Automatic radiopharmaceutical synthesis system and method based on digital microfluidics

Abstract

The invention discloses an automatic radiopharmaceutical synthesis system and method based on digital microfluidics, and belongs to the technical field of automatic equipment. The synthesis system comprises a synthesis module consisting of a digital micro-fluidic chip and a chip control circuit, a liquid adding module consisting of a manipulator device, a pipette assembly and a liquid adding bottle, a sample discharging module consisting of a movably arranged sample discharging platform and a sample discharging capillary tube arranged on the platform, and a solvent replacement module. According to the invention, the manipulator device capable of moving in a three-dimensional space and the pipette assembly are arranged to realize automatic liquid adding on the micro-fluidic chip, the movable sample outlet platform and the pipeline design are arranged to realize automatic extraction of reaction products, and a plurality of pinch valves and peristaltic pumps are utilized to realize automatic solvent replacement. The synthesis device provided by the invention is used for completing automatic production of the radiopharmaceutical on the micro-fluidic chip, and has the advantages of miniaturization, integration, automation, high efficiency and low cost.

Description

Technical Field

[0001] The present invention relates to the technical field of automated equipment, and in particular to an automated radiopharmaceutical synthesis system and a synthesis method based on digital microfluidics. Background Art

[0002] Digital microfluidics (DMF) is a new droplet manipulation technology that independently manipulates discrete droplets. The core technology is to use electronic circuits to control the surface tension of liquids, thereby controlling the generation, movement, splitting, and merging of droplets. The fluid channels in microfluidic chips are tiny in size, and the fluid has a short mass transfer and heat transfer path when flowing through them. The reaction can quickly reach equilibrium, and the reaction time is greatly shortened. At the same time, it can improve the stability and controllability of the reaction, and has the characteristics of high throughput, high sensitivity, and low consumption. It is also called chip laboratory technology, which has many advantages in the field of life science research.

[0003] Digital microfluidics enables complex laboratory analysis through precise manipulation of droplets in the microliter to nanoliter range. Specifically, in digital microfluidics, the generation and manipulation of droplets are supported by the three principles of electrowetting, dielectrophoresis, and immiscible fluid flow. The programmability of dielectric electrowetting technology is combined with computers and integrated circuit layout design algorithms to automatically plan the droplet movement path. Complex experimental procedures can be achieved by combining and repeating multiple operations in a series of steps at a series of levels.

[0004] The emergence of digital microfluidics makes it possible to produce radiochemical tracers at the microliter level, such as positron emission tomography (PET) tracers labeled with 18F or other isotopes. For example, patent document CN118831662A discloses a digital microfluidic chip system with temperature-controllable dielectric electrowetting, which can design the movement path of reaction reagents according to the radiopharmaceutical synthesis process flow, and complete the reaction program by driving reagent droplets in multiple different areas on the chip. Working at this microliter volume scale can not only reduce reagent costs, increase specific activity (SA) by reducing stable isotope contamination, but also use very small doses of chemical and biological drugs for rapid and automated on-chip reactions and detection.

[0005] However, there is no microfluidic automation equipment suitable for radiopharmaceutical production on the market. Experimenters need to perform manual operations such as adding reaction reagents on the chip according to the requirements of different experimental types and reaction conditions. The experimenters need to be on duty and cooperate throughout the reaction process. In addition, there is a lack of protection for the experimenters, which leads to problems such as inconvenience in use and operational safety. Therefore, it is necessary to develop an automated microfluidic technology platform to reduce the on-duty time of experimenters during the reaction process. Summary of the invention

[0006] The purpose of the present invention is to provide an automated device for synthesizing radioactive drugs based on digital microfluidics technology. During the synthesis process, experimenters can complete the preparation of radioactive drugs through remote control and micro-collaboration, overcoming the shortcomings of existing microfluidics devices such as low automation and high collaboration of experimenters.

[0007] To achieve the above object, the present invention adopts the following technical solution: The invention provides an automated radiopharmaceutical synthesis system based on digital microfluidics, comprising a synthesis module, a liquid adding module, a sample output module, a solvent replacement module and a control module.

[0008] The synthesis module is used to realize the synthesis reaction of radioactive drugs, and its components include: a digital microfluidic chip and a chip control circuit. The synthesis reaction of the radioactive drug is carried out on the digital microfluidic chip, and the chip control circuit controls the driving of the electrodes on the digital microfluidic chip to realize the driving of the droplets on the chip. The present invention uses a microfluidic chip to complete the production of radioactive drugs on a small volume scale, designs the movement path of the reaction reagent droplets according to the synthesis process flow, and completes each synthesis step in different areas of the chip. The radioactive drug is a substance containing radionuclides, which is used for clinical diagnosis or treatment, and can be but not limited to positron-type radioactive drugs and single-photon radioactive drugs.

[0009] Specifically, the digital microfluidic chip includes a conductive top plate and a bottom plate, which are arranged in parallel to form a fluid channel for droplet displacement. A plurality of independently controllable drive electrodes are arranged on the bottom plate. The chip control circuit is used to connect the drive electrode and the conductive layer of the top plate to the positive and negative electrodes of the power supply, respectively, and form a closed loop with the droplets on the electrodes. The adjacent drive circuits are powered on and off in sequence to achieve the movement of the droplets along the planned path. The chip control circuit is controlled by a control module, which provides a drive signal to the chip control circuit to control its connection with the power supply.

