High-throughput biological culture system

Abstract

The invention discloses a high-throughput biological culture system, which comprises a box body with an inlet and an outlet, and is characterized by further comprising a monitoring-lifting integrated device and a culture device which are arranged in the box body, the culture device comprises a rotating platform mechanism which is rotatably arranged in the box body and is used for placing a culture pore plate; the monitoring-lifting integrated device comprises a central cantilever which is coaxially connected with the rotating platform mechanism in a rotating mode. The lifting mechanism is arranged at one end of the central cantilever and used for lifting the pore plate to move in the Z-axis direction; the monitoring mechanism is arranged at the other end of the central cantilever and is used for illuminating and observing the cell state of the pore plate. Compared with an existing cell or organoid biological culture device, the cell or organoid biological culture device has the advantages that the integration degree is higher, the observation and analysis speed is higher, strict environmental conditions can be kept in the culture and analysis process, disturbance to other pore plates is lower when the pore plates are taken, and the cost is lower; and the requirements of high throughput and low disturbance of a high throughput biological culture system under the industrial and automatic background can be met.

Description

Technical Field

[0001] The invention relates to a high-throughput biological culture system, belonging to the technical field of automation equipment. Background Art

[0002] Automated equipment can accurately complete various fixed mechanical actions, freeing up manpower, and is therefore gradually being applied to all walks of life. The current mainstream solution for cell or organoid culture and analysis is: using a biological incubator to culture cells or organoids in batches using well plates (8) (see the instructions Fig. 20 ), when the well plate needs to be observed and analyzed, the incubator needs to be opened, the layer where the well plate is located is moved out, the robot arm takes out the well plate, the layer where the well plate is located is moved in, the incubator is closed, and the robot arm places the well plate on the living cell analyzer for analysis. After the analysis is completed, the well plate is taken out, the incubator is opened, the robot arm puts the well plate back in place, and another well plate is taken for observation and analysis. The operation is repeated until all the well plates are observed and analyzed.

[0003] The above mainstream solutions can meet the high-content, low-throughput needs of scientific researchers for cell culture. However, since the existing living cell analyzers contain a variety of optical analysis devices, the optical path is complex, and the camera lens cannot move over a large range, the number of single observations and analyses is limited, which cannot meet the requirements of industrial high-throughput. At the same time, this solution requires step-by-step cultivation and analysis, with low integration and high cost. When taking out a single well plate, other well plates on the same layer will be disturbed; some biological observation analyzers even disturb the well plates when they are working, and the solutions adopted in the prior art have a large disturbance on other well plates. In addition, due to the static layout of the well plate array in the existing biological incubator, there are differences in the living environment of cells or organoids in different well plates, which greatly reduces the precision and accuracy of the experiment; and the incubator needs to be opened and closed many times when analyzing the well plate, and the cultivation of cells or organoids requires extremely strict environmental control, which is very easy to cause contamination to the remaining well plates. Therefore, the existing technical solutions have defects and need to be improved. Summary of the invention

[0004] The technical purpose of the present invention is to propose a high-throughput biological culture system. The present invention analyzes the limitations of the existing mainstream cell or organoid culture and analysis solutions under the background of industrial high-throughput requirements, and integrates the culture and analysis functions into a single device and optimizes the existing array fixed culture layout to a rotating mobile culture layout. The culture environment of all well plates is kept consistent during the culture process, and the remaining well plates are not disturbed when the well plates are taken out. The goal of maintaining strict environmental conditions during the culture and observation process and achieving a faster observation and analysis speed is achieved.

[0005] The technical solution adopted by the present invention is:

[0006] A high-throughput biological culture system comprises a box body with an entrance and an exit, and also comprises a monitoring-lifting integrated device and a culture device arranged in the box body; the culture device comprises a rotating platform mechanism arranged in the box body for placing a culture well plate; the monitoring-lifting integrated device comprises a central cantilever, a lifting mechanism and a monitoring mechanism.

[0007] Specifically, the monitoring-lifting integrated device comprises:

[0008] A central cantilever coaxially connected to the rotating platform mechanism;

[0009] A lifting mechanism provided at one end of the central cantilever for lifting the orifice plate to move along the Z-axis direction;

[0010] A monitoring mechanism is provided at the other end of the central cantilever for illuminating and observing the status of cells in the well plate.

[0011] The monitoring and lifting integrated device and the culture device are all placed in a box body, and a sliding door mechanism is provided above the box body. A lifting mechanism is connected to the A side of the central cantilever; a monitoring mechanism is provided on the B side of the central cantilever. The lifting mechanism cooperates with an external robotic arm to realize automatic replacement and pipetting operations of the well plate. Through the monitoring mechanism and the rotating platform mechanism, in-situ online monitoring and recording of any well can be automatically realized. Preferably, a sliding door mechanism is provided on the box body, and the sliding door mechanism includes a baffle that cooperates with the entrance and exit, and a baffle motor that drives the baffle to realize the closing and opening operations of the input port. Furthermore, the output end of the baffle motor is fixed to the baffle screw slide, and the baffle is fixed on the baffle screw slide, and moves synchronously with the baffle screw slide to realize the closing and opening operations.

[0012] Furthermore, the box body includes an upper box body and a lower box body. In actual use, the lower box body is placed on the working platform, and the upper box body is fastened to the lower box body to form a closed space; as an option, the monitoring and lifting integrated device and the culture device are placed in the lower box body; the plate replacement or liquid transfer is achieved through the entrance and exit. Furthermore, the entrance and exit are provided on the upper box body; and the sliding door mechanism is arranged on the upper box body.

[0013] Preferably, the culture device comprises:

[0014] A C-shaped support mechanism disposed in the box;

[0015] The rotating platform mechanism is arranged in the C-shaped supporting mechanism.

[0016] The rotating platform mechanism is used for cell or organoid culture.

[0017] Furthermore, the C-shaped supporting mechanism is provided with a heating unit, a humidifying unit, an oxygen vent and a carbon dioxide vent; the box body is provided with a temperature sensor, a humidity sensor, an oxygen sensor and a carbon dioxide sensor.

