The attractive structural and mechanical properties of cellulose substrates (paper, cloth, and thread), including passive fluid transport, biocompatibility, durability, and flexibility, have attracted researchers in the past few decades to explore them as alternative microfluidic platforms. The incorporation of electrochemical (EC) sensing broadened their use for applications such as clinical diagnosis, pharmaceutical chemical analyses, food quality, and environmental monitoring. This article provides a review on the microfluidic devices constructed on paper, cloth, and thread substrates. It begins with an overview on paper-based microfluidic devices, followed by an in-depth review on the various applications of EC detection incorporated on paper-based microfluidic devices reported to date. The review on paper-based microfluidic devices attempts to convey a few perspective directions that cloth- and thread-based microfluidic devices may take in its development. Finally, the research efforts on the development and evaluation, as well as current limitations of cloth- and thread-based microfluidic devices are discussed. Microfluidic devices constructed on paper, cloth, and thread substrates are still at an early development stage (prototype) requiring several improvements in terms of fabrication, analytical techniques, and performance to become mature platforms that can be adapted and commercialized as real world products. However, they hold a promising potential as wearable devices.
In recent decades, microfluidic devices have been widely used in biology, chemistry, and biomedical fields to control the movement of liquids in microchannels, contributed by their main characteristic of having micrometer scaled fluidic structures (Kim 1976). The main purpose of using such technology is to develop lab-on-chip devices that enable the integration of common processes used in such disciplines within a single platform. In the healthcare area, this technology is particularly important since consumption of low volumes of reagent and sample solution, as well as miniaturization of bioanalytical techniques, are essential to reduce the overall cost and time of biochemical analyses.
The earlier microfluidic devices were made of glass (Álvarez-Martos et al., 2013; Kotowski et al., 2013) or silicon (Kao et al., 2011; Keohane et al., 2014) and relied heavily on microelectronics fabrication techniques. A shift in this technology has seen microchannels being fabricated using polymers such as polydimethylsiloxane (PDMS) (Fujii, 2002; Li et al., 2013; Schrott et al., 2010), polymethylmethacrylate (Holmes et al., 2011; Romoli, Tantussi & Dini, 2011), polycarbonate (Wang et al., 2010), etc. This led toward a reduction of cost and production time, as well as eliminated the need of clean room facilities, thus enabling a wider spread in the fabrication of microfluidic devices for various proof-of-concept demonstrations. Nevertheless, little progress has been made in the fabrication of microfluidic devices as real-world products (Yetisen, Akram & Lowe, 2013). Some of the issues with the fabrication of microfluidic devices are the need for specialized equipment and employment of trained personnel, as well as the integration of external components (pumps, valves, mixers, etc.) to manipulate the fluid flow within the device. These issues cause the devices to be complex and economically unviable for mass production, and their use is hence limited, especially in the developing world (Martinez et al., 2009; Nilghaz et al., 2012; Nilghaz, Ballerini & Shen, 2013).
Hence, the development of microfluidic devices as diagnostic technologies that are cost-effective, minimally instrumented, and can be handled by untrained health personnel is fundamental (Kao et al., 2011; Mabey et al., 2004; Yetisen, Akram & Lowe, 2013). A list of general guidelines introduced by the World Health Organization to describe an ideal diagnostic device for developing countries is summarized by the acronym ASSURED (affordable, sensitive, specific, user-friendly, rapid and robust, equipment-free, and deliverable to end-users) (Mabey et al. 2004). The use of low-cost materials such as paper (Apilux et al., 2010; Carvalhal et al., 2010; Cunningham, Brenes & Crooks, 2014; Cunningham et al., 2016; de Araujo & Paixao, 2014; Dossi et al. 2013a; 2013b; 2014; Dungchai, Chailapakul & Henry 2009; 2011; Glavan et al., 2014; Kong et al., 2014; Lankelma et al., 2012; Li et al. 2013; 2014; 2014; Li, Zhao & Liu, 2015; Liu & Crooks, 2012; Lu et al., 2012; Määttänen et al., 2013; Martinez et al., 2007; Nie et al. 2010a; 2010b; Noiphung et al., 2013; Rattanarat et al. 2014; 2012; Renault, Anderson & Crooks, 2014; Santhiago, Henry & Kubota, 2014; Santhiago & Kubota, 2013; Shi et al., 2012; Shiroma et al., 2012; Wang et al., 2012; Wu et al. 2013; 2014; Zang et al., 2012; Zhao, Thuo & Liu, 2013), yarn/thread (Bhandari, Narahari & Dendukuri, 2011; Nie et al., 2010b; Reches et al., 2010; Vatansever et al., 2012; Xing, Jiang & Pan, 2013; Zhou, Mao & Juncker, 2012), and cloth (Bagherbaigi, Corcoles & Wicaksono, 2014; Bhandari, Narahari & Dendukuri, 2011; Chuang et al., 2010; Guan, Liu & Zhang, 2016; Guan et al., 2015; Malon et al., 2014; Nilghaz et al., 2012; Vatansever et al., 2012; Windmiller & Wang, 2013) has gained interest since this group of cellulosic substrates met the demands of the aforementioned guidelines; there is no need of additional components and power sources as the fluid flow is driven by capillary forces without the need of external pressure. Furthermore, the excellent mechanical properties exhibited by these materials (durability, flexibility, etc.), despite their lightweight nature, allow the formation of various three-dimensional (3D) microfluidic devices that are useful for multiplexed assays (Cunningham, Brenes & Crooks, 2014; Li et al. 2013; 2014; Nilghaz et al., 2012; Vatansever et al., 2012; Wang et al., 2012; Wu et al. 2013; 2014; Zang et al., 2012).
In this paper, an in-depth review on the development of a variety of microfluidic paper-based electrochemical devices (μPEDs), as well as paper-based electrochemical devices (PEDs), reported to date will be described. Since cloth- and thread-based microfluidic devices in general follow a similar path than paper-based microfluidic devices, the review attempts to convey a few perspective directions that cloth- and thread-based microfluidic devices may take in its development. Finally, the research efforts on the development and evaluation, as well as current limitations and future trends of cloth- and thread-based microfluidic devices, are discussed.
