JP2011210734A - Ion collector - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a mechanism in which ions in the vicinity of a surface of a sample board are collected to the maximum in a desorption ionization method.SOLUTION: An ion capturing port having a width and a height equal to or more than spread of generated ions is installed and is positioned so as to be contacted with the sample board. Alternatively, a face lower than that on which a sample is placed is installed by providing level difference on the sample board, and an opening bottom face of the ion capturing port having the width and the height equal to or more than the spread of the generated ions is installed lower than the face on which the sample is loaded.

Description

  The present invention relates to an analysis system for a sample containing various kinds of components, and more particularly to a mass spectrometry system, an analysis method, and an apparatus used for analysis of drugs and biological materials and detection of substance surface components.

  In recent years, mass spectrometry has come to be adopted as an analytical means in many fields as ionization methods for various samples have been developed. For example, mainly in the fields of biotechnology, drug discovery, and food, it is becoming a major means for analyzing biological materials such as proteins, sugar chains, and metabolites contained in biological tissues and body fluids. In the security field, a technique for detecting explosives and the like adhering to the surface of an object by mass spectrometry is being established.

  In mass spectrometry, many ion ionization methods have been studied so far. Among them, electrospray ionization (ESI) is known as one that can be ionized under atmospheric pressure. ESI ionizes a sample by spraying the sample solution into an electric field under atmospheric pressure. Matrix-assisted laser ionization (MALDI) is usually performed in a vacuum, but recently, a method for generating ions under atmospheric pressure has been developed. In this atmospheric pressure MALDI, a sample is irradiated with a laser, and sample ions released near the sample stage are guided to an ion intake port of a mass spectrometer by a gas flow (Non-patent Document 1). However, the atmospheric pressure MALDI has problems such as requiring a matrix, laser equipment, and being expensive.

  Therefore, recently, an ionization method called desorption electrospray ionization (DESI) has been developed as an intermediate ionization method between ESI and atmospheric pressure MALDI. In DESI, substances on the surface of an object are ionized by applying charged droplets generated by ESI under atmospheric pressure. The advantage is that the substance on the surface of the object can be analyzed as it is without applying a matrix to the surface of the object, which can be realized only by the voltage application means. Among DESI methods, there is a method in which charged droplets generated by electrospray using a nebulizer gas are applied to a sample. This method has advantages such as mild ionization conditions, simplicity, and the ability to ionize various substances (Patent Document 1).

US 2005/0230635 A1

Analytical Chemistry (2000) p.652-657 (Analytical Chemistry 2000, paragraphs 652 to 657)

  In desorption ionization using a nebulizer gas, a gas flow strikes a sample table holding a sample and flows along the surface of the sample table. Ions generated from the sample also ride along this gas flow and flow along the surface of the sample stage. Therefore, in the method of collecting ions with an ion intake tube approaching the sample from above the sample stage and tilting it at an angle of 10 degrees as described in Patent Document 1, one of the generated ions is collected. Only the part can be collected. Further, when another sample exists in the direction of the gas flow, the charged droplet reaches the other sample, ionization occurs, and ions other than the target sample are observed. Therefore, in order to perform selective measurement with higher sensitivity, a mechanism for maximally collecting target ions in the vicinity of the surface of the sample stage is necessary.

  Therefore, in the present invention, an ion intake port having a width and height greater than the spread of the generated ions is provided in the traveling direction of the gas flow flowing along the surface of the sample stage, and is positioned so as to be in contact with the sample stage. Alternatively, the surface of the sample stage in the direction of the gas flow that flows along the surface of the sample stage is provided with a surface that is lower than the surface on which the sample is loaded with a step, and ions with a width and height that are greater than the spread of the generated ions. Set the bottom of the opening of the intake port lower than the surface on which the sample is loaded. The sample stage is provided with a region for placing the sample and a region for placing the ion intake port.

  According to the present invention, ion desorption efficiency of sample ions can be improved in a desorption ionization method using a nebulizer gas. Moreover, it can prevent that another sample is ionized accidentally and the accuracy of a measurement improves.

