Emerging Considerations for the Future Development ...

Accepted Article Title: Emerging Considerations for the Future Development of Electrochemical Paper-based Analytical Devices Authors: Waldemir Jose Paschoalino, Sergio Kogikoski Jr, Jose T. C. Barragan, Juliana de Fatima Giarola, Lory Cantelli, Thais Maria Rabelo, Tatiana Marques Pessanha, and Lauro Tatsuo Kubota This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: ChemElectroChem 10.1002/celc.201800677 Link to VoR: http://dx.doi.org/10.1002/celc.201800677

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Rabelo,[a] MSc Tatiana M. Pessanha,[a] Prof. Lauro T. Kubota*[a]

the Future Development of Electrochemical Paper-based Dr. Waldemir J. Paschoalino,[a] Dr. Sergio Kogikoski Jr.,[a] Dr. José T. C. Barragan,[a] MSc. Juliana F. Giarola,[a] MSc Lory Cantelli,[a] MSc Thais M.

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Analytical Devices

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REVIEW and faster analyses that also follow the principles of green analytical chemistry requires novel analytical chemistry strategies. Since the appearance in this century of the first device based on a paper platform, many studies have been presented in the literature, providing a wide range of designs and possibilities for the application of paper platforms to electroanalytical systems. This review gives an overview of the field and can pave the way for the future development of electrochemical paper-based analytical devices. We also present a critical point of view regarding what has been investigated and developed and what is still missing. This review discusses the efforts made in the field related to important topics such as the choice of the paper substrate, the device construction process, the characterization of the device, and applications in different areas. In this way, we indicate some steps necessary for optimizing the design of the devices, with a focus on multidisciplinary collaborations that could move entire systems from the bench of the laboratory to the field.

1. Introduction Analytical chemistry can be considered the oldest and one of the most important fields in chemistry, since the development of modern chemistry and many other scientific areas benefit directly from the development of novel analytical methods and instruments.[1] It is even more noticeable in the continuous advances seen in daily life that are directly related to the development of analytical chemistry. Furthermore, in the laboratory, we routinely see and use the devices responsible for those advances. While this field has brought important results, it also brought difficulties, since many procedures require several preparation steps, specialized and sophisticated equipment, and personal skills and knowledge to obtain a significant result. [2] To fulfil the current need to make analysis easier, more precise and faster while also following the principles of green analytical chemistry,[3] the use of novel analytical chemistry strategies is required. Large advances in miniaturized analytical systems are being developed by minimizing the number of reagents and samples used in analysis protocols, decreasing energy consumption, generating simple platforms with low cost, reducing the time of analysis, and making such systems portable and less invasive.[4] These advantages can be achieved through the use of microfluidic devices. Microfluidics stand out as an emerging area in the construction of analytical microdevices, and this field consists of the manipulation of small amounts of fluids in channels of reduced dimensions.[5]

[a]

Dr. W. J. Paschoalino, Dr. S. Kogikoski Jr., Dr. J. T. C. Barragan, MSc. J. F. Giarola, MSc L. Cantelli, MSc T. M. Rabelo, MSc T. M. Pessanha, Prof. L. T. Kubota* Department of Analytical Chemistry, Institute of Chemistry, State University of Campinas (UNICAMP), P.O. Box 6154, 13083-970, Campinas-SP (Brazil).

The miniaturization provides simplified systems that are relevant to the strategy of decentralizing the analyses and for the development of devices capable of performing simple chemical reactions and separating and detecting products in an integrated method, which is known as a micro total analysis system (μTAS) or a lab-on-a-chip [6] and especially for paper, lab-on-paper.[7] One of the most versatile materials for the construction of microfluidic devices is paper, and herein, we discuss and propose to revise recent contributions in the area from a critical point of view.

2. Electrochemical devices

paper-based

analytical

The emergence of portable on-site testing devices, known as point-of-care (POC) devices,[8] has initiated fast growth in the microfluidic field and led to their use in various applications, e.g., clinical diagnosis and application to the pharmaceutical industry and the environment.[4b] In the past decade, low-cost, efficient, reliable and rapid monitoring POC devices that use paper as a platform have gained attention in the scientific community, and they are known as microfluidic paper-based analytical devices (μPADs).[8] The μPAD concept was reported for the first time by George Whiteside’s group,[9] who described a simple paper device with hydrophobic barriers that create well-defined hydrophilic channels. There are currently POC devices being tested for different applications such as diagnostics, [10] environmental analysis[11] and food and water analysis.[12] The use of paper as a platform for analytical purposes has various advantages, such as paper being easily available, inexpensive, capable of absorbing and percolating fluids by capillarity action, lightweight, easy to transport, disposable and biodegradable, in addition to allowing the easy design of hydrophilic paths with the creation of hydrophobic zones using printing or cutting technologies.[12e] A new class of the paperbased analytical devices includes the electrochemical paperbased analytical devices (ePADs), since electrodes can also be miniaturized and/or deposited onto paper by means of several technologies. Electrochemical detectors are inexpensive, have high sensitivity and selectivity, are available in a wide variety of available detection formats, and can be portable and used in different assays.[13] The scheme 1 presents a summary diagram about ePAD and its applications. Several ePADs have been reported for sensing applications, and the main application examples will be further detailed in this text. [10b, 12d, 14] Paper is not only useful for information storage, it is also one of the most versatile substrates for chemical analysis and confined chemical reactions.[15] Papyrus has been used as a substrate for chemical reactions since antiquity, [16] and at the beginning of the past century, paper had a very important role in the development of analytical chemistry; due to the lack of specialized analytical instrumentation, many methods relied on the sensitivity of specific chemical reactions that resulted in a colored product, which qualitatively generated information about the species present. Many times, this color change was carried out on paper since it could facilitate optical comparison between samples.

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Abstract: Meeting the current needs for easier, more precise

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Scheme 1. Summary diagram about electrochemical paper-based analytical device (ePAD) and its applications

For colorimetric tests, paper is an excellent platform, principally because it provides a white background, which does not significantly alter the final observed color. This property is one of the most important for paper-based analytical devices, since paper usually does not have contaminants in high concentrations and provides a very good background response for other techniques such as electrochemical assays and surface enhanced plasmon resonance (SERS).[17] Furthermore, it provides a cheap platform for the performance of multiple tests and has already been used for multiple colorimetric spot tests and enzyme-linked immunosorbent assays (ELISAs).[18] Since the appearance of the first device based on a paper platform, many studies have been presented in the literature that provide a range of designs for application in analytical systems. The fabrication of these devices could play an important part in analytical performance, especially for electrochemical detection, where so many variables that can affect the results, e.g., the electrode position, flow rates, migration, and contamination. Our group, the third group to publish a manuscript in this area,[19] just behind Charles Henry’s group[20] and George Whitesides’ group,[21] has published a considerable number of papers on microfluidics that provided large contributions to the field of performing electrochemical detection on paper. [22] The idea of using paper as a platform for electrochemical detection comes with many questions that makes the field challenging; one can choose different paper substrates and apply multiple electrochemical techniques without considering any information about the format of the device fabrication; however, there are

some points to be considered for the development of a great microfluidic chip. This review has the purpose to give an overview of the field, pave the way for the future development of electrochemical paper-based analytical devices and present a critical point of view regarding what has been studied and developed. This review will discuss the efforts in the field related to such issues as the choice of the paper substrate, the device construction process, the characterization of the device (not only the electrochemical process characterization), and several applications in different areas. In this way, we provide some necessary steps that should be taken when aiming to optimize the design of the devices.

Dr. Waldemir J. Paschoalino received his BSc degree in Chemistry from University of São Paulo (USP, Brazil) and his PhD in Science also from University of São Paulo (USP, Brazil). His PhD studies were focused on electrocatalysis of hydrogen and sodium borohydride oxidation reactions on dispersed catalysts formed by metal hydride alloys. He joined the group of Prof. Lauro T. Kubota in 2017 as a Postdoctoral fellow at the State University of Campinas (UNICAMP, Brazil), conducting a project involving the investigation of the electrocatalytic activity of sensors based on graphene oxide by

.

Scanning Electrochemical Microscopy

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Dr. José Tiago C. Barragan received his master degree in chemistry from São Paulo State University – UNESP (Brazil) in 2007, and PhD in science from State University of Campinas – UNICAMP (Brazil) in 2016. Currently is postdoctoral researcher, coordinated by Prof. Dr. Lauro T. Kubota (Unicamp, Brazil) where develop a collaborative research with private sector. His principal interest research is focused in advances for electrochemical detection in ion chromatography.

MSc. Juliana F. Giarola received her Master degree in Science focusing on Physics and Chemistry of Materials in 2016 from Federal University of São João del-Rei (UFSJ), Brazil. She is a PhD student in State University of Campinas (UNICAMP), since 2016, in the laboratory coordinated by Prof. Dr. Lauro T. Kubota. Her current research is focused on paper-based analytical devices, specifically on the development of a paperbased lateral flow assay for disease biomarkers.

