Patterning and Modelling Three-Dimensional Microfluidic Devices

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Patterning and Modelling Three-Dimensional Microfluidic Devices Fabricated on a Single Sheet of Paper Maria F Mora, Carlos Diego Garcia, Federico Schaumburg, Pablo A. Kler, Claudio Luis Alberto Berli, Michinao Hashimoto, and Emanuel Carrilho Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b01020 • Publication Date (Web): 14 May 2019 Downloaded from http://pubs.acs.org on May 15, 2019

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Analytical Chemistry

Patterning and Modelling Three-Dimensional Microfluidic Devices Fabricated on a Single Sheet of Paper Maria F. Mora,1,‡ Carlos D. Garcia,2* Federico Schaumburg,3 Pablo A. Kler,4 Claudio L. A. Berli,3 Michinao Hashimoto,1,§ Emanuel Carrilho,1,5* 1Department

of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138; of Chemistry, Clemson University, Clemson, SC 29631, USA; 3INTEC (Universidad Nacional del LitoralCONICET), Santa Fe, Argentina; 4CIMEC (Universidad Nacional del Litoral-CONICET), Santa Fe, Argentina; 5Instituto de Química de São Carlos, Universidade de São Paulo, 13566-590 São Carlos, SP, Brazil. KEYWORDS: Paper-based Microfluidic Devices, photoresist, 3D devices.

2Department

ABSTRACT: This work describes a method to fabricate three-dimensional paper microfluidic devices in one step, without the need of stacking layers of paper, glue, or tape. We used a non-transparent negative photoresist that allows patterning selectively (vertically) the paper, creating systems of two or three layers, including channels. To demonstrate the capabilities of this methodology, we designed, fabricated, and tested a six-level diluter. The performance of the device was also simulated using a simple numerical model implemented in the program PETSc-FEM. The resulting µPAD is small (1.6 cm x 2.2 cm), inexpensive, requires low volumes of sample (5 µL), and is able to perform mixing and dilution in 2 min.

1. INTRODUCTION Driven by smaller sample volumes and shorter analysis times than conventional methods, applications of microfluidics can nowadays be found in almost every field of science and engineering. Although multifunctional microfluidic devices can be fabricated in glass or a variety of polymeric materials,1,2 most of them still require a suite of associated instrumentation for operation. Aiming to overcome these requirements, paper microfluidic devices have been introduced.3-5 As a significant difference to the traditional paper-based lateral flow assays, microfluidic platforms can avoid cross-contamination, perform multiple analyses with the same sample, and integrate a series of analytical operations (dilutions, preconcentration, signal amplification,6 and separation7) within the device. As a consequence, the versatility of the assay can be significantly improved4 and (semi)quantitative information be obtained. Paper devices also have several attractive features including low cost, versatile functionality, low surface tension, transportability, and disposability making them an excellent choice for point-ofcare platforms for biochemically-relevant analyses. A variety of systems have been proposed recently to fabricate paperbased microfluidic devices.8 Among others, it is worth mentioning classic photolithography (SU-83, 9), direct printing (PDMS,10 polystyrene,11 wax,12-13 or toner14), liquid molding,15 plasma treatment,16 laser cutting,17-18 thermal transferring,19 and stamping.20 To further enhance the functionality of paperbased devices, a series of elements have also been recently presented. Chen et al. described the possibility of fabricating fluidic diodes, valves, and sequential circuits on layered paper.21 Noh et al. included a fluidic timer to allow timedependent operations22 than can be complemented with sequential fluid delivery architectures.23 Although great

progress has been made, most current architectures are limited to 2D designs, performed in a lateral fashion.24-26 In this regard, it is worth mentioning the development of paper-based tree-like networks,27 co-flows in Y-shaped channels,28 and multiple co-flows in single channels.29 In principle, 3D devices can allow shortening the path length of the channels, the time required to distribute the fluids,30 enable performing operations that a 2D arrangement simply can’t, and further increase the throughput and applicability of the devices. Although some of the limitations associated with lateral designs could be overcome by stacking series of twodimensional structures,4,30-33 the development of simple methods to fabricate multiple layers is a critical need to bolster the development of bioanalytical applications. Aiming to address this shortcoming, this manuscript describes a simple method to pattern three-dimensional (3D) structures for microfluidic devices on a single sheet of paper. Here, 3D patterning was achieved through the use of a negative photoresist (based on cyclized polyisoprene rubber material, SC Resist) that absorbs UV light. This selfabsorption made it possible to control the depth of the polymerization reaction, which proceeds from the surface to the center of the paper. Therefore, a 3D network of microchannels can be patterned in a single sheet of paper using two masks (top and bottom) and enabling the development of microfluidic devices with more sophisticated architectures than those that could be generated with singlelayer fabrication. Upon defining the type of features that this method can generate and the protocol for formation of twolayer microfluidic systems, the advantages of the method were demonstrated by the fabrication of a chip to perform a serial dilution of analytes or standards, and a combinatorial mixer capable of mixing two reagents. The results are complemented

