An automated sample processing and chromatography mass spectrometry integrated device

Abstract

The application relates to an automatic sample processing and chromatography-mass spectrometry integrated device, a sample tube working area of which comprises a movable sample tube bearing mechanism and a rotatable gripper for positioning and grabbing each sample tube; a sample processing area provided with a second mechanical arm comprises a high-speed centrifuge, a transfer rack for transferring centrifuge tubes between areas, and a centrifuge tube opening and closing cover and mixing integrated module for opening and closing the cover of the centrifuge tube to add reagents and applying shock mixing; a processing area provided with a third mechanical arm comprises a nitrogen blowing module, a sample injection module for moving and injecting reagents in the centrifuge tube to the rear end chromatography for detection, and the centrifuge tube opening and closing cover and mixing integrated module. The device covers pipetting, shock mixing, high-speed centrifugation, constant-temperature nitrogen blowing and online capture functions, realizes the coverage of current chromatography and mass spectrometry sample processing methods through different function combinations, and simultaneously sets a multi-channel chromatography separation in the rear end chromatography part, so that the detector is maximally utilized.

Description

TECHNICAL FIELD

[0001] The present application relates to a laboratory-related equipment, in particular to an automatic sample processing and chromatography-mass spectrometry integrated device. BACKGROUND

[0002] Sample pretreatment is a prerequisite step for most genomics, chemistry and clinical experiments, and its quality directly affects the results of subsequent data analysis, especially the chromatography and mass spectrometry detection system widely used in clinical recently. Since most samples need to go through a series of pretreatment processes (including separation, purification, concentration, derivation and other steps), in order to reduce matrix interference and improve sensitivity, so as to achieve stable and accurate detection of target objects.

[0003] The current sample pretreatment technology is also a key and difficult point of chromatography and mass spectrometry analysis. Due to the defects exposed by actual application, such as long sample pretreatment time, complex operation, and difficulty in achieving high throughput and automation, the efficiency of chromatography and mass spectrometry analysis and the application range are seriously restricted. According to data statistics, sample pretreatment accounts for more than 60% of the time of personnel, and even so, 32% of the errors still come from the sample pretreatment link.

[0004] Although detection institutions and hospitals at home and abroad have begun to introduce fully automatic sample pretreatment equipment to replace manual operation, the automatic equipment on the market is still mainly for single sample processing. In this field, an automatic equipment integrating sample processing and sample testing has not yet appeared.

[0005] Moreover, the commonly used chromatography and mass spectrometry testing technology is to pretreat a batch of samples first, and then inject them one by one into the instrument for separation and testing by the chromatographic column. The separation of the chromatographic column and the balance before and after the separation require a certain time. If a single chromatographic column is used, high-throughput testing cannot be achieved, and it is also not flexible. For example, when there is an urgent sample that needs to be tested first, the urgent sample must wait until the previous sample is finished.

[0006] Based on the above analysis of the previous technology, the designer of the present application proposes an automatic sample processing and chromatography-mass spectrometry integrated device, which is beneficial to realize automatic sample pretreatment and automatic testing of chromatography and mass spectrometry, so as to meet the application requirements of sample pretreatment. SUMMARY

[0007] To solve the above problems, the present application provides an automatic sample processing and chromatography-mass spectrometry integrated device, which itself includes pipetting, oscillation mixing, high-speed centrifugation, constant-temperature nitrogen blowing and online capture functions. Therefore, different function combinations are used to realize the coverage of the current chromatography and mass spectrometry sample processing method.

[0008] To achieve the above object, the present application adopts the following technical solutions:

[0009] An automatic sample processing and chromatography-mass spectrometry integrated device has a plurality of working areas arranged in sequence and cooperates with a chromatography or mass spectrometry device, and the device comprises:

[0010] A sample tube working area with a first mechanical arm comprises a movable sample tube carrying mechanism, a rotatable sample tube gripper arranged below the first mechanical arm for positioning and grabbing each sample tube, a camera arranged below the first mechanical arm for scanning a code of the sample tube and identifying a sample liquid level in the sample tube, and the sample tube is subjected to a cap pulling operation in the sample tube working area to be moved to the next area for sample operation.