[0018] A rotating platform mechanism is provided at the center of the C-shaped supporting mechanism.

[0019] Preferably, the rotating platform mechanism comprises:

[0020] A shaft member fixed in the C-shaped support mechanism;

[0021] A tray disposed on the shaft member;

[0022] The central cantilever is simultaneously connected and arranged on the shaft;

[0023] The tray and the central cantilever can be independently rotated around the shaft when driven by the corresponding driving mechanism.

[0024] The tray is evenly provided with a plurality of orifice plate placement openings in the circumferential direction, and the length and width directions of the orifice plate placement openings are both greater than the length and width of the largest orifice plate used.

[0025] Preferably, the rotating platform mechanism further comprises a bidirectional clamping mechanism arranged on the tray, and the bidirectional clamping mechanism comprises a radial clamping assembly for achieving radial clamping of the orifice plate and a circumferential clamping assembly for achieving circumferential clamping of the orifice plate.

[0026] As a further preference, the radial clamping assembly and the circumferential clamping assembly are driven by the same driving mechanism. More specifically, the driving mechanism adopts a steering gear. The orifice plate placement opening is provided with radial limiting edge and circumferential limiting edge structures, which cooperate with the radial clamping assembly and the circumferential clamping assembly to achieve radial and circumferential fixation of the orifice plate.

[0027] The radial clamping assembly includes a radial clamping jaw guide rail, a radial clamping jaw slidably arranged on the radial clamping jaw guide rail, a driving mechanism for driving the radial clamping jaw to release the orifice plate, and a radial elastic member for causing the radial clamping jaw to clamp. Driven by the driving mechanism, the radial clamping jaw slides along the radial clamping jaw guide rail to achieve an unfolding action and release the orifice plate thereon. When clamping is required, the driving mechanism releases the radial clamping jaw, and under the pulling force of the radial elastic member, the inner side of the orifice plate abuts against the radial limiting edge, and the radial clamping jaw realizes the clamping operation of the orifice plate.

[0028] Furthermore, a pulley is provided on one side of the radial clamp for clamping. A positioning protrusion (which may also be a pin) is provided on the radial clamp. A transmission member is provided between the drive mechanism and the radial clamp, and the positioning protrusion is used to fix the transmission member. For example, the transmission member may be a long rope and a plurality of matching guide wheels, and the long rope is wound around the guide wheel and is respectively fastened to the positioning protrusion and the drive mechanism (such as a steering gear). The radial elastic member is a spring, and the two ends of the spring are respectively fastened to the tray and the radial clamp.

[0029] The tray is provided with a fan-shaped opening; the circumferential clamping assembly includes a tangential clamping jaw, a driving mechanism for driving the tangential clamping jaw to release the orifice plate, a tangential rotary arm connected between the output end of the driving mechanism and the tangential clamping jaw, and a tangential elastic member for causing the tangential clamping jaw to clamp the tangential clamping jaw. The tangential rotary arm is arranged to rotate around the center hole in the fan-shaped opening, and the fan-shaped opening is used to guide and limit the rotation direction of the tangential rotary arm. At the same time, the other end of the tangential rotary arm is connected to the tangential elastic member. The tangential clamping jaw is driven to open circumferentially by the driving mechanism; the tangential clamping jaw is retracted circumferentially by the tangential elastic member, and the inner side of the orifice plate abuts against the circumferential limit edge, so that the tangential clamping jaw clamps the orifice plate.

[0030] Furthermore, the tangential elastic member may be a spiral spring. One end of the tangential swing arm is wound around the center of the spiral spring, and the other end is fixed to the tangential clamping claw through a fan-shaped opening. The tangential swing arm can rotate along the fan-shaped opening under the drive of the spiral spring or the driving mechanism. The transmission member between the driving mechanism and the tangential clamping claw may be a short rope, the two ends of which are respectively fastened to the steering gear and the tangential swing arm, and the tangential clamping claw rotates around the center of the other end of the tangential swing arm.

[0031] The C-shaped support mechanism is used to integrate various sensors and environmental control devices. Further, the C-shaped support mechanism includes a lower base plate, an upper base plate, and a heat sink that fixes the lower base plate and the upper base plate to each other. Furthermore, the rotating platform mechanism is installed between the upper base plate and the lower base plate in the C-shaped support mechanism.

[0032] Specifically, the lower base plate is used to fix the lower center semi-axis, and a lower center semi-axis fixing hole and a line collecting groove α are arranged in the lower base plate, and a humidifier is arranged on the periphery of the lower base plate; a heat sink is arranged behind the lower base plate, and an oxygen vent and a carbon dioxide vent are arranged in the center of the heat sink, a heating rod is arranged on one side of the heat sink, and a sensor fixing plate is arranged on the other side, and a humidity sensor, a carbon dioxide sensor and an oxygen sensor are arranged on the sensor fixing plate; an upper base plate is arranged above the heat sink, and an upper center semi-axis fixing hole and a line collecting groove β are arranged in the upper base plate.

[0033] Further, the shaft member includes an upper central semi-axis and a lower central semi-axis. The upper central semi-axis is coaxially and tightly connected with the lower central semi-axis. The lower central semi-axis and the upper central semi-axis tightly connected thereto are respectively fixed between the lower bottom plate and the upper bottom plate of the C-shaped support mechanism in the culture device. The central cantilever is transferred to the lower central semi-axis, and the central cantilever rotates around the lower central semi-axis of the rotating platform mechanism in the culture device.

[0034] Furthermore, the top of the upper center semi-shaft is provided with a hole for connecting to the upper base plate of the C-shaped support mechanism, and the middle of the upper center semi-shaft is fastened to the DD motor that drives the tray to rotate. The upper center semi-shaft is fastened concentrically with the lower center semi-shaft, and the lower center semi-shaft is provided with a hole for connecting to the lower base plate of the C-shaped support mechanism.