Paper-based microfluidic devices
Paper-based microfluidic devices have become an expanding research field (Adkins, Boehle & Henry, 2015; Cate et al., 2015; Tomazelli Coltro et al., 2014; Yang et al., 2016) since its introduction in 2007 by Whitesides group (Martinez et al. 2007). Throughout this review paper, paper-based microfluidic devices are referred to as microfluidic paper-based analytical devices (μPADs) for simplification. It has to be highlighted that the paraffin-patterned paper reported by Müller and Clegg (1949) was the rudiment of μPADs developed over recent years. In brief, a confined channel was patterned on a filter paper using paraffin barrier for conducting preferential elution of a mixture of pigments. The method was evidenced to increase the sample diffusion process and reduce the sample consumption. Since then, many new approaches for fabricating μPADs have been reported in the literature, and their underlying principles can be divided into four general categories: (i) physical blocking of pores using agents such as photoresist and PDMS; (ii) physical deposition of hydrophobizing agents such as wax and polystyrene; (iii) chemical fiber surface modification using cellulose reactive agents such as alkyl ketene dimer; and (iv) two-dimensional cutting/shaping using a computer-controlled plotter (Li, Ballerini & Shen, 2012; Yetisen, Akram & Lowe, 2013). Each method presents its own advantages and limitations. Thus, the choice of fabrication method depends on several factors, including material costs, equipment availability, fabrication simplicity, and intended application of the device (Kao et al., 2011; Li, Ballerini & Shen, 2012). However, it is worth mentioning that of the current approaches, wax-based fabrication techniques (wax screen printing, dipping, printing, stamping, etc.) have been the most popular method since it is simple and low cost and involve nontoxic reagents (Cardoso, Garcia & Coltro, 2015; Yetisen, Akram & Lowe, 2013).
The flexibility of paper substrate, as well as the vast fabrication techniques reported in the literature, also allowed the construction of 3D μPADs. The 3D μPADs enabled fluid transport in the vertical (z-) direction, hence allowing the integration of complex channel designs, useful for multistep, as well as multiplex analysis using minimal sample volume (Liana et al., 2012). Several other functionalities such as the incorporation of circuits and electrodes, as well as the immobilization of biological or chemical molecules like enzymes, antibodies, deoxyribonucleic acid (DNA), and nanoparticles on the μPADs have also been explored (Nery & Kubota, 2013). These research efforts have led toward the development of μPADs that can be analyzed using a number of detection techniques such as colorimetric, electrochemical (EC), chemiluminescence, and electrochemiluminescence (ECL) detection (Li, Ballerini & Shen, 2012; Nery & Kubota, 2013). Among these detection methods, colorimetric detection and EC detection have been most widely exploited in μPADs due to their simple yet robust working principles (Li, Ballerini & Shen, 2012; Yetisen, Akram & Lowe, 2013). The former detection technique was based on enzymatic or chemical color-change reactions (Li, Ballerini, and Shen 2012), while the latter relied on the direct measurement of electrical signals generated from the interaction between the electrodes and sample solution. Colorimetric-based μPADs will not be discussed in this paper as they form a separate and large field of study. However, a review of the development of a variety of μPEDs, as well as PEDs, reported to date will be discussed in the following subsections.
Dungchai, Chailapakul, and Henry (2009) from Henry’s group was the pioneer to report the integration of EC detection and μPAD. The applicability of the μPED was demonstrated for rapid quantitative determination of multiple analytes [glucose, lactate, and uric acid (UA)] in human control serum samples by using a three-electrode array (Figure 1A). In brief, the microfluidic channel on the device was fabricated using photolithography technique introduced by Martinez et al. (2007, 2008) , while the electrodes were patterned at the other end of the microfluidic channel with a screen-printing method using carbon inks containing Prussian Blue (PB). The three separate reaction areas were then spotted with different oxidase enzymes [glucose oxidase (GOx), lactate oxidase (LOx), and uricase, respectively] for the specific analyte of interest. For analysis, the standard or sample solution was dropped at the center of the device, which subsequently wicked to the reaction areas and reacted with the previously applied enzymes to produce hydrogen peroxide (H2O2). The reaction that took place at the device can be described as in Eq. (1) to Eq. (4), in which the analytes were oxidized and PB on the electrodes was reduced to Prussian White (PW) Therefore, quantification of the analytes was performed using chronoamperometric measurement of the reduced PB. The adoption of PB as a mediator on the electrodes was useful because it is inexpensive and operates at a relatively low potential (0 V vs. Ag/AgCl), hence making it highly selective for H2O2 detection. In this work, the feasibility of employing EC detection for μPAD in medical diagnosis was demonstrated for the very first time, consequently yielding a wide variety of μPEDs for different types of measurements and analytes with a range of new or improved features, which are also discussed in this section.
Similar design, materials (except for the PB mediator), and fabrication technique were utilized to develop a μPAD with dual detection, EC and colorimetric, for determination of gold in industrial waste solutions (Figure 1B) (Apilux et al. 2010). The reason for the coupling of two detection techniques within a single device was the presence of iron, which can be a potential interfering substance when present in more than 2.5-fold of gold concentration during the EC determination of gold. Therefore, colorimetric determination of iron was performed simultaneously during EC quantification of gold to overcome the aforementioned limitation. The combination of both, colorimetric method for screening and EC method for quantitative analysis, within the device provides a more reliable analytical tool. In the following year, in an effort to develop the dual-detection μPAD using a more simple, economical, and rapid fabrication approach, the same group introduced wax screen-printing method instead of photolithography (Apilux et al., 2010; Dungchai, Chailapakul & Henry, 2009) for patterning the microfluidic channel on the device (Dungchai, Chailapakul, and Henry 2011). The utility of the device was then shown for simultaneous EC detection of glucose and colorimetric detection of iron in human control serum samples.
The possibility of substituting commercialized glucose test strips made of plastic substrates that are often too expensive (price including margin in the range of ∼US$0.50 to US$1.00 per strip) with μPEDs (at current stage of development, ∼$0.014 per strip) for applications in the developing world was demonstrated by Nie et al. (2010b). The compatibility of μPED with a commercially available glucometer provided rapid, field-based point-of-care (POC) analyses of various analytes (glucose, cholesterol, lactate, and ethanol) as exhibited in Figure 2. Based on the success of glucometer, it is predicted that the μPEDs may also follow a similar model in terms of its development (Maxwell, Mazzeo & Whitesides, 2013). However, the glucometer can only accommodate a single μPED at a time and require repeated human operations such as pipetting, signal acquisition, and device exchanging (Zhao, Thuo, and Liu 2013). This poses a barrier in situations that demand simultaneous multiple analyte detection for more comprehensive analyses. In addition, commercially available EC readers (potentiostat) are quite costly (>$1000) to be affordable in low-income countries. Therefore, a paper-based EC biosensor array with eight individual sensing modules that can be interfaced with a custom-made handheld and inexpensive (∼$90) multiplexed EC reader was developed by Zhao, Thuo, and Liu (2013). Both the paper-based analytical device (PAD) and potentiostat formed a highly throughput biosensing platform.