[0011] A sample processing area with a second mechanical arm comprises a high-speed centrifuge, a transfer rack for transferring centrifuge tubes between areas, and a centrifuge tube cap opening and mixing integrated module for opening and closing the cap of the centrifuge tube to add reagents and shake for mixing, and a pipettor below the second mechanical arm for grabbing a tip on a tip tray, and a centrifuge tube negative pressure suction disc for grabbing a centrifuge tube on a centrifuge tube tray.

[0012] A sample processing area with a third mechanical arm comprises a nitrogen blowing module, a sample injection module for moving and injecting reagents in the centrifuge tube to a rear-end chromatography for detection, and a centrifuge tube cap opening and mixing integrated module, and a centrifuge tube tray is arranged below the third mechanical arm, and a pipettor tip tray is arranged on one side of the centrifuge tube tray.

[0013] A chromatography system is adjacent to the sample processing area with the third mechanical arm, and comprises a multi-channel online capture column, a multi-channel chromatography column separation column, and a sample detector.

[0014] The three mechanical arms control corresponding areas respectively, and form an associated and orderly sample processing flow among the three areas.

[0015] For the sample tube working area, the movement state of the sample tube gripper comprises:

[0016] Firstly, the sample tube is positioned at each position along the X and Y axes;

[0017] Secondly, the sample tube is grabbed, moved, and rotated, so that the code scanning camera scans and reads information of the sample tube and identifies the sample liquid level in the sample tube;

[0018] Thirdly, the cap of the sample tube is pulled up to complete the cap pulling operation of the sample tube;

[0019] Fourthly, the sample tube is capped;

[0020] Fifthly, the sample tube is moved back to the tube rack.

[0021] For the processing area where the second mechanical arm is located:

[0022] The centrifugal tube negative pressure suction disc will transfer the centrifugal tube in the consumable area to the open and close cover module through negative pressure suction and grabbing, so as to open the cover of the centrifugal tube.

[0023] For the processing area where the third mechanical arm is located:

[0024] After the nitrogen blowing drying is completed, the nitrogen blowing needle is returned to the original position, the reagent is removed by the pipette and added to the centrifugal tube after nitrogen blowing, and the cover is closed and mixed.

[0025] The skilled person can form corresponding technical solutions in combination with the further implementation of the above main technical solutions. These technical means include the following:

[0026] Among them, the movable sample tube bearing mechanism includes a tube rack for placing sample tubes, a movable tube rack tray for bearing the tube rack, and a sample tube fixing base provided on the tube rack tray.

[0027] Among them, the sample tube gripper has at least two directions of movement controlled by different motors.

[0028] Among them, a camera is installed above the second mechanical arm on one side of the centrifugal tube tray to identify the materials in the area.

[0029] For the chromatography system:

[0030] 0-n capture columns can be set, which control the sample inlet by the flow path switching valve to select whether to capture through the capture column or through which capture column or multiple capture columns in parallel;

[0031] 1-n chromatography separation columns can be set, which control the distribution of the captured sample for separation by the flow path switching valve.

[0032] The technical solution of the present application is beneficial to realize complete automation of sample testing, reduce the time of manual participation, and reduce the dependence on manual operation. In particular, because the device itself includes functions such as pipetting, oscillation mixing, high-speed centrifugation, constant-temperature nitrogen blowing, and online capture, it can cover the current chromatography and mass spectrometry sample processing methods through different combinations of functions. At the same time, multiple channel chromatography separation is set in the rear end chromatography part, cross testing between different separation chromatography columns is performed, and only the time period of testing the target object is tested, while the balance time before and after the chromatography column is not tested, which maximizes the use of the detector and reduces the hardware cost of the detector. BRIEF DESCRIPTION OF DRAWINGS

[0033] The present application will be further described in detail below with reference to the accompanying drawings.

