Microfluidics and Nanofluidics (2020) 24:17 https://doi.org/10.1007/s10404-020-2321-z

REVIEW

Challenges and perspectives in the development of paper‑based lateral fow assays

Surasak Kasetsirikul1,2 · Muhammad J. A. Shiddiky1,3 · Nam‑Trung Nguyen2

Received: 4 September 2019 / Accepted: 29 January 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract Lateral fow assays (LFAs) have been introduced and developed over the last half century. This technology is widely used as a tool for diagnosis in several felds such as environment, food quality and healthcare. Point-of-care (POC) diagnosis using LFAs has been attracting attention of the research community, particularly aiming for the development of a platform that can evaluate of biological markers in bodily fuids such as saliva and urine. The existence of a disease or the pregnancy can be determined by a test device, before further investigation and medical treatment. LFAs make use of a disposable test strip, which can provide diagnosis result on the spot within minutes. Thus, LFAs is a promising alternative of preliminary diagnosis for laboratory instruments that are costly, time consuming and require trained personnel. This paper includes a brief over- view of the conventional LFAs: material selection based on its roles and characteristics, working principles, fundamentals, applications, and design criteria. We mainly discuss the technical challenges in both engineering and biochemical aspects and recommends possible solutions. We identify current research trends and provide perspectives of advanced technologies for enhancing assay performance.

Keywords Paper-based microfuidics · Lateral fow assays · Point-of-care diagnosis

1 Introduction dedicated and large instruments to be diagnosed, resulting in high operation cost, delay of treatment and inaccessibility, Recently, the need for low-cost medical diagnostic devices particularly in remote areas (Kasetsirikul et al. 2016; Millot has been increasing, particularly in developing countries due et al. 2017). Consequently, point-of-care (POC) diagnostic to limited facilities and lack of qualifed medical personnel device is a well-suited alternative for replacing laboratory- (Morbioli et al. 2017; Yetisen et al. 2013). The gold stand- based equipment and skilled staf for relatively simple diag- ards of medical diagnosis such as polymerase chain reaction nosis (Sajid et al. 2015). (PCR) and enzyme-linked immunosorbent assay (ELISA) The World Health Organization (WHO) provides seven are traditionally based on lab-bench protocols, well-trained major guidelines for the development of POC devices sum- personnel and well-maintained diagnostics labs (Yager et al. marised in the acronym “ASSURED”: (1) afordable: rea- 2008; Clark et al. 2016). Moreover, advanced medical diag- sonable prices for settings composed of population at risk nosis can detect a disease in the initial stage, leading to early of infection, (2) sensitivity: few false negative and lower and successful treatment. However, some diseases require limit of detection, (3) specifcity: few false positives (4) user friendly: a few days of training and ease of use, (5) rapid and robust: acceptable waiting time, long shelf lives * Nam‑Trung Nguyen nam‑[email protected] without refrigerators and high throughput, (6) equipment- free: self-powered sources, on-site analysis, easily dis- 1 Queensland Micro and Nanotechnology Centre (QMNC), posable, and easy sample handling, and (7) deliverable: a Grifth University Nathan Campus, Nathan, QLD 4111, portable or hand-held device (Drain et al. 2014; Grace and Australia Zaman 2012; Mashamba-Thompson et al. 2017). Meet- 2 School of Engineering and Built Environment, Grifth ing these WHO guidelines, paper-based devices have been University Nathan Campus, Nathan, QLD 4222, Australia attracting extensive attention, especially because of their 3 School of Environment and Science, Grifth University Nathan Campus, Nathan, QLD 4111, Australia

Vol.:(0123456789)1 3 17 Page 2 of 18 Microfluidics and Nanofluidics (2020) 24:17 capability to be used in rural and limited resource environ- principles as well as applications of conventional LFAs is ments (Cate et al. 2015; Jiang and Fan 2016). also included to provide fundamentals for understanding Paper-based devices are cost efective, disposable and LFAs and their design criteria. can be used with different biomolecules. Paper-based devices are especially simple because of the power-free fuid transport by capillary action (Cate et al. 2015; Hos- 2 State of the art of LFAs seini et al. 2017). Paper-based materials have been used for a range of applications since the 2nd century AD in 2.1 Materials for LFAs China (Rooz 2010; Wong et al. 2009). To date, paper has been employed in lateral fow assays (LFAs), dipsticks LFAs are portable strips assembled on a plastic backing and microfuidic paper-based analytical devices (µPAD) card, consisting of diferent parts: sample pad, conjugate (Parolo et al. 2013). LFAs were frst reported in 1956 pad, fowing membrane and absorbent pad, as shown in by Plotz and Singer, who established the fundamentals Fig. 1. The fowing membrane is the area performing the of LFAs for latex agglutination assay (Singer and Plotz test, where the pre-immobilised reagents capture the analytes 1956). Since then, the working principle of LFAs has been in the sample. elaborated more and initiated extensive applications for LFAs utilise a number of biorecognition molecules, labels rapid detection of infectious diseases (Wong et al. 2009). and detection methods toward the diagnosis applications. LFAs have rapidly grown over the last few decades for The roles and material selection criteria are discussed below. qualitative and quantitative diagnosis and became a rela- tively mature technology (Sajid et al. 2015; Yager et al. 2.1.1 Sample pad 2006). Currently, LFA market value is approximately 6.0 billion USD at a compound annual growth rate (CARG) Sample pad is the frst area to get in contact with the sample. of 7.7% and is expected to reach 8.7 billion USD by 2023 The major purpose of a sample pad is to allow and maintain (Report et al. 2018). The LFA market is mainly driven liquid sample to fow through continuously. In certain cir- by the high exposure to infectious disease throughout the cumstances, if the concentration of the analytes in the sam- world, ageing population growth, high demand of POC ple is too high, fltration or dilution is required to treat the testing and home-based LFA platform (Report et al. 2018). sample before passing it through the later parts (O’Farrell LFAs beneft from advantages such as long shelf lives— 2015). Additionally, this part can be used to pretreat sample generally of 12–24 months without fridge, low cost, broad by depositing dry reagents to adjust pH for achieving proper range of applications, small sample volume, and ease of conditions for an assay (Wong et al. 2009). Therefore, the use (Sajid et al. 2015; Wong et al. 2009). Moreover, the sample pad requires a high tensile strength when it is wet. sensitivity and specifcity are determined by fow char- If the pad fails, the sample cannot be delivered through the acteristics optimisation. It depends on membrane matrix subsequent parts and the assay cannot be used for testing. and labels for biorecognition used in the assay to provide The common materials for this section are cellulose, glass acceptable qualitative and semi-quantitative readout (Sajid fbre, rayon or modifed fltration matrices (Sajid 2015; et al. 2015; Wong et al. 2009). Wong et al. 2009; Millipore 2013). During the last decade, several published review papers have discussed the recent applications of LFAs and novel materials for enhancing their performance (Yetisen et al. 2013; Sajid et al. 2015; Bahadır and Sezgintürk 2016; Hu et al. 2014). The major trend in assay enhancement is devel- oping novel materials to express more sensitivity and speci- fcity to the target, or to have multiple functions (Chen et al. 2014; Li et al. 2012; Shen et al. 2015). In addition, sample preparation can be optimised and enhanced to control and prepare the samples before introducing them into the device (Carrell et al. 2019; O’Farrell 2015). Current challenges must be clearly identifed to better understand the limitations and to provide guidelines for assay performance improve- ment. Therefore, this review mainly focuses on challenges and provides perspectives to overcome them. The review also identifes future trends of employing advanced tech- nologies in LFAs. A brief overview on materials, working Fig. 1 Conventional lateral fow assay

