Next Article in Journal
Characterizing Flow-Induced Vibrations of Fuel Assemblies for Future Liquid Metal Cooled Nuclear Reactors Using Quasi-Distributed Fibre-Optic Sensors
Previous Article in Journal
Axial Fan Blade Vibration Assessment under Inlet Cross-Flow Conditions Using Laser Scanning Vibrometry
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Applied Sciences
Volume 7
Issue 8
10.3390/app7080863
applsci-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Perspective

Paper and Fiber-Based Bio-Diagnostic Platforms: Current Challenges and Future Needs

by
Samira Hosseini
1,2,*,
Patricia Vázquez-Villegas
1 and
Sergio O. Martínez-Chapa
1,*
1
Escuela de Ingeniería y Ciencias, Tecnologico de Monterrey, Ave. Eugenio Garza Sada 2501, Monterrey 64849, NL, Mexico
2
Research Laboratory of Electronics (RLE), Massachusetts Institute of Technology, Cambridge, MA 02139, USA
*
Authors to whom correspondence should be addressed.
Appl. Sci. 2017, 7(8), 863; https://doi.org/10.3390/app7080863
Submission received: 14 July 2017 / Revised: 17 August 2017 / Accepted: 18 August 2017 / Published: 22 August 2017
Versions Notes

Abstract

:
In this perspective article, some of the latest paper and fiber-based bio-analytical platforms are summarized, along with their fabrication strategies, the processing behind the product development, and the embedded systems in which paper or fiber materials were integrated. The article also reviews bio-recognition applications of paper/fiber-based devices, the detected analytes of interest, applied detection techniques, the related evaluation parameters, the type and duration of the assays, as well as the advantages and disadvantages of each technique. Moreover, some of the existing challenges of utilizing paper and/or fiber materials are discussed. These include control over the physical characteristics (porosity, permeability, wettability) and the chemical properties (surface functionality) of paper/fiber materials are discussed. Other aspects of the review focus on shelf life, the multi-functionality of the platforms, readout strategies, and other challenges that have to be addressed in order to obtain reliable detection outcomes.

1. Introduction

There is an increasing demand in the field of bio-sensing for inexpensive, reliable, portable, rapid, and high throughput analytical devices. The World Health Organization (WHO) defined seven key guidelines for the development of diagnostics platforms suitable for resource-limited areas as major needs for extreme point of care (EPOC): “(i) affordability, (ii) sensitivity, (iii) specificity, (iv) user-friendliness, (v) rapid and robust, (vi) equipment-free, and (vii) deliverable to those in need for such technologies” [1]. These seven requirements recommended by WHO rightfully accumulate to the acronym “ASSURED” [1].
Through diverse applications, in areas such as tissue engineering, controlled drug release, dressings for wound healing, molecular separation, preservation of bioactive compounds, environmental analysis, and food and beverage quality control, etc., paper and fiber-based platforms are now of great importance in healthcare [2,3,4]. By addressing WHO’s guidelines, paper/fiber-based bio-analytical platforms have attracted considerable attention for their effective application in remote/rural and resource-limited areas serving EPOC [5]. Paper and fiber-based materials are generally cost effective, while offering a large, available surface area for biomolecular interaction due to their highly porous structures. Different types of reagent can be stored within their network and benefit from the power-free fluid transport environment occurring through capillary action [2].
Analytical applications of paper in science date to the early 17th century with the use of cellulose papers for chromatographic purposes [6] and pH sensing [7,8]. A paper-based dipstick for quantifying glucose in urine was first introduced to the scientific community in the 1950s, followed by commercialization of the product for a diabetes test one decade later [9]. Historically used for filtration purposes, nitrocellulose membranes were first proposed for molecular recognition in the 1970s [10]. The following decades marked a significant expansion in the application of paper materials for serological lateral flow tests, particularly as pregnancy tests emerged and evolved [11]. Recent advances, particularly in visual bio-diagnostics and hand-held bio-analytical devices, have opened a new and exciting chapter in the development of paper/fiber materials within embedded platforms [12].
Various paper-based bio-sensing platforms were designed and fabricated in recent decades, including dot-immunobinding assays (DIAs), microfluidic paper-based analytical devices (μPADs), lateral flow immunoassay (LFIA), laminated paper-based analytical devices (LPADs), immunospot, nitrocellulose pads (NC-PADs) and paper-based ELISA (P-ELISA) well plates [2,3,4]. Fabrication of these platforms involves a wide variety of techniques, including plotting [13,14], wax-printing [15,16,17,18,19], inkjet-printing [20,21], flexographic printing [22], computer-controlled knife cutting [23], laser cutting [24,25], vapor-phase polymer deposition [26,27,28], photolithography [29,30,31,32,33,34], spraying [35], electrospinning [5,6,36] and coating [37], among others (Table 1) [2,21]. Different aspects of paper-based bio-diagnostic devices, including fabrication strategies, applications for the recognition of various biomolecular entities, the storability as well as the marketability of the paper-based products have been extensively reviewed [2,3,21,38,39,40,41].
Considerable potentials of fiber materials in analytical fields offered a vibrant area of research to the scientific community initiated by the introduction of textile materials for chromatographic stationary phases [42]. The high-performance liquid chromatography (HPLC) technique has drawn a great deal of attention toward polymer fibers for separation purposes [43]. High capacity/mass transfer rates, desirable chemistry as well as non-denaturing and re-generable surfaces established fibers as favorable candidates for protein separation with a specific focus on preparative scale separations [43]. In the area of medical diagnostic carbon-based platforms such as single-walled carbon nanotubes (SWCNTs), carbon micro/nano-fibers and composite carbon fibers offered significant advancement in the bio-recognition of a wide range of bio-molecular entities through electrochemical detection [44,45,46]. Extensive review articles cover significant improvement of carbon-based biosensors in a great detail [46,47,48,49]. Polymer-based fibers, in turn, have attracted a great deal of attention in medical diagnostics. Reukov et al., reported nano-coated nylon fibers, which were surface modified to possess positively charged characteristics for bacterial vaginosis detection and pregnancy diseases monitoring [36]. A triple-blend electrospun fiber mat has been used for the clinical diagnostic of colorectal cancer [50]. Wu et al., reported electrospun poly(ε-caprolactone) (PCL) fibers for the fluorescent detection of antibody against human serum albumin (anti-HSA) [51]. Polyvinylidene fluoride (PVDF) nano-fiber membrane was used for protein immobilization via Western blotting process [52]. Other examples of fiber platforms are provided in Table 1.
The current perspective article outlines the challenges in controlled physical and chemical properties of the paper/fiber materials, the shelf life, the multi-functionality of the devices, the readout strategies and the ease of operation for the proposed platforms. In that regard, papers and fibers from different categories have been reviewed for their application as bio-receptive platforms for the detection of a broad range of biomolecular entities. Table 2 summarizes some of the latest applications of paper/fiber materials in bio-recognition, particularly for the detection of antibodies, antigens, whole viruses, bacteria, and different classes of proteins via ELISA. Table 2 also presents the type of applied assay, the approximate duration of the assay, and the important evaluation parameters reported for the developed assay. Table 3 outlines some of the major advantages and disadvantages of each technique. Although the presented information in these three tables provides a general insight on how diverse the bio-analytical applications of the paper/fiber materials have been, it also reveals aspects of performance variation amongst the techniques and the shortages and needs that are yet to be addressed.
When actual clinical practice is concerned, a small percentage of these techniques open a way for translation from the laboratory bench to the hands of the final users and thus patient care. Even though the currently applied fabrication strategies are promising and the developed prototypes possess tremendous value, further efforts should be dedicated to overcoming the existing limitations. By opening a wide perspective into the bio-sensing domain, the application of papers and fibers has produced an obvious and important shift in the healthcare paradigm. However, several of the developed platforms suffer from a critical lack of reproducibility and limited detection options, as well as insufficient level of sensitivity [4,76]. In this perspective article, some of the principal challenges of the developed strategies and the opportunities for future development targets are discussed.

2. Major Challenges and Opportunities

2.1. Physical Characteristics of the Paper and/or Fiber Materials

The development of a unique surface for improved biomolecular interaction is critical. It requires specifically tailored physical properties of the paper/fiber that can highly encourage analyte–surface interaction through a multitude of forces. In spite of the significant advances in fabrication strategies, paper-based platforms suffer from a lack of control over their physical properties [4,77]. Paper segments in most of the developed platforms are selected from commercially available products (Table 1) possessing certain physical characteristics, including capillary flow rate, surface area, porosity, permeability, and wettability. However, these parameters vary significantly from one manufacturer/batch to another, raising the specter of inconsistency [6,78,79].
Capillary flow rate defines the movements of the flow along the length of the paper in the different designs of bio-diagnostic devices. It is the key parameter in assay performance, as the concentration of the target analyte correlates with the speed of the flow rate [78]. While paper is an excellent material for leading and transporting fluids without external forces, control over fluid transfer, the consistency of the flow rate, and the precise direction of the flow are some of the main challenges faced by researchers in this area [2]. Recognizing those challenges, a variety of solutions have been offered to provide a higher degree of control over flow rate. In 2010, Martinez et al. positioned a digital valve that introduced designed gaps to separate the paper's layers, thus strategically connecting and disconnecting the flow [80]. Other groups reported approaches for controlling fluid transport by changing the geometry of the channels and altering the width, length, and thickness of the junctions in paper-based microfluidic designs [81,82,83]. Applications of the fluidic barriers made from soluble materials for carrier flow were also presented in the literature. These bridges wick fluids until complete dissolution disconnects the flow [82,84,85]. Other techniques, such as phase-switching [86] and razor-crafting channels [87] have also introduced innovative strategies to address this challenge. These techniques have successfully offered higher sensitivity of the assay, enhanced accommodation of small sample volumes within the channels, and the increased retention of the analyte of interest in the network of the paper [87,88].
Although relative hydrophilicity and porosity are desirable features in paper-based devices, as they involve capillary forces for leading fluids in specific directions, those characteristics may also introduce background signal and error into the assay [5,6,37,89]. A high degree of hydrophilicity and porosity are not always favorable for protein immobilization and the subsequent detection of analytes as they may induce biomolecule entrapment, which leads to a false positive signal [5,6,90]. Due to the incomplete washing process, and because proteins could be trapped within the highly porous hydrophilic paper matrix, paper-based 96-well plates are normally used to perform double sandwich assays, while evoking a considerable false positive signal [5,6,37,89,91,92,93,94]. In these assays, a secondary labeled antibody could specifically bind to the primary antibody that is attached to the analyte of interest (Table 2 provides examples of double sandwich assays). If, due to the porosity or swelling condition of the paper or fiber platforms, an excessive level of primary antibodies becomes entangled in the paper matrix, secondary antibodies would most likely bind to the primary antibodies without direct attribution to the presence of the analyte, hence producing false signals [3,5,6,95]. This phenomenon is, perhaps, the leading cause of non-specific binding inside paper-based devices, which makes them somewhat less reliable and reproducible than other types of bio-analytical platforms with rather impenetrable characteristics. To normalize this effect, negative controls are typically performed in which the analyte of interest is absent thus the biomolecular chain is intentionally broken. The outcomes of the negative readouts are deducted from the actual detection results to obtain reliable detection outcomes. Nonetheless, in evaluating the assay, false positive signals leave an undesirable effect on the specificity and accuracy of the technique [96,97,98,99,100]. High porosity might also be a drawback in lateral flow-based systems due to the lack of control over diffusion of the reagents into the structure of the paper that, in turn, makes the consistency of the flow rate questionable [3]. If the reagents are pushed back into the channels due to the highly porous structure of the paper/fiber materials there is an additional chance for a false positive signal and errors in the assay [3]. The capillary flow rate in leading reagents to the detections zones is of a crucial importance when a reproducible detection outcome with acceptable sensitivity level is the functional target. There is an important need for finely-tuned physical properties of newly developed paper/fiber materials, which could significantly impact their performance and reproducibility in bio-recognition to enhance clinically-relevant results.