[0034] Figure 1This is a schematic diagram of the overall structure of the integrated automated sample processing and chromatography-mass spectrometry testing device implemented in this invention;

[0035] Figure 2 This is a schematic diagram of the area division of the integrated automated sample processing and chromatography-mass spectrometry testing device implemented in this invention;

[0036] Figure 3 This is a schematic diagram of the component connections in region one of the integrated automated sample processing and chromatography-mass spectrometry testing device implemented in this invention.

[0037] Figure 4 This is a schematic diagram of the component connections in region two of the integrated automated sample processing and chromatography-mass spectrometry testing device implemented in this invention.

[0038] Figure 5 This is a schematic diagram of the component connections in region three of the integrated automated sample processing and chromatography-mass spectrometry testing device implemented in this invention.

[0039] Figure 6 This is a schematic diagram of the connection of the chromatographic system of the integrated automated sample processing and chromatography-mass spectrometry testing device implemented in this invention. Detailed Implementation

[0040] like Figures 1-2 As shown, the integrated automated sample processing and chromatography-mass spectrometry testing device implemented in this invention has the following overall technical concept: implementing a pretreatment module comprising three regions and combining it with a chromatography device 4. The pretreatment module is divided into three regions (i.e., a sample tube working area and two processing areas) based on the spatial position of the component assembly, and each region is controlled by a separate robotic arm. The chromatography system 4 includes functions such as online capture, chromatographic separation, and detection. The detector can be a conventional device, such as an ultraviolet detector, an electrochemical detector, a fluorescence detector, or a triple quadrupole mass spectrometer.

[0041] like Figure 3 As shown, the automated sample processing and chromatography-mass spectrometry testing integrated device implemented by the present invention includes a tube rack 101 for placing sample tubes 108, a tube rack tray 103 for supporting the tube rack 101, and a sample tube fixing base 102 disposed on the tube rack tray 103. A camera 104 is disposed below the first robotic arm 1 in this area near the sample tube 108.

[0042] Accordingly, combined Figure 3The XYZ three-axis coordinates shown, for the first mechanical arm 1, sequentially assemble the Y-axis motor 106, the Z-axis motor 107, and the rotatable sample tube gripper 105 below the first mechanical arm 1; in the working operation, the tube rack tray 103 can move along the X-axis, the rotatable sample tube gripper 105 can be controlled by the Z-axis motor 107 to move in the Z-axis direction and can be controlled by the Y-axis motor 106 to move in the Y-axis direction, so as to realize the positioning and grabbing of each sample tube 108 of the tube rack 101.

[0043] Further, after the rotatable sample tube gripper 105 grabs the sample tube 108, the sample tube 108 is moved to the X-axis direction of the camera 104, and the sample tube 108 is rotated, and the sample tube 108 is scanned and recognized by the camera 104.

[0044] Finally, in the area one, the sample tube 108 is placed on the sample tube fixing base 102 for cap pulling operation, and after the cap is pulled, the second mechanical arm 2 in the area two is waited for sample moving operation.

[0045] As shown in the XYZ three-axis coordinates shown, Figure 4 The automatic sample processing and chromatography mass spectrometry integrated device implemented by the application includes a centrifuge tube opening and closing cap and mixing integrated module 209 for opening and closing the cap of the centrifuge tube for reagent addition and oscillation mixing, a high-speed centrifuge 210 arranged adjacent to the module position for high-speed centrifugation of the centrifuge tube, and a transfer rack 211 located in the periphery of the high-speed centrifuge 210, wherein the implemented transfer rack 211 can run in the X-axis direction to transfer the centrifuge tube between areas. In terms of position, the second mechanical arm 2 is assembled below the centrifuge tube tray 213, and the gun head tray 212 and the waste box 214 are arranged on both sides of the centrifuge tube tray 213, and the centrifuge tube tray 213 is assembled adjacent to the reagent tank 215 for storing reagents required in the sample processing process.

[0046] Correspondingly, in combination with the XYZ three-axis coordinates shown, Figure 4 For the second mechanical arm 2, a pipettor 217 and a centrifuge tube negative pressure suction disc 216 are sequentially assembled below the second mechanical arm 2, and a camera 218 is assembled above the mechanical arm on one side of the centrifuge tube tray 213 to identify the materials in the area.

