Device and method for preparing radioactive hydrogel microspheres

Abstract

The embodiment of the present application relates to the technical field of radioactive interventional therapy, and particularly discloses a radioactive hydrogel microsphere preparation device and a preparation method. The preparation device comprises a mixing reactor, a heating module, a heat tracing pipeline, an injection needle and a microsphere forming reactor arranged in a glove box. The mixing reactor is used for accommodating radioactive nanoparticle suspension and polymer solution, and an outlet is arranged at the bottom of the mixing reactor. The heating module is used for heating the radioactive nanoparticle suspension and the polymer solution to form radioactive polymer mixed solution. One end of the heat tracing pipeline is connected with the outlet of a stop valve. The injection needle is arranged at the other end of the heat tracing pipeline. The microsphere forming reactor is used for accommodating oil phase medium. The injection needle is located below the oil phase liquid surface. When the radioactive polymer mixed solution enters the oil phase through the injection needle, hydrogel microspheres are formed. The radioactive hydrogel microsphere preparation device disclosed by the present application can be stably operated for a long time in the glove box without being blocked.

Description

Technical Field

[0001] This application relates to the field of radioactive interventional therapy technology, and in particular to a device and method for preparing radioactive hydrogel microspheres. Background Technology

[0002] Radioactive hydrogel microspheres are a class of composite biomaterials that possess both the excellent physicochemical properties of hydrogels (high water content, biocompatibility, controllable degradation, and sustained drug release) and the diagnostic and therapeutic functions of radionuclides. They have significant clinical application value in areas such as interventional embolization therapy for tumors, internal radiotherapy, and targeted radionuclide therapy. The core technology involves uniformly dispersing and embedding radionuclide-labeled nanoparticles (such as 188Re, 177Lu, 90Y, 131I, and 90Sr) within a hydrogel microsphere matrix. This enables the local, slow, and sustained release of radionuclides, thereby increasing the local radiation dose to the tumor and reducing systemic toxicity.

[0003] Currently, microfluidics is one of the main methods for preparing radioactive hydrogel microspheres in the closed environment of shielded glove boxes. When preparing radioactive hydrogel microspheres using microfluidics, radionuclide-labeled nanoparticles are first dispersed in an aqueous medium to form a radioactive nanoparticle suspension. This suspension is then mixed with water-soluble polymers (such as sodium alginate, gelatin, and polyethylene glycol diacrylate) and photo / chemical crosslinking initiators as the dispersed phase (aqueous phase), while an oil phase (such as mineral oil or fluorinated oil) that is immiscible with water serves as the continuous phase. The aqueous and oil phases are injected separately into the dispersion channels of a microfluidic chip using a precision injection pump. The microfluidic chip is internally designed with cross-shaped, flow-focusing, or coaxial capillary microchannel structures (channel sizes typically ranging from tens to hundreds of micrometers). At the junctions of the microchannels, the aqueous phase breaks off as droplets from the continuous flow under the shearing action of the oil phase, forming uniformly sized monodisperse hydrogel microsphere precursors containing uniformly dispersed radioactive nanoparticles. The droplets are then cross-linked and solidified (e.g., by ultraviolet light irradiation, temperature-induced gelation, or ionic cross-linking) to obtain the final radioactive hydrogel microspheres.

[0004] However, when preparing microspheres using microfluidics in a sealed environment such as a shielded glove box, nanoparticles in the radioactive nanoparticle suspension tend to agglomerate and settle. The microchannels of the microfluidic chip are extremely small (usually only tens to hundreds of micrometers in size), and nanoparticles are very likely to deposit on the inner wall of the channel and gradually block the channel, causing the preparation process to be interrupted. Once blockage occurs, cleaning or replacing the chip requires operators to perform delicate disassembly and assembly with the help of a robotic arm inside the glove box, which is extremely difficult and time-consuming. Summary of the Invention

[0005] The summary section introduces a series of simplified concepts, which will be further explained in detail in the detailed description section. This part of the invention is not intended to limit the key features and essential technical features of the claimed technical solution, nor is it intended to determine the scope of protection of the claimed technical solution.

[0006] The present invention aims to solve at least one of the technical problems existing in the prior art or related art.

[0007] Therefore, a first aspect of the present invention provides an apparatus for preparing radioactive hydrogel microspheres.

[0008] A second aspect of the present invention provides a method for preparing radioactive hydrogel microspheres.

