CN114758945A - Ionization probe, electrospray method and use - Google Patents
Ionization probe, electrospray method and use Download PDFInfo
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- H—ELECTRICITY
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- H01J49/00—Particle spectrometers or separator tubes
- H01J49/02—Details
- H01J49/10—Ion sources; Ion guns
- H01J49/16—Ion sources; Ion guns using surface ionisation, e.g. field-, thermionic- or photo-emission
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
- G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
- G01N30/724—Nebulising, aerosol formation or ionisation
- G01N30/7266—Nebulising, aerosol formation or ionisation by electric field, e.g. electrospray
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J49/00—Particle spectrometers or separator tubes
- H01J49/0027—Methods for using particle spectrometers
- H01J49/0031—Step by step routines describing the use of the apparatus
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Abstract
The invention discloses an ionization probe, an electrospray method and application, wherein the ionization probe comprises the following components: the capillary comprises a stage body part and a columnar part, wherein the stage body part is provided with a first opening and a second opening, the diameter of the first opening is smaller than that of the second opening, the columnar part is provided with a third opening and a fourth opening, the second opening is connected with the third opening, the inner wall of the stage body part is provided with a porous material, and the porous material is a hydrophilic material or a hydrophobic material. Therefore, the ionization probe can rapidly and efficiently sample components to be detected in a sample to be detected, simultaneously remove the interference of salt and matrix components in the sample to be detected, further directly carry out electrospray ionization on the collected components to be detected, realize in-situ mass spectrometry, and is suitable for various mass spectrometry detection applications such as field rapid detection, high-throughput mass spectrometry, single cell detection and the like of small-sized and portable mass spectrometry instruments.
Description
Technical Field
The invention relates to the field of mass spectrometry, in particular to an ionization probe, an electrospray method and application.
Background
The liquid chromatography-mass spectrometry is one of the most widely used chemical analysis techniques at present, and has powerful analysis functions, but generally requires pretreatment of a sample, and a single analysis is long in time. In order to shorten the time for sample pretreatment and obtain the mass spectrum information of the sample to be detected more quickly, an in-situ ionization technology is proposed and developed rapidly. The in-situ ionization technology has the characteristics of no or only a small amount of sample pretreatment, high analysis speed, high flux and the like, and is widely applied to a plurality of fields of food safety, public safety, life medicine and the like. In-situ ionization techniques have important applications in biological sample analysis, and many in-situ ionization techniques have been developed for biosolid samples, such as desorption electrospray ionization, low temperature plasma probes, and the like. The development of in situ ionization techniques for biological fluid samples has received less attention and still requires further research.
Thus, current ionization probes, electrospray methods, and applications remain to be improved.
Disclosure of Invention
The present invention is based on the discovery and recognition by the inventors of the following facts and problems:
the biological fluid sample to be detected usually contains impurity components such as salt and matrix components, which can seriously affect the sensitivity and quantitative accuracy of the mass spectrometer for detecting the components to be detected, so that the biological fluid sample to be detected needs to be pretreated before mass spectrometry to remove the interference of the salt and the matrix components and simultaneously enrich the components to be detected. The inventor finds that in the related technology, the pretreatment process of the biological fluid sample is long in time consumption, the treatment process is complex, expensive special professional equipment is needed, waste of the biological fluid sample can be caused in the pretreatment operation, the volume requirement of the biological fluid sample reaches the milliliter level, the acquisition difficulty of the sample to be detected is greatly increased, and for precious samples to be detected, such as clinical samples and the like, great loss and waste can be caused, so that the problems of low detection efficiency in the direct mass spectrometry process, high sample loss rate and the like can be caused, and the advantages of rapid detection of a mass spectrometer, small sample demand and the like can not be embodied.
The present invention aims to alleviate or solve at least to some extent at least one of the above mentioned problems.
In one aspect of the invention, the invention provides an ionization probe comprising: the capillary comprises a stage body part and a columnar part, wherein the stage body part is provided with a first opening and a second opening, the diameter of the first opening is smaller than that of the second opening, the columnar part is provided with a third opening and a fourth opening, the second opening is connected with the third opening, the inner wall of the stage body part is provided with a porous material, and the porous material is a hydrophilic material or a hydrophobic material. Therefore, the ionization probe can rapidly and efficiently sample components to be detected in a sample to be detected, simultaneously remove the interference of salt and matrix components in the sample to be detected, further directly carry out electrospray ionization on the collected components to be detected, realize in-situ mass spectrometry, and is suitable for various mass spectrometry detection applications such as field rapid detection, high-throughput mass spectrometry, single cell detection and the like of small-sized and portable mass spectrometry instruments.