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2.1.2 Conjugate pad fowing in the membrane (Millipore 2013). In addition to physical characteristics of the membrane, the properties In LFAs, each strip test needs a label for capturing analytes of liquid fowing in the membrane also afect the capillary in a liquid sample and for generating a signal at the testing fow rate. Contact angle, viscosity and surface tension play and control lines. The label is modifed with protein linked important roles in regulating fow rate, because the interac- passively or covalently for specifc analytes existing in the tion between liquid and porous membrane is determined by liquid sample for biorecognition in this area. Substantial the capillary force. The governing equations for fuid fow research on labels used for LFAs has been performed. Exam- are discussed in the later section. ples are nanoparticles made of gold (Jawaid et al. 2013; Lee The stability of protein binding to the membrane mainly et al. 2015; Mdluli et al. 2014), carbon (Bogdanovic et al. afects assay performance. Long-term bonding of protein 2006; O’Keefe et al. 2003) and other metals (Park et al. prefers to employ the hydrophobic and hydrogen bonds 2015) or composited metals (Jiang et al. 2016; Yan et al. (Wong et al. 2009). Hence, selecting reagents for protein 2014) as well as modifed nanoparticles such as magnetic immobilisation needs careful consideration. Besides the fow nanoparticles (Duan et al. 2015; Wang et al. 2009), fuores- and protein binding issues, non-specifc binding is another cent nanoparticles (Li et al. 2009; Salminen et al. 2016; Jun- concern to be considered. Non-specifc binding can result in tunen et al. 2012) or quantum dot (Chen et al. 2014; Li et al. misinterpretation such as false-positive result, which causes 2012; Shen et al. 2015). There are also alternative labels overstress to the patient (Wong et al. 2009; Millipore 2013). such as carbon nanotubes (Qiu et al. 2015), enzymes (Fung The most common material for the fowing membrane is et al. 2009) and liposome (Edwards and Baeumner 2006; nitrocellulose, because it is chemically modifed with amine Wen et al. 2005). After passing through the sample pad, group which enhances protein immobilisation as well as the the analyte could be bound to the conjugated label and then proper fow characteristics which can be controlled and fow together. As a result, the most important characteristic provide acceptable reproducibility (Sajid et al. 2015; Wong of conjugate pad is releasing the label continuously as well et al. 2009; Millipore 2013). as selecting and optimising labels for proper biorecognition (Wong et al. 2009). Additionally, the matrix needs to provide 2.1.4 Absorbent pad and backing materials low binding capacity to minimise the natural bond between the label and the matrix. The common materials used for After passing through the test and control areas, the sam- conjugate pad are glass fbre, polyester or rayon. (Sajid et al. ple gets through to the absorbent pad. The purpose of this 2015; Wong et al. 2009; Millipore 2013). section is to continue wicking the liquid which allows the remaining labels and analytes to reach the test lines and pre- 2.1.3 Flowing membrane vents backfow which may cause false positive (O’Farrell 2015). Consequently, the characteristic of this part is the After following through the conjugate pad, the sample enters ability to absorb liquid sample at the end of the device and the membrane, where the testing and control area are bound high capacity for liquid drainage. The absorbent pad can with immobilised protein for capturing the analytes. This improve assay sensitivity, because it ensures that all labels is the most signifcant part that determines the assay sen- are wicked through the testing and control area. The same sitivity. The porous characteristics of the membrane allow materials as the sample pad can be used for the absorbent consistent fow of liquid sample, maintain protein stability pad (Wong et al. 2009; Millipore 2013). For backing materi- bound to the membrane for the whole shelf life and pre- als, to improve the strength and ease of handling, all pads are vent non-specifc binding. In addition to the consistent fow generally backed with a plastic card. Moreover, the backing in the membrane, the run time determined by the capillary card can maintain the assay to provide consistency for the fow rate of each membrane also afects the sensitivity of device during the operation. Otherwise, liquid sample may the assay, because the speed of the fuid fow indicate the not fow properly in the paper-based device, leading to false time exposure between the label and the capture probes at results. Backing the assay can be done in two ways which the testing and control areas (Wong et al. 2009; Millipore are hot lamination and adhesive tape. The typical materials 2013). The capillary fow rate depends on the physical prop- are polystyrene, polyester or adhesive polymer (Sajid et al. erties of the membrane: pore size, pore size distribution and 2015; Millipore 2013). porosity (Millipore 2013). Pore size is used to indicate the largest size of pore related to flter application, whereas pore 2.2 Assay formats size distribution determines the entire range of pore sizes in the membrane and defnes the capillary fow rate (Millipore Detection of biorecognition molecules is categorised into 2013). Porosity is relevant to the liquid volume acquired two basic formats: sandwich assay and competitive assay, as by the membrane, so it impacts the distribution of reagents shown in Fig. 2. For sandwich assay, the analyte reacts with

