Biological sample automatic extraction system and device

Abstract

A system for automated extraction of biological samples from a set of biological samples has a small footprint and minimal movement of consumable sets, thereby reducing potential contamination during the extraction process. The extraction system includes a set of reaction tubes, a storage unit for storing a set of consumables, a sample preparation unit, a sample extraction unit, a waste unit, a plurality of robots for moving the tubes, samples, and cassettes, and a programmable control system programmed to process the samples in a serial mode in which a series of samples are processed sequentially in time one after another, thereby maintaining a continuous mode. Thus, a fixed processing turnaround time for each sample is maintained regardless of when the sample starts processing.

Description

[0001] This application is a divisional application of the parent application having application number 2020800942321 (international application number PCT / CA2020 / 050258), filed on February 27, 2020, entitled “Automated Biological Sample Extraction System and Device”. TECHNICAL FIELD

[0002] The present invention relates generally to automated sample extraction systems that serve a variety of analytical processing systems and techniques. BACKGROUND

[0003] Sample preparation and extraction for analytical processing systems involves the manipulation and handling of multiple biological samples in a substantially sterile environment. It is important that samples are not contaminated when being handled, otherwise the results will be inaccurate, compromised and can lead to false positives in subsequent analytical processing and testing.

[0004] A variety of analytical processing systems require the preparation of biological samples, such as polymerase chain reaction “PCR” systems. “PCR” is a technique used in molecular biology to amplify a single or few copies of a piece of nucleic acid (such as deoxyribonucleic acid “DNA” or ribonucleic acid “RNA”) across several orders of magnitude, producing thousands to millions of copies of a particular sequence.

[0005] “PCR” is generally considered to amplify a focused piece of nucleic acid that can be used for diagnostic and monitoring of genetic diseases, studying the function of a piece of interest, for forensic individual identification, and other related uses.

[0006] Another example of an analytical processing system that can utilize samples prepared by a preferred system is an enzyme-linked immunosorbent assay (ELISA), which detects antigens or antibodies for use in immunology and toxicology. The purity of the biological sample is important for the analytical processing system to produce accurate results in subsequent analytical processing. One problem in preparing samples for analytical processing systems (such as PCR or ELISA enzyme-linked immunosorbent assays) is that there is a risk of contamination during the preparation process when the amplification vessel is open and the sample is being prepared. In addition, the potential for spillage, droplet formation, and / or aerosolization during the movement of the sample and when the cap is removed can lead to a risk of contamination. Cross-contamination can also occur during the introduction and removal of pipettes from the system as the contaminated pipette moves above the open sample vessel. This contamination can quickly lead to false results or biased and incorrect test results. Care must be taken to prevent such contamination.

[0007] Physical separation between sample preparation, amplification, and detection areas is typically used to limit contamination between samples and from the surrounding environment. These measures are cumbersome, expensive, and require rigorous training to prevent material transfer to lab coats, gloves, pipettes, or lab equipment between these isolated areas.

[0008] A biological material processing system includes a mobile pipette assembly in which multiple individual pipettes are mounted on a movable frame that is movable in longitudinal and lateral directions relative to a sample tray that includes sample tubes preferably loaded with biological material such as whole blood, serum, or other biological material for nucleic acid amplification. Multiple stops and starts of the pipette assembly on the sample tubes, typically after the pipettes are in contact with the samples in the sample tubes, cause cross contamination of the sample tubes on the robotic frame as the robotic frame moves, starts, stops, and vibrates, resulting in widespread potential contamination of all samples on the sample tray, failure of expensive and precise tests.

[0009] It would be desirable to design a sample processing system that reduces or eliminates the risk of cross contamination as the contaminated pipettes move, stop, and start, and as the sample tray is subjected to potential vibrational loads. The sample tubes also require samples and other materials in the sample tubes (e.g., buffers) to be accessed through a top opening, which further creates potential contamination issues.

[0010] Many methods of processing samples include steps of shaking, heating, applying a magnetic field to a magnetic bead-target compound complex, and discarding liquid waste. Typically, these steps are performed in separate and discrete stations, such as using a tube shaking device, a magnetic separation device, a heater, and a waste container.

[0011] The above-described conventional shaking, heating, magnetic bead separation, and waste liquid discarding processes require separate stations and take up too much space on a workbench. Using these separate stations also requires manual handling of the samples and transporting them from one station to another, which is both time consuming and leads to the potential for cross contamination between samples. Accordingly, there is a need to address these issues. SUMMARY

[0012] The present invention relates generally to an automated system for isolating and extracting target compounds from biological samples. In particular, the present invention is an automated sample extraction system that can be used to prepare samples for a variety of analytical processing systems and techniques, such as PCR systems.

[0013] The system is comprised of units configured to process samples in series so that it maintains a fixed processing turnaround time for each sample regardless of when the sample starts processing. The present invention processes samples in a serial mode, in which a series of samples are processed sequentially in time. The main units of the system are controlled by a computer to enable automated extraction of nucleic acids.