MSc. Lory Cantelli Carossi received her degree in Chemistry from Federal University of São Carlos (UFSCar, Brazil) and her masters in Materials Science also from Federal University of São Carlos (UFSCar, Brazil). She is a PhD student at State University of Campinas (UNICAMP, Brazil) under Prof. Lauro T. Kubota supervision. Her current study is focused on the development of paper-based sensors for the diagnosis of depression. MSc. Thais Maria Rabelo Alves received her bachelor in Chemistry with Technological Assignments in 2011, from the Federal University of Rio de Janeiro, and received a Master's Degree in Chemistry in 2013 by the same university. She is currently studying for a doctorate at the State University of Campinas. Her research field is the development of news point-of-care devices with electrochemical detection for species of clinical interest.

MSc. Tatiana Marques Pessanha received her degree in Chemistry from Federal University of Rio de Janeiro (UFRJ, Brazil) and Master in Science also from Federal University of Rio de Janeiro (UFRJ, Brazil). She is a PhD student at State University of Campinas (UNICAMP, Brazil) under Prof. Lauro T. Kubota supervision. Her current study is focused on the development of graphene-based derivatives capacitive sensors for detection of biomarkers.

Professor Dr. Lauro Tatsuo Kubota became Full Professor of the Institute of Chemistry at the State University of Campinas (UNICAMP, Brazil) in 2009. He is member of Brazilian Academy of Science (ABC) and the Academy of Science of Sao Paulo State (ACIESP). Currently, he is the coordinator of the National Institute of Science and Technology in Bioanalytics (INCTBio) and Director of the Institute of Chemistry at UNICAMP. He is also the leader of the Laboratory of Electrochemistry, Electroanalytics and Development of Sensors (LEEDS), focusing his research on the development of sensors and biosensors, aiming the construction of POC devices.

3. Which paper substrate to use? Paper choice is one of the most important parts in the construction of these devices, since differences in paper types can result in different responses. Different substrates possess distinct properties that can be tuned depending on the requirements and potentially increase the sensitivity of the analysis. Properties such as porosity, hydrophilicity, fiber size, and thickness can influence the final analytical response. In this way, the appropriate paper should be chosen to obtain maximum analytical performance. Moreover, depending on the intended analytical method and the device construction, different papers can be used in a single device, where each kind of paper has a specific role such as filtering, flowing, acting as a test zone, and absorbing. Depending on the specific application needed, a wide range of paper substrates can be utilized: chromatography paper,[23] filter paper,[24] office paper,[25] cardboard,[26] and other papers.[4b, 27] Paper is an excellent substrate for electrochemical analyses, since it provides a nonresponsive background, can be used in aqueous and nonaqueous analyses, and allows a full device with high sensitivity and functionality to be obtained in a few steps.[22f] However, the selection criteria for choosing the paper substrate are not always stated, even though selection is a critical step in device development. In Figure 1, scanning electron microscopy (SEM) images of the most common paper substrates used for electrochemical analysis are shown, and the images show the porous and fibrous structure of the papers. A recent report by Evans et al.[28] showed the importance in choosing the right paper in order to improve color intensity and uniformity in colorimetric assays. The study compared six different papers, three grades of Whatman filtration paper and three grades of Whatman chromatography paper. The papers were characterized by their filtration, wicking ability,

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Dr. Sergio Kogikoski Jr. received his BSc degree in Science and Technology from Federal University of ABC (UFABC, Brazil) and his PhD in Science and Technology in Chemistry also from Federal University of ABC (UFABC, Brazil). His PhD studies were focused on the synthesis and characterization of supramolecular materials based on polymer and peptides for electrochemical applications. He joined the group of Prof. Lauro T. Kubota in 2016 as a Postdoctoral fellow at State University of Campinas (UNICAMP, Brazil), studying the electrochemical properties of DNA based supramolecular nanostructures for bioanalytical applications.

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porosity, fiber diameter distribution, etc.; then, considering the paper properties, the analytical response towards glucose colorimetric detection was improved using the appropriate experimental setup. In this case, the results showed that thicker papers (Whatman No. 3) presented worse results than thinner substrates (Whatman Nos. 1 and 2); in addition, the Whatman No. 1 chromatography paper presented the best response of the substrates in the present study. Unfortunately, we did not find a similar description studying the improvement of the electrochemical response by rational paper choice, and such a study is very important.

Figure 1. A) Scanning electron microscopy (SEM) images of the nitrocellulose and pure cellulose substrates, showing the differences in the fibers and surface structures. Adapted from Credou et al. (Copyright 2015 Royal Society of Chemistry).[29] B) Office paper SEM images and electron dispersive energy spectroscopy (EDS) maps showing the distribution of the elements in the surface of paper; they primarily show the high amount of calcium present in the structure. Adapted from Marques et al. (Copyright 2015 Nature).[30]

The most-used paper substrate for electrochemical paper-based devices is Whatman No. 1 chromatography paper, principally because it has a smooth surface, uniform structure, a high content of α-cellulose, and very good wicking properties and is free of hydrophobic binders and freely commercially available. In addition to these properties, it is very suitable for enzyme and protein immobilization due to its high degree of nonspecific binding of biomolecules.[4b, 26, 28, 31] Since the first reports by

Whiteside’s group, which used this paper, its use for the initial development of paper-based electrochemical devices has continued.[19-21, 32] Due to its structure and properties, Whatman No. 1 can be easily modified, and since the beginning, sets of electrodes have been deposited or printed on top of the paper, turning it into an excellent substrate for versatile electrochemical POC analysis.[21, 32-33] The main application using the separation and microfluidic properties of paper is the quantification of small molecules such as glucose, lactate, uric acid, and ascorbic acid.[19-20, 32] With the development of this area, better understanding of the construction principles of these devices, different strategies for the application of nontreated samples, better electrochemical interfaces, etc., it is now possible to detect a wide variety of analytes in different matrixes such as metals, [34] ions, [22d, 35] bacteria,[12a] pollutants,[36] disease biomarkers,[37] drugs, and food contamination.[38] Whatman’s paper is also easily modified to produce even better results: its hydrophobicity can be tuned,[37, 39] it can be made omniphobic,[40] its conductivity can be enhanced by incorporating carbon materials or soaking with conducting polymer,[41] it can be modified by different nanomaterials,[42] etc. However, as discussed previously, it is also necessary to evaluate whether Whatman No. 1 paper is the principal paper for most studies due to its properties or its large commercial availability. Another substrate that is widely used in bioassays is nitrocellulose paper.[26, 43] Since the 1960s, when it was first studied in the immobilization of biomolecules such as DNA conjugates, proteins, enzymes, it has evolved to be a prominent material in POC diagnostics, principally in the form of lateral flow immunoassays (LFIAs).[44] Nitrocellulose is a hydrophobic substrate with smaller pores and porosity than Whatman No. 1 chromatography paper. It is also an amorphous polymer with worse mechanical properties than other cellulosic papers; however, it has exceptional protein adsorption properties that are essential for LFIAs.[26, 45] Even though LFIAs have a very accurate and precise response, they often function as a qualitative test that lacks precise quantification of the analyte. The first reports using electrochemical tests coupled to LFIAs used an indirect procedure to quantify the analyte; the first report used the breaking of ferricyanide-loaded liposomes to increase the current at the electrode,[46] and a later work labeled antibodies with bismuth and quantified it by anodic stripping voltammetry.[47] However, those two works did not enhance the quantification limit of the process relative to optical tests. This advance was later achieved by Liu et al.[48] when using quantum dots as electrochemical probes, which were analyzed by stripping cadmium and examining it by square wave voltammetry. Due to the difficulty in working with nitrocellulose, principally because it is brittle and difficult to handle, many works use nonintegrated electrodes or external electrodes. Few examples of the printing of conductive circuits on nitrocellulose paper exist,[49] even though nitrocellulose polymer is used as a stabilizer for the development of conductive inks for printed electronics.[50] One recent example is that for the LFIA for myeloperoxidase detection,[51] the authors screen-printed a three-

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electrode system consisting of one Ag pseudoreference electrode and two graphite electrodes, which served as working and counter electrodes, on the back of the nitrocellulose paper, obtaining a fully integrated device. To fully develop the potential of electrochemical LFIAs, it is necessary to further study the generation of integrated devices in nitrocellulose, which is still a challenge. Of course, the use of nitrocellulose for electrochemical devices is not recommended for some analytes, since it might interfere with the results due to the oxidation of the nitro groups at high anodic potentials. Other paper that is of commercial interest is office paper, which is available worldwide in local stores; however, compared to Whatman No. 1, it contains a series of modifiers to improve its mechanical properties, hydrophobicity and printability. One of the modifiers is calcium carbonate (CaCO3), which is also part of the paper production process;[52] there is no information about this compound interfering with the electrochemical analysis, but it certainly provides a pH change. The first work using office paper was authored by de Araujo and Paixão, [53] and they constructed

silver electrodes for multiple electrochemical analyses. In this work, one device made with the proposed methodology was discussed to cost only 3 % of the price if it was made the same but with Whatman No. 1 chromatography paper. In Table 1, we present some of the most common paper substrates used for electrochemical analysis. Office paper has been used in a variety of electrochemical applications. It was modified with electrochromic tungsten oxide to quantify the electrochemically active bacteria Geobacter sulfurreducens.[30] Recently, Cinti et al.[25] used office paper of two different grammage (80 and 100 g m -2) for the electrochemical biosensing of ethanol in beverages, and no difference was observed in the electrochemical detection due to the grammage difference. Santhiago et al.[54] modified office paper with carbon black to obtain conductive substrates for electrochemical, electronic and wearable devices. The same authors also reported the use of pencil-drawn electrodes on office paper to obtain a nicotinamide adenine dinucleotide (NAD) sensor.[55]

