Methods and systems for high throughput compound screening

Abstract

The invention relates to a method and system for high throughput compound screening. The method includes: at a control device, controlling a robot arm to transfer a compound plate in a first liquid treatment device to treat a compound contained in the compound plate and transfer the treated compound from the compound plate to a test plate; and controlling the mechanical arm to transfer the test plate in the second liquid treatment device so as to treat the test plate, so that the test plate is filled with to-be-tested liquid for cell activity detection, and compound screening is realized. The efficiency and the automation degree of the whole compound screening process can be remarkably improved, and high-throughput compound screening can be accurately and repeatedly achieved.

Description

Technical Field

[0001] The present invention relates generally to the control of biological experiments, and in particular, to methods and systems for high-throughput compound screening. Background Art

[0002] High-throughput compound screening is an important step in the drug development process. It uses large-scale cells inoculated in multi-well plates as a model. By adding compounds during the cell culture process to observe the effects of the compounds on cells (for example, biological processes such as cell activity, cell proliferation, and apoptosis, as well as cell gene expression), the activity of the compounds can be determined and active compounds can be screened out.

[0003] Traditional high-throughput compound screening methods usually rely on manual operation of a single instrument to perform compound transfer, compound loading, cell sample preparation, and other operations. However, the above process is highly dependent on manual operation, making the entire compound screening process time-consuming and low-throughput. In addition, the operations of different operators will affect the results of the experiment, resulting in large differences between experimental processing batches, low repeatability, and low accuracy.

[0004] In summary, the shortcomings of traditional high-throughput compound screening methods are: high time and labor costs, and low experimental repeatability and accuracy. Summary of the invention

[0005] The present invention provides a method and system for high-throughput compound screening, which can significantly improve the efficiency and automation of the entire compound screening process, and can accurately and repeatably achieve high-throughput compound screening.

[0006] According to a first aspect of the present invention, a method for high-throughput compound screening is provided, comprising: at a control device, controlling a robotic arm to transfer a compound plate in a first liquid handling device to process the compounds contained in the compound plate, and transferring the processed compounds from the compound plate to a test plate; controlling the robotic arm to transfer the test plate in a second liquid handling device to process the test plate, so that the test plate is filled with a test liquid that can be used for cell activity detection, to achieve compound screening.

[0007] In some embodiments, the first liquid processing device includes: a heating and shaking unit, a centrifugal unit, and an ultrasonic liquid processing unit; the second liquid processing device includes: a first liquid addition unit, a second liquid addition unit, and a cell culture unit.

[0008] In some embodiments, processing the compounds contained in the compound plate includes: controlling the robot arm to transfer the compound plate to the heating and shaking unit to perform heating and shaking operations on the compounds contained in the compound plate so that the compounds are completely dissolved to form uniform compounds; controlling the robot arm to transfer the compound plate that has undergone heating and shaking operations to the centrifugation unit to perform centrifugation operations on the uniform compounds in the compound plate; controlling the robot arm to transfer the compound plate that has undergone centrifugation operations to the ultrasonic liquid processing unit to transfer the centrifuged compounds from the compound plate to the test plate through ultrasonic waves.

[0009] In some embodiments, processing the test plate includes: controlling the robot arm to transfer the test plate to the first liquid addition unit to add cell-free culture medium to a first designated position of the test plate; controlling the robot arm to transfer the test plate with added culture medium to the second liquid addition unit to add cell suspension to a second designated position of the test plate; controlling the robot arm to transfer the test plate with added cell suspension to the cell culture unit to perform an incubation operation on the test plate; controlling the robot arm to transfer the test plate that has undergone the incubation operation to the first liquid addition unit to add cell activity detection reagent to the test plate.

[0010] In some embodiments, the method for high-throughput compound screening also includes: controlling the robotic arm to transfer the test plate to which the cell activity detection reagent is added to the oscillation unit to perform an oscillation operation on the test plate; controlling the robotic arm to transfer the test plate after the oscillation operation to the input-output unit, so that the test plate can be transferred to the test platform, so as to perform cell activity detection on the liquid to be tested contained in the test plate.

[0011] In some embodiments, the method for high-throughput compound screening further includes: controlling the robot arm to receive the compound plate from the input-output unit and transfer the compound plate to the first liquid handling device.

[0012] According to the second aspect of the present invention, a system for high-throughput compound screening is also provided, the system comprising: a first liquid handling device, configured to process the compounds contained in the compound plate based on the instructions of the control device, and transfer the processed compounds from the compound plate to the test plate; a second liquid handling device, configured to process the test liquid contained in the test plate based on the instructions of the control device, so as to transfer the treated test liquid to the test platform for detection; a robotic arm, configured to realize the transfer of the compound plate or the test plate based on the instructions of the control device; and a control device, used to execute the steps of the method according to the first aspect of the present invention.

[0013] In some embodiments, the first liquid handling device includes: a heating and shaking unit for heating and shaking the compounds contained in the compound plate; a centrifugation unit for centrifuging the compounds in the compound plate; and an acoustic liquid handling unit for transferring the centrifuged compounds from the compound plate to the test plate by acoustic waves.

[0014] In some embodiments, the second liquid handling device includes: a first liquid adding unit for adding cell-free culture medium and cell activity detection reagent to the test plate; a second liquid adding unit for adding cell suspension to the test plate; and a cell culture unit for performing incubation operations on the test plate.

[0015] In some embodiments, the system for high-throughput compound screening also includes: a temporary storage unit for temporarily storing compound plates containing compounds and test plates containing liquids to be tested; a consumables stacking unit for storing empty test plates; and a track for assisting the movement of the robotic arm.

