Traditional detectors mostly consist of complex structures that are difficult to use. However, paper-based microfluidic chips combine the advantages of small size, high efficiency, easy processing and environmental protection. Paper-based microfluidic chips for biomedical applications focus on efficiency, accuracy, integration and innovation. As a result, continuous progress has been observed in the transition from single-channel to multi-channel detection and from qualitative to quantitative detection. These developments have improved the efficiency and accuracy of single cells and biochemical markers detection. Paper-based microfluidic chips can provide insights into multiple fields, including biomedicine and other related fields.
- paper-based microfluidics chips
- biomedicine
- biomarker
- clinical detection
1. Introduction
2. Overview of Paper-Based Microfluidic Chips
2.1. Characteristics of Paper-Based Microfluidic Chips
Microfluidic chips are small and lightweight devices with highly integrated detection. It integrates sample preparation, reaction, separation, detection, and other components at the micron scale level with fine processing technology. As a result, it can carry out complex physical and chemical processes as well as complete the whole experimental analysis, from adding samples to reading results. Therefore, it is also isalsocalled “lab on “labonchip” [5][6][7][ 5、6、7 ]. Whitesides’ research group at Harvard University in the United States proposed the concept of paper-based microfluidic analytical devices (μ µ PADs) in 2007 [8][ 8 ]. For “lab on papers”, filter paper is used as a substrate for microfluidic chips instead of inorganic or polymeric materials. There are several advantages to using paper-based microfluidic chips: the paper itself has a capillary effect, which can guide reagent flow without requiring additional power sources. Paper is relatively inexpensive, easy to obtain and process, so chip preparation cost is reduced. Similarly, the size is small and the volume is light, making it easy to transport and store. As it degrades more easily than other synthetic materials, it reduces the environmental restrictions on chips’ use and is more environmentally friendly. Thus, μ µ PADs are more economical, safer, and easier to use and transport than other microfluidic chips [ [9][10][11]9、10、11 ].2.2. Materials of Paper-Based Microfluidic Chips
The design and preparation of a paper-based material plays a decisive role in determining how well the µ μPADs will perform. There are currently three paper-based materials widely used for the production of paper chips: filter paper [ [12]12 ], nitrocellulose paper [13][ 13 ] , and glass fiber paper [14][ 14 ]. All of them have their own characteristics and applications (described in Table 1), and can also be used alone or combined with each other to achieve the overall function. Furthermore, parameters such as the thickness of the paper and the porosity of the paper also affect fluid velocity. These parameters should be taken into consideration when performing more detailed fluid control calculations [15][ 15 ].
Material |
Characteristics |
Applications |
Filter paper |
Suitable water absorption, easy to obtain, low cost, poor strength |
Suitable for all kinds of paper chips, the most widely used paper-based materials |
Nitrocellulose paper |
Preparation method of paper-based microfluidic chips.
| Methods |
Methods |
Advantages |
Advantages |
Disadvantages |
Disadvantages |
|---|
It can bind and fix protein, and high cost |
Detection based on Western blot reaction, colloidal gold test paper reaction zone |
|
Glass fiber paper |
Stable properties, not easy to break, high temperature resistance, corrosion resistance |
Detection based on chemical reactions |
3. Preparation Method of Paper-Based Microfluidic Chip
3.1. Two-Dimensional Paper Chip Preparation
Paper-based chips differ from glass, plastic, or other materials-based chips. For example, the hydrophilic channels flanked by hydrophobic barriers in paper-based microfluidic devices guide liquid flow and the reaction is etched on the substrate. As technology develops, paper chip preparation methods become more sophisticated. Paper in a broad sense includes various analytical devices prepared by simple splicing or stacking of paper-derived materials. Fluid control is undoubtedly a top priority in paper chip design [16][ 16 ]. This section focuses on common methods for making channels on paper for fluid flow (as described in Table 2) [
| Photolithography |
Photolithography |
The earliest method for making paper chips, precise channel structure [ | ||||||||
| Colorimetric method |
Colorimetric method | 20] |
The earliest method for making paper chips, precise channel structure [ 20 ] |
Intuitive results, easy to read with the naked eye, low cost [47][48] |
Intuitive results, easy to read with the naked eye, low cost [ 51 , 52 ] | The process is complicated The resulting paper chips are not suitable for bending |
Unable to achieve accurate quantitative detection [49][8 |
Unable to achieve accurate quantitative detection [ 53 ] | ] |
The process is complicatedThe resulting paper chips are not suitable for bending[ 8 ] |
| Plasma treatment technology |
Plasma treatment technology |