Sectional drawing of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and an example of arrangement | positioning. The graph which shows the relationship between the deviation | shift from the center axis | shaft of the charged droplet spray of an ion intake tube, and the amount of ions collected. The graph which shows the relationship between the distance from the metal plate surface of an ion intake tube, and the amount of ions collected. Sectional drawing of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and an example of arrangement | positioning. Sectional drawing of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and an example of arrangement | positioning. Sectional drawing of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and an example of arrangement | positioning. Sectional drawing of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and an example of arrangement | positioning. Sectional drawing of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and an example of arrangement | positioning. The figure of the example of the sample stand used for the ion collector by this invention, and sample arrangement | positioning. The figure of the example of the sample stand used for the ion collector by this invention, and sample arrangement | positioning. The figure of the example of the sample stand used for the ion collector by this invention, and sample arrangement | positioning. Sectional drawing of the sample stand shape example used for the ion collector by this invention. The figure of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and the example of arrangement | positioning. The figure of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and the example of arrangement | positioning. The figure of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and the example of arrangement | positioning. Sectional drawing of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and an example of arrangement | positioning. The figure of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and the example of arrangement | positioning. (A) Stereo view (b) Sectional drawing of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and an example of arrangement. Sectional drawing of the sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and an example of arrangement | positioning. The sample stand used for the ion collector by this invention, the shape of an ion uptake tube, and the three-dimensional figure of the example of arrangement | positioning. The sample stand used for the ion collector by this invention, the solid drawing of the shape and arrangement example of an ion uptake tube. The figure stand (b) sectional view seen from the sample stand used for the ion collection device by the present invention, the shape of an ion uptake tube, and arrangement example (a). The figure of an example of the liquid chromatograph / mass spectrometer which used the ion collector by this invention. The figure of an example of the charged droplet production | generation apparatus used for the ion collection apparatus by this invention. The figure of the shape and example of arrangement | positioning of an ion uptake tube used for the ion collector by this invention. The figure of the shape and example of arrangement | positioning of an ion uptake tube used for the ion collector by this invention.

  FIG. 1 shows an apparatus configuration example for realizing the ion collection method according to the present invention. The sample is held on the sample stage. The sample is irradiated with the charged substance together with the nebulizer gas at an appropriate angle with the sample stage. As the charged substance, charged droplets generated by ionization means such as electrospray and sonic spray can be considered. By contact with the charged charged substance, the sample is ionized and desorbed from the sample stage, or desorbed from the sample stage and then ionized. What is necessary to irradiate the sample for ionization is any other particles having energy necessary for ionization of the sample, such as electron beam, ion beam, fast atom, laser beam, and droplet.

  In FIG. 2, a charged droplet spray generated by electrospray using a nebulizer gas is applied to the plate at an angle of 45 degrees, and the ion in the lateral direction is advanced by 4 mm from the applied point to the applied direction. The result of measuring the spread is shown in the graph. From this graph, it can be seen that the ions have a width of about 6 mm. FIG. 3 is a graph showing the result of measuring the spread of ions in the direction perpendicular to the plate. It can be seen that the ions flow in a range of 1.2 mm or less in height. From these experimental results, it can be seen that the generated ions flow in a strip shape having a width of 6 mm and a height of 1.2 mm on the surface of the sample stage with the flow of the nebulizer gas. Therefore, it can be seen that it is better to arrange the ion intake tube in the direction in which the ions flow.

  In FIG. 1, a groove is provided in a region of the sample table where no sample is present, and the ion intake tube is placed in contact with the groove bottom surface. By setting the ion intake tube at a temperature higher or lower than room temperature, ionization of target ions can be promoted. When the charged droplet generator used in the experiments of FIGS. 2 and 3 is used, the width and height of the opening of the ion intake tube are 6 mm wide and 1.2 mm or higher where the sample ions spread. It is desirable that The central axis of incident ions and the axis of the ion intake tube are arranged on the same plane. With this arrangement, sample ions generated by charged droplets irradiated on the sample are efficiently collected, and highly sensitive measurement is possible.