[0016] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the invention, nor is it intended to limit the scope of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 A schematic top view of a system for high-throughput compound screening according to an embodiment of the present invention is shown.

[0018] Figure 2 A flow chart of a method for high-throughput compound screening according to an embodiment of the present invention is shown.

[0019] Figure 3 A flow chart of a method for processing a compound contained in a compound plate and a test plate according to an embodiment of the present invention is shown.

[0020] Figure 4 The schematic diagram of an electronic device suitable for implementing the embodiment of the present invention is schematically shown.

[0021] In the various drawings, the same or corresponding reference numerals represent the same or corresponding parts. DETAILED DESCRIPTION

[0022] The preferred embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although the preferred embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided to make the present invention more thorough and complete, and to fully convey the scope of the present invention to those skilled in the art.

[0023] As used herein, the term "including" and its variations mean open inclusion, i.e., "including but not limited to". Unless otherwise stated, the term "or" means "and / or". The term "based on" means "based at least in part on". The terms "an example embodiment" and "an embodiment" mean "at least one example embodiment". The term "another embodiment" means "at least one additional embodiment". The terms "first", "second", etc. may refer to different or the same objects.

[0024] As described above, the traditional high-throughput compound screening method has the following shortcomings: high time and labor costs, and low experimental repeatability and accuracy.

[0025] In order to at least partially solve the above problems and one or more of other potential problems, an exemplary embodiment of the present invention proposes a scheme for high-throughput compound screening. In this scheme, by controlling the mechanical arm at the control device to transfer the compound plate in the first liquid handling device to treat the compound contained in the compound plate, and transferring the treated compound from the compound plate to the test plate; and controlling the mechanical arm to transfer the test plate in the second liquid handling device to treat the test plate, so that the test plate is equipped with a liquid to be tested that can be used for cell activity detection, the present invention can realize the automatic transfer of materials between the processing devices through the mechanical arm to improve the automation and efficiency of the entire compound screening process, thereby reducing labor costs and time costs, and reducing experimental errors caused by human factors, thereby improving the repeatability and accuracy of compound screening experiments. Therefore, the present invention can efficiently perform high-throughput compound screening.

[0026] Figure 1 FIG. 1 is a schematic top view of a system 100 for high-throughput compound screening according to an embodiment of the present invention. Figure 1 As shown, the high-throughput compound screening system 100 includes a control device 110 , a robot arm 120 , a first liquid handling device 130 , and a second liquid handling device 140 .

[0027] The first liquid processing device 130 is configured to process the compounds contained in the compound plate based on the instruction of the control device 110, and transfer the processed compounds from the compound plate to the test plate. Figure 1 As shown, the first liquid treatment device 130 may include a heating and shaking unit 132 , a centrifugal unit 134 , and an acoustic wave liquid treatment unit 136 .

[0028] Regarding the heating and shaking unit 132, it is used to perform heating and shaking operations on the compounds contained in the compound plate. In some embodiments, the heating and shaking unit 132 can be composed of a separate heating unit and an shaking unit, which is not limited here.

[0029] The centrifugal unit 134 is used to perform centrifugal operation on the compounds in the compound plate. In some embodiments, the centrifugal unit 134 can be an automated centrifuge.

[0030] The sonic liquid handling unit 136 is used to transfer the centrifuged compounds from the compound plate to the test plate by sonication. In some embodiments, the sonic liquid handling unit 136 may be an Echo sonic liquid handling system.

[0031] The second liquid processing device 140 is configured to process the liquid to be tested contained in the test plate based on the instruction of the control device 110, so as to transfer the processed liquid to be tested to the test platform for testing. Figure 1 As shown, the second liquid processing device 140 may include a first liquid adding unit 142 , a second liquid adding unit 144 , and a cell culture unit 146 .

[0032] The first liquid adding unit 142 is used to add cell-free culture medium and cell activity detection reagent to the test plate. In some embodiments, the first liquid adding unit 142 can be a plate washer, such as an EL406 plate washer.

[0033] The second liquid adding unit 144 is used to add cell suspension to the test plate. In some embodiments, the second liquid adding unit 144 can be an automated liquid handling station, such as a Hamilton automated liquid handling station.

[0034] The cell culture unit 146 is used to perform incubation operations on the test plate. In some embodiments, the cell culture unit 146 may be a fully automatic cell culture incubator, such as a Cytomat fully automatic cell culture incubator.

[0035] Regarding the robot arm 120, it is configured to transfer the compound plate or the test plate based on the instruction of the control device 110. For example, the robot arm 120 can be configured to transfer the compound plate, the test plate, etc. between various units based on the instruction of the control device 110.

[0036] Regarding the control device 110, it is used to perform the steps of the method for high-throughput compound screening. Specifically, the control device 110 is used to control the mechanical arm 120 to transfer the compound plate in the first liquid treatment device 130 to treat the compound contained in the compound plate, and transfer the treated compound from the compound plate to the test plate. The control device 110 is also used to control the mechanical arm 120 to transfer the test plate in the second liquid treatment device 140 to treat the test plate so that the test plate is equipped with a test liquid that can be used for cell activity detection to achieve compound screening. In some embodiments, the control device 110 may have one or more processing units, including dedicated processing units such as GPU, FPGA and ASIC, and general processing units such as CPU. In addition, one or more virtual machines may also be running on each computing device. In some other embodiments, the control device 110 may also be used to receive error information of each unit in the system 100 (such as heating and shaking unit 132, centrifugal unit 134, acoustic liquid treatment unit 136, first liquid addition unit 142, second liquid addition unit 144, cell culture unit 146, etc.).

[0037] In some embodiments, Figure 1 As shown, the system 100 further includes a temporary storage unit 150 , a consumable material stacking unit 160 , a track 170 and an input / output unit 180 .