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Fig. 2 The mechanism of assay formats: a sandwich assay; b competitive assay the label, and then form a label–analyte complex. Subse- sample pad and conjugate pad. In this step, if hCG exists in the quently, the complex is captured at the test line by the inter- urine, hCG will be bound to the colour particles conjugated action between the complex and capture probes, and then with hCG antibody and form a label–analyte complex. The they aggregate to form the line. The analyte-free labels are complex fows together with the urine then pass through the also able to interact with capture probes at the control lines test line that has another hCG antibody which captures the to confrm the validity of the assay using the same mecha- complex with sandwich assay mechanism. Once the capture nism. For competitive assay, it is suitable for analytes, which occurs, the complex aggregates and forms the signal at the test- are too small to bind the label. In the presence of analytes, ing line, determining that the owner of this urine is pregnant they compete for binding site at the test line resulting in no (Yetisen et al. 2013; Hu et al. 2014; O’Farrell 2015). As the aggregation to form at the testing line (Liu et al. 2011). On expression of hCG in an early expectant mother is signifcantly the other hand, in the absence of analytes, there is no analyte higher than a non-pregnant woman, the assay easily distin- competing at the testing line, so the result of the assay would guishes these two groups. Nonetheless, in some diseases, the show two lines (Sajid et al. 2015; Hu et al. 2014). biomarker which is a disease indicator is extremely rare at the earlier stage. The sensitive assay is highly required to detect 2.3 Working principle of LFAs such a very low amount of the targets in the sample and get the treatment in time. We use the example of pregnancy strip test, to illustrate the working principle of LFAs. In an expectant mother, human chorionic gonadotropin hormone (hCG) increases signifcantly in the body shortly after the fertilization and can be found in the urine after around 7–10 days (Wide 1969). When the assay is dipped into the urine, the liquid is wicked through the

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3 Fundamental to the momentum balance equation and expressed the cor- relation of velocity term instead of acceleration towards a Flowing in porous media is mainly driven by capillary driving force (Bosanquet 1923). action resulting from hydrophilicity, surface tension and Washburn’s equation is used to predict the time of fuid porosity defned by the media properties (Yetisen et al. transport in wet-out condition so that the strip developer 2013). Capillary fuid transport can be categorised into can optimise parameters such as antibody concentration, two modes which are wet-out (dry) and fully wetted con- label concentration and the length of the strip. This equa- ditions. In this section, the governing equations of fow tion is limited to only to constant width strip. Fu et al. conditions are discussed. demonstrated that Washburn’s relation is broken when the paper strip has an expanded or contracted section (Fu et al. 2011). The fow in expansion or contraction part 3.1 Wet‑out condition still maintained the linear relation between the fuid front distance and square root of time. However, the slope deter- The fuid transport in wet-out condition of porous media mined by the width of the channel was diferent. There- can be explained by Washburn’s equation considering the fore, this equation is used to approximately predict the one-dimensional fuid fow through a bundle of small cap- time for fuid fow in the constant width. Generally, the illary tubes, neglecting gravity and evaporation. The equa- supplier provides this information for customers to choose tion of capillary flling is described as: the membrane suitable for their applications. Dt 2 = cos . L  (1) 4 3.2 Fully wetted condition With the constant strip width, L is the distance moved by fuid front (m), t is the fow time (s), γ is the sur- When the fuid approaches the absorbent pad, the pad will face tension coefcient (N/m), cosθ is the contact angle absorb the remaining fow in the membrane due to the dependence, and µ is fuid viscosity (Pa.s). The fuid prop- high density cellulose, which can acquire water and change erties also determine the fow characteristic in the mem- the fow rate. Therefore, the fuid velocity is steady. The brane. Therefore, sample treatment is preferred for some equation is derived initially from Navier–Stokes equation applications because of its impacts on the fow rate of the under the assumption of homogenization (Whitaker 1986), fuid in the membrane as well as on the sensitivity and reducing the equation described by Darcy’s law in one the specifcity of the assay (Sajid et al. 2015; O’Farrell dimension (1-D) as: D −kA 2015; Millipore 2013). is the average pore diameter Q = ΔP, (m). It is worth noting that pore size reported from the l (2) supplier is the largest diameter for fltration application 3 (Millipore 2013). Ideally, the pore size can be measured where Q is the volumetric fow rate ­(m /s), k is the per- 2 by the largest hard particles able to pass through the mem- meability of the material to fuid ­(m ), A is the area of the 2 brane. However, this method is not preferred due to the channel perpendicular to the fow ­(m ), ∆P is the pressure complexity and impractical method to implement in QC diference (Pa) along the direction fow over the length l process. Therefore, the pore size can be determined by (m) (Darcy 1856). Defning permeability coefcient of k is other techniques such as bubble point, pressure required still a problem in reality as the porous structure is not well to push air through a wet membrane. As a result, the aver- organized, because the paper is made of compressed cel- age pore diameter may introduce errors into the calcula- lulose fbre (Yetisen et al. 2013). It is difcult to simulate tion. Equation (1) indicates that the distance moved by a structure, which is random both in size and orientation the fuid front is proportional to the square root of time (Koponen et al. 1998). Numerical simulation was employed (Yetisen et al. 2013; Bell and Cameron 1905; Byrnes for another option to solve this problem. The model can be et al. 2013; Lucas et al. 1918; Washburn 1921). Conse- obtained by simulating random models or using 3D imag- quently, various researchers investigated and added some ing of the materials to generate a model for simulation. The neglected terms in Lucas–Washburn equation to the New- common numerical method used to deal with complex and ton’s second law to verify the derived solution and state irregular shapes of porous media is the lattice Boltzmann the impact of neglected term (Bosanquet 1923; Hamraoui method (Koponen et al. 1998; Benzi et al. 1992; Ginzbourg and Nylander 2002; Hamraoui et al. 2001; Ichikawa and and d’Humières 1996; Qian et al. 1992). Alternatively, the Satoda 1994; Lavi et al. 2008; Rideal 1922; Siebold et al. porosity and permeability of the membranes were measured 2000). Bosanquet et al., for instance, added fuid inertia with empirical calculation by weighing the absorbed water