[0014] The system comprises five different units: a storage unit, a sample preparation unit, a sample extraction unit, a waste disposal unit and a reaction tube unit. All units are configured to minimize the amount of sample movement and reduce the risk of contamination.

[0015] The reaction tube unit is a specially designed reaction tube with an upper part for sample extraction and a lower part for receiving waste liquid from the upper part. The two parts are separated by a control valve.

[0016] The storage unit stores consumable boxes that are easily accessible. The storage unit also stores sample tubes and magnetic beads. The magnetic beads are kept in a cooler.

[0017] The sample preparation unit comprises a rotating stage with a transfer unit that comprises sample tube holders that hold sample tubes and reaction tube holders that hold reaction tubes next to each other. The rotating stage can also hold box-shaped consumables and reaction tubes for quick access each time. The sample preparation unit also has a sample holder to hold sample tubes, which is located at one side of the rotating stage. The rotating stage rotates to position the sample holder next to the sample tube holder on the transfer unit, and then the sample tube is transferred. This minimizes the amount of sample movement. The sample preparation unit also comprises a cooler to hold magnetic beads.

[0018] The sample extraction unit, which is located next to the rotating stage, comprises a set of tube shaking devices to receive and shake the reaction tubes and a set of magnet holders with magnets to manipulate the magnetic beads inside the reaction tubes.

[0019] The waste disposal unit comprises separate trash bins for disposal of consumables, disposal of waste liquid and disposal of tubes.

[0020] The design of the sample preparation unit is to minimize the amount of sample movement to reduce the risk of contamination. The sample has to be moved from the sample tube to the reaction tube for the extraction process. To minimize the amount of sample movement, the sample tube holders and the reaction tube holders are placed side by side on the rotating stage. A sample robot moves the sample tubes from the sample tube box into the sample tube holders while moving the reaction tubes from the reaction tube box into the reaction tube holders. Then, the sample robot prepares the sample in the reaction tube by adding different types of solutions, such as lysis buffer.

[0021] Once the sample in the reaction tube is prepared, the rotating stage rotates to position the reaction tube holder with the reaction tube next to the sample extraction unit.

[0022] A reaction robot grabs the reaction tube and moves it from the rotating stage to the tube shaking device in the sample extraction unit. The extraction unit is composed of separate tube shaking devices and separate magnetic units. Each tube shaking device with a reaction tube can be placed at different distances from the magnetic units to change the strength of the magnetic field and the position of the magnetic beads inside the reaction tube.

[0023] First, the reaction tube is positioned in a location where the magnetic effect is less, and is subjected to shaking. Then magnetic beads and binding buffer are added to the solution, and the reaction tube is further shaken.

[0024] Next, the reaction tube is moved to a second position, such that the reaction tube is positioned between the vertical legs of an L-shaped magnet. The magnet will attract the magnetic beads with the sample to the tube wall. The waste valve is opened, and the waste is drained into the second compartment of the reaction tube. The control valve is closed, the wash buffer is added, and the tube is shaken. The shaking tube device is then moved back into position close to the magnet, which is secured to the tube wall, while the control valve is opened to discard the waste into the second compartment. This process can be repeated multiple times (two or more washes), depending on the sample requirements to wash off impurities.

[0025] After the sample is purified, the elution buffer is added to the sample in the reaction tube, and the tube is shaken to separate the sample from the magnetic beads. The reaction tube is then moved to a third position, where the magnetic beads are fully attached to the top of the tube, allowing the sample to be easily taken out by a pipette. The reaction robot grabs the pipette, takes the purified sample from the reaction tube, and places it in a capped purified sample tube for storage.

[0026] Integrating each of these units onto the frame reduces the footprint of the sample preparation system and reduces the need to transport related components over relatively long distances, thereby reducing potential contamination.

[0027] It is therefore an object of the present invention to provide a biological sample extraction system and method that can reduce and eliminate the risk of contamination.

[0028] It is another object of the present invention to process samples in a serial mode, where a series of samples follow one another in a time sequence to be processed.

[0029] It is another object of the present invention to provide a fully automated sample extraction device to automatically process a large number of biological samples per day with minimal manual operation and shorter operation time.

[0030] It is another object of the present invention to provide a system that reduces cross-contamination by reducing the transfer time of the pipette and the liquid. BRIEF DESCRIPTION OF DRAWINGS

[0031] Embodiments will be described below with reference to the accompanying drawings, provided for the purpose of illustration only, and in which the same reference numerals indicate corresponding parts throughout the several views in which:

[0032] Figure 1 is a front perspective view of a biological sample extraction system of the present invention.

[0033] Figure 2is a front view of the biological sample extraction system of the present invention.

[0034] Figure 3 is a left side perspective view of the biological sample extraction system of the present invention.

[0035] Figure 4 is a top view of the biological sample extraction system of the present invention.

[0036] Figure 5 is a perspective view of the rotating table of the present invention.

[0037] Figure 6A is a front perspective view of the shaking tube device and the reaction tube.