2.2. Chemical Characteristics of the Paper/Fiber Materials and the Need for Surface Modification

A variety of paper types have been used, or integrated into, a wide range of analytical designs to produce bio-sensing platforms (Table 1 and Table 2). Porous cellulose is perhaps the most widely used commercial material in a majority of these designs (Table 1). Although the chemical structure of cellulose offers an abundance of hydroxyl (–OH) functional groups, these moieties are not highly reactive towards biomolecular entities. Consequently, in most cases, surface modification is required to modulate the functional nature of the paper materials [2,4]. Strategic alterations of the surface could also result in the enhanced control of fluidic flow, improved color uniformity (in the case of colorimetric detection), enhanced chemical stability of the surface, the fabrication of microfluidic valves (in the case of μPADs), as well as the generation of chemically reactive functionalities [2]. The presence of chemically reactive space through functionalization by carboxyl (–COOH) and/or amine (–NH2) groups, highly encourages the development of analyte–surface interactions through both physical and covalent immobilization. If active functional groups, such as –COOH and/or –NH2, are optimally generated on the surface, there is a high chance for involving biomolecules in ionic attractions and hydrophobic interactions, as well as for hydrogen bonding opportunities [5,94]. These forces and reactions are known to play prominent roles in protein immobilization, which would result in the subsequent attachment of the complementary biomolecules, thereby producing an improved final biological response generated from the bio-receptive surfaces.
Apart from the intricacy of the modification strategies, the natural characteristics of the paper materials are frequently compromised during the treatment procedures [2]. Aggressive treatments might also contaminate papers due to exposure to the different chemicals and reagents (Table 3) [2]. In addition, papers are reported to lose their original shape subsequent to chemical treatment, having a tendency to curl or wrinkle after modifications are made. This may make their application difficult for specific types of bio-diagnostic platforms [3]. Furthermore, even if the properties of the paper are not affected by modification techniques, there might be no ability to carefully control the generation of active functional groups and their focused distribution on the paper surface [101,102]. Optimal generation and distribution of the surface functional groups are crucial in biomolecule immobilization and subsequent detection of the analyte of interest. Overly functionalized surfaces tend to reject/hinder approaching biomolecules due to the steric repulsion, while an insufficient concentration of active functionalities may cause the biomolecules to fall on the surface and lose activity [91,102,103]. Therefore, a suitable bio-receptive platform would be credited for its substantial surface area and controlled wettability and porosity, and for an effective chemical design that can offer a protein-friendly surface with high occurrence and reproducibility for bimolecular interaction associated with binding stability.
In that perspective, the development of customized paper/fiber materials with improved control over physical and chemical material properties would appear to be a highly desirable solution. Different characterization techniques are typically used to analyze the physical and the chemical properties of the newly developed materials. Water-in-air contact angle analysis can determine the wettability of the paper/fiber samples [5,6,104,105]. The morphology of the papers/fibers can be recorded by scanning electron micorscopy (SEM) and the fiber diameter range can be subsequently measured by analyzing SEM micrographs by using different software such as Image J [5,6,37,106]. Porosity and permeability of the paper/fiber networks can be analyzed by bulk density method, gas permeability techniques or X-ray computed tomography (X-CT) [106,107,108,109]. Other techniques such as Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS) can provide detailed information regarding the chemistry of the surface. These analytical techniques are well established in the laboratory and industrial setups. Nonetheless, close control over material properties and reproducibility of the products can be achieved through fabrication strategies. The consistency of the physical and chemical characteristics of the developed paper/fiber materials eliminates the risk of errors in the analytical assays and provides with accurate detection outcomes.
One alternative approach to overcome such limitations could be the use of and electrospinning technique (particularly three-dimensional (3D) electrospinning setup) in which the diameter range of the fiber and the porosity could be closely controlled, and different classes of bulk materials could be selected for fabrication of the fibers. If the chosen material or one of the combined materials has desirable active functional groups in its chemical structure, then the fabrication process can be finely adjusted in order to obtain and optimal concentration of the necessary functional groups without the need for surface modification strategies [5,6]. Unlike the chemical modification techniques, this alternative approach would not harm the original nature of the paper material, and the stability of the surface functionalities is guaranteed, as they are an integral aspect of the chemical fingerprint of the constructed matrix, and would not lose their activity over time.

2.3. Shelf Life of the Paper/Fiber Materials

Apart from the efficiency of the developed platforms, the reproducible shelf life of the products is also of a great importance. With the significant advances in the fabrication of paper-based devices, the resulting paper products remain sensitive materials, with low tensile strength, and high vulnerability to modulations in environmental conditions, particularly temperature and humidity [3,54,55]. Table 4 summarizes the shelf life details of some of the conventional, commercial, and novel paper/fiber materials. Researchers face challenges maintaining the shelf life of the commonly used paper materials (e.g., porous cellulose and nitrocellulose) even prior to the application of surface modification techniques [54,55]. Porous cellulose products such as Ahlstrom A-55 and Whatman CHR (chromatography) # 1 can provide reproducible results for at least five weeks if it is stored at 4 °C under sealed conditions (Table 4) [54,55]. The shelf life of nitrocellulose and nylon materials is reported to be approximately 3 and 7 months, respectively [110,111]. Fiber substitutes, such as polyhydroxybutyrate (PHB) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), however, are reported to be more stable towards temperature change and possess relatively high degradation temperatures (Table 4) [112,113,114,115,116].
Apart from the bio-receptive material itself, the duration in which the impregnated proteins in the structure of the papers/fibers remain active is vital. Higher stability of the biomolecules and a longer shelf life for the developed materials permits the long-distance transportation of the platforms to where they are mostly needed, under-privileged areas. Immobilized antibodies in the network of porous cellulose (Whatman CHR # 1 and Ahlstrom A-55) were found to lose their activity with increasing temperature (~40 °C) while the stability of the impregnated product over time was significantly affected with an increase in relative humidity (RH) (Table 4) [54,55]. Other studies have established that antibodies can remain active for a long period under optimal storage conditions (−20 °C) if impregnated using a dry-reagent technique [67,119].
Papers are often harshly affected by the treatment processes, which may make them even more sensitive than in their original states. As mentioned, papers are reported to lose their shape on treatment, tending to curl, fold, or wrinkle after modifications, which makes their application difficult in the specific design of bio-diagnostic platforms [3]. When conducting immunoassays, untreated papers seldom undergo numerous steps of washing and incubation, which makes them very difficult to preserve. If, prior to use in immunoassays, the papers are also subjected to additional harsh treatments, it is even less likely for them to remain intact throughout the assay. Therefore, fabrication strategies should be designed to minimize surface modification steps while generating active functional groups and providing a higher chance for preservation of the platforms. An alternative strategy could be customization of the bio-receptive paper/fiber platforms (as presented in Table 1, PHB and PHBV), which would permit choices of reference materials with tailored properties that can naturally offer desirable features and improved stability over time [5,6].

2.4. Readout Outcomes

One of the critical steps in working with paper-/fiber-based devices is the ability to quantify the analytes of interest with minimal requirements. The major challenge, particularly when EPOC in remote/rural areas is the aim, is to achieve reasonably accurate bio-diagnosis without needing centralized clinical facilities and sophisticated, expensive equipment. In the context of on-site diagnosis, reliable quantitative or semi-quantitative readouts are anticipated to dictate the treatment by a simple “yes/no” or “normal/abnormal” responses [2,120]. In this path, significant progress has been made.
A variety of techniques, including colorimetry [120,121,122,123], fluorescent [29,123,124,125,126,127], luminescent [128], chemiluminiscent [128,129], photo-electro-chemiluminiscent, electrochemical [130,131], electro-chemiluminiscent [132,133], and photo-electrochemical [134] detections have been reported for paper and/or fiber-based bio-diagnostic platforms [2,3,4,135,136]. In the case of fluorescence readout, an important question is: “To what extent does the whiteness of the paper play a role in producing a background signal or perhaps participating in the bleaching effect?”. The most commonly-used analytical detection technique for paper/fiber-based devices is colorimetric (Table 2) [2,3]. This analysis is known to be relatively straightforward; the color intensity is proportional to the concentration of the analyte; the operating time is relatively short, and the detectors are normally portable and inexpensive, while the technique is mainly compatible with smart devices [2].
The likelihood of telemedicine using digital cameras, cell phones, and smart devices was demonstrated since 2008 for glucose detection in artificial urine [137,138]. Detection via smart devices has rapidly penetrated the worldwide market introducing tremendous opportunities for the on-site processing of data, instead of sample transfer to a centralized clinical facility (Table 2) [2,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,128,139]. With their storage capacity, smart devices serve clinical practice well, enabling information to be collected and stored to a much greater extent than previously possible. Modern smart devices possess both a light source (LED flash) and a digital camera for detection; therefore they are capable of performing tasks that are normally performed by expensive techniques, such as fluorometers, spectrophotometers, or silicon photodetectors [140].
Novel attempts have also been dedicated to non-instrumented analysis or equipment-free detection techniques for fabricating easy-to-use paper-based devices that can play vital roles in EPOC [121]. Such strategies would reduce the cost of bio-diagnosis, while increasing the portability of the devices that do not require external readout instrumentation [141,142]. One approach to perform equipment-free analysis relies upon color intensity comparators using an external calibration or standard calibration integrated within the device [143,144]. Weaver et al. reported a cost-effective “color barcode” test for the rapid screening and quality control of pharmaceutical drugs [145]. The fabricated device was divided into twelve individual lanes, on which the solid pharmaceutical product was mounted and the edge dipped into the chosen media. Each lane specifically reacted to one type of analyte (e.g., ampicillin, amoxicillin, and rifampicin) and a corresponding colored lane, visually compared with the reference was indicative of a “positive I.D.” [145]. Another interesting study by Zhu et al. reported a self-calibrating sensor for glucose measurement. The tree-shaped, branched structure of the designed platform minimized the ambient effects, such as temperature and humidity [146]. Pollock et al. reported self-calibration of the device based on alteration of the incubation time [147]. This study suggests that the sensitivity of the device was in an acceptable range (84%), even though the readout outcome was semi-quantitative [147]. Such studies establish that visual assessment of the detection outcomes can be adequately robust if a reliable control over the ambient conditions is implemented.
Other interesting non-instrumented approaches are known as distance-based detections [148,149]. Zuk et al. reported the measurement of biological samples by calculating a total distance a colorimetric reagent has traveled across the paper channel. In this method, the distance wicked by the product is proportional to the analyte concentration [148]. A similar strategy that gained considerable popularity due to its simplicity and applicability was presented by Lou et al. [150]. This distance-based detection strategy introduced breaking points in the continuous flow path. Each discrete segment that turned colored participated in the final calculation of the analyte concentration [150].
Another alternative, equipment-free, detection approach is known as time-based analysis. In this strategy, the time required for signal development is the performance merit. Lewis et al. developed a system for enzyme quantification with a control zone to account for the ambient conditions (e.g., temperature, humidity, pressure, and sample viscosity) [151]. Combined with a self-calibrating system, this time-based detection strategy changes the incubation time to minimize the influence of external parameters and to elicit a reliable readout signal. Further advances in the time-based measurement involved a phase-switching design of the platform in which specific types of oligomers depolymerize themselves in the presence of target analyte [86]. Oligomers are hydrophobic in their nature; however, they tend to become hydrophilic after depolymerization, thereby allowing the flow to travel through the channel and reach the detection zone. Once the analyte of interest arrives at the final destination, the color change occurs; an indication of assay completion. The rate and the time of depolymerization were found to be proportional to the concentration of the target analyte. In these types of assay, all that is required is a timer, which makes the technique highly favorable for EPOC application in remote/rural areas.

2.5. Multi-Functionality of the Platforms

One of the major missions of the paper-based devices, especially in the area of microfluidics, is to increase the functionality of the devices. The ability to achieve multi-step processing and performance makes μPADs highly favorable for EPOC applications [23,39,41]. Lutz et al. and Fu et al. studied the sequential delivery of multiple reagents by creating flow paths of varying lengths in order to automate a sandwich ELISA assay [119,152]. Li et al. demonstrated devices capable of performing a multi-step assay by incorporating a magnetically-timed valve [153]. By placing it down or raising it above the channel, the valve would close or open the path for the fluids in a controlled manner. This method, however, had its own limitations, as the valve is for a single use only and it consumes large quantities of the reagents, since a unique timing sequence has to be designed for every new assay.
One of the beneficial strategies to increase multi-functionality of the paper-/fiber-based devices is the dry-reagent approach. If all the necessary reagents are added to the device in the dry state it will provide (i) a reduced number of steps to be taken by the final user; (ii) easier shipment of the kits, since reagents are loaded within the network of the paper; and (iii) higher stability of the product when dealing with environmental changes, such as temperature and humidity [154]. Reported examples of μPADs combined with a dry-reagent strategy have proven to be more amenable to the multi-step processing employed in the assay [154].

