CN113969232A - Digital micro-fluidic chip device for nucleic acid detection and use method - Google Patents
Digital micro-fluidic chip device for nucleic acid detection and use method Download PDFInfo
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- CN113969232A CN113969232A CN202111337020.4A CN202111337020A CN113969232A CN 113969232 A CN113969232 A CN 113969232A CN 202111337020 A CN202111337020 A CN 202111337020A CN 113969232 A CN113969232 A CN 113969232A
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Abstract
The invention discloses a digital micro-fluidic chip device for nucleic acid detection and a using method thereof, wherein a nucleic acid detection water phase solution and an oil solution with specific gravity smaller than that of water are added into a chip sample inlet at one time, then the chip is fixed on a centrifugal device, and the water phase and the oil phase can be driven into the chip by centrifugation for 10-20 minutes. Finally, the result that the water phase is distributed in the micro-cavity of the chip and the oil phase is distributed in the micro-pipeline is obtained. The chip assay of the present invention requires only 1-3 nanoliter volumes of reagents. Greatly reduces the analysis cost and the requirement on the content of the sample. The water phase and the oil phase can be simultaneously injected into the chip, so that impurities are prevented from being introduced in a multi-step experiment, and the accuracy of analysis is improved. The chip design principle is simple, and the separation of the sample can be completed by one step only by a centrifugal device, so that the detection of the digital PCR is realized.
Description
Technical Field
The invention relates to a digital micro-fluidic chip device for nucleic acid detection and a using method thereof, belonging to the field of medical inspection and analysis.
Background
Liquid biopsies have gained significant development in recent years due to their minimal invasiveness and potential for assessing various disease biomarkers. It comprises Circulating Tumor Cells (CTCs), circulating tumor dna (ctdna), cell free dna (cfdna), Extracellular Vesicles (EV), etc. Plasma is a common carrier for liquid biopsies and is a dynamic medium from which circulating nucleic acids can be shed by cells and released into the blood. Thus, circulating nucleic acids provide a unique opportunity to diagnose or monitor cancer dynamics.
The nucleic acids released by tumor cells constitute a small fraction of the plasma, and therefore, highly accurate and robust methods are needed to detect and quantify small amounts of nucleic acid molecules. However, the current clinical nucleic acid detection method is real-time quantitative PCR (real-time qPCR), but the real-time qPCR detects the reaction kinetics of nucleic acid amplification, so that the quantitative accuracy may be interfered by inherent factors such as an amplification inhibitor and enzyme activity, and environmental factors such as an amplification temperature and a fluorescence detection sensor. And the target with too low concentration cannot be detected, so that the detection requirement of precise medicine is difficult to meet.
Digital polymerase chain reaction (dPCR) techniques allow counting of individual molecules in a sample, allowing analysis of the concentration of nucleic acids in a target with greater sensitivity and accuracy.
dPCR each partition acts as a separate PCR microreactor, and the proportion of PCR reaction positive partitions is sufficient to determine the concentration of target nucleic acid without the need for calibration.
Common methods for digital PCR are droplet digital PCR (ddPCR) and cavity digital PCR (cdPCR). ddPCR causes contamination by some droplet coalescence and edge effects during PCR due to thermal movement or evaporation of oil. And they require a complex workflow including micro-droplet generation, droplet transfer, microplate sealing and droplet reading. These devices tend to be bulky and expensive.
Compared with the ddPCR method, the chamber digital PCR has the advantages of physical partition, real-time single-molecule amplification detection and the like. Particularly, in the detection aspect, the digital PCR result of the chip can be easily detected by using a fluorescence microscope.
For digital PCR, we need to consider the following 3 points. First, the liquid should be flowed into the wells of the chip using a built-in driving force. Second, each microwell should be effectively separated. Third, single nucleic acid molecule amplification should be ensured. Although great progress has been made in cdPCR research, they still require complicated manufacturing and additional control components such as syringe pump, air pressure, control system, etc., and thus are not widely used. Therefore, there is a need to develop a cheap, easy-to-operate and cost-effective digital analysis platform for nucleic acids to meet the needs of researchers.