[0035] Preferably, a plurality of orifice plate positions and electronic tags for recording orifice plate information (orifice plate coding information and temperature, etc.) are arranged in a circular array on the tray, and a wireless scanner for reading and writing information in the electronic tags is also arranged in the box.

[0036] Through the above structural design, the rotating platform mechanism can achieve precise control of the tray and effectively record and read the orifice plate information.

[0037] Preferably, the lifting mechanism comprises:

[0038] Z-axis lifting platform with orifice plate placement;

[0039] An axial driving mechanism and an axial transmission mechanism for driving the Z-axis lifting platform to move in the vertical direction;

[0040] The monitoring agencies include:

[0041] Microscopic monitoring components and lighting components;

[0042] A radial driving mechanism and a radial transmission mechanism drive the microscopic monitoring assembly and the lighting assembly to move synchronously along the horizontal direction (i.e., the radial direction of the rotating platform mechanism).

[0043] Furthermore, the radial transmission mechanism or the axial transmission mechanism is a belt transmission mechanism, and the microscopic monitoring assembly and the lighting assembly or the Z-axis lifting platform are respectively fixed to the belt transmission mechanism through corresponding sliders or synchronous sliders; the driving mechanism is a servo motor.

[0044] The belt transmission mechanism can be a simple belt mechanism for realizing single-direction transmission, or a belt mechanism for realizing multiple-direction circuitous transmission. Preferably, in the radial transmission mechanism, the belt transmission mechanism is a synchronous belt transmission mechanism, which includes a plurality of transmission gears and a synchronous belt, and the synchronous belt is arranged circuitously, and there are at least two horizontal sections with the same transmission direction, and the microscopic monitoring assembly and the lighting assembly are respectively fixed to the above two horizontal sections through their corresponding synchronous sliders.

[0045] Furthermore, as a preferred embodiment, in the monitoring mechanism, the output end of the driving mechanism is connected to the corresponding synchronous belt transmission mechanism through a coupling and a linear screw slide; the synchronous belt transmission mechanism is further fixed to the microscopic monitoring component and the lighting component respectively through two synchronous slide blocks.

[0046] Preferably, the lifting mechanism or the monitoring mechanism further includes a guide member for guiding the moving direction of the slider or the synchronous slider. The guide member may be a polished slide or a linear guide. For example, in the lifting mechanism, the slider fixed to the Z-axis lifting platform is guided by the polished slide; in the monitoring mechanism, the synchronous sliders fixed to the microscopic monitoring assembly and the lighting assembly are guided by corresponding linear guides.

[0047] Furthermore, the integrated monitoring and lifting device includes a central cantilever, and a central axis platform is provided at the center of the central cantilever to realize the rotation of the central cantilever around the axis; one side of the central axis platform (for example, the top end) is provided with a hole position and a groove structure for connecting the orifice plate tray in the rotating platform mechanism, and the other side of the central axis platform (for example, the bottom end) is provided with a hole position and a groove structure for connecting the DD motor to drive the orifice plate to rotate; the two holes are coaxial and interconnected for the shaft in the rotating platform mechanism to pass through.

[0048] Furthermore, the central cantilever is arranged under the pallet, with a C-shaped structure for fixing the monitoring mechanism at one end (on the side of the central axis platform B), and a fork arm structure for fixing the lifting mechanism at the other end (on the side of the central axis platform A), and a hole for connecting with the shaft is provided in the middle.

[0049] Furthermore, a lifting mechanism is provided on one side of the central cantilever, and the lifting mechanism includes a servo motor α fixed on the fork arm structure on the A side of the central cantilever, and a belt transmission mechanism is provided at the output end of the servo motor α. One side of the belt transmission mechanism is fastened (fixed) to the Z-axis slider that moves along the linear light rod slide to realize the linear displacement of the Z-axis slider along the Z-axis direction; the inner side of the Z-axis slider is fastened to the Z-axis lifting platform to ensure the synchronous movement of the Z-axis slider and the Z-axis lifting platform.

[0050] Furthermore, a monitoring mechanism is provided on the other side of the central cantilever, and the monitoring mechanism includes a servo motor β fixed on the F side of the C-shaped structure on the B side of the central cantilever. The servo motor β drives the linear screw slide to move along the X-axis direction through a coupling. An X-axis slider α for transporting the synchronous slider α is provided above the linear screw slide. The X-axis slider α is fastened (fixedly connected) to the D end of the synchronous slider α. The central area of ​​the synchronous slider α is fastened to the J area of ​​the synchronous belt transmission mechanism. The E end of the synchronous slider α is fastened to the X-axis slider β and the microscopic monitoring component. The X-axis slider β moves along the linear guide rail α fixed on the G side of the C-shaped structure. The synchronous belt transmission mechanism is fixed to the F side of the C-shaped structure. The K area of ​​the synchronous belt transmission mechanism is fastened to the H end of the synchronous slider β. The upper end of the I end of the synchronous slider β is fastened to the lighting component. The lower end of the I end of the synchronous slider β is fastened to the X-axis slider γ. The X-axis slider γ moves along the linear guide rail β fixed above the C-shaped structure.

[0051] Preferably, under the control of the host computer, the monitoring-lifting integrated device automatically completes the well plate changing operation and the in-situ online monitoring function of any culture well through the entrance and exit, and the culture device automatically completes the control of the culture conditions and the writing and reading of the well plate information.

