Multilayered Microfluidic Paper-Based Devices: Characterization, Modeling, and Perspectives.

Paper-based microchannels are important components in paper-based microfluidic devices. Paper-based microchannels are usually manufactured by creating lines with hydrophobic patterns enclosing an area of hydrophilic paper inside. Among the many techniques for making hydrophobic lines, the printing method in general and inkjet printing in particular have become more common because of their advantages in terms of material saving, high precision, low-cost, etc. In this paper, the electrohydrodynamic (EHD) inkjet printing method, which has been studied and developed in recent years, has been used to drop glycol ether solvent-based ink onto a nitrocellulose paper. The results of the field emission scanning electron microscope (FE-SEM) show that the solvent based ink could dissolve through membrane and form a transparent hydrophobic layer on the created space. The width of the barrier lines can be controlled from about 200 μm to 260 μm, which is quite small when compared to other manufacturing methods. Based on this fabrication process, paper-based microfluidic analytical devices have been designed and fabricated for use in analytical biochemistry assays. Human chorionic gonadotropin (hCG) was selected as the biological target for this assay. Initial results have shown that the target for hCG can be quantitatively determined by these devices with a coefficient of determination (R2) of approximately 0.99. Therefore, EHD inkjet printing technology can be used for the manufacture of paper-based microfluidic analytical devices (μPADs) that may be applied in the future for analytical biochemistry assays.

Lung deposition of budesonide from the novel dry powder inhaler AirmaxTM

Paper-based microfluidic devices have many advantages such as low cost, flexibility, light weight and easy disposability. Especially, since they can intrinsically generate capillary-driven flow (no pumps are needed), paper-based microfluidic devices are widely used in analytical or diagnostic platforms. Along with advancements in microfluidic paper-based analytical devices (μPADs), energy generation using paper materials has received significant attention. In this study, environment-friendly and flexible paper-based energy harvesting with a simple configuration is demonstrated by using the principle of reverse electrodialysis (RED). RED is a promising clean energy generation method, which converts Gibbs free energy into electricity by salinity gradients without discharging any pollutants. However, the power efficiency in a conventional RED device is limited by the essential requirement of active pumping for providing high and low concentration electrolytes. Capillary pumping from the proposed paper-based RED can save this waste of energy, and moreover, the flexible device is realized with cost effective materials and a simple fabrication step, and is environmentally friendly. By thoughtful analysis of voltage-current experiments and capillary flow rates in paper channels, the optimized channel width interfacing with a selective membrane is determined as 2 mm and the maximum power and power density are achieved as 55 nW and 275 nW cm(-2), respectively. 25.8% of the generated maximum power is successfully saved by realizing the pumpless RED system. This paper-based RED device can be integrated directly with μPADs as a practical application.

Electrochromatographic separations of three metal complexes were achieved through observing the visualization evolution process of moving chelation boundaries (MCBs) on microfluidic paper-based analytical devices (μPADs). A simplified photolithography was developed to pattern the μPADs within 5–10 min with three steps only, manually gelatinize, expose and develop, through thinning SU-8 2150 with trichloromethane. With a cutting method, many bubbles were clearly observed in the single-component MCB system on the μPADs, but were not found with this photolithography method under the same voltages. It was demonstrated that this photolithography for patterning narrow paper channels rejected Joule heating more effectively than the cutting paper method did. It was observed simultaneously that the apparent distances of electrophoretic and electroosmotic migrations of the blue [Cu-EDTA]2− chelation boundary increased with increasing electrical field strength and width of the paper channels, respectively. The higher the Cu2+ concentrations were, the slower the electrophoretic migrations of the blue boundary were, and the faster the electroosmotic migrations of the blue boundary were on the μPADs with this photolithography. The separations and concentrations of the coloured zones, pink [Co–EDTA]2−, blue [Cu–EDTA]2− and yellow [Fe–EDTA]2−, were clearly observed in the applied electric fields on the μPADs. The studies benefit extending the application of μPADs as low-cost, disposable analysis tools and deepen understanding of the comprehensive mechanisms concerning MCBs, partition adsorption and electroosmotic flow on μPADs.

