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Quantifying the formation and decomposition of amyloid is a crucial issue in the development of new drugs and therapies for treating amyloidosis. The current technologies for grasping amyloid formation and decomposition include fluorescence analysis using thioflavin-T, secondary structure analysis using circular dichroism, and image analysis using atomic force microscopy or transmission electron microscopy. These technologies typically require spectroscopic devices or expensive nanoscale imaging equipment and involve lengthy analysis, which limits the rapid screening of amyloid-degrading drugs. In this study, we introduce a technology for rapidly assessing amyloid decomposition using capillary flow-based paper (CFP). Amyloid solutions exhibit gel-like physical properties due to insoluble denatured polymers, resulting in a shorter flow distance on CFP compared to pure water. Experimental conditions were established to consistently control the flow distance based on a hen-egg-white lysozyme amyloid solution. It was confirmed that as amyloid is decomposed by trypsin, the flow distance increases on the CFP. Our method is highly useful for detecting changes in the gel properties of amyloid solutions within a minute, and we anticipate its use in the rapid, large-scale screening of anti-amyloid agents in the future.

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Herein, a flexible near-infrared (NIR) light-actuated photoelectrochemical (PEC) lab-on-paper device was constructed toward miRNA-122 detection, utilizing the combination of DNA-programmed NaYF4/Yb,Tm upconversion nanoparticles (UCNPs) and the Z-scheme AgI/WO3 heterojunction grown in situ on gold nanoparticle-decorated 3D cellulose fibers. The UCNPs were employed as light transducers for converting NIR light into ultraviolet/visible (UV/vis) light to excite the nanojunction. The multiple diffraction of NaYF4/Yb,Tm matched the absorption band of the Z-scheme AgI/WO3 heterojunction, resulting in enhanced PEC photocurrent output. This prepared Z-scheme heterojunction effectively directed charge migration and highly facilitated the electron-hole pair separation. Target miRNA-122 activated the nonenzyme catalytic hairpin assembly signal amplification strategy, generating duplexes which caused the exfoliation of NaYF4/Yb,Tm UCNPs from the biosensor electrode and lowered the photocurrent under 980 nm irradiation. Under optimized circumstances, the proposed NIR-actuated PEC lab-on-paper device presented accurate miRNA-122 detection within a wide linear range of 10 fM-100 nM with a low limit of detection of 2.32 fM, providing a reliable strategy in the exploration of NIR-actuated PEC biosensors for low-cost, high-performance bioassay in clinical applications.

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This perspective explores the feasibility of smart sampling with dried blood spots for the determination of proteins and peptides from human biomatrices using liquid chromatography coupled to mass spectrometry for clinical purposes. The focus is on innovative approaches to transform filter paper from a mere sample carrier to an active element in sample preparation, with the aim of reducing the need for extensive and intensive sample preparation in the conventional sense. Specifically, we discuss the use of modified cellulose to integrate sample preparation at an early stage of sample handling. The use of paper immobilized with either trypsin or monoclonal antibodies for protein digestion and affinity clean-up is discussed as a potential benefit of starting sample preparation instantly at the moment of sampling to optimize time efficiency and enable faster analysis, diagnosis, and follow-up of patients.

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Bifunctional nanocrystals which combine two kinds of materials into single nanoparticles hold great promise in photoelectrochemical (PEC) analysis, particularly for nanocrystals based on perovskite quantum dots (QDs) which generally exhibit excellent photoelectric activity yet poor stability and upconversion nanoparticles (UCNP) that normally suffer from negligible photoelectric activity. Therefore, to achieve good performance of the PEC bioassay platform, it is valuable to combine perovskite QDs with UCNP encapsulation and promote their advantages to form hybrid nanocrystals that are stable, NIR excitable, and photoelectric. Herein, the core-shell configuration of perovskite/upconversion CsPbBr2I@NaYF4:Yb,Tm (CPBI@UCNP) nanocrystals coupled with a NiMn-layered double hydroxide (NiMn-LDH)/CdS heterojunction to form a cascade sensitization structure was proposed to construct the lab-on-paper PEC device for ultrasensitive detection of malathion pesticides. Concretely, the bifunctional CPBI@UCNP nanocrystals that encapsulated CPBI QDs into UCNPs were employed as a nanoscale light source and sensitizer in the lab-on-paper system, which not only prevented the degradation of perovskite QDs but also overcame the negligible photoelectric performance of pristine UCNPs with the cooperation of photoactive CPBI QDs. The synergistic quenching effect, including fluorescence energy resonance transfer (FRET) and photoinduced electron transfer (PET), was created to realize enhanced PEC signal readout. Benefiting from the dynamic cascade sensitization structure of CPBI@UCNP/NiMn-LDH/CdS and synergistic quenching effect of FRET/PET, the ultrasensitive detection of malathion was achieved with high selectivity, reproducibility, and stability, which provided guidelines to employ perovskite/upconversion nanomaterials for lab-on-paper PEC analysis.

