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The appearance and quick spread of the new severe acute respiratory syndrome coronavirus disease, COVID-19, brought major societal challenges. Importantly, suitable medical diagnosis procedures and smooth clinical management of the disease are an emergent need, which must be anchored on novel diagnostic methods and devices. Novel molecular diagnostic tools relying on nucleic acid amplification testing have emerged globally and are the current gold standard in COVID-19 diagnosis. However, the need for widespread testing methodologies for fast, effective testing in multiple epidemiological scenarios remains a crucial step in the fight against the COVID-19 pandemic. Biosensors have previously shown the potential for cost-effective and accessible diagnostics, finding applications in settings where conventional, laboratorial techniques may not be readily employed. Paper- and cellulose-based biosensors can be particularly relevant in pandemic times, for the renewability, possibility of mass production with sustainable methodologies, and safe environmental disposal. In this review, paper-based devices and platforms targeting SARS-CoV-2 are showcased and discussed, as a means to achieve quick and low-cost PoC diagnosis, including detection methodologies for viral genomic material, viral antigen detection, and serological antibody testing. Devices targeting inflammatory markers relevant for COVID-19 are also discussed, as fast, reliable bedside diagnostic tools for patient treatment and follow-up., The authors acknowledge funding through projects Eco2Covid (POCI-01-02B7-FEDER-068174) and TecniCov (POCI-01-02B7-FEDER-069745), co-funded by FEDER through COMPETE2020 and Lisboa2020. T.P., A.R.C. and A.C.M. acknowledge funding to National Foundation for Science and Technology, I.P., FCT, through their PhD grants, references DFA/BD/8606/2020, SFRH/BD/130107/2017 and SFRH/BD/115173/2016, respectively, info:eu-repo/semantics/publishedVersion

Graphical abstract Enzyme-linked immunosorbent assay (ELISA) is widely used for the detection of disease biomarkers. However, it utilizes time-consuming procedures and expensive instruments, making it infeasible for point-of-care (POC) analysis especially in resource-limited settings. In this work, a multicolorimetric ELISA biosensor integrated on a paper/polymer hybrid microfluidic device was developed for rapid visual detection of disease biomarkers at point of care, without using costly equipment. This multicolormetric ELISA platform was built on multiple distinct color variants resulted from the catalytic oxidation of 3,3′,5,5′-tetramethylbenzidine (TMB) and the etching of gold nanorods (AuNRs). The vivid color changes could be easily distinguished by the naked eye, and their red mean values allowed quantitative biomarker detection, without using any sophisticated instruments. When this multicolorimetric ELISA was integrated on a paper/polymer hybrid analytical device, it not only provided integrated processing and high portability but also enabled fast assays in about 50 min due to the unique advantages of paper/polymer hybrid devices. The limit of detection of 9.1 ng/μL of the hepatitis C virus core antigen, a biomarker for hepatitis C, was achieved using this multicolorimetric ELISA platform. This multicolor ELISA analytical device provides a new versatile, user-friendly, affordable, and portable immunosensing platform with high potential for on-site detections of various viruses, proteins, and biomarkers for low-resource settings such as at home, public venues, rural areas, and developing nations. Supplementary Information The online version contains supplementary material available at 10.1007/s00216-021-03359-8.

In the tourism industry, the sales of local specialties is an important part, and the package design and integrity of the specialties are very important. This paper first introduced the support vector machine (SVM) algorithm that was used for detecting defects on the surface of paper packages. Then, the design of red wind packages was briefly described, and the simulation experiment was carried out on SVM algorithm using red wine packages with different degrees of surface defects. Proper parameters were tested using the k-fold cross-validation method. The results demonstrated that the properties of paper improved the value of packages and the SVM algorithm had better accuracy than artificial recognition in recognizing different degrees of defects on the surface of packages. In conclusion, this paper describes the application of paper in packages and provides an effective method for the defection of defects on the surface of packages. This study provides an effective references to the improvement of package values and the enhancement of package integrity.

One of the most cited limitations of biochemical detection is its poor sensitivity, owing to the relatively high complexity of micro-samples. Moreover, some samples cannot be easily self-replicated and their abundance cannot be increased through traditional technologies. Therefore, the preconcentration of low-abundance samples is a key requirement for microfluidic biological analysis. In recent years, the ion-concentration polarization phenomenon has aroused widespread interest in the application of microfluidic technology. In addition, paper-based materials are readily available, easy to modify, and exhibit good hydrophilicity. The study of the ion-concentration polarization preconcentration of micro-samples in paper-based microfluidic chips is of considerable significance. In this review, we discuss the development and applications of ion-concentration polarization paper-based preconcentrator in the past 5 years, with emphasis on key progresses in chip fabrication and performance optimization under different conditions. The current needs and development prospects in this field have also been discussed.

A newly developed research topic, fabricated paper-based microfluidic sensors, was discussed in the field of low-cost environmental detection. Distinguished with the traditional dipstick or lateral-flow setups, these paper-based microfluidic sensors can serve as a tool for onsite quantitative and semi-quantitative measurements, without risks to cause environmental pollution. They have attracted increasing interest since the first easy-fabricated paper-based setup reported by Whitesides group in 2007. Most of the publications utilized paper-based sensors in clinical detection. In recent years, some groups started to use these sensors in environmental measurement, leading to precise, easy operation, low-cost, and eco-friendly methods for onsite detection. In this review, paper-based microfluidic sensors were briefly introduced, followed by literatures review and discussion for future perspectives.

The development of industry and of the Internet of Things (IoTs) have brought energy issues and huge challenges to the environment. The emergence of triboelectric nanogenerators (TENGs) has attracted wide attention due to their advantages, such as self-powering, lightweight, and facile fabrication. Similarly to paper and other fiber-based materials, which are biocompatible, biodegradable, environmentally friendly, and are everywhere in daily life, paper-based TENGs (P-TENGs) have shown great potential for various energy harvesting and interactive applications. Here, a detailed summary of P-TENGs with two-dimensional patterns and three-dimensional structures is reported. P-TENGs have the potential to be used in many practical applications, including self-powered sensing devices, human–machine interaction, electrochemistry, and highly efficient energy harvesting devices. This leads to a simple yet effective way for the next generation of energy devices and paper electronics.

