CN115350733A - Microfluidic chip of liquid drop storage cavity with single-layer inclined structure and preparation method thereof - Google Patents
Microfluidic chip of liquid drop storage cavity with single-layer inclined structure and preparation method thereof Download PDFInfo
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- 238000003860 storage Methods 0.000 title claims abstract description 41
- 239000002356 single layer Substances 0.000 title abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 239000000758 substrate Substances 0.000 claims abstract description 10
- 238000001514 detection method Methods 0.000 claims abstract description 7
- 239000004568 cement Substances 0.000 claims abstract description 6
- 239000003292 glue Substances 0.000 claims description 11
- 108090000623 proteins and genes Proteins 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
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- 238000000465 moulding Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
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- 125000006850 spacer group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000003752 polymerase chain reaction Methods 0.000 description 11
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- 241001678559 COVID-19 virus Species 0.000 description 4
- 230000003321 amplification Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000003199 nucleic acid amplification method Methods 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000007847 digital PCR Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
- B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6813—Hybridisation assays
- C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
- C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
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Abstract
The invention relates to a microfluidic chip of a liquid drop storage cavity with a single-layer inclined structure and a preparation method thereof, wherein the chip comprises: the liquid drop storage device comprises a structural sheet and a substrate sheet, wherein the surface of the substrate sheet is provided with solidified plastic cement, and the structural sheet covers the solidified plastic cement and forms an inclined structure liquid drop storage cavity. Aiming at liquid drops with different sizes, the liquid drop detection device can be adapted by simply replacing gaskets with different thicknesses, and has high compatibility; simple structure, low manufacturing cost and easy mass production.
Description
Technical Field
The invention belongs to the field of microfluidic chips, and particularly relates to a microfluidic chip with a single-layer inclined structure liquid drop storage cavity and a preparation method thereof.
Background
Nucleic acids are carriers of biogenetic information and any disease can find evidence at the genetic level. The gene analysis is helpful to deeply exploring the root cause of diseases, designing targeted drugs and comprehensively understanding the interaction mechanism of individuals and the environment.
In 1985, mullis invented the Polymerase Chain Reaction (PCR), a simple DNA amplification method. Vogelstein et al proposed the concept of digital PCR (dPCR) at the end of the 20 th century. A sample is diluted in a large quantity and distributed to different reaction units, each reaction unit comprises at least one copy molecule (DNA template), then the molecules in each reaction unit are amplified, and after the amplification is finished, the fluorescence signal in each reaction unit is statistically analyzed, so that the single-molecule amplification is really realized, and the method is called as an absolute quantitative technology.
Commercial digital PCR instruments available on the market include the QX200 system developed by BioRad and the Naica crystal microdroplet PCR system of Stilla Technologies. The QX200 system needs three instruments for completing the generation, amplification and technical analysis of liquid drops, disperses the prepared PCR reaction reagent into tens of thousands of liquid drops, and collects the liquid drops in a structure similar to a centrifugal tube; then, carrying out PCR reaction; and finally, guiding the reacted liquid drops into an analysis chip for reading the result. The Naica crystal microdroplet PCR system of Stilla Technologies company collects the dispersed sample liquid drops in the liquid drop collecting cavity of the chip in a monolayer arrangement, then the liquid drops do not need to be transferred any more, PCR reaction is carried out, and finally the reaction result is read. The oil phase adopted by the two systems is fluorinated oil which is easy to volatilize, so that higher requirements are provided for the design of a reaction container, and the cost is increased.
The influence of bubbles on the stability of liquid drops is one of important factors for restricting the application of the liquid drop microfluidic chip. In order to meet the market application requirements of the droplet microfluidic chip, improve the stability of the droplet microfluidic chip, simplify the operation and reduce the manufacturing cost, the droplet microfluidic chip with a novel structure is designed to have certain practical significance.
Disclosure of Invention
The invention aims to solve the technical problem of providing a microfluidic chip with a liquid drop storage cavity of a single-layer inclined structure and a preparation method thereof.
The invention provides a microfluidic chip, which comprises: the liquid drop storage device comprises a structural sheet 1 and a base sheet 2, wherein the surface of the base sheet 2 is provided with solidified plastic cement 3, and the structural sheet 1 covers the solidified plastic cement 3 and forms an inclined structure liquid drop storage cavity 4.
The structural sheet 1 is a structural sheet with a micro-channel, and the surface of the structural sheet is provided with micro-droplet generation water phase holes 11 and micro-droplet generation oil phase holes 12.
The solidified plastic adhesive 3 is arranged between the structure sheet 1 and the base sheet 2 and plays a supporting role.
The micro-droplet generation water phase hole 11 and the micro-droplet generation oil phase hole 12 are respectively arranged at two sides of the structural sheet.
The solidified plastic cement 3 is U-shaped.
The inclined structure liquid drop storage cavity 4 is a U-shaped inclined structure liquid drop storage cavity, wherein the height of the opening side of the U shape is higher than that of the closed side of the U shape.