More recently, two separate studies on 2D μPEDs with functionalized working electrode (WE) was reported for the determination of acetaminophen (Lee et al. 2016) and a cancer marker, carcinoembyronic antigen (CEA) (Wang et al. 2016), respectively. The μPED for the detection of acetaminophen in the presence of ascorbic acid (AA) was comprised of a micropatterned single-walled carbon nanotube electrode that was deposited with gold nanoparticles (AuNPs) and polyglutamic acid, as well as a nafion-modified nitrocellulose membrane to allow selective determination of acetaminophen and block the oxidation of AA on the electrode surface. On the other hand, μPED immunosensor for the detection of CEA was composed of a sample tab and an auxiliary tab, where the microfluidic channel was fabricated using wax printing and the electrodes through screen printing. The main highlight of the immunosensor was the synthesis and coating of a nanocomposite of amino functional graphene/thionine/AuNPs on the WE for the immobilization of anti-CEA, thus allowing sensitive determination of CEA.
3D configurations can also be used to develop μPADs with multiple detection assays. The techniques reported in literature range from stacking to folding such as origami style. For example, Henry’s group reported dual detection within a single μPAD using a 3D configuration integrated with biosensing nanomaterials. The device was composed of two separate layers for each detection technique, in which colorimetric method was used for nickel, iron, copper, and chromium detection, while EC method was used for lead and cadmium detection (Rattanarat et al. 2014) (Figure 3A). It is noteworthy that nanomaterials such as multiwalled carbon nanotube (MWCNT) modified carbon electrodes incorporated with bismuth and ferricyanide were also adopted in the device to improve its EC performance. Overall, the reported device demonstrated the ability to perform simultaneous detection of multiple metals using distinct analytical assays, all within a single device.
More recently, a μPED that integrated zinc oxide nanowires (ZnO NWs) as the biosensing component for EC enzymatic detection of glucose in human serum sample was reported (Li, Zhao, and Liu 2015). The device was also composed of two separate layers of chromatography paper: (i) a top layer that was composed of a wax-patterned reaction area with a stencil printed carbon counter electrode (CE) and a Ag/AgCl reference electrode (RE) on top of the reaction area and (ii) a bottom layer of a stencil printed carbon WE with ZnO NWs grown over and immobilized with GOx enzyme. The reason for the 3D configuration of the device was to simplify the process of growing ZnO NWs on the WE only at the underneath layer. The ZnO NWs glucose μPED evinced tunable biosensing performance that is superior to that of commercial glucose meters and other previously reported glucose μPEDs. In addition, it also presents potential for other nonenzymatic applications such as antigen/antibody and DNA detection.
μPADs are also gaining ground for more challenging applications such as EC determination of cancer markers (Dossi et al., 2014; Li et al. 2013; 2014; Wang et al., 2012; Wu et al. 2013; 2014; Zang et al., 2012) and DNA molecules (Cunningham, Brenes & Crooks, 2014; Cunningham et al., 2016; Lu et al., 2012). Wang et al. (2012) from Yu’s group presented the first EC immunoassay (EI) on paper substrate. The 3D μPED was utilized for simultaneous detection of two cancer markers, carcinoma antigen 125 (CA125) and CEA, in human serum samples. In brief, the immunodevice was comprised of (i) one layer of wax patterned paper immobilized with the corresponding capture antibodies at the respective paper working zones and (ii) one layer of screen-printed electrodes (SPEs) (two WEs, one CE, and one RE) on a transparent polyethylene terephthalate substrate. When the layers were stacked together, the two WEs shared the same CE and RE, thus allowing simultaneous detection of the two markers using a section-switch to alternate the EC reaction between the two WEs. The same group (Zang et al. 2012) then developed a 3D μPED design for multiplexed (eight WEs) EI detection of four cancer markers (every two WEs for one cancer marker), namely r-fetoprotein (AFP), CA125, carcinoma antigen 199 (CA199), and CEA in human serum samples. In both cases (Wang et al., 2012; Zang et al., 2012), MWCNT modification, chitosan coating, and glutaraldehyde cross-linking were adopted at the paper working zones, while horseradish peroxidase-O-phenylenediamine-H2O2 EC system was employed as the detection system. In a subsequent study, the group also presented a 3D μPED for DNA detection using folding method, instead of stacking (Lu et al. 2012). It is noteworthy that the sandwich-type DNA device employed a newly fabricated bioconjugate (nanoporous [NP] gold coupled with complementary single-stranded DNA) and signal double stranded DNA with thionine as the signal amplification label. Detection of DNA and thrombin (Cunningham, Brenes, and Crooks 2014) was also possible with 3D PEDs that were constructed based on SlipChip concept introduced by Ismagilov’s group (Li & Ismagilov, 2010; Pompano et al., 2011). The device was composed of two layers: (i) a base layer that was fabricated using double-sided printing of wax, followed by the three-electrode configuration, and (ii) a slip layer with a hydrophilic T-shaped region patterned using wax, in which the vertical section was removed to leave an open space. Finally, the base and slip layers were aligned and a paper flap with a hole from the base layer was folded over the top of the slip layer to expose the WE. The detection principle adopted in this device was based on target-induced conformational switching of an aptamer that was linked to the EC label. The aforementioned device was recently further improved by eliminating the presence of predispensed chemical oxidant that exhibited poor stability, and instead electrogenerating the oxidant on demand. The new methodology also eliminated the need for slip layer, hence creating a more user-friendly device design, which is known as NoSlip (Cunningham et al. 2016).
The art of paper folding has served right for these kinds of 3D devices. A 3D origami μPED was developed to perform multiplexed EI by using NP silver modified paper WE as the sensor platform, while different metal ion functionalized NP gold-chitosan was used as a tracer for simultaneous detection of CEA and AFP in human serum samples. The immunodevice was composed of (i) one side separated into two regions, one paper auxiliary zone on auxiliary pad and one paper working zone on sample tab; and (ii) the reverse side comprised of the SPEs in which the WE was printed at the sample tab, while the CE and RE were printed at the auxiliary pad. All the three SPEs were connected to each other when the paper device was folded and filled with sample solution (Li et al. 2013). In order to further enhance the sensing sensitivity for EI on μPEDs, Wu et al. (2013, 2014) presented two different signal amplification strategies: (i) using graphene to modify the immunodevice surface and silica nanoparticles as a tracing tag to label the signal antibodies (Wu et al. 2013) and (ii) introducing a controlled radical polymerization reaction and graphene to modify the immunodevice surface (Wu et al. 2014). Both the devices (Wu et al. 2013; 2014) were demonstrated for quantitative analysis of four cancer markers that includes AFP, CEA, CA125, and carbohydrate antigen 153 (CA153) in human serum samples using the same EC detection system discussed previously (Wang et al., 2012; Zang et al., 2012). In terms of construction, the immunodevices were comprised of (i) one paper layer with a central connecting zone surrounded by eight working zones that were screen-printed with carbon ink and silver paint for the WEs and conductive pads, respectively, and (ii) another paper layer with one circular connecting zone that was screen-printed with carbon ink, Ag/AgCl ink, and silver paint for the CE, RE, and conductive pads, respectively. All the SPEs were connected to each other when the two paper layers were stacked together. Two other different approaches for 3D origami μPED were (i) polyaniliine-AuNP modified paper WE as the sensor platform and 3D graphene sheets combined with methylene blue and carboxyl ferrocene nanocomposites as the redox probes (Li et al. 2014) and (ii) cuboid silver modified paper WE as the sensor platform and different metal ions coated NP silver-chitosan as the labels (Dossi et al. 2014). The immunodevices were composed of two circular paper working zones, namely sample and auxiliary tab for screen-printing the electrodes. Finally, the auxiliary tab was folded down below the sample tab, clamped with a home-made device, and connected to the EC workstation for simultaneous detection of CEA and AFP in human serum samples.
