阅读说明：本技术 试样预处理装置、包括此装置的分析系统及自动取样器 (Sample pretreatment device, analysis system including the same, and automatic sampler ) 是由 金丸训明 马场晶子 渥美俊介 村上宏明 岩田庸助 于 2019-07-10 设计创作，主要内容包括：试样预处理装置在配置有进行预处理的各工序的单元的平台(21)上包括搬送机构(22),此搬送机构(22)包括在X轴、Y轴的二轴方向直线移动且在Z轴方向伸缩的Z轴导件(22),液体处理器(224)与握柄(225)相互指向反方向而一体地设置于Z轴导件(22)。在自动取样器侧的框体(20)的侧壁面设置试样搬送用开口部(201),若试样的预处理结束,则Z轴导件(223)以由夹持器(228)来握持预处理完毕的盘的状态,移动至接近于开口部(201)的位置。臂(227)从开口部(201)以及形成于自动取样器的开口部通过而进入此自动取样器的框体内,将盘设置于既定位置。这样一来,在试样预处理装置中,能够省去作业者将预处理完毕的试样设置于分析装置的劳力。(The sample pretreatment device comprises a conveying mechanism (22) on a platform (21) provided with units for performing each step of pretreatment, wherein the conveying mechanism (22) comprises a Z-axis guide (22) which moves linearly in two-axis directions of an X axis and a Y axis and expands and contracts in the Z-axis direction, and a liquid processor (224) and a grab handle (225) point to opposite directions and are integrally arranged on the Z-axis guide (22). A sample transport opening (201) is provided in the side wall surface of the frame (20) on the side of the auto-sampler, and when the pretreatment of the sample is completed, the Z-axis guide (223) is moved to a position close to the opening (201) in a state where the pretreated disk is held by the clamper (228). An arm (227) passes through the opening (201) and an opening formed in the auto-sampler, enters the frame of the auto-sampler, and sets the disk at a predetermined position. In this way, the sample pretreatment device can eliminate the labor of the operator for setting the pretreated sample in the analyzer.)

1. A sample pretreatment device for pretreating a sample to be analyzed by an analyzer, comprising:

a frame body forming an outer shape of the sample pretreatment device;

an opening for sample transport formed in a wall surface of the housing on the side where the analyzer is located; and

and a sample transport unit including a grip portion for gripping a sample container containing a pretreated sample in the housing, wherein the grip portion is moved in the housing, and the sample transport unit is moved into the housing of the analyzer through an opening for transporting the sample and an opening formed in the housing of the analyzer.

2. The specimen pretreatment device according to claim 1, wherein

Further comprises a shutter for opening and closing the opening for sample transport,

when the sample transport unit transports the sample container from the sample pretreatment apparatus to the analysis apparatus, the shutter is in an open state, and

the shutter is in a closed state when the sample transport unit does not transport the sample container from the sample pretreatment apparatus to the analysis apparatus.

3. The specimen pretreatment device according to claim 1, wherein

The opening for sample transport and the opening of the analyzer are set to dimensions that allow the grip portion and the sample container held by the grip portion to pass therethrough, in a state where the sample pretreatment device and the analyzer are arranged in a predetermined positional relationship.

4. The specimen pretreatment device according to claim 1, wherein

The sample transfer section includes: a movable body linearly movable in three mutually orthogonal axial directions within the housing; and the holding portion provided to the movable body.

5. The specimen pretreatment device according to claim 4, wherein

The grip portion is provided on a surface of the movable body on a side on which the analysis device is seated, and a dispensing portion that sucks and discharges the liquid is provided on a surface of the movable body opposite to the side on which the analysis device is seated.

6. The specimen pretreatment device according to claim 5, wherein

The sample transport unit does not include a rotation drive mechanism for rotating the grip unit and the dispensing unit,

the movable body is linearly moved in three mutually orthogonal axial directions in a state where the grip portion is always present on a side on which the analysis device is seated and the dispensing portion is always present on an opposite side to the side on which the analysis device is seated.

7. The specimen pretreatment device according to claim 5, wherein

The holding part comprises an arm and a clamp holder,

the length of the arm and the position of the gripper are set to: when the movable body moves to a predetermined position on the side where the analyzer is located, the sample container held by the holder is positioned in the analyzer corresponding to a portion where the sample container is to be placed.

8. The specimen pretreatment device according to claim 5, wherein

A region in which the dispensing unit can move, i.e., a dispensing operation region, and a region in which the gripping unit can perform a conveying operation are set so as to overlap with each other in a plan view of the inside of the housing, and the region is set so that the gripping unit can perform a conveying operation region

In the overlapping region, cells requiring both a dispensing operation and a sample transport operation in the preprocessing step are arranged, in regions other than the overlapping region where the dispensing operation can be performed, cells requiring only the dispensing operation in the preprocessing step are arranged, and in regions other than the overlapping region where the transport operation can be performed, cells requiring only the sample transport operation in the preprocessing step are arranged.

9. The specimen pretreatment device according to claim 8, wherein

The unit that requires both the dispensing operation and the sample transfer operation in the pretreatment step includes at least one of a vacuum suction filtration unit and a constant temperature oscillation unit;

the means that only requires the dispensing operation in the pretreatment step includes a reagent reservoir means; and is

The means that only requires the sample transfer operation in the pretreatment step includes at least one of a sealer unit and a storage area.

10. An analysis system comprising the specimen pretreatment device according to any one of claims 1 to 9 and the analysis device,

the analyzer includes an analyzer main body for performing analysis, and an autosampler for storing a plurality of samples to be analyzed in the analyzer main body in advance, selecting the plurality of samples in sequence, collecting the selected samples, and supplying the collected samples to the analyzer main body, and the sample transport unit of the sample preprocessing device transports the samples to the autosampler.