Table 1. Some examples of paper substrates employed in electroanalytical devices and their analytes. Paper substrate

Analyte

Whatman No. 1 filter paper

Dopamine, glucose and pH

Ref.

miR-21 (miRNA) Staphylococcus aureus Cholesterol Alpha-Fetoprotein Influenza virus (H1N1) Human chorionic gonadotropin (HCG) Human Cardiac Troponin T Ferricyanide, hydroquinone, p-aminophenol Na+ and K+ ClRabbit IgG and Plasmodium falciparum HRP2 Alpha-fetoprotein Na+, Ca2+, NH4+, K+, anions Whole blood lithium Pb+2 and Cd+2 DNA and thrombin Cl- in sweat and serum Carcinoembryonic antigen (CEA)

Electrochemical analysis CV, amperometry and potentiometry DPV DPV Amperometry SWV DPV DPV CV CV and amperometry Potentiometry Potentiometry SWV SWV Potentiometry Potentiometry SWV SWV CV DPV

Whatman filter paper (qualitative, 114) Whatman chromatography paper 3 mm Whatman No. 1 filter paper Whatman No. 1 filter paper Whatman filter paper (qualitative, 4) Whatman No. 1 filter paper Whatman No. 1 filter (LFIA) Whatman No. 1 chromatography paper Whatman No. 1 filter paper Whatman Nos. 1 and 3 filter papers Whatman No. 1 chromatography paper Whatman No. 1 filter Whatman No. 1 Qualitative filter paper Whatman No. 1 filter paper Whatman No. 1 chromatography paper Filter paper Whatman No. 1 chromatography paper Whatman No. 1 filter with Reduced Graphene Oxide (RGO) Nitrocellulose (LFIA) and Whatman No. 1 chromatography paper Nitrocellulose (LFIA) Nitrocellulose (LFIA) Nitrocellulose (LFIA) Nitrocellulose (LFIA) Nitrocellulose(LFIA) Nitrocellulose (LFIA) Nitrocellulose (LFIA)

Carcinoembryonic antigen (CEA)

DPV

[41c]

Paraoxon in environment

Amperometry

Acetaminophen DPV Prostate-specific antigen (PSA) SWV Myeloperoxidase Amperometry DNA oxidative damage Amperometry Myeloperoxidase (MPO) Amperometry Organophosphorous SWV Dengue NS1 protein EIS Foodborne bacteria Escherichia coli and Salmonella Nitrocellulose (LFIA) Amperometry enterica Nanocellulose paper Glucose and E. coli Amperometry and EIS Mixed cellulose ester (MCE) Nitrite DPV Office paper Picric acid, Cl- and Pb+2 CV and SWV Office paper (80 and 100 g m-2) Ethanol Amperometry Office paper NADH CV and amperometry Office paper Li+, Na+ and K+ Conductimetry Cardboard Ascorbic, caffeic and picric acids CV and DPV CV=cyclic voltammetry, DPV=differential pulse voltammetry, SWV=square wave voltammetry, EIS=Electrochemical Impedance Spectroscopy.

A careful look into published articles showed little or no information on why a certain paper type is chosen for the development of devices, and we believe that more studies that relate the electrochemical response to the paper type, quality, and

[56] [14b] [12a] [57] [58] [59] [10b] [60] [61] [35b] [35a] [37] [58] [22d] [35d] [34] [62] [63] [64]

[65] [14a] [48] [51] [66] [51] [67] [68] [69] [70] [14c] [53] [25] [55] [71] [72]

properties are extremely necessary to further develop precise and advanced sensing strategies. The paper type and its pretreatments are important for better performance of these devices, and we thus tend to be more critical of the development

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of strategies that clarify the standardization of these processes. We propose that future manuscripts that will be published should explain the choice of paper based on its properties and attempt to correlate electrochemical behavior with paper structure. The development of a procedure for choosing the proper paper for electrochemical applications must be considerably improved for a better understanding of paper-based electrochemical devices.

4. Fabrication of paper-based electrochemical devices Paper is a porous, hydrophilic, flexible material that makes writing and printing on its surface possible, allowing the formation of structures desirable for electrodes. For the fabrication of paperbased electrochemical devices, it is primarily necessary to choose the type of paper, which acts as a substrate material, supporting the entire electronic system, including the sample holder and the detection zone. Fabrication methods play an important part in obtaining an optimum device; however, the method depends principally on the device application. The first step in the construction of a paper-based device is the formation of hydrophobic zones that delimit the region of analysis, where the fluid percolates by capillarity from the sample pad to the region of detection.[73] These microfluidic channels are made using hydrophobic materials or by establishing physical limits by cutting the paper substrate. The second step is related to the manufacturing of the detection system and the electrode, which are other fundamental parts for the development of the device; these parts especially important for electrochemical sensing that offers the advantage of quantitative detection, which is associated with selectivity and increased sensitivity. [74] Thus, here we present the fabrication methods most commonly used to generate electrochemical paper devices, both in the construction of the hydrophobic barriers and in the fabrication of electrodes, showing the advantages and disadvantages of each technique.

diffusion of wax onto paper fibers by heating the sample on a hot plate, followed by cooling the sample to room temperature. Although the formation of hydrophobic channels using a metal stamp on paper has been demonstrated by Müler and Clegg, [77] the use of wax printing reported by Whitesides’ group facilitated the construction of these devices.[78] Their method uses a commercial wax printer to print the designed patterns of hydrophobic regions. This method has a low resolution compared to photolithography due to the greater width of the produced hydrophobic barrier but has the advantage that it does not require further cleaning steps with organic solvents. [79] Another simple and cheap method used to build the hydrophobic barriers on paper is wax screen-printing.[80] The process consists of designing a screen (or mask) on a transparency film, followed by cutting, by laser or by hand. After that step, wax is applied over the mask, which contacts the paper substrate, with constant pressure, uniformly creating the hydrophobic zones. This system is set on a hot plate to facilitate the diffusion of the hydrophobic species, and afterwards, the wax is applied and rapidly cooled to room temperature. [24] One disadvantage of this technique is its low resolution, which is caused by the wax being physically overspread through the mask.[81] The wax methods have many points that make their use interesting for the field, especially the utilization of molds on simple and inexpensive substrates such as transparency film, which increases the method’s accessibility for a larger community. One of this method’s drawbacks is its low resolution in manufacturing the hydrophobic patterns since the wax is physically wiped out through the mask; [81] many results also showed that attention must be given to the thickness of the deposited wax, the porosity and orientation of the fibers in the paper, and the possibility of wax components contaminating the electrochemical system.

4.1.2. Photolithography

4.1. Hydrophobic zones There are several well-established techniques used to create the hydrophobic zones, which are responsible for restricting fluid percolation to detection regions. In this section, we present wax printing, wax screen-printing and photolithography techniques in more detail, because nowadays these methods being those most commonly applied for the development of paper-based electrochemical devices.[4b, 31b, 75] In Table 2, the principal methods for the construction of hydrophobic barriers are given along with their advantages and disadvantages in the construction of ePADs.

4.1.1. Wax printing and wax screen-printing Wax printing methods are cheaper and nontoxic than the other methods presented in the literature, and they are among the methods most used for the construction of hydrophobic barriers.[76] Generally, the process of wax printing is done in two steps: (i) the deposition of wax on paper substrate and (ii) the

Photolithographic processes have been widely used in the manufacture of microfluidic devices.[82] For the development of paper-based devices, the use of this technique was first reported by the Whitesides group.[83] The authors used modified photolithography as a more accessible method for the delimitation of the hydrophilic regions in the paper substrate. First, the chromatography paper was impregnated with an SU-8 photoresist and then exposed to UV light through a photomask. The uncured photoresist was removed with solvent; in this way, the hydrophobic barriers were formed in the paper. [84] The developed method is very similar to conventional photolithography; however, it offers more range once it can be used with reduced infrastructure. In addition, the masks for photolithography can be prepared by different techniques such as the use of an inkjet printer or photocopying machine or being drawn by hand. [24, 84] As another example, Gupta and co-authors[57] have used photolithography to construct a paper-based electrochemical microfluidic device for cholesterol diagnosis. The paper was spincoated with a photoresist, baked and then exposed to UV through a photomask, resulting in hydrophobic barriers.

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REVIEW Unlike the wax methods, photolithography presents a good reproducibility and high resolution. On the other hand, depending on the goals of the research (for instance, obtaining microchannels), this technique can be expensive to use once because a precise alignment system is necessary, requiring

instrumentation of greater sophistication that is not always readily accessible to researchers.[82] The mechanical properties of the photoresist are also not good for flexible devices, since it is brittle and fragile, and after the impregnation, these properties are also transferred to paper.

