Cutting sleeve device for preparing radionuclide labeled cell preparation and control method

Abstract

The invention discloses a clamping sleeve device for preparing a radionuclide labeled cell preparation and a control method, and relates to the technical field of radioactive biological medicines. The clamping sleeve device comprises a filtering assembly, a conveying assembly, a cleaning assembly, a waste liquid collecting bottle, a marking assembly, a cell preserving fluid assembly and a preparation collecting bottle, and a first three-way valve, a second three-way valve, a third three-way valve, a fourth three-way valve, a fifth three-way valve and a sixth three-way valve which are arranged corresponding to the assemblies respectively. According to the clamping sleeve device, automatic preparation of the radionuclide labeled cell preparation can be achieved, and the product can be prevented from being polluted while the preparation efficiency is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of radioactive biomedicine, and particularly relates to a cartridge device and a control method for preparing a radionuclide-labeled cell preparation. Background Art

[0002] Cell therapy is a major breakthrough in the medical field in recent years. It treats diseases by using the body's own cells or modified cells, showing great therapeutic potential for many intractable diseases such as cancer, severe infections, autoimmune diseases, and neurodegenerative diseases. Internationally, a few cell preparations for therapeutic use have been approved for marketing and are used in the clinical treatment of diseases such as Crohn's disease, graft-versus-host disease, osteoarthritis, spinal cord injury, decompensated liver cirrhosis, hematological malignancies, or other malignancies. There are also a large number of various cell therapies in the clinical trial stage. Various living cell products for treatment need to be developed in accordance with relevant drug administration regulations. Measuring and evaluating the absorption, distribution, metabolism, and excretion of drugs in vivo, as well as their pharmacokinetic properties, are crucial in drug development. However, it is difficult to evaluate these properties of therapeutic living cells through traditional drug analysis techniques. Although flow cytometry and polymerase chain reaction (PCR) analysis methods can be used to evaluate the pharmacokinetic properties of transgenic cells, these techniques require collecting ex vivo tissue samples, are difficult to perform, and are not suitable for evaluating other types of therapeutic cells.

[0003] In the prior art, cell radionuclide labeling and nuclear medicine imaging techniques provide a clinically applicable non-invasive and highly sensitive detection method for evaluating the distribution and pharmacokinetic properties of this type of "living" drug, cells, in vivo. For example, metal radionuclides (M), such as 68Ga, 111In, and 89Zr, react with 8-hydroxyquinoline (Oxine) to form M-Oxine complexes, which can effectively label living cells under mild conditions. Moreover, in vitro experimental results show that the radioactive M-Oxine labeling of living cells is quite stable and will not transfer from the labeled living cells to other surrounding cells. Therefore, radiolabeling cells with M-Oxine and then performing nuclear medicine SPECT or PET imaging can accurately evaluate the distribution and kinetic behavior of living cells in vivo after infusion. However, the preparation of existing radionuclide-labeled cells is basically manually operated by experimental personnel, lacking automation technology, and it is difficult to meet the requirements of good manufacturing practice (GMP). Moreover, the preparation process includes multiple centrifugation steps, and the cells will be exposed in an open environment, with a high risk of cell contamination, seriously affecting the popularization of the radioactive-labeled cell imaging method in the clinical trials of new cell drugs. Summary of the Invention

[0004] An object of the first aspect of the present invention is to provide a cartridge device for the preparation of radionuclide-labeled cell preparations, which solves the technical problem that it is difficult to ensure the GMP production conditions and product quality of cell preparations in the prior art when manually preparing radionuclide-labeled cell preparations.

[0005] Another object of the first aspect of the present invention is to improve the convenience of use of the cartridge device.

[0006] An object of the second aspect of the present invention is to provide a control method applied to the above-mentioned cartridge device.

[0007] According to the object of the first aspect of the present invention, the present invention provides a cartridge device for the preparation of radionuclide-labeled cell preparations, comprising:

[0008] A filtration assembly for filtering and separating cells and solutions;

[0009] A conveying assembly including a cell preparation bottle and a gas conveying member, the gas conveying member being communicated with the cell preparation bottle through a first three-way valve, and the gas conveying member being used for conveying the cell preparation in the cell preparation bottle to the filtration assembly;

[0010] A cleaning assembly is connected to the cell preparation bottle and the filtration assembly through a second three-way valve, and the cleaning assembly is used for conveying cell cleaning liquid to the filtration assembly;

[0011] A waste liquid collection bottle is located downstream of the filtration assembly, and the waste liquid collection bottle is arranged to be communicated with the filtration assembly through a third three-way valve, and the waste liquid collection bottle is used for collecting the waste liquid of the filtration assembly;

[0012] A labeling assembly is located between the third three-way valve and the waste liquid collection bottle, and the labeling assembly is communicated with the third three-way valve through a fourth three-way valve, and the labeling assembly is used for conveying a radionuclide-labeled solution for labeling cells to the filtration assembly;

[0013] A cell preservation liquid assembly is located downstream of the filtration assembly, and the cell preservation liquid assembly is arranged to be communicated with the third three-way valve through a fifth three-way valve, and the cell preservation liquid assembly is used for conveying cell preservation liquid to the filtration assembly;

[0014] A preparation collection bottle is located between the second three-way valve and the filtration assembly, and the preparation collection bottle is arranged to be communicated with the second three-way valve and the filtration assembly through a sixth three-way valve, and the preparation collection bottle is used for collecting the radionuclide-labeled cell preparation in the filtration assembly; wherein,

[0015] The second three-way valve and the sixth three-way valve are connected through a conveying pipeline, and the fourth three-way valve and the waste liquid collection bottle are connected through the conveying pipeline.

