CN110873657B - Sampling method of micro-sample - Google Patents
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- CN110873657B CN110873657B CN201811007289.4A CN201811007289A CN110873657B CN 110873657 B CN110873657 B CN 110873657B CN 201811007289 A CN201811007289 A CN 201811007289A CN 110873657 B CN110873657 B CN 110873657B
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/02—Devices for withdrawing samples
- G01N1/10—Devices for withdrawing samples in the liquid or fluent state
- G01N1/14—Suction devices, e.g. pumps; Ejector devices
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Abstract
The invention discloses a sampling method of a micro sample, which comprises the following steps: providing a sample container and disposing a sample liquid and a first spacer liquid immiscible or reactive with the sample liquid within the sample container, wherein the first spacer liquid is disposed closer to the bottom of the sample container than the sample liquid, and a first liquid-liquid interface is formed between the first spacer liquid and the sample liquid; inserting a sampling end of a sampling tube through said sample liquid into said first spacer liquid; a sampling operation is started. The method can reduce the residue of sample liquid during sample suction. In addition, the sample sucked by the method can be stably pushed out during pushing, and the method is favorable for obtaining liquid drops with uniform sizes in some occasions such as the field of digital PCR liquid detection.
Description
Technical Field
The invention relates to a method for sampling a trace sample, which is particularly suitable for chemical, biological and medical detection and experiments.
Background
With the change of medical treatment mode and the continuous development of individual medication, the medical inspection world needs a fast and accurate detection means, and the molecular detection exerts unique advantages.
At present, molecular detection techniques mainly include nucleic acid molecular hybridization, Polymerase Chain Reaction (PCR), biochip techniques, and the like. The molecular detection product is mainly applied to detection of clinical departments such as tumor, infection, heredity, prenatal screening and the like, and aspects such as a physical examination center, a technical service center, a third-party detection mechanism, a microorganism rapid detection market and the like.
As an important technical means of molecular detection, PCR can qualitatively and quantitatively detect target nucleic acid molecules, under the background of increasing application requirements of low abundance detection, rare mutation detection and the like, digital PCR is taken as an absolute nucleic acid molecule quantitative technology, a fluorescent quantitative PCR reaction system is distributed into a large number of tiny reactors, each microreactor contains 1 or more copies of target nucleic acid molecules, single-molecule template PCR amplification is carried out, after the amplification is finished, the copy number of target genes in an original sample is calculated by the number of positive reaction units and a statistical method, and the digital PCR can be accurately and absolutely detected without depending on a reference substance and a standard curve.
Currently, the examination means such as blood routine, cytology, pathology and immunology are developed towards automation, integration and standardization, but due to the technical complexity of molecular detection, a plurality of technical problems which are difficult to solve exist in the process from sample to result automation. In the sample introduction step of the digital PCR detector, in the case of a small sample input amount (10 ul-20 ul), the prior art mostly adopts a method of directly sucking a sample introduction needle into a sample, and obviously, the prior art cannot insert the sample introduction needle into the bottom of a tube (the needle can be hit or blocked), so that a certain degree of sample residue is inevitably caused.
Moreover, in order to make the experimental result more ideal, the generated droplets are required to be kept uniform in size to a certain extent, the sample flow rate during sample pushing is indirectly required to be as stable as possible so as to ensure that the generated droplets are uniform in size, the complete sample pushing process relates to three stages of flow rate establishment, flow rate maintenance, flow rate reduction to zero and the like, wherein the flow rate establishment and the flow rate reduction to zero are two inevitable flow rate fluctuation stages, the longer the time required by the two stages is, the more unfavorable the experimental result is, the traditional sample pushing process does not have the establishment and reduction of buffer oil auxiliary flow rate, the sample is directly pushed, contact media of the first section and the last section of the sample are respectively air and pipeline driving oil during direct sample pushing, the viscosity of the two media is greatly different from that of the sample, and the time consumed for establishing and reducing the sample flow rate is longer.