Table 2. Methods for the fabrication of hydrophobic microchannels and their advantages and disadvantages. Adapted from Akyazi et al. (Copyright 2018 Elsevier).[76] Advantages

Cutting

Sharp and defined borders

Photolithography

High resolution of microfluidic channels; sharp barriers

Polydimethylsiloxane (PDMS) printing

Cheap patterning agent (PDMS); flexible devices

Inkjet etching

Low cost; requires only a single printing apparatus to create microfluidic channels and to print bio/chemical sensing reagents

Wax dipping

Very cheap and easy method

Flexography printing

Allows direct roll-to-roll production in preexisting printing machinery; avoids heat treatment of the printed patterns

Screen-printing

Low cost; simple fabrication steps

Wax printing

Produces massive devices with a simple and fast fabrication process

Stamping

Low cost, simple

Drawbacks Requires expensive equipment; wastes raw material; yields low mechanical stability; needs cover tape for preventing pollution and increasing the robustness of the device Requires expensive equipment, complex steps, and expensive reagents; brittle and fragile Inconsistent control over hydrophobic barrier formation; low resolution; requires a curing step; cannot be readily applied to highthroughput production Requires multiple printing steps for the creation of the microfluidic channels; the printing apparatus must be customized; several complex steps; not suitable for mass fabrication Inconsistent batches due to the variation in dipping; not good for mass production High cost; complex reagents and templates; surface requires frequent cleaning to avoid contamination; printing quality depends on smoothness of paper surface; requires different printing plates Low resolution of microfluidic channels; rough barriers; requires different printing screens for creating different patterns; not good for mass production Poor availability in resource-limited settings; low resolution; requires an extra heating step after wax deposition Inconsistent process; low resolution; preheating of the stamp and oxidization of the paper are needed in the case of paraffin stamping with a metal stamp

Ref. [85]

[31a, 86]

[87]

[88]

[89]

[90]

[80, 91]

[92]

[93]

Uses very cheap patterning agent, Alkyl Ketene Dimer (AKD) or fluorocarbon; dramatically reduces the cost of materials High resolution; requires only a desktop printer to produce devices and to print sensing reagents Simple steps; complex patterns can be accomplished

High cost; requires different masks or glass slides for creating microfluidic patterns on paper

[94]

Requires modified inkjet printers; different ink compositions for each printing; mostly requires an extra heating step after deposition

[95]

Expensive equipment

[96]

Wet etching

Simple and fast

Expensive; needs a paper mask with specific designs

[97]

Hand-held corona treatment

Low cost; simple fabrication steps

Heating process is needed

[98]

Plasma treatment

Inkjet printing Vapor phase deposition

4.2. Electrode fabrication methods

4.2.1. Screen/Stencil printing

After colorimetric detection, electrochemical detection is the technique most used to monitor responses generated by analytes, and it has the advantage of quantifying with high sensitivity and selectivity (depending on the analyte). Another advantage is that unlike colorimetric paper devices, the electrode material is usually not affected by light or turbidity.[81] Electrode fabrication is the most important part of electrochemistry systems, and this is also true for electrochemical paper-based devices. Thus, the fabrication of the electrode is a determinant for the good performance of these devices. There are several methods for fabricating electrodes on paper substrate, e.g., screen-printing, stencil printing, drawing with pencil/pen, sputtering, e-beam deposition, inkjet printing, nanoparticle growth, [15b] and microwire placement,[74, 99] and here, we describe in more detail some of the most used techniques.[20, 100]

The screen-printing technique can be used to both create hydrophobic zones on paper (wax screen-printing) and prepare the electrodes. Charles Henry’s group reported the first device using electrochemical detection on paper by applying a homemade screen-printing technology on paper, which had previously been patterned by photolithography. [20] Initially, the screen-printed electrode was designed using Corel Draw 9® software to optimize the area and the geometry of the system, minimizing the effects of uncompensated resistance. The working and counter electrodes were screen-printed using carbon ink containing Prussian blue (PB), and the reference electrode was based on silver/silver chloride ink. This technique was the first used for the fabrication of paper-based electrochemical devices and is still one of the most used methods for electrode fabrication.

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The fabrication methods can be different depending on the mold that is applied to obtain the electrodes. It is possible to use customized screens (usually made from Nylon or silk) or stencils, which are materials easily made from solid or transparent films using hand or laser cutters. The main advantages of using stencils over the screen is their low cost and rapid prototyping; however, both techniques are applied to fabricate electrode patterns on paper with metallic and carbon-based inks. The screen/stencil is placed on the paper substrate, and the ink is pressed, allowing its diffusion to the open regions of the screen and thus obtaining the desired electrode. [15b, 20, 74] Another point that must be taken into consideration with these methods is the production of the inks, and the most common inks here are carbon-based materials such as graphite, graphene, carbon nanotubes and their derivatives.[101] The use of nanomaterials as screen-printed inks is still a field of study, and the dispersion, viscosity and agglomeration of materials are some of the limiting parameters in the production of new inks. Gold nanoparticles (AuNPs) are the most used nanoparticles for the manufacture of new metal nanoparticle inks; however, the use of nanoparticle inks of silver, copper, iron and platinum has also been reported.[102] An advantage of the screen/stencil printing technology is the accessibility of the materials. The patterned screens can be shaped within any lab but are also commercially available, and they can be obtained by mass production techniques, which is important in electrode fabrication for reliable repeatability. [4b, 31b] The inks limit the screen-printing technique because their formulation uses organic solvents that are susceptible to temperature and humidity, which vary the standardized concentrations and viscosity. Furthermore, the technique presents low resolution, high ink waste, and imprecision due to the low contact pressure during fabrication. [15b, 103]

One of the problems for pencil-drawn electrodes is the presence of microdefects during the cleaning process, which raises some questions about the time scale of the experiments. The greatest strength of this technique is the utilization of graphite as a working electrode; however, more research must be done to improve the three electrodes system, since the reference and the counter electrodes are usually made of expensive materials and more techniques must be applied for their fabrication. Another issue for this kind of process is a requirement for the better standardization and repeatability of the electrodes, which is strongly related to the pressure applied. This pressure must be continuous and constant during the fabrication of each electrode, and the different graphite compositions from different manufacturers must be considered.

4.2.2. Pencil-drawn electrodes

Microwire electrodes have been proposed by Crooks and co-authors [106a] for the development of ePADs, where the microwire electrodes maintain contact with paper substrate. The authors used Au wires as electrodes for the fabrication of the device, and Ag conductive adhesive and Cu tape were used for the electrical contact. This ePAD configuration has advantages over the printed screen, since it allows the working electrode to be cleaned (for instance, using piranha solution) and the modification of the electrodes without causing any damage to the paper substrate structure. Henry and Adikins [107] developed an ePAD using microwires as an alternative for screen-printed electrodes. As proof of concept, the authors used different metals such as Pt, Au, W and Ir with different microwire diameters for the construction of the electrodes and compared their performances against those of carbon ink electrodes. Microwires have advantages over the widely used carbon ink electrodes due to their properties such as higher surface areas, higher surface-to-volume ratios and lower resistance than the carbon ink electrodes. Another advantage of microwire electrodes is the possibility of incorporating different materials into their composition.

The use of pencil graphite as a carbon-based material for electrode construction on paper devices was one of the most interesting strategies to minimize costs in the fabrication stage; the process is simple, and the pencil is commercially available. [74] Pencil graphite consists of a composite containing graphite, clay and resin, and it is graded according to its hardness. For instance, the HB grade means that the graphite is hard (H) and black (B) and presents equal proportions of graphite and clay. [104] The fabrication of electrodes on paper using pencil graphite can be done barehanded by scratching the paper surface or even by using a customized stencil pattern designed on specialized software. Another advantage of using pencil-drawn electrodes is the fact that they are free of waste, which makes their disposal greener and easier than disposal of the ink system.[105] In a report by Santhiago et al.,[55] a flexible device using a 4B pencil previously standardized with wax was fabricated. The reference electrode was fabricated using silver paint, and the counter electrode was fabricated using a thermal deposition method, forming a 150 nm gold film. To show the applicability of the device, NADH was used for a proof of concept of the electrode.

4.2.3. Microwire In the manufacture of paper-based electrochemical devices, carbon inks are widely used because they are cheap and widely available and have a wide potential range of analytes that they can detect. Screen-printing and pencil-drawing are among the most commonly used methods to produce carbon electrodes, which present high surface area.[106] In addition, carbon presents some drawbacks such as poor electrical properties and irreproducibility as a chemical surface. [74] As an alternative, metallic ink electrodes have also been used, since they have high conductivity and catalytic activity. Noble metals such as gold and silver are usually applied via thin film deposition, nanoparticle growth and inkjet printing for the fabrication of working electrode (Au) and also reference electrode (Ag). The disadvantages of the metallic inks and pastes are their high electrical resistance and low electroactive surface area. [15b, 74]

4.3. Fabrication of 3D paper-devices

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Three-dimensional (3D) paper-based microfluidic devices with electrochemical detection, also referred to as ePADs, offer several advantages over two-dimensional (2D) devices.[108] The conventional 2D devices use a nonhomogeneous porous paper substrate, which has different functions such as deposition, percolation and analyte detection, and this feature can lead to variations in sample volume and problems in the electroactive area of the electrode due to the nonspecific absorption of species present in the sample (Figure 2).[109] In contrast, 3D devices can be composed of layers that present different functions and are made from different materials such as membranes, which can separate species that are interfering in the analysis, and even materials that can incorporate different detection methods such as colorimetric detection and the use of printed electrodes. [84] In addition, the use of microfluidic devices based on 3D paper makes it possible to simultaneously detect multiple analytes.[110] For example, Sonkusale [109] and co-authors developed a 3D ePAD that has a hollow analyte reservoir built into the paper.