1 3 17 Page 6 of 18 Microfluidics and Nanofluidics (2020) 24:17 volume to calculate velocity of fuid fow in diferent widths Thereupon, understanding the fow and establishing a math- of the test strip (Parolo et al. 2013). ematical model to predict the liquid fow in the paper strip Even though fully wetted condition cannot be applied can be used to design and handle the liquid sample in a when the fuid is frst introduced to the paper strip due to the predictable manner. There are a few methods for handling wet-out condition, Darcy’s law including its extended form the fuid fow in paper-based devices, which are discussed of Brinkman model can also be used to understand the wick- as follows. ing mechanism and to improve assay performance (Liu et al. 2018). Many studies applied Darcy–Brinkman model for 4.1.1 Varying geometries velocity fuid in many confgurations such as diferent sizes (Parolo et al. 2013), wax-printed pillar (Rivas et al. 2014) Varying geometry of the paper strip can infuence the fuid and PDMS barrier (Choi et al. 2016). Nonetheless, Darcy’s fow in the strip. Medina et al. studied the imbibition of dif- law cannot solve time-dependent problem, because this ferent shapes of the paper strip by making use of Darcy’s law equation is used for fully wetted condition which means the and Young–Laplace equation as shown in Eq. (2) to predict paper strip needs to be frst saturated, resulting in inaccurate the fow characteristic (Medina et al. 2001). The team found prediction. Moreover, Darcy’s law can be derived to simulate that their theoretical prediction was in good agreement with the electrical circuit analogy (ECA). The ECA model is a the experimental data and the model has the potential to useful technique to explain wicking behaviour. The model predict more complex shapes. Mendez et al. used numeri- utilises the analogy between fuid fow and electrical current. cal simulation to predict and design the lateral fow device Briefy, the fuid fow rate, pressure drop, and fuidic resist- by varying shapes at the end of the paper strip without ance dominated by its geometry are analogous to current, using the absorbent pad as shown in Fig. 3a (Mendez et al. voltage diference and electrical resistance, respectively. 2010). From the observation, fuid fow was divided into The ECA provides a simple way to design a complex fuidic two phases. Fluid fow in the frst phase was governed by circuit. For instance, Toley et al. introduced the ECA model Lucas–Washburn equation due to constant width of rectan- for designing the paper strip with shunt (Toley et al. 2013). gular paper strip. However, when the fuid enters the second Similarly, some studies reported that the ECA model could phase which was circularly expanded with diferent angles, be used and provided a good agreement with their experi- the velocity of liquid front broke the Washburn’s equation mental results (Cummins et al. 2017; Dharmaraja et al. because of the sudden increase of dry bed space for the fuid 2013; Tang et al. 2017). Therefore, the ECA model can be to fll. The authors suggested that this confguration could be used to explain the fuid fow of a wicking process with dif- used to replace absorbent pad which wicked the excessive ferent paper strip width. However, this model required many fuid in the system. The team found that experimental and parameters such as capillary pressure, porosity and perme- computational data were in good agreement. Nevertheless, ability, which are experimentally determined and possibly the computational data cannot be used for prediction in many result in variation in prediction. cases. Every material used for LFAs has its variation due to the fabrication. Accordingly, the constant values and defned parameters used in the model are specifc to a case and 4 Fluid handling require validation before trying new materials. Furthermore, 1-D Darcy’s law was applied to describe the fow in varying Conventional LFAs are known as a one-dimensional immu- geometries by the ECA model. Fu et al. varied paper strip noassay. The fow rate can be dictated by the type of mem- geometry using an equivalent system to predict and control brane including sample fuid properties. This section dis- the fow rate in the strip. For the expansion, from a small cusses potential applications for handling fuid fow in the to a large width, the fuid velocity becomes slower because assay including additional functions that can enhance the more time is needed to fll the pores in the wider segment. overall assay performance. This section categorised fuid From this observation, the velocity of the liquid front was handling into three main strategies: controlling the fow rate, not obeying the Washburn’s relation. While, in the case of mixing and separation. constriction, from a large to a small width, the fuid velocity remained the same (Fu et al. 2011). The liquid front velocity 4.1 Controlling the fow rate still followed the Washburn’s equation. Finally, according to the understanding of fuid fow in contraction–expansion To attain better and alternative ways to replace lab-bench paper model, a two-dimensional paper network (2DPN) approaches, a paper-based device requires a multistep pro- depicted in Fig. 3b was introduced by varying the geometry cess to allow chemicals to react in time sequences (Martinez and had potential to make a programmable paper network to et al. 2010; Wang et al. 2010). Timing is a key in control- achieve multistep process in a paper-based device (Fu et al. ling and performing multistep assay on paper-based devices. 2012; Lutz et al. 2011). Though the experiment result was