[0016] Optionally, the filtering component includes:

[0017] A filter tube having a cavity inside, and interfaces communicating with the delivery pipeline are respectively provided at both ends of the filter tube;

[0018] A cell sieve plate located at the bottom of the cavity, and the cell sieve plate is used to separate cells and a solution to retain the cells in the filter tube.

[0019] Optionally, the pore size of the cell sieve plate is any value in the range of 0.6 μm - 10 μm.

[0020] Optionally, the ferrule device further includes:

[0021] A needle filter assembly including a first sterile needle filter and a plurality of second sterile needle filters. The first sterile needle filter is located at one end of the first three-way valve, and each of the gas delivery member, the cleaning component, the cell preservation solution component, and the marking component is correspondingly connected to one of the second sterile needle filters.

[0022] Optionally, the needle filter assembly further includes:

[0023] A third sterile needle filter connected to the preparation collection bottle.

[0024] Optionally, the cleaning component is a sterile syringe filled with a cell cleaning solution.

[0025] Optionally, the cleaning component further includes:

[0026] A reagent bottle for containing the cell cleaning solution;

[0027] An air delivery assembly for delivering air into the reagent bottle, and the air delivery assembly is used to deliver the cell cleaning solution to the filtering component.

[0028] Optionally, the ferrule device further includes:

[0029] A controller component for controlling the opening and closing of the first three-way valve, the second three-way valve, the third three-way valve, the third three-way valve, the fifth three-way valve, and the sixth three-way valve, as well as the delivery component, the cleaning component, the marking component, and the cell preservation solution component.

[0030] According to the object of the second aspect of the present invention, the present invention further provides a control method applied to the ferrule device described in any one of the above, including the following steps:

[0031] Control the first three-way valve to connect the gas delivery component and the cell preparation bottle, the second three-way valve to connect the cell preparation bottle and the sixth three-way valve, and the sixth three-way valve to connect the second three-way valve and the filtration component, so as to deliver air into the cell preparation bottle through the gas delivery component, and deliver the cell preparation in the cell preparation bottle to the filtration component through the second three-way valve and the sixth three-way valve. Control the fourth three-way valve to connect the third three-way valve and the waste liquid collection bottle, so that the liquid in the filtration component flows into the waste liquid collection bottle;

[0032] Control the second three-way valve to connect the cleaning component and the sixth three-way valve, and the sixth three-way valve to connect the second three-way valve and the filtration component, so as to deliver the cell cleaning solution of the cleaning component to the filtration component. Control the third three-way valve to connect the filtration component and the fourth three-way valve and control the fourth three-way valve to connect the third three-way valve and the waste liquid collection bottle, so that the cleaning waste liquid flows into the waste liquid collection bottle;

[0033] Control the fourth three-way valve to connect the labeling component and the third three-way valve, and the third three-way valve to connect the filtration component and the third three-way valve, so as to deliver the radionuclide labeling solution of the labeling component into the filtration component. After reacting for a preset time, control the reaction waste liquid to flow into the waste liquid collection bottle through the third three-way valve and the fourth three-way valve;

[0034] Control the second three-way valve to connect the cleaning component and the sixth three-way valve, and the sixth three-way valve to connect the second three-way valve and the filtration component, so as to deliver the cell cleaning solution of the cleaning component to the filtration component. Control the third three-way valve to connect the filtration component and the fourth three-way valve and control the fourth three-way valve to connect the third three-way valve and the waste liquid collection bottle, so as to deliver the cleaning waste liquid into the waste liquid collection bottle;

[0035] Control the fifth three-way valve to connect the cell preservation solution component and the third three-way valve, and the third three-way valve to connect the filtration component, so as to deliver the cell preservation solution of the cell preservation solution component to the filtration component; At the same time, control the sixth three-way valve to connect the filtration component and the preparation collection bottle, so as to transfer the radionuclide-labeled cell preparation to the preparation collection bottle.

[0036] The present invention inputs a cell preparation, a cell cleaning solution, a radionuclide labeling solution, a cell cleaning solution, and a cell preservation solution into a filtration assembly by sequentially using a conveying assembly, a cleaning assembly, a labeling assembly, a cleaning assembly, and a cell preservation solution assembly and a plurality of three-way valves arranged correspondingly, and retains the cells in the cell preparation in the filtration assembly through the filtration assembly, and conveys the cell carrier, the cell cleaning solution, and the reacted radionuclide labeling solution to a waste liquid collection bottle, significantly reducing manual operations and avoiding the exposure of cells in an open environment. Through an automated production process, the product quality of the radionuclide-labeled cell preparation is ensured, which can well meet the requirements of in vivo distribution and pharmacokinetic clinical trial medications of live cells, and can have a positive promoting effect on the clinical evaluation research of various live cell drugs for treatment, accelerating the development process of live cell drugs.