Besides the aforediscussed, 3D μPEDs have also been constructed on hollow channel (HC) format (Renault, Anderson, and Crooks 2014). Basically, cellulose fibers were removed from the microfluidic channel on the paper to create a HC, thus allowing direct contact between the electrodes and sample solution. This new paper format yielded better convective mass transfer similar to that of traditional microelectrochemical devices. Using the same concept, a 3D enzyme-linked immunosorbent assay (ELISA) μPED was fabricated on a hydrophobic paper, known as C10H paper, as illustrated in Figure 3B (Glavan et al. 2014). The device was composed of (i) an embossed microwell, in which the antigen or antibody immobilization and recognition events take place, and (ii) a detection zone with printed electrodes. The two different zones were brought into contact by folding the device along its central crease. The applicability of the device was then demonstrated for EC direct and sandwich ELISA, in particular, (i) the detection of rabbit immunoglobulin G (IgG) as model antigen and alkaline phosphatase-labeled antirabbit IgG as model antibody and (ii) the detection of malarial histidine-rich protein from Plasmodium falciparum in spiked human serum.
In a more recent study, the simultaneous measurement of multiple diabetes markers, namely hemoglobin and glycated hemoglobin, was possible through the fabrication of a label-free 3D μPED composed of a dual SPE on wax-patterned paper coupled with multilayer of magnetic paper using impedance method (Boonyasit, Chailapakul & Laiwattanapaisal, 2016).
Based on the literature reported for 3D μPEDs, it can be derived that the versatility of paper platform allowed the creation of various simple yet robust 3D μPEDs with functionalized WEs to detect a wide array of biomarkers. These 3D μPEDs were able to perform multiplexed immunoassays within a single biological sample, thereby demonstrating its potential as a sensitive and specific POC diagnostic tool useful for life science research, as well as clinical diagnostics.
The aforementioned μPEDs were mostly constructed on filter or chromatography papers due to its good wicking properties that are particularly important for microfluidic applications. However, there are a variety of other paper choices available for the construction of PEDs, in which the choice depends on the fabrication procedures and intended applications (Liana et al. 2012). For instance, Metters et al. (2013) fabricated PEDs using screen-printing technique on three different paper substrates that include inkjet, ruled pad, and filter papers. At low magnification, the SPEs on the three paper substrates were observed to be highly reproducible and possessed well-defined electrode geometry, except for the slight curling after curing that could be overcome with a proper storage procedure. However, under critical observation, it was noticed that the geometry of the SPEs on filter paper deviated from the ideal electrode geometry, unlike the SPEs on inkjet and ruled pad papers. This was attributed by the highly porous and fibrous surface of filter paper. The mentioned physical characteristics consequently resulted in an unsatisfactory EC performance. Thus, the use of filter paper substrate was recommended for applications that require continuous flow of sample solutions only. Since SPEs on inkjet paper demonstrated an excellent EC performance compared to the other paper substrates, it was further investigated and compared with commercially available SPEs printed on traditional polyester substrate for the sensing of nicotinamide adenine dinucleotide (NADH) and nitrite. In another independent study, a disposable PED was constructed on office paper and its utility for quantification of various analytes such as explosive, halide, and heavy metal ions in aqueous solutions was investigated (de Araujo & Paixao, 2014). Hence, it can be concluded that various types of paper substrate and modifications are also worth investigating to provide a suitable platform for constructing reliable PEDs.
In terms of fabrication method, the majority of the electrodes on the prior reported PEDs were constructed using screen-printing technology. In an effort to introduce a simple and economical electrode fabrication method that does not require physical mask or stencil, Määttänen et al. (2013) presented inkjet-printing technology to construct a three-electrode configuration system on a coated paper substrate. The method demonstrated its competence even under modifications for various applications. Using a different approach, Santhiago and Kubota (2013) developed a two-electrode configuration system using silver ink as the RE and CE and a graphite pencil as the WE. Despite using a low-cost electrode material (US$0.12 per graphite pencil electrode), the PED exhibited excellent analytical performance for determination of glucose in artificial blood serum samples. This was attributed by the absence of contact between the paper substrate and electrode. Using a simpler method, Dossi et al. (2013b) presented PEDs and μPEDs that consisted of using commercial pencil lead to draw three-electrode configuration defined by printed wax barrier. The utility of the μPED was then shown for EC detection and separation of azo dye sunset yellow from AA. In a subsequent study, the applicability of the μPED was shown for simultaneous determination of either dopamine or paracetamol in the presence of AA (Dossi et al. 2013a). Later, the same group introduced a simple technique for preparing doped pencil leads and adopted them for constructing PEDs with pencil-drawn electrodes (Dossi et al. 2014). On the other hand, Santhiago, Henry, and Kubota (2014) constructed 3D PEDs on conventional printing paper substrate, in which the RE and CE were fabricated using drawing process with graphite pencil, while the WE was composed of graphite pencil electrode (Santhiago & Kubota, 2013) that was attached to the substrate using double-sided tape. A quick response (QR) code was also printed on one of the device faces to enable the results to be transferred via scanning in a readable format by smartphones. The applicability of the device was then demonstrated for determination of p-nitrophenol in water samples. Since pencil-drawn electrodes have exhibited good reliability and reproducibility for the development of PEDs, it was also recently adapted to perform capacitively coupled contactless conductivity detection measurements on office and chromatographic paper-based microchip electrophoresis system (Chagas et al. 2015). The device was then utilized to perform quantitative analysis of inorganic cations such as potassium and sodium in human tear samples. The unique electrode fabrication approaches reported in this section seem to be promising for the production of various simple and low-cost PEDs and μPEDs, as well as other potentially complex EC circuits on paper matrix. Additionally, the introduction of smartphone-supported technology such as QR code for simple readout and interpretation of PED results is a great effort to improve the user friendliness and applicability of the device, especially in field settings (Nilghaz et al., 2016).
