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Article Cite This: ACS Omega 2019, 4, 6192−6198
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Microfluidic Modules with Integrated Solid-State Sensors for Reconfigurable Miniaturized Analysis Systems ́ ez,* Ceś ar Fernań dez-Sań chez, and Antonio Baldi Pablo Gimeń ez-Gom Instituto de Microelectrónica de Barcelona (IMB-CNM, CSIC), Campus UAB, Bellaterra, 08193 Barcelona, Spain
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S Supporting Information *
ABSTRACT: The fast and simple fabrication of modular microfluidic devices comprising different fluidic components and configurations that can rapidly be assembled and reconfigured depending on the requirements of a particular application is very attractive. The application of these modular systems as complete analysis systems requires the incorporation of flow-cell modules capable of selectively detecting chemical species. Here, a new magnetic clamping approach is presented that allows both interconnection of microfluidic modules and reversible integration of solid-state sensors. Planar and optically transparent materials are used to easily assess device fluidic performance. Double-sided polyacrylic adhesive layers, sandwiched between two transparent polycarbonate films, are mechanized to produce fluidic structures containing the required inlets and outlets. The latter also include chemically bonded poly(dimethylsiloxane) gaskets for easy leak-free interconnection of the different modules and the incorporation of chemical sensors without adding dead volumes. Microfluidic channels, junctions, mixers and flow cells with solid-stated sensors are thus fabricated. Different microfluidic modules are assembled with the aid of poly(methyl methacrylate) clamping structures containing embedded magnets. By using a magnetic breadboard, complete microfluidic analysis systems can be arranged in a few minutes. Three systems incorporating conductivity, amperometric, or pH sensors are thus assembled and fully characterized to show the advantages of the presented approach for analytical applications.
1. INTRODUCTION Microfluidics science and technology has greatly evolved over the past two decades thanks to the continuous development of microelectronics manufacturing processes including the application of a wide variety of materials and microfabrication techniques.1 The number of microfluidic applications has grown exponentially and is currently an essential tool in fields as diverse as analytical chemistry, environmental monitoring, microbiology, or molecular diagnosis. Microfluidic devices offer exceptional benefits over conventional laboratory instruments2 such as precise fluid flow control under laminar conditions, low consumption of reagents and sample volumes, short response times, multiplex analysis, low-power operation or production cost-effectiveness. Besides, they can be applied for on-line sample analysis and can be integrated into portable instruments, thus enabling the in situ real-time determination of target analytes. Most of the microfluidic devices are designed and fabricated in a monolithic configuration to meet the requirements of one particular application. This means that even small variations in, for instance, the measurement protocol that would require a slight modification of the system involves the manufacturing of a new device, giving rise to extra consumption of time and materials with a concomitant increase of cost. During the past few years, some research efforts have been directed to the fabrication of modular microfluidic systems that can be reconfigured and thus adapted to different applications and assay conditions.3 In the case of analysis systems, by fabricating different microfluidic modules for various processes, such as © 2019 American Chemical Society
sample collection and preparation, reagent incorporation, mixing or calibration, and chemical species detection, the modular microfluidic system can be configured and optimized to fulfil the requirements of the target analytical application. One key point in the development of modular microfluidic device systems is the design of the interconnections between two consecutive microfluidic modules. These should be reversible while guaranteeing perfect module alignment and fluid tightness and without adding a significant extra volume to the final device. First approaches to modular microfluidic systems consisted of tubing-based interconnections between the different modules,4,5 which increased the required volumes of sample and reagents. In order to solve these drawbacks, other better-suited reversible interconnections for modular lab-on-a-chip (LoC) devices have been developed. Thus, Grodzinski et al. described an approach where several individual microfluidic units were interconnected using barber connectors.6 A more advanced device was shown by Shaikh et al. based on a multilayer modular approach and a cross-layer fluidic interconnection.7 Also, the use of microgaskets for obtaining high-performance microfluidic interconnections was introduced by Miserendino et al.8 Yuen9 pioneered the application of 3D printing for developing modular microfluidic devices mainly based on the LEGO concept.10−19 Good-resolution microfluidic modules could be fabricated with this methodology by using low-cost polymeric materials. Received: January 8, 2019 Accepted: March 13, 2019 Published: April 3, 2019 6192
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Figure 1. Fabrication of the microfluidic modules and clamping structures. (A) Laser cutter-machined PC and PSA parts (before release of color protection layers); (B) schematic representation of the PC−PSA bonding steps using a PMMA alignment structure; (C) complete microfluidic modules with bonded PDMS gaskets; (D) schematic of the interconnection between two consecutive microfluidic modules; (E) schematic 3D drawing of the modules assembled with magnetic clamping structures; and (F) picture of the magnetic clamping plates, some of them including connections to external tubing.