According to an embodiment of the invention, the material of the capillary comprises at least one of glass, metal, polyetheretherketone and fluorinated ethylene propylene copolymer; the porous material includes at least one of an organic polymer, a metal-organic framework, and a covalent organic framework. Therefore, the mass spectrometer can be suitable for mass spectrometers with various detection requirements.
According to an embodiment of the invention, the diameter of the first opening is 1-200 μm and the thickness of the porous material is 0.1-100 μm. Thereby, the enrichment effect of the porous material can be improved.
In another aspect of the invention, the invention provides a method of electrospray using the aforementioned ionization probe, comprising: step S1: enabling a first opening of the ionization probe to be in contact with a solution to be detected, and performing first treatment, wherein the first treatment comprises the steps of sequentially sucking and releasing the solution to be detected; step S2: contacting the first opening of the ionization probe with a cleaning solution and performing a second treatment comprising sequentially drawing and releasing the cleaning solution; step S3: contacting the first opening of the ionization probe with an elution solution and aspirating the elution solution; step S4: and applying a voltage to the ionization probe sucking the elution solution to perform the electrospray, wherein the cleaning solution has hydrophilicity and hydrophobicity different from those of the porous material, and the elution solution has hydrophilicity and hydrophobicity identical to those of the porous material. Therefore, efficient, rapid and accurate mass spectrometry can be realized.
According to an embodiment of the present invention, the step S1 further includes: and repeating the first treatment, wherein the frequency of repeating the first treatment is 1-10Hz, and the number of times of repeating the first treatment is 1-200. Thereby, a high enrichment of the component to be detected within the ionization probe can be achieved.
According to an embodiment of the invention, the volume of the elution solution is 10pL to 10 μ L. Therefore, efficient and accurate mass spectrometry can be realized through a small amount of samples to be detected.
According to an embodiment of the present invention, the time for sucking up the elution solution is 0.1 to 10 min. Therefore, the components to be detected enriched in the ionization probe can be effectively transferred to the elution solution.
According to an embodiment of the present invention, further comprising: the electrospray includes contact electrospray and non-contact induction electrospray. Therefore, the method of electrospray in various modes can be satisfied.
In a further aspect of the invention, the invention provides a use of an electrospray method as hereinbefore described for high-throughput mass spectrometry comprising: providing an ionization probe array, a solution array to be detected, a cleaning solution array and an elution solution array; sequentially performing step S1, step S2, and step S3 on the ionization probe array; sequentially applying a voltage to the ionization probes of the ionization probe array for electrospray. Thereby, high-throughput mass spectrometry can be achieved.
In yet another aspect of the present invention, the present invention provides a single cell detection method using the aforementioned electrospray method, wherein the solution to be detected is a cell content. Thereby, a mass spectrometric analysis of a very small volume of the cell content can be achieved.
Drawings
The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 shows a schematic structural diagram of an ionization probe according to one embodiment of the present invention;
FIG. 2 shows a schematic structural diagram of an ionization probe according to yet another embodiment of the present invention;
FIG. 3 shows a schematic flow diagram of an electrospray process according to one embodiment of the present invention;
FIG. 4 shows a block diagram and a microscopic magnification at the dashed box of an ionization probe according to one embodiment of the present invention;
FIG. 5 shows scanning electron micrographs at different magnifications of a porous material of an inner wall of an ionization probe according to one embodiment of the invention;
FIG. 6 shows a positive ion mode mass spectrum of a test solution as a plasma sample according to one embodiment of the present invention;
FIG. 7 shows a high-quality end-anion mode mass spectrum of a test solution as a plasma sample according to an embodiment of the present invention;
FIG. 8 shows a low mass end anion mode mass spectrum of a test solution as a plasma sample according to one embodiment of the present invention;
FIG. 9 shows a graph of the contrast of lipid signals measured by analysis of the same plasma sample using the ionization probe method of the present invention and a conventional liquid-liquid extraction method, respectively;
FIG. 10 shows a schematic flow diagram for high-throughput mass spectrometry according to an embodiment of the present invention;
FIG. 11 shows a schematic flow chart for single cell sample analysis according to one embodiment of the present invention.