[0052] In actual use, the operation steps are as follows: turn on the power, the humidifier, heating rod, oxygen vent and carbon dioxide vent start working, the humidity sensor, the electronic tag with the function of sensing and recording temperature, the oxygen sensor and the carbon dioxide sensor feed back various information to the host computer in real time, and after a period of time, the internal conditions of the incubator meet the requirements for cell or organoid culture. Further, the host computer controls the DD motor fixed on the upper center semi-axis to drive the tray to rotate, and at the same time controls the servo fixed on the rotating platform to drive the two-way clamping mechanism to open, and the mechanical arm places the orifice plate on the tray in turn, and then the servo rotates in the opposite direction, the tension spring and the scroll spring release the elastic potential energy, the two-way clamping mechanism fixes the orifice plate, the servo is powered off, and the wireless scanner fixed on the upper bottom plate writes the corresponding orifice plate information (such as the time of entry, culture time, number of liquid changes, survival status, etc.) into the electronic tag of the corresponding orifice plate, and starts the culture of cells or organoids. When the plate needs to be changed or lifted, the host computer controls the DD motor to drive the central cantilever to rotate so that the lifting mechanism reaches the bottom of the orifice plate required for lifting and liquid change. The servo motor α fixed on the C-shaped structure on the A side of the central cantilever drives the belt transmission mechanism to move, so that the Z-axis slider fastened to one side of the belt transmission mechanism moves along the linear polished rod slide, and the Z-axis lifting platform fastened to the Z-axis slider lifts the well plate to be lifted and transferred to a certain height. The upper computer controls the DD motor to drive the central cantilever to rotate, so that the lifted well plate rotates to the right below the plate changing or transfer entrance and exit, and the servo drives the two-way clamping mechanism to open, and the Z-axis lifting platform is further raised to lift the well plate out of the incubator. After the mechanical arm completes the plate changing or transfer operation, the Z-axis lifting platform drives the well plate to descend, and the above operation is performed in reverse to put the well plate back to its original position. Repeating the above operation can realize the lifting and liquid changing functions of all well plates. Taking monitoring the survival status of cells in a 2×3-size plate as an example, the operation steps are as follows: the upper computer controls the DD motor to drive the central cantilever to rotate, so that the lighting component in the monitoring mechanism reaches the top of the row of culture holes in the desired observation plate that is closest to the monitoring mechanism, and the microscopic monitoring component in the monitoring mechanism reaches the bottom of the row of culture holes in the desired observation plate that is closest to the monitoring mechanism. The servo motor β drives the linear screw slide to move along the X-axis direction through the coupling, and the X-axis slider α drives the microscopic monitoring component to move along the linear guide rail α to the bottom of the desired observation culture hole through the synchronous slider α; at the same time, the synchronous belt transmission mechanism J area fastened to the central area of ​​the synchronous slider α moves the same distance as the microscopic monitoring component in the same direction, and the synchronous belt transmission mechanism K area rotates around the wheel to achieve two changes of direction relative to the synchronous belt transmission mechanism J area, so that the movement direction and movement distance of the synchronous belt transmission mechanism K area and the synchronous belt transmission mechanism J area are always consistent; the synchronous slider β fastened to the synchronous belt transmission mechanism K area drives the lighting component to move along the linear guide rail β to the top of the desired observation culture hole, so as to achieve the effect of synchronous operation of the lighting component and the microscopic monitoring component.When the in-situ online monitoring of a single culture well is completed, the monitoring mechanism repeats the above positioning operation in the X-axis direction according to the host computer signal, and is driven by the DD motor to rotate a certain angle relative to the well plate in the angular direction to realize the monitoring function of the remaining culture wells. When the monitoring of the six culture wells in a single well plate is completed, the above operation is repeated according to the host computer signal to realize the monitoring function of all well plates.

[0053] Compared with the existing structure, the beneficial effects of the present invention are: the present invention has a higher degree of integration than the existing cell or organoid biological culture device, faster observation and analysis speed, can maintain strict environmental conditions during the culture and analysis process, the culture environment of all well plates during the culture process is more consistent, the disturbance to the remaining well plates when taking the well plates is lower, the well plates being observed will not be disturbed during observation and analysis, strict environmental conditions can be maintained during the culture and observation process, and the cost is lower. It can meet the high-throughput and low-disturbance requirements of high-throughput biological culture systems in the context of industrialization and automation, and provides technical and theoretical possibilities for the success of intelligent automated production lines for cell or organoid culture and observation. In order to make the above-mentioned purposes, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0055] Figure 1 3D is a three-dimensional structural diagram of a high-throughput biological culture system in an embodiment, in which the box body is partially transparent.

[0056] Figure 2 It is a schematic structural diagram of the three-dimensional structure of the high-throughput biological culture system in the embodiment, omitting the box part.

[0057] Figure 3 yes Figure 2 Top view of the .

[0058] Figure 4 It is a schematic diagram of the structure of the monitoring and lifting integrated device.

[0059] Figure 5 It is a structural diagram of the monitoring and lifting integrated device from another angle.

[0060] Figure 6 It is a schematic diagram of the central cantilever structure.

[0061] Figure 7This is the structural diagram of the central cantilever from another angle.

[0062] Figure 8 It is a schematic diagram of the lifting mechanism structure.

[0063] Fig. 9 It is a schematic diagram of the monitoring organization structure.

[0064] Fig.10 It is the left view of the monitoring mechanism.

[0065] Fig.11 It is a schematic diagram of the structure of the culture device.

[0066] Fig.12 It is a schematic diagram of the structure of the culture device after removing the upper bottom plate.

[0067] Fig.13 It is a top view of the rotating platform mechanism.

[0068] Fig.14 It is the front view of the rotating platform mechanism.

[0069] Fig.15 It is a schematic diagram of the C-shaped support mechanism structure.

[0070] Fig.16 It is another structural schematic diagram of the C-shaped support mechanism.

[0071] Fig.17 It is a schematic diagram of the local structure of the bidirectional clamping mechanism.

[0072] Fig.18 It is a partial top view of the bidirectional clamping mechanism.

[0073] Fig.19 It is a schematic diagram of the structure of the bidirectional clamping mechanism from an upward angle.

[0074] Fig. 20 It is a schematic diagram of the structure of an existing biological culture device.

[0075] Fig.21 This is a schematic diagram of the structure after the box is partially disassembled.