2.6. Easy Operation for Onsite Health Check

Even though the majority of paper/fiber-based platforms are aimed at hand-held diagnosis, sample collection and preparation for such devices may introduce considerable challenges. The necessity for sample processing steps, such as separation (e.g., whole blood, serum, and plasma), mixing, adding reagents, and washing among others, falls short of the principles of user-friendliness [38]. In the case of whole blood, specific components/proteins must be removed from the sample to increase the sensitivity and specificity of detection [155]. Normally, plasma should be separated from the whole blood prior to the measurements to minimize errors related to light scattering, absorption, hemolysis, or coagulation of the red blood cells [40]. In the ideal case of a test system, no sample preparation, system calibration, data interpretation, or calculation for end users should be expected [38]. In reality, however, even in well-equipped laboratories, sample preparation suffers from various shortfalls, such as inhomogeneity and the variable viscosity of the samples, as well as presence of interfering agents [3]. The most error-prone aspect of diagnostic tests in laboratories is known to be the pre-analytical phase (sample processing) that includes blood tube sorting, centrifugation, cap removal, sample aliquoting, and recapping [40]. A number of techniques have been developed to offer analysis by individuals with minimal training outside centralized laboratories, such as in doctor’s offices, emergency rooms, ambulances, etc. In the context of onsite POC/EPOC and for the technologies to be broadly accepted by the end users in remote/rural areas or elderly people, clear results have to be obtained without the need of any additional processing or external instrument.
High throughput systems incorporated into the paper-based devices have automated the separation step by using a diverse range of solid materials, including beads, microparticles, fiber matrices, and coated tubes and plates [147,156,157,158,159,160,161,162,163]. Additionally, application of pre-depositing agglutination antibodies, concentrated salt solution for blood cell deformation and filtering via paper pores using capillary force are known to be effective techniques for sample separation [164,165,166]. In the case of paper strips, the platforms generally contain segments that are designed for automated mixing of the specimen with dry reagents [40,158]. In such devices, a manual step is normally required to finalize the sample separation. More sophisticated platforms, which enable automation of several sample preparation steps without manual intervention have also been reported. While offering beneficial features, such as automated multistep assays, generally the result is an enlargement of the device dimensions and additional material costs [38,167,168]. Readers are recommended to study the excellent reviews by Yamada et al., 2017 and Cunningham, 2001 for detailed information [38,40]. In nucleic acid analysis, sample preparation comprises labor-intensive multiple steps, including suspension, mixing, centrifugation, washing, and elution of the nucleic acids, that are generally performed in dedicated laboratories to minimize cross-contamination and the generation of false positive results [40,169].
According to the Clinical Laboratory Improvement Amendments (CLIA) guidelines (formulated by the U.S. Food & Drug Administration (FDA), any user with a 7th-grade English level should be able to readily operate the diagnostic devices aimed for application outside laboratories after following the instructions provided by the manufacturer [38,170]. Despite advances in sample preparation and fluidics handling, there is obviously considerable room for improvements in the commercialization of more user-friendly devices.

2.7. Other Considerations

Have the great potential of paper/fiber materials been fully acknowledged by diagnosis manufacturers? Can paper/fiber materials overcome the existing limitations of bio-diagnostic platforms? Would it be possible for an entire bio-analytical assay to be built upon a single type of paper/fiber material? If so, can paper/fiber meet the necessary performance requirements of an efficient bio-analytical platform, such as sensitivity, specificity, cost-effectiveness, and rapid analysis, etc.? To exploit the full potential of paper/fiber materials for bio-analytical applications, these questions need to be addressed. Several other essential points are also worthy of consideration; the following section outlines some of these aspects:
(1)
In paper/fiber diagnostic platforms (especially dipsticks), certain segments of the platforms are impregnated with different biomolecular entities, such as antibodies, that specifically bind to the analyte of interest [3]. In this regard, the question might be raised about the yield for such specific binding when dealing with impregnated paper/fiber networks. What is the variation in the uptake or conjugation of the analytes? How consistent is the occurrence of conjugation and the release from conjugation? How fast or slow do these binding and release processes occur? Are these rates reproducible for such assays?
(2)
Another aspect of paper/fiber platforms that requires attention is the possibility of contamination of the platforms during the fabrication or treatment processes (Table 3). Cross-contamination from the run-over (spillage) between adjacent reagents remains a separate issue [171,172,173]. Several efforts have been made to curtail these contamination effects, including the development of hydrophobic barriers designed within the structure of the paper-based devices that partially addresses the spillage of the reagents [171,172,173,174]. However, there is also a risk of toxicity for the biological samples when they are in close contact with the fabrication materials, such as waxes, paraffins, or toxic chemicals used in the techniques for functional modification [3]. How can the risk of contamination be fully eliminated from the fabrication, treatment, and operation procedures of paper-/fiber-based devices? Can the incompatibility of the surfactants with proteins be carefully evaluated?
(3)
Some of the latest advances in the development of paper-/fiber-based devices offer complex platforms that are hard to be reproduced on an industrial scale. Intricacies can also occur in the protocols, which are then beyond the expertise of the laboratory technicians who perform the tests as their everyday routine (Table 3). Multilayered platforms that are composed of several different segments that need to be carefully assembled prior to test application, layers that are often attached with adhesive components that most likely denature/deactivate analytes when placed in close proximity of the biomolecules, seem less likely to become the next generation of conventional, reproducible, bio-analytical devices used in day-to-day clinical practice. In that perspective, the development of novel platforms with less complexity in fabrication and application should provide a higher probability for prototype development and commercialization.

3. General Conclusions

Paper and fiber materials are some of the main components in many analytical devices used in the healthcare domain. They offer a number of advantages, including cost-effectiveness, rapid diagnostic, as well as desirable characteristics, such as relative hydrophilicity, porosity, permeability, and high surface area. When bio-sensing is the target function, additional steps of improvement are necessary when applying paper/fiber materials. Firstly, the physical and chemical properties of the materials, such as surface wettability, porosity, and the presence of active surface functional groups must be closely controlled. Shelf life and stability of the developed platforms should also be considered and monitored, since paper materials incorporated in bio-analytical platforms often undergo lengthy incubations and numerous pipetting processes. Surface modification strategies may impose unintentional changes on the nature of the paper, as well as modulating its chemical/physical properties. In conclusion, suitable paper- and/or fiber-based bio-sensing platforms should be created for high throughput detection performance and specificity, and be associated with great stability of the functional material, as well as the selected and impregnated biomolecules in the paper matrix, while the platforms should be easy to manipulate technically, have the capacity to provide unambiguous and reproducible results, and be amenable to mass production.

Acknowledgments

The authors would like to acknowledge the financial support of Tecnologico de Monterrey, for the grant (002EICII01) awarded to the Sensors and Devices Focus Group, School of Engineering and Sciences, Tecnologico de Monterrey, Monterrey, Mexico. Samira Hosseini would like to thank Professor David Danielson Eaton for his support and the helpful discussion. The authors deeply appreciate the assistance of Professor Emeritus Geoffrey A. Cordell for the English editing of this manuscript.