Description of the reference numerals:
1: an ionization probe; 2: a porous material; 3: a component to be tested; 4: impurity components; 5: a solution to be tested; 6: a cleaning solution; 7: eluting the solution; 8: a wire electrode; 9: a mass spectrometer; 10: an ionization probe immobilization stage; 11: a one-dimensional electric guide rail; 12: a perforated plate; 13: a single cell sample; 100: a stage part; 110: a first opening; 120: a second opening; 300: a columnar portion; 330: a third opening; 340: a fourth opening.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to the same or similar elements or elements having the same or similar functions throughout. 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.
In one aspect of the invention, the invention proposes an ionization probe, with reference to fig. 1, comprising: the capillary tube comprises a stage part 100 and a column part 300, wherein the stage part 100 is provided with a first opening 110 and a second opening 120, the diameter of the first opening 110 is smaller than that of the second opening 120, the column part 300 is provided with a third opening 330 and a fourth opening 340, and the second opening 120 is connected with the third opening 330, wherein the inner wall of the stage part 100 is provided with a porous material 2, and the porous material 2 is a hydrophilic material (namely, an oleophobic material) or a hydrophobic material (namely, an oleophilic material). The ionization probe with the capillary tube is capable of achieving rapid and convenient sampling operation and simultaneously has the function of direct electrospray ionization by modifying a layer of porous material on the inner wall of the platform body of the capillary tube (namely the tip of the capillary tube). When the ionization probe is used for mass spectrometry, enrichment of components to be detected in a solution to be detected can be achieved through simple absorption-release operation, impurity components in the solution to be detected can be removed simultaneously, the pretreatment steps of being tedious and time-consuming and causing loss of a sample to be detected are omitted, mass spectrometry detection of efficient sampling is achieved, and then electrospray ionization can be directly carried out on the collected components to be detected, in-situ mass spectrometry is achieved, and the ionization probe is suitable for field rapid detection, high-throughput mass spectrometry, single cell detection and other mass spectrometry detection applications of small and portable mass spectrometry instruments.
It is understood that at the intersection of the three phases of water (liquid phase), material (solid phase) and air (gas phase), the tangent to the surface of the water drop forms an angle θ with the contact surface of the water and material, which is called the contact angle, and the angle θ is between 0 and 180 °, wherein when θ <90 °, the material is hydrophilic; when theta is greater than 90 DEG, the material is hydrophobic. The smaller the angle θ, the better the hydrophilicity, and conversely, the better the hydrophobicity.
For ease of understanding, the following description is provided for the principle of the ionization probe of the present application having the above-described advantageous effects:
when a sampling operation for mass spectrometry is performed using the ionization probe 1 in the present application, specifically, with reference to fig. 3:
firstly, a platform body part of an ionization probe 1 is soaked into a solution 5 to be detected and is quickly absorbed and released, so that the solution 5 to be detected quickly enters and exits from the tip of the ionization probe 1, and then the porous material 2 on the inner wall of the tip is repeatedly impacted, and because the porous material and the component 3 to be detected have the same hydrophilicity or hydrophobicity or are close to each other, and the impurity component 4 in the solution 5 to be detected is completely opposite to the hydrophilicity or hydrophobicity of the porous material 2 or has a larger difference, the component 3 to be detected in the solution 5 to be detected can be fully extracted by the porous material 2 through multiple absorption and release, and the impurity component 4 in the solution 5 to be detected can not be greatly adsorbed on the porous material 2.
The stage portion of the ionization probe 1 is then immersed in the cleaning solution 6 for rapid suck-and-release to perform a cleaning process, by which a small amount of the impurity components 4 adhering to the porous material 2 can be further removed due to the impurity components 4 having completely opposite hydrophilicity or hydrophobicity to the porous material or having a large difference, for example, when the solution to be measured is a plasma sample, the salt adhering to the porous material 2 and the matrix components 4 can be further removed by this step.
Then, the table body part of the ionization probe 1 which is cleaned is immersed into the elution solution, and a small amount of elution solution 7 is absorbed into the table body part of the ionization probe, because the hydrophilicity or hydrophobicity of the elution solution 7 is closer to the component 3 to be detected than that of the porous material 2, the component 3 to be detected is transferred from the porous material 2 to the elution solution 7 after being eluted, and finally the elution solution 7 containing the component 3 to be detected is obtained. And finally, transferring the ionization probe 1 subjected to elution treatment and an elution solution 7 containing the component 3 to be detected in the ionization probe to a sample introduction end of a mass spectrometer 9, and then carrying out electrospray mass spectrometry.