Microfluidic paper-based analytical devices (μPADs) have developed rapidly in recent years, because of their advantages, such as small sample volume, rapid detection rates, low cost, and portability. Due to these characteristics, they can be used for in vitro diagnostics in the laboratory, or in the field, for a variety of applications, including food evaluation, disease screening, environmental monitoring, and drug testing. This review will present various detection methods employed by μPADs and their respective applications for the detection of target analytes. These include colorimetry, electrochemistry, chemiluminescence (CL), electrochemiluminescence (ECL), and fluorescence-based methodologies. At the same time, the choice of labeling material and the design of microfluidic channels are also important for detection results. The construction of novel nanocomponents and different smart structures of paper-based devices have improved the performance of μPADs and we will also highlight some of these in this manuscript. Additionally, some key challenges and future prospects for the use of μPADs are briefly discussed.

Compared with a single chemical indicator, the use of multivariate chemical indicators in aging status assessment of transformer cellulose paper insulation can improve the reliability of the evaluation. In this study, a non-destructive method based on multivariate chemical indicators was proposed to evaluate the remaining life of cellulosic paper insulation. The selected chemical indicators closely related to the aging of the insulating paper were analyzed. Additionally, by applying the subjective and objective weighting method, the evaluation information of each indicator was fully extracted to obtain reasonable comprehensive evaluation weights. Besides, the comprehensive evaluation index of multivariate chemical indicators was obtained by using the technique for order preference by similarity to ideal solution method, which is consistent with the deterioration law of paper insulation. Then, the correlation lifespan model between the comprehensive evaluation index of multivariate chemical indicators and the degree of polymerization of insulating paper under different aging stages was established. The effectiveness of the proposed model was verified by experiments. This promising model can increase the accuracy of the condition assessment for the transformer cellulosic paper insulation.

Introduction We developed low-cost, portable paper-based diagnostic devices for detection of human immunoglobulin M (IgM) and immunoglobulin G (IgG) in serum without any sample preparation. These devices can be used to help identify presence of diseases, used to provide rapid results ( Materials and Methods We successfully accomplished colorimetric detection of human IgG and human IgM using a sandwich-style assay within the microfluidic paper device via vertical flow immunoassay configuration. The reaction zone in the wax printed paper layer is a small circular pattern. Gold nanoparticles conjugated with anti-human IgG and IgM antibodies have been used for colorimetric detection of IgG or IgM by naked eye. Colorimetric signal can be precisely quantified through implementation of image analysis software which can be developed as an app for a smartphone. The size of the device is 2 cm × 2 cm × 1 mm. Results Colorimetric detection of human IgG was accomplished at 100 fg/mL concentration using a gold nanoparticle–conjugated anti-human IgG antibody. The developed platform has a dynamic range of IgM and IgG concentrations between 0.1 pg/mL and 100 μg/mL. These devices provided a color readout in Conclusions Because of the inherent simplicity of the device operation and their ease of use, there is no variation between samples and users of the device. This low-cost approach enables multiplexing with >1 measurement performed in parallel at the same time. We anticipate that because of the sensitivity, specificity, ease of use, and overall reliability, this approach will become a standard for diagnosis of diseases and health conditions.

Infectious diseases cause millions of deaths annually in the developing world. Recently, microfluidic paper-based analytical devices (μPADs) have been developed to diagnose such diseases, as these tests are low cost, biocompatible, and simple to fabricate. However, current μPADs are difficult to use in resource-limited areas due to their reliance on external instrumentation to measure and analyze the test results. In this work, we propose an electricity and external instrumentation-free μPAD sensor based on the colorimetric enzyme-linked immunosorbent assay (ELISA) for the diagnosis of infectious disease (3D-tPADs). Designed based on the principle of origami, the proposed μPAD enables the sequential steps of the colorimetric ELISA test to be completed in just ∼10 min. In addition, in order to obtain an accurate ELISA result without using any instrument, we have integrated an electricity-free "timer" within the μPAD that can be controlled by the buffer viscosity and fluid path volume to indicate the appropriate times for washing and color development steps, which can avoid false positive or false negative results caused by an extended or shortened amount of washing and development times. Due to the low background noise and high positive signal intensity of the μPAD, positive and negative detection results can be distinguished by just the naked eye. Furthermore, the ELISA result can be semi-quantified by comparing the results shown on the μPAD with a color chart diagram with a detection limit of HIV type 1(HIV-1) p24 antigen as low as 0.03 ng mL-1. These results demonstrate the proposed sensor can perform infectious disease diagnosis without external instrumentation or electricity, extending the application of the μPAD test for on-site detection and use in resource-limited settings.

Process-monitoring laboratories in the pulp and paper industry generally use a combination of wet chemical analyses and physical measurements to certify the fitness of a production pulp for a specific end-use. These laboratory tests require time and the effort of trained personnel, limiting their utility for real-time process control. Here we show that Raman probes of unrefined cellulosic pulps, well-suited to the online measurement of in-process materials, can predict the quality attributes of manufactured papers. The accuracy of prediction improves when the covariance is modelled in a reduced measurement space selected by a data-driven, feature-selection technique referred to as a Template Oriented Genetic Algorithm (TOGA). TOGA, combined with discrete wavelet transform (DWT), isolates functional-group features that correlate best with mechanical properties paper derived from refined pulp. Paper makers refine market pulps to build sheet strength using a beating process that decreases freeness as it increases fibre-fibre bonding. Methods demonstrated here predict manufactured sheet properties obtainable after any specified degree of refining from the Raman spectrum of an unrefined pulp. This analysis capacity will enable both vendors of market pulp and makers of sheet paper to specify in advance the amount of beating required to produce a desired product, thereby saving cost and conserving resources.