[0037] Further, the two interfaces of the filter tube of the present invention are arranged to be communicated with a third three-way valve and a sixth three-way valve respectively through a conveying pipeline, so as to realize the opening or closing of the filtration assembly by controlling the opening or closing of the third three-way valve and the sixth three-way valve, preventing the cells in the filter tube from directly contacting the external environment and causing contamination, and by arranging a cell sieve plate in the filter tube to separate the cells and the solution in the cell preparation and be used for subsequent cell cleaning, radionuclide labeling, and filtering of waste liquid, enabling the filtration assembly to realize multiple functions and improving the environmental safety and use convenience of cell preparation of the ferrule device.

[0038] The above description is only an overview of the technical solution of the present invention. In order to be able to understand the technical means of the present invention more clearly and implement it according to the content of the specification, the following takes the preferred embodiments of the present invention and describes them in detail in conjunction with the drawings as follows. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Some specific embodiments of the present invention will be described in detail hereinafter with reference to the drawings in an exemplary but non-limiting manner. The same reference numerals in the drawings denote the same or similar components or parts. Those skilled in the art should understand that these drawings are not necessarily drawn to scale. In the drawings:

[0040] Figure 1 is a schematic structural diagram of a ferrule device according to an embodiment of the present invention;

[0041] Figure 2 is a schematic structural diagram of a ferrule device according to another embodiment of the present invention;

[0042] Figure 3 is a schematic structural diagram of a ferrule device according to another embodiment of the present invention;

[0043] Figure 4 is a schematic flow diagram of the cell preparation according to an embodiment of the present invention;

[0044] Figure 5 is a schematic flow chart of the cell cleaning solution according to an embodiment of the present invention;

[0045] Figure 6 is a schematic flow chart of the radionuclide labeling solution according to an embodiment of the present invention;

[0046] Figure 7 is a schematic flow chart of the cleaning waste liquid according to an embodiment of the present invention;

[0047] Figure 8 is a schematic flow chart of the cell preservation solution according to an embodiment of the present invention;

[0048] Figure 9 is a schematic flow chart of the ferrule device according to an embodiment of the present invention.

[0049] Reference numerals:

[0050] 100 - ferrule device, 10 - filtration component, 20 - conveying component, 21 - cell preparation bottle, 22 - gas conveying part, 23 - first three-way valve, 30 - cleaning component, 31 - second three-way valve, 32 - reagent bottle, 33 - air conveying component, 40 - waste liquid collection bottle, 41 - third three-way valve, 50 - labeling component, 51 - fourth three-way valve, 60 - cell preservation solution component, 61 - fifth three-way valve, 70 - preparation collection bottle, 71 - sixth three-way valve, 80 - conveying pipeline, 90 - needle filter component, 91 - first sterile needle filter, 92 - second sterile needle filter, 93 - third sterile needle filter. Detailed implementation manners

[0051] The following combines the drawings and embodiments to further describe in detail the specific implementation manners of the present invention. The following embodiments are used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0052] To make the above objects, features, and advantages of the present application more obvious and understandable, the following combines the drawings to make a detailed description of the specific implementation manners of the present application. It can be understood that the specific embodiments described herein are only used to explain the present application, rather than limiting the present application. Additionally, it should be noted that for the sake of description, only parts related to the present application are shown in the drawings rather than all structures. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present application.

[0053] The term "comprising" and "having" and any variations thereof in this application are intended to cover non-exclusive inclusion. For example, a process, method, system, product or device that includes a series of steps or units is not limited to the listed steps or units, but optionally further includes steps or units not listed, or optionally further includes other steps or units inherent to these processes, methods, products or devices.

[0054] Reference to "an embodiment" in this context means that a particular feature, structure, or characteristic described in connection with the embodiment can be included in at least one embodiment of the present application. The phrase may not necessarily refer to the same embodiment when it appears in various places in the specification, nor is it an independent or alternative embodiment mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described herein can be combined with other embodiments.

[0055] Figure 1 is a schematic structural diagram of a ferrule device according to an embodiment of the present invention, Figure 2 is a schematic structural diagram of a ferrule device according to another embodiment of the present invention, Figure 3 is a schematic structural diagram of a ferrule device according to another embodiment of the present invention, Figure 4 is a schematic flow diagram of a cell preparation according to an embodiment of the present invention, Figure 5 is a schematic flow diagram of a cell cleaning solution according to an embodiment of the present invention, Figure 6 is a schematic flow diagram of a radionuclide labeling solution according to an embodiment of the present invention, Figure 7 is a schematic flow diagram of a cleaning waste liquid according to an embodiment of the present invention, Figure 8 is a schematic flow diagram of a cell preservation solution according to an embodiment of the present invention.