[0076] In the picture

[0077] 1. Central cantilever; 1-1. Fork arm structure; 1-2. Hole position of orifice plate tray; 1-3. Hole position of DD motor; 1-4. C-shaped structure; 2. Lifting mechanism; 2-1. Servo motor α; 2-2. Belt transmission mechanism; 2-3. Z-axis slider; 2-4. Z-axis lifting platform; 2-5. Linear light rod slide; 3. Monitoring mechanism; 3-1. Servo motor β; 3-2. Coupling; 3-3. Linear lead screw slide; 3-4. X-axis slider α; 3-5. Synchronous slider α; 3-6. X-axis slider β; 3-7. Linear guide α; 3 -8, microscopic monitoring assembly; 3-9, synchronous belt transmission mechanism; 3-10, linear guide β; 3-11, X-axis slider γ; 3-12, lighting assembly; 3-13, synchronous slider β; 4, rotating platform mechanism; 4-1, wireless scanner; 4-2, electronic tag; 4-3, upper center semi-axis; 4-4, DD motor; 4-5, tray; 4-6, lower center semi-axis; 5, C-shaped support mechanism; 5-1, humidifier; 5-2, lower base plate; 5-2-1, lower center semi-axis fixing hole; 5-2-2, line collection slot α; 5-3, heat sink; 5-3-1, oxygen vent; 5-3-2, carbon dioxide vent; 5-4 heating rod; 5-5, upper base plate; 5-5-1, upper center semi-axis fixing hole; 5-5-2, line collection slot β; 5-6, humidity sensor; 5-7, sensor fixing plate; 5-8, carbon dioxide sensor; 5-9, oxygen sensor; 6, box; 6-1, upper box; 6-2, lower box; 7, sliding door assembly; 7-1, baffle; 7-2, screw slide; 7-3, motor; 8, orifice plate; 9, entrance and exit ; 10. Bidirectional clamping mechanism; 10-1. Radial clamp; 10-1-1. Pulley α; 10-1-2. Pin α; 10-2. Pin β; 10-3. Guide wheel α; 10-4. Long rope; 10-5. Pin γ; 10-6. Guide wheel β; 10-7. Servo; 10-8. Short rope; 10-9. Volute spring; 10-10. Tangential swing arm; 10-11. Fan-shaped opening; 10-12. Tangential clamp; 10-12-1. Pulley β; 10-13. Tension spring; 10-14. Radial clamp guide. DETAILED DESCRIPTION

[0078] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0079] like Figures 1 to 3 , Fig.19 As shown, in this embodiment, a high-throughput biological culture system includes a box body 6, a sliding door assembly 7 arranged on the top of the box body, and a monitoring and lifting integrated device, a culture device, etc. arranged in the box body 6. An entrance and exit 9 is provided on the top of the box body 6.

[0080] The monitoring and lifting integrated device is mainly composed of a central cantilever 1, a lifting mechanism 2, a monitoring mechanism 3, etc., and the culture device is mainly composed of a rotating platform mechanism 4, a C-shaped support mechanism 5, a bidirectional clamping mechanism 10, etc. Generally speaking, the C-shaped support mechanism 5 is fixed in the box 6 to provide installation space for other mechanisms. The central cantilever 1 is transferred to the C-shaped support mechanism 5 and can rotate in a set direction and speed under the drive of the corresponding driving mechanism. The lifting mechanism 2 and the monitoring mechanism 3 are installed at both ends of the central cantilever 1 and can rotate synchronously with the central cantilever 1. The rotating platform mechanism 4 is coaxially transferred with the central cantilever 1 in the C-shaped support mechanism 5, and similarly, can rotate in a set direction and speed under the drive of the corresponding driving mechanism. The rotating platform mechanism 4 and the central cantilever 1 are driven by their corresponding driving mechanisms and rotate independently at a set speed and direction. The rotating platform mechanism 4 provides a positioning and placement space for the well plate 8 for cell culture. The bidirectional clamping mechanism 10 is used to realize the positioning of the well plate 8 on the rotating platform mechanism 4.

[0081] The present invention will be further described below in conjunction with the accompanying drawings:

[0082] like Figures 4 to 10 As shown, in this embodiment, the integrated monitoring and lifting device includes a central cantilever 1, a lifting mechanism 2 and a monitoring mechanism 3.

[0083] See also Figure 6 and Figure 7 , the middle part of the central cantilever 1 is the central axis platform, and the two sides are respectively the fork arm structure 1-1 and the C-shaped structure 1-4. Specifically, the upper part of the central axis platform is provided with a hole position 1-2 and a groove structure for connecting the orifice plate tray, the lower part of the central axis platform is provided with a hole position 1-3 and a groove structure for installing the DD motor, the A side of the central axis platform is provided with a fork arm structure 1-1, and the B side of the central axis platform is provided with a C-shaped structure 1-4. The fork arm structure 1-1 is provided with a hole position α1-5 for fixing the servo motor α2-1, a hole position β1-6 for fixing the belt transmission mechanism 2-2, and a hole position γ1-7 for fixing the linear light rod slide 2-5. The C-shaped structure 1-4 is provided with a mounting plate α1-8 for fixing the servo motor β3-1 and the linear screw slide 3-3, a hole δ1-9 (F side of the C-shaped structure 1-4) for fixing the synchronous belt transmission mechanism 3-9, a mounting plate β1-10 for installing the linear guide β3-10, and a mounting plate γ1-11 for installing the linear guide α3-7. Each component in the lifting mechanism 2 and the monitoring mechanism 3 is fixed on the central cantilever 1 through the above-mentioned holes and mounting plates.

[0084] See also Figure 8The lifting mechanism 2 includes a servo motor α2-1, whose output end is provided with a belt transmission mechanism 2-2. The Z-axis slider 2-3 fastened to one side of the belt transmission mechanism 2-2 can move along the linear polished rod slide 2-5. The inner side of the Z-axis slider 2-3 is fastened to the Z-axis lifting platform 2-4, and the Z-axis lifting platform 2-4 is used to lift the orifice plate 8. The belt transmission mechanism 2-2 is composed of a plurality of transmission gears ( Figure 8 The Z-axis lifting platform 2-4 is provided with a lifting structure that cooperates with the orifice plate.

