CN111398613B - Automatic liquid transferring system and control method thereof - Google Patents
Automatic liquid transferring system and control method thereof Download PDFInfo
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Abstract
The invention discloses an automatic liquid transfer system, which comprises a cell culture box, a liquid preparation and transfer operation device and an automatic arrangement device for a gun head, wherein a hollow cylindrical upper and lower multi-layer circular platform component is arranged in the cell culture box and used for placing a cell culture plate; a rotary robot which is arranged at the hollow position of the circular platform component and takes and delivers the cell culture plate by moving up and down and rotating in the horizontal plane; the automatic gun head arranging device arranges disordered gun heads into a gun head array by using vibration and steric hindrance; the liquid preparation and pipetting operation device comprises a pipetting gun or a pipetting gun array, the pipette head array finished by the automatic pipette head finishing device is assembled and taken, and the pipetting operation or the liquid adding operation is carried out on the pipetting operation platform for the cell culture plate transmitted from the cell culture box. The present invention enables automated cell inoculation, culture medium replacement, addition of regulatory factors or lead compounds, automatic storage of cell culture plates, and the like.
Description
Technical Field
The invention relates to the technical field of life science, in particular to an automatic liquid transferring system for cell culture and a control method thereof.
Background
Gene function research and drug lead compound screening based on cell level are two important links in the basic research of life science and the drug research and development process, and regulating factors or small molecule compounds with different concentrations are required to be added into cell culture solution, and then the physiological state and the function of cells are detected. The above studies all involve the steps of large-scale culture of cells, addition of small molecule compounds at different concentrations to the cultured cells, and detection of the influence of the added compounds on the cells. Under the current situation, most laboratories at home and abroad mainly complete the processes by means of small-sized equipment, such as pipettors, electrophoresis apparatuses, centrifuges, PCR apparatuses and the like. These devices provide material support for the development of many experiments, but most of the devices can only be used as tools or semi-automatic devices, the operation of which usually requires the participation of researchers in the whole process and can only be completed in one or more links in a complete experimental process, so that the cost of the experimenters, the experimental efficiency, the stability of experimental results and other aspects have great problems, and errors or mistakes are easily caused by factors such as experimental methods and technical stability among the researchers. Especially in the research and development of new drugs, most basic research laboratories related to life science cannot bear the labor input pressure brought by repeated cell culture and compound screening work, so that few laboratories relate to the research work related to drug lead compound screening.
How to make the research flow more standardized and automated is not only a main problem related to research cost and efficiency, but also a key factor for promoting life health related research and rapid discovery of product research and development.
Although many of the screening of lead compounds at the pharmaceutical enterprise level of pharmaceutical companies and the like rely on mechanical operations, no equipment is available for fully automatically performing operations such as cell culture with high throughput, changing of liquid, addition of different compounds to different culture wells, and further functional detection on a microplate, by using instruments, automated culture of cells, or detection of cultured cells.
Disclosure of Invention
In view of the above, the present invention has been developed to provide a solution that overcomes, or at least partially solves, the above-mentioned problems. Therefore, the temperature of the molten metal is controlled,
the invention provides an automatic liquid transfer system, which comprises a cell culture box, a liquid preparation and transfer operation device and a gun head automatic arrangement device, wherein a hollow cylindrical upper and lower multi-layer circular platform component is arranged in the cell culture box and used for placing a cell culture plate; a rotary robot which is arranged at the hollow position of the circular platform component and takes and delivers the cell culture plate by moving up and down and rotating in the horizontal plane; the automatic gun head arranging device arranges disordered gun heads into a gun head array by using vibration and steric hindrance; the liquid preparation and pipetting operation device comprises a pipetting gun or a pipetting gun array, the gun head array finished by the automatic gun head finishing device is assembled and taken, and liquid suction operation or liquid adding operation is carried out on the cell culture plate conveyed from the cell culture box.
Optionally, the rotary robot is arranged upside down on the top of the cell culture box.
Optionally, the liquid preparation and pipetting operation device comprises a liquid preparation and storage box storage library, and the liquid preparation and storage box is sucked to the liquid preparation platform through the vacuum gun head.
Optionally, the liquid preparation and pipetting device comprises a first rectilinear coordinate robot, and a pipettor is installed at the end of an arm of the first rectilinear coordinate robot and used for sucking the culture solution from the total sample and injecting the sucked culture solution into the liquid preparation and storage box on the liquid preparation platform.
Optionally, the liquid preparation and pipetting device comprises a second rectangular coordinate robot, a multi-channel pipettor is mounted at the tail end of an arm of the second rectangular coordinate robot, the pipette heads are mounted in the pipette head array, liquid is sucked from the liquid preparation and storage box, and the liquid is injected into the cell culture plate on the pipetting platform.
Optionally, the system includes a central processing unit, where the central processing unit loads an upper computer software operating system based on the ROS platform, and controls the rotary robot, the first cartesian robot, and the second cartesian robot to cooperatively operate.
Optionally, the liquid preparation and pipetting device comprises a conveyor belt for conveying the liquid preparation and storage box to the liquid preparation and storage box recovery device.
The invention provides a control method based on the automatic pipetting system, which comprises the following steps:
identifying label information of the warehoused cell culture plate;
distributing storage positions for the cell culture plates put in storage according to the existing storage state information of the cell culture box and updating the storage
Status information;
storing operation information for each cell culture plate according to user input or cell culture plate label identification results;
controlling the rotary robot to move according to the operation information and the storage state information, and transferring the stored cell culture plate to an in-out warehouse platform;
transferring the cell culture plate to a pipetting platform by sensing the cell culture plate;
and controlling a liquid shifter to assemble and take the gun heads from the gun head array according to the cell culture plate operation information, and performing liquid preparation and liquid shifting operations.
Optionally, the first right-angle coordinate robot and the second right-angle coordinate robot are controlled to act at the tail ends of the arms of the robots so as to squeeze the gun heads out when the gun heads need to be replaced.
Optionally, control according to cell culture board operation information and carry out the pipettor and adorn the rifle head from rifle head array to join in marriage liquid, move liquid operation, include:
controlling a first rectilinear coordinate robot carrying a liquid transfer device to suck liquid from a total sample; injecting the sucked liquid into a liquid preparation storage box at a liquid preparation platform;
after the liquid is prepared, controlling a second rectangular coordinate robot to absorb the liquid in the liquid preparation and storage box on a liquid preparation platform, and transferring the liquid to a liquid transfer platform to perform liquid adding operation on a cell culture plate to be operated;
after the liquid preparation and storage box is used, the conveying device is controlled to convey the liquid preparation and storage box to the recovery device.
Optionally, the automatic arranging device for the gun heads is controlled according to the operation information of the cell culture plate to arrange the gun heads so as to provide at least one gun head array.
The technical scheme provided in the embodiment of the application at least has the following technical effects or advantages:
the method and the equipment provided by the invention can realize the functions of carrying out automatic cell inoculation, culture solution replacement, addition of regulating factors or lead compounds, automatic taking out of specific 96 cell culture plate samples for further detection and the like aiming at cell culture plates (including currently common 96 cell culture plates) for culturing cells, and can be used for sorting bulk pipette tips on line and providing the bulk pipette tips for pipette tip arrays. Compared with the similar products on the market, the equipment provided by the invention has the advantages of comprehensive functions, obviously reduced price and the like, meets the use requirement of a laboratory, and is suitable for being popularized into a marketized product, so that the international competitiveness of China in the corresponding instrument field is improved, and the development of related researches is promoted.
The above description is only an overview of the technical solutions of the present invention, and the embodiments of the present invention are described below in order to make the technical means of the present invention more clearly understood and to make the technical solutions of the present invention and the objects, features, and advantages thereof more clearly understandable.
Drawings
Various other advantages and benefits will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the invention. Also, like reference numerals are used to refer to like parts throughout the drawings. In the drawings:
FIG. 1 is a top view of the automated pipetting system according to the invention;
FIG. 2 is a top view of a three-dimensional storage device for cell culture plates;
FIG. 3 is a side view of the liquid dispensing and pipetting device of the present invention;
FIG. 4 is a perspective view of the liquid dispensing and pipetting device together with a three-dimensional storage device according to the present invention;
FIG. 5 is a three-dimensional structure diagram of the automatic arrangement device for the gun head according to the present invention;
FIG. 6 shows a detailed structure diagram of a roller part of the gun head automatic finishing device provided by the invention;
fig. 7 shows a detailed structure diagram of a gun head guide part in the gun head automatic finishing device provided by the invention;
fig. 8 is a perspective view showing a part of the gun head automatic arrangement device according to the present invention arranged in an array;
fig. 9 is a plan view showing a part of the gun head automatic arrangement device according to the present invention arranged in an array;
figure 10 shows a side view of the take-off assembly configuration.