[0038] Figure 6B is a front perspective view of the reaction tube of the present invention.

[0039] Figure 7 is a front view of the sample extraction unit and the shaking tube device pushing system of the present invention.

[0040] Figure 8 is a side view of the sample extraction unit of the present invention.

[0041] Figure 9 is a top view of the sample extraction unit of the present invention.

[0042] Figure 10A represents the reaction tube of the present invention.

[0043] Figure 10B represents the reaction tube of the present invention.

[0044] Figure 10C represents the reaction tube of the present invention.

[0045] Figure 10D represents the reaction tube of the present invention.

[0046] Figure 11 is a perspective view of the L-shaped magnet holder of the present invention (reaction tube in position 1).

[0047] Figure 12 is a perspective view of the L-shaped magnet holder of the present invention (reaction tube in position 2).

[0048] Figure 13 is a perspective view of the L-shaped magnet holder of the present invention (reaction tube in position 3).

[0049] Figure 14 is a perspective view of the waste treatment unit of the present invention.

[0050] Figure 15A is a side view of the shaking tube device pushing system.

[0051] Figure 15Bis a top view of the shake tube device push system.

[0052] Figure 16 is an isometric view of the robotic system of the present invention.

[0053] Figure 17 is a front view of the robotic system of the present invention.

[0054] Figure 18 is a front view of the robotic system of the present invention.

[0055] Figure 19 is a top view of the robotic system of the present invention.

[0056] Figure 20A shows the process of nucleic acid extraction in the system.

[0057] Figure 20B shows the process of nucleic acid extraction in the system.

[0058] Figure 20C shows the process of nucleic acid extraction in the system.

[0059] Figure 21 shows the reaction of magnetic beads in the reaction tube in three cases: position 1 (corresponding to Figure 11 ), position 2 (corresponding to Figure 12 ), position 3 (corresponding to Figure 13 ). DETAILED DESCRIPTION

[0060] Figures 1 to 5 An automated sample extraction system 100 is described that can be used to prepare samples for a variety of analytical processing systems and techniques. The automated sample extraction system 100 includes a plurality of units that are each controlled by a computer to effectuate automated sample extraction. The automated sample extraction system 100 can process samples in a serial mode, with a series of samples being processed in a time sequence following one another.

[0061] The automated sample extraction system 100 includes a frame 10 having a horizontal platform 11 that divides the frame into a top section 12 and a bottom section 13. Preferably, the frame 10 is constructed of a relatively rigid, strong and sterilizable material that is assembled to provide structural support to the various units of the automated sample extraction system 100 and to enable the automated sample extraction system to operate. For example, the frame 10 can be constructed of stainless steel that is biocompatible and sterilizable for use with the automated sample extraction system 100. The automated sample extraction system 100 includes a plurality of units that are located in the interior space of the frame and are supported by the frame 10, which are movable in a manner that operates the automated sample extraction system.

[0062] The storage unit: The sample automatic extraction system comprises a storage unit. The storage unit comprises a rotary storage device 20 installed on the bottom section 13 near the left side of the frame 10. The rotary storage device 20 comprises a plurality of movable trays 21 (preferably eight trays 21) assembled in a vertical position and each tray 21 comprises a plurality of accommodation spaces (preferably five accommodation spaces), which accommodate five consumable boxes 22. The operator of the machine can remove the trays 21 and load the consumable boxes 22. The consumable boxes 22 comprise samples and additional elements for the extraction process. The rotary storage device 20 stores a large number of consumable boxes for the extraction process, approximately a total of forty boxes, and can rotate around the Z axis. Preferably, the rotary storage device 20 comprises a plurality of consumable storage spaces, including reaction tube boxes, buffer boxes, elution tube boxes, and various pipette tip boxes, which are stored in the rotary storage device 20 and transported by the box lifting robot 30 for replacement. The rotary storage device 20 can accommodate a large number of consumables for easy access. For example, 16 reaction tube boxes, 2 buffer boxes, 2 elution tube boxes, 12 (1ml) pipette tip boxes, 4 (175 μL) pipette tip boxes, and 4 (25 μl) pipette tip boxes.

[0063] As Figure 4 As clearly shown, the storage unit also comprises a sample rack 50 installed on the top section 12 of the left side of the frame, which comprises a plate with guide rails, on which the sample tubes 1 are positioned in the sample automatic extraction system. The sample tubes 1 can be automatically or manually loaded onto the sample rack 50 by the machine or the operator.

[0064] The storage unit also comprises a cooler 90 to store consumables that need to be stored in a low-temperature (e.g. 4°C) environment. For example, magnetic bead solution is stored in the cooler and then transferred to the reaction tube 201. The cooler 90 can be any type of available cooler, preferably a thermoelectric cooler. The function of the cooler 90 is to keep the solutions between 4-8°C so that they can work.