According to the method, the porous material is modified on the inner wall of the capillary tip to form the ionization probe, the characteristic of the difference of the hydrophilicity and hydrophobicity of the component to be detected and the impurity component is combined, the solution to be detected is repeatedly absorbed and released, namely, the enrichment of the component to be detected on the porous material is realized through multiple extraction treatments, the impurity components such as matrix, salt and the like in the solution to be detected are further cleaned and removed through further cleaning treatment, and finally, the component to be detected enriched in the extraction treatment is completely transferred into the elution solution through elution treatment, so that the electrospray mass spectrometry can be directly carried out, the complex steps of impurity removal in pretreatment and the enrichment of the component to be detected are omitted, and the in-situ electrospray ionization and mass spectrometry are realized. In summary, the ionization probe in the present application enables the ionization probe to realize rapid and convenient sampling operation, and simultaneously has the function of direct electrospray ionization. The interference of impurity components can be removed while the components to be detected in the solution to be detected are rapidly and efficiently sampled through simple absorption-release operation, and the collected components to be detected can be directly subjected to electrospray ionization and mass spectrometry.
According to some embodiments of the present invention, a material forming the capillary is not particularly limited, for example, the material forming the capillary may include at least one of glass, metal, polyetheretherketone, and fluorinated ethylene propylene copolymer. According to other embodiments of the present invention, the kind of the porous material is not particularly limited, for example, the porous material may include at least one of an organic polymer, a metal organic framework, and a covalent organic framework, and further, in order to improve the hydrophilicity or hydrophobicity of the porous material, the porous material may be modified, and specifically, hydrophilic or hydrophobic groups such as polydopamine, cysteine, and the like may be further modified on the foregoing porous material.
According to some embodiments of the present invention, the diameter of the first opening is not particularly limited as long as the diameter of the first opening is greater than twice the thickness of the porous material at the first opening, that is, after the inner wall of the first opening is provided with the porous material, the remaining pores of the first opening are sufficient for the solution to be measured to pass through. Specifically, the diameter of the first opening may be 1 to 200 μm. According to other embodiments of the present invention, the thickness of the porous material is not particularly limited, and for example, the thickness of the porous material may be 0.1 to 100 μm.
It is understood that, for the capillary tube, the diameter of the cross section of the stage body part is gradually increased in the direction in which the first opening points to the second opening, that is, the diameter of any cross section parallel to the first opening in the stage body part is larger than that of the cross section formed by the first opening, so that the thickness of the porous material at the middle position of the inner wall of the stage body part can be larger than that of the porous material at the first opening, that is, the porous material on the inner wall of the stage body part can be unequal in thickness. Specifically, the ratio of the thickness of the porous material at the first opening to the diameter of the first opening may range from 0 to 1/3. For example, when the diameter of the first opening is 60 μm, the thickness of the porous material at the first opening may be 0 μm, 0.1 μm, 0.5 μm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 10 μm, 15 μm, and 20 μm. Referring to fig. 5 (the first opening is viewed from the second opening of the stage portion), fig. 5 (a) is an overall schematic view of the ionization probe, and it can be seen that the first opening has a diameter of about 50 μm, and the thickness of the porous material at the first opening is 0 μm. Fig. 5 (b), (c) and (d) are schematic cross-sectional views of the mesa portion taken along a cross-section parallel to the first opening, and it can be observed that the inner wall of the mesa portion has a porous material at an intermediate position, and the thickness of the porous material is in the range of 50 to 100 μm.
According to some embodiments of the present invention, the position of the porous material on the inner wall of the capillary stage body is not particularly limited as long as the porous material is provided on the inner wall of the stage body. For example, referring to fig. 1, the porous material 2 may cover only a partial region of the inner wall of the capillary table body 100 near the first opening 110; referring to fig. 2, the porous material 2 may also cover the entire area on the inner wall of the capillary table body 100; the porous material 2 may also cover only the intermediate region of the inner wall of the capillary table portion 100 remote from the first opening 110 and remote from the second rest opening 120; the porous material 2 may further cover a part or all of the area of the columnar portion in addition to the entire area on the inner wall of the capillary table body portion 100.
In another aspect of the invention, the invention provides a method of electrospray using the aforementioned ionization probe, in particular comprising the steps of:
step S1: contacting the first opening of the ionization probe with the solution to be measured, and performing a first treatment comprising sequentially sucking and releasing the solution to be measured
According to some embodiments of the present invention, in the step, the tip of the ionization probe is rapidly absorbed and released in the solution to be tested, so that the solution to be tested is rapidly moved into and out of the tip of the ionization probe to impact the porous material on the inner wall, so that the porous material is sufficiently contacted with the solution to be tested, and the component to be tested in the solution to be tested is enriched on the porous material.