[0010] The liquid adding module is used to add reaction reagents to the digital microfluidic chip, and its components include: a manipulator device, a pipette assembly, and a liquid adding bottle. The pipette assembly includes a pipette and a pipette head; the manipulator device is used to clamp the pipette, replace the pipette head, and use the pipette to transfer the reagents in the liquid adding bottle to the reaction point of the digital microfluidic chip. The present invention uses a manipulator device that can be raised and lowered and moved horizontally to complete freely defined actions within the range of the X-axis, Y-axis, and Z-axis, and realizes the pipetting of trace reagents using a pipette. The manipulator device is controlled by a control module, and the control module completes the corresponding action by sending a drive signal to the motor or cylinder of each component in the manipulator device.

[0011] The sample discharging module is used to extract the reaction products in the digital microfluidic chip, and its components include: a movably arranged sample discharging platform and a sample discharging capillary arranged on the platform. When discharging the sample, the orifice of the sample discharging capillary moves with the sample discharging platform to the product point of the digital microfluidic chip. The movement of the sample discharging platform is controlled by the control module, and the slide cylinder drives the movement of the sample discharging platform. After the reaction is completed, the control module sends a driving signal to the slide cylinder, and the sample discharging platform is pushed toward the microfluidic chip along the slide track so that the orifice of the sample discharging capillary contacts the reaction solution on the microfluidic chip.

[0012] The solvent replacement module is used for adsorption and elution of radioactive raw materials and solvent replacement of synthetic products, and its components include: a medicine rack for placing reagent bottles, a liquid extraction needle arranged on a manipulator device for extracting liquid from reagent bottles, a solid phase extraction column I for adsorbing radioactive elements, and a solid phase extraction column II for solvent replacement of reaction products. The sample outlet of the solid phase extraction column I is connected to the liquid addition bottle through a pipeline, and the sample inlet of the solid phase extraction column II is connected to the sample outlet capillary through a pipeline. The pipeline is driven by a plurality of peristaltic pumps, and the switching direction is controlled by a plurality of pinch valves. The manipulator device, peristaltic pump and pinch valve are all controlled by a control module.

[0013] Specifically, the reagents include radioactive raw materials, radionuclide eluent, impurity washing solution, product eluent, and product diluent, and the reagent bottles containing the above reagents are respectively placed on the medicine rack.

[0014] The present invention connects the sample inlet and sample outlet of the solid phase extraction column I to the liquid extraction needle and the liquid addition bottle for collecting the radioactive isotope eluent respectively through a hose pipeline. When the radioactive raw material is subjected to adsorption elution, the control module sends an action instruction, and the manipulator device inserts the liquid extraction needle into the raw material bottle. Under the action of the peristaltic pump, the raw material liquid passes through the solid phase extraction column I, and the radioactive element is adsorbed on the extraction column. Then the manipulator device inserts the liquid extraction needle into the eluent bottle, and the eluent passes through the solid phase extraction column I to elute the radioactive element and flows into the liquid addition bottle.

[0015] The present invention connects the sample inlet of the solid phase extraction column II with a sample outlet capillary and a liquid extraction needle through a branch pipeline, the sample outlet is connected with a waste liquid bottle and a product collection bottle, and a pinch valve is installed on the branch pipeline to realize pipeline switching. When the synthetic product is subjected to solvent replacement, the control module sends an action instruction, firstly switching the pinch valve to connect the inlet and outlet of the solid phase extraction column II to the outlet capillary and the waste liquid bottle, under the action of the peristaltic pump, the reaction liquid on the chip is sucked into the solid phase extraction column II by the outlet capillary, and the product is adsorbed on the extraction column; then switching the pinch valve of the inlet to connect the liquid extraction needle pipeline, the manipulator device inserts the liquid extraction needle into the washing liquid reagent bottle, under the action of the peristaltic pump, the washing liquid is washed by the solid phase extraction column II; then switching the pinch valve of the outlet to connect the product collection bottle, the manipulator device inserts the liquid extraction needle into the eluent reagent bottle, under the action of the peristaltic pump, the eluent elutes the product through the solid phase extraction column II and flows into the product collection bottle, next, the manipulator device inserts the liquid extraction needle into the diluent reagent bottle, under the action of the peristaltic pump, the diluent flows into the product collection bottle to dilute the product.

[0016] The control module is used to send work instructions to each module to control the work of each component. Specifically, the present invention realizes the controllability of the instrument system through the operation of a software program. The control module is connected to the chip control circuit, the manipulator device, the sample discharging platform, the peristaltic pump and the pinch valve in communication, and controls the lifting and horizontal movement of the manipulator device, the use of the pipette gun, the operation of the peristaltic pump, the pipeline switching of the pinch valve, the power on and off of the chip control circuit, and the movement of the sample discharging platform.

[0017] Preferably, the synthesis system further comprises an operation platform, and the synthesis module, liquid addition module, sample output module and solvent replacement module are all arranged on the operation platform. In the present invention, each module component can be arranged on the operation platform according to actual needs.

[0018] Preferably, the manipulator device includes a robotic arm that can be raised and lowered and moved horizontally, and a clamp fixedly mounted on the robotic arm for clamping and placing the pipette. The robotic arm is also provided with a telescopic motor adapted to the pipette control button, and a pen-shaped cylinder adapted to the pipette tip detachment button; the robotic arm, the clamp, the telescopic motor and the pen-shaped cylinder are all controlled by a control module.

[0019] In the present invention, the clamp is controlled by the clamp cylinder to complete the clamping and releasing action, and the clamp cylinder is controlled by the control module. The telescopic motor and the pen-shaped cylinder are also controlled by the control module. The telescopic motor controls the action of pressing down and lifting up the control button of the liquid transfer gun, which can realize the liquid suction and liquid discharge of the liquid transfer gun tip, and the liquid transfer amount is controlled by the degree of pressing down and lifting up the control button; the pen-shaped cylinder controls the action of pressing down and retracting the disengagement button of the liquid transfer gun tip, which can realize the disengagement of the liquid transfer gun tip.