11. The analytical system of claim 10, wherein

The analysis device body part is a liquid chromatography device or a liquid chromatography mass spectrometry device.

12. An analysis system comprising the specimen pretreatment device according to any one of claims 1 to 9 and the analysis device, and

the frame of the sample pretreatment device and the frame of the analysis device include a common frame.

13. An autosampler for use in an analysis system according to claim 10, comprising:

a frame body; and

a sample receiving opening formed in a wall surface of the frame on the side where the sample pretreatment device is located

The holding portion of the sample transport portion, which holds a sample container containing a pretreated sample in the frame of the sample pretreatment device, is moved into the frame of the autosampler by passing through the opening for sample transport and the opening for sample reception.

14. An autosampler according to claim 13, wherein the autosampler is a capsule in the form of a capsule, a capsule in the capsule, a

Further comprising a shutter for opening and closing the sample receiving opening,

when the sample transport unit transports the sample container from the sample pretreatment device to the autosampler, the shutter is in an open state, and

the shutter is in a closed state when the sample transport unit does not transport the sample container from the sample pretreatment apparatus to the autosampler.

Technical Field

The present invention relates to a liquid sample to be analyzed in an analyzer, and relates to: a sample pretreatment device that performs a series of operations or processes related to pretreatment such as removal of a predetermined component, labeling of a predetermined component, concentration, or dilution, and an analysis system that includes the device and analyzes a liquid sample pretreated by the device; and an autosampler for use with the analysis system. The sample pretreatment device of the present invention is preferably used in combination with a Liquid Chromatography device (LC) or a Liquid Chromatography-Mass Spectrometry device (LC-MS) including an autosampler, particularly for automatically analyzing a plurality of samples in sequence.

Background

In recent years, chemical analysis using LC, LC-MS, or the like has been widely used in various fields, and as the use thereof expands, there is a strong demand for efficiency and labor saving of analysis. In such an analyzer, in order to automatically select a plurality of samples and analyze them sequentially, an automatic sampler is used which performs the following operations: a sample is selected from a plurality of samples prepared in advance according to a predetermined procedure, and only a predetermined amount of the sample is collected and transferred to an analyzer.

In analysis using an analysis device such as LC or LC-MS, pretreatment is often performed on a sample (specimen) to be analyzed. For example, the sample to be analyzed is a biological sample such as blood (whole blood, serum, plasma, blood on filter paper, etc.) or urine, and when it is desired to quantitatively analyze a specific component in the sample, the following pretreatment is usually performed: unnecessary components that are unnecessary or that are an obstacle in analysis are removed, specific components are labeled, or specific components are extracted (see patent document 1 and the like).

For example, in research institutions and entrusted analysis institutions that require efficient analysis of a large number of samples, a relatively large-scale pretreatment apparatus is used to pretreat a large number of samples. Such pretreatment devices generally independently include two movable mechanisms as follows: a dispensing mechanism including a pipette, a small-sized pump, or the like for dispensing a liquid reagent or a sample; and a transport mechanism for holding laboratory vessels such as a well plate and a sample bottle rack and transporting the laboratory vessels between units for performing each step of pretreatment. Therefore, it is considerably large compared with the analysis apparatus. In general, such a large-scale pretreatment apparatus is a stand-alone type, and a laboratory vessel containing a pretreated sample is manually transported from the pretreatment apparatus to an analysis apparatus by an operator.

Documents of the prior art

Patent document

Patent document 1: japanese patent laid-open No. 2016-170079

Disclosure of Invention

[ problems to be solved by the invention ]

As described above, in the conventional sample pretreatment device, it is necessary for the operator to take out a laboratory dish containing a liquid sample pretreated by the device from the device and set the dish at a predetermined position of an auto-sampler of an analyzer. Therefore, it takes a lot of labor, which may increase analysis cost or decrease analysis efficiency. In addition, since the reagent used may be harmful to the human body, the worker needs to pay attention to the reagent when transporting the laboratory vessel containing the pretreated sample to the analyzer, which causes a large burden on the worker.

Further, in the conventional sample pretreatment device, the dispensing mechanism and the transport mechanism have complicated structures, and thus the device is considerably large. Therefore, a large area is required for installing the sample pretreatment device, and the installation location is greatly restricted. As a result, the sample pretreatment device and the analysis device are often not disposed close to each other, and the laboratory vessel transportation operation by the operator is troublesome and labor-consuming.

The present invention has been made to solve the above-described problems, and a main object thereof is to provide a sample pretreatment device capable of transferring a pretreated liquid sample to a sample mounting portion of an analyzer without human hands, an analysis system including the same, and an autosampler.

Another object of the present invention is to provide a sample pretreatment device, an analysis system and an automatic sampler including the device, which can reduce the installation area and increase the degree of freedom of the device layout by downsizing the device, and which can reduce the cost of the device itself.

[ means for solving problems ]

A sample pretreatment device according to a first aspect of the present invention for solving the above problems is a sample pretreatment device for pretreating a sample to be analyzed by an analyzer, comprising:

a frame body forming an outer shape of the sample pretreatment device;

an opening for sample transport formed in a wall surface of the housing on the side where the analyzer is located; and

and a sample transport section that moves a grip section, which grips a sample container containing a pretreated sample in the housing, into the housing of the analyzer through an opening for transporting the sample and an opening formed in the housing of the analyzer.

The content of the pretreatment performed by the sample pretreatment device according to the first aspect of the present invention is not particularly limited, and for example, when the sample is a liquid sample, at least one or more of operations or processes such as dispensing of the liquid sample, dispensing of a reagent (addition to the liquid sample), shaking/stirring, filtration, and sealing can be performed. In this case, the sample pretreatment device according to the first aspect of the present invention includes a plurality of units or stages for performing a series of steps of the respective operations or treatments in a housing.