According to some embodiments of the present invention, in order to further improve the enrichment effect of the component to be measured on the porous material, the step S1 may further include: the first treatment is repeated, i.e., the solution to be measured is repeatedly sucked-released a plurality of times. According to other embodiments of the present invention, the frequency and the number of times of repeating the first treatment are not particularly limited, and for example, the frequency of repeating the first treatment may be 1 to 10Hz, and the number of times of repeating the first treatment may be 1 to 200 times.
Step S2: contacting the first opening of the ionization probe with a cleaning solution and performing a second treatment comprising sequentially drawing and releasing the cleaning solution
According to some embodiments of the invention, the cleaning solution is different from the hydrophilic-hydrophobic property of the porous material, i.e. when the porous material is a hydrophilic material, the cleaning solution is a non-polar solution; when the porous material is a hydrophobic material, the cleaning solution is a polar solution. At this step, the tip of the ionization probe is subjected to rapid suck-release in a cleaning solution to further remove a small amount of impurity components adhering to the porous material.
According to some embodiments of the present invention, in order to further improve the removal effect of the impurity components, the step S2 may further include: the second treatment, i.e., the sucking-and-releasing of the wash solution is repeated a plurality of times. According to further embodiments of the present invention, the frequency and the number of times of repeating the second treatment are not particularly limited, and for example, the frequency of repeating the second treatment may be 1 to 5Hz, and the number of times of repeating the first treatment may be 1 to 10 times.
Step S3: contacting the first opening of the ionization probe with an elution solution and aspirating the elution solution
According to some embodiments of the invention, the hydrophilicity and hydrophobicity of the elution solution and the porous material are the same, the hydrophilicity and hydrophobicity of the elution solution is greater than the hydrophilicity and hydrophobicity of the porous material, and the binding force of the component to be detected in the elution solution is greater than the binding force of the molecule to be detected and the porous material, i.e. when the elution solution and the porous material are both hydrophilic, the polarity of the elution solution is stronger; when both the elution solution and the porous material are hydrophobic, the elution solution is more non-polar. In the step, the table body part of the ionization probe is immersed into the elution solution, and a small amount of the elution solution is sucked into the table body part of the ionization probe and is kept for a period of time, so that the components to be detected adsorbed on the porous material are fully transferred into the elution solution.
According to some embodiments of the present invention, the volume of the elution solution is not particularly limited as long as the volume of the elution solution is sufficient for the amount of the solution to be measured for the subsequent electrospray mass spectrometry, and for example, the volume of the elution solution may be 10pL to 10 μ L. When the volume of the elution solution is within the range, the electrospray ionization mass spectrometry under various modes can be performed by using a small volume of the sample to be detected.
According to some embodiments of the present invention, the time for waiting for the component to be measured adsorbed on the porous material to be transferred into the elution solution after the elution solution is drawn is not particularly limited, and for example, the time for waiting after the elution solution is drawn may be 0.1 to 10 min. After standing for the time, the components to be detected enriched in the porous material in the ionization probe can be effectively and fully transferred into the elution solution.
Step S4: applying a voltage to the ionization probe sucking the elution solution to perform electrospray
According to some embodiments of the invention, the step of transferring the ionization probe containing the elution solution of the component to be measured in the stage body part to the sample introduction end of the mass spectrometer for electrospray ionization.
According to some embodiments of the invention, the method of electrospray ionization is not particularly limited, for example: electrospray can include contact electrospray and non-contact inductive electrospray. Specifically, the volume of the elution solution may be 10pL to 1 μ L when electrospray ionization is performed using non-contact induction electrospray, and may be 1 μ L to 10 μ L when electrospray ionization is performed using contact electrospray. For example, when electrospray ionization is performed by contact electrospray, a wire electrode 8 may be inserted from the fourth opening 340 of the ionization probe 1, and the wire electrode is contacted with an elution solution containing a component to be detected, and a voltage is applied to the wire electrode, so that electrospray is formed at the first opening of the ionization probe, and finally, the ion of the component to be detected in the electrospray is detected and analyzed by using a mass spectrometer.
In a further aspect of the invention, the invention provides a use of an electrospray method as hereinbefore described for high-throughput mass spectrometry comprising: providing an ionization probe array, a solution array to be detected, a cleaning solution array and an elution solution array; sequentially performing step S1, step S2, and step S3 on the ionization probe array; voltages are sequentially applied to the ionization probes of the ionization probe array for electrospray, so that high-throughput mass spectrometry can be achieved.