  4 to 8 show apparatus configuration examples for realizing the ion collection method according to the present invention. When a plurality of samples are placed on the same sample stage, they are arranged with an interval between the samples. The interval is not less than the contact length of the tip of the ion capturing tube so that the tip of the ion capturing tube can contact only the region where the sample does not exist. Further, the ion uptake tube is arranged to be inclined with respect to the sample stage so that the ion uptake tube does not contact the sample, or the ion uptake tube is bent. The ion uptake tube is placed in contact with the region of the sample stage where there is no sample, and is arranged so that the central axis of the spray tube and the axis of the ion uptake tube are on the same plane. In the case where no groove is provided on the sample stage, it is desirable that the tip of the ion intake tube is in close contact with the sample stage. For example, as shown in FIG. 4, the tip of the round tube can be cut obliquely and brought into close contact with the sample table at the cut surface. At this time, the height of the opening of the ion capturing tube and the width in contact with the sample stage are preferably equal to or higher than the height and width in which ions are spread. With this arrangement, sample ions generated by the charged substance incident on the sample are efficiently collected, and highly sensitive measurement is possible.

  Further, for example, as shown in FIG. 5, the tip of the ion intake tube can be deformed to make a flat portion so that it can be in stable contact with the sample stage.

  Further, for example, as shown in FIG. 6, a projection is formed on the ion intake tube, and a recess is formed on the sample stage corresponding thereto, so that the ion intake tube can be restricted to move only in a certain region. Alternatively, as shown in FIG. 7, a protrusion can be formed on the sample stage, and a depression can be formed in the ion intake tube correspondingly, thereby restricting the ion intake tube to move only in a certain region. By restricting the movement of the ion intake tube, other samples can be prevented from being accidentally damaged.

  Further, for example, as shown in FIG. 8, in the case of a structure in which a groove is formed between the sample in the sample stage, the ion intake tube and the sample stage need not be brought into contact with each other. At this time, the bottom surface of the opening of the ion intake tube needs to be lower than the surface of the convex portion on which the sample is placed. With this arrangement, ions that have flowed along the surface in the vicinity of the surface of the convex portion travel straight even if they reach the boundary between the convex portion and the groove, and enter the ion intake tube. This is effective when it is desired to avoid contact between the sample stage and the ion uptake tube, such as when it is not desired to bring the heated sample uptake tube into contact with the sample stage.

  9 to 12 show examples of sample stands for realizing the ion collection method according to the present invention. FIG. 9 is an example of a method for placing a plurality of samples on one sample stage. By arranging the samples at regular intervals, automatic measurement using an electric XY stage or the like is facilitated. Further, by setting the interval between the samples to be equal to or larger than the ion spreading width, mixing of data between samples is eliminated, and measurement accuracy is improved.

  FIG. 10 is an example of a sample stage in which a groove is provided between samples. By fitting the tip of the ion uptake tube into the groove, the ion uptake tube can move only within the range of the groove portion, and damage to the sample due to the ion uptake tube coming into contact with the sample can be prevented.

  FIG. 11 is an example of a sample stage in which a groove is provided between samples. By fitting the tip of the ion uptake tube into the groove, the ion uptake tube can move only within the range of the groove portion, and damage to the sample due to the ion uptake tube coming into contact with the sample can be prevented.

  FIG. 12 shows an example of the shape of the sample stage and how to place the sample. FIG. 12A shows a case where a sample is simply placed on a flat sample table. Processing of the sample stage is unnecessary, and low cost can be realized. FIG. 12B shows an example in which a flat plate having a depression is used and a sample is held in the depression. Since the sample is accurately placed within a specific range, measurement by an automatic device is facilitated. FIG. 12 (c) uses a flat plate with a depression, and the depression is supplemented with substances for removing unnecessary components (antibodies that bind unnecessary components, gels that absorb only low molecular weight components, and specific metal ions). Chelating agent, etc.), a substance that stabilizes the sample, and a substance that assists ionization of the sample. Due to the action of these substances, better quality data can be obtained. In addition, different types of substances can be placed in the respective depressions, and the degree of interaction between the sample and the known substance and the screening method for improving the ionization efficiency can be performed.

