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Over the last 10 years, researchers have shown that paper is a promising substrate for affordable biosensors. The field of paper-microfluidics has evolved rapidly in that time, with simple colorimetric assays giving way to more complex electrochemical devices that can handle multiple samples at a given time. As paper devices become more complex, the ability to precisely control different fluids simultaneously becomes a challenge. Specifically, automated flow control is a necessary attribute to make paper-based devices more useable in resource-limited settings. Flow control strategies on paper are typically developed experimentally through trial-and-error, with little focus on theory. This is because flow behavior in paper is not well understood and sometimes difficult to predict precisely. Additionally, popular theoretical models are too simplistic, making them unsuitable for complex device designs and application conditions. A better understanding of flow theory would allow devices conceived straight from theoretical models. This could save time and resources by reducing experimental work. In this review, we provide an overview of different theoretical models used to characterize imbibition in paper substrates and document the latest flow control strategies that have been applied to automated fluid control on paper. Additionally, we look at current efforts to commercialize paper-based devices along with challenges facing this industry., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In paper-based microfluidics, the simplest devices are colorimetric, giving qualitative results. However, getting quantitative data can be quite a bit more difficult. Distance-based devices provide a user-friendly means of obtaining quantitative data without the need for any additional equipment, simply by using an included ruler or calibrated markings. This article details the development of a quantitative DNA detection device that utilizes the aggregation of polystyrene microspheres to affect the distance that microspheres wick through filter paper. The microspheres are conjugated to single-stranded DNA (ssDNA) oligomers that are partially complementary to a target strand and, in the presence of the target strand, form a three-strand complex, resulting in the formation of aggregates. The higher the concentration of the target strand, the larger the aggregate, and the shorter the distance wicked by the microspheres. This behavior was investigated across a wide range of target concentrations and under different incubation times to understand aggregate formation. The device was then used to successfully detect a target strand spiked in extracted plant DNA.

We demonstrate the use of patterned aerosol adhesives to construct both planar and nonplanar 3D paper microfluidic devices. By spraying an aerosol adhesive through a metal stencil, the overall amount of adhesive used in assembling paper microfluidic devices can be significantly reduced. We show on a simple 4-layer planar paper microfluidic device that the optimal adhesive application technique and device construction style depends heavily on desired performance characteristics. By moderately increasing the overall area of a device, it is possible to dramatically decrease the wicking time and increase device success rates while also reducing the amount of adhesive required to keep the device together. Such adhesive application also causes the adhesive to form semi-permanent bonds instead of permanent bonds between paper layers, enabling single-use devices to be non-destructively disassembled after use. Nonplanar 3D origami devices also benefit from the semi-permanent bonds during folding, as it reduces the likelihood that unrelated faces may accidently stick together. Like planar devices, nonplanar structures see reduced wicking times with patterned adhesive application vs uniformly applied adhesive.

This article discusses the fabrication of planar and nonplanar 3D paper microfluidic circuits through the use of patterned spray adhesive application and origami techniques. The individual paper layers are held together via semi-permanent adhesive bonds without the need for external clamps. Semi-permanent bonds accommodate the repeated folding and unfolding required by complex origami device structures and allow the device to be unfolded post-use to view internally displayed results. Combinations of adhesive patterns and fluid channel widths were identified that did not prevent the fluid from traveling between layers and through the entire circuit. Further, this method was extended to nonplanar 3D paper microfluidic circuits, demonstrated via multi-fluid wicking within a modified origami peacock. Such nonplanar 3D paper microfluidic circuits are expected to offer an entirely new platform for exploring new designs and functions of paper analytical devices.

In this study, we have developed an integrated microfluidic platform for actively patterning mammalian cells, where poly(ethylene glycol) (PEG) hydrogels play two important roles as a non-fouling layer and a dielectric structure. The developed system has an embedded array of PEG microwells fabricated on a planar indium tin oxide (ITO) electrode. Due to its dielectric properties, the PEG microwells define electrical energy landscapes, effectively forming positive dielectrophoresis (DEP) traps in a low-conductivity environment. Distribution of DEP forces on a model cell was first estimated by computationally solving quasi-electrostatic Maxwell's equations, followed by an experimental demonstration of cell and particle patterning without an external flow. Furthermore, efficient patterning of mouse embryonic stem (mES) cells was successfully achieved in combination with an external flow. With a seeding density of 10⁷ cells/mL and a flow rate of 3 μL/min, trapping of cells in the microwells was completed in tens of seconds after initiation of the DEP operation. Captured cells subsequently formed viable and homogeneous monolayer patterns. This simple approach could provide an efficient strategy for fabricating various cell microarrays for applications such as cell-based biosensors, drug discovery, and cell microenvironment studies.

This paper presents a microfluidic device for sorting embryoid bodies (EBs) with large dynamic size ranges up to 300 microm. The proposed separation scheme utilizes appropriately spaced pillars within a microchannel to alter the fluid flow pathway, thus allowing particles of defined sizes to be diverted towards specific flow paths. We test the device functionality by separating polystyrene beads 90, 175 and 275 microm in diameter, demonstrating separation efficiencies approaching 100%. We then demonstrate for the first time on-chip separation of mouse EBs, which were separated into three size groups. The ability to extract specific size ranges of EBs will greatly facilitate their subsequent differentiation studies.