlling and manipulating the flow of electrons, microfluidics is the study and application of systems that control and manipulate exceedingly small amounts of fluids. That makes a big difference because, unlike electrons, the behavior of fluids is significantly different at the micron scale, allowing microfluidics to open a vast realm of possibilities in chemistry, biology, medicine, and nearly every other area in which there are phenomena to be detected, measured, regulated, and studied.

Biomedical engineer Paul Gordon, who teaches medical device design at the University of Cincinnati, points out that the first big selling point for microfluidics is contained in the very name of the discipline. “Microfluidics is using any number of techniques to manipulate fluid very precisely on a small scale, so that way you don’t need very much of it,” he says. The need for tiny amounts of samples, chemicals, or reactants allows microfluidic devices to be small, portable, and relatively inexpensive.

Even more significant, however, is the intriguing fact that fluid behavior is quite different in very small spaces at about 100 nm up to 500 µm. “At small scales, fluids behave in unintuitive ways,” writes University of Washington bioengineer Albert Folch in an online review. Rather than  “the turbulent, chaotic flow coming out of a garden hose or your shower head,” microscopic fluid flows are quite orderly and even “eerily stable.”

Folch observes that such micron-scale fluid behavior is “the subject of long reviews and textbooks.” One phenomenon is surface tension giving rise to capillarity and wicking effects that can be used to draw fluids through microchannels, as in glucose testing strips. Surface tension also allows the formation of millions of tiny droplets from an initial sample, which can then be combined, separated, or analyzed. In effect, each droplet becomes a tiny chemical laboratory inside of which molecular structure or genetic material can be examined.

Photo credit: Courtesy of the Folch Lab

The “eerie stability” Folch mentions at the microfluidic scale is the result of laminar flow where viscosity dominates inertial forces. Instead of the undisciplined, unpredictable, every-which-way cascade coming from a faucet or garden hose, fluid moves in parallel separate streams at the microscale, not mixing unless induced to do so by precisely patterned microchannels. And when mixing is desired, it can be accomplished very quickly. Says Folch, “diffusive mixing is very fast at small distances, contrary to the mixing of your coffee and milk which you need to stir if you want to homogenize.” Fluid movement can be induced not only by the mechanical pumping used at the macroscale but by the phenomena that become dominant in the microworld, such as capillary flow or wicking, or electro-osmotic flow which uses differences in electrical potential to propel liquids or droplets.

Gordon’s work has parlayed these microfluidic phenomena into the design of diagnostic applications, his particular specialty, developing ways to manipulate blood samples so that only very small samples that can be made very flat, thin, and uniform are required. He explains that this allows laminar flow to be preserved so that “you have the opportunity to manipulate the fluids much more precisely.”  Because phenomena such as surface tension and capillary force tend to become driving properties at the micron-level, Gordon and his colleagues can actually create thin blood smears that are pumpless, “because we knew that capillary force would basically wick our material through our microfluidic device.” This, he explains, “is an example of leveraging a physical property that changes because of the predominant forces in the microfluidic scale.”

Microfluidic phenomena allow for several different design approaches. Some use the photolithography techniques originally developed for creating microelectronic integrated circuit chips to create tiny microchannel patterns on a substrate. When early microfluidic devices were first invented in the 1980s, silicon or glass substrates were used, but these have since been largely supplanted by various polymeric substances, with polydimethylsiloxane (PDMS) one of the most popular because of its transparency, elasticity, gaseous permeability, and low cost. Other microfluidics devices are made of paper, creating microchannels through a printing process, or by cutting a paper substrate.

Paper microfluidics is especially popular in the manufacture of inexpensive or even disposable point-of-care medical diagnostic devices. Gerald Cote, a professor of bioengineering at Texas A&M University, heads a team working on these approaches. “We’re developing point-of-care devices [e.g., hand-held device plus the cartridge] for chronic and infectious disease diagnosis or monitoring,” he says. His team works mostly with paper microfluidic cartridges using optical, laser, and nanoparticle-based sensors, developing bench-top approaches that can then be turned into hand-held devices for diabetes- and cardiovascular monitoring,  for example, or even to diagnose a  heart attack.

The odd world of microfluidic behavior provides more than subject matter for textbooks or the basis for consumer conveniences. Beyond the established applications already making use of it lay an entire range of scientific and engineering research efforts promising significant, possibly revolutionary, advances, particularly in medicine. These encompass not only new and vastly improved diagnostic capabilities, but better ways to develop novel therapeutic approaches. One such approach is known broadly as “organ-on-a-chip.”

The organ- or lab-on-a-chip concept is somewhat analogous to the ways in which various electronic devices such as transistors and capacitors have been steadily shrunk to near-invisible scale by advanced microelectronics. Individual organs or organ systems can be modeled using microfluidic techniques so that normal and abnormal functions can be studied, or the efficacy of new drugs can be tested, replacing or complementing animal or human studies. The approach can be either broad-based or highly individualized. Folch’s lab is focused on developing “tumor-on-a-chip” platforms that can be used to test possible cancer treatments for individual patients.