[0085] See also Fig. 9 and Fig.10 The monitoring mechanism 3 includes a servo motor β3-1, which drives the X-axis slider α3-4 on the linear screw slide 3-3 to move through a coupling 3-2. The X-axis slider α3-4 can move back and forth under the drive of the linear screw slide 3-3. The X-axis slider α3-4 is fastened to the synchronous slider α3-5, so that the synchronous slider α3-5 can move synchronously with the X-axis slider α3-4. One end (end D) of the synchronous slider α3-5 is fixed to the X-axis slider α3-4, the middle part is fixed to the synchronous belt transmission mechanism 3-9, and the other end (end E) is fixed to the X-axis slider β3-6 and the microscopic monitoring component 3-8. The synchronous belt transmission mechanism 3-9 is composed of a number of transmission gears (two sets of horizontally arranged gear sets and one set of vertically arranged gear sets in the figure, and the vertically arranged gear sets are mainly used to adjust the horizontal direction and position of the belt) and a synchronous belt. The synchronous belt is arranged in a circuitous manner, and there are at least two horizontal sections with the same transmission direction. The synchronous slider α3-5 and the synchronous belt fixed X-axis slider β3-6 of the horizontal section (J part) thereof move along the linear guide rail α3-7 to guide the synchronous slider α3-5. The other horizontal section (K part) of the synchronous belt transmission mechanism 3-9 is fastened to one end (H end) of the synchronous slider β3-13 at the same time. The other end (I end) of the synchronous slider β3-13 is fixed to the X-axis slider γ3-11 and the lighting assembly 3-12. The X-axis slider γ3-11 moves along the linear guide rail β3-10.

[0086] like Figures 11 to 16 As shown, in this embodiment, the culture device includes a rotating platform mechanism 4 and a C-shaped support mechanism 5. Fig.12The rotating platform mechanism 4 includes an upper center semi-axis 4-3, the middle of which is fastened to the DD motor 4-4 and is connected to the tray 4-5. The rotation of the tray 4-5 is driven by the DD motor 4-4. The tray 4-5 is evenly provided with a plurality of orifice plate placement openings 4-7 in the circumferential direction, and the shape of the orifice plate placement openings 4-7 corresponds to the shape of the orifice plate; the tray 4-5 is provided with electronic tags 4-2 corresponding to the corresponding orifice plates around it. A wireless scanner 4-1 for scanning and reading the information of the electronic tag 4-2 is provided above the tray 4-5. The upper center semi-axis 4-3 is fastened to the lower center semi-axis 4-6.

[0087] See Fig.14 and Fig.15 The C-shaped support mechanism 5 includes an upper base plate 5-5, a lower base plate 5-2, and a heat sink 5-4 that fixes the upper base plate 5-5 and the lower base plate 5-2 to each other. Among them, the lower base plate 5-2 is provided with a lower center semi-axis fixing hole 5-2-1 and a line collection groove α5-2-2, and a humidifier 5-1 is provided on the periphery of the lower base plate 5-2. A heat sink 5-3 is provided behind the lower base plate 5-2. An oxygen vent 5-3-1 and a carbon dioxide vent 5-3-2 are provided in the center of the heat sink 5-3; a heating rod 5-4 is provided on the left side of the heat sink 5-3, and a sensor fixing plate 5-7 is provided on the right side. A humidity sensor 5-6, a carbon dioxide sensor 5-8, and an oxygen sensor 5-9 are provided on the right side of the sensor fixing plate. An upper base plate 5-5 is provided above the heat sink, and an upper center semi-axis fixing hole 5-5-1 and a line collection groove β5-5-2 are provided in the upper base plate. At the same time, the electronic tag has a temperature detection function. Through the cooperation of the temperature detection function of the electronic tag and the heating rod 5-4, the temperature in the box can be accurately controlled. The humidifier 5-1 and the humidity sensor 5-6 can be used to accurately control the humidity in the box. The carbon dioxide sensor 5-8 and the oxygen sensor 5-9 can detect and control carbon dioxide and oxygen in the box.

[0088] In the present invention, the trays 4-5 and the central cantilever 1 can be driven separately by independent DD motors.

[0089] like Figures 17-18As shown, in this embodiment, the bidirectional clamping mechanism 10 is arranged at a position corresponding to the orifice plate placement opening 4-7 on the tray 4-5. The bidirectional clamping mechanism 10 includes a radial clamping claw guide 10-14 arranged along the radial direction of the tray 4-5, and a radial clamping claw 10-1 arranged on the radial clamping claw guide 10-14 and capable of sliding along the radial clamping claw guide 10-14. The radial clamping claw 10-1 is in the shape of a long strip and arranged along a vertical radial direction, and is mainly used for positioning the orifice plate in the radial direction; a pulley α10-1-1 is provided inside the radial clamping claw 10-1, and a pin α10-1-2 is provided above. The tray 4-5 is provided with a pin β10-2, a pin γ10-5 and a steering gear 10-7. The steering gear 10-7 is a driving mechanism, and the transmission member is a long rope 10-4. The pin β10-2 and the pin γ10-5 are provided with a guide wheel α10-3 and a guide wheel β10-6 respectively. One end of the long rope 10-4 is fixed to the output end of the steering gear 10-7, and the other end passes through the guide wheel α10-3 and the guide wheel β10-6 and is fastened to the pin α10-1-2. The two ends of a radially arranged tension spring 10-13 are fastened to the tray 4-5 and the radial clamp 10-1 respectively, and are stretched toward the direction close to the central axis of the tray 4-5. A tangential clamp 10-12 is also provided on the tray 4-5 for realizing circumferential positioning of the orifice plate; a pulley β10-12-1 is provided on the inner side of the tangential clamp 10-12; a fan-shaped opening 10-11 and a tangential swing arm 10-10 arranged along the circumference are also provided on the tray 4-5, one end of the tangential swing arm 10-10 is connected to the center of the spiral spring 10-9, and the other end passes through the fan-shaped opening 10-11 arranged on the tray and is connected to the tangential clamp 10-12, driving the tangential clamp 10-12 to rotate synchronously; one end of the tangential swing arm 10-10 connected to the spiral spring 10-9 is fastened to the output end of the steering gear 10-7 through a short rope 10-8, and the tangential clamp 10-12 rotates around the center of the other end of the tangential swing arm 10-10.