Continuous-flow and self-powered PADs
The previously described technologies are based on economic disposable devices for single use only. However, the capabilities of μPADs have also been explored for continuous use. Nie et al. (2010a) from Whiteside’s group also developed μPEDs using similar fabrication method as reported by Dungchai, Chailapakul, and Henry (2009). The utility of the device was demonstrated for determination of glucose in urine and lead (Pb (II)) in aqueous solutions using chronoamperometry and square wave anodic stripping voltammetry (SWASV) techniques, respectively. Nevertheless, in the case of Pb (II) measurement, the design of the device was modified by introducing a pad of cellulose blotting paper as a sink at the opposite end of the paper channel. This modification enabled continuous flow of sample solution across the electrodes until the system entered the equilibration region during the SWASV process. In some studies, this characteristic of paper substrate that allows passive liquid transport via capillary action was also exploited by integrating it with electrodes printed on other conventional substrates to create a multifunctional device. For example, Shi et al. (2012) demonstrated the coupling of filter paper and commercial screen-printed carbon electrode (SPCE) for simultaneous determination of Pb (II) and cadmium (Cd (II)) in commercial salty soda water and dirty ground water using the SWASV method. The device was designed for pipetteless and continuous flow of sample solution along the paper and SPCE by dipping the front end of the paper strip in the sample solution. In both the aforementioned cases (Nie et al., 2010a; Shi et al., 2012), the continuous flow of sample solution for heavy metal detection was useful to (i) provide highly sensitive detection of heavy metals due to the efficient metal deposition on the electrodes surface and (ii) eliminate the need for sample pretreatment by removing any dissolved analytes on the electrodes. More recently, the continuous-flow concept was adapted to develop a fully integrated PED for the determination of a nerve agent stimulant called Paraoxon (Cinti et al., 2017). The PED coupled two different types of paper, first a nitrocellulose membrane impregnated with the substrate (butrylthiocholine), followed by a waxed filter paper printed with SPE and infused with a buffered solution and enzyme (butrylcholinesterase). Therefore, when solution was applied on the edge of the nitrocellulose membrane, the substrate from the membrane flowed toward the waxed filter paper, where the enzymatic reaction took place and produced electrochemically detectable by-product. Using a similar concept, Carvalhal et al. (2010) developed a microfluidic paper-based separation device coupled with amperometric detection for quantification of the analytes of interest (AA and UA) in a mixture solution. In brief, a narrow strip of Whatman cellulose chromatography paper was put into contact with a gold EC microcell that was fabricated on a polyester film. A sample solution was then spotted onto the paper and the front end of the paper was immersed in eluent to allow it to wick through the paper by capillary action and dissolve the sample. During the wicking process, the analytes in the sample were separated depending on two factors: (i) solubility in the eluent and (ii) interaction with the polar cellulose fibers within the paper substrate. When the analyte reached the electrodes, it resulted in analytical response that can be continuously recorded using chronoamperometric measurement. This concept was later adopted and modified by Shiroma et al. (2012), in which both the microfluidic channel and electrodes were incorporated within the chromatography paper, together with an absorbent pad at the opposite end of the device to allow continuous flow of the eluent. The device was then demonstrated for separation and EC detection of paracetamol and 4-aminophenol in pharmaceutical products. Although the analysis time of the device was relatively longer (25 min) compared to conventional separation methods such as capillary electrophoresis and high-performance liquid chromatography, the device displayed other attractive properties such as (i) low sample (500 nl) and eluent consumption; (ii) does not require sample pretreatment for the removal of particulate materials; (iii) does not require organic solvents to assist the separation process; and (iii) allows reusability (60 separations in a single device).
Another study worth mentioning is the system presented by Lankelma et al. (2012) that utilized gravitational pumping for continuous flow of fluid using paper substrate to allow EC flow-injection analysis. The system was employed for the determination of glucose in urine samples using chronoamperometric measurement. In brief, the system was comprised of three parts: (i) platinum (Pt) WE sputtered on glass or glassy carbon that was covered with a nitrocellulose pad immobilized with GOx enzyme; (ii) buffer (upper) reservoir that positions the CE and RE; and (iii) tap water with acetic acid (lower) reservoir that behaves as the sink. The nitrocellulose pad placed on the WE was connected to both the upper and lower reservoir using strips of polyester-cellulose blend paper, thus allowing constant flow of buffer throughout the measurement. The experimental setup of the aforementioned system is illustrated in Figure 4.
The intrinsic characteristics of paper have meant that it can be used as microfluidic devices integrated with EC detection by means of patterning electrodes, but this integration has also allowed for the fabrication of batteries in order to develop self-powered devices. The first self-powered EC sensing platform using paper substrate was reported in an interesting study by Liu and Crooks (2012). The device that was employed for qualitative determination of glucose in artificial urine samples was patterned using a wax pencil and ruler into two parts that consisted of the battery and sensor sections. The battery section was comprised of a metal foil as the anode, an activated carbon as the cathode, and paper as the separator, while at the sensor section, the paper was preloaded with the sensing reagents [GOx enzyme and ferricyanide In both the parts, indium tin oxide (ITO) electrodes were used for electrical contact to the paper. To enable the electrochromic read-out at the sensor section, PB/PW was deposited on the upper ITO electrode and a Nafion membrane was used to separate the paper preloaded with the sensing reagents from the ITO electrode. Finally, the device was sandwiched and clamped between two PDMS layers. When the battery electrolyte (artificial urine) was introduced at the paper reservoir, the battery was powered immediately and subsequently drove the GOx electrocatalytic reaction and generated an electrochromic read-out. Therefore, the device demonstrated the possibility of developing a simple, low-cost, and most importantly, an equipment-free (meets ASSURED criterion) EC sensing platform on paper substrate.
Paper-based bipolar EC devices
The fabrication of arrays via screen printing methods requires the same effort as to fabricate one single sensor; hence, a single μPAD device can integrate multiple SPEs for multiplexed assays. However, traditional three-electrode EC approaches require a direct electrical connection to each SPE, a difficult task on a simple POC sensor. Bipolar electrochemistry has solved this problem since no direct electrical connection to power supply is required to drive faradaic processes (Renault et al., 2013). A bipolar electrode (BPE) is an electrically conductive material that even in the absence of a direct ohmic contact promotes EC reactions at its extremities (poles). The potential difference between the BPE and the solution, generated when a sufficient voltage is applied, drives oxidation and reduction reactions (Fosdick et al., 2013).