Paper-based microfluidic devices are popular for their ability to automate multistep assays for chemical or biological sensing at a low cost, but the design of paper microfluidic networks has largely relied on experimental trial and error. A few mathematical models of flow through paper microfluidic devices have been developed and have succeeded in explaining experimental flow behavior. However, the reverse engineering problem of designing complex paper networks guided by appropriate mathematical models is largely unsolved. In this article, we demonstrate that a two-dimensional paper network (2DPN) designed to sequentially deliver three fluids to a test zone on the device can be computationally designed and experimentally implemented without experimental trial and error. This was accomplished by three new developments in modeling flow through paper networks: (i) coupling of the Richards equation of flow through porous media to the species transport equation, (ii) modeling flow through assemblies of multiple paper materials (test membrane and wicking pad), and (iii) incorporating limited-volume fluid sources. We demonstrate the application of this model in the optimal design of a paper-based signal-enhanced immunoassay for a malaria protein, PfHRP2. This work lays the foundation for the development of a computational design toolbox to aid in the design of paper microfluidic networks. ©

The growing need for reliable analytical tools to perform measurements at the point-of-need has prompted the development of novel sensors that are low cost, portable, sensitive, easy to use, and capable of multiplexed analysis. Miniaturization of the sensors into microfluidic platforms has become a promising approach to achieve these self-contained sensors. However, traditional microfluidics often require relatively expensive and complicated pumping mechanisms that increase the cost and limit the portability of the sensors. From a material perspective, paper is an attractive substrate for constructing point-of-need sensors because of its affordability, vast availability, and self-pumping ability, particularly when combined with electrochemical detection. In this mini-review, we discuss various strategies to achieve multiplexing or simultaneous detection of multiple analytes in electrochemical paper-based devices and provide a brief guide on selecting the detection strategy based on the electrochemical property of the analytes.

Development of paper-based microfluidic devices that perform colorimetric measurements requires quantitative image analysis. Because the design geometries of paper-based microfluidic devices are not standardized, conventional methods for performing batch measurements of regularly spaced areas of signal intensity, such as those for well plates, cannot be used to quantify signal from most of these devices. To streamline the device development process, we have developed an open-source program called ColorScan that can automatically recognize and measure signal-containing zones from images of devices, regardless of output zone geometry or spatial arrangement. This program, which measures color intensity with the same accuracy as standard manual approaches, can rapidly process scanned device images, simultaneously measure identified output zones, and effectively manage measurement results to eliminate requirements for time-consuming and user-dependent image processing procedures.

Microfluidic paper-based analytical devices (μPADs) allow user-friendly and portable chemical determinations, although they provide limited applicability due to insufficient sensitivity. Several approaches have been proposed to address poor sensitivity in μPADs, but they frequently require bulky equipment for power and/or read-outs. Universal serial buses (USB) are an attractive alternative to less portable power sources and are currently available in many common electronic devices. Here, USB-powered μPADs (USB μPADs) are proposed as a fusion of both technologies to improve performance without adding instrumental complexity. Two ITP USB μPADs were developed, both powered by a 5 V potential provided through standard USB ports. The first device was fabricated using the origami approach. Its operation was analyzed experimentally and numerically, yielding a two-order-of-magnitude sample focusing in 15 min. The second ITP USB μPAD is a novel design, which was numerically prototyped with the aim of handling larger sample volumes. The reservoirs were moved away from the ITP channel and capillary action was used to drive the sample and electrolytes to the separation zone, predicting 25-fold sample focusing in 10 min. USB μPADs are expected to be adopted by minimally-trained personnel in sensitive areas like resource-limited settings, the point-of-care and in emergencies. Fil: Schaumburg, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; Argentina Fil: Kler, Pablo Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Centro de Investigaciones en Métodos Computacionales. Universidad Nacional del Litoral. Centro de Investigaciones en Métodos Computacionales; Argentina Fil: Carrell, Cody S.. State University of Colorado - Fort Collins; Estados Unidos Fil: Berli, Claudio Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Desarrollo Tecnológico para la Industria Química. Universidad Nacional del Litoral. Instituto de Desarrollo Tecnológico para la Industria Química; Argentina Fil: Henry, Charles S.. State University of Colorado - Fort Collins; Estados Unidos

This paper presents the design and analysis of a paper-based chipless RFID sensor for wetness content measurement in plant leaves. The sensor is designed using a passive microwave resonator to measure the ambient physical parameter. The resonator is designed with a rectangular loop inductively coupled with an interdigital capacitor. The experimental analysis of the designed sensor is illustrated here to prove its efficacy. The resonator provides adequate backscattered signal for wireless measurement in the microwave frequency band. When interrogated with a couple of UWB antennas and a VNA, it yields accurate leaf wetness response of the plant. The commercial competence of this sensing device is validated through its experimental analysis on three different types of leaf samples. This sensor is suitable for plant health monitoring in any small-scale gardening applications such as nurseries and greenhouses.

Recently, portable sensing devices with point of care testing (POCT) capability have attracted great attention due to their inherent affordability and accessibility in low resource areas. Paper sensors possess excellent potential as POCT platforms because of low cost, ease of operation, disposability and high-volume manufacturing. Paper sensors that incorporate functional nucleic acids (FNAs) as recognition elements are particularly attractive given that FNAs can be isolated from random-sequence nucleic acid pools to recognize, or respond to, virtually any target of interest. In this review, the advantages of FNAs, particularly DNA aptamers and DNAzymes, as recognition elements for the design of paper sensors are first discussed. This is followed by reviewing three specific types of FNA based paper sensors: dot blots, lateral flow assays, and microfluidic paper-based analytical devices. Furthermore, advances in the signal reporting methods used by FNA based paper sensors are summarized. Finally, limitations of current FNA based paper sensors are discussed along with considerations of future research directions.

Detection of biomarkers is essential for diagnosis and prognosis of diseases for healthcare teams to provide timely appropriate treatments. Reliable, inexpensive, and sensitive devices are desirable to serve this purpose. Paper-based analytical devices (PADs) have gained enormous attention during the past decade as point-of-care devices for biomarker detection due to their simplicity, portability, and biocompatibility. Importantly, the devices highly comply with the WHO "ASSURED" concept (i.e. Affordable, Sensitive, Specific, User-friendly, Rapid and Robust, Equipment free, and Deliverable to end-users). Thus, PADs could be sustainably alternative tools for biomarker detection, especially in resources-constraint areas where budget, skillful operators, and health infrastructure are limited. First, this review introduces overviews of biomarkers, their detection and brief history of PADs. Second, description of common fabrication and detection techniques in PADs are provided. Then, it highlights recent state of the art technologies and applications of PADs for various biomarker detection published during 2018 to May 2019. Applications for tumor marker, cardiac and coronary heath disease, and metabolic disorder biomarker detection are tabulated and selected examples are described in details. Finally, it discusses the current challenges, advances, and novel applications of PADs. The review would be valuable for healthcare workers using PADs as cost-effective point-of-care devices for biomarker detection and for researchers working on future developments of the devices.

