Paper-based analytical devices for clinical diagnosis: recent advances in the fabrication techniques and sensing mechanisms

Abstract

There is a significant interest in developing inexpensive portable biosensing platforms for various applications including disease diagnostics, environmental monitoring, food safety, and water testing at the point-of-care (POC) settings. Current diagnostic assays available in the developed world require sophisticated laboratory infrastructure and expensive reagents. Hence, they are not suitable for resource-constrained settings with limited financial resources, basic health infrastructure, and few trained technicians. Cellulose and flexible transparency paper-based analytical devices have demonstrated enormous potential for developing robust, inexpensive and portable devices for disease diagnostics. These devices offer promising solutions to disease management in resource-constrained settings where the vast majority of the population cannot afford expensive and highly sophisticated treatment options. Areas covered: In this review, the authors describe currently developed cellulose and flexible transparency paper-based microfluidic devices, device fabrication techniques, and sensing technologies that are integrated with these devices. The authors also discuss the limitations and challenges associated with these devices and their potential in clinical settings. Expert commentary: In recent years, cellulose and flexible transparency paper-based microfluidic devices have demonstrated the potential to become future healthcare options despite a few limitations such as low sensitivity and reproducibility.

Keywords: Point-of-care diagnostics; biosensors; cellulose paper-based analytical devices; device fabrication; flexible transparency paper-based analytical devices; microfluidics.

Figure 1

(a) (Adapted from [16]) Microchip composed of flexible polymer. (b) (Adapted from [16]) Polyester transparency-based biosensing platform. (c) (Adapted from [16]) Image acquisition of the sample spot using the cell phone camera. (d) (Adapted with permission from Delaney et al. [17]. Copyright (2011) American Chemical Society) Image capture and analysis using cell phone.

Figure 2

(a) (Adapted from [23] with permission from the Royal Society of Chemistry) Schematic design lateral flow assay device modified with wax fabricated pillars for the detection of protein using dual gold nanoparticles AuNP. (b) (Adapted from [24] with permission from Elsevier) Pictorial illustration of the electrochemical immunoassay procedure using CEA.

Figure 3

(Adapted from [27] with permission from John Wiley and Sons) Chromatography paper having patterns made by photoresist (a) device after absorbing Waterman red ink (5 mL). (b) Reagents added to perform glucose and protein assays. (c) Negative assay for glucose and urine using artificial urine (5 mL) (d) Positive assay of glucose and urine using artificial urine solution containing 550 mm glucose and 75 mm BSA. (e) Results of glucose and BSA detection assays with their varying concentrations. Full color available online.

Figure 4

(a) (Adapted from [3] under the Creative Commons Attribution 4.0 International Public License https://creativecommons.org/licenses/by/4.0/legalcode) 3D Microfluidic device (i) Schematic of device consisting of PMMA, DSA and glass cover slip. (ii) Dimensions of microfluidic channel. (iii) Image of device where channels are filled with blood and food dyes. (b) (Adapted with permission from Lucio do Lago et al. [54]. Copyright 2003 American Chemical Society) Schematic representation of laser printing and laminating processes for the fabrication of microfluidic devices (i) Perforated transparency film. (ii) Printed polyester base (I, toner layer) (iii) Lamination of cover sheet and base and (iv) Final microfluidic device. (II, liquid reservoirs).

Figure 5

(Adapted from [72] with permission of The Royal Society of Chemistry) Schematic representation of modification process of a conventional LFIA pad into multi-step LIFA using thermally actuated wax-ink valve. (a) Front view. (b) Back view.

Figure 6

(Adapted from [43] with permission from Elsevier) Schematic diagram of wax dipping process for the fabrication of μPADs (a) Method of microfluidic channel fabrication using wax dipping: (i) wax dipping apparatus. (ii) Method of patterning paper by wax dipping process in top view (left side) and lateral view (right side). (b) Photographs of fabricated paper using wax dipping method (i) hydrophilic and hydrophobic areas captured under microscope (40x). (ii) Hydrophilic area soaked with food dye color. (iii) Comparison of hydrophobic and hydrophilic zones using a drop of colored food dye. (c) μPAD fabricated by wax dipping technique: (i) basic structure and size and shape measurements of iron mold. (ii) Top view of final paper-based microfluidic device. (iii) Device after protein and glucose detection.

Figure 7

(a) (Adapted from Zhang et al. [73]. Copyright (2014) American Chemical Society) Schematic representation of movable-type wax printing (MTWP) technique for the fabrication of μPADs: (i) a set of iron parts assembled into specific pattern. (ii) Wax patterned μPADs. (b) (Adapted from [74] permission of The Royal Society of Chemistry) Schematic illustration of microfluidic device printing method based on stamping: (i) placement of paraffined paper (p-paper) on native paper (n-paper) (ii) preheated metal stamp brought in contact with layered papers. (iii) Final microfluidic device manufactured by handheld stamping process. (iv) Optical micrograph of manufactured device.

Figure 8

(a) (Adapted from [42] with permission from Elsevier) Schematic representation of wax screen-printing process (i) Paper and screen. (ii) Screen placed on the surface of paper. (iii), (iv) Solid wax utilized as a squeegee and rubbed through the screen. (v) Wax patterns formed on the surface of paper. (vi) Screen-printed paper placed in an oven for wax penetration into paper substrate and formation of the paper microzone plate. (b) (Adapted from Olkkonen et al. [57]. Copyright (2010) American Chemical Society) Illustration of flexographic printing process: (i) Schematic representation of flexographic printing equipment (ii) Final printed device using flexography.

Figure 9

(Adapted from [78] Copyright (2008) National Academy of Sciences, U.S.A.) A three dimensional μPAD (a) Schematic representation of layers of tape and paper in a 3D microfluidic device. (b) Photograph showing the front of the dual-assay device. (c) Back of the device containing reagents for colorimetric detection of glucose and proteins. (d) Device containing a sample of artificial urine with 2-mM glucose and 40 μM BSA. 25 μL of sample is poured into device in 2 min. (e) Pictorial representation of the results of the assays for control and sample. (f) Top of the four-assay device. (g) Back of the three dimensional paper-based microfluidic device. (h) Device containing samples. Each corner of the device was dipped into a specific artificial urine sample. (i) Picture showing the results of the assays.