A disposable paper-based BPE was reported for the first time for the sensitive ECL detection of a prostate-specific antigen. This paper-based BPE device consists of two hydrophilic cells patterned using hydrophobic wax and connected by a carbon ink BPE and, on the other end of the two cells, the screen printed anode and cathode. The system was used to detect H2O2 in the sensing cell via the Ru(bpy)32+ ECL generated from the anode in the reporting cell (Feng et al., 2014). Following this, others have reported the coupling of open BPE-ECL and paper-based microfluidics for visual detection. This imaging sensing method allowed the authors to perform a high-throughput screening and in addition avoided effectively the background interference signals from the driving electrodes (Liu, Zhang & Liu, 2015). The fabrication of a wireless, label-free, low-cost, and disposable BPE-ECL was possible by coupling the device with the light-switch molecule [Ru(phen)2dppz]2+ for a sensitive analysis of DNA from pathogenic bacteria. The ECL of [Ru(phen)2dppz]2+ is quenched in aqueous solution, but this molecule displays intense ECL when intercalated into double-stranded DNA, which was then applied to the paper-based bipolar ECL electrode. The authors reported with this method that as little as 10 copies/μl of the genomic DNA of Listeria monocytogenes could be detected (Hu et al. 2009). In a recent work, a hand-held paper-based BPE-ECL system that included battery for power supply and a smartphone application for the read-out signal was proposed. The applicability of the system was then demonstrated for the detection of glucose in phosphate buffer solution and artificial urine samples, showing its capabilities as a POC device (Chen, Zhang & Xing, 2016). This technology provides great promises on the development of wearable devices with multiple detections, integrated battery, and read-out systems on a single platform.
Other analytical applications of paper substrates
The aforediscussed μPEDs (and PEDs) mostly involved the direct printing of electrodes onto the paper substrate. However, there are also several paper-based devices developed by integrating paper substrate onto SPEs. For instance, Rattanarat et al. (2012) presented a multilayer paper device integrated with SPCE for selective determination of dopamine in model serum samples. The device was comprised of three layers: (i) a patterned filter paper for sample preconcentration; (ii) a transparency film with two holes, in which the first one was to allow sample preconcentration and the second one to transfer the sample solution to the third layer via a surfactant (sodium dodecyl sulfate) modified paper disk; and (iii) SPCE. The sample preconcentration layer contributed to the low limit of detection, while the adoption of SDS surfactant layer resulted in a highly selective device for dopamine detection.
Paper matrix was also used to work with whole blood samples as an alternative to the conventional centrifugation method to separate plasma or serum from whole blood samples. The sample separation was followed by EC measurement of glucose in the sample using a PB modified SPE (Noiphung et al. 2013). This was followed by a study conducted by Kong et al. (2014), in which a chromatography paper disk was demonstrated to prestore the glucose standard or blood sample solution and transfer it with the application of buffer solution to the underneath graphene/polyaniline/AuNs/GOx biocomposite modified SPCE surface for the EC detection.
The different fabrication approaches, EC detection techniques, and analytical applications of the μPEDs and PEDs that were discussed above are summarized in Table 1.
|Hydrophilic-hydrophobic contrast patterning technique||Electrode patterning technique||EC detection technique||Analyte of interest||Application; sample|
|Photolithography (Dungchai, Chailapakul, and Henry 2009)||Screen-printing||Chronoamperometry||Glucose, lactate, UA||Clinical; human control serum samples|
|Photolithography (Apilux et al. 2010)||Screen-printing||Square wave voltammetry (SWV)||Gold||Environmental; industrial waste solutions|
|Wax screen-printing (Dungchai, Chailapakul, and Henry 2011)||Screen-printing||Chronoamperometry||Glucose||Clinical; human control serum samples|
|Wax printing (Nie et al. 2010b)||Screen-printing||Amperometric||Glucose, cholesterol, lactate, ethanol||Clinical and food quality; human plasma and water samples|
|Wax printing (Zhao, Thuo, and Liu 2013)||Screen-printing||Chronoamperometry||Glucose, lactate, UA||Clinical; artificial urine samples|
|Wax printing (Rattanarat et al. 2012)||Screen-printing||SWASV||Pb (II), Cd (II)||Environmental; dust samples|
|Wax printing (Li, Zhao, and Liu 2015)||Stencil printing||Chronoamperometry||Glucose||Clinical; human serum samples|
|Wax printing (Wang et al. 2012)||Screen-printing||Differential pulse voltammetry (DPV)||CA 125, CEA||Clinical; human serum samples|
|Wax screen printing (Zang et al. 2012)||Screen-printing||DPV||AFP, CA125, CA199, CEA||Clinical; human serum samples|
|Wax printing (Lu et al. 2012)||Screen-printing||DPV||DNA||Clinical; human serum samples|
|Wax printing (Li et al. 2013)||Screen-printing||DPV||CEA, AFP||Clinical; human serum samples|
|Photoresist patterning (Wu et al. 2013; 2014)||Screen-printing||DPV||CEA; AFP; CA125, CA153||Clinical; human serum samples-|
|Wax printing (Dossi et al., 2014; Li et al., 2014)||Screen-printing||DPV||CEA, AFP||Clinical; human serum samples|
|Dielectric paste ink printing (Metters et al. 2013)||Screen-printing||Cyclic voltammetry||NADH, nitrite||Environmental; canal water sample|
|Wax printing (de Araujo & Paixao, 2014)||Screen-printing||DPV; cyclic voltammetry; SWASV||Picric acid, halide ions Pb(II).||Environmental; aqueous solutions|
|Wax printing (Santhiago & Kubota, 2013)||Masking||Chronoamperometry||Glucose||Clinical; artificial blood serum samples|
|Wax printing (Dossi et al. 2013a)||Drawing||Amperometric||AA||Food analysis; aqueous solutions|
|Wax printing (Dossi et al. 2013b)||Drawing||Amperometric||Dopamine, paracetamol, AA||Pharmaceutical; pharmaceutical sample|
|Wax melting (Santhiago, Henry, and Kubota 2014)||Drawing and attachment||DPV||p-nitrophenol||Environmental; tap water samples|
|Wax printing (Shiroma et al. 2012)||Sputtering||Chronoamperometry||Paracetamol, 4-aminophenol||Pharmaceutical; pharmaceutical samples|
Although μPEDs and PEDs have demonstrated their potential utility in a variety of applications, they still present several limitations, which include (i) low efficiency of fluid delivery due to fluid retention within the microfluidic channels and evaporation during the wicking process (Li, Ballerini, and Shen 2012); (ii) limited durability, for instance it can be extremely fragile and easily torn when saturated with aqueous solutions (low wet tensile strength); and (iii) limited flexibility, for instance it becomes physically deformed when folded and unfolded. To circumvent the mentioned limitations, cloth was introduced as an attractive alternative platform for the fabrication of economical and flexible microfluidic devices.