For ease of understanding, the following is a brief description of the application of the electrospray method to high throughput analysis of solutions to be tested, with reference to fig. 10:
firstly, an ionization probe array 10 (such as 10-100 ionization probes) can be fixed on the same operation platform, wherein each ionization probe 1 is internally inserted with a wire electrode 8; then, through the control platform 11, the control platform 11 can drive the ionization probe array to complete vertical movement, so that the ionization probe array simultaneously performs absorption-release operation on a plurality of solutions to be detected 5, and then the solution array to be detected is replaced by a plurality of cleaning solutions 6 to complete cleaning of impurity components 4; and finally, replacing the cleaning solution array with a plurality of elution solutions 7 to finish the operation of absorbing the elution solutions. Standing and waiting for the component 3 to be detected to be eluted by the elution solution 7, and integrally transferring the ionization probe array 10 to a mass spectrum sample introduction end. And sequentially applying voltage to the electrode wires, and sequentially detecting and analyzing the component ions to be detected in the electrospray generated by each ionization probe 1 by using mass spectrometry.
According to some embodiments of the present invention, in order to facilitate the solution replacement, a plurality of solutions to be measured 5, a plurality of washing solutions 6, and a plurality of elution solutions 7 may be placed on the multi-well plate 12, respectively, thereby achieving a rapid replacement of the solution to be pipetted.
In yet another aspect of the invention, the invention provides the use of the electrospray method as described above for single cell detection, where the solution to be detected is the cell content, thereby allowing mass spectrometry of very small volumes of cell content.
For ease of understanding, the following is a brief description of the application of the electrospray method to single cell detection, with reference to FIG. 11:
firstly, the tip, namely the platform body part of an ionization probe 1 is penetrated into a single cell sample 13, cell contents are absorbed into the tip of the ionization probe, and after a porous material extracts components to be detected in the single cell sample, the cell contents are released, namely primary treatment is completed; then sucking a small amount of cleaning solution 6 into the tip of the ionization probe, and releasing the cleaning solution after the cleaning solution elutes the salt and matrix components adhered to the porous material; then, a small amount of elution solution 7 is sucked into the ionization probe tip, and the elution solution is waited to elute the component to be detected adsorbed on the porous material, so that the elution solution of the component to be detected is obtained; and finally, transferring an ionization probe of the elution solution of the component to be detected containing the unicellular sample 13 in the table body part to a mass spectrum sample introduction end, inserting an electrode wire from the tail end of the sampling probe, forming electrospray of the elution solution in the tip by using a non-contact induction electrospray ionization mode, and detecting and analyzing the component ions to be detected in the electrospray by using a mass spectrometer.
In summary, the application of the electrospray method to single cell detection in qualitative analysis can be used for determining the element composition and molecular structure of the component to be detected, and analyzing sn isomers and carbon-carbon double bond position isomers of phospholipid; in the aspect of quantitative analysis, the method can be used for realizing the quantitative detection of the components to be detected by adding an internal standard substance on the porous material or in the elution solution.
The following embodiments are provided to illustrate the present application, and should not be construed as limiting the scope of the present application. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are conventional products which are commercially available, and are not indicated by manufacturers.
Example 1:
the material forming the capillary tube is glass, and the porous material is acrylamide-ethylene glycol dimethacrylate copolymer globules, the diameter of which is about 2 μm. Referring to fig. 5, the thickness of the porous material at the middle position of the inner wall of the capillary tube is 50-100 μm, the diameter of the first opening is 50 μm, and the thickness of the porous material at the first opening is 0 μm. The solution to be tested is plasma, and the components to be tested are lipids and fatty acids in the plasma.
The electrospray method was as follows:
1. rapidly absorbing and releasing the tip of the ionization probe in a solution to be detected, wherein the absorption-release times are 100 times, and the frequency is 1 Hz;
2. rapidly sucking and releasing the tip of the ionization probe in a cleaning solution, wherein the sucking and releasing times are 5 times, and the frequency is 1 Hz;
3. sucking a small amount of elution solution into the ionization probe tip, wherein the volume of the elution solution is 10 mu L, and waiting for 10 minutes to obtain the elution solution of the component to be detected;
4. transferring an ionization probe containing an elution solution of a component to be detected in a tip to a sample introduction end of a mass spectrometer, inserting a wire electrode from the tail end of the ionization probe, enabling the wire electrode to contact the elution solution of the component to be detected, applying voltage on the wire electrode, forming electrospray at the tip of the ionization probe, and detecting and analyzing the component ions to be detected in the electrospray by using the mass spectrometer.