The sample pretreatment device according to the first aspect of the present invention is generally provided close to the side of the analyzer. In the case where the analyzer includes a plurality of independent units each including a housing, the sample pretreatment device according to the first aspect of the present invention is provided on a side of a unit on which a sample is to be first provided, among the plurality of units. In this sample pretreatment device, a sample transport opening having an appropriate size is formed in a wall surface on the side where the analyzer forming the outer frame is located. The opening for sample transport facing the sample pretreatment device, that is, the opening having the same size as the opening formed adjacently to the frame of the analyzer, is formed.

In the sample pretreatment device according to the first aspect of the present invention, the grip portion of the sample transport section grips the sample container in which the pretreated sample is accommodated in the housing of the device. The sample container is, for example, a sample bottle holder in which a large number of small sample bottles are stored, or a micro-well plate or a deep-well plate in which a large number of wells for storing samples are formed. The sample transport section moves the holding section holding the sample container to the inside of the housing of the analyzer through both the opening of the sample pretreatment device and the opening of the analyzer. When the sample container reaches a predetermined position in the housing of the analyzer, the grip portion releases the grip to separate the sample container. Thus, the sample container containing the sample after the pretreatment is automatically set at a predetermined position in the housing of the analyzer.

As described above, in the sample pretreatment device according to the first aspect of the present invention, the sample container containing the pretreated sample can be automatically transported to a predetermined position in the frame of the adjacently installed analysis device, for example, without human hands. The predetermined position in the frame of the analyzer may be, for example, a position in which the automatic sampler or the rack changer accommodates the sample bottle rack or the well plate.

In an analyzer, in a unit that needs to temporarily store a plurality of samples, such as an automatic sampler and a rack changer, the temperature inside a housing is adjusted to a predetermined temperature in order to prevent the samples from being deteriorated. In this case, if an opening portion that can enter the inside from the outside of the housing is provided, it is difficult to perform stable temperature adjustment.

Therefore, the sample pretreatment device according to the second aspect of the present invention is the sample pretreatment device according to the first aspect of the present invention, and is preferably configured as follows:

further comprises a shutter for opening and closing the opening for sample transport,

the shutter is in an open state when the sample transport unit transports the sample container from the sample pretreatment apparatus to the analysis apparatus,

the shutter is in a closed state when the sample transport unit does not transport the sample container from the sample pretreatment apparatus to the analysis apparatus.

According to the sample pretreatment device of the second aspect of the present invention, even in a state where the opening provided in the housing of the analysis device is open, the sample pretreatment device can block the flow of air from the side of the sample pretreatment device toward the side of the analysis device or the direction opposite thereto by closing the opening for sample conveyance with the shutter. Thus, for example, when the temperature of the inside of the sample pretreatment device is adjusted, the temperature of the inside of the sample pretreatment device can be stabilized. In addition, when the temperature of the inside of, for example, an autosampler of an analysis apparatus, which is a destination of sample transfer, is adjusted, the temperature inside the autosampler can be stabilized.

A sample pretreatment device according to a third aspect of the present invention is the sample pretreatment device according to the first or second aspect of the present invention,

the opening for sample transport and the opening of the analyzer are set to a size that allows the grip and the sample container held by the grip to pass therethrough, in a state where the sample pretreatment device and the analyzer are arranged in a predetermined positional relationship.

According to the sample pretreatment device of the third aspect of the present invention, the sample transport unit can smoothly transport the sample container to the predetermined position of the analyzer.

A sample pretreatment device according to a fourth aspect of the present invention is the sample pretreatment device according to the first to third aspects of the present invention,

the sample transfer section includes: a movable body linearly movable in the frame in three mutually orthogonal directions; and the holding portion provided to the movable body.

According to the sample pretreatment device of the fourth aspect of the present invention, the movable body three-dimensionally moves to an appropriate position in the housing, and the sample container placed at each position in the housing can be held and smoothly moved to another position. In particular, by allowing the grip portion to be movable not only in the horizontal direction but also in the height direction, even when the units or stages for performing the respective steps in the pretreatment as described above are disposed close to each other, the sample containers can be smoothly transported between the units or stages while avoiding obstacles.

A sample pretreatment device according to a fifth aspect of the present invention is the sample pretreatment device according to the fourth aspect of the present invention,

the grip portion is provided on a surface of the movable body on a side on which the analysis device is seated, and a dispensing portion that sucks and discharges a liquid is provided on a surface of the movable body opposite to the side on which the analysis device is seated.

In the sample pretreatment device according to the fifth aspect of the present invention, the dispensing unit is used when a predetermined amount of the liquid sample is collected, a solvent is added to the collected liquid sample to dilute the liquid sample, or an appropriate reagent is added to the liquid sample. In the sample pretreatment device according to the fifth aspect, the dispensing unit and the grip unit are not independent from each other but are integrally moved, and therefore, there is a restriction that the dispensing unit and the grip unit cannot simultaneously and concurrently perform their respective operations, but a mechanism for moving the dispensing unit and the grip unit is simplified. This can reduce the cost and suppress the space for installing the mechanism.

A sample pretreatment device according to a sixth aspect of the present invention is the sample pretreatment device according to the fifth aspect of the present invention, and is configured as follows:

the sample transport unit does not include a rotation drive mechanism for rotating the grip unit and the dispensing unit,

the movable body is linearly moved in three mutually orthogonal axes in a state where the grip portion is always present on a side on which the analysis device is seated and the dispensing portion is always present on an opposite side to the side on which the analysis device is seated.

According to the sample pretreatment device of the sixth aspect of the present invention, the sample pretreatment device can be downsized.