[0056] Such as Figure 1As shown in the figure, the present invention provides a cartridge device 100 for the preparation of radionuclide-labeled cell preparations. The cartridge device 100 includes a filtration assembly 10, a delivery assembly 20, a cleaning assembly 30, a waste liquid collection bottle 40, a labeling assembly 50, a cell preservation liquid assembly 60, and a preparation collection bottle 70. The filtration assembly 10 is used to filter and separate cells and cell carriers in the cell preparation. The delivery assembly 20 includes a cell preparation bottle 21 and a gas delivery member 22. The gas delivery member 22 is connected to the cell preparation bottle 21 through a first three-way valve 23. The gas delivery member 22 is used to deliver the cell preparation in the cell preparation bottle 21 to the filtration assembly 10. The cleaning assembly 30 is connected to the cell preparation bottle 21 and the filtration assembly 10 through a second three-way valve 31. The cleaning assembly 30 is used to deliver cell cleaning liquid to the filtration assembly 10. The waste liquid collection bottle 40 is located downstream of the filtration assembly 10. The waste liquid collection bottle 40 is arranged to be connected to the filtration assembly 10 through a third three-way valve 41. The waste liquid collection bottle 40 is used to collect the waste liquid from the filtration assembly 10. The labeling assembly 50 is located between the third three-way valve 41 and the waste liquid collection bottle 40. The labeling assembly 50 is connected to the third three-way valve 41 through a fourth three-way valve 51. The labeling assembly 50 is used to deliver a radionuclide-labeled solution to the filtration assembly 10. The radionuclide-labeled solution is used to perform radionuclide labeling on cells. The cell preservation liquid assembly 60 is located downstream of the filtration assembly 10. The cell preservation liquid assembly 60 is arranged to be connected to the third three-way valve 41 through a fifth three-way valve 61. The cell preservation liquid assembly 60 is used to deliver a cell preparation medium to the filtration assembly 10. The preparation collection bottle 70 is located between the second three-way valve 31 and the filtration assembly 10. The preparation collection bottle 70 is arranged to be connected to the second three-way valve 31 and the filtration assembly 10 through a sixth three-way valve 71. The preparation collection bottle 70 is used to collect the radionuclide-labeled cell preparation in the filtration assembly 10. Among them, the second three-way valve 31 and the sixth three-way valve 71 are connected through a delivery pipeline 80. The connection between the fourth three-way valve 51 and the waste liquid collection bottle 40 is through a delivery pipeline 80.

[0057] In this embodiment, by sequentially using the delivery assembly 20, the cleaning assembly 30, the labeling assembly 50, the cleaning assembly 30, the cell preservation liquid assembly 60, and a plurality of corresponding three-way valves, a cell preparation, a cell cleaning liquid, a radionuclide-labeled solution, a cell cleaning liquid, and a cell preparation medium are input into the filtration assembly 10. The filtration assembly 10 retains the cells in the cell preparation within the filtration assembly 10, and delivers the cell carrier, the cell cleaning liquid, and the reacted radionuclide-labeled solution to the waste liquid collection bottle 40, significantly reducing manual operations and avoiding the exposure of cells in an open environment. Through an automated production process, the product quality of the radionuclide-labeled cell preparation is ensured, which can well meet the requirements of in vivo distribution and pharmacokinetic clinical trial medications of living cells, and will have a positive promoting effect on the clinical evaluation research of various therapeutic living cell drugs, accelerating the development process of living cell drugs.

[0058] In this embodiment, the radionuclide-labeled solution is a radioactive M-Oxine (8-hydroxyquinoline) solution, the cell washing solution is phosphate-buffered saline, the cell preparation includes cells and cell carriers that can be used for disease treatment research, and the cell preparation medium is a storage solution suitable for preserving the corresponding cell products. Among them, the radioactive M-Oxine (8-hydroxyquinoline) solution includes metal ion-8-hydroxyquinoline complexes formed by the reaction of 68Ga, 111In, 89Zr, etc. with 8-hydroxyquinoline (Oxine). The phosphate-buffered saline includes Hanks balanced salt solution and physiological saline, and the pH is any value in the range of 7.0-7.4. The cell types in the cell preparation include stem cells, bone marrow cells, red blood cells, white blood cells, macrophages, as well as CAR-T cells, CAR-NK cells, CLT cells, and TIL cells. Here, the pH of the phosphate-buffered saline can be 7.1, 7.2, 7.3, or 7.4, or any value in the range of 7.0-7.4.

[0059] In this embodiment, the reaction time between the radionuclide-labeled solution and the cells is any value in the range of 15 min - 30 min, that is, the reaction time between the radionuclide-labeled solution and the cells can be 15 min, 20 min, 25 min, or 30 min, or any value in the range of 15 min - 30 min. By setting the reaction time between the radionuclide-labeled solution and the cells within the above range, the cells can be completely labeled with the radionuclide, and at the same time, the preparation efficiency of the radionuclide-labeled cell preparation will not be affected due to too long reaction time.

[0060] In a further embodiment, the filtration assembly 10 includes a filtration tube and a cell sieve plate. An installation cavity is formed inside the filtration tube. Interfaces communicating with the delivery pipeline 80 are respectively provided at both ends of the filtration tube. The cell sieve plate is located in the installation cavity and is used to separate cells and cell carriers to retain the cells inside the filtration tube. In this embodiment, the two interfaces of the filtration tube are arranged to communicate with the third three-way valve 41 and the sixth three-way valve 71 respectively through the delivery pipeline 80, so as to open or close the filtration assembly 10 by controlling the opening or closing of the third three-way valve 41 and the sixth three-way valve 71, preventing the cells inside the filtration tube from directly contacting the external environment and causing contamination. And by arranging the cell sieve plate inside the filtration tube to separate the cells and cell carriers in the cell preparation and filter the waste liquid in the subsequent cell washing and labeling processes, the filtration assembly 10 can achieve multiple functions, further improving the environmental safety and use convenience of the cell preparation of the ferrule device 100.