[0047] Further, the second mechanical arm 2 can be moved along the X, Y and Z axes by corresponding motors, wherein the pipettor 217 on the mechanical arm is used to grab the gun head on the gun head tray 212, and the centrifuge tube negative pressure suction disc 216 is used to grab the centrifuge tube on the centrifuge tube tray 213.

[0048] As shown in the XYZ three-axis coordinates shown, Figure 5As shown, the automatic sample processing and chromatography-mass spectrometry integrated device implemented by the present application includes a third area, which includes a third area centrifuge tube opening and closing cover and mixing integrated module 319, a nitrogen blowing module 320 arranged adjacent to the module position, and a centrifuge tube opening and closing cover module 321 assembled on the periphery of the nitrogen blowing module 320. In terms of position, the third mechanical arm 3 is assembled below a centrifuge tube tray 323, and a pipette gun head tray 322 is arranged on one side of the centrifuge tube tray 323. The centrifuge tube tray 323 is assembled adjacent to a reagent tank 324 used to store reagents required in the sample processing process.

[0049] Correspondingly, the implemented third area is also provided with a sample injection module 325 to take the reagent in the centrifuge tube and inject it into the rear-end chromatography for detection.

[0050] Further, the third mechanical arm 3 and the second mechanical arm 2 are the same in structure; wherein the centrifuge tube opening and closing cover module 321 can open and close the centrifuge tube to facilitate the taking of the reagent in the centrifuge tube.

[0051] In combination Figures 3-5 As shown, the above automatic sample processing and chromatography-mass spectrometry integrated device implemented by the present application, in operation, the original sample tube 108 is placed on the tube rack tray 103, the tube rack tray 103 can move left and right (i.e. along the X axis), the sample tube gripper 105 can move forward and backward (i.e. along the Y axis) and up and down (i.e. along the Z axis), movement along the X and Y axes facilitates positioning of each hole sample tube 108 on the tube rack tray 103, after positioning of the sample tube 108 to be grabbed is completed, the sample tube gripper 105 moves downward (i.e. along the Z axis), grabs the top cover part of the sample tube 108, grabs the sample tube 108 and moves above the sample tube fixing base 102, rotates the sample tube 108, and the code scanning camera 104 reads the information of the barcode on the sample tube 108 and identifies the sample liquid level in the sample tube 108, so as to facilitate subsequent sample taking; then, the sample tube 108 is placed in the sample tube fixing base 102, the clamp on the base clamps the sample tube 108, and the sample tube gripper 105 pulls out the sample tube cover to complete the cover pulling operation of the sample tube 108; immediately, the sample tube 108 moves to the right with the tube rack tray 103 to the liquid taking position for pipetting, moves to the left after pipetting to below the sample tube gripper 105, and the sample tube gripper 105 moves downward to cover the sample tube 108 with a cover; finally, the clamp of the sample tube fixing base 102 is loosened, and the sample tube gripper 105 moves the sample tube 108 back to the tube rack 101.

[0052] Since the pipette 217 and the centrifugal tube negative pressure suction disc 216 in area two can move up and down along the Z axis, the movement coverage in a certain range is completed, the centrifugal tube in the consumable area can be transferred to the opening and closing cover module by the centrifugal tube negative pressure suction and grabbing, the centrifugal tube is opened, and then the pipette 217 on the mechanical arm takes the gun head on the gun head tray 212, the sample and reagent are taken by the gun head and added into the opened centrifugal tube, after the taken liquid is added into the centrifugal tube, the opening and closing cover module closes the centrifugal tube, and then the opening and closing cover module rotates as a whole to mix the liquid in the centrifugal tube thoroughly; after the mixing, the centrifugal tube is transferred to the high-speed centrifuge 210 by the suction disc on the mechanical arm to perform high-speed centrifugation (if the high-speed centrifuge 210 is in a working state, the centrifugal tube to be centrifuged can be placed on the waiting rack for temporary storage), and after the centrifugation is completed, the centrifugal tube can be transferred to the transfer rack 211, which can move along the X axis to area three.