In addition, the system has a screen-printed electrode (SPE) system. The electrode sensors were manufactured using waxand screen-printing, and the reservoir allowed the utilization of the entire electrode surface. Wang and collaborators have recently published a paper on a 3D paper device.[111] The paper was folded to create three zones: the first zone is a sample port; the second, an enzymatic reaction zone; and the third, the detection zone. For the formation of channels in chromatography paper, they used wax printing. Detection region electrodes were designed to be coupled to a commercial glucometer and were implemented using stencil printing and carbon-based ink printing. This work used simple techniques and managed to obtain a device with low cost for POC applications. The device is referred to as a "pop-up," which is a reversible mechanism with a mechanical valve that transitions from an “off” to an “open” position with the application of pressure exerted between fingers; this switch allows the sample to flow between the leaves and the three zones to arrive at the detection zone (Figure 3).

Figure 2. Examples of 3D electrochemical devices. A) Multilayer device composed by a bottom toner layer, bottom Ag-NW circuit layer, top toner layer and top AgNW circuit layer. Adapted from Huang et al. (Reprinted with permission from (G.-W. Huang, Q.-P. Feng, H.-M. Xiao, N. Li, S.-Y. Fu, ACS Nano 2016, 10, 88958903). Copyright (2016) American Chemical Society);[112] B) Stack paper device. Adapted from Zang et al. (D. Zang, L. Ge, M. Yan, X. Song, J. Yu, Chem. Comm. 2012, 48, 4683-4685. Reproduced by permission of The Royal Society of Chemistry);[113] C) Origami device containing a solution reservoir. Adapted from Punjiya et al. (M. Punjiya, C. H. Moon, Z. Matharu, H. Rezaei Nejad, S. Sonkusale, Analyst 2018, 143, 1059-1064. Reproduced by permission of The Royal Society of Chemistry).[56]

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Figure 3. A schematic representation of the “pop-up” ePAD using a glucometer.[111] (Adapted with permission from (C.-C. Wang, J. W. Hennek, A. Ainla, A. A. Kumar, W.-J. Lan, J. Im, B. S. Smith, M. Zhao, G. M. Whitesides, Anal. Chem. 2016, 88, 6326-6333.). Copyright (2016) American Chemical Society).

4.4. Partial conclusions and comments As mentioned before, fabrication plays an important role in the development of paper-based devices, since many steps can be applied until the final product is reached. This section is limited to issues in fabrication, from the formation of the hydrophobic barrier to electrode formatting. From an electrochemical point of view, it is important to decrease the number of steps in production, avoiding problems with contamination, electrode properties and cracking, electrolyte evaporation, temperature effects, and so on. We believe that techniques of greater efficiency must be applied to obtain a proper device, since it is clear that the biggest issues for paper-based electrochemical devices are their reproducibility, standardization and mass production. From our point of view, 3D paper-based fabrication might provide better resolution and applicability once it can be automated and reach different scales of production. Another problem is that most of the applications are limited to the laboratory bench due to their systems of detection, i.e., the electrode and the analyzer are distant, limiting the device portability. We see the development of new portable multiplex analyzers as the future of the area and important for local detection and quantification.

5. Advanced characterization of paper devices Materials characterization is a very interdisciplinary topic in science that requires efforts from different types of professionals such as engineers, physicists and chemists to create novel useful methodologies for understanding the properties of desired materials. The development of electrochemically based paper devices requires obtaining a well-planned device that can allow the sequential delivery of reagents, the occurrence of the

chemical reaction, the separation of byproducts, the obtaining of the relevant analytical signal, etc.[114] Even with all the physicalchemical characterization equipment available worldwide, the characterization of devices is often done only superficially and without a comprehensive understanding of the system. We believe that a more detailed characterization of paper devices should be performed in order to bring relevant contributions to the area. Some of the studies in our group are dedicated to the understanding of which steps are necessary to obtain a reproducible device with an optimized analytical signal and to properly characterize it by a variety of techniques. Our group has made contributions to some important aspects of these devices such as the flow in microfluidic paper channels, [115] entrapment methods to immobilize enzymes,[22c] and necessary steps to optimize a colorimetric LFIA device.[10a] Paper is an excellent substrate for automatic multistep processes, since it integrates a passive fluid pumping through the capillary forces of cellulose fibers; however, this property is dependent on not only paper type [116] but also many other parameters. It is dependent on the geometry of the microfluidic channel,[116-117] the presence of wax boundaries,[118] the ambient conditions (such as temperature and moisture), [116, 119] the confinement of the space,[33b, 120] etc. These articles give insights into the physical mechanisms involved in the passive pumping of paper, making the subject possible to be studied by anyone, since it is observed by the naked eye. For electrochemical sensing, the articles by Nery et al.[115b] investigated how the device shape influences the flow of glucose and uric acid, and later, Channon et al.[33b] showed that a multilayer device must to be optimized for the analyte and the electrochemical technique used to obtain the analytical signal. Wicking behavior is a fundamental property of paper that is often neglected in the device construction, but it should be accounted for and properly characterized for further advances in these devices. For colorimetric tests, more efforts are being made

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REVIEW believe that a more profound characterization of these devices is extremely necessary to the field to reach the next stage of their analytical applications. The ePADs hold great promise because they potentially have applications of greater complexity and lower limits of detection than the colorimetric-based devices; however, more characterization must be done.

6. Applications of paper devices The use of paper in typical analytical applications is ancient. A description of the detection of ferrous sulfate as an adulterant using papyrus as a substrate is found in Pliny the Elder manuscripts from 23 to 79 AD.[16] As described by Nery and Kubota,[132] numerous contributions to the development of microfluidic paper-based electrochemical devices (µPEDs) have occurred over time. In 2007, Martinez et al.[133] achieved a new milestone in this technology with the introduction of a complete low-cost colorimetric analytical device whose results are observed by naked eye; moreover, the developed device can be used in less industrialized countries, remote regions or at home. In addition, in 2009, Dungchai, Chailapakul and Henry[134] described the first analytical device on paper with electrochemical detection. Although colorimetric assays are the best choice for some applications, electrochemical sensors provide a more versatile and quantitative methodology for others. [135] Although this proposal is quite recent, there are already numerous applications of μPEDs, ranging from heavy metal and water determinations[136] to complex analyses such as the detection of prostate cancer markers.[137]. A more detailed description of selected applications for samples of environmental, pharmaceutical, food and clinical interests in the literature is below, and Table 3 provides a summary of the main characteristics found for each device.

6.1. Environmental analyses 6.1.1. Determination of metal ions Heavy metal ions, such as lead (Pb+2), cadmium (Cd+2), copper (Cu+2), mercury (Hg+2) and zinc (Zn+2), are of great environmental concern because they are a main source of environmental pollution. Those ions can cause great problems to living organisms, leading to several disorders in the immune, central nervous and reproductive systems.[34, 138] Contamination by Pb+2 ions can come from different sources such as the chemical and automotive industries and recurrent mining and construction activities, and they can contaminate air, soil and water. Residual water has Pb+2 ions, and according to the World Health Organization, the safe concentration threshold of these ions is 4.8 nmol L-1.[21] Cadmium is another highly toxic heavy metal, and at concentrations above 26.8 μg L-1, it is considerate harmful to health.[139] Martín-Yerga et al.[34] developed a microfluidic paper sensor capable of performing colorimetric and electrochemical analyses simultaneously. Figure 4A shows the sensor fabricated

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to optimize devices in order to enhance their analytical responses relative to the responses of electrochemically based assays; these efforts include optimizing the device shape to reduce sample loss in the microfluidic channel and thus obtain a maximum response,[33b] quantifying the distribution of proteins on devices, and accounting for the interactions of the proteins on the cellulose fibers.[121] Even though the fundamental characteristics of both types of devices are the same, there are differences that must be accounted for and properly characterized. Spectroscopies and SEM are other widely used characterization techniques because they directly characterize the material’s chemical properties and observe the material’s surface. However, those techniques are again being used to perform a simple surface characterization of the modified electrode. Techniques that allow the observation of the device without destroying the samples are essential for the advancement of this area. A technique that is very interesting for characterizing paper-based devices is optical profilometry or white-light interferometry, which is based on the difference in the superposition of light waves after the sample is irradiated with a white light source. This technique is useful because it allows the observation of large samples, such as those on the scale of ePADs, with a resolution on the order of nano- to micrometers, allows the direct visualization of a surface pattern and its roughness and is also nondestructive.[122] Santhiago et al.[75] used the technique to accurately observe the shape of laser-engraved microelectrodes, and Lessing et al.[123] studied paper surface modification, showing that a modified surface served to focus the deposition of silver ink onto smaller areas of paper. At the same time, Ruecha et al.[124] compared the deposition of a conducting graphene-polyaniline nanocomposite onto paper and a plastic substrate and showed that in the paper, the nanocomposite penetrated the porous capillary network, which resulted in a lower surface area and consequently less electrochemical activity than the much rougher surface that resulted when the nanocomposite was deposited over plastic substrate. Recently, Secor et al.[125] used this technique to examine how a graphene ink changes its surface roughness depending on its composition. These results show the versatility of the technique and how it can contribute to understanding the obtained electrochemical results. Unlike optical profilometry, X-ray micro-computed tomography (Micro-CT) is a versatile technique for studying polymer and paper 3D properties[126] such as fiber orientation,[127] porosity,[128] ink deposition,[129] and adhesiveness[130] and even the presence of strange bodies in the paper structure. [131] However, it is more expensive than other imaging techniques. Micro-CT is based on a 3D reconstruction of 2D X-ray snapshots of a region of material; due to differences in the X-ray absorptivity of materials, it is possible to separate the contributions from different constituents of the sample. However, as far as we know, it has not been used to study paper-based devices. Although not applicable to all cases, Micro-CT is primarily interesting in the development of novel 2D and 3D devices with various materials. Herein, we showed some approaches and techniques that are not usually used characterization techniques but could aid in making paper devices more efficient and advanced. We