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by a simulation that accounts for the fluid properties, the characteristics of the porous matrix, the molecular diffusion of the solute, the fluid velocity, and the species’ concentration. 2. MATERIALS AND METHODS 2.1 Reagents and Instrumentation. All aqueous solutions were prepared using 18.2 MΩ.cm ultrapure water (MilliQ, Millipore, Billerica, MA) and analytical reagent grade chemicals. Experiments herein described were performed using a 600 W metal halide lamp (UVitron Intelliray 600). This lamp delivers high intensity (100 mW cm−2), long-wave (365 nm) ultraviolet light. To define the patterns, masks were designed using CleWin (PhoeniX Software, The Netherlands) and printed on a transparency film using an HP Deskjet D2430 inkjet printer (Hewlett-Packard Company, Palo Alto, CA). To produce masks of better quality, mirror images of each design were printed in a transparency, aligned, and glued together. Because the procedure described here requires the use of two masks (identical or not, according to the three-dimensional structure desired), these were also aligned and held together with tape. In this way, the paper to be patterned could be placed in the middle and then exposed to UV light on each side. 2.2 Fabrication of paper devices. Paper devices were fabricated using Whatman chromatography paper #1 as the substrate. As reported elsewhere,18 this substrate features an adequate balance of thickness (180 µm), porosity (10.9 s), and wicking speed (130 mm / 30 min). In order to define the 3D architecture, a negative photoresist (SC series, Fujifilm Chemicals Cat. # 820024) was selected. This resist is composed of a hydrophobic matrix (cyclized polyisoprene) and a photo-initiator dissolved in xylene (see Supplementary Information, Figure SI-1). Upon exposure to UV light, an insoluble polymer is formed, changing the optical properties of the resist, and defining the structures on the surface of the paper (see Supplementary Information, Figure SI-2). It is also important to state that the selected photoresist is also relatively inexpensive (approximately $100/L) and that it can be processed without baking steps, representing a significant advantage over the traditional SU-8 (typically, approx. $800/L). To simplify the fabrication process and to decrease the viscosity and cost of the final device, the commercial SC photoresist was diluted in xylenes (to a final concentration of either 50% or 10% wt.). In all cases, the paper (12.5 cm x 9.5 cm) was soaked in 2.5 mL of the SC solution and then allowed to evaporate at room temperature. Then, both sides of the composite were exposed to UV light (using either 100 mW cm−2 or 50 mW cm−2) through the corresponding masks. Next, the paper was sequentially rinsed with xylenes (3 min) and methanol (3 min) to remove all non-polymerized SC resist and any residual xylenes left. After the methanol was allowed to evaporate under ambient conditions (~15 min under the fume hood), the devices were ready to use. Finally, the patterned paper was oxidized for 5 sec at 600 millitorr (SPI Plasma-Prep II, Structure Probe, Inc) to increase the hydrophilicity of the channels created. Figure 1 summarizes the patterning procedure used. It is also important to state that the first step of the patterning procedure of 3D devices included the use of a protection mask, to polymerize the photoresist around the channels of the actual device, as schematically shown in the Supplementary Information (Figure SI-3). The protection

mask consists of the features of both masks (I and II) combined.

Figure 1. Schematic diagram showing the standard procedure employed to pattern 3D-devices on paper using SC resist. Although the masks used for the process are both black, in the figure they are represented with different colors to aid the visualization. First, 2.5 mL of SC solution are spread over the paper. Once the paper is dry, it is aligned between the two masks (I and II) using two quartz plates (not shown in the Figure). Then, each side of the paper is exposed to UV light with either Mask I or Mask II. In the case of using two masks that have different features, an additional step using a protection masks is required before exposing the paper to UV light with Mask I and II.

