Programmable Paper-Based Microfluidic Devices for Biomarker Detections
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micromachines Review Programmable Paper-Based Microfluidic Devices for Biomarker Detections Veasna Soum , Sooyong Park, Albertus Ivan Brilian , Oh-Sun Kwon and Kwanwoo Shin * Department of Chemistry, Institute of Biological Interfaces, Sogang University, Seoul 04107, Korea * Correspondence: [email protected] Received: 1 July 2019; Accepted: 1 August 2019; Published: 2 August 2019 Abstract: Recent advanced paper-based microfluidic devices provide an alternative technology for the detection of biomarkers by using affordable and portable devices for point-of-care testing (POCT). Programmable paper-based microfluidic devices enable a wide range of biomarker detection with high sensitivity and automation for single- and multi-step assays because they provide better control for manipulating fluid samples. In this review, we examine the advances in programmable microfluidics, i.e., paper-based continuous-flow microfluidic (p-CMF) devices and paper-based digital microfluidic (p-DMF) devices, for biomarker detection. First, we discuss the methods used to fabricate these two types of paper-based microfluidic devices and the strategies for programming fluid delivery and for droplet manipulation. Next, we discuss the use of these programmable paper-based devices for the single- and multi-step detection of biomarkers. Finally, we present the current limitations of paper-based microfluidics for biomarker detection and the outlook for their development. Keywords: paper-based microfluidic device; flow control; droplet actuation; multi-step assay; biomarker detection; digital microfluidic device 1. Introduction Because of cost, disposable, paper-based microfluidic devices have become an attractive tool for point-of-care testing (POCT) and medical screening in the developing world. Paper-based, continuous-flow microfluidic (p-CMF) devices were first invented in 1949 by Müller and Clegg [1]; however, no proof of concept for the use of such devices for portable, onsite detection in biosensing applications was reported until 2007 when Whitesides’ group published their report [2]. Not only are p-CMF devices cost-effective and eco-friendly, they can also transport fluid samples via capillary action. Because capillary action in a paper channel is passive, it limits the flexibility of fluid handling. Being the focus of research by many academics, p-CMF devices were soon developed so that they could be programmed to transport fluid samples to target locations within a set time. These programmable p-CMF devices can automatically transport fluid samples in sequence for the whole of detection protocols. Therefore, they can be used in a wide range of analytical assay applications involving both single- and multi-step detection protocols. Another type of paper-based microfluidic device is the paper-based digital microfluidic (p-DMF) device, which was introduced by Shin’s group [3] and Wheeler’s group [4] in 2014, even though the first DMF had been reported by Pollack et al. in 2000 [5]. P-DMF devices transport a fluid sample (droplet) by using the electrowetting on dielectric (EWOD) technique in which a droplet is actuated by applying an electric field to electrode arrays coated with a hydrophobic dielectric layer [6,7]. Although p-DMF devices are based on the same principle as other DMF devices, they have advantageous features such as portability and the capability to deliver, delay, merge, and split small-volume samples. Because p-DMF devices are inexpensive and easy to fabricate, they are more suitable for POCT than DMF devices fabricated on plastic films [8–10], printed circuit boards (PCBs) [11,12], and glass substrates [13,14] are. Micromachines 2019, 10, 516; doi:10.3390/mi10080516 www.mdpi.com/journal/micromachines Micromachines 2019, 10, x 2 of 24 Micromachines 2019, 10, 516 2 of 25 suitable for POCT than DMF devices fabricated on plastic films [8–10], printed circuit boards (PCBs) [11,12], and glass substrates [13,14] are. Since the initial reports on p-CMF and p-DMF devices, they haveSince become the initial attractive reports onresearch p-CMF topics and p-DMF and have devices, been they developed have become for real-world attractive applications research topics in biomarkerand have been detection. developed for real-world applications in biomarker detection. Easy,Easy,low-cost low-cost fabricationfabrication is is a majora major advantage advantage of paper-basedof paper-based microfluidic microfluidic devices devices [15]. [15]. The p-CMFThe p- CMFis commonly is commonly fabricated fabricated by patterning by patterning a hydrophobic a hydrophobic material (fluidmaterial barrier) (fluid on barrier) the surface on the of hydrophilic surface of hydrophilicpaper [1,2,16 paper–18] and [1,2,16–18] cutting