Disclosure of Invention
In order to solve the problems, the invention provides a digital microfluidic chip device for nucleic acid detection and a use method thereof, wherein the digital microfluidic chip device is driven by a centrifugal force, a nucleic acid detection water phase solution and an oil (such as silicon oil and mineral oil) solution with the specific gravity smaller than that of water are added into a chip sample inlet at one time, then the chip is fixed on a centrifugal device, and the water phase and the oil phase can be driven into the chip by centrifugation for 10-20 minutes. Finally, the result that the water phase is distributed in the micro-cavity of the chip and the oil phase is distributed in the micro-pipeline is obtained.
In order to achieve the purpose, the invention adopts the following technical scheme:
a digital micro-fluidic chip device for nucleic acid detection comprises an upper substrate and a lower substrate sealed with the upper substrate and provided with a micro-fluidic channel; the microfluidic channel in the bottom plate with the lower layer consists of a sample inlet, an array chamber, a water storage tank and a sample outlet.
The array chamber consists of a plurality of independent micro-chambers and a micro-pipeline, the micro-pipeline is provided with a plurality of independent micro-chambers, and the micro-chambers are arranged on one side of the micro-pipeline in parallel; the sample inlet is connected with the inlet of the micro-pipeline in the array chamber, the outlet of the micro-pipeline in the array chamber is communicated with the water storage tank of the cuboid, and the water storage tank is connected with the sample outlet; the sample inlet and the sample outlet are used for flowing in and flowing out of a liquid sample and oil, and the water storage tank is used for storing redundant liquid; the micro-chamber is used for separating the liquid sample and the oil and amplifying the nucleic acid in situ, and the micro-pipeline is used for circulating the liquid sample and the oil.
Further, the liquid sample includes a specimen and a reaction reagent.
Furthermore, the depth of the array chamber arranged on the lower bottom plate is 10-200 microns, and the width of the micro-pipeline is 1-10 millimeters; the width of the micro-chamber is 1-10 mm.
Further, the upper substrate has a size of 25x76 mm; the lower floor panel has a size of 23x50 mm;
furthermore, the upper substrate is made of glass; the lower substrate is made of Polydimethylsiloxane (PDMS), Cyclic Olefin Copolymer (COC) or Cyclic Olefin Polymer (COP).
A method of using a digital microfluidic chip device for nucleic acid detection, comprising the steps of:
(1) firstly, performing hydrophobic treatment on the surfaces contacted with all liquid in the chip device;
(2) injecting the solution containing the nucleic acid amplification reactant and the oil with the density less than that of the solution containing the nucleic acid amplification reactant into a sample injection port at one time by using a pipette, fixing the solution on a centrifugal machine after sample injection is finished, and sequentially pushing the water and the oil into a chip by taking centrifugal force as driving force;
(3) when the water phase flows through the micro-chamber firstly, the water phase can be pushed into the micro-chamber due to the centrifugal force and the vertical and pointing direction of the micro-pipeline, the redundant water continuously advances, and the oil phase follows the micro-chamber;
(4) when the oil phase passes through the micro-chamber, the oil does not enter the micro-chamber but continues to advance along the micro-pipeline because the specific gravity of the oil is smaller than that of the water;
(5) until all the redundant liquid in the chip is pushed into a liquid storage tank, finally the oil fills the whole pipeline, and the water phase is independently divided into micro-chambers; closing the centrifuge after sample introduction; the inlet and outlet of the chip are sealed with oil, and the chip is transferred for subsequent experiments.
Further, the hydrophobic processing step in step S1 is: if the lower substrate is made of polydimethylsiloxane, the substrate needs to be heated at 110 ℃ for 12-24 hours after bonding, and if the lower substrate is made of cyclic olefin copolymer or cyclic olefin polymer, the substrate does not need to be subjected to hydrophobic treatment.
Further, the rotation speed of the centrifuge in the step S2 is 1000-2000 rpm/min.
Advantageous effects
(1) In the traditional nucleic acid analysis experiment, the single sample needs reagents in microliter (mu l) scale, and the chip analysis of the design only needs 1-3 nanoliter (nl) volume of reagents. Greatly reduces the analysis cost and the requirement on the content of the sample. The water phase and the oil phase can be simultaneously injected into the chip, so that impurities are prevented from being introduced in a multi-step experiment, and the accuracy of analysis is improved.