[0020] Preferably, the pipette assembly further comprises a pipette holder, a gun tip hole, and a gun tip discarding slot arranged on the operating platform. The pipette is mounted on the pipette holder, and the pipette holder is arranged correspondingly at a position directly opposite to the opening of the fixture when in standby mode. When in standby mode, the components of the manipulator device are in an initial position. The gun tip hole is used to insert the pipette tip; the gun tip discarding slot is used to accommodate the pipette tip after use. The gun tip hole, gun tip discarding slot, and liquid adding bottle are all arranged on the operating platform between the pipette holder and the initial standby position of the fixture.

[0021] Preferably, an X-axis slide rail is provided on the operating platform, a Y-axis slide rail is installed on the slider of the X-axis slide rail, a Z-axis slide rail is installed on the slider of the Y-axis slide rail, and the robotic arm is installed on the slider of the Z-axis slide rail. The sliders on the X-axis, Y-axis, and Z-axis slide rails are controlled by independent motors, which are controlled by a control module. The movement of the sliders in three directions enables the robotic arm to operate in a three-dimensional space above the operating platform. Specifically, two X-axis slide rails are arranged in parallel at the edge of the operating platform, and the two ends of the Y-axis slide rail are respectively fixedly installed on the sliders of the two X-axis slide rails. In the standby state, the Y-axis slide rail is at the edge of the operating platform.

[0022] Preferably, the operating platform is provided with a digital microfluidic chip fixing position and a chip top plate placement position, and the mechanical arm is also provided with a suction cup for sucking the chip top plate, and the suction and air-off of the suction cup are controlled by the control module. In the present invention, when adding liquid using a pipette gun, the bottom plate of the digital microfluidic chip is placed in the digital microfluidic chip fixing position, and the top plate is placed in the chip top plate placement position, exposing the bottom plate reaction point position for easy liquid addition; after the liquid addition is completed, the mechanical arm drives the suction cup to run to the chip top plate placement position and contact the chip top plate, and the control module controls the suction of the suction cup to achieve the suction of the chip top plate, and the top plate moves to the digital microfluidic chip fixing position with the mechanical arm and is assembled with the bottom plate.

[0023] Preferably, the chip control circuit is arranged on a fixed position of the digital microfluidic chip, the power supply contacts correspond to the chip electrodes one by one, and the fixed position and the chip are provided with mutually cooperating limiting mechanisms. When the limiting mechanisms are installed in coordination, the chip and the power supply contacts can be in contact.

[0024] Preferably, a chip pressing plate is provided on one side of the fixing position for pressing the chip down to make it contact with the power supply contact. The chip pressing plate is driven by a rotary cylinder which is controlled by a control module.

[0025] Preferably, the sample discharging platform is arranged corresponding to the fixed position of the digital microfluidic chip, and can move horizontally along the slide track, and as the sample discharging platform is pushed toward the digital microfluidic chip, the sample discharging capillary tube mouth extends into the chip to contact the reaction solution. Specifically, the sample discharging capillary tube is made of peek material.

[0026] Preferably, the inlet of the solid phase extraction column I is connected to the liquid extraction needle through the pipeline, and the outlet is connected to the recovery bottle and the liquid addition bottle through the branch pipeline; the inlet of the solid phase extraction column II is connected to the sample outlet capillary and the liquid extraction needle through the branch pipeline, and the outlet is connected to the waste liquid bottle and the product collection bottle through the branch pipeline. Pipeline switching can be achieved by installing a pinch valve on the branch pipeline.

[0027] The solid phase extraction column I can be but not limited to a QMA solid phase extraction column; the solid phase extraction column II can be but not limited to an HLB solid phase extraction column.

[0028] Preferably, the solid phase extraction column is a column structure of peek material, and a cavity for liquid circulation is provided inside the column, and the cavity is divided into an upper threaded interface section, an upper hydrophobic sieve plate installation section, a filling section, a lower hydrophobic sieve plate installation section, and a lower threaded interface section in sequence. Each section of the cavity is cylindrical and coaxially arranged, and the diameters of the filling section, the hydrophobic sieve plate installation section, and the threaded interface section increase in sequence; the filling section is filled with solid phase extraction resin; the upper and lower hydrophobic sieve plate installation sections are provided with hydrophobic sieve plates; the upper and lower threaded interface sections are used to connect to a pipe with an inverted cone joint.

[0029] In order to meet the requirements of adsorption and elution of trace-level radionuclides and solvent replacement of synthetic products, the size of the filling section can be 1.0-1.5 mm in diameter and 1.5-2.0 mm in height.

[0030] Preferably, the pipe is made of peek material, which has the advantages of chemical corrosion resistance, high temperature resistance, high mechanical strength and rigidity, low friction coefficient, biocompatibility, good processing performance, low adsorption, and easy cleaning.