Example 2:
example 2 was identical to example 1, except that the porous material was ZIF-8, 0.1 μm thick. The diameter of the first opening of the ionization probe is 200 μm. The solution to be detected is blood plasma, and the component to be detected is the concentration of the drug metabolite in the blood plasma.
The electrospray method was as follows:
1. fixing an array consisting of 96 ionization probes on an ionization probe fixing platform, wherein electrode wires are inserted in the probes;
2. so that the ionization probe array can simultaneously perform the sucking-releasing operation on 96 liquids in the 96-well plate 12. A96-pore plate loaded with 96 parts of different solutions to be detected is placed first, and the ionization probe array is controlled to complete 100 times of absorption-release operations, wherein the frequency is 5 Hz.
3. Placing all 96 pore plates loaded with cleaning solution, and controlling the ionization probe array to complete 10 times of absorption-release operations, wherein the frequency is 5 Hz;
4. placing a 96-hole plate which is completely loaded with the elution solution, controlling an ionization probe array to absorb 10 mu L of elution solution into the tip of each ionization probe, waiting for 10 minutes, and integrally transferring the ionization probe array to a mass spectrum sample introduction end;
5. and selecting a conventional electrospray ionization mode, sequentially applying voltage to the electrode wires, and sequentially detecting and analyzing the component ions to be detected in the electrospray generated by each ionization probe by using mass spectrometry.
Example 3:
example 3 was identical to example 1, except that the ionization probe had a first opening diameter of 1 μm, the single cell to be tested was a Hela cell, and the components to be tested were lipids and metabolites in the Hela cell.
1. Penetrating the ionizing probe tip into a single cell, and sucking a small amount of cell contents into the ionizing probe tip;
2. aspirating a cleaning solution into the tip of the ionization probe, followed by releasing the cleaning solution;
3. absorbing 10pL of the elution solution into the ionization probe tip, and waiting for 1 minute to obtain the elution solution of the component to be detected;
4. transferring an ionization probe containing a single-cell sample to-be-detected component elution solution in a tip to a mass spectrum sample introduction end, inserting an electrode wire from the tail end of the sampling probe, forming electrospray by using a non-contact induction electrospray ionization mode to the elution solution in the tip, and detecting and analyzing component ions to be detected in the electrospray by using a mass spectrometer.
Comparative example 1:
conventional mass spectrometry method, as for example 1.
Taking the traditional lipid extraction method Folch method as an example: adding 1.5mL of methanol into 200 mu L of sample to be detected, and uniformly mixing by vortex. ② 3mL of chloroform was added thereto, and the mixture was shaken at room temperature for 1 hour. ③ 1.25mL of water is added to induce phase separation. After 10 minutes at room temperature and 10 minutes at 1000g acceleration, the lower chloroform phase was collected. Fourthly, the upper phase is washed with 2mL of a solvent mixture (chloroform/methanol/water, volume ratio 86:14:1) and the lower phase is extracted after washing. Combining the lower phase extracted twice, drying in a vacuum centrifuge, and finally dissolving in 1mL of methanol.
The test result shows that: fig. 6, 7 and 8 are a positive ion mode mass spectrum, a high-mass end negative ion mode mass spectrum and a low-mass end negative ion mode mass spectrum of the plasma samples in example 1 and comparative example 1, respectively. From fig. 6, fig. 7 and fig. 8, the positive ion mode spectrum peak of plasma sample lipid, the negative ion mode spectrum peak of plasma sample lipid and the spectrum peak of plasma sample fatty acid can be obtained respectively, which proves that the ionization probe and the use method thereof of the present invention can effectively extract the information of lipid and fatty acid in plasma sample. The ionization probe method of the present invention and the conventional liquid-liquid extraction method were used to analyze lipid signals in the same plasma sample, and the analysis results are shown in fig. 9, in which PC is phosphatidylcholine; SM is sphingomyelin; TAG is triglyceride; PE is phosphatidyl ethanolamine; PI is phosphatidylinositol; FA is fatty acid. As is apparent from the comparison result in fig. 9, the data obtained by performing mass spectrometry analysis by using the ionization probe in the present application is similar to the signal intensity of phosphatidylcholine, sphingomyelin, triglyceride and phosphatidylethanolamine in a plasma sample obtained by using a conventional liquid-liquid extraction method, the signal intensity of phosphatidylinositol obtained by using the ionization probe is half of that obtained by using the conventional liquid-liquid extraction method, and the fatty acid signal obtained by using the ionization probe is slightly higher than that obtained by using the conventional liquid-liquid extraction method.