[0009] In view of this, a radioactive hydrogel microsphere preparation apparatus is provided according to a first aspect of the embodiments of this application, comprising: a mixing reactor, a heating module, a heat tracing pipeline, an injection needle, and a microsphere forming reactor, wherein the mixing reactor, the heating module, the microsphere forming reactor, the heat tracing pipeline, and the injection needle are all disposed inside a glove box; The mixing reactor is used to contain a suspension of radioactive nanoparticles and a polymer solution. The mixing reactor has an outlet at the bottom, and a shut-off valve is installed at the outlet. The heating module is used to heat the radioactive nanoparticle suspension and polymer solution in the mixing reactor to form a radioactive polymer mixture. One end of the heat tracing pipeline is connected to the outlet of the shut-off valve, and the heat tracing pipeline is used to keep the radioactive polymer mixture passing through it warm or heat it. The injection needle is located at the other end of the heat tracing pipeline and is situated inside the microsphere molding reactor. The microsphere forming reactor is used to contain the oil phase medium and can form an oil phase shear flow field. The injection needle is located below the oil phase liquid surface. When the radioactive polymer mixture enters the oil phase through the injection needle, the radioactive polymer mixture can form hydrogel microspheres under the action of the oil phase shear flow field.

[0010] In one feasible implementation, it further includes: An inert gas supply unit is provided, located outside the glove box and connected to the mixing reactor. The inert gas supply unit is used to deliver inert gas into the mixing reactor so that the radioactive polymer mixture is forced into the microsphere forming reactor under gas pressure. Both the shut-off valve and the inert gas supply unit are connected to the control system, which is located outside the glove box.

[0011] In one feasible implementation, it further includes: A radioactive nanoparticle suspension supply unit is provided outside the glove box, the radioactive nanoparticle suspension supply unit is connected to the mixing reactor, and the radioactive nanoparticle suspension supply unit is connected to the control system. A polymer solution supply unit is provided outside the glove box, the polymer solution supply unit is connected to the interior of the mixing reactor, and the polymer solution supply unit is connected to the control system. A first stirring unit is disposed within the mixing reactor. The first stirring unit is used to stir the radioactive nanoparticle suspension and the polymer solution to form the radioactive polymer mixture. The first stirring unit is connected to the control system.

[0012] In one feasible implementation, the heating module is a water bath heating tank, the mixing reactor is placed inside the water bath heating tank, and the water bath heating tank is further provided with: An ultrasonic transducer is provided, and both the water bath heating tank and the ultrasonic transducer are connected to the control system. The ultrasonic transducer is used to assist in ultrasonic dispersion and degassing of the radioactive polymer mixture.

[0013] In one feasible implementation, the inner diameter of the heat tracing pipeline is 1.0 mm to 3.0 mm, the temperature range of the heat tracing pipeline is 55℃ to 75℃, the length of the heat tracing pipeline is 0.3 m to 0.5 m, the heat tracing pipeline is connected to the control system, the inner diameter of the injection needle is 15 G to 32 G, and the needle is immersed 1 cm to 3 cm below the surface of the oil phase.

[0014] In one feasible implementation, it further includes: An oil phase supply unit is provided outside the glove box. The oil phase supply unit passes through the glove box and communicates with the microsphere forming reactor. The oil phase supply unit is also connected to the control system. The second stirring unit is disposed inside the microsphere forming reactor. The second stirring unit is used to drive the oil phase to form an oil phase shear flow field. The second stirring unit is connected to the control system. A refrigeration / heating unit is disposed in the microsphere molding reactor, the microsphere molding reactor is used to control the oil phase temperature, and the refrigeration / heating unit is connected to the control system; A cross-linking and shaping unit is disposed in the microsphere forming reactor, which is used to cross-link and shape the hydrogel microsphere embryo to form the hydrogel microspheres. The cross-linking and shaping unit is connected to the control system. An exhaust port is provided in the microsphere molding reactor and is connected to the exhaust system inside the glove box; A pressurization port is provided in the microsphere molding reactor. The pressurization port is connected to a pressurization pump outside the glove box. The pressurization pump is connected to the control system. The product outlet valve is located at the outlet of the microsphere forming reactor and is connected to the control system.

[0015] In one feasible implementation, it further includes: A microsphere filtration and collection unit is connected to the product outlet valve and is used to filter and retain the hydrogel microspheres. Waste liquid collection unit, which is located outside the glove box and is connected to the microsphere filter collection unit.

[0016] According to a second aspect of the embodiments of this application, a method for preparing radioactive hydrogel microspheres is provided. The method is applied to the radioactive hydrogel microsphere preparation apparatus described above, and the method includes: With the shut-off valve closed, the radioactive nanoparticle suspension is introduced into the mixing reactor, and the polymer solution is introduced into the mixing reactor. The radioactive nanoparticle suspension and the polymer solution are heated by the heating module to maintain the viscosity of the polymer solution and form the radioactive polymer mixture. An oil phase is introduced into the microsphere forming reactor to form a shear flow field in the oil phase. Then, the shut-off valve is opened to allow the heated radioactive polymer mixture to enter the oil phase through the heat tracing pipeline. The radioactive polymer mixture is continuously output from the needle of the injection needle, and hydrogel microsphere embryos are formed under the action of the shear flow field in the oil phase during output. The hydrogel microsphere embryos are cross-linked and shaped to form the hydrogel microspheres.

[0017] Collect the hydrogel microspheres.