A sample pretreatment device according to a seventh aspect of the present invention is the sample pretreatment device according to the fifth aspect of the present invention,

the holding part comprises an arm and a clamp holder,

the length of the arm and the position of the gripper are set to: when the movable body moves to a predetermined position on the side where the analyzer is located, the sample container held by the holder is positioned corresponding to a portion in the analyzer where the sample container is to be placed.

According to the sample pretreatment device of the seventh aspect of the present invention, for example, even when the sample pretreatment device is separated from the analysis device to some extent or a portion of the analysis device where the sample container is to be set is separated from the sample pretreatment device to some extent, the sample container held by the holder can be reliably placed on the portion of the analysis device where the sample container is to be set.

Furthermore, a sample pretreatment device according to an eighth aspect of the present invention is the sample pretreatment device according to the fifth aspect of the present invention,

the dispensing unit is configured such that a movable range of the dispensing unit, i.e., a region where dispensing operation is possible, and a part of a region where transport operation is possible, which is capable of transport operation by the grip unit, overlap each other when viewed from above in the housing, and the cell requiring both dispensing operation and sample transport operation in the preprocessing step is disposed in the overlap region, the cell requiring only dispensing operation in the preprocessing step is disposed in the region where dispensing operation is possible other than the overlap region, and the cell requiring only sample transport operation in the preprocessing step is disposed in the region where transport operation is possible other than the overlap region.

For example, the following can be set: a temperature control unit (or a cooling unit) for keeping a sample before pretreatment (mainly in the case of a biological sample) at a low temperature, a reagent reservoir unit for keeping a reagent reservoir containing a reagent, and the like are arranged in a region other than the overlapping region where a dispensing operation can be performed; a sealing unit for sealing the sample container containing the pretreated sample or a region for storing the prepared sample container and the like is arranged in a region capable of carrying out the conveying operation except the overlapping region; and a means for stirring or filtering by oscillation, for example, is disposed in the overlapping region.

According to the sample pretreatment device of the eighth aspect of the present invention, not only the dispensing section and the grip section are provided together on the movable body, but also the operations of all the steps of the pretreatment can be smoothly performed. In addition, when each step of the pretreatment is sequentially performed, the moving distance of the movable body may be short, which is advantageous in shortening the time required for the pretreatment.

Furthermore, a sample pretreatment device according to a ninth aspect of the present invention is the sample pretreatment device according to the eighth aspect of the present invention,

the means that requires both the dispensing operation and the sample transfer operation in the pretreatment step includes at least one of a vacuum suction filtration means and a constant temperature oscillation means,

the unit requiring only the dispensing operation in the pretreatment step includes a reagent reservoir unit, and

the means that requires only the sample transfer operation in the pretreatment step includes at least one of a sealer unit and a storage area.

The sample pretreatment apparatuses of the above-described embodiments of the present invention can be combined with various types of analyzers, and are particularly suitable for combination with: an analyzer which takes time for analysis and comparison of one sample and efficiently performs continuous automatic analysis; and an analysis device for analyzing a sample to be analyzed, which requires a relatively troublesome pretreatment.

In view of the above, an analysis system according to a first aspect of the present invention is an analysis system including any one of the sample pretreatment devices according to the first to ninth aspects of the present invention and the analysis device, and includes:

the analyzer includes an analyzer main body for performing analysis, and an autosampler for storing a plurality of samples to be analyzed in the analyzer main body in advance, selecting the plurality of samples in sequence, collecting and supplying the selected samples to the analyzer main body, and carrying the samples to the autosampler by the sample carrying unit of the sample preprocessing device.

In the analysis system according to the first aspect of the present invention, for example, the analysis device main body may be a liquid chromatography device or a liquid chromatography mass spectrometer.

An analysis system according to a second aspect of the present invention is an analysis system including any one of the sample pretreatment devices according to the first to ninth aspects of the present invention and the analysis device,

the frame of the sample pretreatment device and the frame of the analysis device include a common frame.

That is, in the analysis system according to the first aspect of the present invention, the sample pretreatment device and the analysis device are not integrated, and in the analysis system according to the second aspect, the sample pretreatment device and the analysis device are substantially integrated. In any of the analysis systems, the sample container does not need to be manually transported. In the analysis system according to the first aspect, the sample preprocessing device and the analysis device can be separated to some extent within a range in which the sample can be transported by the sample transport unit. Thus, the degree of freedom in arrangement of the units constituting the system is relatively high. On the other hand, the analysis system according to the second aspect is advantageous in terms of cost because the housing is shared. Further, since the sample container does not appear outside the housing during the transport from the sample pretreatment device to the analysis device, the safety is further improved when, for example, a substance that may be harmful to the human body is contained in the sample.

The auto-sampler according to the first aspect of the present invention is an auto-sampler used in the analysis system according to the first aspect of the present invention,

the method comprises the following steps: a frame body, and a sample receiving opening formed in a wall surface of the frame body on one side where the sample pretreatment device is located

The holding portion of the sample transport portion, which holds a sample container containing a pretreated sample in the frame of the sample pretreatment device, is moved into the frame of the autosampler by passing through the opening for sample transport and the opening for sample reception.

An auto-sampler according to a second aspect of the present invention is the auto-sampler according to the first aspect of the present invention, and is configured as follows:

further comprising a shutter for opening and closing the sample receiving opening,

the shutter is in an open state when the sample transport unit transports the sample container from the sample pretreatment device to the autosampler,

the shutter is in a closed state when the sample transport unit does not transport the sample container from the sample pretreatment apparatus to the autosampler.

According to the automatic sampler of the second aspect of the present invention, the sample receiving opening of the automatic sampler is closed by the shutter without transferring the sample container from the sample pretreatment device to the automatic sampler. Therefore, when the temperature of the inside of the auto-sampler is adjusted, the temperature of the inside of the auto-sampler can be further stabilized. Further, since the temperature-adjusted air is less likely to escape to the outside, power consumption for temperature adjustment can be suppressed.