poly(dimethylsiloxane) (PDMS) gaskets (250 μm thick and 500 μm inner diameter) were chemically bonded22 to the PC film at the microfluidic inlet (or inlets) of each module to ensure leakfree interconnections. The bonding procedure and the PDMS gasket location are both detailed in Figures S2 and S3, respectively (in the Supporting Information). Some examples of produced microfluidics modules are shown in Figure 1C. Just one PDMS gasket is required per each interconnection of two modules (Figure 1D). Connection to external outlet tubbing was performed with an extension channel having gaskets at both inlet and outlet orifices (Figure 1E). The materials used are fully transparent, and the modules and interconnections are planar, thus enabling the easy inspection of every fluidic path during the system priming and operation. PSA, PC, and PMMA structures were manufactured by using a CO2laser writer (Epilog Mini 24, Epilog Laser, United States). PDMS gaskets were replicated by soft lithography using the Sylgard184A-B prepolymer and curing agents (Sigma-Aldrich, Barcelona, Spain) and a homemade PMMA/Mylar master also fabricated with the CO2-laser writer (Figure S4 in the Supporting Information). The experimental conditions of the manufacturing processes are detailed in Table S1 (in the Supporting Information). 2.2. PMMA−Neodymium Magnetic Clamps. Fluidic connections to external tubing and interconnections between consecutive microfluidic modules were carried out with the help of PMMA magnetic clamping structures (Figure 1E,F). These include two symmetrical PMMA plates (3 mm thick, 10 mm long, and 10 mm wide) with four embedded neodymium disc magnets each (2 mm diameter and 2 mm long, N48, Supermagnete, Gottmadingen, Germany). PMMA plates were machined with the CO2-laser writer (see conditions in Table S1 in the Supporting Information). The inner face of the plates shows a recessed area to host the end of the microfluidic modules to be interconnected and facilitate their alignment (Figure S5A). Each magnet applies a strength force of 1.47 N. The connection to external tubing (Figure S5B) comprised 0.5 inner diameter Teflon tubes (Teknokroma, Barcelona, Spain)
Furthermore, the fabricated modules could be intuitively assembled. Another interesting approach based on magnetic interconnections was more recently described by Yuen.20 Magnetic ring connections were integrated in microfluidic modules fabricated with PMMA or PDMS. The modules could be easily interconnected taking into account the orientation of the magnetic poles. This approach is very appealing. However, the embedded magnets had to be coated with a polyimide film to avoid corrosion, and their opacity limited the visual assessment of proper filling and the absence of bubbles in the fluidic connections. The modular approach presented here is also based on the use of magnetic clamping but solves these disadvantages by using a different configuration that separates the magnets from the fluid path and yields a smaller added volume per interconnection. The same approach is used for the reversible integration of electrochemical silicon sensors with extremely small flow cell volumes. Although detection of chemical species using modular systems based only on optical transduction had been reported previously,21 here, we present for the first time different modular fluidic layouts applied to the measurement of pH, conductivity, and electroactive species with solid-state sensors.
