CN115350733B - Microfluidic chip with single-layer inclined structure liquid drop storage cavity and preparation method thereof - Google Patents
Microfluidic chip with single-layer inclined structure liquid drop storage cavity and preparation method thereof Download PDFInfo
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- CN115350733B CN115350733B CN202210820318.9A CN202210820318A CN115350733B CN 115350733 B CN115350733 B CN 115350733B CN 202210820318 A CN202210820318 A CN 202210820318A CN 115350733 B CN115350733 B CN 115350733B
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- 239000007788 liquid Substances 0.000 title claims abstract description 64
- 238000003860 storage Methods 0.000 title claims abstract description 35
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- 238000002360 preparation method Methods 0.000 title abstract description 7
- 239000003292 glue Substances 0.000 claims abstract description 16
- 239000000758 substrate Substances 0.000 claims abstract description 16
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 108090000623 proteins and genes Proteins 0.000 claims description 9
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- 230000001070 adhesive effect Effects 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 5
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
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- 238000003752 polymerase chain reaction Methods 0.000 description 12
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- 238000003199 nucleic acid amplification method Methods 0.000 description 5
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- 239000013078 crystal Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000011304 droplet digital PCR Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- 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
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 following components: the structure sheet and the substrate sheet, wherein the surface of the substrate sheet is provided with solidified plastic glue, and the structure sheet covers the solidified plastic glue and forms an inclined structure liquid drop storage cavity. Aiming at the liquid drops with different sizes, the invention 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 vectors of biological genetic information and any disease can find evidence at the genetic level. Genetic analysis is helpful for deeply exploring the root cause of diseases, designing targeted drugs and comprehensively understanding the interaction mechanism of individuals and the environment.
The Polymerase Chain Reaction (PCR), a simple DNA amplification method, was invented by Mullis in the United states in 1985. At the end of the 20 th century Vogelstein et al proposed the concept of digital PCR (digitalPCR, dPCR). A sample is diluted in a large quantity and distributed to different reaction units, each reaction unit contains at least one copy of molecules (DNA template), then the molecules in each reaction unit are amplified, and after the amplification is finished, fluorescent signals in each reaction unit are statistically analyzed, so that single-molecule amplification is truly realized, and the absolute quantification technology is called.
The current market commercialized droplet digital PCR instrument includes QX200 system developed by BioRad company and Naica crystal micro-droplet PCR system developed by Stilla Technologies company. The QX200 system needs three instruments to finish droplet generation, amplification and technical analysis, and the prepared PCR reaction reagent is dispersed into tens of thousands of droplets and collected in a structure similar to a centrifuge tube; then, a PCR reaction is performed; finally, the reacted droplets are introduced into an analysis chip for result reading. The Naica crystal micro-droplet PCR system of Stilla Technologies is characterized in that droplets formed by dispersing a sample are collected in a droplet collecting cavity of a chip to form a monolayer arrangement, then the droplets do not need to be transferred, PCR reaction is carried out, and finally the reaction result is read out. The two sets of systems adopt oil phase which is fluorinated oil, the fluorinated oil is volatile, and high requirements are provided for the design of a reaction vessel, so that the cost is increased.
The influence of bubbles on the stability of liquid drops is one of the important factors restricting the application of the liquid drop microfluidic chip. In order to meet the market application requirements of the liquid drop micro-fluidic chip, improve the stability and the operation simplicity of the liquid drop micro-fluidic chip and reduce the manufacturing cost, the liquid drop micro-fluidic chip with a novel structure has a certain practical significance.
Disclosure of Invention
The invention aims to provide a microfluidic chip with a single-layer inclined structure liquid drop storage cavity and a preparation method thereof.
A microfluidic chip of the present invention, the chip comprising: the structure sheet 1 and the substrate sheet 2, wherein the surface of the substrate sheet 2 is provided with a solidified plastic glue 3, and the structure sheet 1 is covered above the solidified plastic glue 3 and forms an inclined structure liquid drop storage cavity 4.
The structure sheet 1 is a structure sheet with micro channels, and the surface of the structure sheet is provided with micro liquid drop generating water phase holes 11 and micro liquid drop generating oil phase holes 12.
The solidified plastic glue 3 is arranged between the structural sheet 1 and the base sheet 2 and plays a supporting role.
The micro-droplet generation water phase holes 11 and the micro-droplet generation oil phase holes 12 are respectively arranged on two sides of the structural sheet.
The solidified plastic glue 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 U-shaped opening side is higher than that of the U-shaped closing side.
Preferably, the difference in height between the height of the U-shaped opening side and the height of the U-shaped closing side is 20 μm to 500 μm.
Further preferably, the height difference is 80-100 μm.
The structural sheet 1 and the base sheet 2 are connected by a spacer.