A transformation of the healthcare industry is necessary and imminent: hospital-centered, reactive care will soon give way to proactive, person-centered care which focuses on individuals' well-being. However, this transition will only be made possible through scientific innovation. Next-generation technologies will be the key to developing affordable and accessible care, while also lowering the costs of healthcare. A promising solution to this challenge is low-cost continuous health monitoring; this approach allows for effective screening, analysis, and diagnosis and facilitates proactive medical intervention. Urine has great promise for being a key resource for health monitoring; unlike blood, it can be collected effortlessly on a daily basis without pain or the need for special equipment. Unfortunately, the commercial rapid urine analysis tests that exist today can only go so far-this is where the promise of microfluidic devices lies. Microfluidic devices have a proven record of being effective analytical devices, capable of controlling the flow of fluid samples, containing reaction and detection zones, and displaying results, all within a compact footprint. Moving past traditional glass- and polymer-based microfluidics, paper-based microfluidic devices possess the same diagnostic ability, with the added benefits of facile manufacturing, low-cost implementation, and disposability. Hence, we review the recent progress in the application of paper-based microfluidics to urine analysis as a solution to providing continuous health monitoring for proactive care. First, we present important considerations for point-of-care diagnostic devices. We then discuss what urine is and how paper functions as the substrate for urine analysis. Next, we cover the current commercial rapid tests that exist and thereby demonstrate where paper-based microfluidic urine analysis devices may fit into the commercial market in the future. Afterward, we discuss various fabrication techniques that have been recently developed for paper-based microfluidic devices. Transitioning from fabrication to implementation, we present some of the clinically implemented urine assays and their importance in healthcare and clinical diagnosis, with a focus on paper-based microfluidic assays. We then conclude by providing an overview of select biomarker research tailored towards urine diagnostics. This review will demonstrate the applicability of paper-based assays for urine analysis and where they may fit into the commercial healthcare market.

Iodine is an essential micronutrient for humans due to its fundamental role in the biosynthesis of thyroid hormones. As a key parameter to assess health conditions, iodine intake needs to be monitored to ascertain and prevent iodine deficiency. Iodine is available from various food sources (such as seaweed, fish, and seafood, among others) and dietary supplements (multivitamins or mineral supplements). In this work, a microfluidic paper-based analytical device (μPAD) to quantify iodide in seaweed and dietary supplements is described. The developed μPAD is a small microfluidic device that emerges as quite relevant in terms of its analytical capacity. The quantification of iodide is based on the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by hydrogen peroxide in the presence of iodine, which acts as the catalyst to produce the blue form of TMB. Additionally, powder silica was used to intensify and uniformize the colour of the obtained product. Following optimization, the developed μPAD enabled iodide quantification within the range of 10-100 µM, with a detection limit of 3 µM, and was successfully applied to seaweeds and dietary supplements. The device represents a valuable tool for point-of-care analysis, can be used by untrained personnel at home, and is easily disposable, low-cost, and user-friendly.

ABSTRACT. Two easy-to-use, rapid, and inexpensive colorimetric-based assays for the detection of active constituent in nasal decongestant phenylephrine hydrochloride (PHP), in solution and their respective pharmaceutical preparations were reported. The assay principle depends on the diazotized sulfadimidine (DSDM) coupling with PHP active pharmaceutical compound under alkaline conditions to produce a colored azo-dye product. A UV/VIS spectrophotometry method was utilized to monitor the color absorbance change at 460 nm, with a linear calibration graph in the concentration range of 1-20 mg L-1 and a limit of detection of 0.22 mg L-1 and limit of quantification of 0.72 mg L-1. A comparison was done using a paper-based microfluidic analytical device (µPADs) and color intensity change was measured using a Samsung note 9 camera to capture digital images and Image J software to analyze the color intensity development. A linear trend was observed above approximately 10 mg L-1. Thus, paper-based microfluidic analytical devices (µPADs) can be used as an alternative platform to conventional methods to perform a semi-quantitative PHP drug analysis. The proposed method was applied for the determination of PHP in commercial pharmaceutical preparations. KEY WORDS: Phenylephrine hydrochloride, Spectrophotometry, Paper-based microfluidic analytical devices (µPADs), Pharmaceutical preparations, Colorimetric detection Bull. Chem. Soc. Ethiop. 2022, 36(4), 727-736. DOI: https://dx.doi.org/10.4314/bcse.v36i4.1

Microfluidic paper-based analytical devices (μPADs), because of their mechanical flexibility, low cost, easy scale-up in manufacturing, small sample volumes and user-friendly properties, show great application prospect in bio-medicine, environmental monitor, food industry, drug industry and so on. As one kind of μPADs, the electrochemical microfluidic paper-based analytical devices (EμPADs) combine the advantages of μPADs with the advantages of electrochemical detection and keep attracting more and more attention. Recently, to improve the performance of EμPADs, applying nanomaterials for the fabrication of biosensors has become the research hotspot. This review presents some of the most prominent applications of nanomaterials in EμPADs over the past five years and also describes the challenges and future perspectives related to the recent application and development of paper-based electrochemical biosensors.