Author Contributions

Samira Hosseini designed the outlines and wrote the paper. Patricia Vázquez-Villegas designed the Tables and contributed in drafting the paper. Sergio O. Martínez-Chapa guided the authors and provided with the scientific insights. All the authors have contributed in the final draft of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Urdea, M.; Penny, L.A.; Olmsted, S.S.; Giovanni, M.Y.; Kaspar, P.; Shepherd, A. Requirements for high impact diagnostics in the developing world. Nature 2006, 444, 73–79. [Google Scholar] [CrossRef] [PubMed]
  2. Cate, D.M.; Adkins, J.A.; Mettakoonpitak, J.; Henry, C.S. Recent developments in paper-based microfluidic devices. Anal. Chem. 2014, 87, 19–41. [Google Scholar] [CrossRef] [PubMed]
  3. Yetisen, A.K.; Akram, M.S.; Lowe, C.R. Paper-based microfluidic point-of-care diagnostic devices. Lab Chip 2013, 13, 2210–2251. [Google Scholar] [CrossRef] [PubMed]
  4. Ahmed, S.; Bui, M.-P.N.; Abbas, A. Paper-based chemical and biological sensors: Engineering aspects. Biosens. Bioelectron. 2016, 77, 249–263. [Google Scholar] [CrossRef] [PubMed]
  5. Hosseini, S.; Azari, P.; Farahmand, E.; Gan, S.N.; Rothan, H.A.; Yusof, R. Polymethacrylate coated electrospun PHB fibers: An exquisite outlook for fabrication of paper-based biosensors. Biosens. Bioelectron. 2015, 69, 257–264. [Google Scholar] [CrossRef] [PubMed]
  6. Hosseini, S.; Azari, P.; Aeinehvand, M.M.; Rothan, H.A.; Djordjevic, I.; Martinez-Chapa, S.O. Intrant ELISA: A Novel Approach to Fabrication of Electrospun Fiber Mat-Assisted Biosensor Platforms and Their Integration within Standard Analytical Well Plates. Appl. Sci. 2016, 6, 336. [Google Scholar] [CrossRef]
  7. Gribnau, T.; Leuvering, J.; Van Hell, H. Particle-labelled immunoassays: A review. J. Chromatogr. B Biomed. Sci. Appl. 1986, 376, 175–189. [Google Scholar] [CrossRef]
  8. Wilson, R. The use of gold nanoparticles in diagnostics and detection. Chem. Soc. Rev. 2008, 37, 2028–2045. [Google Scholar] [CrossRef] [PubMed]
  9. Free, A.H.; Adams, E.C.; Kercher, M.L.; Free, H.M.; Cook, M.H. Simple specific test for urine glucose. Clin. Chem. 1957, 3, 163–168. [Google Scholar] [PubMed]
  10. Towbin, H.; Staehelin, T.; Gordon, J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: Procedure and some applications. Proc. Natl. Acad. Sci. USA 1979, 76, 4350–4354. [Google Scholar] [CrossRef] [PubMed]
  11. A Timeline of Pregnancy Testing. Available online: https://history.nih.gov/exhibits/thinblueline/timeline.html (accessed on 15 May 2017).
  12. Sher, M.; Zhuang, R.; Demirci, U.; Asghar, W. Paper-based analytical devices for clinical diagnosis: Recent advances in the fabrication techniques and sensing mechanisms. Expert Rev. Mol. Diagn. 2017, 17, 351–366. [Google Scholar] [CrossRef] [PubMed]
  13. Bruzewicz, D.A.; Reches, M.; Whitesides, G.M. Low-cost printing of poly (dimethylsiloxane) barriers to define microchannels in paper. Anal. Chem. 2008, 80, 3387–3392. [Google Scholar] [CrossRef] [PubMed]
  14. Nie, J.; Zhang, Y.; Lin, L.; Zhou, C.; Li, S.; Zhang, L. Low-cost fabrication of paper-based microfluidic devices by one-step plotting. Anal. Chem. 2012, 84, 6331–6335. [Google Scholar] [CrossRef] [PubMed]
  15. Lu, Y.; Shi, W.; Jiang, L.; Qin, J.; Lin, B. Rapid prototyping of paper-based microfluidics with wax for low-cost, portable bioassay. Electrophoresis 2009, 30, 1497–1500. [Google Scholar] [CrossRef] [PubMed]
  16. Carrilho, E.; Martinez, A.W.; Whitesides, G.M. Understanding wax printing: A simple micropatterning process for paper-based microfluidics. Anal. Chem. 2009, 81, 7091–7095. [Google Scholar] [CrossRef] [PubMed]
  17. Schilling, K.M.; Lepore, A.L.; Kurian, J.A.; Martinez, A.W. Fully enclosed microfluidic paper-based analytical devices. Anal. Chem. 2012, 84, 1579–1585. [Google Scholar] [CrossRef] [PubMed]
  18. Songjaroen, T.; Dungchai, W.; Chailapakul, O.; Laiwattanapaisal, W. Novel, simple and low-cost alternative method for fabrication of paper-based microfluidics by wax dipping. Talanta 2011, 85, 2587–2593. [Google Scholar] [CrossRef] [PubMed]
  19. Zhang, A.-L.; Zha, Y. Fabrication of paper-based microfluidic device using printed circuit technology. Aip Adv. 2012, 2, 022171. [Google Scholar] [CrossRef]
  20. Abe, K.; Suzuki, K.; Citterio, D. Inkjet-printed microfluidic multianalyte chemical sensing paper. Anal. Chem. 2008, 80, 6928–6934. [Google Scholar] [CrossRef] [PubMed]
  21. He, Y.; Wu, Y.; Fu, J.-Z.; Wu, W.-B. Fabrication of paper-based microfluidic analysis devices: A review. RSC Adv. 2015, 5, 78109–78127. [Google Scholar] [CrossRef]
  22. Olkkonen, J.; Lehtinen, K.; Erho, T. Flexographically printed fluidic structures in paper. Anal. Chem. 2010, 82, 10246–10250. [Google Scholar] [CrossRef] [PubMed]
  23. Fenton, E.M.; Mascarenas, M.R.; López, G.P.; Sibbett, S.S. Multiplex lateral-flow test strips fabricated by two-dimensional shaping. ACS Appl. Mater. Interfaces 2008, 1, 124–129. [Google Scholar] [CrossRef] [PubMed]
  24. Nie, J.; Liang, Y.; Zhang, Y.; Le, S.; Li, D.; Zhang, S. One-step patterning of hollow microstructures in paper by laser cutting to create microfluidic analytical devices. Analyst 2013, 138, 671–676. [Google Scholar] [CrossRef] [PubMed]
  25. Spicar-Mihalic, P.; Toley, B.; Houghtaling, J.; Liang, T.; Yager, P.; Fu, E. CO2 laser cutting and ablative etching for the fabrication of paper-based devices. J. Micromech. Microeng. 2013, 23, 067003. [Google Scholar] [CrossRef]
  26. Haller, P.D.; Flowers, C.A.; Gupta, M. Three-dimensional patterning of porous materials using vapor phase polymerization. Soft Matter 2011, 7, 2428–2432. [Google Scholar] [CrossRef]
  27. Demirel, G.; Babur, E. Vapor-phase deposition of polymers as a simple and versatile technique to generate paper-based microfluidic platforms for bioassay applications. Analyst 2014, 139, 2326–2331. [Google Scholar] [CrossRef] [PubMed]
  28. Chen, B.; Kwong, P.; Gupta, M. Patterned fluoropolymer barriers for containment of organic solvents within paper-based microfluidic devices. ACS Appl. Mater. Interfaces 2013, 5, 12701–12707. [Google Scholar] [CrossRef] [PubMed]
  29. Carrilho, E.; Phillips, S.T.; Vella, S.J.; Martinez, A.W.; Whitesides, G.M. Paper microzone plates. Anal. Chem. 2009, 81, 5990–5998. [Google Scholar] [CrossRef] [PubMed]
  30. He, Q.; Ma, C.; Hu, X.; Chen, H. Method for fabrication of paper-based microfluidic devices by alkylsilane self-assembling and UV/O3-patterning. Anal. Chem. 2013, 85, 1327–1331. [Google Scholar] [CrossRef] [PubMed]
  31. He, Y.; Wu, W.-B.; Fu, J.-Z. Rapid fabrication of paper-based microfluidic analytical devices with desktop stereolithography 3D printer. RSC Adv. 2015, 5, 2694–2701. [Google Scholar] [CrossRef]
  32. OuYang, L.; Wang, C.; Du, F.; Zheng, T.; Liang, H. Electrochromatographic separations of multi-component metal complexes on a microfluidic paper-based device with a simplified photolithography. RSC Adv. 2014, 4, 1093–1101. [Google Scholar] [CrossRef]
  33. Songok, J.; Tuominen, M.; Teisala, H.; Haapanen, J.; Mäkelä, J.; Kuusipalo, J. Paper-based microfluidics: Fabrication technique and dynamics of capillary-driven surface flow. ACS Appl. Mater. Interfaces 2014, 6, 20060–20066. [Google Scholar] [CrossRef] [PubMed]
  34. Sones, C.; Katis, I.; He, P.; Mills, B.; Namiq, M.; Shardlow, P. Laser-induced photo-polymerisation for creation of paper-based fluidic devices. Lab Chip 2014, 14, 4567–4574. [Google Scholar] [CrossRef] [PubMed]
  35. Dungchai, W.; Chailapakul, O.; Henry, C.S. A low-cost, simple, and rapid fabrication method for paper-based microfluidics using wax screen-printing. Analyst 2011, 136, 77–82. [Google Scholar] [CrossRef] [PubMed]
  36. Reukov, V.; Vertegel, A.; Burtovyy, O.; Kornev, K.; Luzinov, I.; Miller, P. Fabrication of nanocoated fibers for self-diagnosis of bacterial vaginosis. Mater. Sci. Eng. C 2009, 29, 669–673. [Google Scholar] [CrossRef]
  37. Farahmand, E.; Ibrahim, F.; Hosseini, S.; Rothan, H.A.; Yusof, R.; Koole, L.H. A novel approach for application of nylon membranes in the biosensing domain. Appl. Surf. Sci. 2015, 353, 1310–1319. [Google Scholar] [CrossRef]
  38. Yamada, K.; Shibata, H.; Suzuki, K.; Citterio, D. Toward practical application of paper-based microfluidics for medical diagnostics: State-of-the-art and challenges. Lab Chip 2017, 17, 1206–1249. [Google Scholar] [CrossRef] [PubMed]
  39. Gong, M.M.; Sinton, D. Turning the Page: Advancing Paper-Based Microfluidics for Broad Diagnostic Application. Chem. Rev. 2017, 117, 8447–8480. [Google Scholar] [CrossRef] [PubMed]
  40. Cunningham, D.D. Fluidics and sample handling in clinical chemical analysis. Anal. Chim. Acta 2001, 429, 1–18. [Google Scholar] [CrossRef]
  41. Xia, Y.; Si, J.; Li, Z. Fabrication techniques for microfluidic paper-based analytical devices and their applications for biological testing: A review. Biosens. Bioelectron. 2016, 77, 774–789. [Google Scholar] [CrossRef] [PubMed]
  42. Friedman, H.; Miller, B.; Meiser, C., Jr. Influence of preadsorbed water on chromatographic detention of organic volatiles by cellulosic substrates. Text. Res. J. 1985, 55, 726–732. [Google Scholar] [CrossRef]
  43. Marcus, R.K. Use of polymer fiber stationary phases for liquid chromatography separations: Part II—Applications. J. Sep. Sci. 2009, 32, 695–705. [Google Scholar] [CrossRef] [PubMed]
  44. Grigoryev, A.; Sa, V.; Gopishetty, V.; Tokarev, I.; Kornev, K.G.; Minko, S. Wet-Spun Stimuli-Responsive Composite Fibers with Tunable Electrical Conductivity. Adv. Funct. Mater. 2013, 23, 5903–5909. [Google Scholar] [CrossRef]
  45. Le Goff, A.; Holzinger, M.; Cosnier, S. Enzymatic biosensors based on SWCNT-conducting polymer electrodes. Analyst 2011, 136, 1279–1287. [Google Scholar] [CrossRef] [PubMed]
  46. Wohlstadter, J.N.; Wilbur, J.L.; Sigal, G.B.; Biebuyck, H.A.; Billadeau, M.A.; Dong, L. Carbon nanotube-based biosensor. Adv. Mater. 2003, 15, 1184–1187. [Google Scholar] [CrossRef]
  47. Georgakilas, V.; Otyepka, M.; Bourlinos, A.B.; Chandra, V.; Kim, N.; Kemp, K.C. Functionalization of graphene: Covalent and non-covalent approaches, derivatives and applications. Chem. Rev. 2012, 112, 6156–6214. [Google Scholar] [CrossRef] [PubMed]
  48. Baptista, F.R.; Belhout, S.; Giordani, S.; Quinn, S. Recent developments in carbon nanomaterial sensors. Chem. Soc. Rev. 2015, 44, 4433–4453. [Google Scholar] [CrossRef] [PubMed]
  49. Zheng, X.T.; Ananthanarayanan, A.; Luo, K.Q.; Chen, P. Glowing graphene quantum dots and carbon dots: Properties, syntheses, and biological applications. Small 2015, 11, 1620–1636. [Google Scholar] [CrossRef] [PubMed]
  50. Tseng, H.-C.; Lee, A.-W.; Wei, P.-L.; Chang, Y.-J.; Chen, J.-K. Clinical diagnosis of colorectal cancer using electrospun triple-blend fibrous mat-based capture assay of circulating tumor cells. J. Mater. Chem. B 2016, 4, 6565–6580. [Google Scholar] [CrossRef]
  51. Steckl, A.; Wu, D.; Han, D. Immunoassay on Free-standing Electrospun Membranes. In Proceedings of the APS March Meeting, Portland, OR, USA, 15–19 March 2010. Abstracts 2010. [Google Scholar]
  52. Cho, E.; Kim, C.; Kook, J.-K.; Jeong, Y.I.; Kim, J.H.; Kim, Y.A. Fabrication of electrospun PVDF nanofiber membrane for Western blot with high sensitivity. J. Membr. Sci. 2012, 389, 349–354. [Google Scholar] [CrossRef]