2. EXPERIMENTAL SECTION 2.1. Design and Fabrication of the Microfluidic Modules. The microfluidic channels were fabricated on transparent double-sided pressure-sensitive adhesive (PSA, 175 μm thick, Sertek Global Technology, Barcelona, Spain) and closed with transparent polycarbonate films (PC, 175 μm thick, MicroPlanet Laboratorios S.L., Barcelona, Spain). Some examples of fabricated PC and PSA structures are shown in (Figure 1A). Channels showing widths down to 500 μm were manufactured. PC layers also include fluidic inlets and outlets. A poly(methyl methacrylate) (PMMA, 3 mm thick, MicroPlanet Laboratorios S.L.) template with the outline of PC/PSA modules was used for enabling the alignment of the PSA and PC structures during their bonding at room temperature (Figure 1B and Figure S1 in the Supporting Information). Cylindrical 6193
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were fabricated with PDMS gaskets chemically bonded to the PC film with inlet and outlet orifices. The bottom PMMA clamping plate exhibited a recessed area to accommodate the sensor and facilitate the precise alignment with the PDMS gasket. 2.4. Leakage Tests. The maximum working pressure withstood by the microfluidic modules and interconnections was evaluated using the setup shown in Figure S7 (in the Supporting Information). The pressure at the inlet of a twomodule system was monitored with a manometer (model 2023P, Digitron, Margam, United Kingdom). For that, the system was filled with a red-colored solution. Then, the outlet of the microfluidic module was blocked, and the pressure at the inlet was increased using an air-filled syringe until fluid leakage in the system was observed. The applied pressures were 0.2, 0.5, 1, 1.5, 2.2, 2.5, 3.5, 4.5, and 5 bar. Each pressure was maintained for 60 s. A module including a silicon sensor was also evaluated in the same fashion. 2.5. Analytical Assessment of Microfluidic Systems with Sensor Modules. Three analysis systems were assembled using the basic modules, each including two T-shaped fluidic junction modules and a sensor module (Figure 3). One of the junction modules was used for sample injection, while the other one was connected to a mixer module and applied for injection of calibration solutions. A three-point calibration (using two calibration solutions and their 1:1 mixture) was initially carried out. Then, samples were successively injected, and the recorded signals were interpolated in the corresponding calibration plot to obtain the target analyte concentrations. Assays were carried out in triplicate for studying the repeatability of the system. All reagents, purchased from Sigma Aldrich (Barcelona, Spain), were of analytical grade and used as received, unless stated otherwise. All solutions were prepared using deionized water. Amperometric and conductivity assays were performed with an Autolab electrochemical workstation (PGSTAT-300 potentiostat galvanostat, Ecochemie, Uthecht, The Netherlands) that includes a FRA32 impedance module, all controlled by NOVA software. An in-house-made ISFET-meter, with constant drain current and constant drain-to-source voltage biasing (100 μA and 0.5 V, respectively), was used for pH measurements. A LabView user interface and a USB-6259 dataacquisition card (both from National Instruments, Austin, USA) were used to record and display the ISFET-meter output signal. For all the measurements, an OB1-MK3 microfluidic flow controller (Elveflow, Paris, France) was used to pump the solutions at a controlled flow rate of 1 μL s−1. For the conductivity analysis system characterization (Figure 3i), two KCl water solutions with conductivities of 146.5 μS
bonded to the top PMMA plate of the clamping structures using epoxy adhesive (Araldite Standard, Ceys, Barcelona, Spain). A PMMA platform with embedded neodymium magnets was also fabricated to work as a “magnetic breadboard”. The breadboard further facilitates the rapid and precise assembly of the modules. 2.3. Integration of Silicon Sensors in Microfluidic Modules. The integration of thin-film sensors fabricated on silicon or glass substrates with the same magnetic clamping approach was evaluated. Three types of sensors were tested: (i) 3 mm × 3 mm chips with four-bar platinum electrodes for conductivity measurements, (ii) 11 mm × 9 mm chips with platinum three-electrode electrochemical cells as amperometric sensors, and (iii) 3 mm × 3 mm ion-sensitive field-effect transistor (ISFET) chips for pH measurements. Detailed information about the sensor design is described in Figure S6 (in the Supporting Information). Chips (3 mm × 3 mm) were wire-bonded and packaged on printed circuit boards (PCBs) following a modified chip-on-board process.23 Amperometric sensor chips were connected using spring-loaded connectors (2.54 mm grid, RS, Switzerland). Modules with different flow cells and clamping structures were fabricated for each type of sensor (Figure 2). The flow cells
Figure 2. Integration of silicon sensors using the magnetic clamping approach. Schematic drawing of the modules (i) for the integration of chips encapsulated on PCBs and (ii) for the integration of bare chips.