Disclosure of Invention
The object of the present invention is to provide an improved method for sampling micro-samples, which method is capable of reducing the residue of sample liquid during the aspiration.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a method for sampling a micro sample comprises the following steps:
a) providing a sample container and disposing a sample liquid and a first spacer liquid immiscible or reactive with the sample liquid within the sample container, wherein the first spacer liquid is disposed closer to the bottom of the sample container than the sample liquid, and a first liquid-liquid interface is formed between the first spacer liquid and the sample liquid;
b) inserting a sampling end of a sampling tube through said sample liquid into said first spacer liquid;
c) a sampling operation is started.
In an embodiment of the present invention, in the step c), when sampling, the position of the sampling tube is kept unchanged, a part of the first isolation liquid is sucked, and then the whole sample liquid is sucked into the sampling tube.
Preferably, the sample container is a container with an open top, and the first isolation liquid and the sample liquid are sequentially arranged from bottom to top in the sample container.
In a specific and preferred embodiment according to the present invention, in step a), a second separation liquid immiscible or reactive with the sample liquid is further provided in the sample container, and a second liquid-liquid interface is formed between the second separation liquid and the sample liquid, and the sample liquid is located between the first liquid-liquid interface and the second liquid-liquid interface.
In an embodiment of the present invention, the sample container is an open-top container, and the first barrier liquid, the sample liquid, and the second barrier liquid are sequentially disposed from bottom to top in the sample container.
In an embodiment of the present invention, in the step c), when sampling, the position of the sampling tube is kept unchanged, a part of the first isolation liquid is firstly sucked, then the whole sample liquid is sucked into the sampling tube, and finally a part of the second isolation liquid is sucked into the sampling tube.
In a preferred embodiment of the present invention, in the step c), after the sampling is completed, the volume ratio of the first isolation liquid to the sample liquid in the sampling tube is 0.1 to 0.9: 1, preferably 0.2-0.5: 1, more preferably 0.2 to 0.4: 1.
in another preferred embodiment of the present invention, in the step c), after the sampling is completed, the volume ratio of the second isolation liquid to the sample liquid in the sampling tube is 0.1 to 0.9: 1, preferably 0.2-0.5: 1, more preferably 0.2 to 0.4: 1.
in one embodiment of the present invention, in the step a), the volume ratio of the first isolation liquid to the sample liquid in the sample container is 0.1 to 1: 1, preferably 0.3 to 0.8: 1.
in one embodiment of the present invention, in the step a), the volume ratio of the second isolation liquid to the sample liquid is 0.1 to 1: 1, preferably 0.3-0.8: 1.
in one embodiment of the present invention, in the step b), the sampling end of the sampling tube is inserted into the first isolation liquid to a height of 1/4-3/4 of the height of the first isolation liquid.
According to the present invention, in the step a), the sample liquid in the sample container may be one or more layers, and each layer of the sample liquid is adjacent to a spacer liquid.
According to the present invention, the first and second barrier liquids are not particularly limited. In a preferred embodiment of the present invention, the first barrier liquid and the second barrier liquid are oils, in particular oils having substantially the same viscosity as the sample liquid.
In some specific applications, such as the field of digital PCR detection, the first isolation liquid and the second isolation liquid respectively include, but are not limited to, fluorocarbon oil, silicone oil, mineral oil, hydrocarbon oil, vegetable oil, and the like.
In a particular embodiment according to the invention, the first spacer liquid has a density which is greater than the density of the sample liquid, which is greater than the density of the second spacer liquid.
Compared with the prior art, the invention has the advantages that:
when the sampling tube sucks a sample, the sampling tube firstly sucks isolation liquid, the sample liquid continuously descends along with the reduction of the isolation liquid until reaching the sampling end of the sampling tube under the action of gravity, the sampling tube continuously sucks the sample liquid and can suck the sample liquid into the sampling tube completely, so that the sample sucking residue can be effectively reduced or avoided under the condition that the sampling tube is not inserted into the bottom of a container. In addition, the sample sucked by the method can be stably pushed out during pushing, and the method is favorable for obtaining liquid drops with uniform sizes in some occasions such as the field of digital PCR liquid detection.