“We first dissect a tumor biopsy from a cancer patient into thousands of microscopic regular pieces that we keep alive,” he writes. “By virtue of their small size, we can use microfluidics to trap the tiny tumor pieces in multiple wells, one well per drug. These samples retain the appropriate cellular environment of the tumor which will allow us to more accurately predict how a drug will work for a specific person.” The goal is to be able to use a biopsy sample to quickly and accurately design a specific, targeted, and effective treatment approach.

Gordon explains, “The whole premise of an organ-on- chip is that you can basically create a microenvironment that responds very similarly to how your body would respond.”  To do that, various substances or cells have to be brought into very close contact with each other in a very controlled way. “Microfluidics is one of the best ways to do that, because once you make your mold and fab your chip, it’s very scalable,” he says. “It takes something that normally would be very precise and time consuming and makes it very cost effective and economical.”

Photo credit: Courtesy of the Folch Lab

Because most microfluidics devices are partially or wholly transparent, photonics technology is often involved with their applications. “From a manufacturing standpoint, it’s not straightforward to integrate light or light-sensing structures into microfluidics, so it’s not something you see in every device,” Folch explains. “But there have been many efforts at integrating the two technologies.”

One example noted by Gordon is using a microfluidic device as a very small flow cytometer. Microfluidics allows such optical sensing techniques to be taken out of the laboratory and made smaller and therefore more accessible at the point of care. “The main utility of photonics is in the sensing and imaging of the fluid/analytes within the devices,” says Cote. “Since [the devices] are transparent in most traditional [micro]fluidic systems, or on the surface for paper, you can see colorimetric, fluorescent, or Raman signals, depending on the device and recognition elements or fluid used.”

Although everyday microfluidics applications (inkjet printers, fuel injection systems) are pervasive, as are some biomedical uses like Covid-19 tests and glucose test strips, more advanced systems such as organs-on-a-chip aren’t quite ready for prime time. While microfluidics is certainly widely employed in biology and medicine, more development is needed, says Folch. The most pressing issue is to improve upon digital manufacturing techniques for microfluidic devices, which are presently limited to high-resolution 3D printers using a single material. “There are not that many materials to choose from, and they can only print on a small footprint,” Folch explains. “Present multimaterial 3D printers have very poor cyto-compatibility ratings, so we are a bit stuck. We would like 3D printers where we could dial inorganic and organic materials at submicron resolution.”

Cote states that “most microfluidic chips, that is traditional polymer/glass based, are at the development stage.” He points out that while many claims to full lab-on-a-chip capabilities have been made, “I would argue they are currently in development as chip-in-a-lab, with a benchtop full of fluidic pumps and devices feeding the chips.” Although such systems may not yet fulfill the promise of completely portable point-of-care devices, Cote believes that “the future is bright for applications in sensing, cellular/tissue engineering, molecular biology, pharmaceutical development, biodefense liquid electronic and microelectronic systems, and other applications.”

Paul Gordon believes that organ-on-a-chip systems will indeed be part of that bright microfluidics future, though it may take a little time. “I do think we are going to eventually see them become economical to the point where they’re more pervasive and commercialized,” he says. “I do think that as we move into a biological revolution that a lot of people are predicting in the next several decades, with the advent of personalized medicine, genomic sequencing, and really tailoring therapy to individuals based on their own unique biology and physiology, the lab-on-chip systems and organ-on-chip systems are likely to grow with that trend.”

As microfluidics and organ-on-a-chip manufacturing and fabrication techniques continue to develop and mature, the technology will steadily expand beyond the laboratory. “Part of the reason we haven’t seen the organ-on-chip systems really take off, in my opinion, is just because the market isn’t there yet,” Gordon says. “I think it’s coming. The things that are already here and are already a part of our lives, the pregnancy tests, the Covid tests, the blood glucose tests, you’re going to start to see people figure out how to make that same technology work for many more different diseases.” As an example, he mentions a colleague who started a company to develop a paper microfluidics test for Lyme disease, a big problem in many parts of the US. “Right now, where Lyme disease is, you go on a hike, you go for a walk in the park, and you’re worried about Lyme disease. People would kill for a three dollar Lyme disease test they could pick up at CVS.” In general, he says, “We’re on the front side of the curve of applying microfluidics technology.”

Just as microelectronics began somewhat slowly and tentatively in the lab, and then exploded into nearly every area of modern life as its applications were developed and commercialized, microfluidics stands to do likewise, particularly in medicine and bioengineering. Perhaps it’s simply a logical progression, because as Folch observes, “every corner of the human body is microfluidic.”

Mark Wolverton is a freelance science writer and author based in Philadelphia.


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