  53. Ortega, G.; Pérez-Rodríguez, S.; Reguera, E. Magnetic paper–based ELISA for IgM-dengue detection. RSC Adv. 2017, 7, 4921–4932. [Google Scholar] [CrossRef]
  54. Wang, J.; Yiu, B.; Obermeyer, J.; Filipe, C.D.; Brennan, J.D.; Pelton, R. Effects of temperature and relative humidity on the stability of paper-immobilized antibodies. Biomacromolecules 2012, 13, 559–564. [Google Scholar] [CrossRef] [PubMed]
  55. Wang, S.; Ge, L.; Song, X.; Yu, J.; Ge, S.; Huang, J. Paper-based chemiluminescence ELISA: Lab-on-paper based on chitosan modified paper device and wax-screen-printing. Biosens. Bioelectron. 2012, 31, 212–218. [Google Scholar] [CrossRef] [PubMed]
  56. Li, X.; Nie, Z.; Cheng, C.; Goodale, A.; Whitesides, G. Paper-based electrochemical ELISA. In Proceedings of the 14th International Conference on Miniaturized Systems for Chemistry and Life Sciences (MicroTAS 2010), Groningen, The Netherlands, 3–7 October 2010; pp. 1487–1489. [Google Scholar]
  57. Chan, S.K.; Lim, T.S. A straw-housed paper-based colorimetric antibody–antigen sensor. Anal. Methods 2016, 8, 1431–1436. [Google Scholar] [CrossRef]
  58. Tiwari, S.; Vinchurkar, M.; Rao, V.R.; Garnier, G. Zinc oxide nanorods functionalized paper for protein preconcentration in biodiagnostics. Sci. Rep. 2017, 7, 43905. [Google Scholar] [CrossRef] [PubMed]
  59. Chen, C.; Lin, B.-R.; Wang, H.-K.; Fan, S.-T.; Hsu, M.-Y.; Cheng, C.-M. Paper-based immunoaffinity devices for accessible isolation and characterization of extracellular vesicles. Microfluid. Nanofluid. 2014, 16, 849–856. [Google Scholar] [CrossRef]
  60. Hsu, C.-K.; Huang, H.-Y.; Chen, W.-R.; Nishie, W.; Ujiie, H.; Natsuga, K. Paper-Based ELISA for the Detection of Autoimmune Antibodies in Body Fluid—The Case of Bullous Pemphigoid. Anal. Chem. 2014, 86, 4605–4610. [Google Scholar] [CrossRef] [PubMed]
  61. Wang, H.K.; Tsai, C.H.; Chen, K.H.; Tang, C.T.; Leou, J.S.; Li, P.C. Cellulose-Based Diagnostic Devices for Diagnosing Serotype-2 Dengue Fever in Human Serum. Adv. Healthc. Mater. 2014, 3, 187–196. [Google Scholar] [CrossRef] [PubMed]
  62. Murdock, R.C.; Shen, L.; Griffin, D.K.; Kelley-Loughnane, N.; Papautsky, I.; Hagen, J.A. Optimization of a paper-based ELISA for a human performance biomarker. Anal. Chem. 2013, 85, 11634–11642. [Google Scholar] [CrossRef] [PubMed]
  63. Mazzu-Nascimento, T.; Morbioli, G.G.; Milan, L.A.; Silva, D.F.; Donofrio, F.C.; Mestriner, C.A. Improved assessment of accuracy and performance indicators in paper-based ELISA. Anal. Methods 2017, 9, 2644–2653. [Google Scholar] [CrossRef]
  64. Hsu, M.-Y.; Hung, Y.-C.; Hwang, D.-K.; Lin, S.-C.; Lin, K.-H.; Wang, C.-Y. Detection of aqueous VEGF concentrations before and after intravitreal injection of anti-VEGF antibody using low-volume sampling paper-based ELISA. Sci. Rep. 2016, 6, 34631. [Google Scholar] [CrossRef] [PubMed]
  65. Busin, V.; Burgess, S.; Shu, W. A Novel Multi-pad Paper Plate (MP 3) Based Assays for Rapid Animal Disease Diagnostics. Procedia Eng. 2016, 168, 1418–1421. [Google Scholar] [CrossRef]
  66. Cheng, C.M.; Martinez, A.W.; Gong, J.; Mace, C.R.; Phillips, S.T.; Carrilho, E. Paper-based ELISA. Angew. Chem. Int. Ed. 2010, 49, 4771–4774. [Google Scholar] [CrossRef] [PubMed]
  67. Khan, M.S.; Pande, T.; van de Ven, T.G. Qualitative and quantitative detection of T7 bacteriophages using paper based sandwich ELISA. Colloids Surf. B Biointerfaces 2015, 132, 264–270. [Google Scholar] [CrossRef] [PubMed]
  68. Shih, C.-M.; Chang, C.-L.; Hsu, M.-Y.; Lin, J.-Y.; Kuan, C.-M.; Wang, H.-K. Paper-based ELISA to rapidly detect Escherichia coli. Talanta 2015, 145, 2–5. [Google Scholar] [CrossRef] [PubMed]
  69. Jones, K. FUSION 5: A New Platform For Lateral Flow Immunoassay Tests. In Lateral Flow Immunoassay; Springer: New York, NY, USA, 2009; pp. 1–15. [Google Scholar]
  70. Lai, Y.-T.; Tsai, J.-S.; Hsu, J.-C.; Lu, Y.-W. Automated paper-based devices by microfluidic timing-valve for competitive ELISA. In Proceedings of the 2017 IEEE 30th International Conference on Micro Electro Mechanical Systems (MEMS), Las Vegas, NV, USA, 22–26 January 2017; pp. 1321–1324. [Google Scholar]
  71. Apilux, A.; Ukita, Y.; Chikae, M.; Chailapakul, O.; Takamura, Y. Development of automated paper-based devices for sequential multistep sandwich enzyme-linked immunosorbent assays using inkjet printing. Lab Chip 2013, 13, 126–135. [Google Scholar] [CrossRef] [PubMed]
  72. Mahmud, M.A.; Blondeel, E.J.M.; Kaddoura, M.; MacDonald, B.D. Creating compact and microscale features in paper-based devices by laser cutting. Analyst 2016, 141, 6449–6454. [Google Scholar] [CrossRef] [PubMed]
  73. Kwong, P.; Gupta, M. Vapor Phase Deposition of Functional Polymers onto Paper-Based Microfluidic Devices for Advanced Unit Operations. Anal. Chem. 2012, 84, 10129–10135. [Google Scholar] [CrossRef] [PubMed]
  74. Zhang, Y.; Rochefort, D. Fast and effective paper based sensor for self-diagnosis of bacterial vaginosis. Anal. Chim. Acta 2013, 800, 87–94. [Google Scholar] [CrossRef] [PubMed]
  75. Mudabuka, B.; Ondigo, D.; Degni, S.; Vilakazi, S.; Torto, N. A colorimetric probe for ascorbic acid based on copper-gold nanoparticles in electrospun nylon. Microchim. Acta 2014, 181, 395–401. [Google Scholar] [CrossRef]
  76. Ge, L.; Wang, P.; Ge, S.; Li, N.; Yu, J.; Yan, M. Photoelectrochemical Lab-on-Paper Device Based on an Integrated Paper Supercapacitor and Internal Light Source. Anal. Chem. 2013, 85, 3961–3970. [Google Scholar] [CrossRef] [PubMed]
  77. Yeow, N.; McLiesh, H.; Guan, L.; Shen, W.; Garnier, G. Paper-based assay for red blood cell antigen typing by the indirect antiglobulin test. Anal. Bioanal. Chem. 2016, 408, 5231–5238. [Google Scholar] [CrossRef] [PubMed]
  78. Chong, H.; Koo, Y.; Collins, B.; Gomez, F.; Yun, Y.; Sankar, J. Paper-based microfluidic point-of-care diagnostic devices for monitoring drug metabolism. J. Nanomed. Biother. Discov. 2013, 3, e122. [Google Scholar] [CrossRef]
  79. Li, X.; Tian, J.; Shen, W. Progress in patterned paper sizing for fabrication of paper-based microfluidic sensors. Cellulose 2010, 17, 649–659. [Google Scholar] [CrossRef]
  80. Martinez, A.W.; Phillips, S.T.; Nie, Z.; Cheng, C.-M.; Carrilho, E.; Wiley, B.J. Programmable diagnostic devices made from paper and tape. Lab Chip 2010, 10, 2499–2504. [Google Scholar] [CrossRef] [PubMed]
  81. Toley, B.J.; McKenzie, B.; Liang, T.; Buser, J.R.; Yager, P.; Fu, E. Tunable-delay shunts for paper microfluidic devices. Anal. Chem. 2013, 85, 11545–11552. [Google Scholar] [CrossRef] [PubMed]
  82. Fu, E.; Lutz, B.; Kauffman, P.; Yager, P. Controlled reagent transport in disposable 2D paper networks. Lab Chip 2010, 10, 918–920. [Google Scholar] [CrossRef] [PubMed]
  83. Tian, J.; Kannangara, D.; Li, X.; Shen, W. Capillary driven low-cost V-groove microfluidic device with high sample transport efficiency. Lab Chip 2010, 10, 2258–2264. [Google Scholar] [CrossRef] [PubMed]
  84. Lutz, B.; Liang, T.; Fu, E.; Ramachandran, S.; Kauffman, P.; Yager, P. Dissolvable fluidic time delays for programming multi-step assays in instrument-free paper diagnostics. Lab Chip 2013, 13, 2840–2847. [Google Scholar] [CrossRef] [PubMed]
  85. Houghtaling, J.; Liang, T.; Thiessen, G.; Fu, E. Dissolvable bridges for manipulating fluid volumes in paper networks. Anal. Chem. 2013, 85, 11201–11204. [Google Scholar] [CrossRef] [PubMed]
  86. Lewis, G.G.; Robbins, J.S.; Phillips, S.T. Phase-switching depolymerizable poly(carbamate) oligomers for signal amplification in quantitative time-based assays. Macromolecules 2013, 46, 5177–5183. [Google Scholar] [CrossRef]
  87. Giokas, D.L.; Tsogas, G.Z.; Vlessidis, A.G. Programming fluid transport in paper-based microfluidic devices using razor-crafted open channels. Anal. Chem. 2014, 86, 6202–6207. [Google Scholar] [CrossRef] [PubMed]
  88. Renault, C.; Anderson, M.J.; Crooks, R.M. Electrochemistry in hollow-channel paper analytical devices. J. Am. Chem. Soc. 2014, 136, 4616–4623. [Google Scholar] [CrossRef] [PubMed]
  89. Hosseini, S.; Ibrahim, F.; Djordjevic, I.; Rothan, H.A.; Yusof, R.; van der Mareld, C. Synthesis and Processing of ELISA Polymer Substitute: The Influence of Surface Chemistry and Morphology on Detection Sensitivity. Appl. Surf. Sci. 2014, 317, 630–638. [Google Scholar] [CrossRef]
  90. Li, L.; Ma, C.; Kong, Q.; Li, W.; Zhang, Y.; Ge, S. A 3D origami electrochemical immunodevice based on a Au@ Pd alloy nanoparticle-paper electrode for the detection of carcinoembryonic antigen. J. Mater. Chem. B 2014, 2, 6669–6674. [Google Scholar] [CrossRef]
  91. Hosseini, S.; Ibrahim, F.; Rothan, H.A.; Yusof, R.; van der Marel, C.; Djordjevic, I. Aging effect and antibody immobilization on –COOH exposed surfaces designed for dengue virus detection. Biochem. Eng. J. 2015, 99, 183–192. [Google Scholar] [CrossRef]
  92. Hosseini, S.; Ibrahim, F.; Djordjevic, I.; Rothan, H.A.; Yusof, R.; van der Marel, C. Synthesis and characterization of methacrylic microspheres for biomolecular recognition: Ultrasensitive biosensor for dengue virus detection. Eur. Polym. J. 2014, 60, 14–21. [Google Scholar] [CrossRef]
  93. Hosseini, S.; Ibrahim, F. Application of Biochips in Dengue Virus Detection. In Novel Polymeric Biochips for Enhanced Detection of Infectious Diseases; Springer: Singapore, 2016; pp. 39–47. [Google Scholar]
  94. Hosseini, S.; Aeinehvand, M.M.; Uddin, S.M.; Benzina, A.; Rothan, H.A.; Yusof, R. Microsphere integrated microfluidic disk: Synergy of two techniques for rapid and ultrasensitive dengue detection. Sci. Rep. 2015, 5, 16485. [Google Scholar] [CrossRef] [PubMed]
  95. Zhong, Z.; Wang, Z.; Huang, G.X. Investigation of wax and paper materials for the fabrication of paper-based microfluidic devices. Microsyst. Technol. 2012, 18, 649–659. [Google Scholar] [CrossRef]
  96. Shrivastava, A.; Gupta, V.B. Methods for the determination of limit of detection and limit of quantitation of the analytical methods. Chron. Young Sci. 2011, 2, 21–25. [Google Scholar] [CrossRef]
  97. Swamy, N.; Prashanth, K.N.; Basavaiah, K. Titrimetric and spectrophotometric assay of diethylcarbamazine citrate in formulations using iodate and iodide mixture as reagents. Braz. J. Pharm. Sci. 2015, 51, 43–52. [Google Scholar] [CrossRef]
  98. Gad, M.; Zaazaa, H.; Amer, S.; Korany, M. Static headspace gas chromatographic method for the determination of residual solvents in cephalosporins. RSC Adv. 2015, 5, 17150–17159. [Google Scholar] [CrossRef]
  99. Bauer, S.M.; Gehringer, M.; Laufer, S.A. A direct enzyme-linked immunosorbent assay (ELISA) for the quantitative evaluation of Janus Kinase 3 (JAK3) inhibitors. Anal. Methods 2014, 6, 8817–8822. [Google Scholar] [CrossRef]
  100. Pereira, A.G.; D’Avila, F.B.; Ferreira, P.C.L.; Holler, M.G.; Limberger, R.P.; Froehlich, P.E. Determination of cocaine, its metabolites and pyrolytic products by LC-MS using a chemometric approach. Anal. Methods 2014, 6, 456–462. [Google Scholar] [CrossRef]
  101. Hosseini, S.; Ibrahim, F.; Djordjevic, I.; Koole, L.H. Recent advances in surface functionalization techniques on polymethacrylate materials for optical biosensor applications. Analyst 2014, 139, 2933–2943. [Google Scholar] [CrossRef] [PubMed]