The preparation method of the microfluidic chip provided by the invention comprises the following steps:
(1) Solidifying plastic glue on the surface of the substrate sheet and forming 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 molding glue is higher than the closing side;
(3) Covering the structural sheet above the solid plastic adhesive, and fixing to form a liquid drop storage cavity with a U-shaped inclined structure;
(4) And solidifying and forming the liquid drop micro-fluidic chip.
The height difference in the step (2) is 20-500 mu m.
The microfluidic chip prepared by the method is provided.
The application of the microfluidic chip in gene detection, such as detection of new coronavirus genes, is disclosed.
The realization principle of the invention is that when a large number of liquid drops (more than 1 ten thousand) enter the storage chambers to be densely arranged after being generated, the chambers with the inclined structures gradually increase along with the space, thereby effectively improving the fluidity of the liquid drops, reducing the occurrence of the phenomena of lamination, 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 statistical analysis of the liquid drops at the later stage. In addition, the mineral oil is combined, so that the advantage that the oil phase is not easy to volatilize in the PCR process is well met, the consistency of liquid drops is enhanced, and the PCR amplification efficiency is improved.
Furthermore, a large number of liquid drops generated by the structural sheet enter the bottom of the storage cavity to be arranged, after the U-shaped bottom is gradually paved with the liquid drops on the closed side of the U-shaped bottom along with the increase of the number, the liquid drops continue to be arranged towards the U-shaped opening side, and the space of the cavity on the opening side is gradually increased, so that the fluidity of the liquid drops is effectively increased, the occurrence of the phenomena of lamination, collision, friction and the like formed by stacking a large number of liquid drops is reduced, the stable and efficient enrichment of the liquid drops in a microenvironment is realized, and the statistical analysis of the liquid drops at the later stage is facilitated. And meanwhile, in the PCR reaction process, the inclined opening chamber is favorable for removing bubbles from the opening side, so that the stability of liquid drops is ensured.
Advantageous effects
The U-shaped inclined structure liquid drop micro-fluidic chip has the following advantages: 1. the design of the U-shaped inclined structural cavity reduces the occurrence of lamination, collision and friction phenomena formed by stacking a large number of liquid drops, and realizes stable and efficient enrichment of the liquid drops; 2. the method is beneficial to removing bubbles in the cavity, reduces the interference influence of the bubbles on liquid drops, and improves the PCR amplification efficiency; 3. aiming at the liquid drops with different sizes, gaskets with different thicknesses can be adapted by simply replacing the gaskets, and the compatibility is high; 4. simple structure, low manufacturing cost and easy mass production.
Drawings
FIG. 1 is a schematic diagram of a microfluidic chip with a single-layer inclined structure droplet storage cavity; wherein 1a structural sheet; 11 micro-droplets generate water phase holes; 12 micro-droplets generate oil phase holes; 2, a substrate sheet; 3, solidifying the molding adhesive;
FIG. 2 is a cross-sectional view of a single-layer tilting structure droplet storage chamber microfluidic chip tilting chamber; 1, a structural sheet; 2, a substrate sheet; 3, solidifying the molding adhesive; 4a droplet storage chamber with an inclined structure;
fig. 3 is a diagram illustrating an example of fabrication of a single-layer tilting-structured droplet storage chamber microfluidic chip;
fig. 4 (a) shows droplet distribution in a storage chamber of a microfluidic chip with an inclined structure before PCR amplification; (B) The liquid drop distribution in the storage cavity of the microfluidic chip with the inclined structure after PCR amplification is realized; (C) a local enlarged droplet distribution effect diagram in the storage cavity;
FIG. 5 shows the distribution of droplets after PCR amplification of a tiled droplet microfluidic chip;
FIG. 6 is a graph showing fluorescence results after PCR amplification of ORF-1ab gene of 2019-nCoV.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Further, it is understood that various changes and modifications may be made by those skilled in the art after reading the teachings of the present invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
Example 1
A microfluidic chip comprising: the structure sheet 1 and the substrate sheet 2, wherein the surface of the substrate sheet 2 is provided with U-shaped curing plastic glue 3, the structure sheet 1 is covered above the U-shaped curing plastic glue 3 and forms a U-shaped inclined structure liquid drop storage cavity 4, and the height of the U-shaped opening side is higher than that of the U-shaped closing side; the structure sheet 1 is a structure sheet with micro channels, and the surface of the structure sheet is provided with micro liquid drop generating water phase holes 11 and micro liquid drop generating oil phase holes 12.
The preparation method comprises the following steps:
(1) Solidifying plastic glue on the surface of the substrate sheet and forming a U shape;
(2) Gaskets are arranged at two ends of the substrate sheet, the gasket placement needs to ensure that the opening side of the solidified molding adhesive is higher than the closing 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 liquid drop storage cavity with a U-shaped inclined structure;
(4) And solidifying and forming the liquid drop micro-fluidic chip.