[0038] The temporary storage unit 150 is used to temporarily store a compound plate containing a compound and a test plate containing a liquid to be tested. In some embodiments, the temporary storage unit 150 may be a temporary plate storage rack.

[0039] Regarding the consumable material stacking unit 160 , it is used to store empty test plates.

[0040] Regarding the track 170 , it is used to assist the movement of the robot arm 120 in the system 100 .

[0041] Regarding the input-output unit 180 , it is used to receive the compound plate from outside the system 100 , and to transfer the test plate containing the test liquid, so as to perform cell activity detection on the test liquid contained in the test plate.

[0042] Further references Figure 1 , Figure 1 The positional relationship between various processing devices and / or units in the system 100 for high-throughput compound screening is exemplarily shown.

[0043] In some embodiments, the heating and oscillating unit 132, the centrifugal unit 134, and the acoustic wave liquid treatment unit 136 in the first liquid treatment device 130 may be located on different sides of the track 170. For example, the centrifugal unit 134 is located on one side of the track 170; the heating and oscillating unit 132 and the acoustic wave liquid treatment unit 136 are located on the other side of the track 170, and the acoustic wave liquid treatment unit 136 is farther away from the input and output unit 180 than the heating and oscillating unit 132.

[0044] In some embodiments, the first liquid addition unit 142, the second liquid addition unit 144, and the cell culture unit 146 in the second liquid processing device 140 may be located on different sides of the track 170. For example, the first liquid addition unit 142 is located on one side of the track 170, the second liquid addition unit 144 and the cell culture unit 146 are located on the other side of the track 170, and the second liquid addition unit 144 is closer to the input / output unit 180 than the cell culture unit 146.

[0045] In one example, the second liquid addition unit 144, the centrifugal unit 134, and the cell culture unit 146 are located on a first side of the track 170 and are arranged in sequence from near to far from the input-output unit 180. The first liquid addition unit 142, the heating and oscillation unit 132, and the sonic liquid treatment unit 136 are located on a second side of the track 170 and are arranged in sequence from near to far from the input-output unit 180.

[0046] In some embodiments, the temporary storage unit 150 is disposed between the track 180 and the second liquid adding unit 144 .

[0047] In some embodiments, the consumables stacking unit 160 is located on the same side of the track 170 as the first liquid adding unit 142. For example, the consumables stacking unit 160 may be arranged at a position farther from the track 170 than the first liquid adding unit 142.

[0048] By arranging the units to have the above-mentioned positional relationship, multiple units for compound screening can be better integrated into one system (e.g., Figure 1 In the system 100 of high-throughput compound screening, the movement range of the robot arm can be shortened, thereby more efficiently performing compound screening. It should be understood by those skilled in the art that the units in the system 100 may also have other positional relationships according to the adjustment of the steps of the method for high-throughput compound screening.

[0049] The following will be combined Figure 2 and Figure 3 A high-throughput compound screening method according to an embodiment of the present invention is described. Figure 2200 is a flow chart of a method 200 for high-throughput compound screening according to an embodiment of the present invention. It should be understood that the method 200 can be, for example, Figure 4 The electronic device 400 described above is executed. Figure 1 The method 200 is executed at the control device 110. It should be understood that the method 200 may further include additional actions not shown and / or may omit the actions shown, and the scope of the present invention is not limited in this respect.

[0050] At step 210 , the control device 110 controls the robot arm 120 to transfer the compound plate in the first liquid handling device 130 to process the compounds contained in the compound plate and transfer the processed compounds from the compound plate to the test plate.

[0051] Regarding the transfer in the first liquid treatment device 130, it includes transfer between the heating and shaking unit 132, the centrifugal unit 134 and the acoustic wave liquid treatment unit 136. For example, the control device 110 controls the robot 120 to transfer the compound plate to the heating and shaking unit 132, then controls the robot 120 to transfer the compound plate from the heating and shaking unit 132 to the centrifugal unit 134, and then controls the robot 120 to transfer the compound plate from the centrifugal unit 134 to the acoustic wave liquid treatment unit 136.

[0052] Regarding the treatment of the compounds in the compound plate, it can be heating, shaking, centrifuging, etc. Figure 3 The detailed description will not be repeated here.

[0053] At step 220 , the control device 110 controls the robot arm 120 to transfer the test plate in the second liquid processing device 140 to process the test plate so that the test plate is filled with the test liquid that can be used for cell activity detection.

[0054] Regarding the transfer in the second liquid processing device 140, it includes the transfer between the first liquid adding unit 142, the second liquid adding unit 144 and the cell culture unit 146. For example, the control device 110 controls the robot 120 to transfer the test plate to the first liquid adding unit 142, then controls the robot 120 to transfer the test plate from the first liquid adding unit 142 to the second liquid adding unit 144, then controls the robot 120 to transfer the test plate from the second liquid adding unit 144 to the cell culture unit 146, and then controls the robot 120 to transfer the test plate from the cell culture unit 146 to the first liquid adding unit 142.

[0055] Regarding the treatment of the test plate, it may include adding a cell-free culture medium, a cell suspension, a cell activity detection reagent, etc. to the test plate, and it may also include incubating the test plate. Figure 3 The detailed description will not be repeated here.

[0056] In some embodiments, the method 200 for high-throughput compound screening may further include: before step 210 , the control device 110 controls the robot arm 120 to receive the compound plate from the input-output unit 180 and transfer the compound plate to the first liquid handling device 130 .

[0057] Regarding receiving the compound plate from the input / output unit 180 , the compound plate received from the input / output unit 180 may be first transferred to the temporary storage unit 150 , so as to control the robot arm 120 to transfer the compound plate from the temporary storage unit 150 to the first liquid processing device 130 at an appropriate time.