In recent years, microfluidic lab-on-paper devices have emerged as a rapid and low-cost alternative to traditional laboratory tests. Additionally, they were widely considered as a promising solution for point-of-care testing (POCT) at home or regions that lack medical infrastructure and resources. This review describes important advances in microfluidic lab-on-paper diagnostics for human health monitoring and disease diagnosis over the past five years. The review commenced by explaining the choice of paper, fabrication methods, and detection techniques to realize microfluidic lab-on-paper devices. Then, the sample pretreatment procedure used to improve the detection performance of lab-on-paper devices was introduced. Furthermore, an in-depth review of lab-on-paper devices for disease measurement based on an analysis of urine samples was presented. The review concludes with the potential challenges that the future development of commercial microfluidic lab-on-paper platforms for human disease detection would face.

The development of diagnostic tools for measuring a wide spectrum of target analytes, from biomarkers to other biochemical parameters in biological fluids, has experienced a significant growth in the last decades, with a good number of such tools entering the market. Recently, a clear focus has been put on miniaturized wearable devices, which offer powerful capabilities for real-time and continuous analysis of biofluids, mainly sweat, and can be used in athletics, consumer wellness, military, and healthcare applications. Sweat is an attractive biofluid in which different biomarkers could be noninvasively measured to provide rapid information about the physical state of an individual. Wearable devices reported so far often provide discrete (single) measurements of the target analytes, most of them in the form of a yes/no qualitative response. However, quantitative biomarker analysis over certain periods of time is highly demanded for many applications such as the practice of sports or the precise control of the patient status in hospital settings. For this, a feasible combination of fluidic elements and sensor architectures has been sought. In this regard, this paper shows a concise overview of analytical tools based on the use of capillary-driven fluidics taking place on paper or fabric devices integrated with solid-state sensors fabricated by thick film technologies. The main advantages and limitations of the current technologies are pointed out together with the progress towards the development of functional devices. Those approaches reported in the last decade are examined in detail.

The wide spread of smartphones and QR codes for various end-user applications has had an impact beyond traditional fields of use, recently also reaching point-of-care testing (POCT). This work presents the integration of QR code recognition into paper-based analytical devices (PADs) with "distance-based" colorimetric signalling, resulting in semiquantitative readout fully relying on straightforward barcode reader solutions. PADs consist of an array of QR codes arranged in series inside a paperfluidic channel. A mask dye concept has been developed, which enables utilisation of colour changing indicators by initially hiding QR codes. The colour change of the indicator induced by the presence of an analyte of interest results in gradual unmasking of QR codes, which become recognisable by the smartphone barcode reader app. To reproducibly fabricate devices, all fabrication steps were performed by commercial desktop solid ink and inkjet printing. The QR code masking function was optimised by controlling the amount of printed mask dye through adjusting the opacity of printing patterns during the inkjet deposition process. For proof-of-concept, a model assay in the form of colorimetric copper ion (Cu2+) detection in the concentration range of 0.4 mM to 3.2 mM was evaluated. Consistent results independent of the smartphone model and environmental light condition were achieved with a free barcode reader app. To the best of our knowledge, this work is the first demonstration of a semiquantitative assay approach fully relying on QR code readout without digital colour analysis, customised app or hardware modification.

Since the introduction of paper-based analytical devices as potential diagnostic platforms a few decades ago, huge efforts have been made in this field to develop systems suitable for meeting the requirements for the point-of-care (POC) approach. Considerable progress has been achieved in the adaptation of existing analysis methods to a paper-based format, especially considering the chemiluminescent (CL)-immunoassays-based techniques. The implementation of biospecific assays with CL detection and paper-based technology represents an ideal solution for the development of portable analytical devices for on-site applications, since the peculiarities of these features create a unique combination for fitting the POC purposes. Despite this, the scientific production is not paralleled by the diffusion of such devices into everyday life. This review aims to highlight the open issues that are responsible for this discrepancy and to find the aspects that require a focused and targeted research to make these methods really applicable in routine analysis.

This paper presents a new approach towards the design of paper based autonomous microfluidic devices. Autonomy in the device operation is achieved through the incorporation of mechanically actuated microfluidic switches that are versatile in their design and may be configured to be simple time triggered ON or OFF switches or more complex switches that can be timed to be in multiple states (timed ON, followed by timed OFF). These switches are self-contained and require no external power for their operation, deriving their functionality solely through stored elastic energy. This paper presents the design and fabrication of these switches as fluidic analogs of electronic transistors, and their integration into microfluidic paper based circuit demonstrating their operation as a programmable paper-based microfluidic device.

Analytical strategies to ensure the quality and safety of food products without the need for skilled personnel are highly required. The simplicity of glucose strips for diabetes monitoring should be translated to the agri-food sector, ensuring easy evaluation of certain molecules and/or the freshness of a beverage/foodstuff. In addition to the well-known advantages that are characteristic of electroanalytical methods over other methods, paper-based materials are being used to further reduce the gap between complex laboratory testing and simple point-of-need testing. This article highlights some of the most recent advances in the development of paper-based electrochemical approaches for food surveillance, specifically focusing on the use of novel paper-based materials. Two examples are discussed: the development of a miniaturized biosensor realized on copy paper for the quantification of ethanol in commercial beers, and the measurement of ascorbic acid in food supplements within printed electronics supports. Paper-based materials have the potential to lower economic costs, simplify the operative tasks, and most importantly reduce waste generation. The continued combination of manufacturing methods and functional (smart) materials will facilitate the implementation of food analysis at the point of need.