out and a channelcutting fromout a thechannel hydrophilic from the paper hydrophi [19–22].lic The paper paper [19–22]. channel The of paperthe p-CMF channel device of the is p-CMF inherently device a porous is inherently matrix a that porous provides matrix continuous that provides capillary continuous action capillary for fluid actiontransport. for Thefluid capillary transport. action The on capillary the paper action surface on canthe bepaper controlled surface by can way be of controlled physical and by chemical way of physicalmodifications and chemical [23–25]. Throughmodifications control [23–25]. of the capillary Through action, control the of p-CMF the capillary device canaction, be programmed the p-CMF devicefor challenging can be programmed detection protocols for challenging to manage detection the fluid protocols flow better to manage [25,26]. the On fluid the otherflow better hand, [25,26]. p-DMF Ondevices the other are fabricated hand, p-DMF by patterning devices ar conductivee fabricated electrode by patterning arrays conductive on paper substrates electrode andarrays then on coating paper substratesthe electrode and arrays then coating with a hydrophobic-dielectric the electrode arrays with layer a hydrophobic-dielectric [3,4]. Because the operation layer of [3,4]. a p-DMF Because device the operationis based on of the a p-DMF EWOD device technique, is based an electricalon the EWOD switching technique, system an and electrical a control switching software system interface and are a controlneeded software to program interface the fluid are transport needed to [27 program,28]. the fluid transport [27,28]. As analytical analytical platforms, platforms, paper-based paper-based microfluidic microfluidic devices devices are arecommonly commonly used used to transport to transport fluid samplesfluid samples and to and store to chemical store chemical reagents reagents for the for colo therimetric colorimetric and electrochemical and electrochemical detection detection of target of analytestarget analytes [29–32]. [ 29The–32 traditional]. The traditional p-CMF is p-CMF limited is by limited low sensitivity by low sensitivity and by difficulty and by in di ffiachievingculty in multi-stepachieving multi-stepassays with assays automatic with automaticprocesses processes[25]. Furthermore, [25]. Furthermore, p-DMF devices p-DMF still devices require still a requireportable a electricalportable electricalswitching switching system systemand a andcontrolled a controlled software software interface interface for forthe the assay assay protocols protocols [33]. [33]. Programming the fluid fluid transport (del (delay,ay, mix, merge, split, valve, and sequential fluid fluid delivery) in the p-DMF device provides flexibility flexibility of fluidic fluidic manipulation and opens a wide range of analytical analytical assays assays forfor a a better better detection detection result. InIn thisthis review,review, we we describe describe the the recent recent advances advances in programmable in programmable paper-based paper-based microfluidic microfluidic devices devicesfrom their from fabrication their fabrication methods methods to their to applications their applications for biomarker for biomarker detection, detection, as schematically as schematically shown shownin Figure in 1Figure. For p-CMF 1. For p-CMF and p-DMF and p-DMF devices, devices, we present we present the methods the methods used forused their for their fabrication fabrication and andthe techniquesthe techniques used used to control to control fluid fluid transport transpor int ain programmable a programmable way. way. We We give give some some examples examples of oflab-on-a-chip lab-on-a-chip applications applications using using programmable programmable paper-based paper-based microfluidic microfluidic devices. devices. We end We this end review this reviewwith a discussionwith a discussion of the current of the limitations current limita on andtions the on future and aspects the future for the aspects use of for programmable the use of programmablepaper-based microfluidic paper-based devices microfluidic in real-world devices applications. in real-world applications. Figure 1. 1. SchematicSchematic illustration illustration of of a a programmable programmable microf microfluidicluidic device device (paper-based (paper-based continuous-flow continuous-flow microfluidicmicrofluidic (p-CMF) (p-CMF) and and paper-based paper-based digital digital microf microfluidicluidic (p-DMF)) (p-DMF)) fabricated fabricated on on a a sheet sheet of of paper. paper. Various developed developed methods methods can can be be used used to toprogram program these these devices devices to manage to manage a fluid a fluidsample sample for high- for sensitivityhigh-sensitivity and multi-step and multi-step assay assaydetection detection of biomarkers