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Fig. 3 The schematic diagram to control fow rate: a the various geometries at the end of the paper strip without using absorbent pad (Mendez et al. 2010); b the use of diferent shapes to program the fow sequence (Lutz et al. 2013) in a good agreement with the computational result, Darcy’s ASSURED guideline, so this issue needs to be taken into law may be limited in practice, which needs paper to be in a account in deciding the device concept. fully wetted condition, resulting in error of the model. 4.2 Mixing 4.1.2 Fluidic valves In addition to controlling fuid fow, mixing is another The concept of valves introduces control of the fuid fow important fuid handling task in paper-based devices, par- as an on/of switch. There are passive and active modes for ticularly for processing reagents in the device. However, in controlling the fuid fow through a specifc area. The passive contrast to conventional microfuidic devices, the irregular method deposits the reagents or chemicals on the paper strip, nature of the porous media leads to unpredictable and non- since the fabrication leads to delay of fuid transport. Vari- uniform fow through the paper (Rezk et al. 2012). Mixing ous materials can be used to delay the fuid transport such in microscale relies on difusion and chaotic advection due as parafn wax (Noh and Phillips 2010), surfactants (Chen to the laminar fow in small geometries (Nguyen and Wu et al. 2012) or dissolvable reagents such as sugar (Lutz et al. 2004). Therefore, increasing the contact surface between 2013). The concentration of reagents can indicate the delay two diferent fuids and decreasing the difusion path are of transport due to the solubility of the chemicals and fuid required. Mixing can be categorised into passive and sample. However, the added chemicals may interfere with active methods. For passive mixing, the system does not and reduce assay performance. Thus, using other chemicals require external forces to actuate mixing process, which is as fuidic valve to block and delay fuids has to be carefully ideal for point-of-care diagnostic device (Rezk et al. 2012). optimised. In addition, the physical delay was also reported Many studies demonstrated simple dye colour mixing in by applying another cellulose pad on top of the main fow paper-based platform with diferent shapes of channel such membrane called as a shunt as shown in Fig. 4a, in which as zigzag and curved channels altogether with various the fow can be delayed depending on size of the pad and paper materials such as conventional Y-shaped qualitative the number of shunts used in the assay (Toley et al. 2013). grade 3 flter as well as polyester cellulose paper shown in Additionally, the mechanical activated valve operated by the Fig. 5a (Rezk et al. 2012; Zhong et al. 2015). Furthermore, user was also reported. The foldable 2D paper in the cassette a single sheet of paper was fabricated as three-dimensional (Fu et al. 2012) and 3D foldable paper (Martinez et al. 2010; channel by a unique photolithography method with two Liu et al. 2013) shown in Fig. 4b also ofer a simple way for diferent masks (Mora et al. 2019). This application illus- the user to control the fow in the device. trated the mixing by dispensing commercial dye solu- On the other hand, the active method requiring automated tions and evaluated the mixing efciency by colorimetric external force is programmable, for instance, with electric measurement. It is worth noting that transverse solute dis- (Koo et al. 2013; Mandal et al. 2012) and magnetic actua- persion mainly dominated by pore space in porous network tor (Li et al. 2013; Fratzl et al. 2018), Fig. 4c. Regardless, accomplished mixing in shorter distances than molecular using external power source and additional steps may reduce difusion. A foundation of transverse solute dispersion ease of use and require more facilities, which are against the has been reported including theory and experiments in a

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Fig. 4 The schematic diagram for delaying fow in the channel: a the use of shunt to increase the fow distance (Toley et al. 2013); b chemical depositing to delay the fow (Lutz et al. 2013); c the magnetic actuator used to lift the channel to cut fow as a switch on/of valve (Li et al. 2013)

Fig. 5 The schematic diagram for mixing in paper-based devices: a passive method using various patterns such as zigzag, curved and straight Y-channel; b SAW activation for mixing enhancement (Rezk et al. 2012)

recent study (Urteaga et al. 2018). However, it may require SAW from SPUDT to focal point on the substrate, where an extensive study for implementing immunoassay strip the channel is located. Fast, uniform and consistent mix- application. On the other hand, an active method requires ing were observed in the paper channel (Rezk et al. 2012). external force to generate disturbance for mixing such as Moreover, the team also showed that SAW increased the electrically or acoustically induced forces. Surface acous- fow rate of the fuid in the paper channel. Nevertheless, tic wave (SAW) was used to perform mixing in a paper- mixing in paper-based devices remains obscure. Precise based device, Fig. 5b. Single-phase unidirectional trans- and predictable model are required to better understand ducer (SPUDT) electrodes deposited on crystal lithium and design paper-based device for improved sensitivity niobate (NB) piezoelectric materials generated a Rayleigh and multistep assay (Carrell et al. 2019).

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4.3 Separation symptoms and mental problems such as anxiety or stress (Nakhal et al. 2012). Therefore, the development of LFAs Paper was introduced for separation applications since the needs to overcome several current limitations, which are 1940s and it is known as paper chromatography (Martin and categorised into engineering and biochemical challenges, Synge 1941; Whelan 1995). This material was frst used as summarised in Fig. 7. to separate amino acid sequence of insulin (Sanger 1988). Since then, researchers have been using paper for various 5.1 Engineering challenges applications. In the 1950s, few studies involved protein characterization with electrophoresis. The protein stained 5.1.1 Materials and fabrication the paper as a band depending on its molecular weight of each molecule under an electric feld (Kunkel and Tiselius Paper-based materials lack control of physical properties 1951; Zweig et al. 1971). This technique was refned and such as capillary fow rate, surface area, pore size distribu- used as a conventional blotting, which is nowadays the gold tion, porosity, permeability, and wettability. Batch-to-batch standard for proteomic studies. Furthermore, separation variation leads to inconsistency particularly the diference on paper-based materials has been also extended to LFAs in fabrication process from diferent manufacturers (Li et al. technology. Shiroma et al. demonstrated the use of chro- 2010). As a consequence, physical and chemical modifca- matographic paper for electrochemical detection. Three tion are required to treat the surface of paper-based devices integrated electrodes separate analytes with low voltage to enhance fuid fow, colour uniformity and protein immo- and can detect paracetamol and 4-aminophenol (Shiroma bilisation (Cate et al. 2015). For example, Park et al. pressed et al. 2012) as shown in Fig. 6a. Zhong et al. used simple the nitrocellulose membrane to reduce the pore size caus- geometry to separate free dye from the mixed protein solu- ing delayed fuid fow (Park et al. 2016). Moreover, treating tion and demonstrated the capability of controlling capillary membrane with surfactant and detergents results in decreas- action, which is potentially useful for future development of ing protein binding, but also leads to improving wettability paper-based devices (Zhong et al. 2015). Due to the com- of the membrane (Millipore 2013). Excessive modifcation plex structure of the paper-based materials, it is difcult to might also contaminate papers when it is exposed to other control the interconnected pores for separation applications. chemicals or reagents (Cate et al. 2015). Therefore, manu- Hence, further research is needed to better control the porous facturers optimised the right detergent concentration to use structure. Correspondingly, the porous paper must be opti- with the membrane in the fabrication process. Furthermore, mised for applications with more complex solutions. environmental factors such as humidity and temperature afect the quality of LFA products, because nitrocellulose membrane is fragile, has a short shelf life and is dependent 5 Current challenges on environment variation, resulting in invalid evaluation of strip test (Hu et al. 2014). Controlling the storage and test Sensitivity and specifcity are important indicators for vali- conditions is another approach for improving the reproduc- dating LFAs. Conventional paper-based platform may not ibility of LFAs. However, it is impractical for use in a harsh have enough sensitivity to perform well in clinical appli- environment such as a feld test. cations, otherwise the result can be misinterpreted as false Devising alternative materials is still challenging, as negative and false positive, which will tremendously impact novel materials need to prove its performance and gain the patient through unsafe behaviour, unexpected consequent acceptance from the market. Further risk is from the cost