[ Effect of the invention ]

According to the present invention, a sample pretreated by the sample pretreatment apparatus can be transported to a predetermined position in the frame of the analyzer placed close to the sample pretreatment apparatus and set without human hands. Thus, labor saving of the analysis work is achieved. In addition, when a substance that may be harmful to the human body is contained in the pretreated sample, the risk of the worker can be reduced.

In particular, according to the sample pretreatment device according to the fourth to eighth aspects of the present invention and the analysis system including the same, it is possible to reduce the size of the conventional relatively large sample pretreatment device, reduce the installation area of the device, and improve the degree of freedom in the layout of the device. In addition, the cost of the sample pretreatment apparatus can be reduced.

Drawings

Fig. 1 is a schematic appearance front view of an LC-MS analysis system according to an embodiment of the present invention.

Fig. 2 is a flowchart showing the operation and flow of the pretreatment performed by the sample pretreatment device in the LC-MS analysis system according to the present embodiment.

Fig. 3 is a schematic plan view in plan view showing the two-dimensional arrangement of each part of the sample pretreatment device in the LC-MS analysis system according to the present embodiment.

Fig. 4 is a schematic perspective view of the internal structure of the sample pretreatment device in the LC-MS analysis system according to the present embodiment.

FIG. 5 is a schematic front plan view of the internal structure for explaining the operation of transferring the microplate from the sample pretreatment device to the auto-sampler in the LC-MS analysis system of this embodiment.

Detailed Description

Hereinafter, an LC-MS analysis system, which is an embodiment of the sample pretreatment device and the analysis system including the same according to the present invention, will be described in detail with reference to the accompanying drawings.

Fig. 1 is a schematic appearance front view of the LC-MS analysis system of the present embodiment.

The LC-MS analysis system of the present embodiment includes an analysis device 1 and a sample pretreatment device 2. The analysis device 1 includes: an auto-sampler 11, a Liquid Chromatography (LC) section 12, and a Mass Spectrometry (MS) section 13. These are independent units and are connected by appropriate piping or wiring not shown. Note that, in fig. 1, only a unit mounted on a dedicated table installed in an analysis room, a laboratory, or the like is illustrated, and besides, a personal computer or the like that is responsible for overall control operations and data processing is present as a component of the LC-MS analysis system of the present embodiment.

In this system, the analyzer 1 and the sample pretreatment device 2 are arranged in a predetermined positional relationship. The predetermined positional relationship is a position at which the sample container containing the sample pretreated in the sample pretreatment device 2 can be transported to the analyzer 1, as will be described in detail later. As shown in fig. 1, in the system of the present embodiment, an autosampler 11 is provided in front view in close proximity to (substantially close to) the right of the sample pretreatment device 2. The sample pretreatment device 2 and the autosampler 11 may be separated to some extent.

The autosampler 11 is a device capable of housing a plurality of microplates (microwell plates or deep well plates), and repeats the following operations according to a predetermined program: the liquid sample stored in one well of one of the microtubes is aspirated to a predetermined amount and supplied to the LC section 12. In addition, although the plurality of holes are formed in the micro plate, the number of holes is, for example, 8 × 12 to 96.

The sample pretreatment device 2 has the following functions: the liquid sample is pretreated, and a microplate (indicated by reference numeral 30c in fig. 1) in which the liquid sample after the pretreatment is stored is automatically set at a predetermined position (indicated by reference numeral 113 in fig. 1) in the auto-sampler 11. The sample pretreatment device 2 includes a substantially rectangular parallelepiped housing 20, and at least a part of the front surface and the upper surface thereof is openable and closable by a door body 203 which can be opened widely upward.

Fig. 3 is a schematic plan view in plan view showing the two-dimensional arrangement of each part inside the sample pretreatment device 2. Fig. 4 is a schematic perspective view showing the internal structure of the sample pretreatment device 2. Fig. 5 is a schematic front plan view of an internal configuration for explaining an operation when the microplate is transferred from the sample pretreatment device 2 to the auto-sampler 11. For convenience of explanation, three axes X, Y, Z orthogonal to each other are defined as shown in fig. 3 to 5. The X-Y plane formed by the X axis and the Y axis is a plane parallel to the top surface of the top plate of the exclusive table on which the sample pretreatment device 2 and the analysis device 1 are mounted (i.e., the mounting surface of the device).

As shown in fig. 3 and 4, the sample pretreatment device 2 includes a stage 21 whose upper surface is parallel to the X-Y plane, and the entire space on the stage 21 is surrounded by the frame 20 (however, the frame 20 is not shown in fig. 3, and only a part of the frame is shown in fig. 4). The area on the stage 21 is divided into a plurality of areas, and disposed on the side opposite to the side on which the auto-sampler 11 is located (the left side in fig. 3): a temperature-adjusting plate 23, a reagent reservoir unit 24, and a waste cassette 25. Disposed adjacent to the right thereof are: a sealer unit 27, a vacuum suction filter unit 29, and a constant temperature oscillation unit 26. Further, a sealer unit 27 and a storage area 28 are disposed adjacent to the right, i.e., on the side where the auto-sampler 11 is located.

Further, a conveying mechanism 22 is provided in the space in the housing 20 above the stage 21. The conveyance mechanism 22 includes: an X-axis guide 221 installed near the top surface in the housing 20 and extending in the X-axis direction; and a Y-axis guide 222 that is movable in the X-axis direction along the X-axis guide 221 and extends in the Y-axis direction. A Z-axis guide 223 is attached to the Y-axis guide 222 so as to be movable in the Y-axis direction along the guide 222. The Z-axis guide 223 is integrally mounted so as to be movable in the Z-axis direction with a grip 225 provided on a surface on the side on which the auto-sampler 11 is located (the right side in fig. 3), and a liquid handler 224 provided on a surface on the side opposite to the side on which the auto-sampler 11 is located (the left side in fig. 3). Thus, the grip 225 and the liquid handler 224 can move in the three-axis direction of X, Y, Z within a predetermined three-dimensional range of the space in the housing 20. The movement is achieved by a plurality of driving mechanisms including motors and the like, not shown.