Detailed Description
Exemplary embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. While exemplary embodiments of the invention are shown in the drawings, it should be understood that the invention can be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
The invention provides an automatic pipetting system, which comprises a cell culture area 1, a pipetting operation area 2 and a gun head automatic finishing device area 3, and is shown in figure 1. The cell culture area 1 and the liquid transfer operation area 2 are arranged in parallel and are closed spaces, and an air purification and exchange device and CO are arranged in each space2Concentration and humidity control means (not shown) are used to ensure that the cell culture area and pipetting platform environments are compatible with the clean, gas and humidity requirements of conventional cell growth. A first conveying device is arranged between the two spaces, and the cell culture plate in the cell culture area is conveyed to the liquid-transferring operation platform through the first conveying device. Because two spaces are the enclosure space, consequently link to each other through the mechanical door that can open and shut between two spaces, the size of mechanical door slightly is greater than 96 hole cell culture plate sizes to guarantee that the cell culture plate can pass through smoothly. The cell culture area comprises a cell culture box 11, a cell culture plate three-dimensional storage device 12 and a rotary robot 13 are arranged in the cell culture box, the rotary robot 13 can take and place a cell culture plate at any storage position on the cell culture plate three-dimensional storage device 12, when the rotary robot 13 receives an instruction of transferring a certain cell culture plate to the liquid-transferring operation area 2, the rotary robot 13 moves up and down and is rotationally positioned to the storage position of the certain cell culture plate on the horizontal plane, the rotary robot 13 grips the certain cell culture plate through the action of the tail end of the arm of the rotary robot 13, transfers the certain cell culture plate to a first preset position (an in-out storage platform) at the bottom of the three-dimensional storage device 12, and then the first conveying device conveys the cell culture plate to a second preset position (an in-out storage platform) in the liquid-transferring operation area 2The first conveying device comprises a first conveying belt, a first sliding trolley or a first rolling trolley, the liquid transferring operation area 2 is divided into a liquid configuration area and a liquid adding area, a first rectangular coordinate robot 21 and a second rectangular coordinate robot 22 are respectively arranged in the liquid configuration area and the liquid adding area, the tail end of the arm of the first rectangular coordinate robot 21 is connected with a liquid transferring device and used for sucking required cells and/or culture liquid from a main sample and injecting the cells and/or culture liquid into a liquid distribution and storage box, and the liquid distribution and storage box is matched with a cell culture plate; the tail end of the arm of the second cartesian robot 22 carries a gun head corresponding to the cell culture plate, and is used for transferring cells and/or culture solution in the solution preparation and storage box to the liquid adding area and injecting the cells and/or culture solution into the target cell culture plate; the injected target cell culture plate is conveyed back to the cell culture box 11 by a second conveying device; the rotary robot 13 places the transferred cell culture plate at the original position of the cell culture plate three-dimensional storage device 12; the system further comprises a central processing unit (not shown in the figure), and the central processing unit loads an upper computer software operating system based on the ROS platform and controls the rotary robot 13, the first rectangular coordinate robot 21 and the second rectangular coordinate robot 22 to cooperatively operate.
Through the technical scheme, the cell culture plate is automatically accessed, and cell inoculation and liquid changing culture are carried out on the cell culture plate.
The three-dimensional storage device 12 is in a hollow cylindrical shape, as shown in fig. 2 and 3, and specifically includes: an upper and lower multi-layer circular platform member 121 for placing a cell culture plate for cell culture; vertical supports (not shown) for supporting the circular platform member 121. The rotary robot 13 is arranged at the hollow position of the circular platform component, freely ascends and descends, and is used for grabbing the cell culture plate from the circular platform component to a first preset position or grabbing the cell culture plate from the first preset position and placing the cell culture plate on the circular platform component based on the cell culture plate identification code; the human-machine interface platform 4 is positioned in front of the three-dimensional storage device and is used for receiving a cell culture plate for cell culture; a first transfer device (not shown) for transferring the cell culture plate from the man-machine interface platform to or from a first predetermined position, the first predetermined position being below the bottom of the circular ring shaped platform member.
In the present invention, the upper and lower multiple layers of circular platform members 121 do not rotate nor move up and down, thereby providing a stable culture environment for the cell culture plate for cell culture and avoiding disturbance to the cultured cells. The rotary robot 13 which can move up and down and rotate 360 degrees in the horizontal plane can realize the fetching and delivering problems of any cell culture plate, and the rotary robot 13 is arranged at the axis position of the circular platform component, so that the technical effects that the length of a robot arm is as short as possible and the stretching distance of a mechanical arm is as short as possible are achieved, the self-balance problem of the rotary robot can be well solved, and the disturbance to the cell culture environment can be reduced to a certain degree.
As a preferred embodiment, the circular platform member 121 is composed of three arc surfaces, a gap may be left between each arc surface, and mechanical connection is not required, each arc surface is fixed on the vertical support column, three vertical support columns may be provided corresponding to the three arc surfaces, the vertical support column is located at the radial middle position of the circular support member, and each support column fixes the arc surface section support members at both sides thereof. As another embodiment, each segment of cambered platform member can be supported by a hollow cylindrical vertical support frame. The structural design of the two embodiments ensures that the vertical supporting column does not influence the operation of the mechanical arm and the mechanical gripper, and is convenient to disassemble and assemble and convenient to clean the stereoscopic storage device.
And each preset number of storage positions on the circular platform component is one unit, and the storage units are used as management units. In capacity, in the up-down direction, multiple layers of support members are designed, and one three-dimensional storage device can store 50-200 cell culture plates. The storage position of every 50 cell culture plates can be defined as one unit, and a user can configure 1-4 storage units according to the requirement, because the storage unit is taken as a management unit, the user can realize certain flexibility in the aspects of equipment purchase and use cost, the storage capacity is expanded according to the requirement of the user, and the flexibility of the use of the system is increased. Generally, the three-dimensional storage device designed in the invention has the storage capacity of 50-200 cell culture plates. The cell culture plate has various specifications, including 6 cell culture plate, 12 cell culture plate, 24 cell culture plate, 96 cell culture plate, 384 cell culture plate, etc., and the 96 cell culture plate is mainly described in the present invention.
Cell culture is environmentally demanding, so cleanliness is a concern and a sufficient consideration in developing a volumetric storage device. As a specific implementation mode, the annular platform component consists of three sections of arc surfaces which are fixed on the three vertical supporting columns, and the structural design is easy to detach and install and convenient to clean.
The rotary robot is arranged at the top of the three-dimensional storage device in an inverted mode, the bottom of the storage device can be guaranteed to be smooth, liquid can be prevented from remaining on the rotary robot, and the storage device is easy to clean. The robot and the bottom of the three-dimensional storage device can be kept clean. The rotary robot comprises a body, a mechanical arm and a mechanical gripper. As a specific embodiment, the rotary machine moves up and down along a vertically arranged track, the track passes through the center of the rotary robot body, so that the robot balance can be easily achieved, the mechanical arm is connected with the local through a rotary table, 360-degree rotation of the mechanical arm is achieved, and the rotary table is driven by a motor arranged on the local.
In consideration of the requirement of cell culture on environmental cleanliness, the rotating shaft of the rotary robot adopts IGUS wear-resistant engineering plastic which is mainly used on airplanes at present so as to avoid powder caused by friction between lubricating oil and metal. The swing robot is installed on the top of the storage device in an inverted form,
as a first embodiment, the mechanical gripper comprises a first clamping piece and a second clamping piece, and the first clamping piece and the second clamping piece can be clamped or loosened by driving the first clamping piece or the second clamping piece through a driving device, so that the cell culture plate can be clamped or released.
As a second embodiment, two or three pairs of "L" shaped members are used for the mechanical gripper. The clamping operation or the releasing operation is carried out by driving each pair of L-shaped components to move oppositely or oppositely through the driving device.