[0053] After the transfer rack 211 transfers the centrifugal tube to area three, the mechanical arm transfers the centrifugal tube to the opening and closing cover module to open the cover, and a new centrifugal tube is placed on the opening and closing cover and mixing module to open the cover, then the supernatant in the centrifugal tube is taken by the pipette and transferred to the centrifugal tube in the mixing module, the nitrogen blowing needle on the nitrogen blowing module 320 rotates above the centrifugal tube to perform nitrogen blowing, the nitrogen blowing time is set, the nitrogen blowing needle can move downward with time to improve the nitrogen blowing efficiency, and the centrifugal tube with the supernatant is placed on the idle centrifugal tube rack by the mechanical arm.

[0054] Finally, after the nitrogen blowing is completed, the nitrogen blowing needle returns to the original position, the reagent is taken by the pipette and added into the centrifugal tube after nitrogen blowing, and the cover is closed and mixed, after the mixing is completed, the suction disc on the mechanical arm is transferred to the opening and closing cover mechanism of the sample injector, the cover is opened after the centrifugal tube cover is opened by the opening and closing cover mechanism, the sample needle takes the sample and injects it into the chromatograph for detection, and after all the samples are injected, the sample is placed on the idle centrifugal tube rack by the mechanical arm.

[0055] As shown in FIG. 1, the automatic sample processing and chromatography-mass spectrometry testing integrated device implemented by the present application has a chromatography system 4, which has the functions of sample capture, separation and detection, and can be provided with 0-n capture columns, the sample injected by the sample injector is controlled by a flow path switching valve, and it is selected whether to capture through the capture column or through which capture column or multiple capture columns in parallel. Figure 6 In addition, 1-n chromatography separation columns can be provided to control the distribution and separation of the captured sample through the flow path switching valve. By setting multiple channel chromatography separation, cross testing between different separation chromatography columns is performed, and only the time period of testing the target object is tested, and the balance time before and after the chromatography column is not tested, so as to maximize the use of the detector.

[0056] The technical solution implemented by the present application mainly provides an integrated device for automatic sample processing and chromatography mass spectrometry, which comprises a sample tube working area and two processing working areas, and covers functions such as pipetting, oscillation mixing, high-speed centrifugation, constant-temperature nitrogen blowing and online capture. Different combinations of functions can realize coverage of current sample processing methods for chromatography and mass spectrometry. In addition, corresponding auxiliary technical means can be additionally added according to different application requirements on the basis of the same concept. Any existing technical means that can be used in the technical solution of the present application can be implemented by the technical solution implemented by the present application.

[0057] In the description of the present application, the terms "embodiment", "the present embodiment", "specific implementation" and the like mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present application or invention. In the present description, the illustrative description of the above terms does not necessarily refer to the same embodiment or example; moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in an appropriate manner.

[0058] In the description of the present application, the terms "connection", "installation", "fixation", "setting", "having" and the like are broadly understood, for example, "connection" can be fixed connection or indirectly through intermediate components without affecting the relationship between components and technical effects, or it can be integrated connection or partial connection, as the case may be for a person skilled in the art. The specific meaning of the above terms in the present application can be understood according to the specific circumstances.

[0059] The above description of the embodiments is for the convenience of understanding and application by ordinary skilled persons in the art, and those skilled in the art can easily make various modifications to these examples, and apply the general principles described herein to other embodiments without creative labor. Therefore, the present application is not limited to the above embodiments, and the following modifications should be within the scope of protection of the present application: ① new technical solutions based on the technical solution of the present application and combined with existing common knowledge, the technical effects generated by the new technical solutions do not exceed the technical effects of the present application, for example, the technical solution for sample processing and chromatography testing formed by the sample tube working area and the two processing areas, and the expected effect does not exceed the present application; ② equivalent replacement of part of the features of the technical solution of the present application using known technology, the technical effects generated are the same as the technical effects of the present application, for example, equivalent replacement of the type of selected motor; ③ expansion based on the technical solution of the present application, the essential content of the expanded technical solution does not exceed the technical solution of the present application; ④ equivalent transformation using the content recorded in the present application, and applying the obtained technical means to other related technical fields.