The mass spectrometry test result of the embodiment 2 shows that the total mass spectrometry of 96 plasma samples can be completed within 15 minutes by using the high-throughput mass spectrometry method of the invention, and the concentration of lipophilic drugs in the plasma samples, including various substances such as doxepin, amitriptyline, epitestosterone and the like, can be effectively detected.
The mass spectrometry test results of example 3 show that lipids including fatty acids, glycerides, and glycerophospholipids in the contents of single cells can be effectively detected using the single cell detection method of the present invention. By utilizing the information of the lipids, the accurate identification of the single cells with different drug resistance characteristics in the cell population can be realized, and an effective analysis means is provided for the research of the single cell lipidomics.
The results show that the ionization probe and the electrospray method thereof have the advantages of small usage amount of solution to be detected, simple detection steps, short detection time, suitability for various electrospray modes, capability of realizing in-situ mass spectrometry, and suitability for various mass spectrometry detection applications such as field rapid detection, high-throughput mass spectrometry, single cell detection and the like of small and portable mass spectrometry instruments.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects. In the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. There may be differences below 10% in the value of each number or reasonably considered by those skilled in the art, such as differences of 1%, 2%, 3%, 4% or 5%.
In the description of the present invention, it is to be understood that the terms "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", and the like, indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, are only for convenience in describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and thus, should not be construed as limiting the present invention.
In the description of the present invention, "the first feature" and "the second feature" may include one or more of the features.
In the description of the present invention, the first feature being "on" or "under" the second feature may include the first and second features being in direct contact, and may also include the first and second features being in contact with each other not directly but through another feature therebetween.
In the description of the invention, "over," "above," and "on" a second feature includes that the first feature is directly above and obliquely above the second feature, or simply means that the first feature is higher in level than the second feature.
Reference throughout this specification to the description of "one embodiment," "another embodiment," or the like means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction. In addition, it should be noted that the terms "first" and "second" in this specification are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. An ionization probe, comprising:
a capillary including a stage portion having a first opening and a second opening, the first opening having a diameter smaller than that of the second opening, and a column portion having a third opening and a fourth opening, the second opening being connected to the third opening,
wherein, the inner wall of the stage body part is provided with a porous material which is a hydrophilic material or a hydrophobic material.
2. The ionization probe of claim 1, wherein the material of the capillary comprises at least one of glass, metal, polyetheretherketone, and fluorinated ethylene propylene copolymer; the porous material includes at least one of an organic polymer, a metal-organic framework, and a covalent organic framework.
3. The ionization probe of claim 1, wherein the first opening has a diameter of 1-200 μm and the porous material has a thickness of 0.1-100 μm.
4. A method of electrospray using the ionization probe of any of claims 1-3, comprising:
step S1: enabling a first opening of the ionization probe to be in contact with a solution to be detected, and performing first treatment, wherein the first treatment comprises the steps of sequentially sucking and releasing the solution to be detected;
step S2: contacting the first opening of the ionization probe with a cleaning solution and performing a second treatment comprising sequentially drawing and releasing the cleaning solution;
step S3: contacting the first opening of the ionization probe with an elution solution and aspirating the elution solution;
step S4: applying a voltage to the ionization probe that has drawn up the elution solution to perform the electrospray,
wherein the cleaning solution and the porous material have different hydrophilicity and hydrophobicity, and the elution solution and the porous material have the same hydrophilicity and hydrophobicity.
5. The method according to claim 4, wherein the step S1 further comprises: and repeating the first treatment, wherein the frequency of repeating the first treatment is 1-10Hz, and the number of times of repeating the first treatment is 1-200.
6. The method of claim 4, wherein the volume of the elution solution is 10pL to 10 μ L.
7. The method of claim 4, wherein the time for drawing the elution solution is 0.1-10 min.
8. The method of claim 4, further comprising: the electrospray includes contact electrospray and non-contact induction electrospray.
9. Use of an electrospray method according to any one of claims 4 to 8 for high-throughput mass spectrometry comprising:
providing an ionization probe array, a solution array to be detected, a cleaning solution array and an elution solution array;
sequentially performing step S1, step S2, and step S3 on the ionization probe array;
sequentially applying a voltage to the ionization probes of the ionization probe array for electrospray.
10. Use of the electrospray method according to any one of claims 4 to 8 for single cell detection, wherein the test solution is the cell content.
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