Here, in order to miniaturize the conveyance mechanism, a rotation drive mechanism for rotating the liquid processor 224 and the grip 225, which is often provided in a conventional apparatus, is not provided. Therefore, the liquid handler 224 and the grip 225 do not rotate, the grip 225 is always present on the side where the automatic sampler 11 is located, and the liquid handler 224 is always present on the side opposite to the side where the automatic sampler 11 is located.

The grip 225 includes a pair of arms 227, and the pair of arms 227 are separated from each other by a predetermined distance in the Y axis direction and are movable so that the distance therebetween can be changed within a predetermined range, and a holder 228 for holding a micro disk or a later-described tip holder is attached to the tip of each arm 227. That is, the handle 225 is used to transport a microplate or tip rack. The length of the arm 227 in the X-axis direction (i.e., the direction in which the autosampler 11 is seated) and the position at which the holder 228 is formed are set to: when the guide rail 222 reaches the end of the autosampler 11 in the X-axis direction, the microplate or the like held by the clamper 228 is positioned to face the upper portion of the microplate installation region, which is the predetermined position of the autosampler 11.

On the other hand, the liquid processor 224 includes a tip group 226 to which a plurality of (eight in this example) pipette tips (hereinafter simply referred to as "tips") are connected so as to be attachable and detachable, and performs dispensing by sucking a liquid sample or a reagent into each tip of the tip group 226 and discharging the sucked liquid. The tip group 226 is configured such that eight tips are connected at the same pitch as the eight wells in order to simultaneously dispense a liquid to the eight adjacent wells of the microplate. Since the tip contains a liquid sample or reagent, the tip unit is disposable and is typically replaced automatically each time it is used in order to avoid contamination.

The temperature control plate 23 temporarily stores a plurality of liquid samples to be pretreated at a predetermined temperature. The temperature control plate 23 is mounted with, for example, a sample bottle holder 32 (or other laboratory vessel) for holding a plurality of small sample bottles each containing a liquid sample. When the liquid sample is a biological sample such as blood, the temperature control plate 23 is set to a low temperature, for example, in the range of about 0 to 10 ℃.

The reagent reservoir unit 24 is used to hold a plurality of reagent reservoirs containing various reagents for pretreatment. The reagents used vary depending on the purpose or kind of pretreatment.

The disposal box 25 includes a disposal opening 251 opened upward for disposing of the used tip. As shown in fig. 3 and 4, the tip rack 31a containing a plurality of (12 in this example) unused tip units can be placed on the flat upper surface of the waste cassette 25, and at this position, a new (unused) tip unit can be attached to the liquid processor 224.

The constant temperature oscillation unit 26 oscillates a microplate (filter type microplate described later) 30a (or other laboratory vessels) placed on the upper surface thereof while maintaining the temperature at a predetermined temperature, thereby stirring the liquid in each well of the microplate 30a and promoting the mixing or chemical reaction of the liquid sample and the reagent.

The vacuum suction filtration unit 29 includes a vacuum manifold, and performs filtration by, for example, vacuum suction of the microplate 30a corresponding to the vacuum suction filtration to remove unnecessary components and the like from the liquid sample.

The sealer unit 27 substantially seals each hole of the microplate 30b by attaching a predetermined sealing material to the upper surface of the microplate 30b containing the liquid sample after the pretreatment. For convenience of explanation, a general micro-disk before the sealing material is attached by the sealer unit 27 is denoted by reference numeral 30b, and a general micro-disk after the sealing material is attached is denoted by reference numeral 30 c.

The tube-holding section 28 includes: a shelf-like first region 281 in which a plurality of unused micro disks (filter-type micro disks and normal micro disks) 30d are stored; and a shelf-like second area 282 in which a plurality of tip racks 31b containing unused tips are stored.

A sample transfer opening 201 is formed at a predetermined position on the right sidewall of the frame 20 facing the automatic sampler 11, and the sample transfer opening 201 is openable and closable by a shutter 202. The sample-conveying opening 201 is generally rectangular, and the longitudinal and lateral lengths of the sample-conveying opening 201 are set to lengths that the arm 227, the clamper 228, and the microplate held by the clamper 228 can pass through.

As described above, in the storage area 28 shown in fig. 3 and 4, the shelves on which the unused micro disks 30d or the tip racks 31b are placed are provided in a plurality of stages, and the above-described shelves do not exist in the space on the left side of the sample transfer opening 201, and no obstacle such as a micro disk or a tip rack exists in the space. This is because the microplate 30c is conveyed to the autosampler 11 by the grip 225 in the horizontal direction as described later.

The parts of the platform 21 can be roughly classified into three types: the liquid processor 224 and the grip 225 are required to be operated by both (group a), the grip 225 is only required to be operated by the grip (group B), and the liquid processor 224 is only required to be operated by the grip (group C).

Specifically, the sealer unit 27 or the storage area 28 is a group B, the reagent reservoir units 24 are a group C, and the blocks other than these units and the temperature control plate 23 are a group a. In the sample pretreatment device 2 of the present embodiment, the blocks that require the operation by the liquid processor 224, i.e., the groups a and C, are arranged in the range of La in fig. 3, and the blocks that require the operation by the grip 225, i.e., the groups a and B, are arranged in the range of Lb in fig. 3. The range where La and Lb overlap is a range where blocks included in group a are arranged.