In the first and second embodiments, in order to facilitate the mechanical gripper to grip the cell culture plate, the radial dimension of the circular platform member needs to be designed, the radial dimension is smaller than the radial dimension of the cell culture plate, and it is ensured that the cell culture plate is stretched out by a sufficient size for the mechanical gripper to grip after the cell culture plate is placed. Or the shape of the circular platform component is designed, so that the shape of the circular platform component is matched with the shape of the clamping piece or the L-shaped component of the mechanical gripper, and the clamping piece or the L-shaped component below the mechanical gripper can be conveniently stretched into the circular platform to clamp and retract. In both embodiments, the mechanical gripper need only perform the extending, tightening, and retracting operations.
As a third embodiment, the mechanical gripper adopts a fork structure, so that the circular ring-shaped platform member for placing the cell culture plate is matched with the fork structure and is in a comb shape in order to facilitate the taking and the delivering of the cell culture plate by the fork. In such an embodiment. The mechanical gripper needs to perform the operations of extension, slight raising and retraction. The fork is inserted under the cell culture plate by the operation of extending, the cell culture plate is supported on the fork by the operation of slightly rising, and the fork completes the process of taking the cell culture plate away from the circular platform member by the operation of retracting.
In the present invention, the cell culture plate may be slightly shaken only when the cell culture plate is being transported or transported, and the cell culture plate is otherwise in a static state, thereby greatly reducing disturbance to the cell culture.
Since identification information of the cell culture plate needs to be identified when the rotary robot receives the cell culture plate at the human-machine interface region, any operation on the cell culture plate is performed thereafter based on the identification information. Therefore, at the end of the arm of the rotary robot, near the mechanical gripper, a recognition device is provided for recognizing the label on the cell culture plate to obtain the identification information thereof.
The rotary robot further comprises a first driving device, a second driving device and a third driving device, wherein the first driving device is arranged on the body and used for driving the body to move up and down along a vertical track, and the second driving device is arranged on the rotary robot body or a rotary table and used for driving the rotary table to rotate in a horizontal plane so as to drive the robot arm to rotate; and the third driving device is arranged on the mechanical arm and used for driving the mechanical gripper to carry out grabbing or loosening operation.
The cell culture plate can be transferred to the three-dimensional storage device in and out warehouse platform from the first preset position through the actions of up and down movement of the body, rotation of the mechanical arm, extension and retraction of the mechanical arm by the rotary robot, a certain distance is further reserved between the first preset position and the man-machine interface platform, the cell culture plate is transferred in the distance by the first transfer device which is a first slide way and a first moving trolley on the first slide way or a first transfer belt, the best mode is that the first preset position and the supporting surface of the moving trolley or the first preset position and the supporting surface of the first transfer belt are on the same horizontal plane, the cell culture plate is conveniently transferred between the first preset position and the moving trolley or the first transfer belt, and the transfer from the first moving trolley or the first conveying belt to the man-machine handover platform can be realized through a first poking rod (or a poking block) and a second poking rod (or a poking block) respectively, and the poking rod (or the poking block), the first moving trolley and the first conveying belt are triggered by sensing equipment for detecting the cell culture plate.
The stereo storage device comprises a central processing unit and a display, wherein the display is used as a human-computer interaction interface besides a display function. The central processing unit and the display are arranged in front of the outer side of the three-dimensional storage device, preferably arranged above the man-machine handover platform, and are convenient for a user to operate. And the central processing unit sends instructions to the first driving device, the second driving device and the third driving device so as to control the rotary robot to transfer the cell culture plate.
The following describes the automatic storage control flow of the stereoscopic storage device:
when a user needs to put the cell culture plate into the three-dimensional storage device, the cell culture plate is placed on the man-machine connection platform.
The man-machine handover platform is provided with a first recognition device (such as a two-dimensional code label reading head), the first recognition device performs recognition operation and sends detected identification information to the central processing unit, and the central processing unit allocates storage positions of the three-dimensional storage device for the first recognition device according to the identification information and stores related setting information of the storage positions. The central processing unit sends an instruction to the rotary robot, and the rotary robot controls the first driving device to drive the robot body to move downwards along the track to the bottom for standby according to the instruction.
After the identification information of the cell culture plate is identified by the identification device, the first deflector rod and the first conveying device are triggered to act, so that the cell culture plate is transferred to the first conveying device and is conveyed by the first conveying device.
Be provided with first induction system on the first preset position, first induction system when sensing the cell culture board, triggers the second driving lever according to the position of the cell culture board of sensing and carries out corresponding action, specifically is: and triggering the second deflector rod to perform a poking action from the first conveying device to a first preset position when the cell culture plate is sensed to be on the first conveying device, triggering the second deflector rod to perform a poking action from the first preset position to the first conveying device when the cell culture plate is sensed to be on the first preset position, and controlling the rotary robot to perform an action by the central processing unit according to a sensing signal of the first sensing device to complete the transfer from the first preset position to the distributed storage position.
By this control flow, automatic storage of the cell culture plate can be realized. When a user needs to take out a certain cell culture plate, the reverse process of the control flow can be completed by the rotary robot and the first conveying device only by inputting cell culture plate identification information, so that automatic taking out is realized.
The three-dimensional storage device is placed in a cell culture box. As shown in FIG. 2, the cell culture chamber is square and provides a closed environment for cell growth, and the three-dimensional storage device 2 is placed in the cell culture chamber 1 to form a closed cell culture environment. An opening is reserved in front of the bottom of the cell culture box 1, and a first isolation door capable of being automatically opened and closed is arranged at the opening and used for isolating the culture box from an external environment. Based on the identification information of first recognition device, the switching of first isolator door of the response information control of first induction system to make the cell culture board can pass in and out the cell culture case. An opening for a cable to go out needs to be reserved under the cell culture box 1.
When the liquid-transferring operation needs to be carried out on the cell culture plates stored in the three-dimensional storage device, the rotary robot grabs the cell culture plates from the circular ring-shaped platform component to the in-out warehouse platform based on the cell culture plate identification information, the first conveying device is further used for transferring the cell culture plates from the in-out warehouse platform to the liquid-transferring operation platform, the in-out warehouse platform is located below the bottom of the circular ring-shaped platform component, and the liquid-transferring operation platform is located on one side of the three-dimensional storage device.
As shown in fig. 3 and 4, the solution preparation and transfer area includes first cartesian robots 21 (preferably two) for transferring the prepared solution to the cell culture plate in the transfer area, and second cartesian robots 22 (preferably two) for sucking the solution from the total sample in the solution preparation area for solution preparation. The liquid distribution area is also required to be processed by the liquid distribution plate, the liquid distribution area is large, the moving path of the liquid distribution plate is a straight line, and the waste liquid distribution plate is conveniently conveyed to the collection port through the conveying belt.
The following describes the work flow of automatically transferring the cell culture plate from the three-dimensional storage device to the pipetting platform for pipetting:
when it is desired to pipette a certain cell culture plate in the volumetric storage device, one case is to operate according to a user's instruction, and one case is to issue an instruction according to the central processing unit based on the setting information about the cell culture plate.
The rotary robot 3 operates according to a pipetting instruction (including identification information and storage position information of the cell culture plate), and takes out the cell culture plate (hereinafter referred to as a target cell culture plate) to be pipetted from the circular ring-shaped support member and transfers the cell culture plate to the warehousing-out platform, and the warehousing-in-out platform is provided with a second sensing device which triggers the first conveying device to operate when sensing the target cell culture plate. And the target cell culture plate is conveyed to the pipetting platform through the first conveying device, and the pipetting operation platform is provided with a second identification device. And the second recognition device performs recognition operation, sends the detected identification information to the central processing unit, the central processing unit acquires the pipetting control related information according to the identification information and sends a pipetting operation instruction to the first rectangular coordinate robot, and before that, the central processing unit controls the second rectangular robot to perform liquid distribution operation according to the cell culture plate operation information.
After the pipetting operation is finished, the central processing unit sends a return instruction to the rotary robot and the second conveying device, and the rotary robot controls the first driving device to drive the robot body to move downwards along the rail to the bottom for standby according to the instruction.
And when the second sensing device detects the target cell culture plate, the second sensing device sends a command to the rotary robot through the central processing unit to transfer the target cell culture plate to the storage position.
Through this control flow, can realize the automatic liquid process of moving of cell culture board.
When a designated cell culture plate needs to be transferred to a liquid transferring operation platform for liquid changing or liquid adding operation, the central processing unit determines the storage position of the cell culture plate and sends a control command to the rotary robot, the rotary robot carries out arm end positioning and action by moving up and down and rotating in a plane, the cell culture plate is grabbed, then the rotary robot transfers the cell culture plate to a second preset position at the bottom of the three-dimensional storage device by moving downwards and rotating in the horizontal plane, and the cell culture plate is transferred to the liquid transferring operation platform 2 through the second transfer device.