Preferably, the height difference between the height of the U-shaped opening side and the height of the U-shaped closing side is 20-500 μm.
Further preferably, the height difference is 80-100 μm.
The structural sheet 1 and the base sheet 2 are connected by a gasket.
The invention discloses a preparation method of a micro-fluidic chip, which comprises the following steps:
(1) The surface of the substrate sheet is solidified with plastic glue and is in a U shape;
(2) Gaskets are arranged at two ends of the substrate sheet, and the gasket arrangement needs to ensure that the opening side of the solidified moulding glue is higher than the closed side;
(3) Covering the structural sheet above the solid plastic adhesive, and fixing to form a U-shaped inclined structure liquid drop storage cavity;
(4) And solidifying and forming the droplet microfluidic chip.
The height difference in the step (2) is 20-500 mu m.
The invention relates to a micro-fluidic chip prepared by the method.
The invention relates to application of the microfluidic chip in gene detection, such as new coronavirus gene detection.
The realization principle of the invention is that when a large number of liquid drops (more than 1 ten thousand) are generated and enter the storage chamber to be densely arranged, the inclined structure chamber is gradually enlarged along with the space, thereby effectively improving the liquidity of the liquid drops, reducing the phenomena of stacking, extrusion, friction and the like among the liquid drops, realizing the stable and efficient enrichment of the liquid drops in a microenvironment and facilitating the later statistical analysis of the liquid drops. In addition, the method combines the mineral oil, well meets the advantage that the oil phase is not easy to volatilize in the PCR process, enhances the consistency of liquid drops and improves the PCR amplification efficiency.
Furthermore, a large amount of liquid drops generated by the structural sheet enter the bottom of the storage chamber to be arranged, the liquid drops on the closed side of the U-shaped bottom gradually fill the U-shaped bottom along with the increase of the number of the liquid drops, then the liquid drops are continuously arranged towards the side of the U-shaped bottom, the space of the chamber on the opening side is gradually increased, the liquidity of the liquid drops is effectively increased, the phenomena of stacking, collision, friction and the like formed by the accumulation of the large amount of liquid drops are reduced, the stable and efficient enrichment of the liquid drops in a microenvironment is realized, and the statistical analysis of the liquid drops in the later period is facilitated. Meanwhile, in the PCR reaction process, the inclined opening chamber is beneficial to the removal of bubbles from the opening side, and the stability of liquid drops is ensured.
Advantageous effects
The U-shaped inclined structure droplet microfluidic chip has the following advantages: 1. the U-shaped inclined structure cavity design reduces the phenomena of stacking, collision and friction formed by accumulation of a large amount of liquid drops, and realizes stable and efficient enrichment of the liquid drops; 2. the air bubbles in the chamber can be moved out easily, the interference influence of the air bubbles on liquid drops is reduced, and the PCR amplification efficiency is improved; 3. aiming at liquid drops with different sizes, the liquid drops can be adapted by simply replacing gaskets with different thicknesses, and the compatibility is high; 4. simple structure, low manufacturing cost and easy mass production.
Drawings
FIG. 1 is a schematic view of a microfluidic chip with a single-layer inclined structure liquid drop storage cavity; wherein 1 is a structural sheet; 11 micro-droplets form a water phase hole; 12 micro-droplets generate oil phase pores; 2 a substrate sheet; 3, solidifying the molding glue;
FIG. 2 is a cross-sectional view of a microfluidic chip inclined chamber of a droplet storage chamber with a single-layer inclined structure; 1, a structural sheet; 2 a substrate sheet; 3, curing the molding glue; 4a tilted structure droplet storage chamber;
FIG. 3 is a diagram of an example of a microfluidic chip with a single-layer inclined droplet storage chamber;
FIG. 4 (A) shows the distribution of droplets in the storage chamber of the microfluidic chip with the inclined structure before PCR amplification; (B) The liquid drops in the storage cavity of the micro-fluidic chip with the inclined structure after PCR amplification are distributed; (C) is a local amplified liquid drop distribution effect diagram in the storage cavity;
FIG. 5 shows the droplet distribution after PCR amplification of the droplet microfluidic chip with a tiled structure;
FIG. 6 is a graph showing the results of fluorescence after PCR amplification of ORF-1ab gene of 2019-nCoV.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Example 1
A microfluidic chip comprising: the structure piece comprises a structure piece 1 and a base piece 2, wherein the surface of the base piece 2 is provided with U-shaped solidified plastic glue 3, the structure piece 1 covers the U-shaped solidified plastic glue 3 and forms a U-shaped inclined structure liquid drop storage cavity 4, and the height of the opening side of the U-shaped inclined structure liquid drop storage cavity is higher than that of the closed side of the U-shaped inclined structure liquid drop storage cavity; the structural sheet 1 is a structural sheet with a micro channel, and the surface of the structural sheet is provided with micro-droplet generation water phase holes 11 and micro-droplet generation oil phase holes 12.