The microfluidic chip of the single-layer inclined structure liquid drop storage cavity is used for detecting ORF-1ab genes of 2019-nCoV, and specifically comprises the following components:
1. ORF-1ab gene plasmid was prepared 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, probes, etc. in proportion as an aqueous phase.
2. The microfluidic chip with the single-layer inclined structure liquid drop storage cavity is used for generating liquid drops, and the chip is placed into a PCR instrument for amplification.
3. The results of the detection of the ORF-1ab gene at each concentration are shown in FIG. 6.
As shown in fig. 4, fig. 4A shows droplet distribution in a storage cavity of a microfluidic chip with an inclined structure before PCR amplification; FIG. 4B shows the distribution of droplets in a storage cavity of a microfluidic chip with an inclined structure after PCR amplification; fig. 4C is a view showing the effect of locally enlarging the distribution of droplets in the storage chamber, and it can be seen that the inclined structure is advantageous for the distribution of droplets, and the occurrence of stacking, collision and friction phenomena caused by accumulation of droplets is 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 2019-nCoV with a liquid drop microfluidic chip with a tiled structure for detection. The liquid drop microfluidic chip (see CN 202011187731.3) with a tiled structure adopts two layers of glass which are horizontally aligned and attached to form a liquid drop storage cavity, and liquid drops enter the cavity to be horizontally spread and arranged after being generated.
As shown in fig. 5, the liquid drops are distributed after PCR amplification of the liquid drop microfluidic chip with a tiled structure, so that larger bubbles in the chip cavity can be obviously seen, the stability of the liquid drops is seriously affected, and the later-stage liquid drop counting and analysis deviation is caused.
By comparing the results of fig. 4B and fig. 5, it can be determined that the design of the storage chamber with the inclined structure improves the storage environment of the liquid drops, ensures the enrichment efficiency of the liquid drops, and is beneficial to the amplification efficiency of the PCR. The ORF-1ab gene plasmid 1X 10 of 2019-nCoV was selected for both chips in FIGS. 4 and 5 5 The concentrations of copies/. Mu.l were compared experimentally.
Claims (7)
1. A microfluidic chip, the chip comprising: the structure sheet (1) and the substrate sheet (2), wherein the surface of the substrate sheet (2) is provided with a solidified plastic glue (3), and the structure sheet (1) is covered above the solidified plastic glue (3) and forms an inclined structure liquid drop storage cavity (4); the liquid drop storage cavity (4) with the inclined structure is a liquid drop storage cavity with a U-shaped inclined structure, the liquid drop storage cavity with the U-shaped inclined structure is gradually increased from a U-shaped closed side to a U-shaped open side, the height of the U-shaped open side is higher than that of the U-shaped closed side, and the height difference is 20-500 mu m.
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 generation water phase holes (11) and micro droplet generation oil phase holes (12).
3. The microfluidic chip according to claim 1, wherein the cured plastic glue (3) is U-shaped.
4. The microfluidic chip according to claim 1, wherein the height difference is 80 μm-100 μm.
5. Microfluidic chip according to claim 1, characterized in that the structural sheet (1) and the base sheet (2) are connected by a spacer.
6. A method of manufacturing the microfluidic chip of claim 1, comprising:
(1) Solidifying plastic glue on the surface of the substrate sheet and forming 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 molding glue is higher than the closing side;
(3) Covering the structural sheet above the solid plastic adhesive, and fixing to form a liquid drop storage cavity with a U-shaped inclined structure;
(4) And solidifying and forming the liquid drop micro-fluidic chip.
7. Use of the microfluidic chip of claim 1 in gene detection.
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| CN202210820318.9A CN115350733B (en) | 2022-07-13 | 2022-07-13 | Microfluidic chip with single-layer inclined structure liquid drop storage cavity and preparation method thereof |
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| CN202210820318.9A CN115350733B (en) | 2022-07-13 | 2022-07-13 | Microfluidic chip with single-layer inclined structure liquid drop storage cavity and preparation method thereof |
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| CN115350733A CN115350733A (en) | 2022-11-18 |
| CN115350733B true CN115350733B (en) | 2023-12-22 |
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| CN117007800A (en) * | 2023-08-09 | 2023-11-07 | 祥符实验室 | Dual-droplet microfluidic chip for escherichia coli detection and application thereof |
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| 双重乳液的微流控制备进展;王锴;李浩;高峥;唐炜洁;张程宾;吴梁玉;刘向东;;化工进展(S2);第24-30页 * |
| 微流控芯片流式细胞术;刘守坤;《微电子学》(第05期);第696-703页 * |
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