  FIGS. 13 to 22 show examples of an ion intake port and a sample stage for realizing the ion collection method according to the present invention.

  FIG. 13 shows an example of a combination of a circular ion uptake tube and a grooved sample stage. Even in the case of a circular tube, the width and height of the opening in contact with the convex surface on which the sample is placed may be larger than the spread of ions. In this case, since a normal tube can be used as an ion uptake tube without any particular processing, it is simple.

  FIG. 14 shows an example of a combination of an ion uptake tube having a rectangular tip and a grooved sample stage. With this shape, the ion uptake tube can be stably placed on the sample stage.

  FIG. 15 shows an example of a combination of an ion uptake tube having a rectangular tip and a grooved sample stage. When the diameter of the ion intake port of the mass spectrometer is smaller than the spread width of the sample ions, the generated sample ions are formed by making the opening width of the ion intake tube wider than the spread width of the sample ions. Efficiently collected and highly sensitive measurement is possible.

  FIG. 16 shows an example of a combination of a flat sample stage and an ion uptake tube having a wedge shape when viewed from a cross-section, with a portion of the tip being flattened to reduce the thickness of the tube in contact with the sample stage. By making the tip of the ion uptake tube wedge-shaped, the flow of generated sample ions can be introduced into the ion uptake tube without being disturbed by the cross section of the opening of the ion uptake tube, reducing the loss of sample ions and measuring with high sensitivity. Is possible.

  FIG. 17 shows an example in which the tip of the ion capturing portion is shaped to cover the top and side surfaces of one sample. This shape can prevent charged substances and generated sample ions from reaching adjacent samples. In addition, the generated sample ions can be collected without loss, and highly sensitive measurement can be performed. In addition, there is no fear that the charged substance will diffuse outside, and the handling is safe. Further, by fixing the charged substance introduction tube, it is possible to prevent the tip of the charged substance introduction tube from coming into contact with the sample.

  FIG. 18 shows an example in which the tip of the ion capturing part has a shape that covers the entire sample, and the charged substance introduction tube is inserted from a part thereof. Further, as shown in FIG. 19, it is possible to insert the gas introduction pipe from a part thereof. This is effective when the gas flow rate sucked by the ion intake tube is larger than the gas flow rate emitted from the charged substance introduction tube. That is, by introducing an appropriate amount of pure gas from the gas introduction pipe, it is possible to prevent the foreign matter from being sucked in from the outside and mixed in. In addition, there is no fear that the charged substance will diffuse outside, and the handling is safe. Further, by fixing the charged substance introduction tube, it is possible to prevent the tip of the charged substance introduction tube from coming into contact with the sample.

  FIG. 20 shows an example in which the tip of the ion intake tube is a closed space and the charged substance introduction tube is inserted from a part thereof. A slot-shaped hole is made in a part of the tip of the ion intake tube. A sample carried on a slide glass, a filter paper slice or the like is inserted from here and used for measurement. This shape is convenient when it is desired to measure individual samples collected one by one.

  FIG. 21 shows an example in which the end of the ion capturing portion is a closed space and a hole is formed in the bottom surface. If it is desired to analyze a sample with an area less than the spread of the charged substance, it can be dealt with by reducing the size of the hole. It is desirable to integrate the charged substance introduction tube and the ion uptake tube, and to make the ion uptake tube movable. By pressing against the surface of the target object, the substance adhering to the object surface can be easily measured.

  FIG. 22 is an example of a sample stage on which a plurality of samples are placed. A plurality of samples are arranged in a row on the periphery of a rotatable disc. The charged substance introduction tube and the ion uptake tube are fixed in the disk surface and a plane perpendicular to the circumferential direction. Since each material can be measured in order by rotating the disk, complicated moving means in the XY directions are unnecessary.