Drawings
FIG. 1 is a drawing of a sample end of a sampling tube through a second spacer fluid with a sample fluid inserted into the first spacer fluid in an embodiment of the present invention;
FIG. 2 is a diagram of a liquid-liquid phase liquid of a sandwich structure of a first buffer liquid-a sample liquid-a second buffer liquid in a sampling tube after a sample is drawn in an embodiment of the present invention;
1. a sampling tube; 11. a sampling end; 2. a sample liquid; 31. a first barrier liquid; 32. a second barrier liquid; 4. a sample container.
Detailed Description
The following detailed description of the preferred embodiments of the present invention, taken in conjunction with the accompanying drawings, will make the advantages and features of the invention easier to understand by those skilled in the art, and thus will clearly and clearly define the scope of the invention.
The invention provides a sampling method of a micro sample, which comprises the following steps: firstly, arranging a sample liquid and a first isolation liquid which is immiscible or reactive with the sample liquid in a sample container, wherein the first isolation liquid is positioned closer to the bottom of the sample container than the sample liquid, and a first liquid-liquid interface is formed between the first isolation liquid and the sample liquid; then pass the sample liquid with the sampling tube and insert the isolation liquid of lower part in, the sampling end of sampling tube and the lower bottom surface of open container contactless can reduce the sample suction and remain when the sample suction pipe takes a sample, can avoid the sampling tube to hit the danger that the lower surface of open container caused the sampling tube to damage again, and the sampling tube inserts first isolation liquid after stable, begins to absorb liquid.
According to the invention, the sample container has various styles, such as a container with an opening at the upper end, a container with an opening at the side surface, a container with an opening at the upper end and the side surface, and the like, and as an optional implementation mode, the container with an opening at the upper end is selected as the sample container; in order to form a liquid-liquid phase liquid in which the sample liquid is above the first barrier liquid, the first barrier liquid may be first introduced into the open container using a filling device, and then the sample liquid may be introduced into an upper portion of the first barrier liquid, such that the sample liquid is spaced from a lower surface of the open container; if the density of the first isolation liquid is greater than that of the sample liquid, the first isolation liquid and the sample liquid can be added into the sample container simultaneously or sequentially by using a liquid adding device; in order to reduce the sample sucking residue as much as possible, the volume ratio of the first isolation liquid to the sample liquid in the sample container is controlled to be 0.1-1: 1, in order to avoid resource waste, the preferred volume ratio is 0.3~ 0.8: 1.
according to the invention, in order to isolate the sample liquid from other media and avoid air suction during sample liquid suction, a second isolation liquid immiscible or reacting with the sample liquid can be arranged in the sample container, a second liquid-liquid phase interface is formed between the second isolation liquid and the sample liquid, and the first isolation liquid, the sample liquid and the second isolation liquid are sequentially arranged from bottom to top in the sample container to form a liquid-liquid phase liquid with a sandwich structure. The liquid adding mode can be, for example: firstly, adding a first isolation liquid into an open container by using a liquid adding device, then adding a sample liquid into the upper part of the first isolation liquid, and then adding a second isolation liquid into the upper part of the sample liquid, wherein in order to reduce the sample absorption residue as much as possible, in the sample container, the volume ratio of the first isolation liquid to the sample liquid is controlled to be 0.1-1: 1, in order to avoid resource waste, the preferred volume ratio is 0.3~ 0.8: 1, the volume ratio of the second isolation liquid to the sample liquid is controlled to be 0.1-1: 1, preferably 0.3-0.8: 1. in an open container, the sample liquid may also be in multiple layers, each layer of sample liquid being adjacent to a spacer liquid.