[0061] In a further embodiment, the pore size of the cell sieve plate is any value in the range of 0.6 μm to 10 μm, that is, the pore size of the cell sieve plate can be 0.6 μm, 3 μm, 5 μm, 7 μm, 9 μm or 10 μm, or can also be any value in the range of 1 μm to 10 μm. In this embodiment, the pore size of the cell sieve plate is set to any of the above values, that is, the cell sieve plate with the corresponding pore size can be selected according to the cell size required for preparation, so as to improve the filtration accuracy of the filtration assembly 10 and prevent the cell sieve plate from having too large a pore size to filter out the cells that need to be retained or prevent the cell sieve plate from having too small a pore size resulting in too low filtration efficiency.

[0062] As Figure 1 shown, in a further embodiment, the ferrule device 100 further includes a needle filter assembly 90. The needle filter assembly 90 includes a first sterile needle filter 91 and a plurality of second sterile needle filters 92 (refer to Figure 2 ), the first sterile needle filter 91 is located at one end of the first three-way valve 23, and each gas delivery member 22, cleaning assembly 30, cell preservation solution assembly 60 and labeling assembly 50 is correspondingly connected to a second sterile needle filter 92. In this embodiment, by providing the corresponding second sterile needle filters 92 at the connection points of the gas delivery member 22, cleaning assembly 30, cell preservation solution assembly 60 and labeling assembly 50 with the delivery pipeline 80, the possible impurities in the delivery solution can be filtered to improve the preparation safety of the radionuclide-labeled cell preparation. At the same time, it can also ensure that the delivery solution can input the liquid to be delivered into the corresponding delivery pipeline 80 through the corresponding three-way valve, preventing liquid leakage or being contaminated by contact with the environment.

[0063] In this embodiment, the first sterile needle filter 91 is provided at the other end of the first three-way valve 23, that is, the three ports of the first three-way valve 23 are respectively connected to the cell preparation bottle 21, the gas delivery assembly and the first sterile needle filter 91, so that when the first three-way valve 23 connects the cell preparation bottle 21 and the gas delivery assembly, sterile air can be delivered into the cell preparation bottle 21 to apply pressure to it, so as to press the cell preparation in the cell preparation bottle 21 into the filtration assembly 10. When the first three-way valve 23 connects the cell preparation bottle 21 and the first sterile needle filter 91, during the air flow process, external pollutants can be further prevented from entering the system, and at the same time, it is ensured that no pollution source is brought in when the gas inside the cell preparation bottle 21 is discharged, preventing the return of contaminated gas.

[0064] As Figure 2 shown, in a further embodiment, the needle filter assembly 90 (refer to Figure 1)It further includes a third sterile needle filter 93, and the third sterile needle filter 93 is connected to the preparation collection bottle 70. In this embodiment, by setting the third sterile needle filter 93 to communicate with the preparation collection bottle 70, it is possible to collect the aerosol or tiny droplets that may be generated by the radionuclide-labeled cell preparation, so that these particles may be carried out by the gas flow during the collection process, effectively blocking the spread of the aerosol, preventing radionuclide contamination of the experimental environment, and improving biosafety.

[0065] As Figure 3 shown, in a further embodiment, the cleaning assembly 30 is a sterile syringe. By setting the cleaning assembly 30 as a sterile syringe, it can ensure that the cleaning solution is not contaminated by the outside world during transportation, maintain a sterile environment during the preparation process of the radionuclide-labeled cell preparation, and avoid microbial contamination of the cell preparation caused by the contamination of the cleaning solution, which affects the safety and reliability of experimental or clinical applications. At the same time, it can accurately control the delivery volume and flow rate of the cleaning solution, ensure the repeatability and consistency of the cleaning process, and avoid the influence of excessive or insufficient cleaning on the experimental results. In addition, the cleaning assembly 30 in the form of a sterile syringe can provide an independent and replaceable cleaning assembly 30 to avoid cross-contamination. Here, both the cell preservation solution assembly 60 and the labeling assembly 50 can be set as sterile syringes.

[0066] As Figure 2 shown, in a further embodiment, the cleaning assembly 30 further includes a reagent bottle 32 and an air delivery assembly 33. The reagent bottle 32 is used to hold the cell cleaning solution, and the air delivery assembly 33 is used to deliver air into the reagent bottle 32. The air delivery assembly 33 is used to deliver the cell cleaning solution to the filtration assembly 10. In this embodiment, the cleaning assembly 30 includes a reagent bottle 32 and an air delivery assembly 33 for delivering air into the reagent bottle 32. The reagent bottle 32 holds the cell cleaning solution and can be used as a closed storage device, reducing the time for the cleaning solution to be exposed to the external environment, reducing the pollution risk, and ensuring the sterile state of the cleaning solution. The air delivery assembly 33 is pressurized and delivered by sterile air, avoiding the pollution problems caused by direct pouring or open operation, and keeping the whole system closed and sterile.

