ReviewEnclosed paper-based analytical devices: Concept, variety, and outlook
Graphical abstract
Introduction
As people become more aware of critical issues, such as disease diagnosis, environmental pollution prevention, and food safety control, demands for inexpensive, portable, and easy-to-read analytical devices are on the rapid increase [1]. Compared to conventional material-based platforms, cellulose paper substrates are viewed as a potent competitor in fabricating devices owing to merits such as low cost, high availability, light weight, and natural decomposition capability [2]. Furthermore, the three-dimensionally entangled fiber structures provide larger permeable spaces and high affinity toward various solutions, allowing paper substrates to be compatible with a wide variety of useful detection methods [1]. The porous structures also simplify the process of altering paper substrate properties, such as hydrophobicity, lowering technical barrier for producing different types of devices [1]. Adequate solution driving force has always been a critical requirement for the design of a miniature device, where importantly, the capillary force provided by porous paper fiber structures enables the liquid solution to propel spontaneously inside this material. This eliminates the need of an external driving source, making paper-based devices ideal for standalone and single use applications [2]. Relying on these unique advantages, a wide selection of analytical strategies has been incorporated in paper substrates, such as immunoassay [3,4], enzymatic array [5], electrochemistry [[6], [7], [8]], and so forth. These rapid-prototyping analytical approaches allow researchers to create paper-based analytical devices for various targets and enable users to obtain the devices at reasonable costs. Consequently, paper-based analytical devices are highly potent in resource-limited settings, e.g. developing countries and rural areas, to perform tasks such as point-of-care health diagnosis and environmental monitoring [2,[9], [10], [11]].
Introduced by Whitesides group in 2007 [5], paper-based analytical devices have sparked tremendous interest in the community. A considerable amount of effort has been dedicated to the immense importance and commercialization potential of paper-based devices [1,[12], [13], [14], [15]]. However, relevant studies often emphasize on developing new analytical methods, novel reagents for better target detection, offering higher sensing capability, and improving usage affordability, leaving out the practicality aspects of platforms. In fact, a real and practical paper-based analytical device should be able to endure the transportation process from manufacturers to end users and the less-than-ideal storage conditions. From this point of view, paper-based analytical devices with enclosed channel systems should be a promising choice because they have been shown to be more durable in terms of mechanical strength [3] and chemical stability [[16], [17], [18]]. Besides, by either enhancing flow rate control [[19], [20], [21], [22], [23], [24], [25]] or altering total fluidic path, the total analysis duration on enclosed channel designs can be finely-tuned to better suit researchers’ needs [[26], [27], [28]]. Despite the merits provided by adopting enclosed designs, a comprehensive introduction and discussions of related research are still lacking in the literature. An informative review article is therefore put together here to help researchers better understand existing ideas in this field.
In this article, a summary of various aspects regarding the design of regular paper-based analytical devices is first provided, including general fabrication techniques and compatible detection methods. Then, an in-depth discussion emphasizing on design with enclosed channel systems is presented. Techniques related to these enclosed paper-based analytical devices are sorted into four categories (Fig. 1): 1) polymer enclosing, where paper substrate is enclosed inside transparent polymer films; 2) stacked devices, where interweaving layers of patterned paper and water-impermeable adhesive are stacked into three-dimensional devices; 3) origami devices, where a device is fabricated by folding a single piece of patterned paper substrate into three-dimensional channel systems; and 4) channel enclosure devices, where enclosed channels are created within a single piece of paper substrate by the careful control of printed materials, such as toner or wax. In these discussions, examples are given for each category of design, with emphasis on how each of them is produced and utilized for practical applications. Aside from the aspects mentioned above, two additional important topics are also discussed, including flow rate control and reagent preservation on relevant platforms, which reinforces the benefits of enclosed paper-based analytical devices. Finally, perspective works for device performance improvement and foreseen challenges are discussed, which might provide some directions for future research in this field in the coming years.
Similar to the concepts of microfluidic device design, analogous approaches on an analytical platform rendering both liquid/reagent reservoirs and flowing channels are often deployed in paper-based analytical device fabrication, as outlined in Fig. 2A. Therefore, devices based on this notion simultaneously allow for multiple pre-treatments or analysis as that on conventional microfluidics for a particular analyte. Functioning reservoirs and fluidic channels are often shaped upon introducing distinct barriers for complex liquid controls on a thin and flat paper substrate. For example, generating hydrophobic walls on a paper substrate by photoresist and wax is the most popular choice among researchers due to the high availability and convenient operation of the substrates. In 2007, Martinez et al. first demonstrated the use of photoresist as hydrophobic barriers on paper-based microfluidic devices [5]. A filter paper substrate was first submerged in SU-8 photoresist then patterned via standard photomask-UV exposure optical lithography with subsequent feature developing processes. The flowing channels and detection zones were defined by hydrophobic photoresist inside paper substrate pores, which prohibits the flowing of aqueous solutions and designates controls over fluidics behavior under an analytical operation. After the demonstration by Martinez et al. several studies followed, and many different appropriate chemicals were also tested with this similar fabrication concept, such as wax, polystyrene, and polydimethylsiloxane [[31], [32], [33], [34]].