According to the invention, when the sampling tube is used for sampling, the sampling tube is preferably prevented from shaking and the position of the sampling tube is kept unchanged so as to ensure the sampling accuracy and stability, part of first isolation liquid is firstly sucked by the sampling tube, the sample liquid continuously descends until reaching the sampling tube, the sampling tube continuously sucks until all the sample liquid is sucked into the sampling tube, if no second isolation liquid exists above the sample liquid in the open container, the sampling is finished, and in order to ensure the stable flow of the sample liquid in the subsequent sample pushing, the volume ratio of the first isolation liquid to the sample liquid in the sampling tube is controlled to be 0.1-0.9: 1, preferably 0.2-0.5: 1, more preferably 0.2 to 0.4: 1; if a second isolation liquid is arranged on the sample liquid, continuously sucking part of the second isolation liquid into the sampling tube, and also controlling the volume ratio of the first isolation liquid to the sample liquid in the sampling tube to be 0.1-0.9: 1, preferably 0.2-0.5: 1, more preferably 0.2 to 0.4: 1, the volume ratio of the second isolation liquid to the sample liquid is controlled to be 0.1-0.9: 1, preferably 0.2-0.5: 1, more preferably 0.2 to 0.4: 1.
according to the present invention, in order to ensure that the sampling tube can suck a proper amount of the first isolation liquid, the height position of the sampling end of the sampling tube in the first isolation liquid needs to be adjusted according to the volume difference between the sample liquid and the first isolation liquid added into the sample container, and the height of the sampling end of the sampling tube inserted into the first isolation liquid is generally 1/4-3/4 of the height of the first isolation liquid.
According to the invention, the specific selection of the first and second spacer fluids is related to the sample fluid, at least satisfying: the first isolation liquid and the second isolation liquid do not react with, fuse with and extract the sample liquid, and other influences the original chemical and physical properties of the sample liquid. As a preferable aspect of the present invention, when the aspirated sample liquid is used for addition to another liquid, for example, in the case of preparing a digital PCR droplet, the first and second partition liquids are preferably liquids miscible with the another liquid, and a homogeneous system can be formed when the first and second partition liquids are mixed with the another liquid. Further, it is also preferable that the first and second barrier liquids have substantially the same viscosity as the sample liquid. Preferably, the first isolation liquid, the second isolation liquid and the sample liquid are considered to have substantially the same viscosity when the ratio of the absolute value of the difference between the viscosities of the first isolation liquid, the second isolation liquid and the sample liquid to the sample liquid is within 20%, and the substantially same viscosity ensures that the three liquids have substantially the same fluidity. Furthermore, in certain applications, such as when the droplets are digital PCR droplets, the first spacer liquid, the second spacer liquid should be able not to affect the stability of the generated droplets or interfere with detection. Generally, the first barrier liquid and the second barrier liquid may be selected to be the same as or similar to the other liquid.
According to some embodiments of the present invention, the first and second barrier liquids may be fluorocarbon oil, silicone oil, mineral oil, hydrocarbon oil, or vegetable oil, respectively.
According to the present invention, the relative density of the sample liquid is not particularly limited with respect to the first and second partition liquids, but preferably, the density of the first partition liquid is higher than that of the sample liquid, and the density of the second partition liquid is lower than that of the sample liquid, in order to reduce the influence of the liquid gravity.
According to the present invention, the sampling tube may be connected to a liquid driving mechanism having a driving capability for sucking and pushing out the liquid, and as an alternative embodiment, the liquid driving mechanism may have a sample pushing speed in a range of 10 nanoliters/minute to 10 microliters/minute.
In a preferred embodiment of the present application, after the sampling tube absorbs the first isolation liquid, the sample liquid and the second isolation liquid, the liquid driving mechanism may be used to push the sample, in the sample pushing process, the second isolation liquid located at the first section of the sampling tube first establishes a flow rate and outputs the flow rate with a constant flow rate value F, after the second isolation liquid is pushed, the smooth transition is the sample liquid flow rate, after the sample liquid is pushed, the liquid path system keeps the original flow rate value F to push the first isolation liquid, and in this process, because the isolation liquid is used to establish the flow rate and end the flow rate, the sample liquid flow rate is always output with the constant flow rate value F.
According to the invention, in order to prevent the influence of temperature fluctuation on the liquid driving precision in the experimental process, before the first isolation liquid is sucked, the liquid driving mechanism and the sampling tube are filled with liquid with low expansion coefficient as a carrier liquid, and as an optional implementation mode, the thermal expansion coefficient of the carrier liquid can be in a range of 0.00001/centigrade to 0.0005/centigrade.