2.3 Optical detection. In order to digitize and analyze the results, a standard desktop scanner (EPSON Perfection 1640 SU) was used. In all cases, 3D devices were first allowed to dry, scanned in color mode, and the corresponding images were imported into Adobe Photoshop. The color intensity in each well of the final row in the diluter was measured by selecting the area with the elliptical marquee tool and by recording the mean pixel intensity in the RGB channel, using the histogram tool. These values were correlated with the concentration of the corresponding analytes. 2.4. Numerical simulations. To simulate the transport of a solution containing a given solute (or even small particles) in paper-based gradient generators, a fluid stream of constant average velocity was considered. These species are subjected to Brownian motion, and hence they naturally diffuse a certain distance controlled by the molecular diffusion coefficient (D0). In the pore space, the alternating variation of fluid velocity, in


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Analytical Chemistry both magnitude and direction, introduces a mechanical dispersion of the solutes. Therefore, and considering the scope of this manuscript, fluid dynamics and mass transfer problems were modeled in the context of continuum transport phenomena. More details related to the parameters and methods used in the simulations are included in the Supplementary Information section. 3. RESULTS AND DISCUSSION 3.1. Differential Patterning of Channels in Paper with SC Resist. The design of microfluidic structures in paper typically requires patterning hydrophobic barriers to define the areas available for the solution to wick. When photoresist is used to define such structures, the entire volume of the paper is first impregnated with the resist and then exposed to UV light through a mask to define the areas where the resist will be crosslinked (negative photoresist). The effect of several experimental factors affecting the permeability of the channels was systematically investigated with the goal of controlling the polymerization of the photoresist (from the surface of the paper). In this case, the channels formed were evaluated as a function of the concentration of resist, exposure time, light intensity, and the opacity/transparency of the masks (variable optical density printed in grayscale). Initially, the effect of the concentration of SC resist (diluted in xylenes) was investigated using a simple design comprised of two wells (5 mm in diameter) connected by a straight channel (2 mm in width) and using a range from 10 – 100% SC. According to these results (data not shown), the solution containing 10% of SC resulted in incomplete barriers that leaked solution. On the other extreme, 100% SC resulted in increased cost and preparation time due to the viscosity of the resist. As a compromise between the quality of patterns and the processing time and cost, a 50 wt.% solution was selected as optimum and used for the remaining experiments. The second parameter that was investigated to define the penetration depth of the polymerization was the exposure time. To evaluate this effect, the thickness of film of polymerized resist in the paper was measured as a function of exposure time using 50 mW cm−2 (the lowest setting available). To determine the thickness of polymerized resist, the channels were filled with blue dye (Coomassie blue) to allow simple analysis of images of the cross-sections of the paper, as obtained with a digital camera (Nikon DXM1200) attached to a stereomicroscope (Leica MZ12). In all cases, the analysis included measurements of the total thickness of the paper (~180 µm), the thickness the resist polymerized into the paper (in several positions in the same channel, n = 8) and the thickness of the unmodified paper (as estimated by the exclusion of the dye). Figure 2 shows representative results of the depth of the polymerized photoresist as a function of the exposure time, where the typical sigmoidal dependence with respect to the exposure time (dose) was obtained. These results demonstrate that is possible to create partial structures in the surface of paper by UV exposure with a transparent mask, using relatively short exposure times (< 40 sec). Moreover, the depth of the polymerization could be controlled from 64 ± 5 m (5 sec) to 112 ± 10 m (> 30 sec). While it is important to note that a more accurate control of the polymerization depth could be achieved by the use of specialized instrumentation, these experiments provide an opportunity to use low-end lamps, therefore maintaining the

cost low for the fabrication procedure. Two additional possibilities were investigated to control the path of fluid on the paper: partial polymerization of the photoresist using a gray-scale masks (similar to a neutral density filter made on a printer) and the use of plasma cleaner. These results (Figure SI-4) indicate that darker masks (≤ 30% gray-scale) yielded the formation of complete channels, whereas more transparent masks allowed sufficient UV light to polymerize enough photoresist to seal the channels. As shown, treating the device with plasma oxidation, increases the hydrophilicity of the channels and facilitates the penetration of the liquid. It is also important to point out that combinations of gray-scale values higher than 30% and longer exposure times (> 10 sec) rendered closed channels where no flow of liquid was observed, even after plasma oxidation (data not shown). A) 180 Thickness of the paper

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Figure 2. A) Effect of exposure time on the thickness of the polymerized layer of SC photoresist. Conditions: 50 wt.% solution of SC resist in xylenes, 50 mW cm−2. The points represent the average of eight measurements and the error bars represent one standard deviation of the mean. B) shows a sideview of the paper occupied by the polymerized photoresist and portion of bare substrate (layer tinted with a 3 mM solution of Coomassie blue).