Figure 3. Schemes of modular systems for (i) conductivity, (ii) amperometric, and (iii) pH measurements including a first junction module for calibration solution injection, a second junction module for sample injection, and the sensor module. 6194
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Figure 4. Assembly of the microfluidic modules. Steps: (i) arrangement of the bottom clamping plates; (ii) alignment of microfluidic modules; (iii) placement of the top clamping plates for sealing the interconnections; and (iv) free-standing modular and flexible structure separated from the master platform.
Figure 5. Details of the microfluidic modules and device assembly. (A) Picture of five different configurations of the microfluidic modules including (i) an encapsulated sensor module and an extension channel; (ii) a T-shaped fluidic junction with a mixer; (iii) a microfluidic module integrating pH sensors; (iv) a module with a non-encapsulated amperometric chip; and (v) three sensor modules connected in series. (B) Images of two microfluidic modular configurations using red- ((i) and (ii)) and blue (i)-colored solutions.
cm−1 and 1028.0 μS cm−1 and the 1:1 (in volume) mixture between them (584.0 μS cm−1) were used to calibrate the system. Subsequently, five KCl samples, showing conductivities in the range of 200.0−811.0 μS cm−1, were analyzed in triplicate. A 1 kHz alternating current was applied through the outer electrodes, and the voltage across the inner electrodes was recorded. The experimental conductivity of each solution was verified using a commercial conductivity meter, Crison Micro CM 2202 (Crison Instruments S.A., Barcelona, Spain), after each measurement. The amperometric analysis system was based on a platinum three-electrode electrochemical cell chip (Figure 3ii). Analytical
assessment was carried out in 0.1 M KNO3 aqueous solutions containing different concentrations of a ferricyanide model redox analyte. A potential of −0.15 V (versus platinum pseudoreference) was applied, and the faradaic current of ferricyanide reduction to ferrocyanide was recorded. A three-point calibration plot was obtained using 0.1 and 10 mM ferricyanide solutions and the 1:1 (in volume) mixture between them (5.1 mM). Then, five 0.1 M KNO3 aqueous solutions containing ferricyanide concentrations in the range of 0.2−8 mM were analyzed in triplicate. The experimental concentrations for each sample after their interpolation in the calibration plot were compared with the theoretical ones. 6195
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Differential pH measurements were carried out by integrating two pH-ISFETs and a gold pseudo-reference electrode in a single sensor module (Figure 3iii). One ISFET was continuously exposed to a pH 4 buffer solution, while the other ISFET and the gold pseudo-reference electrode were exposed to sample and calibration solutions. Commercial pH solutions were used for all the measurements (Panreac, Barcelona, Spain). First, a threepoint calibration curve was obtained by measuring solutions of pH 1.85 and 10.04 and the 1:1 (in volume) mixture between them (pH 6.67). Then, the system was tested using five solutions in the pH range from 2.80 to 10.03. The measurements were performed in triplicate. Recorded differential output voltage values were interpolated in the calibration curve, and results were compared to the values obtained with a commercial pHmeter, Crison pH GLP 22 Plus (Crison Instruments S.A.). The consumption of solutions during calibrations was also studied. In order to estimate the volume of new solution required to completely replace a previous solution, the system with the integrated conductivity sensor was used as follows. The 146.5 μS cm−1 calibration solution was injected, and the sensor signal was recorded in continuous mode. Then, the 1028.0 μS cm−1 calibration solution was injected, and the voltage sensor signal was recorded until stable readings were obtained. Finally, the 146.5 μS cm−1 calibration solution was injected again and analyzed in the same way.
