By Deborah Borfitz
May 17, 2022 | A first-of-its-kind microfluidic diagnostic device that eliminates the usual liquid handling steps could enable pathogen detection, as well as gene sequencing, outside of a lab setting involving a lot of equipment and personnel. The small, no-frills chip is being developed by electrical and computer engineers at the University of Minnesota Twin Cities.
Proof of concept demonstrating critical design features of the novel open-channel microfluidic device was recently documented in an article appearing in Nature Communications (DOI: 10.1038/s41467-022-29405-2). The wireless, smartphone-driven technology provides a “missing link” making more sophisticated portable, at-home diagnostics possible with its ability to move liquid droplets on a microchip without all the tubes, pumps, and wires, according to Sang-Hyun Oh, Ph.D., a professor at the university who holds several of the associated patents.
More than a decade ago, Oh and his colleagues realized that scaling down the spacing between electrodes on a capacitor to mere nanometers generates extremely high electric fields. While difficult to make, they developed new techniques to do so at high throughput, covering large surface areas and at relatively low cost, and one of the first applications was to trap particles—including biomarkers, viruses, and bacteria—in the electrode gap so they could be more precisely tracked, he says.
Conventionally, an electrode would be immersed in a liquid to trap whatever particles it might contain, but the process is always complicated, continues Oh, especially if the device is meant to be portable. The alternative approach taken by Oh and then-student Christopher Ertsgaard, Ph.D. (now an advanced physicist at Quantinuum, a quantum computing company majority owned by Honeywell), was to “trap the liquid itself using electrodes in an open channel configuration.”
The electrodes used were so small and of such high quality that even a very low voltage, like that powering a smartphone, allowed them to capture tiny amounts of liquid “fingers” (aka “capillaries”) and manipulate them in ways not possible before. Interestingly, giving the electrodes a three-dimensional (3D) structure helped break down the surface tension enough to allow the capture of physiological samples in a saline solution, notes Ertsgaard, who shares credit for this discovery.
In previous attempts to trap liquids to concentrate the particles, biological samples would always break down when they became too salty, says Ertsgaard. He and Oh ran into a similar problem until they noticed one of the poorer quality samples, which consequently had larger 3D electrode topography, had the highest particle count. Motivated by this discovery, they decided to purposefully optimize the electrode geometry to reduce surface tension to great success.
They did not fail to notice that the liquid fingers they were generating were very much like the tears of wine that form inside a glass due to surface tension caused by the evaporation of alcohol, says Oh. “Essentially, we are generating tears of liquid on the chip… [but] doing it in a more controlled manner with changes in gradients in surface tension by generating a strong electric field.”
The recently published study focused primarily on demonstrating actuation of the microfluidics chip. But to highlight its diagnostic potential, the research team also did simple sample mixing, filtering out excess material on-chip, and measurements of virus-like particle capsids within the device channels.
Cutting-Edge Developments
Current state-of-the-art microfluidic systems involve classic tubes, pumps, and channels provide a lot of flexibility, but are “very difficult to assemble,” Ertsgaard says. The devices also require a relatively large amount of patient sample to fill up all the tubing, which wastes a lot of that precious resource. These have been some of the challenges in commercializing lab-on-a-chip technology over the past few decades.
Electrowetting, an alternative to microfluidics, is more like open-channel electrofluidics in that it also uses electric fields to process the sample, he continues. The technology doesn’t involve a lot of tubing and is therefore easier to manufacture, but its applications are limited to macroscopic tests. It operates on big droplets, making it burdensome to confine analytes close to the sensors on chip as compared to the narrow channels.
Liquid dielectrophoresis is what parallels the approach being taken with the novel chip—minus the innovation of the closely spaced, 3D-constructed electrodes, says Ertsgaard. The predecessor technology can actuate a confined channel, “but initially only on the order of 1,000 volts and [the liquid] must be low in salinity, below physiological levels, so it is also very limited.”
One of the main challenges of working in the lab-on-a-chip field has been the high voltage requirements of manipulating a liquid droplet, adds Oh. Typically, tens if not hundreds of volts are needed, making the technique incompatible with portable electronics such as smartphones. “We cut the threshold to make the liquid handling technique compatible with common electronic circuitry.”
That opens the door to multiple imagined applications beyond medical diagnoses, says Ertsgaard, including liquid displays and tubular optics if researchers can speed up their liquid-pulling technique. The electronic ink used with eReaders (e.g., Kindle and Nook) is oftentimes “electrically moving an opaque liquid to make screens that aren’t glaring like an LCD [display], he notes.
The prototype microfluidic chip was fabricated by the Minnesota Nano Center at the University of Minnesota. But ultimately, any semiconductor foundry will easily be able to manufacture the device to scale production, says Oh.
The open channel architecture of the novel device means that it only gets selectively wetted where needed rather than immersed entirely into a liquid solution, he says. “I think that’s what makes our design better than [conventional] microfluidics or droplet fluidics … and now we can do that with low voltage compatible [with] microelectronic chips.”
The best first use case for the wireless, smartphone-driven microfluidics device is bio-diagnostics, specifically the detection of pathogens concentrated on the sensing surface that is being pursued by Minnesota startup company GRIP Molecular Technologies, says Oh.
The broader vision, says Ertsgaard, is to have “all the electronics powered on a portable chip brought to either some Third World country or at-home diagnostics where instead of having to do all these mixing steps [as with antigen-based COVID-19 tests] externally … patients could just place a drop [of sample] on this chip and their smartphone could automate the [mixing and purification] steps for them.”
Disease detection would presumably improve, even with very small sample volumes, since the material would be concentrated closer to the sensors, he adds. It may even be possible to do gene sequencing on the chip to, for example, detect the strain of a coronavirus or more comprehensively label what is in the sample. That could potentially enable earlier detection of biomarkers, including cancer cells in the blood.
One more distinct possibility is that the detection platform could be integrated with a portable Nanopore sequencer. “That is already an incredibly powerful platform, and we can make it even more versatile” with the addition of the chip’s liquid handling, mixing, precise guiding of liquids, and sample purifying functionality, says Oh.