The preparation method comprises the following steps:
(1) The surface of the substrate sheet is solidified with plastic glue and is in a U shape;
(2) Placing gaskets at two ends of the substrate sheet, wherein the gasket placement needs to ensure that the opening side of the solidified moulding adhesive is higher than the closed side, and the height difference is 80-100 mu m;
(3) Covering the structural sheet above the solid plastic adhesive, and fixing to form a U-shaped inclined structure liquid drop storage cavity;
(4) And solidifying and forming the droplet microfluidic chip.
The microfluidic chip with the single-layer inclined structure liquid drop storage cavity is used for ORF-1ab gene detection of 2019-nCoV, and specifically comprises the following steps:
1. ORF-1ab Gene plasmid according to 1X 10 5 、1×10 4 、1×10 3 And 0 copies/. Mu.l, and mixed with reagents such as PCR buffer, primers, probe, etc. in a ratio to prepare an aqueous phase.
2. And (3) generating liquid drops by using the microfluidic chip of the liquid drop storage cavity with the single-layer inclined structure, and putting the chip into a PCR instrument for amplification.
3. The results of detection of the respective concentrations of ORF-1ab gene are shown in FIG. 6.
As shown in fig. 4, fig. 4A shows the droplet distribution in the storage cavity of the microfluidic chip with the inclined structure before PCR amplification; FIG. 4B shows the distribution of droplets in the storage chamber of the microfluidic chip with the inclined structure after PCR amplification; fig. 4C is a diagram of the effect of local enlarged droplet distribution in the storage chamber, and it can be seen that the inclined structure is advantageous to droplet distribution and stabilization, and stacking, collision, and friction phenomena caused by accumulation of droplets are reduced.
Comparative example 1
And replacing the microfluidic chip of the single-layer inclined structure liquid drop storage cavity for detecting the ORF-1ab gene of the 2019-nCoV with a flat-type structure liquid drop microfluidic chip for detection. The flatly-laid structure droplet microfluidic chip (see CN 202011187731.3) adopts two layers of glass which are horizontally aligned and attached to form a droplet storage chamber, and droplets enter the chamber to be horizontally spread and arranged after being generated.
As shown in FIG. 5, the droplet distribution after PCR amplification of the droplet microfluidic chip with the tiled structure can obviously show that larger bubbles exist in the chip chamber, which seriously affects the stability of the droplet and causes the deviation of later-stage droplet counting and analysis.
By comparing the results of fig. 4B and fig. 5, it can be determined that the design of the inclined structure storage chamber improves the droplet storage environment, ensures the high efficiency of droplet enrichment, and is beneficial to the PCR amplification efficiency. Both chips in FIG. 4 and FIG. 5 pick the ORF-1ab gene plasmid 1X 10 of 2019-nCoV 5 copies/. Mu.l concentration for experimental comparison.
Claims (10)
1. A microfluidic chip, wherein the chip comprises: the liquid drop storage device comprises a structural sheet (1) and a base sheet (2), wherein the surface of the base sheet (2) is provided with solidified plastic glue (3), and the structural sheet (1) covers the solidified plastic glue (3) and forms an inclined structure liquid drop storage cavity (4).
2. The microfluidic chip according to claim 1, wherein the structural sheet (1) is a structural sheet with micro channels, and the surface of the structural sheet is provided with micro-droplet-generating water phase holes (11) and micro-droplet-generating oil phase holes (12).
3. The microfluidic chip according to claim 1, wherein the solidified plastic cement (3) is U-shaped.
4. The microfluidic chip according to claim 1, wherein the inclined structure droplet storage chamber (4) is a U-shaped inclined structure droplet storage chamber, and the height of the opening side of the U-shaped inclined structure droplet storage chamber is higher than that of the closing side of the U-shaped inclined structure droplet storage chamber.
5. The microfluidic chip according to claim 4, wherein the height difference is 20 μm to 500 μm.
6. The microfluidic chip according to claim 5, wherein the height difference is 80 μm to 100 μm.
7. Microfluidic chip according to claim 1, characterized in that the structural sheet (1) and the base sheet (2) are connected by a spacer.
8. A method for preparing a microfluidic chip comprises the following steps:
(1) The surface of the substrate sheet is solidified with plastic glue and is in a U shape;
(2) Gaskets are arranged at two ends of the substrate sheet, and the gasket arrangement needs to ensure that the opening side of the solidified moulding glue is higher than the closed side;
(3) Covering the structural sheet above the solid plastic adhesive, and fixing to form a U-shaped inclined structure liquid drop storage cavity;
(4) And solidifying and forming the droplet microfluidic chip.
9. The method according to claim 8, wherein the height difference in the step (2) is 20 to 500 μm.
10. An application of the microfluidic chip of claim 1 in gene detection.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117007800A (en) * | 2023-08-09 | 2023-11-07 | 祥符实验室 | Dual-droplet microfluidic chip for escherichia coli detection and application thereof |
| CN117007800B (en) * | 2023-08-09 | 2024-05-10 | 祥符实验室 | Dual-droplet microfluidic chip for escherichia coli detection and application thereof |
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