[0090] In the bidirectional clamping mechanism 10, the radial jaws 10-1, the radial jaw guide rails 10-14 and the tension springs 10-13 constitute a radial positioning assembly, and the tangential jaws 10-12 and the spiral springs 10-9 cooperate with the fan-shaped opening 10-11 to form a circumferential positioning assembly; the servo 10-7 provides driving force for the radial jaws 10-1 and the tangential jaws 10-12 at the same time, which are respectively used to realize the radial outward opening of the radial jaws 10-1 and the circumferential outward opening of the tangential jaws 10-12; the radial jaws 10-1 simultaneously use the tension springs 10-13 to realize the radial inward clamping of the orifice plate; the tangential jaws 10-12 realize the circumferential clamping of the orifice plate under the torsion of the spiral springs 10-9.

[0091] The orifice plate placement opening is provided with radial limiting edge and circumferential limiting edge structures, which cooperate with the radial clamping assembly and the circumferential clamping assembly to achieve radial and circumferential fixation of the orifice plate. When clamping is required, the driving mechanism releases the radial clamping claw, and under the tension of the radial elastic member, the inner side of the orifice plate abuts against the radial limiting edge, and the radial clamping claw achieves the clamping operation on the orifice plate. At the same time, the driving mechanism releases the tangential clamping claw, and the tangential elastic member retracts the tangential clamping claw circumferentially, and the inner side of the orifice plate abuts against the circumferential limiting edge, so that the tangential clamping claw clamps the orifice plate.

[0092] At the same time, an avoidance gap is left between the radial clamping jaw 10-1 and the tangential clamping jaw 10-12 to avoid the Z-axis lifting platform 2-4.

[0093] like Fig.21 As shown, in this embodiment, the box 6 includes an upper box 6-1 and a lower box 6-2, and the monitoring, lifting integrated device and the culture device are placed in the lower box 6-2. The upper box 6-1 is fastened to the lower box 6-2 to form a closed space. The upper left side of the upper box 6-2 is provided with a sliding door mechanism 7 device for controlling the box plate changing or lifting port switch, and the top of the upper box is provided with a plate changing or liquid changing inlet and outlet 9.

[0094] The sliding door mechanism 7 is mainly composed of a baffle 7-1, a baffle screw slide 7-2 and a baffle motor 7-3. A door structure is provided on the upper box body 6-2. The baffle 7-1 corresponds to the above-mentioned door structure and is used to close and open the box body 6. The other end of the baffle 7-1 is fixed to the baffle screw slide 7-2 and can move synchronously. The baffle screw slide 7-2 is connected to the output end of the baffle motor 7-3.

[0095] In this embodiment, when used, the operation process is as follows: first, turn on the power, then activate the humidifier 5-1, the heating rod 5-4, and open the oxygen vent 5-3-1 and the carbon dioxide vent 5-3-2 to start adjusting the environment inside the incubator. At the same time, the humidity sensor 5-6, the electronic tag 4-2 with temperature sensing and recording functions, the oxygen sensor 5-3-1 and the carbon dioxide sensor 5-3-2 will feed back the real-time monitoring data to the host computer. After an appropriate time, the internal environment of the incubator will meet the culture conditions of cells or organoids. Subsequently, the host computer commands the DD motor 4-4 on the upper center semi-axis 4-3 to drive its tray 4-5 to rotate. The robotic arm places the well plate 8 on the rotating tray 4-5 in turn, and the bidirectional clamping mechanism 10 clamps the well plate 8. At this time, the wireless scanner 4-1 on the upper bottom plate 5-5 writes the well plate information (including the time of entry, culture time, number of liquid changes, cell or organoid survival status, etc.) into the electronic tag 4-2 of each well plate, and then starts the cell or organoid culture program. When changing the plate fluid or replacing the plate, the robot arm will accurately move the required plate without disturbing other plates. After the operation is completed, the plate is reset and the tray 4-5 continues to rotate. When the electronic tag 4-2 is aligned with the bottom of the wireless scanner 4-1, the wireless scanner 4-1 will complete the update of the information. After the update, the culture process of cells or organoids will continue.

[0096] Specifically, when it is necessary to change plates or transfer liquids, the upper computer controls the DD motor corresponding to the central cantilever to drive the central cantilever 1 to rotate, and positions the lifting mechanism 2 to be directly below the orifice plate that needs to be lifted or the liquid needs to be changed. The servo 10-7 drives the bidirectional clamping mechanism 10 to loosen the orifice plate. The servo motor α2-1 is located on the C-shaped structure 1-4 on the side of the central cantilever 1A, and drives the Z-axis slider 2-3 to move along the linear light rod slide 2-5 through the belt transmission mechanism 2-2 to lift the orifice plate. Subsequently, the DD motor drives the central cantilever 1 to rotate again, rotating the orifice plate to be directly below the inlet and outlet 9 for changing plates or changing liquids, and the Z-axis lifting platform 2-4 rises to complete the operation of lifting the orifice plate out of the incubator. After the robot arm performs the plate change or liquid change, the orifice plate descends and performs the above steps in reverse, and is put back in place. Repeating this process can achieve the lifting and liquid change of all orifice plates.

[0097] The monitoring operation is as follows: the DD motor is controlled by the upper computer to drive the central cantilever 1, and the lighting component 3-12 of the monitoring mechanism 3 is positioned directly above the culture hole (or target culture hole) closest to the monitoring mechanism 3, and the microscopic monitoring component 3-8 is positioned directly below. The servo motor β3-1 drives the linear screw slide 3-3 to move along the X-axis direction through the coupling 3-2, and the X-axis slider α3-4 drives the microscopic monitoring component 3-8 to move along the linear guide α3-7 to the desired observation culture hole. The synchronous belt drive mechanism 3-9J area moves synchronously with the microscopic monitoring component 3-8, and the synchronous belt drive mechanism 3-9K area realizes two changes of direction relative to the J area to ensure that the movement direction and distance of the two are consistent. The synchronous slider β3-13 drives the lighting component 3-12 to move along the linear guide β3-10 to the desired observation culture hole, completing the synchronous operation of the lighting and monitoring components. After the single culture well is monitored in situ online, the monitoring mechanism 3 repeatedly locates in the X-axis direction according to the host computer signal and rotates a certain angle in the angular direction to monitor the remaining culture wells. When all the culture wells in a single well plate are monitored, the above operation is repeated to achieve monitoring of all well plates.