[0058] In some other embodiments, the method 200 for high-throughput compound screening may further include: after step 220, the control device 110 controls the robotic arm 120 to transfer the test plate to the input-output unit 180, so that the test plate can be transferred to the test platform for performing cell activity detection on the test liquid contained in the test plate.

[0059] Regarding transferring the test plate to the input-output unit 180, the test plate may be first transferred to the heating and oscillating unit 132, and then transferred from the heating and oscillating unit 132 to the input-output unit 180. For example, the control device 110 controls the robot 120 to transfer the test plate from the first liquid adding unit 142 to the oscillating unit in the heating and oscillating unit 132, and then controls the robot 120 to transfer the test plate from the oscillating unit to the input-output unit 180.

[0060] The method 200 for high-throughput compound screening according to an embodiment of the present disclosure further integrates artificial intelligence technology into the process of compound screening, that is, before performing high-throughput compound screening, the compounds are pre-screened by artificial intelligence technology to narrow the scope of the compounds to be screened, thereby reducing the cost and time of compound screening. For example, the compounds can be pre-screened in conjunction with a compound database through, for example, an artificial intelligence model, so as to first narrow the scope of the compounds to be screened based on, for example, the properties of the compounds. In some embodiments, machine learning models such as reinforcement models, regression models, generative models, etc., or deep learning models such as convolutional neural networks, recursive neural networks, etc., can be used to pre-screen compounds with desired chemical structures based on active sites, structures, and target binding capabilities. The following will be combined with Figure 3A method 300 for processing a test plate for a compound contained in a compound plate according to an embodiment of the present invention is described.

[0061] Figure 3 FIG. 3 is a flow chart showing a method 300 for processing a compound contained in a compound plate and a test plate according to an embodiment of the present invention. It should be understood that the method 300 can be implemented in Figure 4 The electronic device 400 described above is executed. Figure 1 The method 300 is executed at the control device 110. It should be understood that the method 300 may also include additional actions not shown and / or may omit the actions shown, and the scope of the present invention is not limited in this respect.

[0062] At step 302 , the control device 110 controls the robot arm 120 to transfer the compound plate to the heating and shaking unit 132 to perform heating and shaking operations on the compounds contained in the compound plate so as to completely dissolve the compounds to form uniform compounds.

[0063] In step 304 , the control device 110 controls the robot arm 120 to transfer the compound plate that has undergone the heating and shaking operations to the centrifugation unit 134 , so as to perform a centrifugation operation on the homogenized compounds in the compound plate.

[0064] Regarding centrifugation of the homogenized compounds in the compound plate, the centrifugation unit 134, such as an automated centrifuge, can cause the homogenized compounds in the compound plate to settle to the bottom of the compound plate by centrifugation, so as to facilitate the transfer of the compounds from the compound plate to the test plate later.

[0065] At step 306 , the control device 110 controls the robot arm 120 to transfer the centrifuged compound plate to the acoustic wave liquid handling unit 136 , so as to transfer the centrifuged compounds from the compound plate to the test plate by acoustic waves.

[0066] Regarding transferring the centrifuged compounds from the compound plate to the test plate by sound waves, for example, an acoustic liquid handling unit 136, such as an Echo acoustic liquid handling system, uses ultrasonic energy to transfer the compounds that have settled to the bottom of the compound plate from the compound plate to a designated test plate in the form of droplets.

[0067] In some embodiments, the control device 110 further controls the robot 120 to grab an available empty test plate from the consumables stacking unit 160 and transfer the empty test plate to the acoustic liquid processing unit 136. For example, after the control device 110 controls the robot 120 to transfer the compound plate subjected to centrifugal operation to the acoustic liquid processing unit 136, the control device 110 controls the robot 120 to grab an available empty test plate from the consumables stacking unit 160 and transfer it to the acoustic liquid processing unit 136, so that the compound is transferred from the compound plate to the test plate in the acoustic liquid processing unit 136. In other embodiments, the control device 110 may first control the robot 120 to transfer the empty test plate to the acoustic liquid processing unit 136, and then control the robot 120 to transfer the compound plate subjected to centrifugal operation to the acoustic liquid processing unit 136.

[0068] When the compound is transferred from the compound plate to the test plate in the acoustic liquid handling unit 136 , at step 308 , the control device 110 controls the robot 120 to transfer the test plate to the first liquid adding unit 142 to add cell-free culture medium to the first designated position of the test plate.

[0069] Regarding the test plate, it can include a few different concentration gradients of multiple compounds, for example, in an example test plate, it includes 2 different concentration gradients of 70 compounds (such as 10 μM and 100 μM). In some other embodiments, the test plate can include more different concentration gradients of fewer compounds, for example, 9 different concentration gradients of 14 compounds (10 μM starting, 3-fold dilution) in an example test plate, for activity detection of active compounds based on different cell types.

[0070] Regarding transferring the test plate to the first liquid addition unit 142, for example, the control device 110 controls the robot arm 120 to transfer the test plate containing the compound from the acoustic liquid handling unit 136 (such as the Echo acoustic liquid handling system) to the first liquid addition unit 142, such as the EL406 plate washer.

[0071] Regarding adding the cell-free culture medium to the first designated position of the test plate, it can be that the first liquid adding unit 142 (such as EL406 plate washer) adds the cell-free culture medium to specific columns of the test plate to serve as a cell-free negative control group. For example, the EL406 plate washer adds the cell-free culture medium to, for example, the first column and the last column of the test plate through a pressure pump.

[0072] At step 310 , the control device 110 controls the robot arm 120 to transfer the test plate to which the culture medium has been added to the second liquid adding unit 144 , so as to add the cell suspension to a second designated position of the test plate.