[0065] The box lifting robot 30 transports the consumable boxes 22 from the rotary storage device 20 to the rotary table 40 on the top section 12 of the frame. The box lifting robot 30 is a vertical motion robot installed on a rod on the bottom section 13 to allow the box lifting robot 30 to move linearly in two axes (X axis and Z axis). The box lifting robot 30 extends through the opening 31 to the top section 12, which can be moved to the desired position to grab the consumable box 22 and lift it from the rotary storage device 20 to the rotary table 40 on the top section 12.

[0066] The sample preparation unit comprises a rotary table 40. The rotary table 40 of the sample preparation unit comprises a plurality of accommodation cavities, preferably six accommodation cavities, which are dimensioned to accommodate consumable cassettes 22 used in the extraction process. The rotary table 40 is rotatably mounted on the horizontal platform 11 on the top section 12 of the frame. It can rotate around an axis and stop at a predetermined position in front of the cassette lifting robot 30 to receive the consumable cassettes 22. Each accommodation cavity of the rotary table 40 can comprise various pipette tip cassettes, including: long pipette tips 42, medium pipette tips 43 and short pipette tips 44. Other consumable cassettes, such as nucleic acid tubes 45, various buffer tubes 46 and reaction tubes 201 are further positioned on the rotary table 40 for the extraction process. A transfer unit 41 is provided on the rotary table 40, which comprises a sample tube rack 2, a reaction tube rack 3 and a waste hole 4. In the transfer unit 41, the sample can be transferred from the sample tube 1 to the reaction tube 201, which is next to the sample tube 1, to reduce the risk of cross contamination.

[0067] For the full automation of the sample extraction, the sample automated extraction system 100 provides a sample robot 60 and a reaction robot 70 for transferring consumables of the extraction process. The sample robot 60 and the reaction robot 70 are Cartesian coordinate robots movable along the Z-axis. The sample robot 60 and the reaction robot 70 are equipped with an electric gripper and an electric pipette assembly. The sample robot 60 and the reaction robot 70 are equipped with an electric gripper and an electric pipette assembly to pick up consumables, place the consumables at different locations, transfer liquids according to the sample extraction purpose of the sample automated extraction system, dispose waste. The gripper is used to carry tubes. As will be appreciated by those of ordinary skill in the art, the pipette assembly is used to move samples during the sample extraction process. The functions of the gripper and the pipette are controlled by a computer program controller during the operation of the sample automated extraction system 100.

[0068] Sample extraction unit: Referring to Figure 1 、 Figures 6A to 13 The sample automated extraction system further comprises a sample extraction unit 80, which is mounted on the top section 12 and located on the right side of the frame 10. It comprises a plurality of (preferably 32) independent tube shaking devices 200. Containing sampling materials, such as magnetic beads and buffers, to break down cells and clean up impurities, the above-mentioned sampling materials flow into the reaction tube 201. The reaction tube 201 is then placed in the tube shaking device 200 for the sampling process.

[0069] One embodiment of the sample auto-extraction system 100 includes a tube rocker device 200 mounted under four magnet racks 81 parallel to each other, wherein each magnet rack 81 receives six tube rocker devices 200. The magnet racks 81 are fixed. The tube rocker device 200 is equipped with a magnetic gear 83 on a rotating shaft 84, and another magnetic gear 83 is installed on the rotating shaft 84. The tube rocker device 200 can move on the guide rail along the X axis to achieve the engagement or disengagement of a pair of magnetic gears, so as to control the opening or closing of the tube rocker device 200. The magnetic gear 83 is installed on the rotating shaft 84, and preferably six magnetic gears 83 are installed on each rotating shaft 84. The rotating shaft 84 preferably operates at 1200 rpm.

[0070] Each tube rocker device 200 is configured to operate independently and provides a rocking motor to integrate track rocking, heating, magnetic bead separation, and waste discharge. Each magnet rack 81 has a plurality of accommodation spaces, each of which is configured to receive one tube rocker device 200. Each accommodation space has a pair of L-shaped magnets 95, which have a vertical leg and a horizontal leg. The tube rocker device 200 can be located at different distances from the magnet rack 81.

[0071] Figures 11-13 Three different positions are shown: as Figure 11 shown, when the tube rocker device 200 is in position 1, the L-shaped magnet 95 cannot attract the magnetic beads inside the reaction tube 201, so the magnetic beads will not gather together. As Figure 12 shown, when the tube rocker device 200 with the reaction tube 201 is placed in position 2, the L-shaped magnet 95 can attract the magnetic beads 48 inside the reaction tube 201, so that the magnetic beads 48 gather together on the side close to the vertical leg of the L-shaped magnet 95, and extend along the inner wall of the reaction tube 201 at a lower position. When the tube rocker device 200 with the reaction tube 201 is placed in position 3 as Figure 13 shown, the L-shaped magnet 95 can attract the magnetic beads 48 inside the reaction tube 201, so that the magnetic beads 48 gather together, and the magnetic beads 48 spread along the inner wall more widely than in position 2, making it easy to remove the sample by pipette. Figure 21 Further shown is the reaction of the L-shaped magnet 95 and the magnetic beads 48 in the reaction tube 201 when the tube rocker device 200 is in different positions.