[0098] Unless otherwise stated, any technical solution disclosed in the present invention disclosed above, if it discloses a numerical range, then the disclosed numerical range is a preferred numerical range, and any technician in the field should understand that the preferred numerical range is only a numerical value with a more obvious technical effect or representative value among many implementable numerical values. Since there are too many numerical values ​​to be exhaustive, the present invention discloses some numerical values ​​to illustrate the technical solution of the present invention, and the numerical values ​​listed above should not constitute a limitation on the scope of protection of the present invention.

[0099] At the same time, if the above-mentioned invention discloses or involves components or structural parts that are "fixed", "fixed to", "fastened" or "fixedly connected" to each other, then, unless otherwise stated, the fixed connection can be understood as: a detachable fixed connection (for example, connected by bolts or screws), and can also be understood as: a non-detachable fixed connection (for example, riveting, welding). Of course, the mutual fixed connection can also be replaced by an integrated structure (for example, manufactured by one-piece molding using a casting process) (except where it is obviously impossible to use an one-piece molding process).

[0100] If the words "first", "second", etc. are used in this article to limit components, those skilled in the art should know that the use of "first" and "second" is only to distinguish the components for the convenience of description. Unless otherwise stated, the above words have no special meaning.

[0101] When "α", "β", "γ" and "δ" are used as suffixes to define component names in this article, it is only for the convenience of distinguishing the components for the purpose of description; unless otherwise stated, the above words have no special meaning and have no other limiting effect.

[0102] In addition, unless otherwise stated, the terms used to indicate positional relationships or shapes in any of the technical solutions disclosed in the present invention include states or shapes that are approximate, similar, or close to them.

[0103] Any component provided by the present invention can be assembled from multiple separate components, or can be a separate component manufactured by an integral forming process.

[0104] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solution of the present invention, which should be included in the scope of the technical solution for protection of the present invention.

Claims

1. A high-throughput biological culture system, comprising a housing with an inlet and an outlet, characterized in that: It also includes a monitoring-lifting integrated device and a culture device arranged in the box; the culture device includes a rotating platform mechanism arranged in the box for placing a culture well plate; The monitoring-lifting integrated device comprises: A central cantilever coaxially connected to the rotating platform mechanism; A lifting mechanism provided at one end of the central cantilever for lifting the orifice plate to move along the Z-axis direction; A monitoring mechanism is provided at the other end of the central cantilever for illuminating and observing the status of cells in the well plate.

2. The high-throughput biological culture system according to claim 1, characterized in that: The culture device comprises: A C-shaped support mechanism disposed in the box; The rotating platform mechanism is arranged in the C-shaped supporting mechanism.

3. The high-throughput biological culture system according to claim 2, characterized in that: The C-shaped supporting mechanism is provided with a heating unit, a humidifying unit, an oxygen vent and a carbon dioxide vent; the box body is provided with a temperature sensor, a humidity sensor, an oxygen sensor and a carbon dioxide sensor.

4. The high-throughput biological culture system according to claim 2, characterized in that: The rotating platform mechanism comprises: A shaft member fixed in the C-shaped support mechanism; A tray disposed on the shaft member; The central cantilever is simultaneously connected and arranged on the shaft; The tray and the central cantilever can be independently rotated around the shaft when driven by the corresponding driving mechanism.

5. The high-throughput biological culture system according to claim 4, characterized in that: The rotating platform mechanism also includes a bidirectional clamping mechanism arranged on the tray, and the bidirectional clamping mechanism includes a radial clamping assembly for realizing radial clamping of the orifice plate and a circumferential clamping assembly for realizing circumferential clamping of the orifice plate.

6. The high-throughput biological culture system according to claim 4, characterized in that: The tray is provided with a plurality of orifice plate placement positions and electronic tags for recording orifice plate information in a circular array, and the box body is also provided with a wireless scanner for reading and writing information in the electronic tags.

7. The high-throughput biological culture system according to claim 1, characterized in that: The lifting mechanism comprises: Z-axis lifting platform with orifice plate placement; An axial driving mechanism and an axial transmission mechanism for driving the Z-axis lifting platform to move in the vertical direction; The monitoring agencies include: Microscopic monitoring components and lighting components are arranged correspondingly in the positions; A radial driving mechanism and a radial transmission mechanism are provided for driving the microscopic monitoring component and the lighting component to synchronously move radially along the rotating platform mechanism.

8. The high-throughput biological culture system according to claim 7, characterized in that: The radial transmission mechanism or the axial transmission mechanism is a belt transmission mechanism, and the microscopic monitoring component and the lighting component or the Z-axis lifting platform are respectively fixed to the belt transmission mechanism through corresponding synchronous sliders; the driving mechanism is a servo motor.

9. The high-throughput biological culture system according to claim 4, characterized in that: The central cantilever is arranged below the tray, with a C-shaped structure for fixing the monitoring mechanism at one end and a fork arm structure for fixing the lifting mechanism at the other end, and a hole for connecting with the shaft member in the middle.

10. The high-throughput biological culture system according to claim 1, characterized in that: Under the control of the host computer, the monitoring-lifting integrated device automatically completes the plate changing operation and the monitoring function of any culture well through the entrance and exit, and the culture device automatically completes the control of the culture conditions and the writing and reading of the well plate information; the box body is provided with a sliding door mechanism, which includes a baffle that cooperates with the entrance and exit, and a baffle motor that drives the baffle to realize the closing and opening operations of the input port.

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