  102. Goddard, J.M.; Hotchkiss, J.H. Polymer surface modification for the attachment of bioactive compounds. Prog. Polym. Sci. 2007, 32, 698–725. [Google Scholar] [CrossRef]
  103. Hosseini, S.; Ibrahim, F. Current Optical Biosensors in Clinical Practice. In Novel Polymeric Biochips for Enhanced Detection of Infectious Diseases; Springer: Singapore, 2016; pp. 1–12. [Google Scholar]
  104. Tsai, C.-C.; Gu, Y.; Kornev, K.G. Wetting of nanofiber yarns. Colloids Surf. Physicochem. Eng. Asp. 2014, 459, 22–30. [Google Scholar] [CrossRef]
  105. Saraf, R.; Lee, H.J.; Michielsen, S.; Owens, J.; Willis, C.; Stone, C. Comparison of three methods for generating superhydrophobic, superoleophobic nylon nonwoven surfaces. J. Mater. Sci. 2011, 46, 5751–5760. [Google Scholar] [CrossRef]
  106. Guo, A.; Roso, M.; Modesti, M.; Maire, E.; Adrien, J.; Colombo, P. Characterization of porosity, structure, and mechanical properties of electrospun SiOC fiber mats. J. Mater. Sci. 2015, 50, 4221–4231. [Google Scholar] [CrossRef]
  107. Dinger, D.R. Characterization Techniques for Ceramists; Dinger Ceramic Consulting Services: Clemson, SC, USA, 2005. [Google Scholar]
  108. Etiemble, A.; Adrien, J.; Maire, E.; Idrissi, H.; Reyter, D.; Roué, L. 3D morphological analysis of copper foams as current collectors for Li-ion batteries by means of X-ray tomography. Mater. Sci. Eng. B 2014, 187, 1–8. [Google Scholar] [CrossRef]
  109. Biasetto, L.; Colombo, P.; Innocentini, M.D.; Mullens, S. Gas permeability of microcellular ceramic foams. Ind. Eng. Chem. Res. 2007, 46, 3366–3372. [Google Scholar] [CrossRef]
  110. Kamikawa, C.M.; Mendes, R.P.; Vicentini, A.P. Standardization and validation of Dot-ELISA assay for Paracoccidioides brasiliensis antibody detection. J. Venom. Anim. Toxins Trop. Dis. 2017, 23, 11. [Google Scholar] [CrossRef] [PubMed]
  111. Xu, F.; Wang, W.-H.; Tan, Y.-J.; Bruening, M.L. Facile trypsin immobilization in polymeric membranes for rapid, efficient protein digestion. Anal. Chem. 2010, 82, 10045–10051. [Google Scholar] [CrossRef] [PubMed]
  112. Hosseini, S.; Ibrahim, F.; Djordjevic, I.; Koole, L.H. Polymethyl methacrylate-co-methacrylic acid coatings with controllable concentration of surface carboxyl groups: A novel approach in fabrication of polymeric platforms for potential bio-diagnostic devices. Appl. Surf. Sci. 2014, 300, 43–50. [Google Scholar] [CrossRef]
  113. Mahalik, N.P.; Nambiar, A.N. Trends in food packaging and manufacturing systems and technology. Trends Food Sci. Technol. 2010, 21, 117–128. [Google Scholar] [CrossRef]
  114. Cabrera-Padilla, R.Y.; Lisboa, M.C.; Fricks, A.T.; Franceschi, E.; Lima, A.S.; Silva, D.P. Immobilization of Candida rugosa lipase on poly (3-hydroxybutyrate-co-hydroxyvalerate): A new eco-friendly support. J. Ind. Microbiol. Biotechnol. 2012, 39, 289–298. [Google Scholar] [CrossRef] [PubMed]
  115. Ma, X.; Liu, X.; Xiao, H.; Li, G. Direct electrochemistry and electrocatalysis of hemoglobin in poly-3-hydroxybutyrate membrane. Biosens. Bioelectron. 2005, 20, 1836–1842. [Google Scholar] [CrossRef] [PubMed]
  116. Cheng, M.-L.; Sun, Y.-M.; Chen, H.; Jean, Y. Change of structure and free volume properties of semi-crystalline poly (3-hydroxybutyrate-co-3-hydroxyvalerate) during thermal treatments by positron annihilation lifetime. Polymer 2009, 50, 1957–1964. [Google Scholar] [CrossRef]
  117. Ferraz, A.S.; Belo, E.F.; Coutinho, L.M.; Oliveira, A.P.; Carmo, A.M.; Franco, D.L. Storage and stability of IgG and IgM monoclonal antibodies dried on filter paper and utility in Neisseria meningitidis serotyping by Dot-blot ELISA. BMC Infect. Dis. 2008, 8, 30. [Google Scholar] [CrossRef] [PubMed]
  118. Nargang, T.M.; Runck, M.; Helmer, D.; Rapp, B.E. Functionalization of paper using photobleaching: A fast and convenient method for creating paper-based assays with colorimetric and fluorescent readout. Eng. Life Sci. 2016, 16, 525–531. [Google Scholar] [CrossRef]
  119. Lutz, B.R.; Trinh, P.; Ball, C.; Fu, E.; Yager, P. Two-dimensional paper networks: Programmable fluidic disconnects for multi-step processes in shaped paper. Lab Chip 2011, 11, 4274–4278. [Google Scholar] [CrossRef] [PubMed]
  120. Lopez-Ruiz, N.; Curto, V.F.; Erenas, M.M.; Benito-Lopez, F.; Diamond, D.; Palma, A.J. Smartphone-based simultaneous pH and nitrite colorimetric determination for paper microfluidic devices. Anal. Chem. 2014, 86, 9554–9562. [Google Scholar] [CrossRef] [PubMed]
  121. Wang, H.; Li, Y.-J.; Wei, J.-F.; Xu, J.-R.; Wang, Y.-H.; Zheng, G.-X. Paper-based three-dimensional microfluidic device for monitoring of heavy metals with a camera cell phone. Anal. Bioanal. Chem. 2014, 406, 2799–2807. [Google Scholar] [CrossRef] [PubMed]
  122. Zhang, Y.; Zhou, C.; Nie, J.; Le, S.; Qin, Q.; Liu, F. Equipment-free quantitative measurement for microfluidic paper-based analytical devices fabricated using the principles of movable-type printing. Anal. Chem. 2014, 86, 2005–2012. [Google Scholar] [CrossRef] [PubMed]
  123. Zhang, M.; Ge, L.; Ge, S.; Yan, M.; Yu, J.; Huang, J. Three-dimensional paper-based electrochemiluminescence device for simultaneous detection of Pb 2+ and Hg 2+ based on potential-control technique. Biosens. Bioelectron. 2013, 41, 544–550. [Google Scholar] [CrossRef] [PubMed]
  124. Ali, M.M.; Aguirre, S.D.; Xu, Y.; Filipe, C.D.; Pelton, R.; Li, Y. Detection of DNA using bioactive paper strips. Chem. Commun. 2009, 43, 6640–6642. [Google Scholar] [CrossRef] [PubMed]
  125. Allen, P.B.; Arshad, S.A.; Li, B.; Chen, X.; Ellington, A.D. DNA circuits as amplifiers for the detection of nucleic acids on a paperfluidic platform. Lab Chip 2012, 12, 2951–2958. [Google Scholar] [CrossRef] [PubMed]
  126. Yildiz, U.H.; Alagappan, P.; Liedberg, B. Naked eye detection of lung cancer associated miRNA by paper based biosensing platform. Anal. Chem. 2012, 85, 820–824. [Google Scholar] [CrossRef] [PubMed]
  127. Noor, M.O.; Shahmuradyan, A.; Krull, U.J. Paper-based solid-phase nucleic acid hybridization assay using immobilized quantum dots as donors in fluorescence resonance energy transfer. Anal. Chem. 2013, 85, 1860–1867. [Google Scholar] [CrossRef] [PubMed]
  128. Delaney, J.L.; Hogan, C.F.; Tian, J.; Shen, W. Electrogenerated chemiluminescence detection in paper-based microfluidic sensors. Anal. Chem. 2011, 83, 1300–1306. [Google Scholar] [CrossRef] [PubMed]
  129. Yu, J.; Wang, S.; Ge, L.; Ge, S. A novel chemiluminescence paper microfluidic biosensor based on enzymatic reaction for uric acid determination. Biosens. Bioelectron. 2011, 26, 3284–3289. [Google Scholar] [CrossRef] [PubMed]
  130. Rattanarat, P.; Dungchai, W.; Cate, D.; Volckens, J.; Chailapakul, O.; Henry, C.S. Multilayer paper-based device for colorimetric and electrochemical quantification of metals. Anal. Chem. 2014, 86, 3555–3562. [Google Scholar] [CrossRef] [PubMed]
  131. Scida, K.; Cunningham, J.C.; Renault, C.; Richards, I.; Crooks, R.M. Simple, sensitive, and quantitative electrochemical detection method for paper analytical devices. Anal. Chem. 2014, 86, 6501–6507. [Google Scholar] [CrossRef] [PubMed]
  132. Wu, L.; Ma, C.; Ge, L.; Kong, Q.; Yan, M.; Ge, S. Paper-based electrochemiluminescence origami cyto-device for multiple cancer cells detection using porous AuPd alloy as catalytically promoted nanolabels. Biosens. Bioelectron. 2015, 63, 450–457. [Google Scholar] [CrossRef] [PubMed]
  133. Li, W.; Li, M.; Ge, S.; Yan, M.; Huang, J.; Yu, J. Battery-triggered ultrasensitive electrochemiluminescence detection on microfluidic paper-based immunodevice based on dual-signal amplification strategy. Anal. Chim. Acta 2013, 767, 66–74. [Google Scholar] [CrossRef] [PubMed]
  134. Sun, G.; Wang, P.; Ge, S.; Ge, L.; Yu, J.; Yan, M. Photoelectrochemical sensor for pentachlorophenol on microfluidic paper-based analytical device based on the molecular imprinting technique. Biosens. Bioelectron. 2014, 56, 97–103. [Google Scholar] [CrossRef] [PubMed]
  135. Maxwell, E.J.; Mazzeo, A.D.; Whitesides, G.M. Paper-based electroanalytical devices for accessible diagnostic testing. MRS Bull. 2013, 38, 309–314. [Google Scholar] [CrossRef]
  136. Liu, B.; Du, D.; Hua, X.; Yu, X.Y.; Lin, Y. Paper-Based Electrochemical Biosensors: From Test Strips to Paper-Based Microfluidics. Electroanalysis 2014, 26, 1214–1223. [Google Scholar] [CrossRef]
  137. Martinez, A.W.; Phillips, S.T.; Carrilho, E.; Thomas, S.W., III; Sindi, H.; Whitesides, G.M. Simple telemedicine for developing regions: Camera phones and paper-based microfluidic devices for real-time, off-site diagnosis. Anal. Chem. 2008, 80, 3699–3707. [Google Scholar] [CrossRef] [PubMed]
  138. Martinez, A.W.; Phillips, S.T.; Whitesides, G.M.; Carrilho, E. Diagnostics for the developing world: Microfluidic paper-based analytical devices. Anal. Chem. 2010, 82, 3–10. [Google Scholar] [CrossRef] [PubMed]
  139. Aungst, T.D.; Clauson, K.A.; Misra, S.; Lewis, T.L.; Husain, I. How to identify, assess and utilise mobile medical applications in clinical practice. Int. J. Clin. Pract. 2014, 68, 155–162. [Google Scholar] [CrossRef] [PubMed]
  140. Doeven, E.H.; Barbante, G.J.; Kerr, E.; Hogan, C.F.; Endler, J.A.; Francis, P.S. Red–green–blue electrogenerated chemiluminescence utilizing a digital camera as detector. Anal. Chem. 2014, 86, 2727–2732. [Google Scholar] [CrossRef] [PubMed]
  141. Fu, E. Enabling robust quantitative readout in an equipment-free model of device development. Analyst 2014, 139, 4750–4757. [Google Scholar] [CrossRef] [PubMed]
  142. Phillips, S.T.; Lewis, G.G. Advances in materials that enable quantitative point-of-care assays. MRS Bull. 2013, 38, 315–319. [Google Scholar] [CrossRef]
  143. Fang, X.; Wei, S.; Kong, J. Paper-based microfluidics with high resolution, cut on a glass fiber membrane for bioassays. Lab Chip 2014, 14, 911–915. [Google Scholar] [CrossRef] [PubMed]
  144. Hao, Y.; Chen, W.; Wang, L.; Zhou, B.; Zang, Q.; Chen, S. A naphthalimide-based azo colorimetric and ratiometric probe: Synthesis and its application in rapid detection of cyanide anions. Anal. Methods 2014, 6, 2478–2483. [Google Scholar] [CrossRef]
  145. Weaver, A.A.; Reiser, H.; Barstis, T.; Benvenuti, M.; Ghosh, D.; Hunckler, M. Paper analytical devices for fast field screening of beta lactam antibiotics and antituberculosis pharmaceuticals. Anal. Chem. 2013, 85, 6453–6460. [Google Scholar] [CrossRef] [PubMed]
  146. Zhu, W.-J.; Feng, D.-Q.; Chen, M.; Chen, Z.-D.; Zhu, R.; Fang, H.-L. Bienzyme colorimetric detection of glucose with self-calibration based on tree-shaped paper strip. Sens. Actuators B Chem. 2014, 190, 414–418. [Google Scholar] [CrossRef]
  147. Pollock, N.R.; McGray, S.; Colby, D.J.; Noubary, F.; Nguyen, H.; Khormaee, S. Field evaluation of a prototype paper-based point-of-care fingerstick transaminase test. PLoS ONE 2013, 8, e75616. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  148. Zuk, R.; Ginsberg, V.; Houts, T.; Rabbie, J.; Merrick, H.; Ullman, E. Enzyme immunochromatography—A quantitative immunoassay requiring no instrumentation. Clin. Chem. 1985, 31, 1144–1150. [Google Scholar] [PubMed]
  149. Cate, D.M.; Dungchai, W.; Cunningham, J.C.; Volckens, J.; Henry, C.S. Simple, distance-based measurement for paper analytical devices. Lab Chip 2013, 13, 2397–2404. [Google Scholar] [CrossRef] [PubMed]