(2) The analysis sample amount can be easily improved by changing the structural design of the chip, so that the requirement of sample sensitivity in clinic is met, and the chip has good clinical and commercial values.
(3) The chip design principle is simple, and the separation of the sample can be completed by one step only by a centrifugal device, so that the detection of the digital PCR is realized.
(4) The whole sampling process is short in time, so that the efficiency can be improved, and the requirement of clinical rapid inspection can be met.
(5) The sample introduction can be completed only by centrifugal force, and the operation is simple; multiple chips can be run simultaneously on the same centrifuge.
(6) The chip device has small volume and is convenient to store and carry. The chip has the visual characteristic and can directly obtain an analysis result according to the fluorescent signal.
(7) The operation is simple, and the detection personnel do not need to have a complex professional background.
Drawings
Fig. 1 is a schematic structural diagram of a chip device according to the present invention.
FIG. 2 is a schematic diagram of a partial structure of an array chamber according to the present invention.
FIG. 3 is a basic structure diagram of a chip array chamber for microscope imaging.
Fig. 4 is a sample view of a microscope imaging chip.
FIG. 5 is a diagram showing the in-chip sample introduction under the centrifugal force.
FIG. 6 is an enlarged view of the sample after the partial sample injection is completed.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are illustrative only for the purpose of explaining the present invention, and are not to be construed as limiting the present invention.
As shown in fig. 1, a digital microfluidic chip device for nucleic acid detection includes an upper substrate and a lower substrate sealed with the upper substrate and having a microfluidic channel; the microfluidic channel in the bottom plate with the lower layer consists of a sample inlet, an array chamber, a water storage tank and a sample outlet; the upper substrate is made of glass and has the size of 25x76 mm; the lower bottom plate is made of polydimethylsiloxane, cyclic olefin copolymer or cyclic olefin polymer and has the size of 23x50 mm; the depth of an array chamber arranged on the lower bottom plate is 10-200 microns, and the width of a micro-pipeline is 1-10 mm; the width of the micro-chamber is 1-10 mm.
As shown in fig. 2 and 3, the array chamber is composed of a plurality of independent micro-chambers and micro-pipes, the micro-pipes are provided with a plurality of independent micro-chambers, and the micro-chambers are arranged at one side of the micro-pipes in parallel; the sample inlet is connected with the inlet of the micro-pipeline in the array chamber, the outlet of the micro-pipeline in the array chamber is communicated with the water storage tank of the cuboid, and the water storage tank is connected with the sample outlet; the sample inlet and the sample outlet are used for flowing in and flowing out of a liquid sample and oil, and the water storage tank is used for storing redundant liquid; the micro-chamber is used for separating the liquid sample and the oil and amplifying the nucleic acid in situ, the micro-pipeline is used for circulating the liquid sample and the oil, and finally the micro-chamber containing the aqueous phase is separated by the oil. The liquid sample includes a specimen and a reaction reagent.
A method for using the digital micro-fluidic chip device for nucleic acid detection is shown in FIG. 4 (white transparent area is oil phase, black area is water phase) and FIG. 5 (white area is air, black area is water phase, gray area is oil phase).
The method specifically comprises the following steps:
(1) firstly, performing hydrophobic treatment on the surfaces contacted with all liquid in the chip device; if the lower substrate is made of polydimethylsiloxane, the substrate needs to be heated at 110 ℃ for 12-24 hours after bonding, and if the lower substrate is made of cyclic olefin copolymer or cyclic olefin polymer, the substrate does not need to be subjected to hydrophobic treatment.
(2) Injecting the solution containing the nucleic acid amplification reactant and the oil with the density less than that of the solution containing the nucleic acid amplification reactant into a sample injection port at one time by using a liquid transfer gun, fixing the solution on a centrifuge after sample injection is finished, wherein the rotation speed of the centrifuge is 1000-2000rpm/min, and water and oil are sequentially pushed into a chip by taking centrifugal force as driving force;
(3) when the water phase flows through the micro-chamber firstly, the water phase can be pushed into the micro-chamber due to the centrifugal force and the vertical and pointing direction of the micro-pipeline, the redundant water continuously advances, and the oil phase follows the micro-chamber;
(4) when the oil phase passes through the micro-chamber, the oil does not enter the micro-chamber but continues to advance along the micro-pipeline because the specific gravity of the oil is smaller than that of the water;
(5) until all the redundant liquid in the chip is pushed into a liquid storage tank, finally the oil fills the whole pipeline, and the water phase is independently divided into micro-chambers; closing the centrifuge after sample introduction; the inlet and outlet of the chip are sealed with oil, and the chip is transferred for subsequent experiments. FIG. 6 is a schematic diagram after partial sample injection is completed. Black is that the micro-chamber is filled with water phase and the grey pipeline is filled with oil phase.