[0072] The tube rocker device advancing robot advances the tube rocker device to different positions. As Figure 7 , 15AAs shown in Figures 15A and 15B, the sample extraction unit 80 is also provided with a two-axis (X and Y) linear motion rocker device push system 82. The rocker device push system 82 is used to push the rocker device 200 to different positions. The push pad 85 pushes the rocker device closer to or further away from the rotating shaft 84. When the distance to the rotating shaft 84 is about 1 mm, the rocker device 200 will start to rock. The metal sheet 87 is further installed at the bottom of the rocker device to guide the rocker device 200 closer to or further away from the rotating shaft 84.

[0073] Reaction tube: Each reaction tube 201 comprises two chambers. According to Figures 10A to 10D , the top chamber is a reaction chamber 202, which is a cylindrical compartment for receiving the sample, buffer and magnetic beads used in the extraction process. The lower compartment is a waste chamber 203, which is a cylindrical container with a larger diameter than the reaction chamber 202, which is used to receive the liquid waste generated during the sampling process. The reaction chamber 202 and the waste chamber 203 are connected to each other, so that the reaction chamber 202 is individually formed and connected to the waste chamber 203. The reaction tube 201 is provided with a control valve 204, which is located between the reaction chamber 202 and the waste chamber 203, and the waste chamber 203 is in communication with the waste liquid treatment device. When the control valve 204 is opened, the waste liquid generated during the extraction process is treated in the waste chamber 203. During the extraction process, the control valve 204 seals the opening between the reaction chamber 202 and the waste chamber 203. The opening and closing of the control valve 204 is controlled by pushing a series of buttons 205 installed on the reaction tube 201, which will press down the spring element 208. Whenever the waste liquid is to be treated, the force on these buttons can open the control valve.

[0074] The opening and closing of the control valve 204 is achieved by the force acting on the buttons 205, which is applied by the reaction robot 70. After the entire extraction process is completed, the reaction robot 70 carries the reaction tube 201, the waste liquid is retained in the waste chamber 203, and it is discarded into the waste liquid tank. This action prevents the reaction sample from flowing into the waste chamber 203. The reaction tube 201 can be made of biocompatible, sterilizable material.

[0075] The gripper of the reaction robot 70 has a rod gripper (not shown) that can be moved in a vertical position to insert the reaction chamber 202 to grip and transfer the reaction tube 201. The reaction robot 70 also has a sleeve (not shown) that slides on the rod gripper. The sleeve pushes the buttons 205 on the reaction tube 201 to open the control valve 204.

[0076] Waste unit: According to Figure 14The sample automated extraction system provides two waste bins on the bottom section 13. During liquid transfer, the sample robot 60 and the reaction robot 70 transfer all waste except for the waste liquid, such as the used pipette aspirate in the first waste liquid bin 51 or the second waste liquid bin 52. When the control valve 204 is open, the waste liquid is placed in the waste chamber 203 of the reaction tube 201. After the entire extraction process is completed, the reaction robot 70 carries the reaction tube 201 with the waste liquid remaining in the waste chamber 203 to the second waste liquid bin 52. The waste liquid is disposed of through a set of openings provided on the horizontal platform 11 of the frame.

[0077] Referring again to Figure 5 The transfer unit 41 includes a sample tube rack 2 to hold the sample tube 1, a reaction tube rack 3 to hold the reaction tube 201, and a waste hole 4. The sample robot 60 begins the sample process by removing the reaction tube 201 from the reaction tube cartridge on the rotary table 40 and placing it on the reaction tube rack 3. The sample robot 60 further removes the sample tube 1 from the sample rack 50 and places it on the sample tube rack 2. Then, the sample robot 60 selects pipette tips from various pipette tip cartridges, such as long pipette tips 42, medium pipette tips 43, or short pipette tips, depending on the extraction process to transfer the sample from the sample tube 1 to the reaction tube 201.

[0078] Each used pipette tip and pipette is discarded into the first waste liquid bin 51 through the waste hole 4 after use. The waste hole 4 is in close proximity to the transfer unit 41, so there is a risk of cross-contamination of the samples during movement, and the likelihood of spillage, droplet formation, and / or aerosol formation is significantly reduced when the lid is removed. This design of the system not only reduces cross-contamination but also reduces the movement time of the pipettes and liquid transfer.

[0079] The sample automated extraction system 100 further includes a computer program for commanding and controlling the operation of the system units. A non-transitory computer readable memory includes one or more data structures that alone or collectively contain stored information related to the operation of the system, including the various ways the system can be operated. The controller of the system is coupled with a sample extraction application to store information related to the various types of sample extraction. The sample automated extraction system 100 further includes a control application for sample extraction. The at least one control application includes sample extraction instructions to cause the sample extraction units to move and cause the sample automated extraction system 100 to prepare an extraction sample using one or more selected consumables corresponding to a selected sample.