Claims

1. An integrated automated sample processing and chromatography-mass spectrometry testing device, comprising several sequentially adjacent working areas and compatible with chromatography or mass spectrometry equipment, characterized in that, The integrated automated sample processing and chromatography-mass spectrometry testing device includes: The sample tube working area equipped with a first robotic arm includes a movable sample tube carrying mechanism and a rotatable sample tube gripper located below the first robotic arm for positioning and gripping each sample tube. A camera is located below the first robotic arm for scanning the sample tube and identifying the sample liquid level inside the sample tube. The sample tubes are capped in the sample tube working area in preparation for sample removal operations in the next area. The sample processing area equipped with a second robotic arm includes a high-speed centrifuge, a transfer rack for transferring centrifuge tubes between areas, and a centrifuge tube opening and closing cap and mixing module for opening and closing the caps of centrifuge tubes to add reagents and apply vortex mixing. Below the second robotic arm, a pipette for gripping pipette tips on the pipette tip tray and a centrifuge tube negative pressure suction cup for gripping centrifuge tubes on the centrifuge tube tray are sequentially assembled. The sample processing area is equipped with a third robotic arm, which includes a nitrogen blowing module, an injection module for transferring reagents from centrifuge tubes and injecting them into the downstream chromatograph for detection, and a centrifuge tube opening and closing and mixing module. A centrifuge tube tray is mounted below the third robotic arm, and a pipette tip tray is set on one side of the centrifuge tube tray. The chromatographic system, which is adjacent to the sample processing area where the third robotic arm is located, includes a multi-channel online capture column, a multi-channel chromatographic separation column, and a sample detector; The chromatographic system includes 0-n capture columns and 1-n separation columns; After the nitrogen gas has dried the centrifuge tube, return the nitrogen blowing needle to its original position, use a pipette to transfer the reagent into the centrifuge tube after the nitrogen blowing process, and then close the cap and mix well.

2. The integrated automated sample processing and chromatography-mass spectrometry testing device according to claim 1, characterized in that: Each of the three robotic arms controls its corresponding area, and the three areas form an interconnected and orderly sample processing flow.

3. The integrated automated sample processing and chromatography-mass spectrometry testing device according to claim 1, characterized in that, The motion states of the sample tube gripper include: The sample tube is positioned at each location by moving along the X and Y axes; The sample tube is grasped, moved, and rotated so that the barcode scanning camera can scan the barcode of the sample tube to read the information and identify the sample liquid level inside the sample tube. Pull the cap of the sample tube upwards to complete the cap removal process. Cover the sample tube with the cap; Move the sample tubes back onto the tube rack.

4. The integrated automated sample processing and chromatography-mass spectrometry testing device according to any one of claims 1-3, characterized in that: The centrifuge tube negative pressure suction cup uses negative pressure adsorption to grab and transfer centrifuge tubes in the consumables area to the opening and closing module so that the centrifuge tubes can be opened.

5. The integrated automated sample processing and chromatography-mass spectrometry testing device according to claim 1, characterized in that: The movable sample tube support mechanism includes a tube rack for placing sample tubes, a movable tube rack tray for supporting the tube rack, and a sample tube fixing base disposed on the tube rack tray.

6. The integrated automated sample processing and chromatography-mass spectrometry testing device according to claim 1, characterized in that: The sample tube gripper is controlled by different motors and has the ability to move in at least two directions.

7. The integrated automated sample processing and chromatography-mass spectrometry testing device according to claim 1, characterized in that: A camera is mounted above the second robotic arm on one side of the centrifuge tube tray to identify materials in the area.

8. The integrated automated sample processing and chromatography-mass spectrometry testing device according to claim 1, characterized in that: The centrifuge tube tray is equipped with a nozzle tray and a waste box on both sides.

Images