Claims (8)
1. A digital micro-fluidic chip device for nucleic acid detection is characterized by comprising an upper substrate and a lower substrate which is sealed with the upper substrate and provided with a micro-fluidic channel; the microfluidic channel in the bottom plate with the lower layer consists of a sample inlet, an array chamber, a water storage tank and a sample outlet;
the array chamber consists of a plurality of independent micro-chambers and a micro-pipeline, the micro-pipeline is provided with a plurality of independent micro-chambers, and the micro-chambers are arranged on one side of the micro-pipeline in parallel; the sample inlet is connected with the inlet of the micro-pipeline in the array chamber, the outlet of the micro-pipeline in the array chamber is communicated with the water storage tank of the cuboid, and the water storage tank is connected with the sample outlet; the sample inlet and the sample outlet are used for flowing in and flowing out of a liquid sample and oil, and the water storage tank is used for storing redundant liquid; the micro-chamber is used for separating the liquid sample and the oil and amplifying the nucleic acid in situ, and the micro-pipeline is used for circulating the liquid sample and the oil.
2. The digital microfluidic chip device for nucleic acid detection according to claim 1, wherein the liquid sample comprises a sample and a reaction reagent.
3. The digital microfluidic chip device for nucleic acid detection according to claim 1, wherein the depth of the array chamber on the lower substrate is 10-200 μm, and the width of the microchannel is 1-10 mm; the width of the micro-chamber is 1-10 mm.
4. The digital microfluidic chip device for nucleic acid detection according to claim 1, wherein the size of the upper substrate is 25x76 mm; the lower floor has a size of 23x50 mm.
5. The digital microfluidic chip device for nucleic acid detection according to claim 1, wherein the upper substrate is made of glass; the lower base plate is made of polydimethylsiloxane, cyclic olefin copolymer or cyclic olefin polymer.
6. Use of the device according to any of claims 1-5, characterized in that it comprises the following steps:
(1) firstly, performing hydrophobic treatment on the surfaces contacted with all liquid in the chip device;
(2) injecting the solution containing the nucleic acid amplification reactant and the oil with the density less than that of the solution containing the nucleic acid amplification reactant into a sample injection port at one time by using a pipette, fixing the solution on a centrifugal machine after sample injection is finished, and sequentially pushing the water and the oil into a chip by taking centrifugal force as driving force;
(3) when the water phase flows through the micro-chamber firstly, the water phase can be pushed into the micro-chamber due to the centrifugal force and the vertical and pointing direction of the micro-pipeline, the redundant water continuously advances, and the oil phase follows the micro-chamber;
(4) when the oil phase passes through the micro-chamber, the oil does not enter the micro-chamber but continues to advance along the micro-pipeline because the specific gravity of the oil is smaller than that of the water;
(5) until all the redundant liquid in the chip is pushed into a liquid storage tank, finally the oil fills the whole pipeline, and the water phase is independently divided into micro-chambers; closing the centrifuge after sample introduction; the inlet and outlet of the chip are sealed with oil, and the chip is transferred for subsequent experiments.
7. The use method according to claim 6, wherein the hydrophobic treatment step in step S1 is: if the lower substrate is made of polydimethylsiloxane, the substrate needs to be heated at 110 ℃ for 12-24 hours after bonding, and if the lower substrate is made of cyclic olefin copolymer or cyclic olefin polymer, the substrate does not need to be subjected to hydrophobic treatment.
8. The use method as claimed in claim 6, wherein the rotation speed of the centrifuge in the step S2 is 1000-2000 rpm/min.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116948806A (en) * | 2023-09-19 | 2023-10-27 | 国科温州研究院(温州生物材料与工程研究所) | Digital PCR chip with wide measurement range, use method and manufacturing method |
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