[0031] Another object of the present invention is to provide a method for preparing a radiopharmaceutical using the above synthesis system, comprising the following steps: (1) Adsorption and elution of radioactive elements: The manipulator device is in operation, the liquid extraction needle is inserted into the raw material bottle, the pinch valve is turned, and the peristaltic pump is operated to pump the raw material out through the solid phase extraction column I for adsorption and then into the recovery bottle; the liquid extraction needle is inserted into the eluent bottle, the pinch valve is turned, and the peristaltic pump is operated to pump the eluent out through the solid phase extraction column I to elute the adsorbed radioactive elements into the liquid addition bottle; (2) Adding liquid: The robot device is running, the fixture clamps the pipette, moves the pipette to the tip hole point, presses down to take the tip, and then rises; moves the pipette to the liquid adding bottle point, descends to absorb liquid, and then rises; moves the pipette to the bottom plate point of the microfluidic chip, presses down the pipette control button to release the droplet; moves the pipette to the tip discard slot, presses down the pipette tip detachment button to remove the tip; then repeats the above actions to absorb other reagents from another liquid adding bottle and pipette to other locations on the chip; finally, returns the pipette to its original position; (3) Start the reaction: The robot device is running, the suction cup sucks the top plate of the microfluidic chip, moves it to the fixed position of the bottom plate of the microfluidic chip, and the chip is assembled; the chip program is started, and the reaction begins; (4) Sample discharge: After the reaction is completed, the robot device operates, the suction cup sucks the top plate of the microfluidic chip and moves it back to its original position; the sample discharge platform operates to push the sample discharge capillary forward, and the peristaltic pump works to pump the reaction solution into the solid phase extraction column II; (5) Solvent replacement: The robot device is running, the liquid extraction needle is inserted into the washing liquid bottle, the clamp valve is switched, and the peristaltic pump is operated to pump the washing liquid out through the solid phase extraction column II to wash the impurities and then into the waste liquid bottle; then the liquid extraction needle is inserted into the eluent bottle, the clamp valve is switched, and the peristaltic pump is operated to pump the eluent out through the solid phase extraction column II to elute the product into the product collection bottle.

[0032] The present invention has the following beneficial effects: The present invention provides a highly automated digital microfluidic radiopharmaceutical synthesis device, which completes the production of radiopharmaceuticals on a microfluidic chip, realizes automated liquid addition on the microfluidic chip by setting a manipulator device and a pipette assembly that can move in three-dimensional space, realizes automated extraction of reaction products by setting a movable sample output platform and pipeline design, and realizes automated solvent replacement by using a number of pinch valves and peristaltic pumps. Using the synthesis device provided by the present invention, the experimenter only needs to remotely control, and the preparation of radiopharmaceuticals can be completed by micro-collaboration during the synthesis process, which has the advantages of miniaturization, integration, automation, high efficiency, and low cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is a schematic diagram of the main structure of the present invention.

[0034] Figure 2 Schematic diagram of the cross-sectional structure of the solid phase extraction column.

[0035] Figure 3 A schematic diagram of an operation mode of solvent replacement in the present invention.

[0036] Figure 4 Schematic diagram of the microfluidic chip base. DETAILED DESCRIPTION

[0037] The present invention will be further described below in conjunction with specific embodiments. The following embodiments are only used to illustrate the present invention and are not intended to limit the scope of application of the present invention. Without departing from the spirit and essence of the present invention, modifications or replacements made to the inventive method, steps or conditions all belong to the scope of the present invention.

[0038] Example 1 like Figure 1As shown, this embodiment provides an automated radiopharmaceutical synthesis system based on digital microfluidics, including: an operating platform 1, a synthesis module, a liquid adding module, a sample output module and a solvent replacement module arranged on the operating platform 1, and a control module for controlling the operation of each module.

[0039] The synthesis module is used to realize the synthesis reaction of radioactive drugs, and its components include: a digital microfluidic chip and a chip control circuit. The digital microfluidic chip includes a conductive top plate and a bottom plate, which are arranged in parallel to form a fluid channel for droplet displacement. A number of independently controllable drive electrodes are arranged on the bottom plate. The chip control circuit is used to connect the drive electrode and the top plate conductive layer to the positive and negative electrodes of the power supply, respectively, and form a closed loop with the droplets on the electrodes. The adjacent drive circuits are powered on and off in turn to realize the movement of the droplets along the planned path. The movement path of the reaction reagent droplets is designed according to the synthesis process flow to complete each synthesis step in different areas of the chip.

[0040] Specifically, the operating platform 1 is provided with a digital microfluidic chip fixing position 2 and a chip top plate placement position 3. The digital microfluidic chip fixing position 2 is used to fix the chip bottom plate, and the chip top plate placement position 3 is used to place the chip top plate. When adding liquid, only the chip bottom plate is fixed to the digital microfluidic chip fixing position 2. After the liquid adding is completed, the chip top plate is assembled above the bottom plate to form a complete microfluidic chip device.

[0041] The chip control circuit is arranged on the digital microfluidic chip fixing position 2, and the power supply contacts correspond to the chip driving electrodes one by one. Furthermore, the fixing position 2 and the chip are provided with mutually cooperating limiting mechanisms, and when the limiting mechanisms are installed in coordination, the chip and the power supply contacts can be contacted. The chip control circuit is controlled by the control module, and the control module provides a driving signal to the chip control circuit to control its connection with the power supply.

[0042] A chip pressing plate 4 is provided on one side of the fixing position 2 for pressing the chip down to make it contact with the power supply contact. The chip pressing plate 4 is driven by a rotary cylinder 5, and the rotary cylinder 5 is controlled by a control module.

[0043] The liquid adding module is used to add reaction reagents to the bottom plate of the digital microfluidic chip, and its components include: a manipulator device, a pipette assembly, and several liquid adding bottles 6. The pipette assembly includes a pipette 7, a pipette bracket 8, a pipette tip 9, and a tip discarding tank 10. The manipulator device is used to complete actions such as clamping the pipette, replacing the pipette tip, and using the pipette to transfer the reagents in the liquid adding bottle to the reaction point of the digital microfluidic chip. The operating platform 1 is provided with several mounting positions for placing the liquid adding bottles and tip holes for inserting the pipette tips.