  FIG. 23 shows an example of a liquid chromatograph / mass spectrometer using the ion collection method according to the present invention. A predetermined amount of the sample solution eluted from the liquid chromatograph is dropped on the sample stage. The sample stage is moved by a certain distance, and the next eluate is dropped on the sample stage by a certain amount. This is repeated while the sample is eluted from the liquid chromatograph. The sample stage is set to a temperature suitable for holding the sample. The dropped eluate is dried by means such as a blower, and then charged material is incident and ionized. For ionization, a method of spraying charged droplets generated by means such as electrospray ionization or sonic spray ionization under atmospheric pressure is the simplest and mildest method. The generated sample ions are introduced into the mass spectrometer by the ion intake tube according to the present invention, and mass spectrometry is performed. In such a liquid chromatograph eluate detection method, the same sample can be measured again even if ionization becomes unstable during analysis. Further, by applying in advance a reagent for reacting with a target substance to give a characteristic mass spectrum on a sample stage, more information can be obtained than in general LC / MS.

  FIG. 24 shows an example of means for generating charged droplets used in a mass spectrometry system using the ion collection method according to the present invention. By providing a potential difference between the solvent and the nebulizer gas guide, charged droplets are efficiently generated. Moreover, discharge is suppressed by the nebulizer gas, and stable charged droplet generation can be performed.

  FIG. 25 shows an example of an ion uptake tube for realizing the ion collection method according to the present invention. The ion intake tube opening is appropriately sized to collect ions generated from the sample surface. In addition, a cushion made of a flexible material is attached to the bottom surface of the ion intake tube. As a result, even on an uneven sample surface, the cushion part deforms and adheres closely to the sample surface, allowing contact between the bottom surface of the ion intake tube and the sample without gaps, and capturing the generated ions without escaping. Can do.

  In FIG. 26, an example of the measuring apparatus using the ion collection method based on this invention is shown. The tip of the ion uptake tube is shaped to cover the entire sample, and a charged substance spray tube is inserted from a part thereof. Open a small window at the bottom of the closed space at the tip of the ion uptake tube. The bottom surface of the ion intake tube is brought into direct contact with the liquid sample, and the charged substance is sprayed toward the bottom window. The generated sample ions are sent to a mass spectrometer, and the components of the liquid sample are analyzed by mass spectrometry. The liquid sample can be prevented from entering by adjusting the pressure in the ion intake tube. With this apparatus configuration, component analysis by mass spectrometry of a liquid sample can be performed with a simple operation of immersing the tip of the ion intake tube in the liquid.

DESCRIPTION OF SYMBOLS 1 ... Sample, 2 ... Sample stand, 3 ... Groove, 4 ... Charged substance introduction tube, 5 ... Charged substance, 6 ... Charged droplet, 7 ... Solvent, 8 ... Nebulizer gas, 9 ... Nebulizer gas guide, 10 ... Ion intake tube, 11 ... Ion intake tube tip, 12 ... Gas inlet tube, 13 ... Sample stage insertion port, 14 ···cushion.

Claims (4)

A sample stage on which the sample is placed;
Ionization means for irradiating the sample placed on the sample stage together with gas particles for ionizing the sample;
An ion capturing means for capturing an ionized sample,
The ion trapping device is characterized in that the ion trapping part of the ion trapping means is arranged so as to cover the sample placed on the sample stage.   2. The ion collector according to claim 1, wherein the ionization means is inserted from above an ion intake portion of the ion intake means.   2. The ion collector according to claim 1, wherein the ion take-in unit has an insertion port for inserting the sample stage. A sample stage on which the sample is placed;
An ionization means for irradiating the sample placed on the sample stage with energy for ionizing the sample together with the gas;
An ion capturing means for capturing an ionized sample,
In the sample stage, the sample setting part is convex,
The ion collector is characterized in that a bottom surface of an ion intake port of the ion intake means is disposed at a portion other than the sample installation portion lower than the sample installation portion.

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