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In this paper, we present a novel and cost-effective lab-on-paper microfluidics platform for performing ELISA autonomously, with no user intervention beyond adding the sample. The platform utilizes two Bi-Material Cantilever Valves placed in a specially designed housing. The integration of these valves in a specific channel network forms a complete fluidic logic circuit for performing ELISA on paper. The housing also incorporates an innovative reagent storage and release mechanism that minimizes variability in the volume of reagents released into the reagent pads. The platform design was optimized to minimize variance in the time of fluid wicking from the reagent pad, using a randomized design of experiment. The platform adheres to the World Health Organization's ASSURED principles. The optimized design was used to conduct an ELISA for detecting rabbit immunoglobulin G (IgG) in a buffer, with a limit of detection of 2.27 ng/mL and a limit of quantification of 8.33 ng/mL. This represents a 58% improvement over previous ELISA methods for detecting rabbit IgG in buffer using portable microfluidic technology.

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A dual-mode lab-on-paper device based on BiVO4/FeOOH nanocomposites as an efficient generating photoelectrochemical (PEC)/colorimetric signal reporter has been successfully constructed by integration of the lab-on-paper sensing platform and PEC/colorimetric detection technologies for sensitive detection of carcinoembryonic antigen (CEA). Concretely, the BiVO4/FeOOH nanocomposites were in situ synthesized onto the paper-working electrode (PWE) through hydrothermal synthesis of the BiVO4 layer on cellulose fibers (paper-based BiVO4) which were initially modified by Au nanoparticles for improving the conductivity of three dimensional PWE, and then the photo-electrodeposition of FeOOH onto the paper-based BiVO4 to construct the paper-based BiVO4/FeOOH for the portable dual-mode lab-on-paper device. The obtained nanocomposites with an FeOOH needle-like structure deposited on the BiVO4 layer exhibits enhanced PEC response activity due to its effective separation of the electron-hole pair which could further accelerate the PEC conversion efficiency during the sensing process. With the introduction of CEA targets onto the surface of nanocomposite-modified PWE assisted by the interaction with the CEA antibody from a specific recognition property, a signal-off PEC signal state with a remarkable photocurrent response decreasing trend can be achieved, realizing the quantitative detection of CEA with the PEC signal readout mode. By means of a smart origami paper folding, the colorimetric signal readout is achieved by catalyzing 3,3',5,5'-tetramethylbenzidine (TMB) to generate blue oxidized TMB in the presence of H2O2 due to the satisfied enzyme-like catalytic activity of the needle-like structure, FeOOH, thereby achieving the dual-mode signal readout system for the proposed lab-on-paper device. Under the optimal conditions, the PEC and colorimetric signals measurement were effectively carried out, and the corresponding linear ranges were 0.001-200 ng·mL-1 and 0.5-100 ng·mL-1 separately, with the limit of detection of 0.0008 and 0.013 ng·mL-1 for each dual-mode. The prepared lab-on-paper device also presented a successful application in serum samples for the detection of CEA, providing a potential pathway for the sensitive detection of target biomarkers in clinical application.

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In vitro biosensing chips are urgently needed for early-stage diagnosis and real-time surveillance of epidemic diseases. Herein, a versatile zone with photothermal effects is implanted in the miniature space of a collapsible lab-on-paper photoelectrochemical biosensor for on-site detection of microRNA-141 in body fluids, which can flexibly interconnect the traditional photocurrent signal with functional temperature response. The visualized thermoresponsive results are enhanced by the exciton energy conversion between Fe3O4 nanoparticles (Fe3O4 NPs) and formed Prussian blue nanoparticles under near-infrared irradiation, which not only presents heat energy gradient variations but also generates color changes. Significantly, the controlled release of Fe3O4 NPs is actuated by a target-triggered enzyme assist strand displacement cycle strategy to efficiently improve the accuracy of target temperature signal prediction, which can concurrently mediate photoelectric signal attenuation via promoting the rapid recombination of photoexcited charge carriers on the CuInS2/CoIn2S4 electrode surface, affording dependable ultrasensitive detection results. Benefitting from the ingenious design of the versatile thermoresponsive-photoelectric sensing platform, the preliminary screening and ultrasensitive quantitative analysis can be simultaneously achieved in a single-drop sample. As a consequence, speedy prediction results and satisfied monitoring data are acquired in the ranges of 0.5 pM to 2 nM and 0.001 pM to 5 nM by measuring the temperature change and photocurrent intensity. By right of these advantages, such research paves a prospective paradigm for the manufacture of a visual, rapid, broad-spectrum, and reliable real-time surveillance platform, which allows it to be a promising candidate for epidemic disease home diagnosis and intelligent diagnosis.