[0073] Regarding the cell suspension, it can be a cell suspension of a single cell type. In some other embodiments, the cell suspension can be a cell suspension of different types for use in the activity detection of active compounds based on different cell types. In some embodiments, the cell suspension can be prepared in an additional cell culture module, for example, in a cell culture module such as Figure 1 The system 100 shown is prepared in a fully automated cell culture module connected via rails.

[0074] Regarding adding the cell suspension to the second designated position of the test plate, it can be that the second liquid adding unit 144 (such as the Halmiton automated liquid workstation) adds the cell suspension to the columns of the test plate to which the culture medium without cells is not added. In the above example, the Halmiton automated liquid workstation adds the cell suspension to the remaining columns of the test plate except the first column and the last column.

[0075] Regarding adding the cell suspension, for example, the control device 110 controls the robot 120 to transfer the cell suspension from the additional cell culture module to the second liquid addition unit 144 (such as a Halmiton automated liquid workstation). For example, the control device 110 controls the robot 120 to transfer the cell suspension from the additional cell culture module connected to the system 100 via a guide rail to the Halmiton automated liquid workstation.

[0076] By adopting the above means, the present invention can realize the automated processing and transfer of the compounds to be screened, including automatic compound loading, cell sample preparation, etc., through the automated interaction between the robot arm and each device (or equipment, unit), thereby reducing the time and labor costs in compound processing and transfer, making it possible to screen large-scale compounds within a fixed time, increasing the number of compounds that can be screened within a fixed time and the batches of compounds that can be screened within a fixed time, thereby improving the efficiency of compound processing. At the same time, the differences between the processing of different batches of compounds (for example, compounds contained in different compound plates) are also reduced, thereby improving the uniformity and accuracy of the experiment.

[0077] Back to Figure 3 After adding the cell-free culture medium to the first designated position of the test plate and adding the cell suspension to the second designated position of the test plate, at step 312, the control device 110 controls the robot arm 120 to transfer the test plate with the added cell suspension to the cell culture unit 146 for incubation operation on the test plate.

[0078] Regarding the incubation operation for the test plate, the incubation operation may be performed on the test plate to which the compound to which the cell-free culture medium is added and the compound to which the cell suspension is added.

[0079] As for the time of the incubation operation, it may be, for example, 3 days.

[0080] After the incubation operation is finished, at step 314 , the control device 110 controls the robot arm 120 to transfer the test plate that has undergone the incubation operation to the first liquid adding unit 130 , so as to add a cell activity detection reagent to the test plate.

[0081] Regarding transferring the test plate that has undergone the incubation operation to the first liquid addition unit 130, for example, the control device 110 controls the robot arm 120 to take out the test plate that has undergone the incubation operation from the cell culture unit 146 (such as a fully automatic cell culture incubator), and transfer it to the first liquid addition unit 142 (such as an EL406 plate washer), so that the test plate is allowed to stand in the first liquid addition unit 142 for 30 minutes until it returns to room temperature.

[0082] Regarding the cell activity detection reagent, it is, for example, CellTiter-Glo cell activity detection reagent (i.e., CTG reagent). In some embodiments, the cell activity detection reagent is pre-configured in the first liquid addition unit 130, and the cell activity detection reagent is added to the test plate restored to room temperature by the first liquid addition unit 130. For example, the EL406 plate washer adds the configured cell activity detection reagent CTG reagent to the test plate.

[0083] At step 316 , the control device 110 controls the robot arm 120 to transfer the test plate to which the cell activity detection reagent is added to the oscillation unit to perform an oscillation operation on the test plate.

[0084] Regarding the shaking unit, it is, for example, a part of the heating and shaking unit 132 for performing shaking operation.

[0085] At step 318 , the control device 110 controls the robot 120 to transfer the test plate after the oscillation operation to the input-output unit 180 , so that the test plate can be transferred to the test platform for performing cell activity detection on the test liquid contained in the test plate.

[0086] Regarding transferring the test plate that has undergone the oscillation operation to the input-output unit 180, for example, the control device 110 controls the robot arm 120 to first transfer the test plate that has undergone the oscillation operation to the temporary storage unit 150, and then transfers the test plate from the temporary storage unit 150 to the input-output unit 180 at an appropriate time, so that, for example, the automatic navigation vehicle can transfer the test plate containing the liquid to be tested to the test platform for cell activity detection.

[0087] By adopting the above means, the present invention can significantly improve the automation level of the entire compound screening process, reduce labor costs and time costs, and reduce experimental errors caused by human factors, thereby improving the repeatability and accuracy of the compound screening experiment. In addition, the improvement of the automation level of the entire compound screening process can significantly improve the throughput and accuracy of compound screening.

[0088] The following will be combined Figure 1 , 2 and 3 describe a method for high-throughput compound screening according to an embodiment of the present invention.

[0089] In the first step, the control device 110 controls the robot arm 120 to receive a compound plate containing compounds to be screened from the input and output unit 180 .

[0090] In the second step, the control device 110 controls the robot arm 120 to transfer the compound plate containing the compounds to be screened to the heating and shaking unit 132 via the guide rail 170 to perform heating and shaking operations on the compounds contained in the compound plate so that the compounds are completely dissolved to form a uniform compound.

[0091] In the third step, the control device 110 controls the robot arm 120 to transfer the compound plate that has undergone heating and shaking operations from the heating and shaking unit 132 to the centrifugal unit 134, so as to perform centrifugal operations on the homogenized compounds in the compound plate, so that the homogenized compounds in the compound plate are settled to the bottom of the compound plate.

[0092] In the fourth step, the control device 110 controls the robot arm 120 to transfer the compound plate subjected to the centrifugation operation from the centrifugation unit 134 to the sonic liquid treatment unit 136 .