The three-dimensional storage device provided by the invention is matched with the cell culture box with the corresponding access, a sealed and stable environment can be provided for cell culture, and meanwhile, the three-dimensional storage device is separated from a pipetting operation area in an environmental isolation way, so that the space of the cell culture box is reduced, the maintenance cost of the cell culture environment is reduced, the disturbance caused by the operation and the transmission of the cell culture plate is greatly reduced due to the design of each transmission device, and the cleaning in the cell culture box is facilitated.
The three-dimensional storage device provided by the invention can automatically access a 96-well cell culture plate (or other well culture plates) and perform cell inoculation and liquid change culture on the cell culture plate, can regularly add small molecule compounds with specified concentration to specified culture wells in the 96-well culture plate according to a preset instruction of a user, and supports automatic addition of the same small molecule compounds with different concentrations, different small molecule compounds or a combination of a plurality of small molecule compounds to different culture wells of the same 96-well culture plate.
The three-dimensional storage device provided by the invention can realize automatic in and out of the cell culture plate, thereby providing support for automatic liquid changing and adding operations of the cell culture plate.
When cells are seeded into each well of a cell culture plate, culture fluid is replaced, and compounds are added, the cell culture plate needs to be transferred from the three-dimensional storage device to a pipetting platform, and then the cell culture plate is transferred to the pipetting platform. The pipetting area will be divided into two areas, liquid configuration and liquid addition, each area being configured with at least one cartesian robot. And the first rectangular coordinate robot in the liquid adding area loads the gun head corresponding to the cell culture plate, moves to the liquid configuration area, sucks the cells or the culture solution according to the preset volume, moves back to the liquid adding area, and injects the sucked cells or the culture solution into the target cell culture plate. If the task needs to change the cell culture solution, before executing the task of sucking and adding the culture solution, the first rectangular coordinate robot in the liquid adding area firstly sucks and discards the culture solution in the cell culture plate to be processed, and after the gun head is changed, the operation of sucking and adding the culture solution is executed. In the liquid distribution area, a single-channel pipette (which may be a single tip) is connected to the end of the second cartesian robot, and desired cells and culture liquid (calculated as 110% of the total amount of the desired cells and culture liquid, which is determined in consideration of the loss during pipetting) are aspirated from the total sample according to the amount of the desired cells and culture liquid, and injected into a flat well having a size corresponding to the size of the cell culture plate. In the liquid configuration area, if the task of adding compounds with different concentrations needs to be executed, the tail end of the second rectangular coordinate robot is used for installing a gun head corresponding to the cell culture plate from a gun head array, a culture solution with a specified volume is injected into a blank cell culture plate in the liquid configuration area, then the pipettor at the tail end of the second rectangular coordinate robot is replaced by a single-hole pipettor, and the single-hole pipettor is used for sucking the compounds with the corresponding volume from a compound mother solution according to an experimental plan and injecting the compounds into the culture solution of each target hole site in the cell culture plate. In the process, after the culture solution is injected, attention needs to be paid to replacing the gun head to avoid cross contamination. Repeating the above steps for multiple times can make different wells of the cell culture plate contain different concentrations of small molecule compounds. And then the configured liquid is sucked and added into the target cell culture plate in the liquid adding area by the first right angle coordinate robot in the liquid adding area, so that the small molecule compound or compound combination with different concentrations can be added into the specific hole groove in the cell culture plate. If the same repeated operation is carried out on a plurality of cell culture plates, a specially-made cell culture plate with a large single-hole volume can be used in the liquid configuration area, and the liquid adding requirement of at least 10 cell culture plates can be met after liquid is configured for one time.
The liquid configuration area is provided with a liquid distribution and storage box automatic warehouse which is arranged at the lower part of the liquid transferring operation area 2 and mainly used for storing and distributing empty cell culture plates or flat grooves. When the liquid preparation and storage box needs to be taken and used, the central processing unit determines the type of the adaptive liquid preparation and storage box according to the liquid preparation requirement. And the automatic distribution device of the liquid preparation and storage box automatically takes out the adaptive liquid preparation and storage box according to the determined type of the liquid preparation and storage box and the storage position information of the liquid preparation and storage box and transfers the adaptive liquid preparation and storage box to the third conveying device. In a preferred embodiment, the automatic dispensing device of the dispensing liquid storage box is a movable vacuum adsorption head, and the dispensing liquid storage box is taken out by vacuum adsorption and is conveyed to the dispensing platform by the third conveying device. In the invention, in order to improve the liquid preparation efficiency, two or more liquid preparation platforms can be arranged. At joining in marriage the liquid platform, carry out the liquid feeding operation of various formulas to joining in marriage liquid stock solution box by second cartesian robot, the bottom plate of accomplishing the liquid feeding carries moves liquid imbibition station, joins in marriage the liquid platform and move the liquid platform and need have accurate location. Certain buffering capacity and grouping capacity are needed between the liquid distribution platform and the liquid transfer and absorption station, and the buffering capacity and the grouping capacity are preferably realized through a conveyor belt or a sliding track and a sliding trolley. The empty bottom plate which finishes liquid transfer is automatically discarded into a first waste recovery container, specifically, after the liquid containing flat groove or the cell culture plate in the liquid configuration area is used, the empty bottom plate is conveyed to a waste collection place through a second conveyor belt and discarded. In this embodiment, the automatic reservoir for the liquid preparation and storage box, the conveyor belt for the liquid preparation and storage box, and the disposal opening for the liquid preparation and storage box are arranged on a straight line.
For the liquid with larger dosage, such as cell culture solution, etc., a peristaltic pump is configured to ensure the continuous supply of the liquid.
A fourth transport device is provided between the dispensing station and the pipetting platform and allows up to 4 dispensed cell culture plates to rest on the third transport device simultaneously in order to increase efficiency and maximize the use of the dispensed liquid to be added at one time.
The pipetting operation is completed by a first rectilinear coordinate robot 21, the first rectilinear coordinate robot 21 installs the pipette tips from the pipette tip array, then the operations of pipetting from the interior of the cell culture micro-cell culture plate, pipetting from the culture solution to the cell culture micro-cell culture plate, pipetting from the batching liquid storage box to the cell culture micro-cell culture plate and the like are completed, the pipette tips are automatically discarded and replaced by new pipette tips after each operation is completed, the discarded pipette tips are recovered into a second waste recovery container, and the discarded cell culture solution is discharged into a third waste recovery container by the pipette tips. And the tail end of the arm of the second rectangular coordinate robot is provided with a movable part for squeezing off the gun head after the liquid transfer operation is finished.
The tail ends of the first and second rectangular coordinate robots are provided with actuators which can perform the functions of synchronously sucking and extruding solution and replacing gun heads for 96 gun heads (or a single gun head when the cell culture plate is a 96 cell culture plate), and the functions of sucking and extruding solution of the gun heads are realized by adopting air pressure difference. When no gun heads are arranged on the end effector, the rectangular coordinate pipetting robot moves the end effector to a position right above the gun head box, then vertically moves downwards, and 96 gun heads are simultaneously mounted. The used gun head is extruded out through a moving part arranged on the end effector. By the technical means, the automatic loading and discarding of the cell operation gun head and the automatic collection of cell culture waste liquid can be realized.
The end of the arm of the first rectangular coordinate robot is provided with a liquid-transfering gun, and an array gun head is required to be arranged before each operation, and is supplied by a gun head automatic arrangement device which is specifically described below. In the invention, the first right-angle robot can move among the liquid transfer platform, the liquid preparation platform and the gun head array platform, waste liquid in the cell culture plates is sucked and discharged to a preset position on the liquid transfer platform, the sucked preparation liquid is discharged to each cell culture plate on the liquid transfer platform, and solution in the liquid preparation storage box is sucked on the liquid preparation platform. The invention skillfully designs the relative position relationship among the first rectangular coordinate robot, the second rectangular coordinate robot and the gun head array supply platform by taking the liquid preparation and storage box transmission channel designed as the figure 4 as a straight line, thereby realizing the automatic operation process of liquid preparation and liquid removal.
The invention provides a novel automatic gun head arranging device which supplies gun head arrays for a first rectangular coordinate robot and a second rectangular coordinate robot on a gun head array platform. As shown in fig. 5 and 6, the automatic arrangement device for the gun head comprises: a roller 31, on the inner side wall of which a stop bar is arranged, the stop bar is perpendicular to the rotation direction, the roller is driven by a motor to rotate, and two ends of the roller are opened; the gap component 32 extends into the roller, the width of the gap is larger than the diameter of the thin end of the gun head and smaller than the diameter of the thick end of the gun head, and the length direction of the gap is parallel to the axis of the roller; the part of the gap component extending out is fixed on the device body outside the roller; and a transfer assembly 33 which moves in a direction perpendicular to the length of the gap, and part of which moves up and down to load and transfer the tips on the gap to the array tray.
The invention realizes the rapid sorting and sequencing of bulk gun heads by means of vibration and steric hindrance principles. The gun head and the gun head are driven to vibrate upwards through at least one roller with an opening at one end. Because the two ends of the gun head are respectively a thin end and a thick end, the invention designs a vertical gap, the width of the gap is larger than the thin end of the gun head and smaller than the thick end of the gun head, the gap component extends into the roller, the gun head rotates and vibrates along with the roller and is brought up, when the gun head falls down to the gap under the action of gravity, only the thin end can enter the gap, and the thick end is clamped by the gap opening to be vertical, thereby realizing that the gun heads are arranged in a line. When m gun heads are arranged in the gap, the gun heads are transferred by the transfer assembly, then the gun heads fall into the gap randomly, after the m gun heads are arranged again, the gun heads are transferred by the transfer assembly, the process is repeated, the transferred m gun heads are transferred to the array disk, a row or a column is formed on the array disk, and when n rows (or columns) are formed, a preset gun head array is realized. The spacing between tips of the rows or columns, and the spacing between rows (or columns) may be achieved by adjusting or setting the distance between adjacent noses of the take-off assembly in which tips are inserted.
As an implementation manner, each row of arranged gun heads can be directly transferred to a gun head box on the operation platform, and after the whole box of gun heads are fully arrayed, the whole box of gun heads is conveyed to a preset position through the conveying device, and the next empty box is conveyed to the operation platform.
As another embodiment, after the array of tips is formed, the array of tips may be transferred at a time and inserted into the tip box by the transfer device to form a boxed array of m × n tips (m, n are natural numbers).
The selling price of the boxed gun heads is about 4-5 times of that of the bulk gun heads, so that the boxed gun head array of m multiplied by n (m and n are natural numbers) can be used as a processing product to be operated. In the present invention, 96 cell culture plates are mainly used for explanation. Typically the wells of a 96 cell culture plate are arranged in a 12 x 8 array, m being 12 and n being 8, in order that the array of tips after finishing can be applied to a 96 cell culture plate.
As a third implementation mode, the finished gun head array can also be directly butted with a pipette gun, the pipette gun is used for loading and taking the gun head array to perform liquid suction or liquid adding operation, the distance between adjacent gun heads in the formed gun head array is matched with the distance between the pipettes in the row, so that the gun head array can be automatically provided for the pipettes in the row, the pipettes can be quickly replaced, and the technical problem of the link of automatically supplying the gun heads for the pipettes can be solved. Considering that the cell culture plate has various specification forms, 6 cell culture plates, 12 cell culture plates, 24 cell culture plates, 96 cell culture plates, 384 cell culture plates and the like, the m and n values of the formed gun head array are adjusted according to the combination condition of the inline pipettes aiming at the types of the operated cell culture plates, so that gun heads can be automatically provided for various pipette combinations corresponding to different cell culture plates. Of course, the prepared gun head array is also suitable for the single-gun head liquid-transfering gun.
As a specific embodiment, in the automatic arrangement device for gun tips provided by the present invention, as shown in fig. 6, a stopper perpendicular to the rotation direction is disposed on the inner side wall of the drum 31, the drum 31 is driven by a motor (not shown) to rotate, and two ends of the drum are open; the gap component 32 extends into the roller, the width of the gap is larger than the diameter of the thin end of the gun head and smaller than the diameter of the thick end of the gun head, and the length direction of the gap is parallel to the axis of the roller; the part of the gap component extending out is fixed on the device body outside the roller; and a transfer unit 33 which moves in a direction perpendicular to the longitudinal direction of the gap, and part of which moves up and down to load and transfer the tips on the gap to the array tray. The drum 1 has openings at both front and rear ends thereof through which the gap members 32 protrude, and the protruding portions of the gap members 32 can be fixed to the apparatus body. As a specific embodiment, the gap member 32 is fixed to the apparatus body, protruding from one end of the opening; in order to allow more of the tips that are entrained as the drum rotates and the bars fall onto the gap formation, as shown in figure 7, a funnel 34 is provided within the drum, the funnel 34 being located at an upper and left position within the drum 31, the outlet below the funnel being located directly above the gap formation, the funnel being able to assist in collecting the upwardly entrained tips, a substantial portion of the tips falling into the funnel 34 falling under gravity down into the gap formation. A guide plate 35 is provided on the back side of the funnel and above the gap member, the guide plate 35 helping to guide the lance tip to fall into the gap member.
In order to better collect the gun heads, a slope component is arranged beside the funnel, the funnel and the slope component are both provided with a vertical plane, and the funnel and the slope component are fixedly connected with each other through the vertical plane. Through such structure setting, can improve the arrangement efficiency of rifle head.
In order to increase the probability of the lance head falling into the vertically narrow gap in the drum, to improve the efficiency of the arrangement of the lance head, and to take account of the problem of ease of installation, as shown in fig. 7, the hopper 34 is defined by 4 planes, one pair of planes s1 and s2 being parallel to each other and perpendicular to the horizontal plane l, one plane s3 of the other pair of planes being perpendicular to the horizontal plane and perpendicular to the pair of planes, and the other plane s4 being an inclined plane parallel to the central axis of the drum 31. The cross section of the funnel is rectangular. The funnel is fixed to the body of the device outside the drum by means of a plane s1, on which plane s2 the aforementioned guide plate 35 is arranged. A slope assembly 36 is arranged obliquely above the funnel, and the slope assembly 36 is fixed on the plane s3 and used for gathering the gun head. According to the invention, the upper surface of the baffle strip is in a concave gap shape, so that more gun heads can be lifted by the baffle strip when the roller rotates, and the finishing efficiency can be further improved.
The tips fall in a line on the gap member by the guide of the rotation of the drum, the funnel, the slope member, the guide plate, and the like to the direction in which the tips fall.
The transfer assembly mainly solves the technical problem of transferring a preset number of gun heads formed on the gap member into the array disc.
As shown in fig. 8, the transfer assembly 33 includes: a first moving member 331 controlled by a first motor and moving along a rail 332 provided on the apparatus body, the rail 332 being perpendicular to the gap length direction; a second moving member 33 driven by a second motor or a first cylinder and moving up and down between a first predetermined position and a second predetermined position with respect to the first moving member 331; a plurality of block parts 334 arranged in a row in parallel with the length direction of the clearance structure 32 and having a boss matching the inner diameter of the wide end of the lance tip are provided below the second moving part 333. The first moving member is moved translationally to a first predetermined position with each nose opposing each lance tip on the gapping member and the first moving member 331 is moved translationally to a second predetermined position with each nose opposing each lance tip hole of the array disk, and the m lance tips formed on the gapping member 32 are transferred by the first moving member 331 to the first, second, third, … …, n th rows on the array disk until an m x n array is formed. The distance between the block portions 334 is thus adjustable, and adjustment of the distance between each adjacent pair of noses by adjustment of the distance between the block portions 334 is effected between a first value for the distance between each adjacent pair of tips on the clearance structure 32 and a second value for the distance between each adjacent pair of tip holes on the array plate. When the first moving part 331 is aligned with the lance head in the gap formation, the second moving part 333 is moved downwardly relative to the first moving part 331 to a third predetermined position for loading the lance head in the gap formation with a nose of a size which matches the internal diameter of the lance head. After loading the tips, the second moving part 333 moves up to the original position, then the first moving part 331 moves in translation to the first predetermined position, the pitch between the bosses (block parts) is adjusted during the translation, and then the second moving part 333 moves down to the fourth position, and the tips are unloaded onto the array tray by the retracting action of the bosses or the push-down part provided above the bosses. If the action of retracting and extending the nose is used to unload the lance tip, the nose may be driven by a third motor or a second cylinder, as the lance tip need only be moved between two relatively variable positions. If the lance tip is pushed away by the pushing down part to unload the lance tip, the pushing down part may be driven by a third motor or a second cylinder. The second moving part moves between two relative positions, and can be driven by a second motor or a first air cylinder. In general, a pneumatic cylinder is suitable for the case of a transmission movement between two fixed positions.
As a specific embodiment, as shown in fig. 8, the first moving member 331 is a slider that moves along a slide rail provided in a direction perpendicular to the length of the gap member, and the second moving member 333 is provided below the slider and can move up and down relative to the slider by being driven by an air cylinder. As shown in fig. 10, a block member 334 having a protrusion is disposed below the second moving member 333, the block member 334 is disposed on a horizontal shaft, and the two-step adjustment of the distance between the block members is realized by the position change of the block member on the horizontal shaft. The distance between the first gear and two adjacent gun heads on the gap component is the same, and the distance between the second gear and the adjacent gun head insertion holes on the array disk is the same. The driving shaft is driven by the air cylinder to move up and down, so that the driving shaft drives the transverse shaft to move up and down, the transverse shaft penetrates through a plurality of block parts with the raised heads, the alignment direction is parallel to the length direction of the gap member, and the space between the block parts is adjusted by a third motor or a second air cylinder driven along the transverse shaft direction, so that the space between the adjacent block parts and the raised heads is adjusted.
The device also comprises two array disk supporting platforms, as shown in fig. 8 and 9, the two array disk supporting platforms are respectively arranged at two sides of the gap member, and the array disks are arranged on the array disk supporting platforms. Through setting up two array dish supporting platform, when shifting the rifle head on the array dish of past one side line ground, array dish can equip the rifle head of putting in order to the pipettor on the opposite side, also can adorn the operation of dress with the rifle head of putting in order to prepare next array dish, thereby can improve the efficiency of putting in order the rifle head.
In another aspect, the invention provides a method for automatically arranging gun heads, which comprises the following steps:
s1, pouring hashed gun heads into a roller;
s2, driving a roller, wherein the roller rotates to upwards bring the gun head;
s3, after the gun heads fall into the hopper to be converged, the gun heads with downward heads fall into the gap member extending into the roller;
s4, taking away a preset number of gun heads in the continuously arranged vertical slits and transferring the gun heads to the upper part of the array disc through up-and-down movement and translation movement by a transferring assembly provided with a row of raised heads matched with the inner diameter of the wide end of the gun heads;
s5, adjusting the distance between every two adjacent raised heads in the row of raised heads to a preset value, and then moving the taken gun heads up and down through the transfer assembly to place the taken gun heads in the array disc;
s6, repeating the steps S4 and S5 until the gun heads form a specified array.
As a specific embodiment, step S4 includes:
s41, controlling the transfer assembly to perform translational motion to a first preset position in the direction perpendicular to the gap member, and enabling each raised head matched with the inner diameter of the wide end of the gun head to be opposite to each gun head on the gap member;
s42, controlling the raised heads to move downwards for a first preset distance to a second preset position, and inserting the gun head into each raised head; the first preset distance is the distance from the original position (namely the initial position) of the raised head to the loading, unloading and taking gun head;
and S43, controlling the raised head to move upwards to the original position, and then performing translation movement on the transfer assembly in the direction vertical to the gap member to a second preset position.
Optionally, step S5 includes:
s51, adjusting the distance between every two adjacent raised heads to be the distance between every two adjacent gun head jacks on the array disc;
s52, controlling the transfer assembly to move downwards to a fourth preset position, and enabling each gun head to be inserted into a hole in the array disc;
s53, controlling the raised head to retract so as to push away the gun head, so as to unload the gun head.
Optionally, step S4 includes:
s41', controlling the transfer assembly to perform translational motion in the direction vertical to the clearance member to a first preset position, and enabling each raised head matched with the inner diameter of the wide end of the gun head to be opposite to each gun head on the clearance member;
s42', controlling the raised heads to move downwards for a second preset distance to a third preset position, and inserting the gun heads into each raised head; the second preset distance is the distance from the position of the raised head after the gun head is unloaded to the position of the gun head in the vertical direction;
s43'. the nose is controlled to move upwardly to an initial position and then to move translationally in a direction perpendicular to the clearance member to a third predetermined position.
Optionally, step S5 includes:
s51', adjusting the distance between every two adjacent raised heads to be the distance between every two adjacent gun head jacks on the array disc;
s52', controlling the transfer assembly to move downwards to a fifth preset position, and enabling each gun head to be inserted into the hole in the array disc;
and S53', controlling a movable part (or a pushing-down part) arranged above the raised head to push down relative to the raised head so as to push off the gun head.
The array disks are disposed on both sides of the gap member, and the steps S4, S5, S6 are alternately performed for the first array disk and the second array disk.
The invention also provides a pipetting operation method for the cell culture plate, in the method, a pipetting gun is loaded with the gun head array which is arranged by the automatic gun head arranging method for sucking and releasing liquid.
The automatic arranging device for the gun heads can automatically arrange the gun heads in bulk into an array type arrangement mode, can supply the gun heads for the pipette guns and the pipette gun array, provides support for the realization of an automatic pipetting system, is beneficial to reducing the cost of the automatic pipetting system and saves the space occupied by the gun head box storage.
According to the automatic liquid transferring system, the arranged gun heads or gun head arrays can be automatically provided for liquid transferring and liquid preparation through the gun head arranging device, only bulk gun heads are needed to be supplied, and therefore the automatic liquid transferring system provided by the invention can be completely automatic and does not need to supply the arranged boxed gun head arrays.
In the process of cell culture, a pipetting gun is required to be used for performing liquid suction and liquid adding operations on a cell culture plate, a 96-count matrix combination pipetting machine is used in a pipetting system, the consumption of the pipette heads is very high, and the full load is 10 thousands of pipette heads per day. The on-line gun head arranging device has the advantages that firstly, the storage space of the on-site gun heads is reduced, the density of the gun heads which are stacked out of order is much larger than that of the gun heads which are boxed, secondly, the quantity and the volume of waste materials output by the gun heads are reduced, and thirdly, the operation cost of the system can be reduced.
As shown in FIG. 2, the cell culture chamber is square to provide a closed environment for cell growth, and the three-dimensional storage device is placed in the cell culture chamber. An opening is reserved in the side wall of the bottom of the cell culture box, and an isolating door capable of being automatically opened and closed is arranged at the opening and used for isolating the culture box from an external environment. The cell culture box can be accessed through the first conveyor belt and the isolation door. The cell culture box needs to reserve an opening for the cable to go out. In the invention, the cell culture box can provide an environment for cell growth, and the three-dimensional storage device provides three-dimensional storage and automatic taking and placing for the cell culture plate or the cell culture plate.
In the aforementioned, an opening is reserved in the side wall of the bottom of the cell culture box, and an isolation door capable of being automatically opened and closed is arranged at the opening, so that the cell culture plate can enter and exit the three-dimensional storage device by controlling the opening and closing of the isolation door.
When a designated cell culture plate needs to be transferred to a liquid transfer operation platform for liquid replacement or liquid adding operation, the central processing unit determines the storage position of the cell culture plate and sends a control instruction to the rotary robot, the rotary robot carries out arm end positioning and action by moving up and down and rotating in a plane, the cell culture plate is grabbed, and then the rotary robot transfers the cell culture plate to the storage and delivery position of the three-dimensional storage device by moving downwards and rotating in the horizontal plane.
When a cell culture plate needs to be put in storage in a manual delivery area, an operator sends a storage request instruction through a manual interaction interface or presses a storage request button, the cell culture plate is conveyed to an in-out storage platform through a second isolation door by a first conveying belt, a bar code or RFID code reader is arranged on the first conveying belt, the read code is compared with a storage entry code, and after the label code is correct, a storage position is allocated to the cell culture plate by a central processing unit according to the storage request button, the rotary robot is controlled to move to the bottom of a preset position for shoveling or grabbing, then the cell culture plate is transferred to the allocated storage position through up-down movement and horizontal rotation, and then the cell culture plate is released through releasing. And the central processing unit stores the identification information of the cell culture plate and the corresponding storage position information, and performs subsequent transfer operation and information updating according to the information.
The system can realize automatic storage, automatic taking-out and information updating of the cell culture plate, and can also realize automatic liquid changing and adding operations of the cell culture plate.
When cells are seeded into each well of a cell culture plate, culture fluid is replaced, and compounds are added, the cell culture plate needs to be transferred from the three-dimensional storage device to a pipetting platform, and then the cell culture plate is transferred to the pipetting platform. The pipetting platform will be divided into two areas, liquid configuration and liquid addition, each area being configured with a cartesian robot. In the liquid configuration area, if the tasks of inoculating cells and replacing culture liquid need to be executed, the tail end of the first rectangular coordinate robot is connected with a single-channel liquid shifter (which can be a single gun head), and according to the quantity of the required cells and the culture liquid, the required cells and the culture liquid (calculated according to 110% of the total quantity of the required cells and the culture liquid, which is determined by considering the loss in the liquid shifting process) are sucked out of the total sample and injected into a flat groove with the size consistent with that of the cell culture plate. And then the second cartesian robot in the liquid adding area loads and takes the gun head corresponding to the cell culture plate to move to the liquid configuration area, sucks the cells or the culture solution according to the preset volume, moves back to the liquid adding area, and injects the sucked cells or the culture solution into the target cell culture plate. If the task needs to change the cell culture solution, before executing the task of sucking and adding the culture solution, the second cartesian robot in the liquid adding area firstly sucks and discards the culture solution in the cell culture plate to be processed, and after changing the gun head, the operation of sucking and adding the culture solution is executed.
In the liquid configuration area, if the task of adding compounds with different concentrations needs to be executed, the tail end of the first right-angle coordinate robot is used for installing a gun head corresponding to a cell culture plate from a gun head array, a culture solution with a specified volume is injected into a blank cell culture plate in the liquid configuration area, then the pipettor at the tail end of the first right-angle coordinate robot is replaced by a single-hole pipettor, and the single-hole pipettor is used for sucking the compounds with the corresponding volume from a compound mother solution according to an experimental plan and injecting the compounds into the culture solution of each target hole site in the cell culture plate. In the process, after the culture solution is injected, attention needs to be paid to replacing the gun head to avoid cross contamination. Repeating the above steps for multiple times can make different wells of the cell culture plate contain different concentrations of small molecule compounds. And then the configured liquid is sucked and added into the target cell culture plate in the liquid adding area by the second cartesian robot in the liquid adding area, so that the addition of small molecule compounds or compound combinations with different concentrations into specific wells in the cell culture plate can be realized. If the same repeated operation is carried out on a plurality of cell culture plates, a specially-made cell culture plate with a large single-hole volume can be used in the liquid configuration area, and the liquid adding requirement of at least 10 cell culture plates can be met after liquid is configured for one time.
The liquid distribution area is provided with a liquid distribution and storage box automatic warehouse, as shown in fig. 4, which is arranged below the liquid transfer operation platform 2 and mainly used for storing and distributing empty cell culture plates or flat grooves. When the liquid preparation and storage box needs to be taken and used, the central processing unit determines the type of the adaptive liquid preparation and storage box according to the liquid preparation requirement. And the automatic distribution device of the liquid preparation and storage box automatically takes out the adapted liquid preparation and storage box according to the determined type of the liquid preparation and storage box and the information of the storage position of the liquid preparation and storage box and transfers the liquid preparation and storage box to a second conveyor belt. In a preferred embodiment, as shown in fig. 4, the automatic dispensing device of the dispensing liquid storage box is a movable vacuum adsorption head 24, and the dispensing liquid storage box is taken out by vacuum adsorption and is conveyed to the dispensing platform by the second conveyor belt. In the invention, in order to improve the liquid preparation efficiency, two or more liquid preparation platforms can be arranged. At joining in marriage the liquid platform, carry out the liquid feeding operation of various formulas to joining in marriage liquid stock solution box by first right angle coordinate robot, the bottom plate of accomplishing the liquid feeding carries moves liquid imbibition station, joins in marriage the liquid platform and moves the liquid platform and need have accurate location. Certain buffering capacity and grouping capacity are required between the liquid distribution platform and the liquid-transferring and liquid-absorbing station, and the buffering capacity and the grouping capacity are preferably realized by a third conveyor belt. The empty bottom plate which finishes liquid transfer is automatically discarded into a first waste recovery container, specifically, after the liquid containing flat groove or the cell culture plate in the liquid configuration area is used, the empty bottom plate is conveyed to a waste collection place through a second conveyor belt and discarded. In this embodiment, the automatic reservoir for the liquid preparation and storage box, the conveyor belt for the liquid preparation and storage box, and the disposal opening for the liquid preparation and storage box are arranged on a straight line.
For the liquid with larger dosage, such as cell culture solution, etc., a peristaltic pump is configured to ensure the continuous supply of the liquid. A peristaltic pump 23 is provided on the right side of the system as shown in figure 4.
A third conveyor belt is provided between the dispensing station and the pipetting platform and allows up to 4 dispensed cell culture plates to simultaneously rest on the third conveyor belt for efficiency and maximum use of the liquid to be added once dispensed.
The pipetting operation is completed by a first rectilinear coordinate robot 21, the first rectilinear coordinate robot installs the pipette tips from the pipette tip array, then completes the operations of pipetting from the interior of the cell culture micro-cell culture plate, pipetting from the culture solution to the cell culture micro-cell culture plate, pipetting from the batching liquid storage box to the cell culture micro-cell culture plate and the like, automatically discards the pipette tips and replaces new pipette tips after each operation is completed, the discarded pipette tips are recovered into a second waste recovery container, and the discarded cell culture solution is discharged into a third waste recovery container by the pipette tips. And the tail end of the arm of the first right-angle coordinate robot is provided with a movable part for squeezing off the gun head after the liquid transfer operation is finished.
The system is provided with a cover opening device in a liquid adding area, the upper cover opening operation is carried out on a target cell culture plate in a vacuum grabbing and sucking mode before the operation of the cell culture plate, and the upper cover is closed after the liquid transferring operation.
The tail end of the first rectangular coordinate robot is provided with an actuator which can synchronously suck and extrude solution and replace the gun heads for 96 assembled and disassembled gun heads (when the cell culture plate is a 96 cell culture plate), and the air pressure difference is adopted to realize the functions of sucking and extruding the solution of the gun heads. When no gun heads are arranged on the end effector, the rectangular coordinate pipetting robot moves the end effector to a position right above the gun head box, then vertically moves downwards, and 96 gun heads are simultaneously mounted. The used gun head is extruded out through a moving part arranged on the end effector. By the technical means, the automatic loading and discarding of the cell operation gun head and the automatic collection of cell culture waste liquid can be realized.
In the present invention, the operation of unloading and pipetting the cell culture plates stored in the cell culture plate three-dimensional storage device is performed based on user instructions and automatic detection indexes, and the identification of the stored cell culture plates is realized based on identification codes attached thereto. As a specific embodiment, as shown in fig. 1, a touch display panel is provided outside the cell culture area as a man-machine interface for a user to input commands and display the results of cell culture monitoring and information related to pipetting of cell cultures.
In order to realize the automatic pipetting process, the rotary robot, the first rectangular coordinate robot, the second rectangular coordinate robot, the first conveyor belt, the second conveyor belt, the third conveyor belt and the fourth conveyor belt are respectively provided with a control submodule (or become a driving module), and each control submodule controls each device to carry out corresponding operation according to an operation instruction from the central processing unit. The invention manages each sub-module and coordinates the communication among the sub-modules by carrying an MES software system developed based on an ROS platform on a central processing unit, the communication mode among the sub-modules is realized mainly based on a 'theme/message' mechanism of the ROS platform, and a robot operating program required by ROS platform development equipment is utilized.
The central processor comprises the following modules: the storage position distribution module is used for distributing storage positions for the cell culture plates which are put in storage according to the storage request and the storage state information of the three-dimensional storage device; the information recording module is used for recording and updating the storage state information of the three-dimensional storage device and the related information of the cell culture plate; and the control module controls the rotary robot, the first rectangular coordinate robot and the second rectangular coordinate robot to cooperatively operate according to the serial number and the operating instruction of the cell culture plate.
The following describes specifically a control method of the automatic pipetting system provided by the present invention, where the control method is executed by a central processing unit, and specifically includes:
receiving a user instruction through a human-computer interaction interface;
analyzing the user command, and determining that the cell culture plate in the manual cross connection area is received for storage, the specified cell culture plate on the cell culture plate three-dimensional storage device is taken out to the manual cross connection area, and the specified cell culture plate is transferred to the liquid transferring operation platform for specified liquid transferring operation;
if the cell culture plate of the manual cross-connecting area is received for storage, sending an instruction to the rotary robot control sub-module;
the rotary robot moves to the manual cross connection area according to the instruction, scans the received identification code information of the cell culture plate and captures the cell culture plate;
distributing storage positions for the cell culture plates according to the identification code information and the storage record information of the cell culture plate three-dimensional storage device, and sending the position information to the rotary robot control submodule,
the rotary robot moves according to the position information to transfer the control to the storage location and release the cell culture plate.
If the specified cell culture plate on the cell culture plate three-dimensional storage device is taken out to the manual cross-over area, searching storage position information of the specified cell culture plate in the cell culture plate three-dimensional storage device according to input information, and outputting the storage position information to the rotary robot control submodule;
the rotary robot control submodule controls the rotary robot to move to the storage position, grabs the cell culture plate and transmits the cell culture plate to the stereoscopic storage device warehouse-in/out platform; the cell culture plate triggers a sensor at the end of a fourth conveyor belt, which transports the cell culture plate to an artificial interface.
If the cell culture plate is transferred to the liquid transferring operation platform to perform the designated liquid transferring operation, the rotary robot grabs the cell culture plate according to the cell culture plate storage position information, transfers the cell culture plate to the first preset position and conveys the cell culture plate to the liquid transferring operation platform by the first conveyor belt. In this embodiment, the user needs to input the identification of the cell culture plate to be operated, the name of the liquid to be added, and the dosage in the human-computer interface, and if the cell liquid needs to be sucked out of the target cell culture plate, the sucked dosage. The first rectilinear coordinate robot performs a liquid dispensing operation according to an input. In a preferred embodiment, the arm end of the first rectilinear coordinate robot is provided with a first recognition component for recognizing the total liquid sample, sucking the total liquid sample according to user input or parameter requirements, and configuring the total liquid sample in the liquid preparation and storage box. The processor determines the liquid preparation time according to the total sample type quantity, the total sample dosage, the gun head changing times and the liquid preparation times; and determining the starting time of the transfer of the target cell culture plate, the time of acquiring the liquid from the liquid preparation storage box by the second rectangular coordinate robot and the time of transferring the liquid to the target cell culture plate according to the liquid preparation time, the transfer time (generally fixed time) of the target cell culture plate to the liquid transferring platform and the liquid transferring operation time. And finally, the first rectangular coordinate robot, the second rectangular coordinate robot and the rotary robot are ensured to work in a coordinated manner.
The first right-angle coordinate robots in the liquid preparation area can be two, and because the liquid configured by different cell culture plates is different in the liquid preparation process, the process of injecting liquid into different holes of one liquid preparation liquid storage box cell culture plate for multiple times is possibly needed, so that the liquid preparation time is possibly several times longer than the time of transferring the liquid to a target cell culture plate corresponding to one cell culture plate, and at least two first right-angle coordinate robots can be arranged in the liquid preparation area to improve the working efficiency.
The system provided by the invention can automatically access a 96-well cell culture plate (or other well culture plates) and perform cell inoculation and liquid change culture on the cell culture plate, can regularly add small molecule compounds with specified concentration to specified culture wells in the 96-well culture plate according to the preset instruction of a user, and supports automatic addition of the same small molecule compounds, different small molecule compounds or combination of a plurality of small molecule compounds with different concentrations to different culture wells of the same 96-well culture plate.
The equipment provided by the invention is equipment with strong specialty, has beautiful appearance and accurate function, can maintain the cleanliness, gas and humidity requirements meeting the requirements of cell culture, does not generate any pollutant in the operation process, and does not need to add maintenance materials of lubricating oil. In addition, the cleaning, disinfection and maintenance requirements of the equipment in the operation process are considered in the overall function design of the equipment, the airtightness, the gas exchange function, the humidity maintaining function, the disinfection function and the like of the equipment are brought into the overall design, so that the equipment meets the actual requirements of automatic cell culture and compound screening and has strong market competitive advantages.
In the description provided herein, numerous specific details are set forth. It is understood, however, that embodiments of the invention may be practiced without these specific details. In some instances, well-known methods, structures and techniques have not been shown in detail in order not to obscure an understanding of this description.
Similarly, it should be appreciated that in the foregoing description of exemplary embodiments of the invention, various features of the invention are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the invention and aiding in the understanding of one or more of the various inventive aspects. However, the disclosed method should not be interpreted as reflecting an intention that: that the invention as claimed requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed embodiment. Thus, the claims following the detailed description are hereby expressly incorporated into this detailed description, with each claim standing on its own as a separate embodiment of this invention.
It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be able to design alternative embodiments without departing from the scope of the appended claims. In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim.
Claims (7)
1. An automatic liquid transfer system is characterized by comprising a cell culture box, a liquid preparation and transfer operation device and a gun head automatic finishing device, wherein a hollow cylindrical upper and lower multi-layer circular platform component is arranged in the cell culture box and used for placing a cell culture plate; the rotary robot is arranged at the top of the cell culture box in an inverted manner, the vertical movement is realized along a vertically arranged track, the track penetrates through the center of the rotary robot body, and the rotary robot is used for taking and delivering a cell culture plate in a hollow position of the circular platform component by moving up and down and rotating in a horizontal plane; the automatic gun head arranging device arranges disordered gun heads into a gun head array by using vibration and steric hindrance; the liquid preparation and pipetting operation device comprises a first rectangular coordinate robot and a second rectangular coordinate robot, wherein an array pipettor is arranged at the tail end of the arm of the first rectangular coordinate robot, a pipette head array is arranged on a pipette head array platform, liquid is sucked from a liquid preparation storage box on the liquid preparation platform, and the liquid is injected into the cell culture plate on the pipetting platform; and a pipettor is arranged at the tail end of the arm of the second rectangular coordinate robot and used for sucking the culture solution from the total sample and injecting the sucked culture solution into the solution preparation storage box on the solution preparation platform.
2. The system of claim 1, wherein the dispensing and pipetting device comprises a dispensing reservoir configured to draw the dispensing reservoir to the dispensing platform via a vacuum gun head.
3. The system of claim 1, comprising a central processor, wherein the central processor loads an upper computer software operating system based on the ROS platform to control the rotary robot, the first cartesian robot and the second cartesian robot to operate cooperatively.
4. A control method for an automatic pipetting system as recited in any one of claims 1-3, characterized in that the method comprises:
identifying label information of the warehoused cell culture plate;
distributing storage positions for the cell culture plates which are put in storage according to the existing storage state information of the cell culture box and updating the storage state information;
storing operation information for each cell culture plate according to user input or cell culture plate label identification results;
controlling a rotary robot to move according to the operation information and the storage state information, and transferring the stored cell culture plate to an in-out warehouse platform which is positioned below the bottom of the circular platform component;
transferring the cell culture plate to a pipetting platform by sensing the cell culture plate;
and controlling the pipettor or array to load and unload the pipette heads from the pipette head array according to the cell culture plate operation information, and performing liquid preparation and pipetting operations.
5. A method according to claim 4, wherein the arm ends of the first and second cartesian robots are controlled to act to squeeze the lance tip off when it is required to change it.
6. The method according to claim 4, wherein controlling the pipette or the pipette array to load and unload the tips according to the cell culture plate operation information comprises:
controlling a second cartesian robot carrying a liquid transfer device to load and take the gun head and suck liquid from the total sample;
injecting the sucked liquid into a liquid preparation storage box at a liquid preparation platform;
after the liquid is prepared, controlling the first rectangular coordinate robot to absorb the liquid in the liquid preparation and storage box on the liquid preparation platform, and transferring the liquid to the liquid transfer platform to perform liquid adding operation on the cell culture plate to be operated;
after the liquid preparation and storage box is used, the conveying device is controlled to convey the liquid preparation and storage box to the recovery device.
7. A method according to claim 4, wherein the gun tip automatic arrangement device is controlled to carry out gun tip arrangement according to the cell culture plate operation information so as to provide at least one array of gun tips.
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| CN114634867A (en) * | 2022-03-30 | 2022-06-17 | 上海汇像信息技术有限公司 | Cell strain culture screening system and method |
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| CN115790382A (en) * | 2022-12-13 | 2023-03-14 | 南京诺唯赞生物科技股份有限公司 | Position automatic debugging tool, liquid transfer device debugging assembly and debugging method |
| CN116660566B (en) * | 2023-07-26 | 2023-10-17 | 四川徕伯益自动化技术有限公司 | Position identification method, system, terminal and medium for sample liquid |
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| JP2002202315A (en) * | 2001-12-21 | 2002-07-19 | Matsushita Electric Ind Co Ltd | Dispensing apparatus with incubator |
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