Significance Populations living in remote rural communities would benefit from rapid, highly sensitive molecular, DNA-based diagnostics to inform the correct and timely treatment of infectious diseases. Such information is also becoming increasingly relevant in global efforts for disease elimination, where the testing of asymptomatic patients is now seen as being important for the identification of disease reservoirs. However, healthcare workers face practical and logistical problems in the implementation of such tests, which often involve complex instrumentation and centralized laboratories. Here we describe innovations in paper microfluidics that enable low-cost, multiplexed DNA-based diagnostics for malaria, delivered, in a first-in-human study, in schools in rural Uganda., Rapid, low-cost, species-specific diagnosis, based upon DNA testing, is becoming important in the treatment of patients with infectious diseases. Here, we demonstrate an innovation that uses origami to enable multiplexed, sensitive assays that rival polymerase chain reactions (PCR) laboratory assays and provide high-quality, fast precision diagnostics for malaria. The paper-based microfluidic technology proposed here combines vertical flow sample-processing steps, including paper folding for whole-blood sample preparation, with an isothermal amplification and a lateral flow detection, incorporating a simple visualization system. Studies were performed in village schools in Uganda with individual diagnoses being completed in

The combination of smartphone technology and colorimetric paper-based microfluidics can enable simple, inexpensive diagnostics. However, imaging colorimetric diagnostic results via smartphones currently requires accessories to mitigate the influence of variability in surrounding lighting conditions. Here, we present an accessory-free smartphone-based colorimetric imaging method that enlists the built-in LED light source to dominate ambient lighting in combination with background and colour rescaling. This simple approach enables quantitative measurements from paper-based tests by compensating for different environmental lighting conditions and is universally applicable with respect to phone models and manufacturers. We demonstrate the method with three dominant phone makes and models in a cell counting application with a paper-based yeast detection device. The detection results are in good agreement with cell counting using automated cell counters. Eliminating the need for make/model specific accessories, this approach helps realize the potential for low-cost, broadly applicable paper-based diagnostics.

A new tool for the solution of electromigrative separations in paper-based microfluidics devices is presented. The implementation is based on a recently published complete mathematical model for describing these types of separations, and was developed on top of the open-source toolbox electroMicroTransport, based on OpenFOAM® , inheriting all its features as native 3D problem handling, support for parallel computation, and a GNU GPL license . The presented tool includes full support for paper-based electromigrative separations (including EOF and the novel mechanical and electrical dispersion effects), compatibility with a well-recognized electrolyte database, and a novel algorithm for computing and controlling the electric current in arbitrary geometries. Additionally, the installation on any operating system is available due to its novel installation option in the form of a Docker image. A validation example with data from literature is included, and two extra application examples are provided, including a 2D free-flow IEF problem, which demonstrates the capabilities of the toolbox for dealing with computational and physicochemical modeling challenges simultaneously. This tool will enable efficient and reliable numerical prototypes of paper-based electrophoretic devices to accompany the contemporary fast growth in paper-based microfluidics.

This work reports on fully integrated “sample‐in‐signal‐out” microfluidic paper‐based analytical devices (μPADs) relying on bioluminescence resonance energy transfer (BRET) switches for analyte recognition and colorimetric signal generation. The devices use BRET‐based antibody sensing proteins integrated into vertically assembled layers of functionalized paper, and their design enables sample volume‐independent and fully reagent‐free operation, including on‐device blood plasma separation. User operation is limited to the application of a single drop (20–30 μL) of sample (serum, whole blood) and the acquisition of a photograph 20 min after sample introduction, with no requirement for precise pipetting, liquid handling, or analytical equipment except for a camera. Simultaneous detection of three different antibodies (anti‐HIV1, anti‐HA, and anti‐DEN1) in whole blood was achieved. Given its simplicity, this type of device is ideally suited for user‐friendly point‐of‐care testing in low‐resource environments.

Functional papers are the subject of extensive research efforts and have already become an irreplaceable part of our modern society. Among other issues, they enable fast and inexpensive detection of a plethora of analytes and simplify laboratory work, for example in medical tests. This article focuses on the molecular and structural fundamentals of paper and the possibilities of functionalization, commercially available assays and their production, as well as on current and future challenges in research in this field. Graphic abstract

Paper-based devices have a wide range of applications in point-of-care diagnostics, environmental analysis, and food monitoring. Paper-based devices can be deployed to resource-limited countries and remote settings in developed countries. Paper-based point-of-care devices can provide access to diagnostic assays without significant user training to perform the tests accurately and timely. The market penetration of paper-based assays requires decreased device fabrication costs, including larger packing density of assays (i.e., closely packed features) and minimization of assay reagents. In this review, we discuss fabrication methods that allow for increasing packing density and generating closely packed features in paper-based devices. To ensure that the paper-based device is low-cost, advanced fabrication methods have been developed for the mass production of closely packed assays. These emerging methods will enable minimizing the volume of required samples (e.g., liquid biopsies) and reagents in paper-based microfluidic devices.

Development of wearable devices for in situ monitoring biological analytes in sweat has been fueled up in the past few years. Although microfluidic thread/paper-based analytical device (μTPAD) fulfills the requirements of wearable systems on flexibility and biocompatibility, it has not been employed as a sensing system for the in situ sweat analysis. In this work, we developed a wearable μTPAD containing a cotton thread and a functionalized filter paper for non-invasive, quantitative and in situ monitoring of human sweat glucose with the assistance of a smartphone. The oxygen plasma was applied to tailor the wicking property of the cotton thread. Amounts of enzymes and reagents on the filter papers were optimized to achieve the high-performance colorimetric sensing of glucose. The as-prepared device possesses a dynamic range of 50–250 μΜ and a detection limit of ~ 35 μΜ. Because of its great wearability and compatibility with conventional textile industry, the μTPAD was integrated with an arm guard to sensitively detect glucose in human sweat. This work may provide a low-cost, easy to use wearable device based on the cotton thread and filter paper for human sweat analysis.

In this study, we designed a rapid colorimetric sensing system using competitive ELISA test on a microfluidic paper-based analytical device for the detection of ketamine, a frequently abused drug. Oral fluid was selected for the test to facilitate the collection of samples based on its advantages of low infection risk, noninvasiveness of sample collection, and decreased chance of sample adulteration. After optimization of the operation parameters, including reaction temperature, vibration washing time, reaction time, and antibody concentration, the resulting assay can be completed in as little as 6 min with a detection limit of 0.03 ng/mL. Moreover, we developed an Android smartphone app to analyze and measure the results of the test, further enhancing the test’s portability, and image recording and data transmission capabilities. In order to test the feasibility and performance of the optimized colorimetric assay, 90 oral fluid samples from drug abuse patients were tested. The paper-based platform features 90% sensitivity (confidence interval (CI): 76.34–97.21%) and 92% specificity (CI: 80.77–97.78%) for ketamine analysis. This competitive paper-based ELISA sensing system provides a rapid, convenient, sensitive, and high-throughput approach for drug monitoring.