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Herein, a ratiometric electrochemiluminescence (ECL) lab-on-paper platform, based on enhancing effect of the N-(4-aminobutyl)-N-ethylisoluminol-functionalized glutathione-coated cobalt/gold bimetallic nanoclusters (GCAL) and quenching effect of carbon quantum dots (CQDs), as well as benefiting from high conductivity copper paper electrode, was developed to achieve accurate and sensitive analysis of DNA methylation. Concretely, due to one-to-multiple amplification effect, one target DNA could initiate the formation of supersandwich structure with multiple signal probes labeled with GCAL. Thus, the GCAL signal enhancement effect was realized. Simultaneously, multiple signal probes are connected to hinder the electron conduction rate on the electrode surface, which results in the quenching of CQDs signal. With the method proposed here, wide linear relationship in the range of 1 fM to 10 pM with a low detection limit of 0.27 fM for sensitive detecting methylated DNA was achieved. It is believed that this work provided a rapid, low-cost and stabilized method for specific determination of methylated DNA, and the immediate detection of cancer in the clinic will become possible in the future.

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An electroanalytical platform capable to take and dilute the sample has been designed in order to fully integrate the different steps of the analytical process in only one device. The concept is based on the addition of glass-fiber pads for sampling and diluting to an electrochemical cell combining a paper-based working electrode with low-cost connector headers as counter and reference electrodes. In order to demonstrate the feasibility of this all-in-one platform for biosensing applications, an enzymatic sensor for glucose determination (requiring a potential as low as -0.1 V vs. gold-plated wire by using ferrocyanide as mediator) was developed. Real food samples, such as cola beverages and orange juice, have been analyzed with the bioelectroanalytical lab-on-paper platform. As a proof-of-concept, and trying to go further in the integration of steps, sucrose was successfully detected by depositing invertase in the sampling strip. This enzyme hydrolyzes sucrose into fructose and glucose, which was determined using the enzymatic biosensor. This approach opens the pathway for the development of devices applying the lab-on-paper concept, saving costs and time, and making possible to perform decentralized analysis with high accuracy.

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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.

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Lab-on-paper (LOP) devices are urgently required for the rapid development of point-of-care diagnoses and environmental assays. Herein, an all-sealed paper-based electrochemiluminescence (ECL) platform was developed to achieve lead ions (Pb2+) sensitive analysis via incorporating convenient plastic package technology. Benefiting from transparent plastic encapsulation, the sealed devices effectively avoided the interference of O2. Meanwhile, myrica rubra-like Pt nanomaterials (MPNs) prepared by an economical and easy-to-operate ultrasound method were employed to catalyze H2O2 decomposition. With the help of Pb2+-specific DNAzymes, the oligonucleotide probe functionalized via MPNs could be detached from the device in the presence of target, resulting in the reduced ECL intensity. Moreover, the combination of modified paper electrode with functional regions separated by multiple layers of wax enhanced the practicability of the LOP device for rapid detection. Under the optimal conditions, the all-sealed platform achieved wide linear relationship ranging from 0.01 nM to 0.05 µM with a low detection limit of 0.004 nM for sensitive detecting Pb2+. It is believed that this platform could provide a robust, simple and versatile strategy for sensitive determination of heavy metal ions, and be applied in on-site contamination analysis in the future.