More suitable for mass production and have low cost [ | ||||||||
| Electrochemical method |
Electrochemical method | 21] |
More suitable for mass production and have low cost [ 21 ] |
Quantitatively accurate, fast reading [50][51] |
Quantitatively accurate, fast reading [ 54 , 55 ] | Depends on templates, reducing flexibility [22] |
Depends on templates, reducing flexibility [ 22 ] |
|||
| Rely on electrochemical workstation, increase cost and reduce flexibility | [ | 52] |
Rely on electrochemical workstation, increase cost and reduce flexibility [ 56 ] |
Wax printing |
Wax printing |
Simple processing, environmentally friendly materials [23] | ||||
| Fluorescence method |
Fluorescence method | [24] |
Simple processing, environmentally friendly materials [ 23 , 24 ] |
Low detection limit, very sensitive [53] | Low detection limit, very sensitive | [54] |
[ 57 , 58 ] | Rely on wax spray printers, heating-induced horizontal diffusion reduces structure accuracy [25] |
Rely on wax spray printers, heating-induced horizontal diffusion reduces structure accuracy [ 25 ] |
|
| Relying on fluorescence detection equipment, easily affected by the signal of paper fluorescent agent | [ | 55] |
Relying on fluorescence detection equipment, easily affected by the signal of paper fluorescent agent [ 59 ] |
Inkjet method |
Inkjet method |
|||||
| United electronics |
United electronics | Simple processing can be drawn with ink pen, no heating diffusion, more precise structure [26][27] |
Simple processing can be drawn with ink pen, no heating diffusion, more precise structure [ 26 , |
Combining the aforementioned methods enables non-professionals to obtain accurate results [56 | 27 ] |
][57] |
Combining the aforementioned methods enables non-professionals to obtain accurate results [ 60 , 61 ] | Hydrophobic inks can be toxic, ink pens are inaccurate for hand drawing, still rely on inkjet printers [28] |
Hydrophobic inks can be toxic, ink pens are inaccurate for hand drawing, still rely on inkjet printers [ 28 ] |
|
| Need to install a mobile APP or even larger devices, reducing flexibility | [4] |
Need to install a mobile APP or even larger devices, reducing flexibility [ 4 ] |
Screen printing |
Screen printing |
Ideal for mass production, simple process, and low cost [29][30] |
Ideal for mass production, simple process, and low cost [ 29 , 30 ] |
Rely on templates, greatly reducing flexibility during research [31] |
Rely on templates, greatly reducing flexibility during research [ 31 ] |
||
| Laser processing technology |
Laser processing technology |
Very precise structures can be prepared [32] |
Very precise structures can be prepared [ 32 ] |
Rely on expensive laser equipment and difficult to popularize [33] |
Rely on expensive laser equipment and difficult to popularize[ 33 ] |
|||||
| 3D origami method |
3D origami method |
3D structure has more functions, direct registration of each layer [34][35] |
3D structure has more functions, direct registration of each layer [ 34、35 ] |
Means of fixing are required between layers, only single material can be used [36] |
Means of fixing are required between layers, only single material can be used [ 36 ] |
|||||
| 3D lamination method |
3D lamination method |
3D structure has more functions, can use a variety of materials [37] |
3D structure has more functions, can use a variety of materials [ 37 ] |
Fixed means are required between layers, registration methods are required [38] |
Fixed means are required between layers, registration methods are required [ 38 ] |
|||||
| Other 3D methods |
Other 3D methods |
Highly innovative and has huge development potential [39] |
Highly innovative and has huge development potential [ 39 ] |
Special uses, difficult to promote [40] |
Special uses, difficult to promote [ 40 ] |
3.2. Three-Dimensional Paper Chips Preparation
3.2. Three-Dimensional Paper Chips Preparation
In fact, three-dimensional paper chips are just a superposition of two-dimensional paper chips, but they achieve the goal of “1 + 1 > 2”. By providing a multilayer structure and vertical flow channels, the flux of the paper chip is increased and the layers of the paper chip are enriched, allowing for a more controlled detection reaction in time and space, one of the new directions for paper chip development [41][42][44、45]. In comparison to 2D paper chips, 3D paper chips are more difficult to fabricate at a higher cost, but they are more convenient, accurate, and sensitive [43][46].
4. Analysis Method of Paper-Based Microfluidic Chip
The paper-based microfluidic chip focuses on the results being presented in a visual way. Using colorimetry, electrochemistry, and fluorescence, the paper chip can find out both qualitative and quantitative information about different substances based on their physical, biological, and chemical properties [44][45][46] (described in The paper-based microfluidic chip focuses on the results being presented in a visual way. Using colorimetry, electrochemistry, and fluorescence, the paper chip can find out both qualitative and quantitative information about different substances based on their physical, biological, and chemical properties [ 48、49、50 ] (described in Table 3).
| Methods |
Methods |
Advantages |
Advantages |
Disadvantages |
Disadvantages |
|---|