Wax is another suitable candidate material for defining reservoir and channel structures on a paper substrate because of its high hydrophobicity and heat-induced melting properties. The rising popularity of this material is attributed to the relatively economical price and lower toxicity, compared to photoresists or other chemicals, and the ease of operation. Various methods have been proposed for adopting wax to paper-based microfluidic devices, such as screen printing [38], dipping [39], and regular printing [29]. The printing approach, introduced by Carrilho et al. [29], is a favored fabrication strategy. This approach uses a wax printer to create wax patterns that are pre-designed on a computer and printed onto the paper substrate. The substrate is thereafter heated to allow wax to penetrate into paper material porous structures for the three-dimensional hydrophobic barrier formation.
In addition to the introduction of a different material for desired structure creation, direct shaping of paper substrates is also used to make paper-based analytical devices, which is often accomplished by using a plotter [30]. In this case, the substrates are directly cut into a desired shape and geometry, such as channel lines, and can be used immediately. Nevertheless, owing to the lack of mechanical strength of the paper material, directly shaped paper substrates are often used in conjunction with supportive polymer backings. In 2009, Fenton et al. found that polyester backing or cover tape protection provide paper substrates with sufficient mechanical strength [30]. Other successful examples have also been demonstrated by using the direct shaping method and polyester for paper substrate protection [3,17,40,41] or homemade polymer film [16] lamination.
Ideally, appropriate detection methods incorporating with paper-based analytical devices should minimize the need for specialized equipment or well-trained operators. The use of inexpensive and non-toxic reagents allows in situ, real time, and on-site data interpretation to fulfill the essential needs on paper-based platforms. Owing to the broad compatibility of common laboratory paper material, a variety of detection methods, such as colorimetric [5,[37], [42], [43], [44], [45]], fluorometric [[35], [46], [47]], and electrochemical [[48], [49], [50]] approaches, have been integrated with these analytical devices (Fig. 2B). Other strategies, such as positional readout [51,52] and surface-enhanced Raman spectroscopy [53], have also been demonstrated, but the three types of detection methods mentioned above are still the most prevailing approaches.
Colorimetric detection refers to the use of color-changing reagents for target detection, and the addition of target-containing samples produces distinct color changes and allows the results to be determined by instruments or naked eyes. On a paper-based device, this detection approach can achieve semi-quantification by observing the degree of color changes and advanced quantification results through the aid of computer software post-analysis [17]. Importantly, the native white background of paper substrates is ideal for colorimetric detection because it provides high contrast for analytical data collection based on color changes [1]. The ease of signal readout and convenient experimental design are main advantages of these colorimetric strategies. Nonetheless, achieving accurate detection and delicate analysis with naked eyes might be challenging, so assistance from additional software/mini-instrument could be helpful [17].
Fluorometric detection strategies measure the change of optical emission intensity during analysis under an excitation illumination. Generally, fluorometric detection requires more instruments than colorimetric detection, which might not be suitable for paper-based analytical devices that aim to be facile and low cost. Besides, the noticeable signal background resulting from additives on commercially available paper substrates may further complicate the final analytical assays [54]. Although this signal background issue is inevitable, fluorescent detection remains a valuable tool in this field [54]. Chemiluminescence is similar to fluorometric detection but does not require an excitation light source. It has been adopted in the design of many paper-based analytical devices. The advantages of this approach lie on its simple operation and plausible wide dynamic detection range. However, a common disadvantage of these two luminescent methods is the demand for a dark environment in order to collect better data. Thus, a more specialized experimental setting is often required.