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Milk is a necessity for human life. However, it is susceptible to contamination and adulteration. Microfluidic analysis devices have attracted significant attention for the high-throughput quality inspection and contaminant analysis of milk samples in recent years. This review describes the major proposals presented in the literature for the pretreatment, contaminant detection, and quality inspection of milk samples using microfluidic lab-on-a-chip and lab-on-paper platforms in the past five years. The review focuses on the sample separation, sample extraction, and sample preconcentration/amplification steps of the pretreatment process and the determination of aflatoxins, antibiotics, drugs, melamine, and foodborne pathogens in the detection process. Recent proposals for the general quality inspection of milk samples, including the viscosity and presence of adulteration, are also discussed. The review concludes with a brief perspective on the challenges facing the future development of microfluidic devices for the analysis of milk samples in the coming years.

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A direct-readout photoelectrochemical (PEC) lab-on-paper device based on coupled an electricity generating system and paper supercapacitors was established for highly sensitive detection of adenosine triphosphate (ATP). Concretely, CdSe quantum dots (QDs) decorated ZnO networks assembled sensing surface provided outstanding photoelectric properties, on which glucose oxidase (GOx) labeled aptamer was subsequently immobilized via the hybridization chain reaction. With analytes present, specific recognition was stimulated by aptamer, resulting in labeled GOx released. Such released GOx could flow to electrochemical cell to conduct electrochemical redox reactions, which could effectively produce electricity that was stored by capacitor I. Sequentially, photoactive material produced an outstanding voltage due to the decrease of steric hindrance on the sensing interface, which was utilized for charging an external capacitor II. The two instantaneous current was acquired along with the discharge of capacitor I and II by digital multimeter (DMM) readout, respectively. The summational current values performed an increment in pace with the addition of target ATP concentration with the dynamic working range from 10 nM to 3 µM and a detection limit of 6.3 nM attained. Significantly, the signal amplified strategy utilizing as-generated electricity from electrochemical redox reactions were isolated from the photoelectrodes, which was beneficial for amplifying the signal response in the PEC matrices and the development of more efficient signal performance.

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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.

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Photoacoustic (PA) effect has been widely applied in many fields, e.g., physics, chemistry and biomedicine. Herein, a miniaturized PA device is developed by integrating laser source, photo chopper, PA cell, microphone, and laptop for point-of-care testing in bioassay. With glucose assay as model, a piece of paper strip preloading chitosan, starch-potassium iodide (KI) and glucose oxidase (GOD) as lab-on-paper is employed for loading sample prior to PA detection. In the presence of glucose, the product generated on the paper strip would give rise to a strong PA signal in the PA cell under the irradiation of frequency-modulated laser at 520 nm via laptop readout. With a sample volume of 20 µL, a detection limit of 0.03 mM is obtained for glucose assay, along with a linear range of 0.08-1 mM. The accuracy and practicability of the present PA device is well demonstrated by detecting glucose in whole blood. Differing from the conventional PA instrument, the present PA device is really small in bulk with competitive sensitivity and excellent stability, offering a promising tool for point-of-care testing in bioassay.

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In this work, we present a multiplexed (eight simultaneous measurements) paper-based electrochemical device developed in a very simple way and using low-cost materials, such as paper, carbon ink and multifunctional connector headers. Meanwhile, we have also combined the paper-based electrochemical platform with a glass-fiber strip in order to integrate easily a sampling step. Both approaches, simultaneous measuring and sampling, have been applied to the determination of glucose using bienzymatic biosensors. They are fabricated by adsorbing the mixture of enzymes (glucose oxidase and horseradish peroxidase), as well as the ferrocyanide, mediator of the electron transfer, on the paper-based electrode. After drying, the measuring solution (containing either glucose standards or samples) is added and the eight corresponding chronoamperograms are recorded. In the case of the microfluidic approach for sampling purposes, the glass-fiber pad (sampler) is immersed in a container with the solution, which flows by capillarity until it reaches the working electrode. The integration of one more step of the analytical process advances towards real and useful lab-on-a-chip devices. With these designs, a linear range comprised between 0.5 and 15 mM was achieved for glucose determination, with an excellent precision. If the sampler is employed, it is not necessary to use micropipettes and, nevertheless, precise measurements are obtained. The RSD of the slopes obtained for different calibrations performed in different days, with different arrays of electrochemical cells and different solutions is ca. 1%. Accurate results are obtained in the determination of glucose in real samples (orange fruit and cola beverages).