[0044] Specifically, the manipulator device includes a clamp 11 for clamping and placing the pipette 7 and a mechanical arm 12 fixedly connected to the clamp 11. The clamp 11 is controlled by a clamp cylinder to complete the clamping and placing action. The mechanical arm 12 is provided with a telescopic motor 13 adapted to the pipette control button and a pen-shaped cylinder 14 adapted to the pipette tip detachment button. The telescopic motor 13 controls the action of pressing down and retracting the pipette control button, which can realize the suction and discharge of the pipette tip, and controls the amount of liquid transferred by controlling the degree of pressing down and rising of the control button; the pen-shaped cylinder 14 controls the action of pressing down and retracting the pipette tip detachment button, which can realize the detachment of the pipette tip. The clamp cylinder, telescopic motor 13, and pen-shaped cylinder 14 are all controlled by a control module.

[0045] The robot arm 12 can be raised and lowered and moved horizontally, and can perform freely defined actions within the range of the X-axis, Y-axis, and Z-axis, so as to realize the pipetting of trace reagents using a pipette. Specifically, two X-axis slide rails 15 are arranged in parallel at the edge of the operating platform 1, and the two ends of the Y-axis slide rail 16 are respectively fixedly mounted on the sliders of the two X-axis slide rails 15, and the Z-axis slide rail 17 is fixedly mounted on the slider of the Y-axis slide rail 16. The robot arm 12 is mounted on the slider of the Z-axis slide rail 17. The sliders on the X-axis, Y-axis, and Z-axis slide rails are controlled by independent cylinders, which are controlled by a control module. The movement of the sliders in three directions enables the robot arm 12 to operate in the three-dimensional space above the operating platform 1. In standby mode, the robot arm 12 is at the edge of the operating platform 1.

[0046] The pipette 7 is mounted on a pipette holder 8, which is arranged at a position corresponding to the opening of the clamp 11 when in standby mode. The pipette tip 9, tip waste tank 10, and liquid adding bottle 6 are all arranged on the operating platform 1 between the pipette holder and the initial standby position of the clamp.

[0047] The mechanical arm 12 is also provided with a suction cup 18 for sucking the chip top plate, and the suction and de-airing of the suction cup are controlled by the control module. When the liquid addition is completed, the mechanical arm 12 drives the suction cup 18 to move to the chip top plate placement position 3 to contact the chip top plate, and the control module controls the suction cup to suck the chip top plate, and the top plate moves to the digital microfluidic chip fixing position 2 with the operation of the mechanical arm 12 and is assembled with the bottom plate.

[0048] The sample discharging module is used to extract the reaction products in the digital microfluidic chip, and its components include: a sample discharging platform 19 and a sample discharging capillary 20 arranged on the platform. The sample discharging platform 19 is arranged corresponding to the fixed position 2 of the digital microfluidic chip, and is movable by the slide cylinder 21, and the slide cylinder 21 is controlled by the control module. When discharging the sample, the control module sends a driving signal to the slide cylinder 21, and the sample discharging platform 19 is pushed along the slide track toward the fixed position 2 of the microfluidic chip so that the tube mouth of the sample discharging capillary 20 extends into the interior of the chip and contacts the reaction solution. Specifically, the sample discharging capillary is a peek tube.

[0049] The solvent replacement module is used for adsorption and elution of radioactive raw materials and solvent replacement of synthetic products, and its components include: a medicine rack 22 for placing reagent bottles, a liquid extraction needle 23 arranged on the mechanical arm 12 for extracting liquid from the reagent bottles, and a solid phase column mounting rack 24 for installing a solid phase extraction column. The solid phase extraction column includes a solid phase extraction column I for adsorbing radioactive elements and a solid phase extraction column II for solvent replacement of reaction products. Solid phase extraction column I can be used but not limited to QMA solid phase extraction column; solid phase extraction column II can be used but not limited to HLB solid phase extraction column.

[0050] In order to meet the needs of micro-level sample processing and facilitate integration with microfluidic components, this embodiment provides a self-designed micro solid phase extraction column.

[0051] Structural design: Figure 2 As shown, the solid phase extraction column is a cylindrical structure, and a cavity for sample circulation is provided inside the column, and the cavity is sequentially divided into an upper threaded interface section 25, an upper hydrophobic sieve plate installation section 26, a filling section 27, a lower hydrophobic sieve plate installation section 28, and a lower threaded interface section 29. Each section of the cavity is cylindrical and coaxially arranged, and the diameters of the filling section, the hydrophobic sieve plate installation section, and the threaded interface section increase in sequence. The shape of the cylinder helps to evenly distribute the liquid flow, reduce flow resistance, and ensure stable processing of the sample in the column.

[0052] Specifically, the filling section is used to fill solid phase extraction resin such as QMA or HLB resin, with a diameter of 1.3 mm and a height of 1.6 mm. The mold double-section ejector SKD61 can be used to press the filler (such as QMA resin or HLB resin) into the solid phase column.

[0053] The upper and lower hydrophobic sieve plate installation sections are used to place the hydrophobic sieve plates. The hydrophobic sieve plates are installed at both ends of the filling section to fix and isolate the solid phase extraction resin to prevent it from entering the liquid path, thereby ensuring the stability and reliability of the solid phase column.

[0054] The upper and lower threaded interface sections are used to connect with external pipelines. The threaded interface sections are connected with peek tubes with inverted cone joints. The inverted cone joints can be made of PP material. PP material has strong corrosion resistance and can withstand most organic solvents such as acids, alkalis, salts, alcohols, phenols, aldehydes, and ketones to ensure the stability of the joints in various chemical environments. Use a peek tube with an outer diameter of 1.6 mm in combination with the joint.

