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Micro-engineered liquid flow dissolves solids without dispersing them

Microfluidic devices have revolutionized biological assays, but complex set-ups are required to prevent the unwanted mixing of reagents in the liquid samples being analysed. A simpler solution has just been found.
Robert Hołyst is at the Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw 01-224, Poland.
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Piotr Garstecki is at the Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw 01-224, Poland.
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In a paper in Nature, Gökçe et al.1 report a clever solution to a fundamental problem in microfluidics: a simple and inexpensive method for delivering a liquid to multiple dried reagents that doesn’t mix all the reagents together. By considering diffusion, convection (the flow along a channel) and capillary forces, the authors designed a microfluidic structure that produces a complicated, yet highly reproducible, liquid flow that first passes around dried spots of reagents and then back over them. This dissolves the dried reagents, but minimizes unwanted dispersal within the flow.

The 1990s saw an explosion of interest in microfluidics, driven by a vision of liquid-handling systems that were faster, simpler and smaller than existing devices being used in chemistry and biology. The fluid dynamics of liquids in microfluidic channels is fascinating: streams of distinct liquids typically flow side by side without turbulence or mixing2, unlike liquid flows at larger scales. Convection in these systems can be tuned to rates similar to those of diffusion, which opens up a way to control the concentration gradients of chemical reagents across parallel streams. Surprisingly, it was also found that the flow of immisicible liquids, which involves highly complex surface-tension forces, produces regular patterns of equally sized microdroplets in microchannels3.

The ratio of the surface area of a microchannel-confined liquid (that is, the surface area bounded by the channel walls) to its volume is large, allowing heat and mass to be rapidly transferred to such liquids. Moreover, the flow of the liquid can be tightly controlled. Taken together, these features make microfluidics devices a useful platform for studying chemical reactions and biological processes. For example, miniature water droplets suspended in an oily continuous phase in microchannels can be used as reactors for chemical or biological processes.

The advent of microfluidics and droplet technologies led to breakthroughs in the life sciences. For example, these technologies have enabled digital assays4 that can measure the concentration of specific genes in a sample without calibration. They are also key to the single-cell genetic-sequencing techniques5 currently used in the Human Cell Atlas, a project that aims to characterize every cell type in the human body6. Furthermore, microfluidics technologies are powering a wave of new point-of-care systems that bring diagnostic assays closer to the patient’s bedside7.

But a fundamental problem remains. In most applications, the microfluidic assay must run multiple analytical reactions on the same liquid sample. Each reaction requires a different reagent, which is dried and pre-stored on the cartridge before the sample is added. These reagents should not mix with each other, because this would ruin the assay. But mixing is hard to avoid once the sample has been added, because of dispersion effects in the liquid. Several solutions to this problem have been proposed, always involving two steps — one to deliver the sample to the reagents, and the other to isolate the microchambers in which the reagents are stored from each other. The second step typically either uses an immiscible liquid as a barrier, or the microchambers are enclosed by solid walls, but either option complicates the design, manufacturing and use of these systems.

Gökçe et al. have tackled the problem in a much simpler way. They prepared a straight section of channel that is divided into two along its length by a shallow barrier, and deposited dried spots of reagents in one of the resulting halves (Fig. 1). They then introduced a sample liquid so that it filled the other half of the channel, before changing direction to bend around the end of the barrier and fill the portion of the channel containing the dried spots. Once the whole channel has been filled, the resulting solution of reagents is released through a valve so that it can enter the next section of the microfluidic system. This produces a solution that has an approximately uniform concentration of reagents throughout its volume. By contrast, when dried reagents are dissolved by a liquid in a simple, unstructured microchannel, dispersion processes cause the reagents to become concentrated at the moving front of the liquid.

Figure 1 | A module for microfluidics. a, In Gökçe and colleagues’ microfluidic architecture1, a straight microchannel is divided by a shallow barrier, and dried reagents are spotted along one half. A liquid sample entering from the inlet first passes down one side, and then fills the side containing the reagents. Air pushed ahead of the moving front of the liquid escapes through a vent. b, The dried reagents dissolve, and the resulting solution spills over the shallow barrier to fill the whole channel. The capillary forces generated in the system prevent the reagents from being dispersed so that they become concentrated at the moving front, as they would have been in a simple channel. Once the channel is full, the liquid is released through the diversion barrier to the outlet. The system allows multiple reagents to be dissolved in a liquid sample without being mixed together by dispersion.

The authors went on to demonstrate how their system could be used to precisely control the concentration and the timing of addition of reagents in complex biochemical reactions, in two assays: one that detected DNA sequences of the human papilloma virus, and the other that quantified the activity of an enzyme. In both cases, the assays involved the use of several reagents (enzymes and their substrates, cofactors, fluorescent reporter molecules, and so on).

The key to Gökçe and co-workers’ invention is the shallow barrier in the channel, which acts as a capillary pinning line — an interface with the liquid that constrains the liquid’s motion through capillary forces. The phenomenon of capillary pinning is common in nature; for example, it holds water droplets to minuscule specks of dirt on glass. Capillary-pinning lines underlie such diverse effects as the formation of coffee rings from droplets spilt on a table8, or the unidirectional flow of water in the carnivorous pitcher plant Nepenthes alata9.

Capillary pinning has been used in microfluidics systems before, for example in capillary valves10, which control liquid flow without using mechanical parts. They have also been used in phaseguides, which form barriers to flow perpendicular to the direction of motion of the liquid–air meniscus — these barriers hold the meniscus until enough pressure has built up for liquid to flow over the barrier11. Gökçe et al. have used capillary pinning in a new way: to enable liquids to flow over dried spots of reagents without causing the reagents to disperse uncontrollably within the liquid, thus allowing the concentration profile of the reagents in the resulting solution to be controlled by the positioning of the original spots.

The authors’ use of small-scale capillary forces allowed them to segregate reactions without using solid walls. This opens up a simple approach for preprogramming and implementing large numbers of biochemical reactions in straight microchannels, removing the need for complex microfluidic chips that have large numbers of compartments and valves. The authors also show that the geometries of their microchannel systems can be made using inexpensive mass-production methods. These systems could therefore help to bring increasingly sophisticated biochemical assays closer to patients in point-of-care devices.

Nature 574, 181-182 (2019)

doi: 10.1038/d41586-019-02973-y

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