We present a novel microfluidic paper-based analytical device (μPAD) which utilizes the native high electroosmotic flow (EOF) in nitrocellulose to achieve stationary isotachophoresis (ITP) focusing. This approach decouples sample accumulation from the length of the channel, resulting in significant focusing over short channel lengths. We provide a brief theory for EOF-balanced ITP focusing under continuous injection from a depleting reservoir and present the design of a short (7 mm) paper-based microfluidic channel, which allows a 200 μL sample to be processed in approximately 6 min, resulting in a 20 000-fold increase in concentration - a full order of magnitude improvement compared to previous paper-based ITP devices. We show the stability of the assay over longer (40 min) durations of time, and using Morpholino probes, we present the applicability of the device for amplification-free detection of nucleic acids, with a limit-of-detection (LoD) of 5 pM in 10 min. Finally, we utilize the small footprint of the channel and show a multiplexed platform in which 12 assays operate in parallel in a 24-well plate format.

A simple double-layered three-dimensional (3D) microfluidic paper-based analytical device (μPAD) was designed for the simultaneous determination of six metal ions-Fe(III), Ni(II), Cr(VI), Cu(II), Al(III), and Zn(II)-for the first time. The 3D μPAD was composed of two paper layers: a top pretreatment layer and a bottom colorimetric detection layer. The sample solution added to the central sample reservoir of the 3D μPAD could be automatically divided into eight flow pathways and be automatically pretreated while flowing through the pretreatment zones located in the microfluidic channels, and automatically carried out the chromogenic reactions after reaching the detection zones. Random diffusion of the chromogenic reagents was effectively prevented by transport of the pretreated sample solution to the detection zones through 3D microfluidic channels with an L-type circuitous flow route design, resulting in highly increased color uniformity and reproducibility. Combined with use of a flat LED lamp as an upward lighting source and a smartphone as a convenient detector, improved color perception, highly enhanced sensitivity, and an extended detection range were obtained. Finally, the double-layered 3D μPAD was applied to the multiplexed determination of the six metal ions in mixtures and environmental samples with satisfactory results. Detection limits as low as 0.2, 0.3, 0.1, 0.03, 0.08, and 0.04 mg/L for Fe(III), Ni(II), Cr(VI), Cu(II), Al(III), and Zn(II) detection, respectively, were achieved, which are about one order of magnitude lower than obtained with previously reported μPADs for the detection of metal ions. The present 3D μPAD is simple, fast, selective, sensitive, and user-friendly, and holds great application potential for multiplexed on-site analysis.

In this work, two microfluidic paper-based analytical devices (μPADs) were developed for the quantification of urea and NHx in human saliva to aid in the diagnosis/monitoring of chronic kidney disease (CKD). The NHx determination was based on the conversion of ammonium to ammonia, followed by its diffusion through a hydrophobic membrane and then the color change of bromothymol blue (BTB) indicator. In the urea determination, prior to the ammonium conversion and BTB color change, the enzymatic conversion of urea into ammonium was produced, using urease. Several optimization studies were carried out to attain a quantification range of 0.10–5.0 mM with 0.032 mM limit of detection for the NHx μPAD, and a determination range of 0.16–5.0 mM with 0.049 mM limit of detection for the urea μPAD. The method accuracy was assessed, and the measurements obtained with NHx μPAD were compared with the ones obtained from an ammonia ion selective electrode; while the measurements of the urea μPAD were compared with the ones obtained from a commercially available kit. There were no statistically significant differences between methods, proving that both NHx and urea μPAD were effective on-hand tools for CKD monitoring in saliva. To evaluate their functionality as point-of-care devices, stability studies were also performed and revealed that both NHx and urea μPAD were stable when stored in a vacuum for 2 and 1 month, respectively. After the sample introduction, the NHx μPAD could be scanned within the first 2 h and the urea μPAD within 1 h.