[0080] Figure 3 , Figures 16 to 19A robotic system of the present invention is disclosed. The sample robot 60 and the reaction robot 70 have the same mechanism to provide an automated and continuous sample extraction procedure. Both the sample robot 60 and the reaction robot 70 provide grippers mounted on movable arms. The sample robot 60 is movably mounted to a robot rail 61 which is fixed to the vertical supports of the frame 10 for movement relative to the frame 10 in the storage unit and the sample preparation unit. The sample robot 60 provides grippers on a clamping arm 62 which is downwardly movable to releasably grasp various pipette tips and tubes so that the pipette tips and tubes are moved between different areas.

[0081] The reaction robot 70 is movably mounted on a robot rail 71 which is fixed to the vertical supports of the frame 10 for movement between the sample preparation unit and the sample extraction unit 80 to continue the automated sample processing system. The reaction robot 70 is provided with grippers 73 mounted on a clamping arm 72 which is downwardly movable to releasably grasp various pipette tips and move them between areas and place them in preprogrammed positions. The reaction robot 70 selects pipette tips, e.g. long pipette tips 42, from various pipette tip boxes to add various components to the reaction tube 201.

[0082] According to Figure 1 、 Figure 5 、 Figures 20A to 21 The above figure discloses the sample extraction process of the reaction tube 201 of the sample automated extraction system. In operation, the rotary storage device 20 rotates to a position where the box lifting robot 30 can grasp the desired consumable. At the same time, the rotary table 40 rotates to a position where the box lifting robot 30 can place the consumable on the receiving space of the rotary table 40. Then, the box lifting robot 30 selects one consumable and lifts it up to place the consumable on the rotary table 40. In this way, the box lifting robot 30 can pick up and place six different consumables on the rotary table 40.

[0083] The sample robot 60 takes out the reaction tube 201 from the reaction tube box and places it on the reaction tube rack 3. The sample robot 60 further takes out the sample tube 1 from the sample rack 50 and places it on the sample tube rack 2 next to the reaction tube 201. Then, the sample robot 60 picks up the pipette tip to transfer some sample (nucleic acid) from the sample tube 1 to the reaction tube 201. The rotary table 40 rotates to move the reaction tube 201 filled with sample towards the sample extraction unit 80 in the direction of the right side of the frame. Therefore, the risk of cross-contamination, spillage, droplet formation and / or aerosol that can occur during sample movement is significantly reduced.

[0084] Figures 20A to 20CThe detailed procedure for extracting the sample (nucleic acid) is shown. The reaction robot 70 picks up the pipette tip, adds lysis buffer into the reaction tube 201 for breaking the nucleic acid cells and transferring them to the sample extraction unit 80, and places each reaction tube 201 on the shaker device 200 for extraction. The shaker device 200 shakes the reaction tube 201 for 10 minutes.

[0085] After shaking for 10 minutes, the shaker device pushing system 82 pushes the shaker device 200 away from the rotation shaft, stopping the shaker device 200. The reaction robot 70 then moves to the rotation table 40, picks up and adds some magnetic beads 48 and binding buffer into the reaction tube 201. The binding of the magnetic beads 48 in the sample and the separation efficiency are improved by the movement of the shaker device 200. At this stage, the sample (nucleic acid) is combined with the magnetic beads 48. Then, the shaker device pushing system 82 pushes the shaker device 200 to shake on the L-shaped magnet 95 for 5 minutes. The most useful property of the magnetic beads 48 and the buffer is that they can reversibly bind nucleic acids and can be safely immobilized in multiple washing and manipulation steps when a strong magnet is present. At each stage, the reaction robot 70 will dispose the used pipette tip into the waste bin.

[0086] The process of extracting the sample is achieved in multiple stages by pushing the reaction tube 201 onto the magnet holder, shaking the shaker device 200 to separate the magnetic beads 48 from the sample, washing the impurities from the sample. The shaker device pushing system 82 pushes the reaction tube 201 on the magnet holder 81 to apply a magnetic force to separate the magnetic beads 48 from the sample. The magnetic beads will stick to the inner wall of the reaction chamber 202.

[0087] At this stage, the control valve 204 between the reaction chamber 202 and the waste chamber 203 of the reaction tube 201 is opened by the reaction robot applying a force on the button 205, and the waste produced during the extraction flows from the reaction chamber 202 to the waste chamber 203. The reaction robot 70 then adds some washing buffer (Wash Buffer) to the sample. The shaker device pushing system 82 pushes the shaker device 200 to shake for 1 minute. The shaker device pushing system 82 pushes the reaction tube 201 on the magnet holder 81 to separate the magnetic beads 48 by applying magnetism. The waste produced during the extraction is then discarded from the reaction chamber (extraction zone) 202 into the waste chamber 203. These steps can be repeated several times by adding additional buffer to the reaction tube, magnetizing, rotating, and discarding the waste liquid required by the system. Figure 20B

[0088] According to Figure 20C ​At the final stage of the extraction process to elute the nucleic acid from the magnetic beads 48, the magnetic beads must be dissolved with a small volume of elution solution, which is added to the sample and the shake tube device push system 82 pushes the shake tube device 200 for 30 seconds. The shake tube device push system 82 pushes the shake tube device 200 on the magnet rack to apply the magnetism and the resulting waste is discarded. Cross contamination can also occur during the process of pipette introduction and removal from the system as the contaminated pipette moves above the open sample container. This contamination will quickly lead to false results or errors and incorrect test results. Care must be taken to prevent such contamination.