[0093] In the fifth step, the control device 110 controls the robot arm 120 to grab an available empty test plate from the consumables stacking unit 160 and transfer the empty test plate to the acoustic wave liquid processing unit 136 .

[0094] In the sixth step, the control device 110 controls the acoustic liquid processing unit 136 to transfer the compounds that have settled to the bottom of the compound plate from the compound plate to the designated test plate in the form of droplets through ultrasonic energy, and makes the test plate include a small number of different concentration gradients of multiple compounds (for example, including 2 different concentration gradients of 70 compounds).

[0095] In the seventh step, the control device 110 controls the robot 120 to transfer the test plate containing the compound to the first liquid adding unit 142. The control device 110 then controls the first liquid adding unit 142 to add culture medium without cells to the first column and the last column of the test plate as a negative control group.

[0096] In the eighth step, the control device 110 controls the robot arm 120 to transfer the test plate to which the culture medium has been added from the first liquid adding unit 142 to the second liquid adding unit 144 .

[0097] In the ninth step, the control device 110 controls the robot 120 to transfer the cell suspension having a single cell type to the second liquid adding unit 144. The control device 110 then controls the second liquid adding unit 144 to add the cell suspension to the remaining columns of the test plate except the first column and the last column, that is, the control device 110 controls the second liquid adding unit 144 to complete the step of cell loading.

[0098] In the tenth step, the control device 110 controls the robot arm 120 to transfer the test plate with the added cell suspension to the cell culture unit 146 for a 3-day incubation operation.

[0099] In the eleventh step, after the incubation is completed, the control device 110 controls the robot arm 120 to take out the test plate that has undergone the incubation operation from the cell culture unit 146 and transfer it to the first liquid addition unit 130, so that the test plate is allowed to stand in the first liquid addition unit 142 for 30 minutes until it returns to room temperature.

[0100] In the twelfth step, the control device 110 controls the first liquid adding unit 142 to add the configured cell activity detection reagent (ie, CTG reagent) into the test plate that has been restored to room temperature.

[0101] In the thirteenth step, the control device 110 controls the robot 120 to transfer the test plate to which the cell activity detection reagent is added from the first liquid adding unit 142 to the shaking unit in the heating and shaking unit 132. The control device 110 then controls the shaking unit to shake the test plate to which the cell activity detection reagent is added.

[0102] In the fourteenth step, the control device 110 controls the robot arm 120 to transfer the test board that has undergone the oscillation operation from the oscillation unit to the input-output unit 180 .

[0103] After completing the above steps, optionally, the control device 110 can control the automatic navigation vehicle to transfer the test plate containing the test liquid that has been shaken from the input and output unit 180 to the test platform to perform cell activity detection on the test liquid in the test plate.

[0104] By adopting the above-mentioned means, the present disclosure can realize high-throughput compound screening and significantly improve the efficiency and automation of the entire compound screening process.

[0105] According to other embodiments of the present disclosure, it can also be used for activity detection of active compounds based on different cell types. Figure 1 , 2 and 3 describe a method for activity detection of active compounds based on different cell types according to an embodiment of the present invention.

[0106] In the first step, the control device 110 controls the robot arm 120 to receive the compound plate containing the active compound from the input and output unit 180 .

[0107] In the second step, the control device 110 controls the robot arm 120 to transfer the compound plate containing the compounds to be screened to the heating and shaking unit 132 via the guide rail 170 to perform heating and shaking operations on the compounds contained in the compound plate so that the compounds are completely dissolved to form a uniform compound.

[0108] In the third step, the control device 110 controls the robot arm 120 to transfer the compound plate that has undergone heating and shaking operations from the heating and shaking unit 132 to the centrifugation unit 134 (e.g., an automated centrifuge) to perform centrifugation operations on the homogenized compounds in the compound plate so that the homogenized compounds in the compound plate settle to the bottom of the compound plate.

[0109] In the fourth step, the control device 110 controls the robot arm 120 to transfer the compound plate subjected to the centrifugation operation from the centrifugation unit 134 to the sonic liquid treatment unit 136 .

[0110] In the fifth step, the control device 110 controls the robot arm 120 to grab an available empty test plate from the consumables stacking unit 160 and transfer the empty test plate to the acoustic wave liquid processing unit 136 .

[0111] In the sixth step, the control device 110 controls the acoustic liquid processing unit 136 to transfer the compounds that have settled to the bottom of the compound plate from the compound plate to the designated test plate in the form of droplets through ultrasonic energy, and makes the test plate include multiple different concentration gradients of fewer compounds (for example, including 9 different concentration gradients of 14 compounds).

[0112] In the seventh step, the control device 110 controls the robot 120 to transfer the test plate containing the compound to the first liquid adding unit 142. The control device 110 then controls the first liquid adding unit 142 to add culture medium without cells to the first column and the last column of the test plate as a negative control group.

[0113] In the eighth step, the control device 110 controls the robot arm 120 to transfer the test plate to which the culture medium has been added from the first liquid adding unit 142 to the second liquid adding unit 144 .

[0114] In the ninth step, the control device 110 controls the robot 120 to transfer the cell suspensions with different cell types to the second liquid adding unit 144. The control device 110 then controls the second liquid adding unit 144 to add the cell suspensions to the remaining columns of the test plate except the first column and the last column, that is, the control device 110 controls the second liquid adding unit 144 to complete the step of cell loading.

[0115] In the tenth step, the control device 110 controls the robot arm 120 to transfer the test plate with the added cell suspension to the cell culture unit 146 for a 3-day incubation operation.