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by the authors that allows these colorimetric and electrochemical analyses. The electrochemical sensor was fabricated using the screen-printed method on a polyester film substrate and was coupled to a microfluidic paper system. The colorimetric analyses were carried out in order to guarantee the presence or absence of Cd+2, Pb+2, Fe+2, Cu+2, Ni+2 and Cr+2 ions, and the electrochemical analysis enabled the quantification of Cd +2 and Pb+2 levels. Use of the SWV technique resulted in a detection limit of 8.9 nmol L-1 for Cd+2 and 4.8 nmol L-1 for Pb+2. Although able to achieve the detection limit required to reach the safe threshold concentration, the authors did not conduct tests on real samples. Jianjun Shi et al.[140] developed a microfluidic device combining filter paper strips with screen-printed carbon electrodes for the detection of Pb and Cd ions using square wave anodic stripping voltammetry. The proposed sensor obtained a low detection limit of 4.8 nmol L-1 for Pb+2 and 6.5 μmol L-1 for Zn+2. To show the efficiency of the sensor for real samples, the authors analyzed saline soda water and contaminated ground water. The samples were first analyzed as pure samples and then analyzed again after the addition of a known concentration of Pb+2 and Cd+2. The recovery factor was high, with the device yielding values very close to the amount of metal ions added. In this way, the proposed sensor presents itself as a platform of low cost and as a system with simple operation. Gold is well known for its high economic value and being used in different areas such as electronics, batteries and jewelry. In view of the high cost of precious metals, the recovery of waste containing them is of great importance. Apilux et al. fabricated a paper device by the screen-printed method for Au ion analysis.[141] Using the SWV technique, it was possible to obtain a low detection limit of 1 ppm. The authors also analyzed goldrefinement waste solution using the proposed sensor and the traditional method (inductively coupled plasma-atomic emission spectrometry - ICP-AES). The values obtained by the two techniques were similar, demonstrating that the sensor acts satisfactorily on real samples. Other electrochemical sensors for the detection of metallic ions were mainly proposed to analyze Pb+2.[21, 142] The results in the field indicate the wide applicability of electrochemical sensors in paper platforms to the sensing and detection of the metal ions, and the detection of these ions, even in real samples, is possible.

6.1.2. Analysis of pesticides Pesticides based on organophosphates and carbamates are highly demanded in agriculture because of their high protection efficiency, short half-life and low cost. However, organophosphates and carbamates are very toxic at certain levels and can lead to serious health problems. Therefore, the need to obtain systems for a simple and low-cost analysis that detects these pollutants in real samples arose. [22e, 67, 143] Dan Du et al. developed an electrochemical sensor based on lateral flow systems (Figure 4B) as a bioreactor for the detection of organophosphates using antibodies to acetylcholinesterase. The operation of the sensor is based on the activity of the enzyme acetylcholinesterase. Organophosphorus

pesticides react with the enzyme, decreasing its activity. In this way, pesticides mainly affect acetylcholine, which plays a very important role in the neurotransmission process.[67] The quantification of organophosphorus compounds was performed indirectly through the difference between the enzymatic activity of the acetylcholinesterase after the reaction with organophosphorus compounds and the total enzymatic activity. The higher the exposure of the sensor to organophosphorus compounds was, the lower the enzymatic activity. The proposed sensor, based on the indirect measurement of organophosphorates, makes it possible to trace very low doses of these compounds; in addition, it is a fast, sensitive and selective platform, which allows its use in the field. [67] To quantify p-nitrophenol, Santhiago et al. manufactured a 3D device made from pencil and chromatographic paper integrated to a filtration system with a quick response (QR) code, as shown in Figure 4C. For the fabrication of the sensor, the counter electrode was drawn on paper, and the working electrode was 6B pencil graphite. The limit of detection was 1.1 μmol L-1, sufficient for the analysis of samples of contaminated water. To verify the efficiency of the sensor for actual samples, the authors analyzed tap water contaminated with a known amount of p-nitrophenol, obtaining a good level of recovery and demonstrating the good applicability of the sensor.[22e]

6.2.

Analyses

of

compounds

and

pharmaceutical residues The demand for sensors in the pharmaceutical industry comes from several needs such as the quality control of pharmaceuticals, analysis of biological fluids, and investigation of pharmaceutical residues in the environment.[144] The first work regarding the quality control of pharmaceuticals was based on the construction of a microfluidic paper-based sensor for the separation and detection of paracetamol and 4-aminophenol using chronoamperometry. P81 chromatographic paper was used to separate the peaks of paracetamol and 4-aminophenol, and the detection limit was 25.0 nmol L-1 and 10.0 μmol L-1, respectively. Commercial samples were tested, and the amounts of paracetamol that were quantified were consistent with the concentrations obtained by a traditional method (spectrophotometry).[145] The synthetic hormone ethinylestradiol is used in contraceptives. However, it is not degraded by the liver, and after being consumed, it is eliminated in the urine and can contaminate soil and water. Therefore, ethinylestradiol is considered an emerging pollutant that can pose serious risks to the environment and human and animal health.[36] Benuzzi et al. developed a paper-based sensor for the determination of ethinylestradiol. To obtain the device, the authors used paper microzones (which were modified with silica nanoparticles and specific antiethinylestradiol antibodies). After this step, the paper microzones were placed under a screen-printed carbon electrode that had been modified with reduced graphene oxide. The detection limit obtained using SWV was 0.1 ng L-1. The authors analyzed

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samples of river and tap waters. All samples showed ethinylestradiol. To verify the reliability of the sensor, additions of known amounts of ethinylestradiol were made for hormone recovery analysis. The authors obtained a standard deviation below 4.9 %, which indicates an acceptable accuracy for real samples.[36] Cancer is one of the diseases that most affect the world population. Usually, chemotherapy is performed as treatment for people who have been diagnosed with this disease. Chemotherapy works by killing cancer cells; thus, at the beginning of treatment, cancer cells are at a high concentration, and during treatment, the number of these cells is expected to decay. [146] Min Su et al. fabricated a sensor for the quantification of chemotherapeutic agents. HL-60 cells originate in patients with acute promyelocytic leukemia, and the drugs cycloheximide, etoposide and camptothecin act directly on the apoptosis of HL60 cells. The sensor was made in paper substrate, and the electrodes were screen-printed. Specific aptamers for the identification of HL-60 cells were immobilized on the working electrode.[146] Cellular cultures of HL-60 were cultivated, and these cultures were exposed to the drugs cycloheximide, etoposide and camptothecin. After that, DPV measurements were performed. The authors conclude that camptothecin had a more potent effect on HL-60 apoptosis than the other two drugs. In this way, the sensor can be applied to monitor people receiving leukemia treatments, making it possible to point out which drug is ideal for each person.

6.3. Food analysis In the food and beverage industry, there is great need to quantify impurities and food additives. One example is related to the quantification of sugars such as glucose, fructose and sucrose in foods and beverages. Although these sugars are not toxic, their excessive intake can cause serious health problems, so there is a strong demand for fast and accurate methods for the quantification of these analytes.[147] To quantify these sugars, Adkins et al.[107] fabricated a device using microwires coupled to a microfluidic paper system. Figure 4D shows this device, whose use of microwires allowed greater current density than the use of electrodes made with carbon ink. For the quantification of sugars, the authors used copper microwires, and with this device, they obtained a detection limit of 270 nmol L-1, 340 nmol L-1 and 430 nmol L-1 for glucose,

fructose and sucrose, respectively. To prove the efficiency of the sensor, the total sugars were quantified in samples of commercial drinks; this method obtained statistically equal results. In this way, this sensor could be used to investigate the variability in different batches of beverages.[107] Nitrites and nitrates are frequently used as meat preservatives, acting to inhibit the growth of microorganisms. However, nitrites may react with secondary amines to form Nnitrosamines, which are highly carcinogenic. Therefore, the detection and monitoring of nitrites are essential to avoid the formation of N-nitrosamines. To fabricate a disposable sensor with low cost, Wang et al. built a paper device that had graphene oxide (and later, AuNPs) deposited on the surface of the substrate. Thus, it was possible to avoid the incrustation that occurs due to the adsorption of the oxidation products on the surface of the electrode, which is a recurrent problem in sensors used for the detection of traditional nitrites.[14c] In addition, the obtained limit of detection of 0.1 μmol L-1 allows the analysis of real samples such as lake water, river water, industrial sewage, and milk. The nitrite concentration quantified by the electrochemical sensor was close to that obtained by the traditional method (UV-visible absorption), demonstrating the good applicability of this sensor. [14c] Phenolic acid is a natural phenolic antioxidant found in high concentrations in plants, and it prevents free radical activity, acting as a barrier in the cell membrane. To quantify the phenolic acid in real samples such as food and cosmetics, Tee-ngam et al. fabricated a paper-based device using carbon ink (for work electrodes and counter electrodes) and Ag/AgCl ink (for the reference electrode). Using DPV resulted in a low detection limit (1 ppm) and a good linear range (3-140 ppm).[148] The analysis of real samples of corn cider and corn milk using the sensor resulted in similar concentrations as the traditional method (highperformance liquid chromatography (HPLC)-UV). In addition, phenolic acid additions were made in the real samples for recovery analysis, and values above 96 % were obtained. With these results, the functionality of this sensor was verified for the analysis of real samples. Paper-based electrochemical sensors for pesticide detection and pharmaceutical and food analysis are feasible from the point of view of analyzing real samples with little sample preparation. Moreover, the cost for manufacturing paper-based sensors is usually low, and for the analyses cited, obtaining the results is simple and fast. In this way, the use of such paper platforms becomes increasingly attractive.