3. RESULTS AND DISCUSSION 3.1. Assembly and Fluidic Test. The manufactured microfluidic modules could be easily interconnected by following the steps described in Figure 4. First, the bottom plates of the magnetic clamps were placed on the breadboard (step i). Then, the precise alignment of microfluidic modules was conveniently carried out (step ii). Subsequently, the top magnetic clamping plates were positioned (step iii). Once the whole system was assembled, it could be separated from the magnetic breadboard and used as a free-standing flexible structure (step iv). Free-standing microfluidic systems are appealing for placing them in uneven or curved surfaces or in limited spaces. The use of the breadboard, although not indispensable, made the assembly and re-configuration of the system more rapid and convenient. Several microfluidic systems were assembled following the procedure described above (Figure 5A,B). Liquids with different colored dyes were flowed through the systems to test for proper priming. Since all components in the fluid path are transparent and planar, complete filling of the channels and the absence of trapped air or bubbles in the interconnections were easily verified. The assembly and fluidic test of different configurations is shown in Supporting Information Video 1. The test for maximum pressure tolerance was carried out on a microfluidic channel with an inlet and an outlet connected to microfluidic tubes (Figure S8A in the Supporting Information), on a microfluidic module including an integrated silicon sensor (Figure S8B in the Supporting Information) and on a microfluidic channel interconnected with a T-shaped fluidic junction. Increasing pressures were applied, and no fluid leakage was observed for pressures up to 4.50 bar. At 5 bar, the PC and PSA films started delaminating, and the solution leaked out of the modules. No solution leakage took place in the interconnections at the pressures tested. 3.2. Analytical Performance of the Assembled Systems. The signals recorded for the different sensors integrated in the modular microfluidic devices are shown in Figure 6. First,
Figure 6. Characterization of analysis systems. (A) Signal from the impedance sensor. Inserted values represent measured conductivity using the conductivity-meter (in μS cm−1); (B) chronoamperometric signals obtained from the amperometric sensor. Inserted values represent theoretical concentration of potassium ferricyanide (in mM); and (C) differential voltage from ISFET devices. Inserted values represent measured pH using the pH-meter.
a three-point calibration was carried out with each sensor using two calibration solutions and their 1:1 mixture obtained with the mixer module. The calibration procedure was repeated three times to study the repeatability. Then, five samples were injected, and their concentrations were calculated using the calibration values by a simple linear interpolation. Data of the three measurement cycles is reported in Tables S2−S4, Supporting Information. The real part of the impedance at 1 kHz was recorded for the conductivity sensor. The inverse of the recorded parameter was plotted in Figure 6A. This is proportional to conductance of the solution; therefore, the signal was proportional to conductivity, as expected. The sensitivity (or sensor cell constant) obtained from the three-point calibration was 38.02 ± 0.05 cm−1. The corresponding experimental values were compared to those obtained with the conductivity-meter (see Table S2 in the Supporting Information), showing in all the cases relative errors below 2%. Regarding the repeatability of the assays, results showed a standard deviation below 9.6 μS cm−1 and a coefficient 6196
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Consequently, a high number of calibrations could be carried out despite using small solution containers, which would allow for the development of compact equipment capable of autonomous operation for extended periods of time.