[0055] The material of the solid phase extraction column is selected from peek material, which has the following advantages: 1. Chemical corrosion resistance: Peek has extremely high corrosion resistance to most organic solvents, acids, alkalis and water, and can remain stable in complex chemical environments, ensuring that the solid phase column is not corroded or degraded during various sample processing, thereby extending its service life.

[0056] 2. High temperature resistance: It can be used for a long time at a temperature of up to 260°C and has good thermal stability, which makes it possible for solid phase separation operations that need to be performed under high temperature conditions and broadens the application scenarios of solid phase columns.

[0057] 3. Mechanical strength and rigidity: It has high mechanical strength and rigidity, can withstand high pressure and mechanical load, maintain structural stability and durability during use, and ensure that the solid phase column is not easily damaged during frequent sample processing operations.

[0058] 4. Low friction coefficient: A lower friction coefficient helps to reduce friction loss inside the column, making the sample more fluid in the column, improving separation efficiency, and ensuring that the sample can pass through the solid phase column quickly and evenly.

[0059] 5. Biocompatibility: It is widely used in the biomedical field. Its good biocompatibility prevents it from having adverse reactions with biological samples. It is very suitable for the separation and analysis of biological samples, providing a reliable guarantee for the processing of biological samples.

[0060] 6. Good processing performance: It can be processed by injection molding, extrusion and other methods, which is convenient for making complex shapes and structures. It can manufacture solid phase separation columns of various specifications and sizes according to different experimental requirements to meet diverse application scenarios.

[0061] 7. Cleanliness and inertness: The surface is smooth, not easy to adsorb impurities, easy to clean and regenerate, ensuring the long-term performance and reliability of the solid phase column and reducing the experimental error caused by impurity adsorption.

[0062] 8. Low adsorption: It has little adsorption effect on samples, which can reduce sample loss, improve the accuracy and reproducibility of separation, and ensure the reliability of experimental results.

[0063] The pipeline connection method in the solvent replacement module is as follows: the sample inlet of the solid phase extraction column I is connected to the liquid extraction needle through a hose pipeline, and the sample outlet is connected to the recovery bottle and the liquid addition bottle through a branch pipeline. The branch pipeline can be switched by installing a clamping valve 30, and the pipeline is controlled and driven by a peristaltic pump 31. The clamping valve 30 and the peristaltic pump 31 are controlled by the control module. When the radioactive raw material is adsorbed and eluted, the control module sends an action instruction, the robot arm 12 inserts the liquid extraction needle 23 into the raw material bottle, rotates the clamping valve, and under the action of the peristaltic pump, the raw material liquid passes through the solid phase extraction column I into the recovery bottle, and the radioactive elements are adsorbed on the extraction column. Then the robot arm inserts the liquid extraction needle into the eluent bottle, rotates the clamping valve, and the eluent passes through the solid phase extraction column I to elute the radioactive elements and flows into the liquid addition bottle.

[0064] The sample inlet of the solid phase extraction column II is connected to the sample outlet capillary 20 and the liquid extraction needle through branch pipelines, and the sample outlet is connected to the waste liquid bottle and the product collection bottle through branch pipelines. The pipeline switching can be achieved by installing a clamping valve on the branch pipeline, and the pipeline is controlled and driven by a peristaltic pump. When the solvent is replaced for the synthetic product, the control module sends an action instruction. First, the pinch valve is switched to connect the inlet and outlet of the solid phase extraction column II to the outlet capillary and the waste liquid bottle respectively. Under the action of the peristaltic pump, the reaction liquid on the chip is sucked into the solid phase extraction column II by the outlet capillary, and the product is adsorbed on the extraction column; then the pinch valve of the inlet is switched to connect the liquid extraction needle pipeline, and the robotic arm inserts the liquid extraction needle into the washing liquid bottle. Under the action of the peristaltic pump, the washing liquid is washed by the solid phase extraction column II; then the pinch valve of the outlet is switched to connect the product collection bottle, and the robotic arm inserts the liquid extraction needle into the eluent bottle. Under the action of the peristaltic pump, the eluent elutes the product through the solid phase extraction column II and flows into the product collection bottle. In the next step, the robotic arm inserts the liquid extraction needle into the diluent bottle. Under the action of the peristaltic pump, the diluent flows into the product collection bottle to dilute the product and adjust the osmotic pressure.

[0065] The control module is used to send working instructions to each module and control the operation of each component. Specifically, the controllability of the instrument system is achieved through the operation of the software program.

[0066] The following is synthesized 18 Taking F-organic phosphorus fluoride as an example, one of the operation modes of the device of this embodiment is introduced, as follows: Preparation: Place the raw material reagent bottles in order on the loading position of the medicine rack 22; place a new liquid adding bottle at the liquid adding bottle a position, and fill the liquid adding bottle at the liquid adding bottle b position with the precursor solution; install the QMA column and the HLB column (using the above-mentioned micro solid phase extraction column based on the integrated design with the microfluidic component, and the filling section is filled with QMA resin or HLB resin) on the solid phase column mounting rack 24, and complete the pipeline connection. The pipeline connection method is as follows: Figure 3As shown; the bottom plate and top plate of the digital microfluidic chip are placed at the microfluidic chip fixing position 2 and the chip top plate placement position 3 respectively. The driving electrodes on the bottom plate of the digital microfluidic chip are arranged as shown in FIG. Figure 4 shown.

[0067] The specific operation process of the equipment is as follows: The chip contacts the power supply contacts: the rotary cylinder 5 is rotated, and the chip pressing plate 4 presses down the chip bottom plate so that the chip electrodes contact the power supply contacts.