According to the present invention, in order to prevent the sampling tube liquid from generating bubbles during driving and affecting the flow stability during sample pushing, it is preferable to perform vacuum degassing or ultrasonic degassing treatment on the isolation liquid.
According to the invention, in order to realize the liquid suction of nano-upgrading and reduce the residue of liquid at the sampling end of the sampling tube, the sampling end of the sampling tube is subjected to tip-pulling treatment to reduce the diameter and the cross-sectional area of the tip of the sampling end; the inner wall of the sampling tube and the outer wall of the sampling end are subjected to hydrophobization treatment to prevent the adsorption of the isolation liquid and the sample liquid on the surface of the isolation liquid and the sample liquid.
The technical scheme of the invention is further explained by combining the specific embodiment as follows:
example 1
FIG. 1 is a drawing showing a sample aspirating state in which a sampling tube is inserted into an isolation liquid through a sample liquid, in this embodiment, the sampling tube 1 is connected to a liquid driving mechanism (not shown) having a liquid sucking and pushing-out driving capability, 10ul of a first isolation liquid 31 (3M fluorinated oil HFE 7500) is added to a sample container 4 (200 ul of a centrifuge tube is selected) by a liquid charger (not shown), 20ul of a sample liquid 2 (e.g., an aqueous phase system containing a nucleic acid template to be detected, a buffer aqueous solution, a product labeling substance, etc.) is added to the isolation liquid 32 by the liquid charger, 10ul of a second isolation liquid 32 (3M fluorinated oil HFE 7500) is added to the sample liquid 2, the ratio of the first isolation liquid 31, the sample liquid 2, and the second isolation liquid 32 in the sample container is 1:2:1, a sampling end 11 of the sampling tube 1 is inserted into the first isolation liquid 31 in the centrifuge tube 4, in this embodiment, the sampling end 11 is located at the middle position along the first isolation liquid 31, the sample liquid 2 is continuously descending along with the continuous absorption of the first isolation liquid 31 into the sampling tube 1, when the sampling tube 1 absorbs 5ul of the first isolation liquid 31, the sample liquid 2 descends to the sampling end 11 of the sampling tube 1, the sampling tube 1 starts to absorb the sample liquid 2, when the sampling tube 1 absorbs 20ul of the sample liquid 2, and then absorbs 5ul of the second isolation liquid 32 to complete the liquid absorption, at this time, the ratio of the first isolation liquid 31, the sample liquid 2 and the second isolation liquid 32 in the sampling tube 1 is 1:4: 1. Fig. 2 is a diagram showing a liquid-liquid phase liquid of a sandwich structure of a first spacer liquid-a sample liquid-a second spacer liquid in the sampling tube 1 after the sample aspiration. After the sample suction is finished, pushing the sample at the flow speed of 2.7ul \ min, firstly pushing the second isolation liquid 32 out of the sampling tube 1, establishing stable flow, when the second isolation liquid 32 is pushed out, the stable transition is the flow of the sample liquid 2, and after the sample liquid 2 is pushed out, the liquid path system keeps the original flow to push the first isolation liquid 31, so that the flow of the sample liquid 2 is kept stable all the time when the sample liquid is pushed out.
Example 2
This example provides a liquid-liquid phase liquid that produces a multilayer sandwich structure. Example 2 is similar to example 1, except that the sample liquid in this example has multiple layers, and each layer of sample liquid is adjacent to a spacer liquid, and the specific steps are that, on the basis of example 1, the sample liquid is added to the spacer liquid on the uppermost layer in the container, and the spacer liquid is further added to the added sample liquid to form a liquid-liquid phase liquid with a multilayer sandwich structure, and the process of adding the sample liquid and the spacer liquid can be repeated for multiple times.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (18)
1. A method for sampling a micro sample, comprising the steps of:
a) providing a sample container and disposing a sample liquid and a first spacer liquid immiscible or reactive with the sample liquid within the sample container, wherein the first spacer liquid is disposed closer to the bottom of the sample container than the sample liquid, and a first liquid-liquid interface is formed between the first spacer liquid and the sample liquid;
b) inserting a sampling end of a sampling tube through the sample liquid into the first spacer liquid;
c) starting a sampling operation;
the sample liquid in the sample container is one layer or a plurality of layers, and each layer of the sample liquid is adjacent to a separation liquid.