3.2 Design, Fabrication, and Testing of a Six-level Diluter. Having defined the experimental conditions required to produce channels on the paper, the strategy was applied to perform dilutions/calibrations in a simple step without the need for pipettes. Figure 3A shows the masks employed to


Analytical Chemistry create the device as well as a picture of a 3D device showing the mixing of the two dyes. In this case, the device consists of a top and bottom layer containing wells and channels; each well (d = 3 mm) in one layer overlaps with two other wells in the opposite layer and vice versa. In order to allow the liquid to displace longitudinally on the paper device, the wells are connected through channels in each layer (sides of the paper). This design allows the liquid to flow from the top to the bottom layer, and then from the bottom to the top layer. This process is repeated as many times as rows are included in the mask (picture shown in Figure 3A contains a total of 5 rows). Figure 3B schematically shows the 3D device and how the liquids are mixed as they move through the device. Figure 3C includes an image of the cross-section of the device showing how two wells are connected from the top to the bottom of the paper. The time needed to fill the 3D device shown in Figure 3A with 10 µL (total volume) of solution was 2.2 ± 0.1 min.

dilutions are performed with water, the first well has the same color as the original solution used, while the last well corresponds to water, which is used as reference or as blank for the colorimetric measurement. Then, based on the mixing of the two solutions, the percentage of the original solution remaining on each spot of the final row should be 100% (original solution), 93.8, 68.8, 31.2, 6.2, and 0% (water) from left to right. To test this hypothesis, we performed dilutions of a commercial dye (amaranth), at three different concentrations. For each initial concentration, we performed 10 repetitions and then plotted the color intensity (average ± standard deviation) of each spot as a function of the percentage of the original concentration of the solution dispensed in the device. Figure 4A shows the mean pixel intensity as function of the dilution factor (% of the initial concentrations) for three concentrations of amaranth dye: 0.64, 0.32, and 0.16 mg/mL. A) 250

Mean Pixel Intensity

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240 230 220 210 200 190 180 0.64 mg/mL y= -0.41x + 215.6 R=-0.998 0.32 mg/mL y= -0.32x + 222.3 R=-0.996 0.16 mg/mL y= -0.22x + 223.5 R=-0.994

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Figure 3. Handling fluids three-dimensionally in a single-layer device. A) Maks used to create the 3D dilution device next to a picture showing the mixing of blue and pink dyes (erioglaucine 1 mM and amaranth 1 mM in water). B) Schematic drawing of the 3D device showing the flow of the liquid. C) Side view of one section of the paper showing how the solution is separated into the two hydrophilic wells underneath.

To evaluate the analytical performance of the device shown in Figure 3, we performed dilutions of a commercial dye with water. In this case, we dispensed a solution of known concentration of the dye in one inlet (100%) and water (0%) in the other one. Once the liquids flowed through the device and the paper dried, we imaged the devices with a scanner in order to correlate the expected amount of dye on each detection spot with the color measured in the outlet. After acquiring the images for each experiment, we used Adobe Photoshop to obtain the arithmetic mean of pixel intensity within each test well using the RGB channel. According to the design, when

Figure 4. A) Plot of the color intensity in each well after performing dilutions of 0.64, 0.32, and 0.16 mg/mL of amaranth with water. Each point in the graph corresponds to the average pixel intensity from the RGB channel (n = 10) of each image from each well. Error bars represent one standard deviation of 10 measurements. B) Picture of 3D devices used to perform 10 repetitions of dilutions of two different concentrations of amaranth dye with water.

Figure 4A shows that the three curves converge at a common value (0%) with a mean pixel average of approximately 220. The reason for this is that the 0% concentration corresponds to pure water (as mentioned before) and the pixels measured should match the value for white (maximum value of 255 counts in the RGB 8-bit system) i.e., the color of the paper. Because the paper is somewhat translucent, the thin layer of SC resist polymerized at the bottom of the paper in each hydrophilic well (in the opposite


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Analytical Chemistry side of the image area) affects the image and the value obtained for water was smaller than 255. Figure 4A also shows that the values for 100% are quite different, with lower pixel values (darker colors) for higher concentrations of the dye. We also performed a reference calibration curve using the 3D device by adding the same solution of known concentration in both inlet wells (so there was no dilution effect) and measured the mean pixel value for each spot at the end of the device to better mimic the color-concentration imaging process. In this way, the values obtained can be correlated to the values measured when carrying out the dilutions. The reference calibration curve is included as the Supporting Information (Figure SI 5). Using the reference calibration curve, we calculated the concentration of each spot for the solutions measured in Figure 4. The correlation between the experimental (according to the percent dilution) and the calculated concentrations (based on the pixel intensity and the calibration curve) are shown in Figure 5.