In the sample pretreatment device 2 of the present embodiment, the liquid processor 224 and the grip 225 are attached to the surfaces of one Z-axis guide 223 on the opposite sides to each other, and a rotation drive mechanism for rotating the liquid processor 224 and the grip 225 is not provided. Therefore, the movable range of the liquid processor 224 and the movable range of the grip 225 on the X axis are restricted. On the other hand, by arranging the blocks included in the groups a to C appropriately on the stage 21 as described above, the liquid processor 224 and the grip 225 restricted in the movable range as described above can be used to perform necessary operations. Thus, the structure of the conveyance mechanism 22 is simplified and the installation area is advantageously reduced, compared to the case where the liquid handler 224 and the grip 225 are operated separately or one of them is a rotary drive system instead of a linear drive system.

Here, the configuration of the auto-sampler 11 that collects the microplate 30c containing the pretreated sample from the sample pretreatment device 2 will be described.

As shown in fig. 5, a sample receiving opening 111 is formed in the left sidewall of the automatic sampler 11 that faces the sample pretreatment device 2 and is located inside the housing 110. The sample transport opening 201 in the sample pretreatment device 2 and the sample receiving opening 111 in the autosampler 11 are substantially the same size in the Y-Z plane, and the sample transport opening 201 and the sample receiving opening 111 are substantially at the same position in the X-axis direction in a state where the sample pretreatment device 1 and the autosampler 11 are set at appropriate positions. The sample transport opening 201 and the sample receiving opening 111 are each set to a size that allows passage of the clamper 228 and the microplate or the like held by the clamper 228 in a state where the sample pretreatment device 2 and the autosampler 11 are arranged in a predetermined positional relationship.

As with the sample transport opening 201, the shutter 112 is provided to be openable and closable in the sample receiving opening 111, and the shutter 112 can close the sample receiving opening 111 except when the microplate 30c is transported. In the state where the shutters 202 and 112 are simultaneously opened, the space in the housing 20 of the sample pretreatment device 2 and the space in the housing 110 of the autosampler 11 are substantially communicated with each other through the sample-transporting opening 201 and the sample-receiving opening 111.

Next, an example of the operation of carrying out the pretreatment by the sample pretreatment device 2 until the microplate containing the pretreated liquid sample is transferred from the sample pretreatment device 2 to the autosampler 11 will be described with reference to the flow shown in fig. 2. Here, the sample to be analyzed is a biological sample such as blood.

The operator opens the door 203 of the sample pretreatment device, and places the sample bottle rack 32, in which a plurality of sample bottles containing liquid samples are respectively placed, on the temperature-control plate 23. Then, the door body 203 is closed, and the start of the process is instructed by an operation unit not shown. The temperature control plate 23 cools the sample contained in each sample bottle to an appropriate temperature in a range of about 0 to 10 ℃. This suppresses the deterioration of the components in the sample.

In the sample pretreatment device 2, the liquid handler 224 to which the unused tip group 226 is attached is moved to a predetermined position on the sample bottle rack 32, and the liquid handler 224 suctions the liquid samples from a plurality (8) of sample bottles in the sample bottle rack 32, and dispenses the liquid samples into the wells of the filter type microplate 30a placed in the thermostatic oscillation unit 26 (step S1). The filter-type microplate used here is, for example, a microplate having a structure such as impacter (Impact) (registered trademark) sold by the company philomenex (Phenomenex) that, even if an organic solvent is injected into the interior, the solution does not fall unless vacuum suction is performed.

In the operation of step S1, the constant temperature oscillation unit 26 is stopped, and the temperature thereof is kept low in order to suppress the sample from being deteriorated. The liquid processor 224 repeats the operation of discarding the used tip group 226 in the waste cassette 25 and attaching the unused tip group 226 to dispense the liquid sample into all the wells of the filter-type microplate 30 a.

Then, the liquid processor 224 sucks only a predetermined amount of a predetermined reagent from the reagent reservoir set in the reagent reservoir unit 24, and dispenses the reagent into a predetermined well in the filter-type microplate 30a, thereby adding the reagent to the liquid sample (step S2). The reagent is, for example, a reagent for binding to a specific component in a liquid sample by a chemical reaction to precipitate the specific component, or for denaturing and precipitating the specific component when the removal target is protein.

After adding a reagent to the liquid sample in all the wells of the filter-type microplate 30a, the temperature is moderately raised by the constant temperature oscillation means 26, and the filter-type microplate 30a is oscillated to stir the liquid sample to which the reagent is added for a predetermined time (step S3). This promotes a chemical reaction between the liquid sample and the reagent. Optionally, the reaction is further accelerated by allowing the mixture to stand at a constant temperature for a predetermined time after the stirring (step S4)

Then, the grip 225 is moved to a position where the filter type micro-disk 30a on the thermostatic oscillation unit 26 can be held, and the filter type micro-disk 30a is held and conveyed to the vacuum suction filtration unit 29. The vacuum suction filtration unit 29 filters the liquid sample stored in each hole of the filter-type microplate 30a by vacuum suction filtration, and removes the precipitated solid matter by dropping the filtrate onto a general microplate 30b provided in advance at the lower stage of the vacuum suction filtration unit 29 (step S5). Thereby, unnecessary components and the like in the liquid sample are removed from the liquid sample. The grip 225 then conveys the microplate 30b containing the liquid sample from which the unnecessary component has been removed to a predetermined position in the sealer unit 27. The sealer unit 27 attaches a sealing material to substantially seal each hole of the micro-disk 30b (step S6). Thereby, a series of preprocessing ends.