  150. Lou, S.C.; Patel, C.; Ching, S.; Gordon, J. One-step competitive immunochromatographic assay for semiquantitative determination of lipoprotein (a) in plasma. Clin. Chem. 1993, 39, 619–624. [Google Scholar] [PubMed]
  151. Lewis, G.G.; DiTucci, M.J.; Phillips, S.T. Quantifying Analytes in Paper-Based Microfluidic Devices Without Using External Electronic Readers. Angew. Chem. 2012, 124, 12879–12882. [Google Scholar] [CrossRef]
  152. Fu, E.; Ramsey, S.A.; Kauffman, P.; Lutz, B.; Yager, P. Transport in two-dimensional paper networks. Microfluid. Nanofluid. 2011, 10, 29–35. [Google Scholar] [CrossRef] [PubMed]
  153. Li, X.; Zwanenburg, P.; Liu, X. Magnetic timing valves for fluid control in paper-based microfluidics. Lab Chip 2013, 13, 2609–2614. [Google Scholar] [CrossRef] [PubMed]
  154. Fridley, G.E.; Le, H.; Yager, P. Highly sensitive immunoassay based on controlled rehydration of patterned reagents in a 2-dimensional paper network. Anal. Chem. 2014, 86, 6447–6453. [Google Scholar] [CrossRef] [PubMed]
  155. Whatman, G.H. Catalog CDwb; Whatman, Inc.: Maidstone, UK, 2007. [Google Scholar]
  156. Fiore, M.; Mitchell, J.; Doan, T.; Nelson, R.; Winter, G.; Grandone, C. The Abbott IMx automated benchtop immunochemistry analyzer system. Clin. Chem. 1988, 34, 1726–1732. [Google Scholar] [PubMed]
  157. Smith, J.; Osikowicz, G. Abbott AxSYM random and continuous access immunoassay system for improved workflow in the clinical laboratory. Clin. Chem. 1993, 39, 2063–2069. [Google Scholar] [PubMed]
  158. Sokoll, L.J.; Chan, D.W. Clinical analyzers. immunoassays. Anal. Chem. 1999, 71, 356–362. [Google Scholar] [CrossRef]
  159. Vella, S.J.; Beattie, P.; Cademartiri, R.; Laromaine, A.; Martinez, A.W.; Phillips, S.T. Measuring markers of liver function using a micropatterned paper device designed for blood from a fingerstick. Anal. Chem. 2012, 84, 2883–2891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  160. Noiphung, J.; Songjaroen, T.; Dungchai, W.; Henry, C.S.; Chailapakul, O.; Laiwattanapaisal, W. Electrochemical detection of glucose from whole blood using paper-based microfluidic devices. Anal. Chim. Acta 2013, 788, 39–45. [Google Scholar] [CrossRef] [PubMed]
  161. Songjaroen, T.; Dungchai, W.; Chailapakul, O.; Henry, C.S.; Laiwattanapaisal, W. Blood separation on microfluidic paper-based analytical devices. Lab Chip 2012, 12, 3392–3398. [Google Scholar] [CrossRef] [PubMed]
  162. Pollock, N.R.; Rolland, J.P.; Kumar, S.; Beattie, P.D.; Jain, S.; Noubary, F. A paper-based multiplexed transaminase test for low-cost, point-of-care liver function testing. Sci. Transl. Med. 2012, 4, 152ra129. [Google Scholar] [CrossRef] [PubMed]
  163. Jain, S.; Rajasingham, R.; Noubary, F.; Coonahan, E.; Schoeplein, R.; Baden, R. Performance of an Optimized Paper-Based Test for Rapid Visual Measurement of Alanine Aminotransferase (ALT) in Fingerstick and Venipuncture Samples. PLoS ONE 2015, 10, e0128118. [Google Scholar] [CrossRef] [PubMed]
  164. Yang, X.; Forouzan, O.; Brown, T.P.; Shevkoplyas, S.S. Integrated separation of blood plasma from whole blood for microfluidic paper-based analytical devices. Lab Chip 2012, 12, 274–280. [Google Scholar] [CrossRef] [PubMed]
  165. Nilghaz, A.; Shen, W. Low-cost blood plasma separation method using salt functionalized paper. RSC Adv. 2015, 5, 53172–53179. [Google Scholar] [CrossRef]
  166. Kar, S.; Maiti, T.K.; Chakraborty, S. Capillarity-driven blood plasma separation on paper-based devices. Analyst 2015, 140, 6473–6476. [Google Scholar] [CrossRef] [PubMed]
  167. Yamada, K.; Takaki, S.; Komuro, N.; Suzuki, K.; Citterio, D. An antibody-free microfluidic paper-based analytical device for the determination of tear fluid lactoferrin by fluorescence sensitization of Tb 3+. Analyst 2014, 139, 1637–1643. [Google Scholar] [CrossRef] [PubMed]
  168. Mentele, M.M.; Cunningham, J.; Koehler, K.; Volckens, J.; Henry, C.S. Microfluidic paper-based analytical device for particulate metals. Anal. Chem. 2012, 84, 4474–4480. [Google Scholar] [CrossRef] [PubMed]
  169. Neumaier, M.; Braun, A.; Wagener, C. Fundamentals of quality assessment of molecular amplification methods in clinical diagnostics. Clin. Chem. 1998, 44, 12–26. [Google Scholar] [PubMed]
  170. Improvement RfCL, for AoCWA, Manufacturers of In Vitro Diagnostic Devices. Available online: https://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm079632.htm (accessed on 15 May 2017).
  171. Hunsinger, P.; Zwarun, A. Manufacturing Method for an Occult Fecal Blood Test Slide. U.S. Patent US4,983,416 A, 8 January 1991. [Google Scholar]
  172. Yu, Y.S. Test Strips Having Reaction Zones and Channels Defined by a Thermally Transferred Hydrophobic Barrier. U.S. Patent US6,723,500 B2, 20 April 2004. [Google Scholar]
  173. Fonner, D.E. Diagnostic Composition. U.S. Patent US3001915 A, 26 September 1961. [Google Scholar]
  174. Deiss, F.; Mazzeo, A.; Hong, E.; Ingber, D.E.; Derda, R.; Whitesides, G.M. Platform for high-throughput testing of the effect of soluble compounds on 3D cell cultures. Anal. Chem. 2013, 85, 8085–8094. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Paper and fiber-based bio-analytical platforms along with the detailed fabrication methods and embedded systems.
Table 1. Paper and fiber-based bio-analytical platforms along with the detailed fabrication methods and embedded systems.
Type of Paper/FiberApplied Fabrication MethodEmbedded Platform/PatternRef.
Whatman # 903Dispersion/immersionCircular fragments sliced with paper punch[53]
Ahlstrom A-55Wax screen printing6 × 3 plate array with hydrophobic barriers as black zones on a white background[54]
[55]
Whatmann CHR # 1PhotolithographyμPAD with 5 × 5 paper mat with a set of electrodes on each side[56]
Whatman # 1Commercialized material with a proprietary fabrication methodPaper-based disk produced using a standard paper puncher, dried and taped on a plastic strip[57]
Designed platform mimics 96-well plate[58]
[59]
Wax printing[60,61,62,63,64]
Whatmann CHR # 1Assembly of paper in pre-cut lamination sheets[65]
PHB fibersElectrospinning and dip-coating with poly(MMA-co-MAA)[5]
PHBV fibers[6]
NylonDip-coating with poly(MMA-co-MAA)[37]
CellulosePhotolithography[66]
Filter paper Whatman # 42Commercialized material with proprietary fabrication method~1 cm diameter circles cut into pendent disk shapes to avoid cross contamination[67]
Whatman Fusion 5TM paperSquare shaped layers with surface area of 3 cm2[68,69]
NCWax printingμPAD with printed channels that function as timing valves[70]
Inkjet printing[71]
Whatmann CHR # 1Flexographic printingPolystyrene printed paper (297 mm × 105 mm) with hydrophobic barriers[22]
Polyester-backed paper, Whatmann CHR # 1, NC membraneComputer-controlled knife cuttingStar, candelabra, and other structures[23]
Aluminum foil-baked Whatmann CHR # 1CO2 laser cutting/engravingμPAD design with very small features and narrow barriers[72]
Whatman CHR # 1 coated with functional polymers/copolymersVapor-phase polymer depositionIntegration of multiple advanced unit operations onto a single μPAD device[73]
Whatman # 4 loaded with PEI microcapsules, BCIN, and NBTSuspension mixing followed by filtrationPaper strips[74]
Nylon # 6 fibers blended with PSBMA and PAAElectrospinningblended fiber deposition on a glass slip[50]
PVDF nano-fiber membraneWestern blotting platforms (6 cm × 8 cm)[52]
Nylon # 6 fibers with Cu-Au nanoparticlesPaper strips[75]
PCL fiber membraneFolded and pressed sheet of membrane (25 mm × 40 mm)[51]
Nomenclature: PHB = Poly(3-hydroxybutyrate; poly(MMA-co-MAA) = poly methylmetacrylate-co-methacrylic acid PHBV = Poly(3-hydroxybutyrate-co-3-hydroxyvalerate); NC = nitrocellulose; PEI = poly(ethyleneimine); BCIN = 5-bromo-4-chloro-3-indolyl-α-D-N-acetylneuraminic acid; NTB = nitro blue tetrazolium; PVDF = Polyvinylidene fluoride; Cu-Au: Copper-gold; PCL = Poly(ε-caprolactone). CHR = chromatography.
Table
Table 2. Paper and fiber-based bio-analytical platforms directed towards ELISA assays along with the type of target biomolecules, applied detection techniques, and evaluation parameters of the method, as well as the types and approximate durations of the conducted assay.
Table 2. Paper and fiber-based bio-analytical platforms directed towards ELISA assays along with the type of target biomolecules, applied detection techniques, and evaluation parameters of the method, as well as the types and approximate durations of the conducted assay.
Type of Paper/FiberTarget AnalyteDetection TechniqueType of AssayApprox. Time of AssaySensitivity/Specificity/Limit of Detection (LoD)Ref.
Whatman # 903Anti-dengue IgM antibodyFluorescenceDirect ELISA24 hSpecificity = 99%[53]
The fluorescence spectra were measured in a spectrofluorometer with the excitation at 360 nm and emission at 450 nmLoD = 40 ng/mL in serum and 0.8 ng in serum dilution 1:10,000 as positive control
Whatmann CHR # 1Fetoprotein (AFP)Chemiluminiscence
Readout was performed by ultraweak luminescence analyzer		Sandwich ELISA10 minDetection range of 0.1–35 ng/mL for AFP, 0.5–80 U/mL for CA125, and 0.1–7 ng/mL for CEA[55]
Cancer antigen 125 (CA125)
Carcinoembryonic antigen (CEA)
Haptoglobin in bovine serumThe test zone was scanned using a flatbed desktop scanner and images were transformed into 8-bit gray-scaleSandwich ELISA41.5 minSensitivity was reported to be low; [65]
LoD = 0.73 μg/mL
Rabbit IgG antibodyElectrochemical (cyclic voltammetry)Indirect ELISA30 minLoD ≈ 3.9 fM[56]
Micro-zones in the paper device were imaged by GE Typhoon Trio Scanner. The excitation and emission wavelengths were 532 nm and 580 nm, respectively.
Whatman # 1Ubiquitin and enhanced green fluorescent protein (eGFP)ColorimetricChanges on the paper disk were recorded with a mobile phone camera and quantified by Adobe Photoshop CS2 software in grey mode to obtain the average intensity using a fixed quadrantIndirect ELISA30 minNot specified[57]
Cardiac marker protein, myoglobinThe color changes in the platform were scanned using a desktop scanner and analyzed by Image JSandwich ELISA60 minDetection concentration = 50 ng/mL[58]
Extracellular vesiclesThe test zone was scanned using a desktop scanner and the data were saved in 8-bit format. The intensity of the color was quantified using Image J.Sandwich ELISA40 minNot specified[59]
Auto-antibodiesThe color changes were recorded by a commercial desktop scanner and analyzed by Adobe Photoshop softwareIndirect ELISA70 minSensitivity in serum = 81.8%[60]
Sensitivity in blister fluids = 83.3%
Specificity in serum = 75%
Specificity blister fluids = 85.7%.
Dengue virus antigens and enveloped dengue virusThe colorimetric results were recorded using a commercial Apple, iPhone 4SIndirect ELISA60 minLoD ≈ 100 pg/mL[61]
Sensitivity >40 times than conventional readout
Neuropeptide YFor the purpose of comparison, images were captured using a Canon EPS/Rebel T3i/EOS 600D camera, HTC Droid Eris smartphone as well as HP Color 4540 scanner/printerDirect ELISA60 minPico to nanomolar range[62]
Toxoplasma gondii antibody in serumThe test zones were analyzed by a commercial desktop scanner and Adobe Photoshop software. Digitalized images were converted to the CMYK color mode, and the mean pixel intensity was determined using the histogram toolIndirect ELISA60 minSensitivity = 87%;[63]
Specificity = 96%