[0068] 18 Capture and elution of F: Insert the aspiration needle into the raw material bottle and turn the pinch valve ( Figure 3 Switch valve 1), the peristaltic pump will work 18 The F ionic liquid is pumped out and adsorbed by the QMA column and then enters the recovery bottle ( Figure 3 Then switch the liquid extraction needle to the eluent bottle, turn the pinch valve, and the peristaltic pump will work to pump the eluent through the QMA column to absorb the adsorbed 18 F ions are eluted to the liquid adding bottle at position a ( Figure 3 medium reagent bottle).

[0069] Transferring radionuclides: The robotic arm runs, the fixture clamps the pipette, moves the pipette to the tip hole, presses down to take the tip, and then rises; moves the pipette to point a of the liquid adding bottle, descends, completes the liquid aspiration under the action of the telescopic motor, and then rises; moves the pipette to point A on the bottom plate of the microfluidic chip, presses the pipette control button under the action of the telescopic motor to release the droplet.

[0070] Replace the pipette tip: Move the pipette to the tip discard slot, press the pipette tip detachment button under the action of the pen-shaped cylinder to remove the tip, and the pen-shaped cylinder will cut off the air; move the pipette to the tip box position, press down to take the tip, and then rise.

[0071] Transfer the precursor solution: move the pipette to point b of the liquid adding bottle, lower it, complete the liquid aspiration under the action of the telescopic motor, and then rise; move the pipette to point B on the bottom plate of the microfluidic chip, press the pipette control button under the action of the telescopic motor to release the droplet.

[0072] Return the pipette to its original position: move the pipette to the pipette tip discard slot, press the pipette tip detachment button with the help of the pen-shaped cylinder to remove the pipette tip, move the pipette to the pipette holder, release the clamp cylinder, and put down the pipette.

[0073] Chip assembly: The robot arm runs, the suction cup moves to the chip top plate placement position 3, descends, the suction cup sucks the chip top plate, then rises, moves to the microfluidic chip fixing position 2, descends, the suction cup cuts off the air, the chip top plate is placed on the bottom plate, and the chip is assembled; the suction cup returns to its position.

[0074] Start reaction: Start the chip program and the reaction begins.

[0075] During the experiment, a signal generator was used to generate 10 V, 1 kHz AC, and a high-voltage amplifier was used to amplify the voltage to 130 V, which was applied to the control circuit board. The program set in the control module controlled the relay on and off, thereby controlling the power on and off of the electrodes on the chip, thereby controlling the movement of the droplets on the chip to complete the precursor mixing reaction. The dielectric electrowetting EWOD control system controls the precursor mixing reaction, for example: (1) Start the EWOD and use the EWOD to mix the two droplets: droplet A and droplet B in the channel move to the mixing position C. (2) The mixed droplets are mouth-mixed on the EWOD according to the established program and react at room temperature. (3) Control the droplet to move back to point B.

[0076] The chip top plate returns to its position: After the reaction is completed, the robot arm runs, the suction cup moves to the microfluidic chip fixing position 2, descends, the suction cup sucks the chip top plate, then rises, moves to the chip top plate placement position 3, descends, the suction cup stops breathing, and the chip top plate returns to its position.

[0077] Sample out: The slide cylinder runs, the sample out capillary is pushed forward, the capillary is inserted into the reaction solution at chip point B, and the pinch valve is turned ( Figure 3 Switch valve 2 in the middle), and the peristaltic pump works to pump the reaction solution into the HLB column.

[0078] Solvent replacement: The robot arm is running, the liquid extraction needle is inserted into the injection water bottle, and the pinch valve is switched ( Figure 3 Switch valve 2 and switch valve 3 in the middle), the peristaltic pump works to pump the injection water out through the HLB column and into the waste liquid bottle; then switch the liquid extraction needle to the ethanol bottle, switch the pinch valve ( Figure 3 Switch valve 3 in the middle), the peristaltic pump works to pump ethanol out through the HLB column to elute the product into the product collection bottle; then the extraction needle is switched to saline, and the peristaltic pump works to pump saline into the product collection bottle.

[0079] The above is only one embodiment of the present invention. In different synthesis processes of radioactive drugs, there are differences in reaction conditions, reaction process length, product purification method, etc. Those skilled in the art can select corresponding reagents, solid phase extraction columns, etc. according to different process requirements and selectively connect them through pipelines to achieve free assembly.

Claims

1. An automated radiopharmaceutical synthesis system based on digital microfluidics, characterized in that: include: A synthesis module, comprising a digital microfluidic chip for radiopharmaceutical synthesis and a chip control circuit, wherein the chip control circuit controls the driving of electrodes on the digital microfluidic chip to achieve driving of droplets on the chip; The liquid adding module includes a manipulator device, a pipette assembly, and a liquid adding bottle. The pipette assembly includes a pipette and a pipette head. The manipulator device is used to clamp the pipette, replace the pipette head, and use the pipette to transfer the reagent in the liquid adding bottle to the reaction point of the digital microfluidic chip. The sample discharging module comprises a movably arranged sample discharging platform and a sample discharging capillary arranged on the platform. When discharging the sample, the orifice of the sample discharging capillary moves with the sample discharging platform to the product point of the digital microfluidic chip; The solvent replacement module comprises: a medicine rack for placing reagent bottles, a liquid extraction needle arranged on a manipulator device for extracting liquid from the reagent bottles, a solid phase extraction column I for adsorbing radioactive elements, and a solid phase extraction column II for performing solvent replacement on reaction products, wherein the sample outlet of the solid phase extraction column I is connected to the liquid addition bottle through a pipeline, and the sample inlet of the solid phase extraction column II is connected to the sample outlet capillary through a pipeline, and the pipeline is driven by a plurality of peristaltic pumps, and the switching direction is controlled by a plurality of pinch valves; The control module is connected to the chip control circuit, the manipulator device, the sample discharging platform, the peristaltic pump and the pinch valve for controlling the operation of each component.