Microfluidic paper-based analytical devices are an attractive tool for point of care diagnostics as they facilitate fast detection without the need for any sophisticated instrumentation and skilled professional. These devices are disposable, portable, and affordable; hence, they are utilized in almost all the diagnostic domains for carrying out the detection. There are various aspects associated with the paper-based devices, namely working principle, reaction mechanism, fabrication schemes (2D/3D), detection sensitivity, and readout mechanism. Over the period, continuous progress is envisioned in all these domains to enhance the sensitivity of the detection and several variants, namely miniaturization, the inclusion of nanoparticles, multi-functionalization, etc. are also explored to make the detection more efficient. This chapter provides a state of the art review of the various aspects of paper-based microfluidic devices, including their fabrication scheme, sensing methodology, and their several applications in DNA detection domain. Also, advantages, disadvantages, and future aspects of these devices are also discussed.

Microfluidic paper-based analytical devices (μPADs) have recently attracted the attention of researchers and industry owing to their various advantages. However, µPADs lack a way to control fluid flow; therefore, it is difficult to perform complex immunoassays that use multiple reagents and replace the reagents from the analytical area. We developed a controllable thermoresponsive valve for μPADs by functionalizing a polyvinylidene difluoride porous membrane with plasma-induced graft polymerization of poly(N-isopropylacrylamide) (PNIPAAm), which is a thermoresponsive polymer that changes its hydrophilic properties near the lower critical solution temperature (LCST; 32 °C). Surface analysis by attenuated total reflectance Fourier transform infrared spectroscopy confirmed that the fabricated thermoresponsive valves coated with PNIPAAm. The valve performance was evaluated by sandwiching the thermoresponsive valve between two paper microchannels stacked in a T-shaped paper microfluidic device. The thermoresponsive valve fabricated with a monomer concentration ranging from 2.3 to 3.0 wt% and a polymerization time of 5 h or 2.0 wt% and 20–22 h showed good valve performances. These valves were able to stop the flow at room temperature, and allow the flow by opening within 20 s after heating was initiated using a Peltier element located just under the valve. The valve was successfully closed, thereby stopping the flow, and opened by heating. Although a detailed evaluation of the fluid behavior is necessary, we have demonstrated that our thermoresponsive valve can be opened and closed reversibly by temperature control. We believe that this thermoresponsive valve could potentially be used to control the flow of multiple reagents in µPADs.

This paper describes paper-based micro fluidic devices that can be programmed by a user to implement special micro fluidic analysis. The micro fluidic devices are simple to fabricate, and are made out of paper and tape. These devices are programmed by pressing paper-based micro fluidic switches. Pressing a paper-based micro fluidic switch closes a small gap between paper-based micro fluidic channels, and allows fluids to wick from one channel to the other. A fluidic de-multiplexer and a programmable micro fluidic array have been implemented using programmable paper-based micro fluidic device, and programmable operation experiments have also been done using red dye solution and NaNO2 solution. The programmable paper-based micro fluidic devices provide a simple and low cost method for controlling the movement of fluids in paper-based channels, and expand the applications of micro fluidic devices.

Microfluidic paper-based analytical devices (μPADs) have been widely used in point-of-care testing owing to their simple operation, low volume of the sample required, and the lack of the need for an external force. To obtain accurate semi-quantitative or quantitative results, μPADs need to respond to the challenges posed by differences in reaction conditions. In this paper, multi-layer μPADs are fabricated by the imprinting method for the colorimetric detection of C-reactive protein (CRP). Different lighting conditions and shooting angles of scenes are simulated in image acquisition, and the detection-related performance of μPADs is improved by using a machine learning algorithm. The You Only Look Once (YOLO) model is used to identify the areas of reaction in μPADs. This model can observe an image only once to predict the objects present in it and their locations. The YOLO model trained in this study was able to identify all the reaction areas quickly without incurring any error. These reaction areas were categorized by classification algorithms to determine the risk level of CRP concentration. Multi-layer perceptron, convolutional neural network, and residual network algorithms were used for the classification tasks, where the latter yielded the highest accuracy of 96%. It has a promising application prospect in fast recognition and analysis of μPADs.