Paper-based microfluidics is a rapidly developing field with applications for point-of-care disease and environmental diagnostics. In parallel, printed electronics has grown swiftly, particularly for wearable technologies. By combining these fields, fluidic sample processing and control, as well as automated sensing and readout can be integrated on a single device. Towards this goal, this work highlights the design, manufacture, and testing of paper-based electrochemical sensors, with focus on photo paper and chromatography paper substrates. These substrates are typically used for printed electronics and paper-based fluidics, respectively. The electrochemical sensors were screen printed using manual techniques. For chromatography paper sensors, wax-printed fluidic barriers were used to illustrate the potential integration of the sensors with typical paper-based microfluidic device formats. As an initial example, the detection of heavy metals (Cd(II) and Pb(II)) in buffer solution was demonstrated. Commercial DropSens sensors were used as reference with the limit of detection (LOD) of Cd(II) and Pb(II) on chromatography sensors showing comparable results to commercial DropSens sensors. It is worth noting that the chromatography paper sensors showed a higher repeatability than the commercial DropSens sensors. Tap water samples spiked with Cd(II) and Pb(II) were also tested and showed promising results. Future work will include sensor optimization and exploration of scale-up to provide low-cost solutions for effective point-of-need diagnostics—ranging from environmental monitoring to healthcare applications.

Paper-based electrochemical sensors (PESs) have been evidenced as analytical strategies for employing simple, low-cost, portable and disposable sensing platforms that can be used in many application areas. Recently, PESs have gained extensive attention because of their advantages of advanced sensitivity and selectivity during detection provided by electrochemistry, compared with microfluidic paper-based analytical devices (μPADs) that still lack these advantages. Also, it can be expected that PESs can better meet current user demands, making them a stand-out analytical tool because of their capability for multiple analyte detection and their compatibility in a variety of application areas, like clinical diagnosis, environmental monitoring and food quality control. Herein, in this mini review, we present an overview of recent developments in PESs over the last decade, focusing on existing fabrication techniques and application areas, specifically in relation to clinical diagnostics, food quality control and environmental monitoring, where simple and portable analytical devices are greatly needed. A summary and future outlooks for PESs are also discussed.

Point-of-care diagnostic tests can provide rapid and accurate information about the health of a patient without relying on the expensive equipment found in centralized laboratories. Not only does the development and application of these assays rely on the means of signal transduction, but also the method by which a sample is procured. In order for point-of-care tests to have real clinical utility, they must use sample types and volumes that are relatively easy to obtain (e.g., fingerstick volumes of blood). In this paper, we demonstrate how the design of a paper-based microfluidic device controls the transport of blood within the device and ultimately influences the development of an assay to measure the hematocrit. We show that, with directed design modifications, altering the dimensions of paper-based devices can greatly reduce the volume of blood required to initiate a hematocrit assay (from 50 μL to only 10 μL) without impacting its analytical performance.

The early diagnosis of Alzheimer’s disease (AD) remains a challenge for medical scientists worldwide, leading to a number of research efforts that focus on biosensor development for AD biomarkers. However, the application of these complicated biosensors is limited in medical diagnosis, due to the difficulties in robust sensing platform development, high costs, and the necessity for technical professionals. We successfully developed a robust straightforward manufacturing process for the fabrication of multi-chamber paper devices using the wax printing method and exploited it to detect amyloid beta 42 oligomers (AβO42, a significant biomarker of AD) using copper-enhanced gold nanoprobe colorimetric immunoblotting. Small hydrophilic reaction chambers could concentrate the target sample to the desired size to improve the sensing performance. The copper-enhanced gold nanoprobe immunoblot using the designed multi-chamber platform exhibited a highly sensitive performance with a limit of detection of 320 pg/mL by the naked eye and 23.7 pg/mL by a smartphone camera. This process from sensing manufacture to sensing conduction is simple to perform whenever medical technicians require time- and cost-savings, without complicated instruments or the need for technical professionals, making it feasible to serve as a diagnostic tool worldwide for the early monitoring of AD and scalable devices for the sensing application of various biomarkers in clinical settings.

Pressure sensor, as one of the most common components in the sensing systems, has attracted plenty of attention in recent years with urgent needs. Herein, a highly sensitive flexible pressure sensor based on conducting polymer (CP)-coated paper is developed via an ultra-simple approach of synthesis and fabrication. This paper-based sensor displays an ultra-low detection limit as low as 0.3 Pa level, and outstanding sensitivity (∼2 kPa−1, P ≤ 75 Pa), which can rank the top among that of the reported pressure sensors. The advantages based on paper framework such as low cost, portability, and easy disposability further enhance its feasibility. Meanwhile, combining its rapid and precise response at room temperature and the recognized stability of PPy in the ambient environment, the sensor would ensure direct and continuous environment monitoring with low energy consumption.

The growing socio-economic burden of chronic skin wounds requires the development of new automated and non-invasive analytical systems capable of wirelessly monitoring wound status. This work describes the low-cost fabrication of single-use, omniphobic paper-based smart bandages (OPSBs) designed to monitor the status of open chronic wounds and to detect the formation of pressure ulcers. OPSBs are lightweight, flexible, breathable, easy to apply, and disposable by burning. A reusable wearable potentiostat was fabricated to interface with the OPSB simply by attaching it to the back of the bandage. The wearable potentiostat and the OPSB can be used to simultaneously quantify pH and uric acid levels at the wound site, and wirelessly report wound status to the user or medical personnel. Additionally, the wearable potentiostat and the OPSBs can be used to detect, in an in-vivo mouse model, the formation of pressure ulcers even before the pressure-induced tissue damage becomes visible, using impedance spectroscopy. Our results demonstrate the feasibility of using inexpensive single-use OPSBs and a reusable, wearable potentiostat that can be easily sterilized and attached to a new OPSB during the dressing change, to provide long term wound progression data to guide treatment decisions.