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Figure 4. Examples of microfluidic paper-based electrochemical devices developed for the determination of A) Cd and Pb (Adapted with permission from (P. Rattanarat, W. Dungchai, D. Cate, J. Volckens, O. Chailapakul, C. S. Henry, Anal. Chem. 2014, 86, 3555-3562.).[34] Copyright (2014) American Chemical Society), B) organophosphates (Adapted with permission from (D. Du, J. Wang, L. Wang, D. Lu, Y. Lin, Anal. Chem. 2012, 84, 1380-1385.). Copyright (2012) American Chemical Society),[67] C) para-nitrophenol (Adapted from M. Santhiago, C. S. Henry, L. T. Kubota, Electrochim. Acta 2014, 130, 771-777. Copyright (2014), with permission from Elsevier),[22e] and D) glucose, fructose and sucrose in drinks (Adapted from J. A. Adkins, C. S. Henry, Anal. Chim. Acta 2015, 891, 247-254. Copyright (2015), with permission from Elsevier).[107]

6.4. Clinical analyses 6.4.1. Diabetes mellitus Diabetes mellitus is a group of metabolic diseases in which high blood glucose levels are present over a long period of time. Noiphung et al.[149] developed a device using Whatman No. 1 paper on a SPE and two lateral regions composed of VF2 membranes for the separation of blood plasma. According to the authors, this configuration also helps maintain flow. The device was used in real samples from healthy volunteers and volunteers with diabetes. Samples were not diluted, and the results showed that the plasma was completely separated. PB and an enzymemodified electrode provided a linear range of 0-33.1 mmol L-1 and were suitable for the quantification of glucose in blood using the standard addition method. When blood glucose levels are too high, the body eliminates glucose through urine. Thinking about this fact, Liu and Crooks[150] developed a device for urine samples using a mixed device (Figure 5A) that used an electrochemical sensor whose results were read through a change in color, i.e., an

electrochromic reading in which blue PB turned colorless in the presence of glucose. In this device, urine has two distinct functions. It acts as an electrolyte for the metal-air battery using aluminum foil as an anode and carbon as the interface for the cathode. The paper device has an adjacent compartment containing two electrodes for detection. In this region, the glucose present in the urine also reacts with glucose oxidase that is impregnated on one of the electrodes. Electrons flow through the system and cause a color change in the complementary electrode, which is impregnated with PB. The color change is related to the amount of glucose present in the sample and to the amount of PB present in the spot. Although the authors tested only synthetic samples and did not thoroughly study the limits of detection and the linear range, the developed device was combined with an electric power source in a new way.

6.4.2. Leukemia Leukemia is characterized by the uncontrolled proliferation of normal white blood precursor cells in bone marrow and blood. K562 cells are considered one of the most aggressive human chronic myelogenous leukemia cell lines. Shenguang et al.[151] developed a device for the detection of K-562 cells. In this case,

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an origami electrochemical device was constructed by solid wax printing in chromatographic paper, and a set of three electrodes was added to the device by screen-printing. The working electrode consisted of a 3D hybrid material composed of AuNPs/graphene. Concanavalin A has been immobilized on this surface and acts to capture cells. A concanavalin A sandwich and Pd-Ag nanoparticles were employed in the detection step. Pd-Ag served as a catalyst for thionine oxidation by H 2O2 that was released from K-562 cells via the stimulation of phorbol 12myristate-13-acetate PMA. DPV was used for detection and resulted in a limit of detection of 200 cells mL-1. The observed linear range was from 1.0×103 to 5.0×106 cells mL-1 when normalization by the log K-562 cell concentration was employed.

based device (Figure 5D) that has two parts: one part contains the reference and counter electrodes delineated by a region without wax for the addition of the sample and the other part contains a carbon working electrode. Both parts were joined with the help of double-sided tape. The working electrode was covered with a composite of gold-thionine-graphene nanoparticles functionalized with amino groups. The current response to thionine was proportional to the concentration of a carcinoembryonic antigen due to the formation of an antibodyantigen immunocomplex. DPV was used for quantification. The limit of detection was 10 pg mL-1, which proves the device’s good detectability, and the linear range was from 50 pg mL-1 to 500 ng mL-1.

6.4.3. Influenza H1N1

6.4.6. Prostate cancer

Sivaranjani Devarakonda et al.[59] developed a device for the detection of H1N1 virus (Figure 5B). Whatman chromatography paper grade 4 was modified with hydrophobic silica nanoparticles. Stencil-printed carbon electrodes were obtained and modified with single-walled carbon nanotubes and chitosan. In this case, antibodies were immobilized by crosslinking with glutaraldehyde. The DPV technique was used to provide a detection limit of 113 plaque forming unit (PFU) mL −1 and a linear region between 10 and 104 PFU mL−1.

Ying-Ying Lin and colleagues have developed a paper-based device for the detection of prostate-specific antigen (PSA).[137] In this case, a sandwich assay was also used, but this assay involved labeled antibodies with cadmium-based quantum dot nanoparticles (CdSe@ZnS) (Figure 5E). The test zone located on paper on a SPE contained capture antibodies, and the signal was determined by highly sensitive voltammetric stripping of the dissolved metallic component (cadmium) using hydrochloric acid. A carbon-screen electrode, acetate buffer and 10 ppm mercury were employed in determinations with SWV. This biosensor was very sensitive, with a detection limit of 0.02 ng mL-1 PSA. Its linear range for PSA was from 0.05–4 ng mL-1. However, despite the good functioning of the device and its cost being smaller than that of other diagnostic tools for PSA, the use of reagents containing heavy metals such as cadmium and mercury removes the possibility of the device being disposed of in ordinary waste.

6.4.4. Dengue Prima DewiSinawang et al.[152] constructed an electrochemical lateral flow immunosensor connected to a screen-printed gold electrode for the detection of NS1 nonstructural protein, known to be related to dengue (Figure 5C). The developed device has a pad composed of cellulose glassy fiber paper for the insertion of the sample. In the same region, there is also a pad containing a specific detection antibody labeled with ferrocene acetic acid and immobilized on AuNPs. The NS1 protein interacts with the antibody throughout the course. At the other end, a gold screenprinted electrode containing specific capture antibodies is present, allowing the formation of a sandwich-like structure. The accompanying signal was a resistance obtained using the EIS technique and was related to the NS1 protein concentration. The detection limit was 0.5 ng mL-1, and the linear range was from 1 to 25 ng mL-1 NS1 protein.

6.4.5. Lung Cancer

6.4.7. Myocardial infarction Typical cardiac markers for the diagnosis of myocardial infarction are cardiac myoglobin, creatine kinase-MB and cardiac troponins I and T. In this context, Akanda and collaborators have developed an electrochemical LFIA device.[154]. A highlight of this device is that its great analytical speed allows the detection of troponin I in just 11 min. The developed sensor also needs an applied potential close to 0 V for detection, which is a condition that minimizes possible interferers such as ascorbic acid, acetaminophen and uric acid. The technique used in the detections was chronocoulometry, and the results showed a high detectability with a limit of detection of 0.1 pg mL-1 for troponin I.

Carcinoembryonic antigen is one of the principal markers of lung cancer. Yang Wang et al.[153] developed a Whatman No. 1 paper-

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Figure 5. Examples of clinical electrochemical paper-based devices developed for the determination of A) glucose in urine (Adapted with permission from (H. Liu, R. M. Crooks, Anal. Chem. 2012, 84, 2528-2532).[150] Copyright (2012) American Chemical Society), B) Leukemia (Adapted from S. Ge, L. Zhang, Y. Zhang, H. Liu, J. Huang, M. Yan, J. Yu, Talanta 2015, 145, 12-19. Copyright (2015), with permission from Elsevier),[59] C) dengue (Adapted from P. D. Sinawang, V. Rai, R. E. Ionescu, R. S. Marks, Biosens. Bioelectron. 2016, 77, 400-408. Copyright (2016), with permission from Elsevier),[152] D) carcinoembryonic antigen (Adapted from Y. Wang, H. Xu, J. Luo, J. Liu, L. Wang, Y. Fan, S. Yan, Y. Yang, X. Cai, Biosens. Bioelectron. 2016, 83, 319-326. Copyright (2016), with permission from Elsevier),[153] and E) prostate-specific antigen (Adapted from Y. Y. Lin, J. Wang, G. Liu, H. Wu, C. M. Wai, Y. Lin, Biosens. Bioelectron. 2008, 23, 1659-1665.. Copyright (2008), with permission from Elsevier).[137]

Table 3. Summary of applications in environmental, pharmaceutical, food and clinical analyses using electrochemical paper-based devices. Analyte

Real sample?