[0067] In this embodiment, the waste liquid collection bottle 40 further includes an exhaust needle, and the exhaust needle is installed at the opening of the bottle body of the waste liquid collection bottle 40. During the waste liquid collection process, the liquid in the bottle increases and the gas space decreases. Without an exhaust device, it may cause negative pressure and affect the smooth flow of the waste liquid. By releasing the gas in the bottle through the exhaust needle, the pressure balance inside and outside the bottle is maintained, ensuring that the waste liquid can flow smoothly into the collection bottle and avoiding the phenomenon of blocked flow rate or backflow.

[0068] In a further embodiment, the ferrule device 100 further includes a controller assembly for controlling the opening and closing of the first three-way valve 23, the second three-way valve 31, the third three-way valve 41, the fourth three-way valve 51, the fifth three-way valve 61, the sixth three-way valve 71, the conveying assembly 20, the cleaning assembly 30, the labeling assembly 50, and the cell preservation solution assembly 60. In this embodiment, the opening and closing of each assembly are uniformly managed by the controller assembly, reducing manual operation, improving the automation level of the experiment, avoiding time errors or mistakes that may be caused by manual operation, improving the consistency and repeatability of the preparation of cell labeling preparations, being applicable to high-throughput experiments or production applications, capable of batch processing of multiple samples, and improving the operation efficiency of the laboratory or production line.

[0069] In this embodiment, the controller assembly includes a plurality of time relays, which are respectively connected to the first three-way valve 23, the second three-way valve 31, the third three-way valve 41, the third three-way valve 41, the fifth three-way valve 61, the sixth three-way valve 71, the conveying assembly 20, the cleaning assembly 30, the labeling assembly 50, and the cell preservation solution assembly 60. That is, through the time relays, the opening and closing times of each valve and assembly can be preset to ensure that steps such as gas conveying, cell cleaning, labeling, addition of cell preservation solution, and transfer of radionuclide-labeled cell preparations are carried out in the set time sequence, avoiding human errors, ensuring the standardization of the preparation of radionuclide-labeled cell preparations, and being applicable to scenarios such as GMP environments that require high repeatability. Here, the opening and closing of each valve in the fluid pipeline can also be controlled by a PLC program, or the advancement of a syringe or gas conveying assembly can be controlled, and the time parameters of each step of the radionuclide-labeled cell process can be set through a PC or HMI. In other embodiments, it can also be achieved through other control methods in addition to relays or PLCs.

[0070] Figure 9 It is a schematic flow chart of a ferrule device according to an embodiment of the present invention.

[0071] As Figure 9 shown, in this embodiment, the control method applied to the above-mentioned ferrule device 100 includes the following steps:

[0072] Step S100: Control the first three-way valve 23 to connect the gas conveying member 22 and the cell preparation bottle 21, the second three-way valve 31 to connect the cell preparation bottle 21 and the sixth three-way valve 71, and the sixth three-way valve 71 to connect the second three-way valve 31 and the filtration assembly 10, so as to convey clean air into the cell preparation bottle 21 through the gas conveying member 22, and convey the cell preparation in the cell preparation bottle 21 to the filtration assembly 10 through the second three-way valve 31 and the sixth three-way valve 71;

[0073] Step 200: Control the second three-way valve 31 to connect the cleaning assembly 30 and the sixth three-way valve 71, and the sixth three-way valve 71 to connect the second three-way valve 31 and the filtration assembly 10, so as to transport the cell cleaning solution of the cleaning assembly 30 to the filtration assembly 10. Control the third three-way valve 41 to connect the filtration assembly 10 and the fourth three-way valve 51, and control the fourth three-way valve 51 to connect the third three-way valve 41 and the waste liquid collection bottle 40, so as to allow the cleaning waste liquid to flow into the waste liquid collection bottle 40;

[0074] Step S300: Control the fourth three-way valve 51 to connect the labeling assembly 50 and the third three-way valve 41, and the third three-way valve 41 to connect the filtration assembly 10 and the third three-way valve 41, so as to transport the radionuclide labeling solution of the labeling assembly 50 into the filtration assembly 10. After reacting for a preset time, control the reaction waste liquid to flow into the waste liquid collection bottle 40 through the third three-way valve 41 and the fourth three-way valve 51;

[0075] Step S400: Control the second three-way valve 31 to connect the cleaning assembly 30 and the sixth three-way valve 71, and the sixth three-way valve 71 to connect the second three-way valve 31 and the filtration assembly 10, so as to transport the cell cleaning solution of the cleaning assembly 30 to the filtration assembly 10. Control the third three-way valve 41 to connect the filtration assembly 10 and the fourth three-way valve 51, and control the fourth three-way valve 51 to connect the third three-way valve 41 and the waste liquid collection bottle 40, so as to allow the cleaning waste liquid to flow into the waste liquid collection bottle 40;

[0076] Step S500: Control the fifth three-way valve 61 to connect the cell preservation solution assembly 60 and the third three-way valve 41, and the third three-way valve 41 to connect the filtration assembly 10, so as to transport the cell preservation solution of the cell preservation solution assembly 60 into the filtration assembly 10;

[0077] Step S600: Control the sixth three-way valve 71 to connect the filtration assembly 10 and the preparation collection bottle 70, so as to transfer the radionuclide-labeled cell preparation to the preparation collection bottle 70.

[0078] In this embodiment, the cells to be labeled are washed, labeled, washed again, and the cell preservation solution is added to resuspend the cells in sequence according to the above steps, so as to prepare a radionuclide-labeled cell preparation, thereby realizing the automatic preparation of the radionuclide-labeled cell preparation, avoiding the possible cell contamination during manual preparation, and improving the safety of the preparation of the radionuclide-labeled cell preparation.

[0079] As Figure 4 shown, in step S100, air is transported into the cell preparation bottle 21 through the gas delivery member 22, and the cell preparation in the cell preparation bottle 21 is transported to the filtration assembly 10 through the second three-way valve 31 and the sixth three-way valve 71. That is, the direction indicated by the arrow is the flow direction of air and cell preparation.

[0080] As Figure 5As shown, in step S200, the cell cleaning solution of the cleaning component 30 is transported to the filtering component 10, that is, the direction indicated by the arrow is the flow direction of the cell cleaning solution.

[0081] As Figure 6 shown, in step S300, the radionuclide labeling solution of the labeling component 50 is transported into the filtering component 10, that is, the direction indicated by the arrow is the flow direction of the radionuclide labeling solution.

[0082] As Figure 7 shown, in step S400, the cell cleaning solution of the cleaning component 30 is transported to the filtering component 10 and flows out from the filtering tube into the waste liquid bottle, that is, the direction indicated by the arrow is the flow direction of the waste cell cleaning solution.

[0083] As Figure 8 shown, in step S500, the cell preservation solution of the cell preservation solution component 60 is transported into the filtering component 10, that is, the direction of the arrow is the flow direction of the cell preservation solution.

[0084] As Figure 8 shown, in step S600, the suspension of the radionuclide-labeled cells is transferred to the preparation collection bottle 70 to obtain the radionuclide-labeled cell preparation, that is, the direction of the arrow is the flow direction of the radionuclide-labeled cell preparation.

[0085] The present application will be further described in detail below in conjunction with specific embodiments.

[0086] Example 1

[0087] In this example, the cleaning component 30, the cell preservation solution component, and the labeling component 50 are sterile syringes. The capacity of the filtering component 10 is 3 mL. The cell type in the cell preparation is human umbilical cord mesenchymal stem cells (20 mL, containing 1.0×10 8 cells), and the radionuclide labeling solution in the labeling component 50 is a 89 Zr-Oxine solution with a volume of 3 mL and a radioactivity of 800 μCi. The pH of the cell cleaning solution in the cleaning component 30 is 7.4.

[0088] Example 2

[0089] The difference between Example 2 and Example 1 is only that the cell type in the cell preparation is human white blood cells.

[0090] Example 3

[0091] The difference between Example 3 and Example 1 is only that the cleaning component 30, the cell preservation solution component, and the labeling component 50 are all formed by a reagent bottle 32 and an air delivery component 33.

[0092] Example 4

[0093] Example 4 is different from Example 1 only in that the cleaning component 30, the cell preservation solution component 60, and the labeling component 50 are all formed by a reagent bottle 32 and an air delivery component 33, and the cell type in the cell preparation is TIL cells.

[0094] By performing radioactivity tests, radiochemical purity tests, cell viability tests, and toxin level tests on the radionuclide-labeled cell preparations prepared in Examples 1-4, the test results of the radionuclide-labeled cell preparations prepared in Examples 1-4 as shown in Table 1 were obtained. Here, the toxin level test was the limulus reagent method.

[0095] Table 1. Performance test results of the radionuclide-labeled cell preparations prepared in Examples 1-4

[0096]

[0097] As shown in Table 1, the radionuclide-labeled cell preparations obtained by using the ferrule device 100 in Examples 1-4 all have high radioactivity, chemical labeling rate, and radiochemical purity, indicating that the ferrule device 100 can successfully label the cells in the cell preparation, facilitating subsequent nuclear medicine imaging to evaluate the absorption, distribution, metabolism, excretion, and pharmacokinetic characteristics of the cells in vivo, and the prepared cell viability is high and the toxin levels are all negative, indicating that the ferrule device 100 in Examples 1-4 does not damage or destroy the cells when preparing the radionuclide-labeled cell preparation, improving the drug safety of the radionuclide-labeled cell preparation.

[0098] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0099] The above-described embodiments merely represent several implementation manners of the present invention, and the description thereof is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the appended claims.

Claims

1. A cartridge device for the preparation of radionuclide-labeled cell preparations, characterized in that, Comprising: A filtering component for filtering and separating cells and solution; A conveying component including a cell preparation bottle and a gas conveying member, the gas conveying member being communicated with the cell preparation bottle through a first three-way valve, and the gas conveying member being configured to convey the cell preparation in the cell preparation bottle to the filtering component; A cleaning component connected to the cell preparation bottle and the filtering component through a second three-way valve, the cleaning component being configured to convey cell cleaning solution to the filtering component; A waste liquid collection bottle located downstream of the filtering component, the waste liquid collection bottle being configured to be communicated with the filtering component through a third three-way valve, and the waste liquid collection bottle being used for collecting the waste liquid flowing out of the filtering component; A labeling component located between the third three-way valve and the waste liquid collection bottle, the labeling component being communicated with the third three-way valve through a fourth three-way valve, and the labeling component being configured to convey a radionuclide solution to the filtering component, and the radionuclide solution being used for radionuclide labeling of the cells; A cell preservation solution component located downstream of the filtering component, the cell preservation solution component being configured to be communicated with the third three-way valve through a fifth three-way valve, and the cell preservation solution component being used for conveying a cell preparation medium to the filtering component; A preparation collection bottle located between the second three-way valve and the filtering component, the preparation collection bottle being configured to be communicated with the second three-way valve and the filtering component through a sixth three-way valve, and the preparation collection bottle being used for collecting the radionuclide-labeled cell preparation in the filtering component; wherein, The second three-way valve and the sixth three-way valve are connected through a conveying pipeline, and the fourth three-way valve and the waste liquid collection bottle are connected through the conveying pipeline.

2. The ferrule device according to claim 1, wherein, The filtering component includes: A filtering tube having a cavity inside, and interfaces communicated with the conveying pipeline are respectively provided at two ends of the filtering tube; A cell sieve plate located at the bottom of the cavity, and the cell sieve plate is used for separating cells and solution to retain the cells in the filtering tube.

3. The ferrule device according to claim 2, wherein The aperture of the cell sieve plate is any value in the range of 0.6 μm - 10 μm.

4. The ferrule device according to claim 3, characterized in that, Further comprising: A needle filter component including a first sterile needle filter and a plurality of second sterile needle filters, the first sterile needle filter being located at one end of the first three-way valve, and each of the gas conveying member, the cleaning component, the cell preservation solution component and the labeling component is correspondingly connected with one of the second sterile needle filters.

5. The ferrule device according to any one of claims 1-4, characterized in that, The needle filter component further includes: A third sterile needle filter connected to the preparation collection bottle.

6. The ferrule device according to claim 5, wherein The cleaning component is a sterile syringe filled with cell cleaning solution.

7. The ferrule device according to claim 5, characterized in that The cleaning component further includes: A reagent bottle for containing the cell cleaning solution; An air conveying component for conveying air into the reagent bottle, and the air conveying component is used for conveying the cell cleaning solution to the filtering component.

8. The ferrule device according to claim 7, characterized in that, Further comprising: A controller component for controlling the opening and closing of the first three-way valve, the second three-way valve, the third three-way valve, the fourth three-way valve, the fifth three-way valve, and the sixth three-way valve, as well as the conveying component, the cleaning component, the marking component, and the cell preservation solution component.

9. A control method applied to the ferrule device according to any one of claims 1-8, characterized in that, The method includes the following steps: Controlling the first three-way valve to connect the gas delivery piece and the cell preparation bottle, the second three-way valve to connect the cell preparation bottle and the sixth three-way valve, and the sixth three-way valve to connect the second three-way valve and the filtration component, so as to convey air into the cell preparation bottle through the gas delivery piece, and convey the cell preparation in the cell preparation bottle to the filtration component through the second three-way valve and the sixth three-way valve; controlling the fourth three-way valve to connect the third three-way valve and the waste liquid collection bottle, so that the liquid in the filtration component flows into the waste liquid collection bottle; Controlling the second three-way valve to connect the cleaning component and the sixth three-way valve, and the sixth three-way valve to connect the second three-way valve and the filtration component, so as to convey the cell cleaning liquid of the cleaning component to the filtration component; controlling the third three-way valve to connect the filtration component and the fourth three-way valve and controlling the fourth three-way valve to connect the third three-way valve and the waste liquid collection bottle, so that the cleaning waste liquid flows into the waste liquid collection bottle; Controlling the fourth three-way valve to connect the marking component and the third three-way valve, and the third three-way valve to connect the filtration component and the third three-way valve, so as to convey the radionuclide labeling solution in the marking component into the filtration component; after reacting for a preset time, controlling the reaction waste liquid to flow into the waste liquid collection bottle through the third three-way valve and the fourth three-way valve; Controlling the second three-way valve to connect the cleaning component and the sixth three-way valve, and the sixth three-way valve to connect the second three-way valve and the filtration component, so as to convey the cell cleaning liquid of the cleaning component to the filtration component; controlling the third three-way valve to connect the filtration component and the fourth three-way valve and controlling the fourth three-way valve to connect the third three-way valve and the waste liquid collection bottle, so that the cleaning waste liquid flows into the waste liquid collection bottle; Controlling the fifth three-way valve to connect the cell preservation solution component and the third three-way valve, and the third three-way valve to connect the filtration component, so as to convey the cell preservation solution of the cell preservation solution component into the filtration component; Controlling the sixth three-way valve to connect the filtration component and the preparation collection bottle, so as to transfer the radionuclide-labeled cell preparation to the preparation collection bottle.

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