Fig. 6 The schematic diagram for separation: a the use of paper-based electrochemical device to separate and detect paracetamol and 4-aminophenol (Shiroma et al. 2012); b the illustration of protein separation using paper-based device for simple geometry (Zhong et al. 2015)

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Fig. 7 The summary diagram of the current challenges and possible solutions to improve the LFAs of manufacturing development and scaling up for mass pro- immobilisation of reagents is dispensing or dipping and dry- duction. Some researchers suggested that the development ing in a controlled condition. The dissolution of reagents is of new materials and improved facilities or technology is based on inherent solubility, particle size, viscosity, fow preferred to better control of the LFA performance (Wong rate, pH, ionic strength of the solvent, porosity, uniformity et al. 2009). Advanced printing technology which is one of of paper matrix (Fridley et al. 2012; Osborn et al. 2010). promising technologies can deposit a broad range of materi- Likewise, another challenge involving chemicals used in the als such as metals and nanoparticles that might improve the LFAs is preserving biochemical activity in the strip such as assay performance and yield better reproducibility (Ahmed sugars (discussed later in the Sect. 5.2.4) (Dungchai et al. et al. 2016). For example, Yu et al. demonstrated inkjet- 2010; Guan et al. 2014; Martinez et al. 2008). The ideal printed surface-enhanced Raman spectroscopy (SERS) LFAs need a long shelf life without refrigeration as stated on paper-based surface swab and lateral fow dipstick for by the WHO guideline. On the contrary, some assays using trace chemical detection (Yu and White 2013). The paper natural reagents require special care to preserve the biomol- absorbed the chemical and was later analysed with SERS. ecules, leading to invalid and inefcient testing in remote Moreover, enzymatic solution such as horseradish peroxi- locations or in a harsh environment. As a result, many dase (HRP) could be printed with piezoelectric inkjet print- researchers attempted to replace natural biomolecules by ing without damaging its properties (Di Risio and Yan 2007; developing aptamers, artifcial receptors which is specifc to Khan et al. 2010). Even though many biomolecules could be the target, or nanozymes, nanoparticles possessing enzyme- printed, the viscosity of the solution and biological proper- like activity (Ahmed et al. 2016; Liang et al. 2016; Wei et al. ties are a major concern requiring considerable optimisation. 2016). Recently, these units successfully proved the func- In addition to paper engineering, the selection of rea- tionality of rehydration and biorecognition in LFAs for the gents in LFAs also impacts their reproducibility. The simple possibility to replace natural reagents in LFAs (Dalirirad and

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Steckl 2019; Frohnmeyer et al. 2019). Therefore, market- et al. 2017). Thus, biorecognition activities among these bio- ready LFAs need to be carefully optimised in terms of physi- molecules are another critical challenge to be addressed for cal properties and reagents to ensure that they do not sufer enhancing the sensitivity and specifcity of the assay. from reproducibility and technical issues originating from the fabrication process and the materials. 5.2.2 Pretreatment challenges

5.1.2 Flow characteristics Using human body fuid sample such as blood, urine and saliva without a preparation step is ideal for performing Capillary fow rate is infuenced by the diferent substrates LFAs in clinical applications (Sajid et al. 2015). Complex provided by the manufacturers. For example, Millipore pro- compound suspending in blood sample or others impacts vides broad options of Hi-Flow Plus nitrocellulose mem- assay performance, so it is recommended to flter unneces- brane from HF075 to HF240. The number indicated the sary elements out before loading into the LFAs (Sajid et al. required time in seconds for the fuid to reach a distance of 2015). These elements can chemically block the biorecog- 4 cm. It is worth noting that the membrane with faster capil- nition events at the conjugate pad or testing line leading to lary fow rate has a higher specifcity and lower sensitivity false negative. In the case of blood, complex biomolecules (Millipore 2013). For instance, Mao et al. demonstrated that and high viscosity also afect the fow in the membrane and they can signifcantly get a higher signal at the test line with the sensitivity of the assay (Millipore 2013). In some cases, HF240 rather than with HF180 (Mao et al. 2009). Any assay a high concentration of analytes in the liquid sample also requires the optimal point among the following parameters: results in false negative, which is known as the Hook efect sample working volume, sensitivity, specifcity and espe- (Oh et al. 2014). Many solutions also have been provided cially assay reaction times. Furthermore, the backfow in without using lab-bench equipment such as simple dilution the absence of absorbent pad or defect in the paper might with bufer or flter cassette for red blood cells separation occur, leading to a false-positive signal. Thus, the complete- (O’Farrell 2015). Therefore, LFA developers have to design ness and robustness of each LFA device also need to be additional components, if sample preparation is needed for concerned. easy handling.