[0089] The nucleic acid solution containing purified viral RNA / DNA is transferred to the elution tube. The reaction tube 201 is designed to allow the magnetic beads to gather together close to the bottom of the tube so that the elution solution can effectively and completely contact the magnetic beads. The reaction robot 70 then transports the reaction tube 201 to the waste outlet and the waste is discharged.

[0090] When the magnetic beads 48 are placed in the reaction tube 201 in the shake tube device 200, the substances in the sample are attached to the magnetic beads 48 by collision of the biological material with the magnetic beads 48. The magnetic beads 48 are added to the reaction tube 201 to allow DNA molecules to bind to the magnetic beads 48. The reaction tube 201 is then placed on the shake tube device 200. The shake tube device 200 is used for sample mixing to obtain uniform mixing of the magnetic beads 48 with the sample, thereby improving the yield of DNA bound to the magnetic beads 48. The magnetic beads 48 used in the process can be at least one of stainless steel beads, zirconium oxide beads, ceramic beads, or glass beads.

[0091] The sample automatic extraction system and method according to embodiments of the present application can prepare different biological samples for various analysis procedures. Examples of such biological samples include, but are not limited to, blood, serum, plasma, urine, saliva, feces, organ tissue, etc., preferably biological samples from patients. According to the notes, the processed sample can contain one or more isolated or enriched biological molecules, which can be analyzed, detected or quantified in subsequent procedures. For example, a biological sample (e.g., a biological sample from a subject) can be processed in the sample automatic extraction system of the present application to obtain a processed sample containing isolated or enriched nucleic acid, and the processed sample can be used to amplify, detect or quantify one or more nucleic acids of interest, e.g., as a template in a PCR reaction, or one or more chemiluminescent labeled nucleic acids used in hybridization treatment.

[0092] In one preferred embodiment, a method further comprises detecting or quantifying the nucleic acids of the processed sample using PCR or a chemiluminescent assay. In another example, a biological sample (e.g., a biological sample from a subject) can be processed in the automated sample extraction system of the present application to obtain a processed sample containing a polypeptide or protein, and the processed sample can be used in an immunoassay, such as a radioimmunoassay, ELISA, immunofluorescence assay, or chemiluminescent immunoassay, for detecting or quantifying one or more polypeptides or proteins of interest.

[0093] In another embodiment, the method comprises detecting or quantifying the peptide or polypeptide in the processed sample using an ELISA, immunofluorescence assay, or chemiluminescent immunoassay (CLIA). CLIA is a more sensitive alternative to ELISA that involves the release of energy by a chemical reaction to produce electromagnetic radiation (in the form of light), measuring the intensity of the light. For example, a photomultiplier tube or photodiode and associated electronics are used to convert and record the signal. Known methods and reagents for detecting or quantifying biological molecules, such as PCR, ELISA, immunofluorescence, assay, or CLIA. With the disclosure of the present application, the aforementioned procedures are all capable of use in the present application.