The main problem for the expansion of the use of microfluidic paper-based analytical devices and, thus, their mass production is their inherent lack of fluid flow control due to its uncontrolled fabrication protocols. To address this issue, the first step is the generation of uniform and reliable microfluidic channels. The most common paper microfluidic fabrication method is wax printing, which consists of two parts, printing and heating, where heating is a critical step for the fabrication of reproducible device dimensions. In order to bring paper-based devices to success, it is essential to optimize the fabrication process in order to always get a reproducible device. Therefore, the optimization of the heating process and the analysis of the parameters that could affect the final dimensions of the device, such as its shape, the width of the wax barrier and the internal area of the device, were performed. Moreover, we present a method to predict reproducible devices with controlled working areas in a simple manner. The authors would like to acknowledge funding support from Gobierno de España, Ministerio de Economía y Competitividad, with Grant No. BIO2016-80417-P (AEI/FEDER, UE), the Gobierno Vasco Dpto. Educación for the consolidation of the research groups (IT1271-19) and from Proyectos Colaborativos from the University of the Basque Country UPV/EHU, BIOPLASMOF (COLAB19/05). This project received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 778001.

Foodborne pathogens are responsible for hundreds of thousands of deaths around the world each year. Rapid screening of agricultural products for these pathogens is essential to reduce and/or prevent outbreaks and pinpoint contamination sources. Unfortunately, current detection methods are laborious, expensive, time-consuming and require a central laboratory. Therefore, a rapid, sensitive, and field-deployable pathogen-detection assay is needed. We previously developed a colorimetric sandwich immunoassay utilizing immuno-magnetic separation (IMS) and chlorophenol red-β-D-galactopyranoside for Salmonella detection on a paper-based analytical device (μPAD); however, the assay required many sample preparation steps prior to the μPAD as well as laboratory equipment, which decreased user-friendliness for future end-users. As a step towards overcoming these limitations in resource-limited settings, we demonstrate a reusable 3D-printed rotational manifold that couples with disposable μPAD layers for semi-automated reagent delivery, washing, and detection in 65 minutes. After IMS to clean the sample, the manifold performs pipette-free reagent delivery and washing steps in a sequential order with controlled volumes, followed by enzymatic amplification and colorimetric detection using automated image processing to quantify color change. Salmonella was used as the target pathogen in this project and was detected with the manifold in growth media and milk with detection limits of 4.4 × 102 and 6.4 × 102 CFU mL−1 respectively. The manifold increases user friendliness and simplifies immunoassays resulting in a practical product for in-field use and commercialization.

This review reports on recent advances in state-of-the-art detection methods for microfluidic paper-based analytical devices (μPADs). The review commences by describing the materials, fabrication methods and driving mechanisms employed in μPADs. The review then explores the main detection methods and applications of μPADs proposed over the past five years. The discussions focus on seven detection technologies, namely (1) colorimetric detection, (2) fluorescent detection, (3) electrochemical detection and photoelectrochemical detection, (4) chemiluminescent detection, (5) electrochemiluminescent detection, (6) nanoparticle-based detection, and (7) spectrometry detection. Overall, the review provides a useful insight into recent advances in the μPAD detection field and serves as a useful source of reference for further research and innovation in the field.

A Non-Orthogonal Unicast and Multicast (NOUM) transmission system allows a multicast stream intended to all receivers to be jointly transmitted with unicast streams in the same time-frequency resource blocks. While the capacity of the two-user multi-antenna NOUM with perfect Channel State Information at the Transmitter (CSIT) is known and achieved by Dirty Paper Coding (DPC)-assisted NOUM with Superposition Coding (SC), the capacity and the capacity-achieving strategy of the multi-antenna NOUM with partial CSIT remain unknown. In this work, we focus on the partial CSIT setting and make two major contributions. First, we show that linearly precoded Rate-Splitting (RS), relying on splitting unicast messages into common and private parts, encoding the common parts together with the multicast message and linearly precoding at the transmitter, can achieve larger rate regions than DPC-assisted NOUM with partial CSIT. Second, we study Dirty Paper Coded Rate-Splitting (DPCRS), that marries RS and DPC. We show that the rate region of DPCRS-assisted NOUM is enlarged beyond that of conventional DPC-assisted NOUM and that of linearly precoded RS-assisted NOUM with partial CSIT., 6 pages, 3 figures, accepted by 54th Annual Asilomar Conference on Signals, Systems, and Computers

For in-situ disease markers detection, point-of-care (POC) diagnosis has great advantages in speed and cost compared with traditional techniques. The rapid diagnosis, prognosis, and surveillance of diseases can significantly reduce disease-related mortality and trauma. Therefore, increasing attention has been paid to the POC diagnosis devices due to their excellent diagnosis speed and portability. Over the past ten years, paper-based microfluidic aptasensors have emerged as a class of critical POC diagnosis devices and various aptasensors have been proposed to detect various disease markers. However, most aptasensors need further improvement before they can actually enter the market and be widely used. There is thus an urgent need to sort out the key points of preparing the aptasensors and the direction that needs to be invested in. This review summarizes the representative articles in the development of paper-based microfluidic aptasensors. These works can be divided into paper-based optical aptasensors and paper-based electrochemical aptasensors according to their output signals. Significant focus is applied to these works according to the following three parts: (1) The ingenious design of device structure; (2) Application and synthesis of nanomaterial; (3) The detection principle of the proposed aptasensor. This is a detailed and comprehensive review of paper-based microfluidic aptasensors. The accomplishments and shortcomings of the current aptasensors are outlined, the development direction and the future prospective are given. It is hoped that the research in this review can provide a reference for further development of more advanced, more effective paper-based microfluidic aptasensors for POC disease markers diagnosis.