of variation below 1.4% (n = 3) for all the solutions, demonstrating a good performance of the system for the conductivity measurement. The chronoamperometric signal recorded when flowing different ferrocyanide solutions is shown in (Figure 6B). The three-point calibration plot yielded a sensitivity of −0.061 ± 0.002 μA mM−1. The experimental values for each analyzed sample were compared with the theoretical ones (Table S3 in the Supporting Information), obtaining relative errors below 6% in all cases. In this case, results showed a standard deviation below 0.1 mM and a coefficient of variation below 2.7% (n = 3) for all the analyzed solutions, demonstrating the repeatability of the system for amperometric tests. The same experiments were repeated with the pH sensor (Figure 6C). A sensitivity of 52.7 ± 0.03 mV per pH unit was obtained from the three-point calibration plot, and this was used for calculating the pH of each analyzed sample. Experimental values were compared with those recorded with the pH-meter, obtaining differences below 0.04 units for all the samples (Table S4 in the Supporting Information). A standard deviation below 0.03 units and a coefficient of variation below 1.1% (n = 3) were obtained for all the solutions, demonstrating the good performance of the system for pH assays. In order to estimate the volume of solutions consumed per assay, a test with the system integrating the conductivity sensor was carried out. This consisted of the alternating injection of two solutions showing conductivity values at the higher and lower ends of the corresponding calibration curve (146.5 and 1028.0 μS cm−1, respectively). The recorded response is shown in Figure S9 (in the Supporting Information). Timeframes of about 25 and 30 s at a flow rate of 1 μL s−1 were required to stabilize the signals when the injection sequence was high-low-high conductivity samples. Thus, under the worst-case condition of high-to-low conductivity transition, the required sample volume was around 30 μL. This is about 3 times the internal volume of the microfluidic structures from the inlet to the sensor flow cell (10.3 μL). With this consumption, an analysis system including 50 mL containers for calibration solutions would perform up to 1660 assays before requiring solution replenishment.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b00064. Figure of the structure used for the alignment of the module layers during their bonding, scheme of the steps for the bonding of PDMS gaskets to PC parts, detailed picture of a PDMS gasket chemically bonded to the PC surface at the inlet of a microfluidic module, image of the mold for producing the cylindrical PDMS gaskets, table detailing the experimental conditions of the manufacturing processes with the CO2 laser cutter, images detailing PMMA−neodymium magnetic clamp structures, pictures of the silicon chips integrated in the microfluidic modules, pictures of the experimental setup used for the leakage tests of the microfluidic modules, table detailing the values of conductivity obtained with the modular microfluidic system and with the commercial conductivity-meter for nine samples, table detailing the values of potassium ferricyanide concentration obtained with the modular microfluidic system and theoretical values for nine samples, table detailing the values of pH obtained with the modular microfluidic system and with the commercial pH-meter for 10 samples, and recorded signals for the estimation of the volume of solutions consumed per assay (PDF) Video of the assembly and fluidic test of different configurations (MP4)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Phone: +34935947700. ORCID
Pablo Giménez-Gómez: 0000-0003-3443-802X
4. CONCLUSIONS The fabrication of reconfigurable modular microfluidic devices using flexible and transparent materials and incorporating easily replaceable solid-state sensors were presented. Our modular approach enabled the rapid inspection and test of the assembled systems to check for proper fluid flow and the absence of bubbles or leakage at the interconnections and the sensor flow cells. Fabrication by rapid prototyping techniques like CO2-laser ablation was very convenient for the development of new modules. However, mass production of the modules should rely on more suitable technologies like injection molding or roll-toroll processing. The fluidic leakage between consecutive microfluidic modules and between flow cells and silicon sensors was avoided by using magnetic clamping structures combined with PDMS gaskets. The characterization of different analysis systems assembled with the developed modules gave results in good agreement with those obtained with laboratory equipment, clearly showing the potential of these new microfluidic platforms in monitoring applications. Interconnections and flow cells were designed and fabricated so that they added negligible dead volumes to the final microfluidic device. This helps in keeping the required volume of calibration and cleaning solutions per measurement cycle low.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. All the images presented in this manuscript, including those in the Supporting Information and the TOC one, were taken by Pablo Giménez-Gómez. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge funding from the Spanish R&D National Program (MINECO Project TEC2016-79367-C2-1-R) and from Generalitat de Catalunya (2017 SGR 1771). This work used the Spanish ICTS Network MICRONANOFABS and was partly supported by the Spanish Ministry of Economy, Industry and Competitiveness.
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REFERENCES
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