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Inspired by the design of folding greeting cards and tissue drawing covers, a photoelectrochemical (PEC) lab-on-paper device with a controllable fluid separator, producing both reaction zone and detection zone, was explored for ultrasensitive detection of adenosine 5'-triphosphate (ATP) via mimic peroxidase-transfer enhancement of photocurrent response. To realize it, the DNA1, aptamer, and DNA2 as well as the mimic peroxidase of G-quadruplex/hemin modified Au nanocubes were linked on the graphene oxide-functionalized reaction zone via the DNA hybridization. Meanwhile, three-dimensional CuO nanoflowers (CuO NFs) as a photoactive material with outstanding electron transfer ability and absorption of light were grown in situ on the detection zone, providing a PEC active interface. Besides, an innovative fluid separator was elaborately designed by assembling a strip of paper with a hydrophilic channel, providing an effective way to bridge the gap between the two zones with a controllable drawing way, which could successfully avoid the signal interference caused by modifying biomolecules layer by layer on photosensitive materials. In the presence of ATP, the G-quadruplex/hemin modified in the reaction zone was dissociated due to the specific recognition of ATP with aptamer and released into the detection zone with the assistance of controllable fluid separator. The free G-quadruplex/hemin could catalyze hydrogen peroxide to generate oxygen for the consumption of photo-induced electrons from CuO NFs, which could further promote the electron-hole carriers separation efficiency, and eventually resulting in the enhancement of PEC signal. The proposed PEC lab-on-paper device could be employed for specific detection of ATP in the range from 5.0 to 3.0 × 103 nM with a detection limit of 2.1 nM.

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Over the past several years, a new surge of interest in paper electronics has arisen due to the numerous merits of simple micro/nanostructured substrates. Herein, the latest advances and principal issues in the design and fabrication of paper-based flexible electronics are highlighted. Following an introduction of the fascinating properties of paper matrixes, the construction of paper substrates from diverse functional materials for flexible electronics and their underlying principles are described. Then, notable progress related to the development of versatile electronic devices is discussed. Finally, future opportunities and the remaining challenges are examined. It is envisioned that more design concepts, working principles, and advanced papermaking techniques will be developed in the near future for the advanced functionalization of paper, paving the way for the mass production and commercial applications of flexible paper-based electronic devices.

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A novel dual-mode cytosensor based on polyhedral AuPd alloy nanoparticles (PH-AuPd NPs) and three-dimentional reduced graphene oxide (3D-rGO) was constructed for highly sensitive detection of MCF-7 cells. The 3D-rGO was in situ synthesized on the paper working electrode (PWE) by a pollution-free hydrothermal method, increasing the specific surface area and further facilitating the modification of Au nanoparticles (AuNPs). After modified with AuNPs, the Au@ 3D-rGO/PWE was then functionalized by aptamer H1 to trap MCF-7 cells. To construct the cytosensor, PH-AuPd NPs was prepared as a novel catalytic material, and further modified with aptamer H2 for recognizing MCF-7 cells. With the occurrence of efficient recognition of MCF-7 cells, PH-AuPd NPs were bound onto the surface of the cells, and could catalyze H2O2 to generate •OH, leading to an amplified electrochemical signal. Meanwhile, as the electrolyte solution flowed, the •OH are transferred outward to the colorimetric detection zone, and catalyzed a chromogenic substrate TMB forms a colored product. The electrical signal measurement and colorimetric detection were carried out on a compatibly designed lab-on-paper device (LPD), realizing a dual-mode signal readout. This paper-based dual-mode cytosensor provided a relatively low detection limit of 20 cells mL-1 and a sensitive detection from 50 cells mL-1 to 107 cells mL-1 for MCF-7 cells, providing a reliable pathway of sensitively detecting cancer cells in clinical applications.

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Due to its unique material properties, paper offers many practical advantages as a viable platform for sensing devices. In view of paper-based microfluidic biosensing applications, the covalent immobilization of enzymes with preserved functional activity is highly desirable and ultimately challenging. In the present manuscript, we report an efficient approach to achieving the covalent attachment of certain enzymes on paper fibers via a surface-bound network of hydrophilic polymers bearing protein-modifiable sites. This tailor-made macromolecular system consisting of polar, highly swellable copolymers is anchored to the paper exterior upon light-induced crosslinking of engineered benzophenone motifs. On the other hand, this framework contains active esters that can be efficiently modified by the nucleophiles of biomolecules. This strategy allowed the covalent immobilization of glucose oxidase and horseradish peroxidase onto cotton linters without sacrificing their bioactivities and performance upon surface binding. As a proof-of-concept application, a microfluidic chromatic paper-based glucose sensor was developed and achieved successful glucose detection in a simple yet efficient cascade reaction.