Cloth-based microfluidic devices
Cloth represents an attractive alternative class of substrate, especially for developing wearable sensors, due to its excellent mechanical properties and constant contact with skin surfaces. Besides that, the large surface area provided by cloth also allows the integration of accompanying electronics (Bandodkar & Wang, 2014). Unlike the large body of innovation reported for μPADs, the development of microfluidic cloth-based analytical devices (μCADs) is limited and still in its early stages for colorimetric (Bagherbaigi, Corcoles & Wicaksono, 2014; Benito-Lopez et al., 2009; Bhandari, Narahari & Dendukuri, 2011; Curto et al., 2012; Morris et al., 2009; Nilghaz et al., 2012; Vatansever et al., 2012), EC (Chuang et al., 2010; Malon et al., 2014; Yang et al., 2010), chemiluminescence (Guan et al., 2015; Li et al., 2017; Liu et al., 2016b), and ECL (Guan, Liu & Zhang, 2016; Liu et al., 2016a) detection. The work on μCAD was first reported in the year 2009 for monitoring sweat pH in real time (Figure 5) (Benito-Lopez et al., 2009; Morris et al., 2009). In brief, the device was used to collect sweat sample from the skin surface and wick the sample through a predefined channel (coated using silicone sealant) toward the pH sensing area. In order to ensure continuous fluid flow, a super absorbent material (Absorbtex) was attached at the end of the fluidic channel. The applicability of the device was then demonstrated for real-time measurement of sweat pH during cycling exercise. Further improvements on the microfluidic chip functionality were later carried out through miniaturization of its electrical components (Curto et al. 2012).
Two years later, Bhandari, Narahari, and Dendukuri (2011) introduced silk woven cloth as a substrate for constructing μCAD. In brief, silk yarns of different properties (hydrophilic and hydrophobic) were woven together using handloom to construct hydrophilic channels enclosed by hydrophobic yarns. The applicability of the chip for biodetection was then demonstrated for a direct immunoassay reaction. Although the study showed the possibility to construct a variety of 2D μCADs, the adoption of silk cloth was considered to be too costly to be used as a disposable substrate for microfluidic devices (Nilghaz et al. 2012). In addition, the silk weaving method may be unsuitable for mass production as it involves complex and time-consuming fabrication procedures, which require the employment of skilled craftsmen that are limited to some countries only, such as India. In another independent study, the aforementioned textile weaving method was modified and employed to develop a pH-sensitive μCAD (Vatansever et al. 2012). The μCAD was fabricated by using polypropylene yarns to form the hydrophobic barriers and modified poly(ethylene terephthalate) yarns to construct the microchannels. The pH-sensitive characteristic of the device was attributed by the use of pH-sensitive polymers such as poly(acrylic acid) and poly(2-vinyl pyridine). Overall, the device allowed a pH-sensitive liquid transport that was useful for analytical as well as smart cloth applications.
In an effort to introduce an ubiquitous cloth choice and fabrication method, Nilghaz et al. (2012) proposed the use of cotton cloth substrate and wax-patterning technique that was inspired by an ancient textile processing technique, commonly known as batik painting, for fabricating both 2D and 3D μCADs as shown in Figure 6. The 3D μCADs were simply assembled within 5 min using folding method, similar to the approach of 3D μPADs. The capability of the 2D and 3D μCADs as an analytical tool was evinced by performing colorimetric detection of protein in an artificial urine sample. It is worth mentioning that the device showed close resemblance in terms of performance to the prior discussed μPADs and additionally possessed the flexibility and mechanical strength of cloth. The similar material and method were later employed in a different study to develop a cloth-based ELISA platform and its feasibility for analytical application was shown for the detection of human chorionic gonadotropin hormone (Bagherbaigi, Corcoles, and Wicaksono 2014). In comparison to conventional ELISA assay, the proposed device consumed lower volumes of reagent and sample solutions, as well as reduced incubation time. The device also eliminated the need for immobilization of the biorecognition molecules due to the hierarchical woven structures of cotton cloth.
More recently, the construction of a colorimetric μCAD was reported by also using cotton cloth as the substrate material, but photolithography technique was employed to create the hydrophilic-hydrophobic regions within the device (Wu & Zhang, 2015). Although the fabrication technique allowed the formation of well-defined and uniform boundaries with dimensions as small as 100 μm, the photolithography method involves multiple steps and requires a clean room for the fabrication process and the photoresist can also be easily damaged during bending or folding.
All of the aforementioned μCADs rely on colorimetric detection only. Although colorimetric detection presents several shortcomings in contrast to the highly sensitive and selective EC detection method, the integration of EC detection on μCADs has not been widely explored. However, the development of several cloth-based EC sensors has been reported in the literature (Chuang et al., 2010; Yang et al., 2010). The effort to incorporate EC sensing on cloth substrate was initiated in 2010 by Wang’s group, in line with the aim to develop reliable and wearable healthcare monitoring systems. The first example integrated carbon electrodes through direct screen-printing into briefs as a model garment. The EC measurements were then performed using the cloth-based printed carbon electrode as the WE, while platinum wire and silver/silver chloride (Ag/AgCl) electrode were used as the CE and RE, respectively, in a bulk solution. The printed cloth electrode exhibited favorable EC behavior and mechanical or adhesion properties (Yang et al. 2010). In a subsequent study, all three electrodes were screen-printed directly on water-proof cloth (GORE-TEX), resulting in a cloth-based screen-printed EC sensor (Chuang et al. 2010). The EC measurements were demonstrated by directly placing the sample on the printed electrode surface, where nitroaromatic explosives were detected. The sensor also exhibited preservation of EC activity against laundry washing and repeated bending operations (Chuang et al. 2010). However, these studies (Chuang et al., 2010; Yang et al., 2010) did not investigate the possibility of incorporating an enzyme layer within the cloth-based EC sensor. The first successful incorporation of enzyme, specifically LOx enzyme, using a simple entrapment method on a cotton cloth-based EC device (CED) was reported later (Malon et al. 2014). The electrodes on the device were fabricated using a simple template method for patterning the electrodes, in which carbon graphite paste modified with PB (C-PB) was used for the WE and CE, while Ag/AgCl paste was used for the RE. The quantification of lactate in the sample solution was performed using chronoamperometric measurement of the reduced PB as described in Eq. (4), similar to the previous work on μPEDs by Dungchai, Chailapakul, and Henry (2009). The hydrophilic sample placement/reaction zone was then patterned on the electrode-embedded cotton cloth using wax patterning technique that was introduced by Nilghaz et al. (2012). The overall design and working principle of the CED closely resembled that of PEDs. Finally, the feasibility of the device for practical application was demonstrated for lactate measurement in saliva samples before and after meals.