[0116] In the eleventh step, after the incubation is completed, the control device 110 controls the robot arm 120 to take out the test plate that has undergone the incubation operation from the cell culture unit 146 and transfer it to the first liquid addition unit 130, so that the test plate is allowed to stand in the first liquid addition unit 142 for 30 minutes until it returns to room temperature.

[0117] In the twelfth step, the control device 110 controls the first liquid adding unit 142 to add the configured cell activity detection reagent (ie, CTG reagent) into the test plate that has been restored to room temperature.

[0118] In the thirteenth step, the control device 110 controls the robot 120 to transfer the test plate to which the cell activity detection reagent is added from the first liquid adding unit 142 to the shaking unit in the heating and shaking unit 132. The control device 110 then controls the shaking unit to shake the test plate to which the cell activity detection reagent is added.

[0119] In the fourteenth step, the control device 110 controls the robot arm 120 to transfer the test board that has undergone the oscillation operation from the oscillation unit to the input-output unit 180 .

[0120] After completing the above steps, optionally, the control device 110 can control the automatic navigation vehicle to transfer the test plate containing the test liquid that has been shaken from the input and output unit 180 to the test platform to perform cell activity detection on the test liquid in the test plate.

[0121] By adopting the above-mentioned means, the present disclosure can also realize the activity detection of active compounds based on different cell types, while significantly improving the efficiency and automation of the entire activity detection process.

[0122] Figure 4 The electronic device 400 is schematically shown as a schematic diagram suitable for implementing the embodiment of the present invention. The electronic device 400 may be used to implement the execution Figures 2 to 3 The apparatus of the method 200 to 300 is shown. Figure 4As shown, the electronic device 400 includes a central processing unit (CPU) 401, which can perform various appropriate actions and processes according to computer program instructions stored in a read-only memory (ROM) 402 or computer program instructions loaded from a storage unit 408 into a random access memory (RAM) 403. In the RAM, various programs and data required for the operation of the electronic device 400 can also be stored. The CPU, ROM, and RAM are connected to each other via a bus 404. An input / output (I / O) interface 405 is also connected to the bus 404.

[0123] Multiple components in the electronic device 400 are connected to the I / O interface, including: an input unit 406, an output unit 409, a storage unit 408, and a central processing unit (CPU) performs the various methods and processes described above, such as executing method 200 and method 300. For example, in some embodiments, method 200 and method 300 can be implemented as a computer software program, which is stored in a machine-readable medium, such as storage unit 408. In some embodiments, part or all of the computer program can be loaded and / or installed on the electronic device 400 via ROM and / or communication unit 409. When the computer program is loaded into RAM and executed by CPU 401, one or more operations of method 200 and method 300 described above can be performed. Alternatively, in other embodiments, the CPU can be configured to perform one or more actions of method 200 and method 300 in any other appropriate manner (for example, by means of firmware).

[0124] It should be further noted that the present invention may be a method, an apparatus, a system and / or a computer program product. The computer program product may include a computer-readable storage medium carrying computer-readable program instructions for executing various aspects of the present invention.

[0125] Computer readable storage medium can be a tangible device that can hold and store instructions used by an instruction execution device. Computer readable storage medium can be, for example, but not limited to, an electrical storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination thereof. More specific examples (non-exhaustive list) of computer readable storage medium include: a portable computer disk, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), a static random access memory (SRAM), a portable compact disk read-only memory (CD-ROM), a digital versatile disk (DVD), a memory stick, a floppy disk, a mechanical encoding device, for example, a punch card or a convex structure in a groove on which instructions are stored, and any suitable combination thereof. The computer readable storage medium used here is not interpreted as a transient signal itself, such as a radio wave or other freely propagating electromagnetic wave, an electromagnetic wave propagated by a waveguide or other transmission medium (for example, a light pulse by an optical fiber cable), or an electrical signal transmitted by a wire.

[0126] The computer-readable program instructions described herein can be downloaded from a computer-readable storage medium to each computing / processing device, or downloaded to an external computer or external storage device via a network, such as the Internet, a local area network, a wide area network, and / or a wireless network. The network can include copper transmission cables, optical fiber transmissions, wireless transmissions, routers, firewalls, switches, gateway computers, and / or edge servers. The network adapter card or network interface in each computing / processing device receives the computer-readable program instructions from the network and forwards the computer-readable program instructions for storage in the computer-readable storage medium in each computing / processing device.

[0127] The computer program instructions for performing the operation of the present invention may be assembly instructions, instruction set architecture (ISA) instructions, machine instructions, machine-dependent instructions, microcode, firmware instructions, state setting data, or source code or object code written in any combination of one or more programming languages, including object-oriented programming languages, such as Smalltalk, C++, etc., and conventional procedural programming languages, such as "C" language or similar programming languages. Computer-readable program instructions may be executed entirely on a user's computer, partially on a user's computer, as an independent software package, partially on a user's computer, partially on a remote computer, or entirely on a remote computer or server. In the case of a remote computer, the remote computer may be connected to the user's computer via any type of network, including a local area network (LAN) or a wide area network (WAN), or may be connected to an external computer (e.g., using an Internet service provider to connect via the Internet). In some embodiments, an electronic circuit, such as a programmable logic circuit, a field programmable gate array (FPGA), or a programmable logic array (PLA), may be personalized by utilizing the state information of the computer-readable program instructions, and the electronic circuit may execute the computer-readable program instructions, thereby realizing various aspects of the present invention.

[0128] Here, various aspects of the present invention are described with reference to the flow chart and / or step diagram of the method, device (system), and computer program product according to an embodiment of the present invention. It should be understood that each side step of the flow chart and / or step diagram and the combination of the side steps in the flow chart and / or step diagram can be implemented by computer-readable program instructions.