5.2 Biochemical challenges 5.2.3 Multiplex detection

5.2.1 Reagents and labels In a common practice, several analytes are required to be detected for the accurate diagnosis and confrmation of the One of the most important components determining the disease in one patient. A multiplex assay would be ideal for sensitivity and specifcity is the label for capturing target performing multiple analytes detection in a single test. There analytes in the liquid sample. The most common material are a few assays reported to date. For example, Dineva et al. used in LFAs is colloidal gold nanoparticles due to the ease deposited diferent colour particles and multiple capture of functionalization for better specifcity, chemical inertness probes with diferent test lines. The assay provided the semi- and its exceptional optical properties (Kavosi et al. 2014). quantitative result by evaluating the colour intensity with However, this material is limited for getting higher sensi- score (Dineva et al. 2005). This strategy was implemented tivity in some clinical applications. The diagnosis of some for various diseases with diferent biomarkers in individual diseases may require additional steps to purify the sample test strips (Chen et al. 2016a, b; Lee et al. 2016; Zhang et al. for detecting rare target analytes. The additional steps are 2018). Diferent methods such as multiple parallel channel, against the concept of equipment-free POC and difcult star shape, or arrays of strip were also reported (Fenton et al. to penetrate the clinical practice. Consequently, various 2009; He et al. 2018; Yonekita et al. 2013; Zhao et al. 2016). research groups have introduced alternative labels as men- The major concern of multiplex detection is the specifcity of tioned in the previous section to better capture the target ana- the multiplex assay due to cross-reactivity particularly when lytes and amplify the signal leading to improving sensitivity the assay is involved with multiple analytes in the liquid and specifcity (Bahadır and Sezgintürk 2016). Furthermore, sample. Therefore, the selection of immunological probes the selecting type of biorecognition needs to be carefully in the testing strip needs to be carefully optimised. considered. Typically, conventional LFAs employed immu- noassays which rely on binding between specifc antigen 5.2.4 Readout and antibody. To date, many studies have been reporting diferent approaches such as nucleic acid hybridization or Conventional LFAs are considered as a qualitative or semi- avidin–biotin reaction (Hu et al. 2014; O’Farrell 2015; Tang quantitative assay. The assay only requires some threshold et al. 2017; Mao et al. 2009; Jauset-Rubio et al. 2016; Ying to highlight the indicator line by particle aggregation after

1 3 17 Page 12 of 18 Microfluidics and Nanofluidics (2020) 24:17 binding specifcally between label–analyte complex and data for clinical practice, as these data are important for capture probe known as immunoassay. However, a quanti- screening the patient for preliminary diagnosis or rapidly tative assay needs a tool to evaluate the signal such as colour acquiring the data for follow-up results. intensity or electrochemical signal, which requires multi- function labels to produce a clearer or more amplifed sig- nal to be better quantifed by the reader. For a colorimetric 6 Conclusions and perspectives assay, evaluating by naked eyes results in human bias and misinterpretation (Dungchai et al. 2010). Thus, the assay LFA technology has evolved for over 50 years. Equipped needs a reader to digitize the data from colour to numerical with the ease of use, afordability and rapid diagnosis, LFAs data. The advancement in smartphone technology allows have been employed in a broad range of applications from images to be taken and analysed immediately (Hosseini health monitoring, veterinary feld work, environmental test- et al. 2017; Ahmed et al. 2016; Hayes et al. 2018). Nonethe- ing, agricultural goods and other industries. Being a mature less, image quality may vary depending on diferent soft- technology, LFAs have been proven overtime for maintain- ware and hardware as well as environmental factors such as ing the quality of the assay, which are sensitivity, specifcity, the amount of light while taking the image (Dungchai et al. reproducibility and assay stability, for mass production and 2010). Thereupon, self-calibration strategies were employed market acceptance. A huge change in manufacturing pro- to solve the image quality issue (Fang et al. 2014; Hao et al. cess or technological disruption would lead to high cost of 2014; Weaver et al. 2013). Moreover, the development of investment (Wong et al. 2009). Thus, further development smartphone-based paper sensor rapidly increased in the last of LFAs would need a novel detection concept ofering more few years (Yang et al. 2017). Image acquisition, high quality sensitivity and specifcity without much change in fabrica- of camera and image processing application are combined tion process and more controllable system to better enhance to analyse the data, which are successfully demonstrated in reproducibility to maximise the assay performance. On the a broad range of applications such as monitoring environ- other hand, recent paper-based platforms such as µPAD hav- mental pollutions (Ismail et al. 2016; Sicard et al. 2015) or ing been initiated for a few decades ago have attracted con- disease screening (Jain et al. 2015; Mu et al. 2015). siderable attention from researchers and developers of POC Furthermore, stability of the reagents used in the assay diagnosis. The platform technology also requires reproduc- also afects the outcome signal (Morbioli et al. 2017). Some ible fabrication process to maintain the assay performance studies have made use of enzymatic activity to perform col- and reliable diagnosis. The development of diagnostic assays orimetric assay. However, improper storage can cause loss also needs venture capitalist to support fnancially to further of activity including external environments such as tempera- improve the assay performance or to establish trustworthy ture, pH and humidity (Dungchai et al. 2010; Martinez et al. and controllable facilities. Furthermore, due to the com- 2008). Additives such as sugars are used to stabilise enzyme plex structure of cellulose-based materials resulting in poor in the assay (Dungchai et al. 2010; Guan et al. 2014). For reproducibility, it is difcult to predict and simulate fow example, trehalose was frst used with enzymatic assay in the porous membrane with analytical or numerical mod- (Martinez et al. 2008). Trehalose can keep a large amount of els. Understanding the physics of paper-based system is one water, which helps to maintain the enzyme fresh and active of the possibilities to better control the fow in the porous during storage period. Other sugars like dextran are also membrane and open up the technology to more applications. implemented for the same purposes. Thus, the reagent pres- Early-stage disease detection is vital for medical diag- ervation is one of the potential strategies to allow the signal nosis. The earlier the disease is detected, the higher is the reader to better analyse the data. survival rate of the patient because the treatment can start In addition, several research groups have made use of in time. In some cases, the survival rate of early-detected luminescent labels such as fuorescent, chemiluminescent or cancer can reach up to 93% (Torre et al. 2018). However, at electro-chemiluminescent detection. Luminescent signal can an earlier stage, a disease does not show any symptom and reduce the limit of detection less than that of colorimetric produces a minute amount of specifed biological markers, assays by reducing background noise, which is considered as which is very difcult to detect in common LFAs. Therefore, more sensitive and quantitative detection methods (Morales- developing sensitive and specifc LFAs to detect rare cells Narváez et al. 2015; Hu et al. 2017; Takalkar et al. 2017). is required. Several ways to develop assay performance are However, luminescent assays require a reader with specifc discussed here. Improving materials for multifunctionalities excitation and emission flters. Hence, the development of to avoid sample pretreatment is implemented (Sajid et al. the reader and label selection plays an important role in the 2015). For instance, an additional fltration cassette can be measurement and quantifcation of signal intensity (Cate utilised to remove unnecessary molecules out within minutes et al. 2015) In summary, detecting biological targets such before loading the sample into the lateral fow device as as proteins circulating in bloods may require quantitative shown in Fig. 8a (O’Farrell 2015). Self-fltration function