Figure 5. Correlation between the experimental and theoretical concentrations in each spot (after dilution through the 3D device). The experimental concentration was obtained from the pixel intensity and the reference calibration curve from the Supporting Information. The points represent the average of at least five measurements and the error bars represent one standard deviation of those 5 measurements. The line included represents a linear fit (slope =1, R2=0.97) between the two measurements and it’s included to assess the limits of the technique.

As it can be observed, a very good correlation between the predicted and the experimental values was obtained in the 0.1 – 0.64 mg/mL range, therefore validating the proposed device. Considering the calibration curve for the dye, the deviations observed outside this range can be attributed to a combination of device-to-device variations and the detection method (optical) rather than to a problem with the dilution performed in the device. Although the example presented here is rather simple, this strategy could be extended to fabricate other devices for more complex applications such as screening of enzymatic competitors or inhibitors, titrations, or even monitor reactions for which a change in color is observed. 3.3 Numerical simulation of solute dispersion in 3D devices. To further support the development and application of the single-sheet 3D device, a computer model was developed to describe the flow pattern. It is important to

mention that a handful of simple devices performing concentration gradients have been described in the literature, including conventional tree-like networks,27 co-flows in Yshaped channels,28 or multiple co-flows in single channels.29 In this regard, mixing on paper-based devices could be considered a closely related operation, as long as concentration gradients are formed34-35 and considering that the mixing can be achieved in much shorter distances, because transverse solute dispersion in porous media is dominated by mechanical dispersion in the pore space, which is much more efficient than molecular diffusion. In fact, the foundations of transverse solute dispersion in filter paper have been explored by theory and experiments in a recent study.36 Expanding on these developments, one should first note that the value of the dispersivity constant s was estimated to properly represent experimental data of solute dispersion in the 2D paper-based gradient generator. A quantitative analysis of the reflected light intensity from experimental pictures was carried out for the purpose, as described in the Supplementary Material (Figures SI 6 – 9). The values of s that best matches experimental data is in the range of 35 to 65 m. These results are realistic considering the values of s measured by Urteaga.36 Figure 6 presents an example of the numerical simulation of our 3D device for a gradient generation, with the same channel structure as that from the microchip in Figure 3. Figure 6A shows the contours of dye concentration during the imbibition process, where one may observe the details of the fluid front in all the segments, including out-of-plane movements. Figure 6B includes the streamlines, which allows one to study the details fluid paths in every splitting and mixing steps. The simulation is thus a practical tool to optimize the performance of the diluter, as well as to design different configurations of 3D devices.

Figure 6. A) Amaranth dye concentration in the flow domain of the 3D paper-based gradient generator and B) streamlines in the same device. Plot are numerical results corresponding to 230 s after the beginning of the experiment.

4. CONCLUSIONS This paper describes a unique photolithographic method for creating 3D devices in a single sheet of paper. The developed 3D devices were used to perform sequential dilutions, which required small sample volumes (5 L) and short times (2 min) without the need for pipetting or pumping solutions. One of the disadvantages of the device is the hydrophobicity of the photoresist confining the channels, which delays the movement of the fluids inside the device. However, performing plasma oxidation of the device can minimize this issue. We believe the technology described here opens the unique possibility of handling fluids three-dimensionally in a single sheet of paper, and that such devices could have many



applications in which fast and inexpensive devices are required.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Document includes results related to the characterization of the selected photoresist, design of the protection masks, use of GrayScale Masks and Plasma Cleaner, Numerical Simulations, Calibration Curve for Amaranth Dye on Paper, and Estimation of the Paper’s Dispersion Coefficient (2019_04_SI.docx)

AUTHOR INFORMATION Corresponding Author * Instituto de Química de São Carlos, Universidade de São Paulo, 13566-590 São Carlos, SP, Brazil, [email protected]. * Department of Chemistry, Clemson University, Clemson, SC, 29634, [email protected]

Present Addresses ‡

Currenty at Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA, USA § Currenty at Engineering Product Development, Singapore University of Technology and Design, Singapore

Author Contributions The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENTS This work was funded in part by the Bill & Melinda Gates Foundation under Award Number 51308 and the Micro-Nano Fluidics Fundamentals Focus Center (MF3) at University of California, Irvine. The authors acknowledge a visiting scholar fellowship from the Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP Proc. # 06/02007-9 (E.C.). Authors also thank Dr. George M. Whitesides for kindly providing access to the facilities at Harvard University, where part of the work was performed.

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Patterning and Modelling Three-Dimensional Microfluidic Devices

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