2. A method for sampling a micro sample according to claim 1, wherein: in the step c), during sampling, the position of the sampling tube is kept unchanged, a part of the first isolation liquid is firstly sucked, and then the whole sample liquid is sucked into the sampling tube.
3. A method for sampling a micro sample according to claim 1, wherein: in the step a), a second separation liquid immiscible or reactive with the sample liquid is further disposed in the sample container, a second liquid-liquid interface is formed between the second separation liquid and the sample liquid, and the sample liquid is located between the first liquid-liquid interface and the second liquid-liquid interface.
4. A method for sampling a micro amount of sample according to claim 3, wherein: the sample container is a container with an opening at the top, and the first isolation liquid, the sample liquid and the second isolation liquid are sequentially arranged from bottom to top in the sample container.
5. A method for sampling a micro amount of sample according to claim 3, wherein: in the step c), during sampling, the position of the sampling tube is kept unchanged, a part of the first isolation liquid is firstly sucked, then the whole sample liquid is sucked into the sampling tube, and finally a part of the second isolation liquid is sucked into the sampling tube.
6. A method for sampling a micro-quantity sample according to claim 2 or 5, characterized in that: in the step c), after sampling is finished, the volume ratio of the first isolation liquid to the sample liquid in the sampling tube is 0.1-0.9: 1.
7. a method for sampling a micro amount of sample according to claim 6, wherein: the volume ratio of the first isolation liquid to the sample liquid is 0.2-0.5: 1.
8. a method for sampling a micro amount of sample according to claim 7, wherein: the volume ratio of the first isolation liquid to the sample liquid is 0.2-0.4: 1.
9. a method for sampling a micro amount of sample according to claim 5, wherein: in the step c), after sampling is finished, the volume ratio of the second isolation liquid to the sample liquid in the sampling tube is 0.1-0.9: 1.
10. a method for sampling a micro amount of sample according to claim 9, wherein: the volume ratio of the second isolation liquid to the sample liquid is 0.2-0.5: 1.
11. a method for sampling a micro amount of sample according to claim 10, wherein: the volume ratio of the second isolation liquid to the sample liquid is 0.2-0.4: 1.
12. a method for sampling a micro sample according to claim 1 or 3, wherein: in the step a), the volume ratio of the first isolation liquid to the sample liquid in the sample container is 0.1-1: 1.
13. a method for sampling a micro amount of sample according to claim 12, wherein: the volume ratio of the first isolation liquid to the sample liquid in the sample container is 0.3-0.8: 1.
14. a method for sampling a micro amount of sample according to claim 3, wherein: in the step a), the volume ratio of the second isolation liquid to the sample liquid is 0.1-1: 1.
15. a method for sampling a micro amount of sample according to claim 14, wherein: the volume ratio of the second isolation liquid to the sample liquid is 0.3-0.8: 1.
16. a method for sampling a micro sample according to claim 1 or 3, wherein: in the step b), the height of the sampling end of the sampling tube inserted into the first isolation liquid is 1/4-3/4 of the height of the first isolation liquid.
17. A method for sampling a micro sample according to claim 1 or 3, wherein: the first isolation liquid is one or a combination of more of fluorocarbon oil, silicone oil, mineral oil, hydrocarbon oil and vegetable oil; and/or the first barrier liquid is an oil having substantially the same viscosity as the sample liquid.
18. A method for sampling a micro amount of sample according to claim 3, wherein: the second isolation liquid is one or more of fluorocarbon oil, silicone oil, mineral oil, hydrocarbon oil and vegetable oil; and/or the second barrier liquid is an oil having substantially the same viscosity as the sample liquid.
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