On the other hand, Guan et al. reported the first demonstration of chemiluminescence (Guan et al. 2015) and ECL (Guan, Liu, and Zhang 2016) detection for μCADs. The hydrophilic patterns on the μCADs were fabricated using wax screen printing method, which was faster and require lower melting temperature compared to the wax patterning technique by Nilghaz et al. (2012). Similar to other reported works on cotton cloth (Bagherbaigi, Corcoles & Wicaksono, 2014; Malon et al., 2014), the chemiluminescence and ECL substrate was simply immobilized at the detection chamber using adsorption technique. However, in both cases, the wicking properties were obtained directly using a natural cotton cloth without pretreatment, unlike the prior studies that utilized treated cotton cloth (Bagherbaigi, Corcoles & Wicaksono, 2014; Malon et al., 2014; Nilghaz et al., 2012). More recently, Liu et al. (Liu et al. 2016b) from Zhang’s group reported for the first time a gravity and capillary force-driven flow chemiluminescence lab-on-cloth device, which was used to determine trivalent chromium [Cr(III)] in water samples. A similar concept was later adopted by Li et al. (2017) from the same group to develop a chemiluminescence-based glucose test sensors. Besides that, Zhang’s group also demonstrated the possibility of performing ECL detection using bent μCADs to prove the ultraflexibility characteristic of μCADs (Liu et al. 2016b).
The development of EC μCADs is still slow compared to its sibling μPADs; however, the advantages offered, such as the robustness and the close contact with the user skin, could make these devices gain fast popularity.
Thread-based microfluidic devices
Besides μPADs and μCADs, microfluidic systems utilizing threads as fluidic channels to perform analytical assays, known as microfluidic thread-based analytical devices (μTADs), have also gained popularity. Compared to paper substrate, threads have a high mechanical strength even under wet condition and do not require the creation of hydrophobic barriers for the fabrication of microchannels. There are also a wide variety of fiber materials available to form threads with different functionalities (Agustini, Bergamini & Marcolino-Junior, 2016). Since threads are stainable, it has been explored for colorimetric detection for several qualitative and semiquantitative analyses (Li & Ismagilov, 2010; Nilghaz et al., 2014; Reches et al., 2010; Zhou, Mao & Juncker, 2012).
Wei, Fu, and Lin (2013) reported the first successful electrophoresis separation and EC detection of ion samples (Cl−, Br−, and I−) using polyester threads, thus creating a promising avenue for the incorporation of EC detection within μTADs. However, there were issues with the planar electrode system; thus, Yang, Lin, and Wei (2014) and Yang and Lin (2015) constructed a μTAD with 3D detecting electrodes, which increased the overall effective area for electric signal transductions. Using a similar concept, a microfluidic thread-based EC device (μTED) was fabricated for simultaneous determination of acetaminophen and diclofenac by multiple pulse amperometry (MPA) technique (Agustini, Bergamini, and Marcolino-Junior 2016). Most recently, conventional stainless-steel pins were used as electrodes in a μTED system, where threads were turned surrounding each pin electrode (Glavan et al., 2016). Thus, when a sample solution was applied, the liquid wicked along the thread and formed a cylindrical interface with the shaft of each pin, in which the area of the thread in contact with the shaft determined the area of the electrode-fluid interface.
Similar to the μCADs, it is likely that we see a fast growing body of study of the μTADs, since these offer great possibilities for the technology of wearable systems.
Conclusion, challenges, and future outlooks
Microfluidic devices constructed on paper, cloth, and thread substrates offer many functionality advantages, mainly due to their structural and mechanical properties (Ahmed, Bui & Abbas, 2016). For instance, their porous structure and hydrophilic character enable lateral and capillary-driven fluid flow without the need of external pressure. Besides that, the high surface/volume ratio contributed by the network of cellulose fibers allows the accommodation of a large concentration of biomolecules, which further enhances the sensing capabilities (Ahmed, Bui & Abbas, 2016; Liana et al., 2012). Additionally, the mechanical properties possessed by these substrates such as durability and flexibility also make them attractive platforms for 3D microfluidic devices that enable multianalyte detection, as well as wearable sensors and technology to monitor the health status and environmental hazards of the wearer.
Although the literature has demonstrated that microfluidic devices constructed on paper, cloth, and thread substrates have a promising potential in a wide range of applications, they are still at an early development stage (prototype) and require several improvements in terms of fabrication, analytical techniques, and performance to become mature platforms that can be adapted and commercialized as real-world products. For example, although microchannels on 2D μPADs and μCADs can be easily fabricated from either depositing different hydrophobic materials or performing surface modifications using many well-established techniques, it is observable that the fabrication techniques adopted to construct 3D μPADs and μCADs such as stacking and folding are not favorable, especially for mass production, due to its manual fabrication method that might be time consuming and present reproducibility issues (Ahmed, Bui, and Abbas 2016). In terms of performance, the μPADs, μCADs, and μTADs have relatively lower sensitivity compared to conventional analytical techniques. This is largely contributed by the evaporation and water retention factor that often take place during the fluid delivery process from the sample introduction to the reaction area.
Nevertheless, μPADs, μCADs, and μTADs have the potential to play an important role in the future of wearable devices, a technology that is increasingly being investigated and developed for real-time monitoring of biochemical analytes within biological fluids. These types of devices allow close contact with the wearer to collect and analyze body fluids, maximizing efficiency and minimizing size but maintaining comfort. These microfluidic platforms can be used to deliver the biological fluid to an integrated sensor, allowing for economic replaceable platform within the robust device (Rose et al. 2015). In order to meet the ASSURED “equipment free” criterion, small, portable, and inexpensive EC analyzers/handheld readers can be miniaturized with the aid of microelectronics. For this to be realized, the use of new materials is important, for example flexible and stretchable fibers based on carbon nanotubes or graphene (Choi et al. 2015) or other polymer materials to fabricate flexible electronics circuits to be integrated on clothes or within wearable devices (Gao et al., 2016; Kim et al., 2011). Other consideration for wearable devices such as the power sources, as well as flexible, portable batteries, must be considered for this kind of applications (Song et al. 2015).
This technology is being developed fast in an era where “the Internet of things” is at the forefront of research and development, from hobbies and entertainment to diagnosis and therapeutics. The rapid development of sensors embedded on garments has seen a rise in the last years due to the collaboration between research groups and international sports and technological companies such as Reebok, Google, and Apple, for example, developing shirts, glasses, and watches, respectively. With the rise of small companies and start-ups working on this field, there will soon be many more gadgets and wearable garments in the market using μPADs, μCADs, and μTADs with the correspondent electronic circuit and antennae for communication via smartphones for continuous monitoring of vital signs and biochemical variables.
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