Claims

1. A system for automatically extracting a biological sample from a set of biological samples, characterized in that, The system comprises: a) a set of reaction tubes for preparing samples; the reaction tube comprises: a reaction chamber at the top of the reaction tube for receiving samples, buffers and magnetic beads for the extraction process; the lower part of the reaction chamber is sequentially provided with an opening-reducing section and an opening-increasing section from top to bottom; a waste chamber at the bottom of the reaction tube for receiving waste generated in the extraction process; the diameter of the waste chamber is larger than that of the reaction chamber; a control valve connecting the reaction chamber and the waste chamber; the valve head of the control valve is placed in the opening-increasing section of the reaction chamber, and a set of buttons are arranged around the outside of the valve head; the bottom wall of the reaction chamber is inserted between the valve head and the buttons; the inner surface of the buttons corresponds to the side wall of the lower part of the reaction chamber, and part of the outer surface of the buttons corresponds to the side wall of the upper part of the waste chamber and part of the outer surface extends to the upper part of the waste chamber; a spring element is connected between the valve head of the control valve and the waste chamber; the control valve is opened by pressing a set of buttons located outside the reaction chamber; when the control valve is opened, the valve head of the control valve is separated from the top opening of the opening-increasing section of the reaction chamber, and the waste generated in the extraction process enters the waste chamber; b) a storage unit comprising: i) a rotary storage device for placing a plurality of consumable boxes, the consumable boxes storing a set of consumables; ii) a sample rack comprising a plurality of sample tubes; iii) a cooler for storing a plurality of consumables that need to be stored at a lower temperature; c) a sample preparation unit comprising: i) a rotary table having a transfer unit, the transfer unit comprising a sample tube rack for receiving sample tubes and a reaction tube rack for receiving reaction tubes; the rotary table can rotate around an axis and stop at a predetermined position in front of the box lifting robot to receive the consumable boxes; ii) a plurality of accommodation spaces capable of accommodating a plurality of consumable boxes; wherein the sample tube and the reaction tube on the rotary table are closely arranged together to facilitate the rapid transfer of samples from the sample tube to the reaction tube; d) a waste treatment unit for treating waste; e) a sample extraction unit; wherein the sample extraction unit comprises independent shaking tube devices installed on a plurality of magnet racks; each shaking tube device has a shaking motor to realize orbital shaking; f) a plurality of robots for moving tubes, samples and boxes, comprising: i) a box lifting robot, which is a vertical motion robot, used to grab and transport a plurality of storage boxes storing a set of storage consumables placed by the rotary storage device to the sample preparation unit; ii) a sample robot for transferring sample tubes from the sample rack to the transfer unit, transferring reaction tubes from the consumable box containing a set of consumables to the transfer unit beside the sample tube, and transferring samples to the reaction tube for mixing, with small movement and small footprint, and reducing potential contamination in the extraction process. iii) a reaction robot for transferring a set of consumables into the reaction tube, wherein with each rotation of the rotary stage, the reaction robot picks up a consumable and adds it to the reaction tube, after mixing, the rotary stage rotates and the reaction robot transfers the reaction tube to the sample extraction unit; the reaction robot has a stem gripper and a sleeve that slides on the stem gripper, the sleeve pushes a button on the reaction tube to open a control valve; g) a programmable control system programmed to process samples in a serial mode, wherein a series of samples are processed one after the other in a time sequence, such that each sample maintains a fixed processing turnaround time regardless of when the sample is processed.

2. The system of claim 1, wherein, wherein the consumable cassettes include: a sample cassette, a buffer cassette, a long pipette tip cassette, a mid pipette tip cassette, a short pipette tip cassette, and a reaction tube cassette.

3. The system of claim 1, wherein, wherein the transfer unit has a waste hole near the reaction tube rack and the sample tube rack.

4. The system of claim 1, wherein, The sample is transferred from the sample tube to the reaction tube by the sample robot selecting and grabbing the first pipette.

5. The system of claim 1, wherein, wherein the buffers and magnetic beads are transferred to the reaction tube by the reaction robot selecting and grabbing pipette tips.

6. The system of claim 1, wherein, wherein the waste unit is composed of a waste chamber connected to an opening.

7. The system of claim 1, wherein, wherein the rotary storage device is rotatable about a vertical axis.

8. The system of claim 1, wherein, wherein the system includes a vertical frame divided into a top section and a bottom section by a horizontal platform, wherein the rotary storage unit and the waste disposal unit are installed in the bottom section; the sample preparation unit and the sample extraction unit are installed in the top section.

9. The system of claim 1, wherein, wherein the rotary storage device includes eight vertically mounted trays, wherein each tray includes five holding spaces, the rotary storage device is configured to receive a total of forty consumable cassettes.

10. The system of claim 1, wherein, The reaction tube is made of biocompatible and sterilizable material. iii) a reaction robot for transferring a set of consumables into the reaction tube, wherein with each rotation of the rotary stage, the reaction robot picks up a consumable and adds it to the reaction tube, after mixing, the rotary stage rotates and the reaction robot transfers the reaction tube to the sample extraction unit; the reaction robot has a stem gripper and a sleeve that slides on the stem gripper, the sleeve pushes a button on the reaction tube to open a control valve; g) a programmable control system programmed to process samples in a serial mode, wherein a series of samples are processed one after the other in a time sequence, such that each sample maintains a fixed processing turnaround time regardless of when the sample is processed. wherein the consumable cassettes include: a sample cassette, a buffer cassette, a long pipette tip cassette, a mid pipette tip cassette, a short pipette tip cassette, and a reaction tube cassette. wherein the transfer unit has a waste hole near the reaction tube rack and the sample tube rack. The sample is transferred from the sample tube to the reaction tube by the sample robot selecting and grabbing the first pipette. wherein the buffers and magnetic beads are transferred to the reaction tube by the reaction robot selecting and grabbing pipette tips. wherein the waste unit is composed of a waste chamber connected to an opening. wherein the rotary storage device is rotatable about a vertical axis. wherein the system includes a vertical frame divided into a top section and a bottom section by a horizontal platform, wherein the rotary storage unit and the waste disposal unit are installed in the bottom section; the sample preparation unit and the sample extraction unit are installed in the top section. wherein the rotary storage device includes eight vertically mounted trays, wherein each tray includes five holding spaces, the rotary storage device is configured to receive a total of forty consumable cassettes. The reaction tube is made of biocompatible and sterilizable material.

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