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Fig. 8 Possible strategies for improving assay performance: a the cas- testing lines, parallel channels in a single strip and an array of strip sette for collecting blood, fltering red blood cells out, delivering the tests capturing diferent targets in the samples (Fenton et al. 2009; He running bufer (O’Farrell 2015); b double conjugation by adding sec- et al. 2018; Zhao et al. 2016) ond conjugated pad to amplify the signal (Hu et al. 2013); c multiple could enhance sensitivity and specifcity, because some ele- quantitative data of proteins, nucleic acids and other mark- ments which interfere with the detection process are already ers (Hu et al. 2014). Many research groups have ofered all- removed. In addition, adapting some parts in LFAs was also in-one devices to collect, analyse, and quantify the data in demonstrated. Many studies combined additional conjugated one device. Recently, there are several paper-based devices pads which are specifc to nanoparticles in the other con- with integrated circuits and self-powered systems have been jugated pad as shown in Fig. 8b (Hu et al. 2013; Wu et al. demonstrated for monitoring glucose (Cao et al. 2019; Cho 2018) to amplify the signal as a testing line. Moreover, a et al. 2017; Xiao et al. 2019). Cho et al. demonstrated paper- multiplex platform is required to confrm the existence of the based sensor patch with a self-powered system. Sweat was disease, because identifying some diseases requires multiple wicked through the direction shown in Fig. 9a. When the biomarkers for the diagnosis especially the detection of rare sweat reaches the hydrophilic reservoir layer, the glucose in cells. Thus, detecting multiple analytes with a single test the sweat reacts with glucose oxidase (GOx) on the paper would be ideal as shown in Fig. 8c. There have been sev- and generates free electron by oxidation reaction. In this eral studies performing multiple lines to detect targets in the design, the device can be performed without external power sample, which is probably used to detect multiple rare ana- source because it made use of enzymatic fuel cells (Choi lytes (Song et al. 2014; Tsai et al. 2019). Correspondingly, et al. 2016; Wang et al. 2012; Zhou 2015) which GOx layer combining with advanced material technology, novel mate- (Anode) oxidized glucose and air cathode (Cathode) reduced rials and new detection techniques can be used to perform oxygen. Thus, the current output as a transducing signal was in LFAs for signal enhancement and amplifcation to better related to the glucose concentration (Cho et al. 2017). Xiao detect rare cells in human samples. The label may perform as et al. reported the use of paper-based patch for monitor- a dual-function sensor which is detecting rare cells in human ing glucose, Fig. 9b. The patch was equipped with wearable sample directly before purifcation and reacting with specifc clothes. Sweat from the volunteer during exercise is wicked chemicals or external stimulus to emit the signal at a testing sweat by capillary forces from absorbent pad to testing area area. All possible strategies published recently require an where the glucose oxidase and colorimetric assay were extensive study and knowledge transfer from the lab-bench deposited. The result was analysed with colorimetric assay protocol to commercial products launched in the market. by a smartphone (Xiao et al. 2019). However, the amount of The major limitation is the fact that LFAs are qualita- sweat generated by the users, type of exercises and environ- tive or semi-quantitative assays. Typically, the signal gen- ment conditions such as temperature or humidity may result erated in the LFAs is the colour intensity that only reports in a variation of tests. To overcome these issues, advanced yes/no result. Most clinical applications, however, require technologies of smartphones or self-powered system and

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Fig. 9 The use of paper-based sensor to monitor glucose: a combin- wearable clothes to monitor glucose with a colorimetric assay with ing with a self-powered system on bandaid tape with current response smartphone (Xiao et al. 2019) from the electrochemical activity (Cho et al. 2017); b attaching with artifcial intelligence (AI) enable on-site testing to become video calls. If the test result is abnormal, the doctor can easier due to its multifunction, such as taking high-quality generate electronic prescription. In more serious cases, photos, analysing data with AI or uploading data for cloud the doctor is able to call for further diagnosis if the result computing. With the onset of advanced technology, it also potentially develops an early stage of some severe diseases opens up another medical diagnostic trend such as the shift such as cancer. All steps can be done without going to the in healthcare to a more personalised approach, leading to hospital, thus reducing cost, time and risk of spreading the home-based health monitoring and on-site testing (Ahmed disease in the public. In conclusion, the combination of et al. 2016). LFAs and paper-based platforms as well as smartphone is With the emergence of supportive data infrastructure a trend towards better qualitative and quantitative analyses, such as 5G technology, cloud data storage and retrieval, ofering an alternative for preliminarily disease screening telemedicine will be possible (Yetisen et al. 2013; Stefano at home, on-site as well as in remote locations without the and Kream 2018). In the foreseeable future, people can need for lab-bench equipment. access the assay at the pharmacy near their home with an afordable price. They can do the test at home within Acknowledgements The authors acknowledge the support of the Aus- tralian Research Council (DP180100055) and higher degree research minutes, and then upload the data within seconds directly scholarships GUIPRS and GUPRS Scholarships to S.K. from the Grif- and confdentially to the doctor. Accordingly, patients can fth University. ask for a private consultation with the practitioners using

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