Cd+2 and Pb+2

No

Cd+2 and Pb+2

Yes. River water

Cd+2 and Pb+2

Yes. Saline soda water and contaminated ground water

Zn+2 and Pb+2

No

Au Paracetamol and 4aminophenol Acetylcholinesterase Para-nitrophenol Glucose, fructose and sucrose Dopamine Promyelocytic leukemia cells

LOD -1

Yes. Aqua regia Yes. Commercial samples No Yes. Water Sample Yes. Commercial samples of drinks No Yes. Commercial drugs

+2

-1

8.9 nmol L for Cd and 4.8 nmol L for Pb+2 1.8 nmol L-1 for Cd+2 and 1.4 nmol L-1 for Pb+2 20 nmol L-1 for Cd and 9.7 nmol L-1 for Pb+2 4.8 nmol L-1 (for Pb+2) and 6.5 μmol L-1 (for Zn+2) 1 ppm for Au 25.0 nmol L-1 (for paracetamol) and 10.0 μmol L-1 (for 4-aminophenol) 0.02 nmol L-1 1.1 μmol L-1 270 nmol L-1 (glucose), 340 nmol L-1 (fructose) and 430 nmol L-1 (sucrose) 3.41 mmol L-1 -1

350 cells mL

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Linear range

Ref.

0.05− 1.35 for Cd and 0.03− 1.38 μmol L-1 for Pb

[34]

0.009− 1.34 for Cd and 0.03− 0.72 μmol L-1 for Pb

[142b]

0.5− 1.35 for Cd and 0.03− 1.38 μmol L-1 for Pb

[140]

Not mentioned

[21]

1- 200 ppm for Au

[141]

0.05- 2.0 mmol L-1

[145]

-1

0.05 to 10 nmol L 10- 200 μmol L-1 Not mentioned -1

5– 100 mmol L 5×102 to 8×107 cells mL-1

[67] [22e] [107] [155] [146]

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REVIEW Glucose Glucose K-562 cells H1N1 virus NS1 nonstructural protein Carcinoembryonic antigen Prostate-specific antigen Troponin I

Yes. Lake water, river water, industrial sewage, and milk Yes. Blood of healthy and diabetic volunteers Artificial urine No. Cell culture

0.1 μmol L-1

0.3– 720 μmol L-1

[14c]

Not mentioned

0– 33.1 mmol L-1

[149]

Not mentioned 200 cells mL-1

[150]

Yes. Saliva

113 PFU mL-1

Not mentioned 1.0×103-5.0×106 cells mL-1 10 PFU mL-1 to 104 PFU mL-

Yes. Glassy fiber conjugate, nitrocellulose membrane and Kimwipe paper Yes. Clinical serum samples Yes. Human-serum samples No

0.5 ng mL-1

1- 25 ng mL-1

[152]

10 pg mL-1 0.02 ng mL-1 0.1 pg mL-1

50 pg mL-1 - 500 ng mL-1 0.05– 4 ng mL-1 Not mentioned

[153]

6.5. Partial conclusions and comments The number of different applications shows how important and desirable the development of paper-based electrochemical devices is. Similar to other areas, the development of µPEDs was focused on the construction of the devices itself and did not compare the real field and validation methods of these devices and those of established methodologies for applications. Moreover, this kind of device still needs laboratorial instrumentation; as an example, potentiostats are needed for most of these applications. In addition to these disadvantages, this field presents great potential for future application, from the development of new platforms to field applications, focusing on the creation of a new interface that facilitates the transition between the field and the final result.

7. Outlook and future directions Paper is one of the most important parts in the construction of electrochemical devices and one of their least studied parts. Herein, we described some of the properties that make paper substrates suitable for electrochemical analyses, principally focusing on three different types that are available commercially worldwide, Whatman No.1, nitrocellulose and office paper. Another part of this field that is still emerging and has further space for improvement, development and commercialization is the generation of advanced papers with nanomaterials. Such papers, also called nanopapers, have unique properties such as elevated strain resistance, biodegradability, hydrophobicity, conductivity, magnetism, and bioactivity that incorporate the functionality of a nanoparticle into cellulose paper.[156] This area was recently reviewed by Dufresne et al.,[157] who described several preparation procedures, properties and emerging electronic and electrochemical applications such as use of these materials in batteries, supercapacitors,[158] fuel cells, flexible electronics, and sensing, biomedical and healthcare applications. Another recent review, by Merkoçi et al.,[159] showed the use of nanocellulose in its various forms for sensing and biosensing applications, including several uses of nanocellulose papers in POC analysis. Such nanopapers are also suitable for the development of responsive devices, called electronic skins (E-skins), which use the concept of the “internet of things” (IoT) to wirelessly collect, analyze and deliver a signal from the user body, totally integrating with the

1

[151] [59]

[137] [154]

surroundings to provide personalized healthcare and wellness. Some possibilities of this field were recently reviewed by Ko et al.[160] The development of these strategic areas will bring a great contribution to the area of paper-based electrochemical devices, enabling the construction of fully integrated paper platforms. However, we believe that more studies that correlate the electrochemical response with the paper type, quality, and properties are extremely necessary to further develop precise and advanced sensing strategies. Other authors, in recently published reviews on paperbased analytical devices, have said that to further develop the area, a better understanding of the processes involved in the device and proper, increased characterization are necessary. [15a, 15b, 161] We agree with this statement. Paper properties must be studied, since important questions (and not only those exemplified here) have not been answered. Recently, it was shown that wetting paper substrates results in a temperature increase due to an hydration enthalpy variation and that it is dependent of paper surface and solvent. [162] These results raise many questions such as whether this temperature increase causes problems in the measurement. Can it denature a protein or enzyme? This example is only one regarding a surprisingly interesting property of the paper-solvent interface, and questions of many other properties that can influence electrochemical results can be raised in the future.

8. Conclusions Fundamental questions regarding the device properties instead of the device applicability are currently much more relevant for the field and of high necessity; now is the moment that the field can start to expand from the bench scale into the commercial scale. Even though the first electrochemical paper device was fabricated far more recently than traditional and more common fabrication methods, these older methods still have many disadvantages, especially in regard to production. A paper-based electrochemical device has as its premise use in portable and easy-to-use equipment, with few cases reported in the literature. In addition, the most commonly used electrode fabrication methods of those devices that already exist commercially have low resolution, and their electrodes are not standardized and/or reproducible, especially for a large number of devices. As seen, the examples of applications encompassed the use of these devices in samples of environmental, pharmaceutical, food and clinical interest. This evidence is indisputable proof of the great potential of paper-based electrochemical devices.

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Because the introduction of µPEDs is very recent, most of the reviewed projects have the construction of the devices themselves as their main objective, and little attention is given to real applications and the validation of the results by comparisons with results of already established methodologies. This lack shows that there is great potential for future research in this field. The use of specific laboratory instruments such as bench potentiostats is still quite frequent. However, there is a small but increasing effort to increase portability through the use of glucometers [163] and smartphones.[164] The introduction of printed electrochemical instruments[165] presents itself as a good perspective for the future. As said previously, further research must be done in different areas for the development of paper-based electrochemical devices, since some aspects must still be addressed: (i) the choice and characterization of the paper applied; (ii) the improvement of characterization methods; (iii) fabrication techniques and the modification of paper substrate; (iv) the development of different detection platforms; (v) the criteria used for validation methods. The focus for future development should be on multidisciplinary collaborations aiming at the fabrication of an entire system that can be taken from the bench of the laboratory to the real field. A recent work published by the Whitesides group brings a novel methodology for the application of two different colorimetric devices.[166] In this manuscript, the authors showed all the factors and barriers that POC applications have to overcome, from the design of the device to funding, field evaluation and ethical considerations. We believe that the same type of work must be done for the ePADs because just after this work is complete, the area will prove its versatility and real-life applicability.

[8]

Acknowledgements

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The authors acknowledge the National Council for Scientific and Technological Development and the National Institute of Science & Technology in Bioanalytics (INCTBio CNPq 434303/2016-0), and the São Paulo Research Foundation (FAPESP 2014/508673, 2013/22127-2, JFG 2016/08166-3, SKJr 2016/14507-8, WJP 2017/05213-3), Brazil.

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REVIEW

10.1002/celc.201800677

ChemElectroChem

REVIEW REVIEW Dr. Waldemir J. Paschoalino,[a] Dr. Sergio Kogikoski Jr.,[a] Dr. José T. C. Barragan,[a] Msc. Juliana F. Giarola,[a] Msc Lory Cantelli,[a] Msc Thais M. Rabelo,[a] Msc Tatiana M. Pessanha,[a] Prof. Lauro T. Kubota*[a] Page No. – Page No. Emerging Considerations for the Future Development of Electrochemical Paper-based Analytical Devices

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Accepted Manuscript

This review gives an overview of electrochemical paper-based analytical devices and can pave the way for the future development of the field. We also present a critical point of view regarding what has been investigated and developed and what is still missing. We indicate some steps necessary for optimizing the design of the devices, with a focus on multidisciplinary collaborations that could move entire systems from the bench of the laboratory to the field.