The grip 225 grips the sealed microplate 30c, passes through the sample-transporting opening 201 with the shutter 202 opened and the sample-receiving opening 111 with the shutter 112 opened, and transports the microplate into the housing 110 of the autosampler 11 (step S7). As shown in fig. 5, when the grip 225 is moved to the right end, the arm 227 passes through the sample transport opening 201 and the sample receiving opening 111 and enters the housing 110 of the autosampler 11. Therefore, after the arm 227 is inserted into a predetermined position in the housing 110 of the auto-sampler 11, the grip 225 is moved downward by a predetermined amount, and the gripper 228 is released to release the holding of the microplate 30c, whereby the microplate 30c can be placed at the predetermined position of the auto-sampler 11.

The shutters 202 and 112 are both opened only when the microplate 30c is transferred from the sample pretreatment device 2 to the autosampler 11, and preferably the sample transfer opening 201 and the sample receiving opening 111 are closed during a period other than the period. Thus, when the temperature of the internal space of the auto-sampler 11 or the internal space of the sample pretreatment device 2 is adjusted, it is possible to prevent a temperature change due to, for example, the intrusion of outside air. In addition, the amount of power consumption for temperature adjustment can be suppressed.

As described above, in the LC-MS analysis system according to the present embodiment, the microplate in which the liquid sample that has been subjected to the predetermined pretreatment in the sample pretreatment apparatus 2 is accommodated can be automatically transported from the sample pretreatment apparatus 2 to the autosampler 11. This reduces the labor of the operator involved in the conveyance. In addition, even when a reagent harmful to the human body is used, the risk of the operator contacting the reagent during the operation of transporting the microplate can be reduced. Further, as described above, since the transport mechanism 22 has a simple structure and performs the operation or the processing using the liquid processor 224 and the grip 225 by using one X, Y, Z three-axis drive system, the area of the stage 21 of the sample pretreatment device 2 can be suppressed. This suppresses the installation area of the sample pretreatment device 2, and the sample pretreatment device 2 and the analyzer 1 can be installed on a dedicated stage having a relatively small ceiling area.

Needless to say, the pretreatment performed by the sample pretreatment device 2 is not limited to the above-described treatment, and appropriate treatments may be combined according to the purpose thereof. For example, the pretreatment may be performed not for the purpose of removing unnecessary components or the like in the sample but for labeling or derivatizing a specific component (or a specific site of a specific component) in the sample as follows: a predetermined reagent is added to the sample, and the sample is shaken to promote the labeling or derivatization reaction.

In the sample pretreatment device in the above embodiment, the liquid handler 224 and the grip 225 are provided so as to be movable in the Z-axis direction integrally with the Z-axis guide 223, but the liquid handler 224 and the grip 225 may be movable in the Z-axis direction independently of each other with respect to the Z-axis guide 223. In this case, although the number of drive mechanisms increases, the restriction on the movable range of each of the liquid processor 224 and the grip 225 is reduced, and the space in the housing 20 can be used more effectively.

Further, although it is preferable to provide the shutter 202 for opening and closing the sample-conveying opening 201 of the sample-pretreating apparatus 2 and the shutter 112 for opening and closing the sample-receiving opening 111 of the auto-sampler 11, these are not essential elements. In particular, since the temperature of the entire auto-sampler 11 is often controlled, it is preferable to provide a baffle plate 112 in the sample receiving opening 111 of the auto-sampler 11. On the other hand, in the sample pretreatment device 2, although the temperature is partially controlled by the temperature control plate 23 or the like, the temperature of the entire inside thereof is not controlled (the temperature may be controlled, of course). Therefore, although the shutter 202 may not be present in the sample transport opening 201 of the sample pretreatment device 2, the shutter 202 is preferably present in order to prevent dust and the like from entering from the outside as much as possible.

The positional relationship between the sample pretreatment device 2 and the analyzer 1 is not limited to the one shown in fig. 1, but the sample pretreatment device 2 and the autosampler 11 are preferably disposed close to each other.

Further, the following system configuration may be adopted: the rack changer is disposed close to the sample pretreatment apparatus, and the microplate pretreated in the sample pretreatment apparatus or a laboratory vessel other than the microplate is transferred to the rack changer as described above and then transferred from the rack changer to the autosampler.

The housing of the sample pretreatment device and the housing of the analyzer (autosampler or integrated liquid chromatograph) may be made of a common housing. In the case where the housing is shared as described above, since the temperature inside the autosampler needs to be adjusted, a wall for separating the sample pretreatment device and the autosampler is formed between the two devices, and openings serving as both the sample transport opening and the sample receiving opening are provided in the wall. In addition, a shutter that opens when the sample is transported and closes when other than the opening is provided in the opening. In the above-described configuration, the wall between the sample pretreatment device and the autosampler can be said to be a part of the housing of the sample pretreatment device and the analyzer (or the autosampler). In this case, it is not necessary to arrange the sample pretreatment apparatus and the analysis apparatus in the predetermined positional relationship as described above.

It should be noted that the above-described embodiments are merely examples of the present invention, and it is needless to say that the present invention is included in the scope of the claims of the present application even if appropriately changed, modified, and added within the scope of the gist of the present invention.

[ description of symbols ]

1: analysis device

11: automatic sampler

20. 110: frame body

111: opening for sample reception

112. 202: baffle plate

12: liquid Chromatography (LC) section

13: mass Spectrometry (MS) section

2: sample pretreatment device

201: opening for sample conveyance

203: door leaf body

21: platform

22: conveying mechanism

221: x-axis guide rail

222: y-axis guide rail

223: z-axis guide

224: liquid processor

225: grab handle

226: tip group

227: arm(s)

228: clamp holder

23: temperature adjusting plate

24: reagent reservoir unit

25: abandonment box

251: waste port

26: constant temperature oscillation unit

27: sealer unit

28: pipe protection area

29: vacuum suction unit

30 a: filter type micro-measuring disc

30b, 30 c: micro-measuring disc

30 d: unused microdisk

31a, 31 b: tip rack

32: and (4) a sample bottle holder.