[0129] These computer-readable program instructions can be provided to a processor in a voice interaction device, a general-purpose computer, a special-purpose computer, or a processing unit of other programmable data processing devices, thereby producing a machine, so that when these instructions are executed by a processing unit of a computer or other programmable data processing device, a device that implements the functions / actions specified in one or more steps in a flowchart and / or a step diagram is generated. These computer-readable program instructions can also be stored in a computer-readable storage medium, and these instructions enable a computer, a programmable data processing device, and / or other devices to work in a specific manner, so that a computer-readable medium storing instructions includes a manufactured product, which includes instructions for implementing various aspects of the functions / actions specified in one or more steps in a flowchart and / or a step diagram.

[0130] Computer-readable program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other device so that a series of operating steps are performed on the computer, other programmable data processing apparatus, or other device to produce a computer-implemented process, thereby causing the instructions executed on the computer, other programmable data processing apparatus, or other device to implement the functions / actions specified in one or more steps in the flowchart and / or step diagram.

[0131] The flow chart and step diagram in the accompanying drawings show the possible architecture, functions and operations of the equipment, methods and computer program products according to multiple embodiments of the present invention. In this regard, each square step in the flow chart or step diagram can represent a part of a module, program segment or instruction, and a part of the module, program segment or instruction contains one or more executable instructions for realizing the specified logical function. In some alternative implementations, the functions marked in the steps can also occur in an order different from that marked in the accompanying drawings. For example, two consecutive square steps can actually be executed substantially in parallel, and they can sometimes be executed in the opposite order, depending on the functions involved. It should also be noted that each square step in the step diagram and / or flow chart, and the combination of square steps in the step diagram and / or flow chart can be implemented with a dedicated hardware-based system that performs a specified function or action, or can be implemented with a combination of dedicated hardware and computer instructions.

[0132] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or technical improvements in the market, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

[0133] The above are only optional embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for high-throughput compound screening, comprising: At the control device, controlling the robot arm to transfer the compound plate in the first liquid handling device to process the compounds contained in the compound plate, and transferring the processed compounds from the compound plate to the test plate; as well as The robot arm is controlled to transfer the test plate in the second liquid processing device to process the test plate, so that the test plate is filled with a test liquid that can be used for cell activity detection to achieve compound screening.

2. The method according to claim 1, wherein: The first liquid treatment device comprises: a heating and oscillation unit, a centrifugal unit, and an acoustic liquid treatment unit; The second liquid processing device includes: a first liquid adding unit, a second liquid adding unit, and a cell culture unit.

3. The method according to claim 2, wherein: The processing of the compound contained in the compound plate includes: Controlling the robot arm to transfer the compound plate to the heating and shaking unit to perform heating and shaking operations on the compound contained in the compound plate, so as to completely dissolve the compound to form a uniform compound; Controlling the robot arm to transfer the compound plate that has been subjected to the heating and shaking operations to the centrifugal unit, so as to perform a centrifugal operation on the homogenized compounds in the compound plate; The robot arm is controlled to transfer the compound plate subjected to the centrifugation operation to the acoustic wave liquid handling unit, so as to transfer the centrifuged compound from the compound plate to the test plate by acoustic waves.

4. The method according to claim 2, wherein: The processing for the test board includes: controlling the robot arm to transfer the test plate to the first liquid adding unit to add a culture medium without cells to a first designated position of the test plate; Controlling the robot arm to transfer the test plate to which the culture medium is added to the second liquid adding unit, so as to add the cell suspension to a second designated position of the test plate; Controlling the robot arm to transfer the test plate to which the cell suspension is added to the cell culture unit, so as to perform an incubation operation on the test plate; The robot arm is controlled to transfer the test plate that has undergone the incubation operation to the first liquid adding unit, so as to add a cell activity detection reagent to the test plate.

5. The method according to claim 4, further comprising: Controlling the robot arm to transfer the test plate to which the cell activity detection reagent is added to the oscillation unit to perform an oscillation operation on the test plate; The robot arm is controlled to transfer the test plate that has been vibrated to the input-output unit, so that the test plate can be transferred to the test platform, so as to perform cell activity detection on the liquid to be tested contained in the test plate.

6. The method according to claim 1, further comprising: The robot arm is controlled to receive the compound plate from the input and output unit, and transfer the compound plate to the first liquid processing device.

7. A system for high-throughput compound screening, comprising: A first liquid handling device, configured to process the compound contained in the compound plate and transfer the processed compound from the compound plate to the test plate based on the instruction of the control device; The second liquid processing device is configured to process the liquid to be tested contained in the test plate based on the instruction of the control device, so as to transfer the processed liquid to be tested to the test platform for testing; a robotic arm configured to transfer a compound plate or a test plate based on an instruction of a control device; as well as A control device, configured to execute the steps of the method according to any one of claims 1 to 6.

8. The system according to claim 7, wherein: The first liquid processing device comprises: A heating and shaking unit, used for heating and shaking the compound contained in the compound plate; A centrifugal unit, used for performing a centrifugal operation on the compounds in the compound plate; The sonic liquid handling unit is used to transfer the centrifuged compounds from the compound plate to the test plate by sonication.

9. The system according to claim 7, wherein: The second liquid treatment device comprises: A first liquid adding unit, used for adding a cell-free culture medium and a cell activity detection reagent to the test plate; A second liquid adding unit, used for adding cell suspension to the test plate; The cell culture unit is used to perform an incubation operation on the test plate.

10. The system according to claim 7, further comprising: A temporary storage unit, used for temporarily storing a compound plate containing a compound and a test plate containing a liquid to be tested; Consumables stacking unit for storing empty test plates; A track is used to assist the movement of the robotic arm.

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