Optical strategies mentioned above rely on visual signal outputs, which often requires further photography hardware and software for more precise data analysis [1]. In addition, visual data recordings are easily affected by ambient background when operating without sophisticated setups, and performing calibrated quantification standards on paper-based analytical devices is more challenging [1]. On the contrary, electrochemical methods depend on detecting redox reactions occurring in device reservoirs. These techniques provide advantages such as high sensitivity, rapid response, and numerical data output, and they are not affected by environmental optical backgrounds and are convenient to operate in many designs. Thus the incorporation of electrochemical detection into paper-based devices has become vastly popular [24,55]. The porous nature of a paper substrate makes them suitable for reaction solution storage, which is ideal for electrochemical reactions-related processes. This has been demonstrated on devices designed for detecting creatinine [49], adenosine [36], and hydrogen peroxide [41], etc. However, the operation of electrochemical detection often requires external power sources or signal readouts, which is subject to over-bulks experimental setup on a paper-based analytical device.
Section snippets
Categorizing enclosed paper-based analytical devices
Paper-based devices prepared by most aforementioned methods typically modify the substrates on a two-dimensional level and entail open planar channels while leaving the top side or bottom side exposed to the environment. As opposed to conventional microfluidic devices, such traits may pose problems in terms of long-term storage, accurate analysis, and practical usage [16]. In an operation of a paper-based device, functional reagents/materials are often soaked and stored in the device, which
Flow rate control
The flow rate of applied fluids in paper substrates is a key factor in terms of designing devices for different applications. Spontaneous fluid flow on conventional paper substrates are results of capillary force, which decreases with flow distance before the flow eventually stops due to the loss of solvent [23]. This liquid flow rate in paper substrates can be described by the Lucas-Washburn equation [25].where L is the distance that the fluid front travels, γ is the surface
Preserving reagent integrity
Since miniaturized devices are often aimed at operation in specified conditions and on-site settings, delicate controls of environmental factors, e.g. humidity and temperature regulation, have to be considered. These parameters, importantly, affect experimental outcomes and are correlated to qualities of incorporated chemicals or reagents. Optimal reagent storage and preservation are therefore critical in a practical device design. For instance, soft materials used to construct microfluidic
Current challenges and perspective opportunities
Paper-based analytical devices have shown to be extremely versatile and can be specifically designed to meet demands from different fields of applications. The enclosed design, specifically, pushes the frontiers of the field into a wider future and delivers opportunities for tasks hard to achieve in the past. Representative examples such as medical diagnostics, environmental monitoring, and food analysis have gained enormous support after the introduction of this design concept. The diversity
Summary and outlook
Although the advantages of adopting enclosed designs provide essential guidelines for researchers to fabricate practical devices, published studies and examples of commercialized products are still lacking nowadays due to several problems that still need to be solved by scientists and engineers. First, the enclosure material is of critical importance, as its properties have been demonstrated to provide additional merits for the device, e.g. protection against UV and flow rate control. It is
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
This work was supported by the Taiwan Ministry of Science and Technology (MOST 106-2113-M-002-015-MY2 and 108-2628-M-002-011-MY3).
Chang-Ming Wang obtained his BS and PhD degrees from Department of Chemistry, National Taiwan University in 2015 and 2019, respectively, and received Yen Thesis Award upon graduation. His research is centered around constructing portable analytical device through the use of inexpensive materials and procedures. In addition, he is also interested in the fabrication of micro/nano scale metallic structures and their practical application in diverse fields.
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Cited by (0)
Chang-Ming Wang obtained his BS and PhD degrees from Department of Chemistry, National Taiwan University in 2015 and 2019, respectively, and received Yen Thesis Award upon graduation. His research is centered around constructing portable analytical device through the use of inexpensive materials and procedures. In addition, he is also interested in the fabrication of micro/nano scale metallic structures and their practical application in diverse fields.
Chong-You Chen is currently a researcher in Material and Chemical Research Laboratories of Industrial Technology Research Institute in Taiwan. He earned his PhD degree in 2018 from National Taiwan University with Prof. Wei-Ssu Liao. He was selected as The CAS SciFinder Future Leader, Japan Visiting Researcher, The Phi Tau Phi Scholastic Honor Member, and received Yen Thesis Award in 2018. His research focuses on applying surface chemistry to molecular environment spatial control via chemical lift-off lithography, and manipulation of biomolecule anchoring, nanoparticle alignment, and microdroplet formation for analytical platforms.
Wei-Ssu Liao received his BS from National Cheng Kung University in 2000 and his MS from National Taiwan University in 2002. He received his PhD from Texas A&M University in 2009, working under the direction of Prof. Paul Cremer. Thereafter, he worked as a postdoctoral scholar with Prof. Paul Weiss and Prof. Anne Andrews at UCLA between 2009 and 2013. In 2013, he joined Department of Chemistry, National Taiwan University as a faculty member. His research experience and interests lie in bioanalytical chemistry, surface science, functional nanomaterials, and analytical devices.