Fibrinogen (FIB) plays a key role in blood coagulation and thrombosis and its concentration in blood can directly reflect health conditions, thus efficient detection of FIB would benefit the treatments of certain diseases such as liver and heart diseases. However, there is a lack of sensitive, simple, rapid and cheap FIB detection device currently, in lieu of expensive and sophisticated approaches in laboratories. Here, we propose a novel plasma separation and FIB detection platform based on a microfluidic paper-based analytical device (μPAD). It is the first time that dielectrophoretic (DEP) force is combined with capillary force on paper for plasma separation, and the separation efficiency of plasma reaches about 95%, ensuring reliable downstream FIB detection, for which we also propose a new method called the resistance-fibrinogen detection (RFD) method. It not only avoids the use of large-scale instruments for detection, but also possesses high precision and simplicity. The method is found to be reliable in FIB detection for various concentrations ranging from 127.0 to 508.0 mg dL-1. Moreover, the results obtained from the proposed μPAD show an excellent agreement (R2 = 0.9985) with those obtained from an automatic coagulation analyzer with natural human blood samples. Overall, the proposed platform provides a low-cost and reliable approach for FIB detection, especially for clinical use in resource-limited areas.

Applications of electrochemical detection methods in microfluidic paper-based analytical devices (μPADs) has revolutionized the area of point-of-care (POC) testing towards highly sensitive and selective quantification of various (bio)chemical analytes in a miniaturized, low-coat, rapid, and user-friendly manner. Shortly after the initiation, these relatively new modulations of μPADs, named as electrochemical paper-based analytical devices (ePADs), gained widespread popularity within the POC research community thanks to the inherent advantages of both electrochemical sensing and usage of paper as a suitable substrate for POC testing platforms. Even though general aspects of ePADs such as applications and fabrication techniques, have already been reviewed multiple times in the literature, herein, we intend to provide a critical engineering insight into the area of ePADs by focusing particularly on the practical strategies utilized to enhance their analytical performance (i.e. sensitivity), while maintaining the desired simplicity and efficiency intact. Basically, the discussed strategies are driven by considering the parameters potentially affecting the generated electrochemical signal in the ePADs. Some of these parameters include the type of filter paper, electrode fabrication methods, electrode materials, fluid flow patterns, etc. Besides, the limitations and challenges associated with the development of ePADs are discussed, and further insights and directions for future research in this field are proposed.

Escherichia coli O157:H7 is a severe foodborne pathogen that causes lots of life-threatening diseases. In the search for a rapid, sensitive, portable and low-cost method to detect this pathogen, we developed a wax-printed paper-based enzyme-linked immunosorbent assay (P-ELISA) based on microfluidic paper-based analytical devices (μPADs), with the whole operation time being less than 3 h and only needing 5 μl samples for detection. The limit of detection (LOD) of E. coli O157:H7 reached 104 CFU ml-1, which is an order of magnitude higher than that of conventional ELISA (C-ELISA). The LOD in artificially contaminated beef samples is 1 CFU per 25 g after enriching the culture for 8 h. This method is superior to the molecular biology method in detection sensitivity and superior to C-ELISA and the national standard method in detection time and cost. Thus, the established P-ELISA method has good sensitivity, specificity and repeatability. It can be suitable for point-of-care testing without expensive and bulky instruments and can also provide a platform for detecting other pathogens, especially in areas that lack advanced clinical equipment.

Although the established ELISA-based sensing platforms have many benefits, the importance of cytokine and cancer biomarkers detection for point-of-care diagnostics has propelled the search for more specific, sensitive, simple, accessible, yet economical sensor. Paper-based biosensor holds promise for future in-situ applications and can provide rapid analysis and data without the need to conduct in a laboratory. Electrochemical detection plays a vital role in interpreting results obtained from qualitative assessment to quantitative determination. In this review, various factors affecting the design of an electrochemical paper-based biosensor are highlighted and discussed in depth. Different detection methods, along with the latest development in utilizing them in cytokine and cancer biomarkers detection, are reviewed. Lastly, the fabrication of portable electrochemical paper-based biosensor is ideal in deliberating positive societal implications in developing countries with limited resources and accessibility to healthcare services. Ministry of Education (MOE) Published version The authors would like to acknowledge the financial support for this work funded by Singapore Ministry of Education Academic Research Fund Tier 1 (MOE-2018-T1-001-004).

Non-invasive diagnosis on biological liquid samples, such as urine, sweat, saliva, and tears, may allow patients to evaluate their health by themselves. To obtain accurate diagnostic results, target liquid must be precisely sampled. Conventionally, urine sampling using filter paper can be given as an example sampling, but differences in the paper structure can cause variations in sampling volume. This paper describes precise liquid sampling using synthetic microfluidic papers, which are composed of obliquely combined micropillars. Sampling volume accuracy was investigated using different designs and collection methods to determine the optimal design and sample collecting method. The optimized protocol was followed to accurately measure potassium concentration using synthetic microfluidic paper and a commercially available densitometer, which verified the usefulness of the synthetic microfluidic papers for precision sampling.

A novel strategy for fabricating the paper-based valves on microfluidic paper-based analytical devices (μPADs) was described to control fluid in a user-friendly way. Initial prototypes of 3D μPADs manipulate the spatial distribution of fluid within the device. The movable paper channel in a different layer could be achieved using the channel's connection or disconnection to realize the valve function using plastic comb binding spines (PCBS). The entire valve manipulation process was similar to a desk calendar that can be flipped over and turned back. It is notable that this kind of PCBS valve can control a fluid in a simple and easy way without the timing setting or any trigger, and this advantage makes it user-friendly for untrained users to carry out the complex and high throughput operations. The reusable plastic comb binding spines greatly reduce the cost of fabricating paper-based valves. To evaluate the performance, the actual samples of Fe (II) and nitrite were successfully analyzed. We hope this method will introduce a new approach to fabrication of paper-based valves on μPADs in the future.

Paper-based sensors offer an affordable yet powerful platform for field and point-of-care (POC) testing due to their self-pumping ability and utility for many different analytical measurements. When combined with electrochemical detection using small and portable electronics, sensitivity and selectivity of the paper devices can be improved over naked eye detection without sacrificing portability. Herein, we review how the field of electrochemical paper-based analytical devices (ePADs) has grown since it was introduced a decade ago. We start by reviewing fabrication methods relevant to ePADs with more focus given to the electrode fabrication, which is fundamental for electrochemical sensing. Multiple sensing approaches applicable to ePADs are then discussed and evaluated to present applicability, advantages and challenges associated with each approach. Recent applications of ePADs in the fields of clinical diagnostics, environmental testing, and food analysis are also presented. Finally, we discuss how the current ePAD technologies have progressed to meet the analytical and practical specifications required for field and/or POC applications, as well as challenges and outlook.