2. The automated radiopharmaceutical synthesis system based on digital microfluidics according to claim 1, characterized in that: It also comprises an operating platform, on which the synthesis module, the liquid adding module, the sample output module and the solvent replacement module are all arranged.

3. The automated radiopharmaceutical synthesis system based on digital microfluidics according to claim 1 or 2, characterized in that: The manipulator device includes a mechanical arm that can be raised and lowered and moved horizontally, and a clamp fixedly installed on the mechanical arm for clamping and placing the pipette. The mechanical arm is also provided with a telescopic motor adapted to the pipette control button and a pen-shaped cylinder adapted to the pipette tip detachment button; the clamp, telescopic motor and pen-shaped cylinder are all controlled by a control module.

4. The automated radiopharmaceutical synthesis system based on digital microfluidics according to claim 3, characterized in that: The pipette assembly also includes a pipette support, a pipette tip hole, and a pipette tip discarding groove which are arranged on the operating platform.

5. The automated radiopharmaceutical synthesis system based on digital microfluidics according to claim 3, characterized in that: The operating platform is provided with a digital microfluidic chip fixing position and a chip top plate placement position, and the mechanical arm is also provided with a suction cup for sucking the chip top plate, and the suction and air cutting of the suction cup are controlled by the control module.

6. The automated radiopharmaceutical synthesis system based on digital microfluidics according to claim 5, characterized in that: The chip control circuit is arranged on a fixed position of the digital microfluidic chip, the power supply contacts correspond to the chip electrodes one by one, and the fixed position and the chip are provided with mutually cooperating limiting mechanisms.

7. The automated radiopharmaceutical synthesis system based on digital microfluidics according to claim 6, characterized in that: A chip pressing plate for pressing the chip down to make it contact with the power supply contact is arranged on one side of the fixing position, and the chip pressing plate is driven by a rotating cylinder.

8. The automated radiopharmaceutical synthesis system based on digital microfluidics according to claim 1, characterized in that: The inlet of the solid phase extraction column I is connected to the liquid extraction needle through a pipeline, and the outlet is connected to the recovery bottle and the liquid addition bottle through a branch pipeline; the inlet of the solid phase extraction column II is connected to the sample outlet capillary and the liquid extraction needle through a branch pipeline, and the outlet is connected to the waste liquid bottle and the product collection bottle through a branch pipeline.

9. The automated radiopharmaceutical synthesis system based on digital microfluidics according to claim 1, characterized in that: The solid phase extraction column is a column structure made of peek material, and a cavity for liquid circulation is provided inside the column, and the cavity is divided into an upper threaded interface section, an upper hydrophobic sieve plate installation section, a filling section, a lower hydrophobic sieve plate installation section, and a lower threaded interface section in sequence. Each section of the cavity is cylindrical and coaxially arranged, and the diameters of the filling section, the hydrophobic sieve plate installation section, and the threaded interface section increase in sequence; the filling section is filled with solid phase extraction resin; the upper and lower hydrophobic sieve plate installation sections are provided with hydrophobic sieve plates; the upper and lower threaded interface sections are used to be connected to a pipe with an inverted cone joint.

10. A method for preparing a radiopharmaceutical using the synthesis system according to any one of claims 1 to 9, characterized in that: The following steps are involved: (1) Adsorption and elution of radioactive elements: The manipulator device is in operation, the liquid extraction needle is inserted into the raw material bottle, the pinch valve is turned, and the peristaltic pump is operated to pump the raw material out through the solid phase extraction column I for adsorption and then into the recovery bottle; the liquid extraction needle is inserted into the eluent bottle, the pinch valve is turned, and the peristaltic pump is operated to pump the eluent out through the solid phase extraction column I to elute the adsorbed radioactive elements into the liquid addition bottle; (2) Adding liquid: The robot device is running, the fixture clamps the pipette, moves the pipette to the tip hole point, presses down to take the tip, and then rises; moves the pipette to the liquid adding bottle point, descends to absorb liquid, and then rises; moves the pipette to the bottom plate point of the microfluidic chip, presses down the pipette control button to release the droplet; moves the pipette to the tip discard slot, presses down the pipette tip detachment button to remove the tip; then repeats the above actions to absorb other reagents from another liquid adding bottle and pipette to other locations on the chip; finally, returns the pipette to its original position; (3) Start the reaction: The robot device is running, the suction cup sucks the top plate of the microfluidic chip, moves it to the fixed position of the bottom plate of the microfluidic chip, and the chip is assembled; the chip program is started, and the reaction begins; (4) Sample removal: After the reaction is completed, the robot device is operated, the suction cup sucks the top plate of the microfluidic chip and moves it back to its original position; The sample dispensing platform is running to push the sample dispensing capillary forward, and the peristaltic pump is working to pump the reaction solution into the solid phase extraction column II; (5) Solvent replacement: The robot device is running, the liquid extraction needle is inserted into the washing liquid bottle, the pinch valve is switched, and the peristaltic pump is working to pump the washing liquid out through the solid phase extraction column II and then into the waste liquid bottle; Then insert the extraction needle into the eluent bottle, switch the clamp valve, and operate the peristaltic pump to pump the eluent out through the solid phase extraction column II to elute the product into the product collection bottle.

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