Vascular endothelial growth factor (VEGF)The color changes were recorded by a desktop scanner and smart phone and analyzed by Adobe Photoshop softwareDirect ELISA60 minDetection range = 0.01–100,000 pg/mL; LoD = 0.03 pg[64]
PHB fibersDengue enveloped virusConventional readout was performed by ELISA readerDouble sandwich ELISA24 hSensitivity = 100%;[5]
Specificity = 80%
PHBV fibers8 hSensitivity = 97.49%;[6]
Specificity = 90.83%
Nylon24 hSensitivity = 100%;[37]
Specificity = 93.75%
CelluloseAntibody against HIV-1 envelope antigen (gp41)Using a desktop scannerDirect ELISA51 minLoD = 54 fmol/zone[66]
Whatman #42T7 bacteriophageColor changes were recorded using a desktop scanner. The samples were then analyzed using standard image processing softwareSandwich ELISA60 minDetection range = 100–109 pfu/mL[67]
Whatman Fusion 5TME. coli bacterialColor intensities were recorded by portable scanners or smartphonesIndirect ELISA5 hDetection concentration = 105 cells/mL[68,69]
NitrocelluloseImidacloprid (small molecule pesticide)Color intensities were recorded by a smartphone and the images processed by Image JCompetitive ELISA3 hLoD = 0.01 ppm[70]
Human chorionic gonadotropin (hCG)A digital camera imaged color changes. The mean color intensity of the image at the selected area was quantified using the histogram function with the RGB channel in Adobe Photoshop CS3Sandwich ELISA24 hDetection concentration in urine = 4 ng/mL[71]
Table
Table 3. Paper and fiber-based bio-analytical platforms along with advantages and disadvantages of applied strategies.
Table 3. Paper and fiber-based bio-analytical platforms along with advantages and disadvantages of applied strategies.
Paper/FiberStrategiesAdvantagesDisadvantagesRef.
Whatman # 903Paper segments were fabricated in the circular shape by a dispersion/immersion technique for dengue detectionImproved analytical response, 2-fold enhanced sensitivity with 700-fold greater LoD than traditional ELISA, acceptable accuracy for real sample detectionConducted assay in this study is lengthy[53]
Whatman CHR # 1Chitosan modified paper microarray with hydrophobic barriers was fabricated by wax screen printing for detection of different antigensEasy translation to other signal reporting mechanisms, and other biomolecules in point-of-care devices, with sensitivity and linearity of calibration curve suitable for clinical applicationNeighboring cellulose zones may interfere with each other; a spaced-detection strategy is required[55]
Electrodes integrated μPAD was fabricated by photolithography for electrochemical detection of antibodyHigher sensitivity than colorimetric assay, highly quantitative, fast and efficient, does not require sophisticated expensive equipmentThe method was only used for a model protein to prove the concept[56]
Paper assembly in lamination sheets for haptoglobin detectionCost-effective compared to the conventional platform (88% reduction in cost) and 93% time reduction in assay performanceCommercially available ELISA kit can achieve one order of magnitude lower LoD[65]
Whatman # 1Paper-based disk for protein detectionNon-toxicity of the applied fabrication materials with wide applications in industryAlmost 40% of antibody molecules desorbed from cellulose after absorption proving that the method/material require further optimization[57]
Mimicked 96-well plate for detection of cardiac biomarker through colorimetric recognitionThe high aspect ratio and high surface coverage of nanorods provide a large surface area for binding biomolecules; crystallinity of cellulose supports the growth of nanorodsBiomolecule penetration into the highly porous structure of cellulose can cause non-specific binding and induce errors in the assay[58]
Mimicked 96-well plate for extracellular vesicles detection Compatible with downstream analyses, such as scanning electron microscopy (SEM), enzyme-linked immunosorbent assays (ELISA), and transcriptome analysisExtracellular vesicles were captured on the paper device in a non-specific manner; therefore, the specificity was somewhat compromise[59]
Wax printing technique was applied for fabrication of paper-based 96-well plate aimed for biorecognitionRapid and cost-effective analysis in comparison to conventional ELISA, with similar level of sensitivity and specificity while utilizing simple equipment and small sample volumesMedium range sensitivity and specificity were reported[60]
High sensitivity and specificity, low sample volume, short operating timeFabrication process is relatively complex[61]
It allows the user to print plates “on-demand” and opens opportunities for a wide range of nonstandard formats of customized assaysThe method requires specialty software for image analysis and quantitation[62]
Great multiplexing capacity, improved quantitative outputs, simplified data readout; performed assay at room temperature that dispenses the need for refrigerationLimited to tests with a low number of false negative outputs[63]
Reduced sample volume, higher sensitivity, shorter assay time, and lower fabrication costLow stability and short shelf life, which are typical drawbacks of the wax printing technique[64]
PHBCircle shaped polymer coated electrospun fibers integrated into 96-well plate for dengue virus detectionHigher sensitivity and specificity than the conventional method without needing surface treatmentsThe need to remove the papers from the well plate for final readout makes the platform less efficient[5]
PHBVCustomized fiber material with tailored surface properties, tuned wettability and morphological characteristicsPresence of double-sided adhesive layer might result in contamination of the samples if adhesive layer is not fully covered by fiber mat segments[6]
NylonPolymer/copolymer dip-coated nylon embedded into 96-well plate for dengue virus detectionReasonable price, favorable chemistry of the surface without needing surface treatmentsLow stability of the coated nylon membrane in the assay[37]
CellulosePhotolithography technique was applied to fabricate paper-based 96-well plate for detection of HIV-1 Offers a rapid analysis that requires small volumes of samples and reagents, and utilizes simple equipmentThe technique is less sensitive than conventional ELISA by approximately one order of magnitude[66]
Whatman # 42Paper-based disk for detection of T7 bacteriophageCompatible with the sophisticated laboratory diagnostic techniques applied for bio-recognition of pathogenic viruses and other microorganismsThe sensitivity is comparable to the sophisticated laboratory diagnostic techniques, but it is not improved[67]
Fusion 5TMPaper-based ELISA for E. coli detectionRapid, low cost (<$1 per prototype), short training time, and minimal medical wasteDetection was only performed for E. coli sample within the laboratory, while further clinical validation is required[68,69]
NitrocelluloseWax printing technique was applied to fabricate a μPAD equipped with timing valves for imidacloprid detectionEquipped with timing valve that provides an opportunity for multiple-step performance in assay procedureSimilar discrimination capability than conventional ELISA without any improvement was reported; the method has to be further assessed[70]
Inkjet printing technique was applied to fabricate a μPAD equipped with timing valves for hCG detection Simple, straightforward, and low cost fabrication technique by using inkjet printingThere is a chance for error and over estimation of the sensitivity[71]
Table
Table 4. Shelf life and stability of the paper and fiber materials applied for bio-analytical applications.
Table 4. Shelf life and stability of the paper and fiber materials applied for bio-analytical applications.
Type of Paper/FiberShelf Life/StabilityRef.
Conventional and commercial materialsWhatman CHR # 1Lab-on-paper immuno-devices, constructed with this material can provide reproducible results upon storage at 4 °C (sealed) for at least 5 weeks [54]. In other studies on antibody immobilization on the surface of this material, the stability decreased with increasing temperature and relative humidity (40 °C, half-life was more than 10 days) and was dependent on relative humidity (RH) [55]. However, at 80 °C, the half-life varied from ~3 days at low RH to less than half an hour at 90% RH) [55].[55]
NitrocelluloseThe material is commonly used in lateral flow assays. For the detection of P. brasiliensis B-339 antigen, 91% sensitivity and 95.4% specificity was reported, while the membrane have proved to be viable for use in at least 90 days after sensitization.[110]
NylonThe stability of nylon membranes is relatively high [37]. Impregnated protein in the network of nylon has the shelf life of several months (at least 7 months) with minimal loss in activity; the immobilized enzymes within nylon’s structure remain active for at least 33 h without significant loss of activity [111].[37,111]
Commercial materialsWhatman # 903Thermal degradation of the material occurs above 300 °C [53]. Antibodies dried on filter papers are not affected by the duration of storage if kept frozen for over 1 year at −20 °C [117]. Although reactivity of the antibodies decreases after storage, it was not found to interfere with the specificity of the assay even after 13 years if stored as dry spots on filter paper [117].[53,117]
Fusion 5TMThis glass-fiber based material offers the benefits of a high rate of absorption, an acceptable wicking area, optimal wicking time, and homogeneous color development [68]. As a substrate for DNA biosensor strips, stored at 37 °C, it maintained its activity up to 30 days; this translates to an estimated shelf life of 103.87 days at ambient temperature (24 °C) [69]. Fusion 5 contains a plastic binder to increase its mechanical strength [118].[68,69,118]
Non-commercial materialsPHBPHB is highly crystalline (approximately 80%) with a melting temperature close to 180 °C [116]. PHB provides a great resistance to water, which indicates that relative humidity will not affect its performance [5,113]. Relatively stiff PHB is biodegradable, low cost, biocompatible and non-toxic, which are desirable features for a platform in bio-applications [115].[5,113,115,116]
PHBVPHBV is reported to be highly stable to the effects of temperature and humidity, while it is less stiff and crystalline than PHB [114]. After 12 cycles of reuse, enzymes immobilized on PHBV surfaces retained 50% activity [114]. PHBV copolymers commercially known as Biopol®, offer a range of physical barrier properties for water and gases [116].[114,116]

Share and Cite

MDPI and ACS Style

Hosseini, S.; Vázquez-Villegas, P.; Martínez-Chapa, S.O. Paper and Fiber-Based Bio-Diagnostic Platforms: Current Challenges and Future Needs. Appl. Sci. 2017, 7, 863. https://doi.org/10.3390/app7080863

AMA Style

Hosseini S, Vázquez-Villegas P, Martínez-Chapa SO. Paper and Fiber-Based Bio-Diagnostic Platforms: Current Challenges and Future Needs. Applied Sciences. 2017; 7(8):863. https://doi.org/10.3390/app7080863

Chicago/Turabian Style

Hosseini, Samira, Patricia Vázquez-Villegas, and Sergio O. Martínez-Chapa. 2017. "Paper and Fiber-Based Bio-Diagnostic Platforms: Current Challenges and Future Needs" Applied Sciences 7, no. 8: 863. https://doi.org/10.3390/app7080863

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop