CN212142666U - An automatic pipetting system - Google Patents

Abstract

The utility model discloses an automatic liquid transferring 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 multilayer circular platform component is arranged in the cell culture box; the rotary robot is arranged at the hollow position of the cylinder 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 comprises a roller part and an array forming part, wherein the roller part arranges disordered gun heads into a line shape through vibration and steric hindrance; the array forming part arranges one row of gun heads into an array, and the liquid preparation and pipetting operation device performs liquid suction operation or liquid adding operation on the cell culture plate conveyed from the cell culture box by using the gun head array. Through the utility model discloses, can carry out automatic cell inoculation, culture solution change, the addition of regulation and control factor or guide's compound, the automatic storage of cell culture board etc..

Description

An automatic pipetting system

technical field

The utility model relates to the technical field of life science, in particular to an automatic pipetting system for cell culture.

Background technique

Cell-based gene function research and drug lead compound screening are two important links in the process of basic life science research and drug development. It is necessary to add different concentrations of regulatory factors or small molecule compounds to the cell culture medium. Status and functionality are checked. The above studies all involve the large-scale culture of cells, the addition of different concentrations of small molecule compounds to the cultured cells, and the detection of the effects of the added compounds on the cells. Under the current circumstances, most laboratories at home and abroad mainly rely on small equipment, such as pipettes, electrophoresis instruments, centrifuges, PCR instruments, etc. to complete the above links. These devices provide material guarantee for the development of many experiments, but most of them can only be regarded as tools or semi-automatic devices, and their operation usually requires the participation of researchers in the whole process, and can only complete one or several links in a complete experimental process. There are big problems in the aspects of experiment personnel cost, experiment efficiency and stability of experiment results, and errors or mistakes are easily caused by factors such as experiment method and technical stability among researchers. Especially in the aspect of new drug research and development, most basic research laboratories related to life sciences cannot bear the pressure of human input brought by repetitive cell culture and compound screening work, resulting in very few laboratories involved in research work related to drug lead compound screening. .

How to standardize and automate the research process is not only a major issue related to research cost and efficiency, but also a key factor in promoting rapid discovery of life and health-related research and product development.

Although the screening of lead compounds at the level of pharmaceutical companies such as pharmaceutical companies relies on mechanical operations, the instruments used are either for automated cell culture, or for the detection of cultured cells. There is no equipment that can be fully automated on microplates. High-throughput cell culture, medium exchange, and addition of different compounds to different culture wells for functional detection.

Utility model content

In view of the above problems, the present invention is proposed to provide a technical solution to overcome the above problems or at least partially solve the above problems. Therefore, one aspect of the present utility model provides an automatic pipetting system, which is characterized in that it includes a cell incubator, a liquid dispensing and pipetting operation device, and an automatic pipetting device, wherein a hollow cylinder is arranged in the cell incubator. The upper and lower multi-layer annular platform members of the type are used to place the cell culture plate; the rotary robot is arranged in the hollow position of the cylinder, and the cell culture plate is transported and transported by moving up and down and rotating in the horizontal plane; the automatic arrangement device of the pipette tip It includes a roller part and an array forming part, wherein the roller part arranges the disordered pipette tips into a line through vibration and steric hindrance; the array forming part organizes the line-shaped pipette tips into an array, and the liquid dispensing and pipetting operation The device includes a controlled pipette or an array of controlled pipettes, and the pipette tips or pipette tip arrays arranged by the automatic arrangement device for loading and unloading pipette tips are used to perform suction operation or liquid addition for the cell culture plate transferred from the cell culture incubator. operate.

Optionally, the rotary robot is placed upside down on the top of the cell culture incubator.

Optionally, the annular platform member is composed of at least three arc surfaces.

Optionally, the liquid dispensing and pipetting operation device includes a first rectangular coordinate robot, a single-channel pipette is installed at the end of its arm, and a pipette tip is loaded from the pipette tip array, and the liquid is dispensed according to the specified compound and concentration. The station dispenses the solution to the dosing vessel.

Optionally, the liquid dosing and pipetting operation device includes a liquid dosing container storage library, and the liquid dosing container is sucked to the liquid dosing station by a vacuum suction head.

Optionally, the liquid dispensing and pipetting operation device includes a second Cartesian coordinate robot, a multi-channel pipette is installed at the end of its arm, and the pipette tips are loaded from the pipette tip array, and the liquid is sucked from the liquid dispensing container and pipetted. The workstation fills the cell culture plate with liquid.

Optionally, the system includes a central processing unit, and the central processing unit loads a host computer software operating system based on the ROS platform, and controls the rotary robot, the first rectangular coordinate robot, and the second rectangular coordinate robot to cooperate with each other.

Optionally, movable parts are provided at the ends of the first and second Cartesian coordinate robot arms for squeezing out the tip.

Optionally, the liquid dosing and pipetting operation device includes a conveyor belt for transferring the dosing container to the liquid dosing container recovery device.

Optionally, the drum part includes: a drum, the inner side wall of the drum is provided with a bar perpendicular to the rotation direction, the drum is driven to rotate by a motor, the two ends of the drum are open, and the vertical grooves are located in the drum, Parallel to the central axis of the drum, the width of the groove 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; the vertical groove extends out of one end of the drum opening, and is fixed by the device body outside the end opening, The funnel, which is arranged in the drum, is located just above the vertical groove, and is fixed by the device body outside the end opening; the array forming part includes a transfer assembly, which moves in a direction perpendicular to the length of the gap, and part of the assembly is carried out. The up and down action is used to load and remove the pipette tip on the gap and transfer it to the array plate.

The technical solutions provided in the embodiments of the present application have at least the following technical effects or advantages:

The system provided by the utility model can realize the automatic cell seeding, the replacement of the culture medium, the addition of regulatory factors or lead compounds, and the automatic supply of the pipette tip array for the well plate (including the currently commonly used 96-well plate) for culturing cells. Features such as automatic removal of specific 96-well plate samples for further testing. Compared with similar products on the market, the equipment provided by the utility model has the advantages of comprehensive functions and significantly lower prices. While satisfying laboratory use, it is also suitable for promotion as a market-oriented product, thereby improving my country's popularity in the field of corresponding instruments. International competitiveness and promote the development of related research.

The above description is only an overview of the technical solution of the present invention, in order to be able to understand the technical means of the present invention more clearly, it can be implemented according to the content of the description, and in order to make the above-mentioned technical solution of the present invention and its purposes, features and advantages To make it more obvious and easy to understand, the following specific embodiments of the present invention are given.

Description of 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 accompanying drawings are only for the purpose of illustrating the preferred embodiments, and are not considered to be a limitation of the present invention. Also, the same components are denoted by the same reference numerals throughout the drawings. In the attached image:

Fig. 1 is the overall top view of the automatic pipetting system proposed by the utility model;

2 is a top view of a three-dimensional storage device for a cell culture plate;

Fig. 3 is the side view of the liquid dispensing and pipetting operation device in the utility model;

4 is a perspective view of the liquid dispensing and pipetting operation device together with the three-dimensional storage device in the utility model;

Fig. 5 is the three-dimensional structure diagram of the automatic arrangement device of the gun head proposed by the utility model;

Fig. 6 shows the concrete structure diagram of the drum part of the gun head automatic arranging device proposed by the present utility model;

Fig. 7 shows the specific structure diagram of the guide part of the gun tip in the automatic arranging device of the gun tip proposed by the present invention;

Fig. 8 shows the perspective view of the part arranged into an array in the automatic arrangement device of the gun head proposed by the present invention;

Fig. 9 shows a top view of the parts arranged into an array in the automatic gun head arrangement device proposed by the present invention; Fig. 10 shows a side view of the structure of the transfer assembly.

Detailed ways

Exemplary embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. While exemplary embodiments of the present invention are shown in the accompanying drawings, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided so that the present invention will be more thoroughly understood, and will fully convey the scope of the present invention to those skilled in the art.

The utility model provides an automatic liquid pipetting system, as shown in FIG. 1 , the system includes three parts: a cell culture area 1 , a liquid pipetting operation area 2 , and an automatic pipetting device area 3 . The cell culture area 1 and the pipetting operation area 2 are arranged side by side, both of which are closed spaces, and each space is equipped with an air purification and exchange device, a _CO2 concentration and humidity control device (not shown in the figure), with To ensure that the environment of the cell culture area and pipetting platform meets the cleanliness, gas and humidity requirements for routine cell growth. A first conveying device is arranged between the two spaces, and the orifice plate in the cell culture area is conveyed to the pipetting operation platform through the first conveying device. Since the two spaces are closed spaces, the two spaces are connected by an openable mechanical door. The size of the mechanical door is slightly larger than that of a 96-well cell culture plate to ensure that the well plate can pass through smoothly. The cell culture area includes a cell incubator 11 , a three-dimensional storage device 12 for well plates, and a rotary robot 13 , and the rotary robot 13 is capable of picking and placing well plates at any storage position on the three-dimensional storage device 12 for well plates. , when the rotary robot 13 receives an instruction to transfer a certain orifice plate to the pipetting operation area 2, the rotary robot 13 moves up and down and rotates in the horizontal plane to the storage position of a certain orifice plate, and the end of the arm of the rotary robot 13 moves Grab a certain well plate and transfer it to the first predetermined position at the bottom of the three-dimensional storage device 12 (the storage platform), and then the first transfer device transfers the well plate to the second predetermined position in the pipetting operation area 2 position, the first conveying device includes a first conveying belt, a first sliding trolley, or a first rolling trolley, and the pipetting operation area 2 is divided into a liquid configuration area and a liquid addition area. In the liquid configuration area, the liquid The addition area is respectively provided with a first rectangular coordinate robot 21 and a second rectangular coordinate robot 22. The end of the arm of the first rectangular coordinate robot 21 is connected with a pipette, which is used to transfer the required cells and/or culture solution from the total sample It is sucked out and injected into the liquid dispensing liquid storage box, and the liquid dispensing liquid storage box is adapted to the orifice plate; the end of the arm of the second Cartesian coordinate robot 22 carries a gun tip corresponding to the orifice plate, which is used for dispensing the dispensing liquid storage box. The cells and/or culture liquid in the liquid storage box are transferred to the liquid addition area and injected into the target well plate; the injected target well plate is transferred back to the cell incubator 11 by the second transfer device; the rotary robot 13 will The transmitted orifice plate is placed in the original position of the orifice plate three-dimensional storage device 12; the system also includes a central processing unit (not shown in the figure), and the central processing unit loads the upper computer software operating system based on the ROS platform to control The rotary robot 13 , the first rectangular coordinate robot 21 , and the second rectangular coordinate robot 22 cooperate to operate.

Through the above technical scheme, the cell culture plate is automatically accessed, and the cell inoculation and medium exchange culture are performed on the orifice plate.

The three-dimensional storage device 12 is in the shape of a hollow cylinder, as shown in Figures 2 and 3, and specifically includes: upper and lower multi-layer annular platform members 121 for placing cell culture well plates; not shown in ) for supporting the annular platform member 121 . The rotary robot 13 is arranged in the hollow position of the cylinder and can be lifted and lowered freely, and is used to grab the orifice plate from the annular platform member to the first predetermined position based on the identification code of the orifice plate, or grab the orifice plate from the first predetermined position. The orifice plate is taken and placed on the annular platform member; the human-machine interface platform 4, located in front of the three-dimensional storage device, is used to receive the orifice plate for cell culture; the first transfer device (not shown in the figure) is used to transfer the The orifice plate is transferred from the human interface platform to or from the first predetermined location to the human interface platform, the first predetermined location being below the bottom of the annular platform member.

In the present invention, the upper and lower multi-layer annular platform members 121 do not rotate and do not need to move up and down, so as to provide a stable culture environment for the orifice plate for cell culture and avoid disturbance to the cultured cells . Through the rotary robot 13 that can move up and down and rotate 360 degrees in the horizontal plane, any orifice plate picking problem can be realized, and because the rotary robot 13 is placed at the axis of the cylinder, the length of the robot arm is as short as possible, and the mechanical The technical effect of the arm extension distance is as short as possible, so that the self-balancing problem of the rotary robot can be well solved, and the disturbance to the cell culture environment can also be reduced to a certain extent.

As a preferred embodiment, the annular platform member 121 is composed of three arc surfaces, and a gap can be left between each arc surface, and no mechanical connection is required between them, and each arc surface is fixed in a vertical direction. On the support column, three vertical support columns can be arranged corresponding to the arc surfaces of the three ends. The vertical support columns are located in the radial middle position of the annular support member. . As another embodiment, each segment of the arc-surface platform member may be supported by a hollow cylindrical vertical support frame. The structural design of the two embodiments makes the vertical support column not affect the operation of the mechanical arm and the mechanical gripper, and facilitates disassembly, installation, and cleaning of the three-dimensional storage device.

Each predetermined number of storage locations on the annular platform member is a unit, and the storage unit is used as a management unit. In terms of capacity, up and down, multi-layer support members are designed, and a three-dimensional storage device can store 50-200 orifice plates. The storage location of every 50 well plates can be defined as a unit, and users can configure 1 to 4 storage units according to their needs. The user needs to expand the storage capacity, which increases the flexibility of the system. Generally speaking, the three-dimensional storage device designed in the present invention has a storage capacity of 50-200 orifice plates. The orifice plate has various specifications, such as 6-well plate, 12-well plate, 24-well plate, 96-well plate, 384-well plate, etc. In this utility model, the 96-well plate is mainly used for description.

Cell culture has high environmental requirements, so cleanliness needs to be taken seriously and fully considered when developing a three-dimensional storage device. As a specific embodiment, the annular platform member is composed of three arc surfaces, and the three arc surfaces are fixed on three vertical support columns. This structural design is easy to disassemble and install, and is convenient for cleaning.

The rotating robot is arranged upside down on the top of the three-dimensional storage device, which can ensure that the bottom of the storage device is smooth, which can not only prevent liquid from remaining on the rotating robot, but also easily clean the storage device. It is beneficial to keep the bottom of the robot and the three-dimensional storage device clean. The rotary robot includes 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, and the track passes through the center of the body of the rotary robot, so that the robot can be easily balanced. Rotating, the turntable is driven by a motor set locally.

Taking into account the requirements of cell culture on environmental cleanliness, the rotating shaft of the rotary robot described in this utility model adopts IGUS wear-resistant engineering plastics, which are mainly used in aircrafts at present to avoid powder caused by friction between lubricating oil and metal. . The rotary robot is installed on the top of the storage device in an inverted form,

As a first specific embodiment, the mechanical gripper includes a first clip and a second clip, and the first clip or the second clip is driven by a driving device to move so that the first clip and the second clip can be clamped Tighten or loosen, so that the orifice plate can be clamped or released.

As a second specific embodiment, the mechanical gripper adopts two or three pairs of "L"-shaped members. Each pair of L"-shaped members is driven by a driving device to move toward each other or in opposite directions, so as to perform a clamping operation or a releasing operation.

In the above-mentioned first and second embodiments, in order to facilitate the grasping of the orifice plate by the mechanical gripper, the radial dimension of the annular platform member needs to be designed, and the radial dimension is smaller than the radial dimension of the orifice plate and ensures that the After the orifice plate is placed, the orifice plate protrudes enough to be grasped by the mechanical gripper. Or design the shape of the annular platform member so that its shape matches the shape of the clip or "L"-shaped member of the mechanical gripper, so that the lower clip or the "L"-shaped member of the mechanical gripper can extend into The gripping action is performed under the circular platform and can be retracted. In these two embodiments, the mechanical gripper only needs to complete the operations of extending, tightening, and retracting.

As a third specific embodiment, the mechanical gripper adopts a fork structure. In order to facilitate the fork to take and send the orifice plate, the annular platform member on which the orifice plate is placed is matched with the fork structure and is "comb-shaped". in this embodiment. The mechanical gripper needs to be extended, slightly raised, and retracted. Through the operation of extending, the fork is inserted under the orifice plate, and by the operation of slightly rising, the orifice plate is supported on the fork, and by the operation of retracting, the fork completes the process of removing the orifice plate from the annular platform member.

In the present invention, the orifice plate may vibrate slightly only when the orifice plate is taken or conveyed. In other cases, the orifice plate is in a static state, thereby greatly reducing the disturbance to the cell culture.

Since the identification information of the orifice plate needs to be identified when the rotary robot receives the orifice plate in the man-machine interface area, any operation on the orifice plate thereafter is performed based on the identification information. Therefore, an identification device is provided at the end of the arm of the rotary robot near the mechanical gripper, which is used to identify the label on the orifice plate to obtain its identification information.

The rotary robot further includes a first driving device, a second driving device, and a third driving device. The first driving device is provided on the body and is used to drive the body to move up and down along the vertical track. The second driving device is provided On the rotary robot body or the turntable, it is used to drive the turntable to rotate in the horizontal plane, thereby driving the robot arm to rotate; the third driving device is arranged on the robot arm and is used to drive the mechanical gripper to perform grasping or releasing operations.

Since the rotary robot is installed in the hollow position of the hollow cylindrical three-dimensional storage device, the rotary robot can transfer the orifice plate from the annular member to the three-dimensional through the up and down movement of the body, the rotation of the mechanical arm, and the extending and retracting actions. There is a certain distance from the first predetermined position to the man-machine interface platform for the storage device in and out of the storage platform, and the transmission of the orifice plate over this distance is completed by the first transmission device, and the first transmission device is the first slideway And the first moving trolley on the first slideway, or the first conveyor belt, the best implementation is that the first predetermined position and the supporting surface of the moving trolley or the first predetermined position and the supporting surface of the first conveyor belt are on the same horizontal plane, It is convenient to complete the transfer between the orifice plate, from the first predetermined position to the mobile trolley or the first conveyor belt, and from the first mobile trolley or the first conveyor to the man-machine handover platform The transfer can be done through the first toggle lever ( or a toggle block), a second toggle lever (or toggle block), and the toggle lever (or toggle block), the first moving trolley, and the first conveyor belt are triggered by a sensing device that detects the orifice plate.

The three-dimensional storage device includes a central processing unit and a display. In addition to the display function, the display also serves as a human-computer interaction interface. The central processing unit and the display are arranged in front of the outer side of the three-dimensional storage device, preferably above the man-machine interface platform, so as to facilitate user operation. The central processing unit sends instructions to the first driving device, the second driving device, and the third driving device to control the rotary robot to perform a transfer operation on the orifice plate.

The following describes the automatic storage control process of the three-dimensional storage device:

When the user needs to put the cell culture plate into the three-dimensional storage device, place the cell culture plate on the human-computer interface platform.

The man-machine interface platform is provided with a first identification device (such as a two-dimensional code label reading head), the first identification device performs an identification operation, and sends the detected identification information to the central processing unit, and the central processing unit according to the The identification information assigns the storage location of the stereoscopic storage device to it and saves its related setting information. The central processing unit sends an instruction to the rotary robot, and the rotary robot controls the first driving device according to the instruction to drive the robot body to move downward along the track to the bottom for standby.

After recognizing the identification information of the orifice plate, the identification device triggers the action of the first lever and the first conveying device, so that the orifice plate is transferred to the first conveying device and conveyed by the first conveying device.

The first predetermined position is provided with a first sensing device, and when the first sensing device senses the orifice plate, it triggers the second lever to perform corresponding actions according to the sensed position of the orifice plate, specifically: sensing the orifice plate When the orifice plate is on the first transmission device, the second lever is triggered to perform the toggling action from the first transmission device to the first predetermined position. For the toggle action from the first predetermined position to the first conveying device, the central processing unit where the central processing unit is located controls the rotary robot to perform movement according to the sensing signal of the first sensing device to complete the transfer from the first predetermined position to the allocated storage position.

Through this control process, automatic storage of the orifice plate can be realized. When the user needs to take out a certain orifice plate, he only needs to input the identification information of the orifice plate, and the rotary robot and the first conveying device will complete the reverse process of the above control process, thereby realizing automatic take-out.

The three-dimensional storage device is placed in a cell incubator. As shown in FIG. 2 , the cell culture incubator is square and provides a closed environment for cell growth. The three-dimensional storage device 2 is placed in the cell culture incubator 1 to form a closed cell culture environment. An opening is reserved in front of the bottom of the cell culture incubator 1 , and a first isolation door that can be automatically opened and closed is arranged at the opening to isolate the incubator from the external environment. The opening and closing of the first isolation door is controlled based on the identification information of the first identification device and the sensing information of the first sensing device, so that the well plate can enter and exit the cell culture incubator. Under the cell culture incubator 1, an opening for cables to go out needs to be reserved.

When it is necessary to perform a pipetting operation on the orifice plate stored in the three-dimensional storage device, the rotary robot grabs the orifice plate from the annular platform member based on the orifice plate identification information to the storage platform, and the first conveying device It is also used for transferring the orifice plate from the storage platform to the pipetting operation platform, the storage platform is located under the bottom of the annular platform member, and the pipetting operation platform is located on one side of the three-dimensional storage device.

As shown in FIGS. 3 and 4 , the liquid dispensing and pipetting area includes a first rectangular coordinate robot 21 (preferably two), which is responsible for transferring the dispensing liquid to the cell culture plate in the liquid pipetting area, and a second rectangular coordinate robot 22 (preferably two) in the pipetting area. For two), in the dosing area, it is responsible for drawing the liquid from the original for dosing. The liquid dosing area also needs to deal with the liquid dosing plate. The liquid dosing area is large, and the moving path of the liquid dosing plate is a straight line, which is convenient to transfer the discarded liquid dosing plate to the collection port through the conveyor belt.

The following describes the workflow for the automatic transfer of well plates from the stereo storage device to the pipetting platform for pipetting:

When the pipetting operation needs to be performed on a cell culture plate in the three-dimensional storage device, the operation is performed according to the user's instruction in one case, and the central processing unit issues an instruction according to the setting information of the cell culture plate in the other case.

The rotary robot 3 operates according to the pipetting instructions (including the identification information of the orifice plate and the storage position information), and takes out the orifice plate (hereinafter referred to as the target orifice plate) that needs to be pipetted from the annular support member and transfers it to the warehouse The platform is provided with a second sensing device, which triggers the action of the first transmission device when the target orifice plate is sensed. The target orifice plate is transferred to the pipetting platform through the first transfer device, and a second identification device is provided on the pipetting operation platform. The second identification device performs an identification operation, and sends the detected identification information to the central processing unit, and the central processing unit obtains its pipetting control related information according to the identification information, and sends the pipetting operation to the first rectangular coordinate robot. instruction, before that, the central processing unit controls the second right-angle robot to perform the liquid dispensing operation according to the orifice plate operation information.

After the pipetting operation is completed, 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 down along the orbit to the bottom according to the instruction for standby.

When the second sensing device detects the target orifice plate, it sends a command to the rotary robot through the central processing unit to transfer the target orifice plate to the storage position.

Through this control process, the automatic pipetting process of the orifice plate can be realized.

When a designated orifice plate needs to be transferred to the pipetting operation platform for liquid exchange or liquid addition operation, the central processing unit determines the storage position of the orifice plate, and sends a control command to the rotary robot. Move up and down and rotate in the plane to position and move the end of the arm, grab the orifice plate, and then the rotary robot transfers the orifice plate to the second predetermined position at the bottom of the three-dimensional storage device by moving downward and rotating in the horizontal plane, It is then transferred to the pipetting platform 2 by the second transfer device.

The three-dimensional storage device provided by the utility model cooperates with a cell incubator with corresponding entrances and exits, which can provide a sealed and stable environment for cell culture, and at the same time, is separated from the pipetting operation area in the environment, thereby reducing the space of the cell incubator. At the same time, the maintenance cost of the cell culture environment is reduced, and the design of each conveying device greatly reduces the disturbance caused by the operation of the orifice plate for conveying, and is also conducive to the cleaning of the cell culture incubator.

The three-dimensional storage device provided by the utility model can automatically access the 96-well cell culture plate (or other well culture plate), perform cell inoculation and medium-changing culture on the well plate, and can periodically transfer the 96-well culture plate to the 96-well culture plate according to the user's preset instructions. Add a specified concentration of small molecule compounds to the designated culture wells in the plate, support automatic addition of different concentrations of the same small molecule compound, different small molecule compounds, or multiple small molecule compounds to different culture wells of the same 96-well culture plate The combination.

The three-dimensional storage device provided by the utility model can realize the automatic entry and exit of the orifice plate, thereby providing support for realizing the automatic liquid exchange and liquid addition operations of the orifice plate.

When inoculating cells into each well of the orifice plate, replacing the culture medium and adding compounds, the well plate needs to be transferred from the three-dimensional storage device to the pipetting operation platform, which is realized on the pipetting operation platform. The pipetting operation area will be divided into two areas: liquid configuration and liquid addition, and each area is equipped with at least one Cartesian coordinate robot. The first rectangular coordinate robot in the liquid addition area picks up the pipette tip corresponding to the well plate and moves it to the liquid configuration area. After sucking the cells or culture medium according to the preset volume, it moves back to the liquid addition area and injects the sucked cells or culture medium into the liquid addition area. target well plate. If the task needs to replace the cell culture medium, before performing the task of sucking and adding the culture medium, the first rectangular coordinate robot in the liquid addition area needs to first suck and discard the culture medium in the well plate to be processed, and then perform the operation after replacing the pipette tip. The operation of aspirating and adding culture medium. In the liquid configuration area, the end of the second Cartesian coordinate robot is connected to a single-channel pipette (which can be a single pipette tip), and according to the required amount of cells and medium, the required cells and medium (according to the required cells and medium 110% of the total volume of the culture solution, which is determined by taking into account the loss during pipetting), is drawn from the total sample and injected into a flat groove consistent with the size of the well plate. In the liquid configuration area, if you need to perform the task of adding compounds of different concentrations, the end of the second Cartesian coordinate robot picks up the pipette tips corresponding to the orifice plate from the pipette head array, and first injects the specified volume into the blank orifice plate in the liquid configuration area. Then, replace the pipette at the end of the second Cartesian robot with a single-hole pipette. According to the experimental plan, the single-hole pipette draws the corresponding volume of compound from the compound mother solution and injects it into each target in the well plate. in the culture medium of the well. During this process, after injecting the culture medium, care should be taken to replace the pipette tip to avoid cross-contamination. By repeating the above actions for many times, different wells of the well plate can contain different concentrations of small molecule compounds. Next, the first rectangular coordinate robot in the liquid addition area sucks and adds the configured liquid to the target well plate in the liquid addition area, so that small molecule compounds or compounds of different concentrations can be added to specific wells in the well plate. combination. If the same repeated operation is performed on multiple orifice plates at the same time, a specially-made orifice plate with a larger single-hole volume can be used in the liquid configuration area, and after the liquid is configured once, at least 10 orifice plates can be added.

In the liquid configuration area, there is an automatic library for liquid dispensing and storage boxes, which is arranged at the lower part of the pipetting operation area 2, mainly for storing empty orifice plates or flat tanks for liquid dispensing. When the liquid dispensing and storage box needs to be taken, the central processing unit determines a suitable type of liquid dispensing and storage box according to the liquid dispensing requirements. The automatic dispensing device for the liquid dispensing and storage box automatically takes out the adapted liquid dispensing and storage box according to the determined type of the liquid dispensing and storage box and the storage location information of the liquid dispensing and storage box and transfers it to the third conveying device. As a preferred embodiment, the automatic dispensing device for the liquid dispensing and storage box is a movable vacuum adsorption head, and the liquid dispensing and storage box is taken out by means of vacuum adsorption, and is transferred to the liquid dispensing platform by the third conveying device. In the present invention, in order to improve the liquid dispensing efficiency, two or more liquid dispensing platforms can be provided. On the liquid dispensing platform, the second Cartesian coordinate robot performs various formula adding operations to the liquid dispensing liquid storage box, and the bottom plate that completes the liquid addition is transported to the pipetting and suction station. The liquid dispensing platform and the liquid pipetting platform need to be precise positioning. It is necessary to have a certain buffer capacity and grouping capacity between the liquid dispensing platform and the pipetting and suction station. The realization of the buffering capacity and the grouping capacity is preferably realized by a conveyor belt or a sliding track and a sliding trolley. The empty bottom plate after pipetting is automatically discarded into the first waste recycling container. Specifically, after the liquid holding flat groove or orifice plate in the liquid configuration area is used up, it is conveyed to the waste collection place by the second conveyor belt and discarded. In this embodiment, the automatic warehouse of the liquid dispensing and storage box, the conveyor belt of the liquid dispensing and storage box, and the discarding port of the liquid dispensing and storage box are arranged on a straight line.

For liquids with a large amount, such as cell culture medium, a peristaltic pump will be configured to ensure the continuous supply of liquids.

There is a fourth conveyor between the configuration station and the pipetting platform, and allows up to 4 dosing orifices to stay on the third conveyor at the same time, in order to improve efficiency and maximize the use of one configured liquid to be added.

The pipetting operation is completed by the first rectangular coordinate robot 21, which installs the pipette tips from the pipette head array, and then completes pipetting from the cell culture microplate, pipetting from the culture medium to the cell culture microplate. Orifice plate, pipetting from the ingredient storage box to the cell culture microplate, etc., the pipette tips are automatically discarded and replaced with new pipette tips after each operation. The discarded pipette tips are recycled into the second waste recycling container. The cell culture fluid is discharged by the pipette tip into the third waste recovery container. A movable part is installed at the end of the second Cartesian coordinate robot arm for squeezing off the pipette tip after the pipetting operation is completed.

The first and second Cartesian coordinate robot ends are provided with actuators that can simultaneously suck and squeeze the solution and replace the pipette tips for 96 pipette tips loaded (when the cell culture plate is a 96-well plate or a single pipette head). In the utility model, the air pressure difference is used to realize the functions of sucking liquid and extruding the solution of the gun head. When there is no pipette tip on the end effector, the Cartesian coordinate pipetting robot moves the end effector to the top of the pipette tip box, and then moves vertically downward to install 96 pipette tips at the same time. The used pipette tip is squeezed out by moving parts mounted on the end effector. Through the above technical means, the utility model can realize the automatic loading and discarding of the cell manipulation tip and the automatic collection of the cell culture waste liquid.

The pipette tip installed at the end of the first rectangular coordinate robot arm needs to be equipped with an array tip before each operation. The array tip is supplied by the automatic tip arrangement device described below. In the utility model, the first right-angle robot can move among the liquid transfer platform, the liquid dispensing platform and the pipette tip array platform, and the liquid transfer platform sucks out the waste liquid in the cell culture plate and discharges it to a predetermined position, and in the liquid transfer platform The pipetting platform discharges the sucked dispensing solution to each cell culture plate, and sucks the solution in the dispensing liquid storage box on the dispensing platform. The utility model ingeniously realizes the liquid dispensing, moving, Liquid automatic operation process.

The utility model provides a novel automatic arrangement device for gun tips, which supplies a first rectangular coordinate robot and a second rectangular coordinate robot with a gun tip array on a gun tip array platform. As shown in Figures 5 and 6, the gun head automatic finishing device includes: a drum 31, the inner wall of the drum is provided with a bar perpendicular to the rotation direction, the drum is driven by a motor to rotate, and both ends of the drum are open; The gap member 32 extends into the drum, 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 is parallel to the axis of the drum; the protruding part of the gap member is fixed on the outside of the drum. On the device body; the transfer assembly 33, which moves in the direction perpendicular to the length of the gap, and some of its components move up and down, for loading and unloading the gun head on the gap, and transferring it to the array disk.

The utility model realizes the quick sorting and sorting of the bulk gun heads by means of the principle of vibration and steric hindrance. The gun head and the gun head are driven upward to vibrate through a drum with at least one end open. Since the two ends of the gun head are respectively the thin end and the thick end, the utility model designs a vertical gap, the width of the gap is larger than the thin end of the gun head but smaller than the thick end, the gap member extends into the drum, and the gun head follows the The drum rotates and vibrates and is carried up. When it falls to the gap under the action of gravity, only the thin end can enter the gap, while the thick end is clamped by the gap mouth to stand up, so that the gun heads are arranged in a line. When m tips are placed in the gap, the tips are transferred away by the transfer assembly, and then the gap will randomly drop into the tips, and after the m tips are rearranged, the tips are transferred by the transfer assembly, and so on, transfer The m gun heads are transferred to the array disk, and a row or column is formed on the array disk. When n rows (or columns) are formed, a predetermined gun head array is realized. The spacing between the gun heads in a row or a column, and the interval between each row (or column) can be achieved by adjusting or setting the distance between adjacent protruding heads in the transfer assembly for inserting and taking gun tips.

As an embodiment, each row of gun heads that have been sorted can also be directly transferred to the gun tip box on the operating platform. After the whole box of gun heads is filled up, the whole box of gun heads is transferred to a predetermined position through the conveying device, and the Transfer the next empty box to the operating platform.

As another embodiment, after the pipette tip array is formed, the pipette tip array can be transferred at one time and inserted into the pipette tip box by the transfer device to form a boxed m×n (m, n is a natural number) pipette tip array .

The selling price of boxed tips is about 4 to 5 times that of bulk tips, so the m×n (m, n is a natural number) array of boxed tips can be handled as a processed product. In the present utility model, a 96-well plate is mainly used for description. Generally, the wells of a 96-well plate are arranged in a 12*8 array. In order for the arranged pipette tip array to be suitable for a 96-well plate, m is set to 12 and n is set to 8.

As a third embodiment, the assembled pipette tip array can also be directly docked with the pipette gun, and the pipette tip array can be attached to the pipette tip array for suction or liquid addition operation. In the pipette tip array formed by the present invention The spacing between adjacent pipette heads matches the spacing of the row pipettes, so that the pipette head array can be automatically provided for the row pipettes, which is convenient for the pipette to quickly replace the pipette heads. The utility model can solve the problem of The technical problem of the pipette automatically feeding the pipette tip. Considering that the orifice plate has a variety of specifications, 6-well plate, 12-well plate, 24-well plate, 96-well plate, 384-well plate, etc., adjust the combination of the row pipette according to the type of well plate for the operation, adjust The m and n values of the formed pipette tip array can automatically provide pipette tips for various combinations of pipettes corresponding to different well plates. Of course, the organized tip array is also suitable for single tip pipettes.

As a specific embodiment, in the gun head automatic arranging device provided by the present invention, as shown in FIG. 6 , the inner wall of the drum 31 is provided with a bar perpendicular to the rotation direction, and the drum 31 is driven by a motor (not shown in the figure). shown) drive to rotate, the two ends of the drum are open; the gap member 32 extends into the drum, the width of the gap is greater than the diameter of the thin end of the gun head, smaller than the diameter of the thick end of the gun head, and the length direction is parallel to the axis of the drum; The protruding part of the gap member is fixed on the device body outside the drum; the transfer assembly 33 moves in a direction perpendicular to the length direction of the gap, and some of its components move up and down, for loading and unloading the gun head on the gap, and Move it to the array disk. The front and rear ends of the drum 1 have openings for the gap members 32 to protrude, and the protruding parts of the gap members 32 can be fixed on the device body through the openings. As a specific embodiment, the gap member 32 protrudes from one end of the opening and is fixed on the device body; in order to make the gun tips that are brought up with the rotation of the drum and the rails fall on the gap member more, as shown in FIG. 7 , the drum is also provided with a funnel 34, the funnel 34 is arranged in the upper and left positions of the drum 31, the outlet under the funnel is located just above the gap member, and the funnel can help to collect the gun tips that are brought up and fall into the funnel 34. A substantial portion of the pipette tip under gravity enters the gap member head down. A guide plate 35 is provided on the back side of the funnel and above the gap member, and the guide plate 35 helps guide the tip of the gun to fall into the gap member.

In order to better collect the gun tips, an inclined plane member is arranged beside the funnel, the funnel and the inclined plane member both have a vertical plane, and the funnel and the inclined plane member are fixedly connected to each other through the vertical plane. With such a structural arrangement, the arrangement efficiency of the gun head can be improved.

In order to increase the probability of the gun head falling into the vertical narrow gap in the drum, to improve the cleaning efficiency of the gun head, and to consider the problem of convenient installation, as shown in FIG. 7 , the funnel 34 is surrounded by four planes, of which a pair of planes s1, s2 are parallel to each other and perpendicular to the horizontal plane 1, one plane s3 of the other pair of planes is perpendicular to the horizontal plane and is respectively perpendicular to the pair of planes, and the other plane s4 is an inclined plane and is parallel to the central axis of the drum 31. The funnel is rectangular in cross section. The funnel is fixed on the device body outside the drum through the plane s1, and the aforementioned guide plate 35 is arranged on the plane s2. There is an inclined surface component 36 on the obliquely upper part of the funnel, and the inclined surface component 36 is fixed on the plane s3 for gathering the gun head. In the utility model, by making the upper surface of the barrier into the shape of a concave gap, when the drum rotates, more gun heads can be brought up by the barrier, and the finishing efficiency can be further improved.

Through the guidance of the falling direction of the gun tips by the rotation of the drum, the funnel, the inclined surface member, the guide plate and other components, a row of gun tips will be formed on the gap member.

The main technical problem solved by the transfer assembly is to transfer a predetermined number of gun heads formed on the gap member into the array disk.

As shown in FIG. 8 , the transfer assembly 33 includes: a first moving part 331 controlled by a first motor and moving along a track 332 provided on the device body, the track 332 being perpendicular to the length direction of the gap; a second moving part 33. Driven by the second motor or the first cylinder, it moves up and down between the first predetermined position and the second predetermined position relative to the first moving member 331; a plurality of block members 334 with protruding heads arranged in a row, It is arranged at the lower part of the second moving part 333, the row direction is parallel to the length direction of the gap member 32, and the protruding head matches the inner diameter of the wide end of the gun head. The first moving part translates to move to a first predetermined position, each protruding head is opposite to each gun head on the gap member, the first moving part 331 translates and moves to a second predetermined position, and each protruding head is aligned with the array The holes of each pipette head of the disk are opposite, and the m pipette heads formed on the gap member 32 are transferred to the first row, the second row, the third row, . . . , on the array disk through the first moving part 331. The nth row, until an m*n array is formed. Therefore, the distance between the block parts 334 can be adjusted. By adjusting the distance between the block parts 334, the distance between each adjacent two protruding heads can be adjusted between two values. The first value is the gap member. 32 is the distance between every two adjacent pipette tips, and the second value is the distance between every two adjacent pipette tip holes on the array disk. When the first moving part 331 is aligned with the gun tip on the gap member, the second moving part 333 moves downward relative to the first moving part 331 to a third predetermined position, so as to load the gun tip on the gap member through the protruding head, The tip matches the inside diameter of the pipette tip. After loading the gun head, the second moving part 333 moves up to the original position, and then the first moving part 331 translates to the first predetermined position. During the translation process, the distance between the protruding heads (block parts) is adjusted. , and then the second moving part 333 moves down to the fourth position, and the gun head is unloaded on the array disk by the retracting action of the protruding head or the push-down part provided above the protruding head. If the nose is used to unload the tip by retracting and extending, the nose can be driven by a third motor or a second air cylinder since the tip only needs to move between two relatively changing positions. If a push-down member is used to push the tip off to unload the tip, the push-down member can be driven by a third motor or a second air cylinder. The second moving part moves between two relatively changing positions up and down, and can be driven by the second motor or the first air cylinder. In general, cylinders are suitable for sending movements between two fixed positions.

As a specific implementation manner, as shown in FIG. 8 , the first moving part 331 is a slider, which moves along a sliding rail arranged in a direction perpendicular to the length of the gap member, and the second moving part 333 is arranged under the slider and passes through the air cylinder. The drive can move up and down relative to the slider. As shown in FIG. 10 , a block-shaped member 334 with a protruding head is disposed below the second moving member 333 , the block-shaped member 334 is inserted on a horizontal axis, and the block-shaped member is realized by changing the position of the block-shaped member on the horizontal axis. Two-step adjustment of the spacing between. The distance between the first gear and the two adjacent gun heads on the gap member is the same, and the distance between the second gear and the adjacent gun head sockets on the array disk is the same. The cylinder drives the drive shaft to move up and down, so that the drive shaft drives the horizontal shaft to move up and down, and the horizontal shaft passes through a plurality of block parts with the protruding heads arranged in a row, and the row direction is parallel to the length direction of the gap member, so The distance between the block parts is adjusted along the transverse axis direction by the third motor or the second air cylinder to adjust the distance between the block parts, so as to adjust the distance between the adjacent block parts and the protruding heads.

The device further includes an array disk support platform, as shown in FIGS. 8 and 9 , there are two array disk support platforms, which are respectively arranged on both sides of the gap member, and the array disk is arranged on the array disk support platform. By setting two array disk support platforms, when transferring the pipette tips row by row to the array disk on one side, the array disk on the other side can equip the pipette with the tidy pipette tips, and can also arrange the pipette tips on the other side of the array disk. The pipette tips are boxed and prepared for the next array disk, so that the efficiency of sorting the pipette tips can be improved.

On the other hand, the present utility model provides a method for automatically arranging a gun head, the method comprising:

S1. Pour the hashed tip into the drum;

S2. Drive the drum, and the drum will bring the gun head up by rotating;

S3. After the gun head falls into the funnel and converges, the downward gun head falls into the gap member extending into the drum;

S4. The transfer assembly with a row of protruding heads matching the inner diameter of the wide end of the gun head removes a predetermined number of gun heads in the continuous vertical slits and transfers them to the top of the array disk by moving up and down and moving in translation;

S5. Adjust the distance between every two adjacent protruding heads in the row of protruding heads to a predetermined value, and then place the removed tip into the array disk by moving the transfer assembly up and down;

S6. Repeat steps S4 and S5 until the gun tips form a prescribed array.

As a specific implementation manner, step S4 includes:

S41. control the transfer assembly to perform translational movement in the direction perpendicular to the gap member to the first predetermined position, and make each protruding head matched with the inner diameter of the wide end of the gun head to be opposite to each gun tip on the gap member;

S42. Control the protruding head to move down a first predetermined distance to a second predetermined position, so that each protruding head is inserted into the gun tip; the first predetermined distance is when the protruding head is in the original position (ie the initial position) to the loading and unloading the distance of the gun head;

S43. Control the protruding head to move upward to the original position, and then the transfer assembly performs translational movement in the direction perpendicular to the gap member to the second predetermined position.

Optionally, step S5 includes:

S51. Adjust the distance between every two adjacent protruding heads to the distance between every two adjacent gun head sockets on the array disk;

S52. Control the transfer assembly to move down to a fourth predetermined position, so that each gun tip is inserted into the hole on the array disk;

S53. Control the protruding head to perform a retracting action to push the pipette head off, so as to remove the pipette head.

Optionally, step S4 includes:

S41'. Control the transfer assembly to perform translational movement in the direction perpendicular to the gap member to the first predetermined position, and make each protruding head matched with the inner diameter of the wide end of the gun tip to be opposite to each gun tip on the gap member;

S42'. Control the protruding head to move down a second predetermined distance to a third predetermined position, so that each protruding head is inserted into the gun tip; the second predetermined distance is the position of the protruding head after the gun head is removed to the point where the gun is loaded and removed The vertical distance of the head position;

S43'. Control the protruding head to move upward to an initial position, and then perform a translational movement in a direction perpendicular to the gap member to a third predetermined position.

Optionally, step S5 includes:

S51'. Adjust the distance between each adjacent two protruding heads to the distance between each adjacent two gun head sockets on the array disk;

S52'. Control the transfer assembly to move down to the fifth predetermined position, so that each gun tip is inserted into the hole on the array disk;

S53'. Control a movable part (or specifically a push-down part) disposed above the protruding head to push down relative to the protruding head, so as to push off the gun head.

Array disks are arranged on both sides of the gap member, and steps S4, S5, and S6 are alternately performed on the first array disk and the second array disk.

The utility model also provides a liquid pipetting operation method for a cell culture plate. In the method, the pipette gun is loaded with the pipette tip array arranged by the automatic tip arrangement method described above to absorb and release the liquid.

Through the automatic arrangement device of the pipette tip proposed by the utility model, the loose pipette tips can be automatically arranged into an array arrangement, and the pipette tips can be supplied to the pipette gun and the pipette gun array, and the realization of the automatic pipetting system is provided. Supports and helps reduce the cost of automated pipetting systems, saving space for tip box storage.

The utility model can automatically provide the organized pipette tips or pipette tip arrays for pipetting and dispensing through the above-mentioned pipette tip arrangement device. The utility model only needs the supply of bulk pipette tips. Therefore, the automatic pipetting system provided by the present utility model is provided. It can be fully automated, eliminating the need to supply an array of organized, boxed tips.

In the process of cell culture, it is necessary to use a pipette gun to aspirate and add liquid to the cell culture plate. The pipetting system uses a 96-piece matrix combination pipette, which consumes a lot of pipette tips and is fully loaded. 100,000 pieces/day, the automatic arrangement and sorting device of the gun head provided by the utility model, the finishing speed of the gun head can reach 100 pieces/min, which can meet the use requirement of the mobile system. There are many advantages to use the online pipe arrangement device. First, it reduces the storage space of the pipe head on site. The density of the pipe head in disorderly stacking is much higher than that of the pipe head. Second, it reduces the quantity and volume of waste output by the pipe head. Third, the operating cost of the system can be reduced.

As shown in FIG. 2 , the cell incubator is square, providing a closed environment required for cell growth, and the three-dimensional storage device is placed in the cell incubator. An opening is reserved on the bottom side wall of the cell culture incubator, and an isolation door that can be automatically opened and closed is arranged at the opening to isolate the incubator from the external environment. The cell culture incubator is accessible through the first conveyor belt and the isolation gate well plate. Cell culture incubators need to reserve openings for cables to go out. In the present invention, the cell incubator can provide an environment for cell growth, and the three-dimensional storage device provides three-dimensional storage and automatic pick-and-place for well plates or cell culture plates.

As mentioned above, an opening is reserved on the bottom side wall of the cell culture incubator, and an isolation door that can be automatically opened and closed is provided at the opening. By controlling the opening and closing of the isolation door, the orifice plate can enter and exit the three-dimensional storage device.

When a designated orifice plate needs to be transferred to the pipetting operation platform for liquid exchange or liquid addition operation, the central processing unit determines the storage position of the orifice plate, and sends a control command to the rotary robot. Move up and down and rotate in the plane to position and move the end of the arm, grab the orifice plate, and then the rotary robot transfers the orifice plate to the storage and exit position of the three-dimensional storage device by moving downward and rotating in the horizontal plane.

When the orifice plate needs to be put into the warehouse in the manual handover area, after the operator sends a storage request instruction through the manual interface or presses the storage request button, the first conveyor belt transfers the orifice plate to the storage and exit through the second isolation door On the platform, a barcode or RFID reader is installed on the first conveyor belt, and the read code is compared with the entry code in the warehouse. After the label code is correct, the central processor assigns a storage location to the orifice plate according to the entry request button. And control the rotary robot to move to a predetermined position, perform shoveling or grabbing action, and then transfer the orifice plate to the assigned storage position by moving up and down and rotating in the horizontal plane, and then perform a release action to release the orifice plate. The central processing unit stores the identification information of the orifice plate and the corresponding storage location information, and performs subsequent transfer operations and information update according to the above-mentioned information.

In addition to the automatic storage, automatic removal and information update of the orifice plate, the system can also realize the automatic liquid exchange and addition of the orifice plate.

When inoculating cells into each well of the orifice plate, replacing the culture medium and adding compounds, the well plate needs to be transferred from the three-dimensional storage device to the pipetting operation platform, which is realized on the pipetting operation platform. The pipetting operation platform will be divided into two areas: liquid configuration and liquid addition, and each area is equipped with a Cartesian coordinate robot. In the liquid configuration area, to perform the tasks of inoculating cells and replacing the culture medium, the end of the first rectangular coordinate robot is connected to a single-channel pipette (which can be a single pipette tip). The required cells and culture medium (calculated according to 110% of the total amount of required cells and culture medium, which is determined by taking into account the loss during pipetting) are drawn from the total sample and injected into a flat groove consistent with the size of the well plate Inside. Then the second Cartesian robot in the liquid addition area picks up the pipette tip corresponding to the well plate and moves it to the liquid configuration area, sucks the cells or culture medium according to the preset volume, and then moves it back to the liquid addition area, and removes the sucked cells or culture medium. Inject into the target well plate. If the task needs to replace the cell culture medium, before performing the culture medium suction and addition tasks, the second Cartesian coordinate robot in the liquid addition area is required to suck and discard the culture medium in the well plate to be processed. After replacing the pipette tip, execute the The operation of aspirating and adding culture medium.

In the liquid configuration area, if you need to perform the task of adding compounds of different concentrations, the end of the first rectangular coordinate robot loads the pipette tips corresponding to the orifice plate from the pipette head array, and injects the specified volume into the blank orifice plate in the liquid configuration area. Then replace the pipette at the end of the first rectangular coordinate robot with a single-hole pipette. According to the experimental plan, the single-hole pipette sucks the corresponding volume of compound from the compound mother solution and injects it into each target in the well plate. in the culture medium of the well. During this process, after injecting the culture medium, care should be taken to replace the pipette tip to avoid cross-contamination. By repeating the above actions for many times, different wells of the well plate can contain different concentrations of small molecule compounds. Next, the configured liquid is sucked and added to the target well plate in the liquid addition area by the second Cartesian robot in the liquid addition area, so that small molecule compounds or compounds of different concentrations can be added to specific wells in the orifice plate. combination. If the same repeated operation is performed on multiple orifice plates at the same time, a specially-made orifice plate with a larger single-hole volume can be used in the liquid configuration area, and after the liquid is configured once, at least 10 orifice plates can be added.

In the liquid configuration area, there is an automatic library for liquid dispensing and storage boxes. As shown in Figure 4, it is arranged at the lower part of the pipetting operation platform 2, and is mainly used for storing empty orifice plates or flat grooves for liquid dispensing. When the liquid dispensing and storage box needs to be taken, the central processing unit determines a suitable type of liquid dispensing and storage box according to the liquid dispensing requirements. The automatic dispensing device for the liquid dispensing and storage box automatically takes out the adapted liquid dispensing and storage box according to the determined type of the liquid dispensing and storage box and the storage location information of the liquid dispensing and storage box and transfers it to the second conveyor belt. As a preferred embodiment, as shown in FIG. 4 , the automatic dispensing device for the liquid dispensing and storage box is a movable vacuum adsorption head 24. Dosing platform. In the present invention, in order to improve the liquid dispensing efficiency, two or more liquid dispensing platforms can be provided. On the liquid dispensing platform, the first rectangular coordinate robot is used to add various formulas to the liquid dispensing liquid storage box, and the bottom plate after adding liquid is transported to the pipetting and suction station. The liquid dispensing platform and the liquid pipetting platform need to be precise positioning. It is necessary to have a certain buffering capacity and grouping capacity between the liquid dispensing platform and the pipetting and suction station, and the realization of the buffering capacity and the grouping capacity is preferably realized by the third conveyor belt. The empty bottom plate after pipetting is automatically discarded into the first waste recycling container. Specifically, after the liquid holding flat groove or orifice plate in the liquid configuration area is used up, it is conveyed to the waste collection place by the second conveyor belt and discarded. In this embodiment, the automatic warehouse of the liquid dispensing and storage box, the conveyor belt of the liquid dispensing and storage box, and the discarding port of the liquid dispensing and storage box are arranged on a straight line.

For liquids with a large amount, such as cell culture medium, a peristaltic pump will be configured to ensure the continuous supply of liquids. The peristaltic pump 23 is arranged on the right side of the system, as shown in FIG. 4 .

There is a third conveyor belt between the configuration station and the pipetting platform, and allows up to 4 dosing orifices to stay on the third conveyor belt at the same time, in order to improve efficiency and maximize the use of one configured liquid to be added.

The pipetting operation is completed by the first rectangular coordinate robot 21, which installs the pipette tips from the pipette head array, and then completes pipetting from the cell culture microplate and from the culture medium to the cell culture microwells. After each operation, the pipette tips are automatically discarded and replaced with new ones. The discarded pipette tips are recycled into the second waste recycling container, and the discarded cells The culture fluid is discharged by the pipette tip into the third waste recovery container. A movable part is installed at the end of the first rectangular coordinate robot arm for squeezing off the pipette tip after the pipetting operation is completed.

The system is provided with a lid opening device in the liquid adding area. Before the operation of the cell culture plate, the upper lid of the target orifice plate is opened by vacuum suction, and the upper lid is closed after the pipetting operation.

The end of the first rectangular coordinate robot is provided with an actuator, which can perform the functions of synchronously sucking and squeezing the solution and replacing the pipette tips for the 96 pipette tips that are loaded (when the cell culture plate is a 96-well plate). To achieve the pipette tip's function of aspirating and extruding solution. When there is no pipette tip on the end effector, the Cartesian coordinate pipetting robot moves the end effector to the top of the pipette tip box, and then moves vertically downward to install 96 pipette tips at the same time. The used pipette tip is squeezed out by moving parts mounted on the end effector. Through the above technical means, the utility model can realize the automatic loading and discarding of the cell manipulation tip and the automatic collection of the cell culture waste liquid.

In the present invention, the cell culture plates stored in the orifice plate three-dimensional storage device are stored in the library, and the pipetting operation is performed based on user instructions and automatic detection indicators. identification code to achieve. As a specific embodiment, as shown in FIG. 1 , a touch display panel is set outside the cell culture area as a human-computer interaction interface for the user to input instructions and display the results of cell culture monitoring and the pipetting related information of cell culture. .

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 all have corresponding control sub-modules (or called as Drive module), each control sub-module controls each device to perform corresponding operations according to the operation instructions from the central processing unit. The utility model manages each sub-module and coordinates the communication between the sub-modules by carrying the MES software system developed based on the ROS platform on the central processor, and the communication mode between the sub-modules is mainly based on the "topic/message" mechanism of the ROS platform To achieve, and use the ROS platform to develop the robot operation program required by the device.

The central processing unit includes the following modules: a storage location allocation module, which allocates storage locations for the orifice plates in storage according to the storage request and the storage state information of the three-dimensional storage device; an information recording module is used to record and update the storage state of the three-dimensional storage device. Information, orifice-related information; the control module controls the rotary robot, the first rectangular coordinate robot, and the second rectangular coordinate robot to operate cooperatively according to the orifice plate number and operation instructions.

The following specifically describes the control method of the above-mentioned automatic liquid pipetting system provided by the present utility model. The control method is executed by the central processing unit, and specifically includes:

Receive user instructions through the human-computer interface;

Analyze the user's instructions and determine whether to receive the well plate in the manual transfer area for storage, to take out the designated well plate on the three-dimensional storage device of the well plate to the manual transfer area, or to transfer the designated well plate to the pipetting operation platform for designated pipetting. operate;

If it is to receive the orifice plate in the manual handover area for storage, send an instruction to the rotary robot control sub-module;

The rotary robot moves to the manual handover area according to the instruction, scans the received identification code information of the orifice plate, and grabs the orifice plate;

Allocate a storage location for the orifice plate according to the identification code information and the storage record information of the orifice plate stereoscopic storage device, and send the location information to the rotary robot control sub-module,

The rotary robot moves according to the position information to transfer the control to the storage position and release the orifice plate.

If the specified well plate on the well plate stereo storage device is taken out to the manual handover area, the storage location information of the specified well plate in the well plate stereo storage device is searched according to the input information, and the storage location information is output to the Rotary robot control sub-module;

The rotary robot control sub-module controls the rotary robot to move to the storage position, grabs the orifice plate, and transfers it to the in-out platform of the three-dimensional storage device; the orifice plate triggers the end of the fourth conveyor belt. The sensor, the orifice plate is transported to the manual handover area by the fourth conveyor belt.

If the orifice plate is transferred to the pipetting operation platform for the specified pipetting operation, the rotary robot will grab the orifice plate according to the storage position information of the orifice plate and transfer it to the first predetermined position, and then it will be transferred to the pipetting operation by the first conveyor belt platform. In this embodiment, the user needs to input the identification of the well plate to be operated, the name of the liquid to be added, and the dose in the human-computer interface. The first rectangular coordinate robot performs the dispensing operation according to the input. As a preferred embodiment, the end of the arm of the first rectangular coordinate robot is provided with a first identification component, which is used to identify the liquid master sample, and according to user input or parameter requirements, the liquid master sample is sucked and configured in the liquid dispensing liquid storage box. . The processor determines the dosing time according to the total number of sample types, the total sample dose, the number of pipette tips, and the number of dosing; The liquid operation time determines the transfer start time of the target orifice plate, the time for the second Cartesian coordinate robot to obtain the liquid from the liquid dispensing storage box, and the time for pipetting to the target orifice plate. Finally, the coordinated work of the first rectangular coordinate robot, the second rectangular coordinate robot, and the rotary robot is guaranteed.

Two first rectangular coordinate robots can be set in the liquid dispensing area. Since different orifice plates may have different liquid configurations during the liquid dispensing process, it may be necessary to send multiple orifices to different orifice plates for one liquid dispensing and storage box. The process of injecting liquid on the well, so corresponding to a well plate, the time of liquid dosing may be several times longer than the time of pipetting to the target well plate, so in order to improve work efficiency, at least two first right angles can be set in the dosing area Coordinate robot.

The system provided by the utility model can automatically access the 96-well cell culture plate (or other well culture plate), perform cell inoculation and medium exchange culture on the well plate, and can periodically transfer the cells to the 96-well culture plate according to the user's preset instructions. Add a specified concentration of small molecule compounds to the designated culture wells, support automatic addition of different concentrations of the same small molecule compound, different small molecule compounds, or a combination of multiple small molecule compounds to different culture wells of the same 96-well culture plate .

The equipment provided by the utility model is a highly professional equipment, has beautiful appearance and precise functions, can maintain the cleanliness and gas and humidity requirements that meet the requirements of cell culture, does not generate any pollutants during operation, and does not need to be added. Maintenance material for lubricants. In addition, the overall functional design of the equipment takes into account the cleaning, disinfection and maintenance requirements during the operation of the equipment, and incorporates the airtightness, gas exchange function, humidity maintenance function, and disinfection function of the equipment into the overall design, so that the equipment can meet the requirements of automated cell culture and chemical compounds. Screen the actual needs and have a strong market competitive advantage.

In the description provided herein, numerous specific details are set forth. It will be 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 will be appreciated that in the above description of the exemplary embodiments of the invention, various features of the invention are sometimes grouped together in order to simplify the invention and to aid in the understanding of one or more of the various aspects of the invention. in a single embodiment, figure, or description thereof. However, this method of disclosure should not be construed to reflect an intention that the claimed invention requires more features than are expressly recited in each claim. Rather, as the following claims reflect, utility model 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-described embodiments illustrate rather than limit the invention, and that alternative embodiments may be devised by those skilled in the art 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 (10)

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; a rotary robot which is arranged at the cylindrical hollow position 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 comprises a roller part and an array forming part, wherein the roller part arranges disordered gun heads into a line shape through vibration and steric hindrance; the array forming part arranges one row of gun heads into an array, the liquid preparation and pipetting operation device comprises a controlled pipetting gun or a controlled pipetting gun array, the gun heads or the gun head array arranged by the automatic gun head arranging device are assembled and taken, and liquid absorption operation or liquid adding operation is carried out on the cell culture plate conveyed from the cell culture box.

2. The system of claim 1, wherein the rotary robot is disposed upside down on top of the cell culture chamber.

3. The system of claim 1, wherein the circular platform member is comprised of at least three segments of arcuate surfaces.

4. The system of claim 1, wherein the dispensing and pipetting device comprises a first rectilinear coordinate robot having arms terminating in a single channel pipette for loading tips from the array of tips and dispensing solutions to dispensing containers at the dispensing station according to a specified compound and concentration.

5. The system of claim 1, wherein the dispensing pipetting device comprises a dispensing container reservoir configured to aspirate a dispensing container through a vacuum tip to a dispensing station.

6. The system of claim 1, wherein the dispensing pipetting device comprises a second cartesian robot having arms terminating in a multi-channel pipette, an array of tips for loading tips from the tips array, a container for dispensing fluid from the dispensing container and a pipetting station for dispensing fluid to the cell culture plate.

7. 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.

8. The system of claim 7, wherein the movable members are disposed at the ends of the arms of the first and second cartesian robots for squeezing off the tips.

9. The system of claim 1, wherein the dispensing pipetting device comprises a conveyor belt for transporting dispensing containers to a dispensing container recovery device.

10. The system of claim 1, wherein the roller section comprises: the device comprises a roller, a motor, a plurality of vertical grooves and a plurality of clamping pieces, wherein a blocking strip vertical to the rotating direction is arranged on the inner side wall of the roller, the roller is driven by the motor to rotate, two ends of the roller are opened, the vertical grooves are positioned in the roller and are parallel to the central axis of the roller, and the width of each groove is larger than the diameter of the thin end of a gun head and smaller than the diameter of the thick end of the gun head; the funnel is arranged in the roller, is positioned right above the vertical groove and is fixed by the device body outside the end opening; the array forming part comprises a transfer assembly which moves along the direction vertical to the length direction of the gap, and part of assemblies of the transfer assembly move up and down and are used for loading and taking the gun heads on the gap and transferring the gun heads to the array disc.

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