[0018] In one feasible implementation, it further includes: After the oil phase is introduced, the second stirring unit is controlled to stir so as to form the oil phase shear flow field; After the shut-off valve is opened, inert gas is simultaneously introduced into the mixing reactor through the inert gas supply unit so that the radioactive polymer mixture is forced into the oil phase under pressure.

[0019] In one feasible implementation, it further includes: After the hydrogel microspheres are formed through cross-linking and shaping, the second stirring unit is controlled to stop stirring. Then, a cleaning solution is added to the microsphere forming reactor to transfer the hydrogel microspheres from the oil phase to the aqueous phase; Open the product outlet valve to pressurize the hydrogel microspheres and liquid mixture to the microsphere filtration and collection unit, where the hydrogel microspheres are collected after filtration and washing.

[0020] Compared with the prior art, the present invention has at least the following beneficial effects: The radioactive hydrogel microsphere preparation device provided in this application uses a heating module to heat the radioactive polymer mixture in the mixing reactor, so that the polymer solution is in a low-viscosity sol state. At the same time, the radioactive nanoparticle suspension and the polymer solution are fully diffused to form a uniform polymer mixture. The polymer mixture is continuously kept warm during the subsequent transmission through the heated pipeline, which can effectively prevent the polymer mixture from cooling and solidifying before reaching the needle, ensuring that the radioactive polymer mixture always has good fluidity. Furthermore, because the inner diameter of the injection needle used is much larger than the microchannel size of the microfluidic chip, the nanoparticles in the radioactive nanoparticle suspension can pass smoothly through the needle without depositing and clogging the inner wall of the needle. Therefore, the radioactive hydrogel microsphere preparation device disclosed in this embodiment can operate stably for a long time in the glove box without clogging, overcoming the technical obstacles of easy clogging and difficult maintenance in the microfluidic method when preparing microspheres from radioactive nanoparticle suspension.

[0021] The above description is merely an overview of the technical solution of the present invention. In order to better understand the technical means of the present invention and to implement it in accordance with the contents of the specification, and in order to make the above and other objects, features and advantages of the present invention more apparent and understandable, specific embodiments of the present invention are described below. Attached Figure Description

[0022] Various other advantages and benefits will become apparent to those skilled in the art upon reading the following detailed description of preferred embodiments. The accompanying drawings are for illustrative purposes only and are not intended to limit the scope of this application. Furthermore, the same reference numerals denote the same parts throughout the drawings. In the drawings: Figure 1 A schematic diagram of the structure of the radioactive hydrogel microsphere preparation apparatus provided in the first embodiment of this application; Figure 2This is a schematic diagram of the structure of a mixing reactor; Figure 3 This is a schematic diagram of the microsphere molding reactor. Figure 4 This is a schematic diagram of the injection needle installation. Figure 5 An optical microscope image of the non-radioactive gelatin microspheres prepared in Example 1 of this invention; Figure 6 SEM image of the non-hydrophobic gel microspheres prepared in Example 1 of this invention; Figure 7 Light microscopy images of the radioactive hydrogel microspheres prepared in Example 2 (small particle size group). Figure 8 Light microscopic images (medium particle size group) of the radioactive hydrogel microspheres prepared in Example 2. Figure 9 Light microscopy images of the radioactive hydrogel microspheres prepared in Example 2 (large particle size group). Figure 10 The spectrum for the activity determination of 90Y radioactive microspheres prepared in Example 3 of this invention is shown.

[0023] in, Figures 1 to 7 The correspondence between the reference numerals and component names in the attached drawings is as follows: 1. Mixing reactor; 2. Heating module; 3. Microsphere forming reactor; 4. Heating pipeline; 5. Injection needle; 6. Microsphere filtration and collection unit; 7. Glove box; 8. Polymer solution supply unit; 9. Oil phase supply unit; 10. UV curing lamp assembly; 11. Radioactive nanoparticle suspension supply unit; 12. Shut-off valve; 13. First stirring unit; 14. Second stirring unit; 15. Cooling / heating unit; 16. Product outlet valve. Detailed Implementation

[0024] The following description provides numerous specific details to offer a more thorough understanding of the technical solutions provided by this invention. However, it will be apparent to those skilled in the art that the technical solutions provided by this invention can be implemented without one or more of these details.

[0025] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms “comprising” and / or “including” are used in this specification, they indicate the presence of the stated features, integrals, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integrals, steps, operations, elements, components, and / or combinations thereof.

[0026] Exemplary embodiments according to the present invention will now be described in more detail with reference to the accompanying drawings. However, these exemplary embodiments may be implemented in many different forms and should not be construed as being limited to the embodiments set forth herein. It should be understood that these embodiments are provided so that the disclosure of the invention is thorough and complete, and that the concept of these exemplary embodiments is fully conveyed to those skilled in the art.

[0027] To better understand the above technical solutions, the technical solutions of the embodiments of this application will be described in detail below with reference to the accompanying drawings and specific embodiments. It should be understood that the embodiments of this application and the specific features in the embodiments are detailed descriptions of the technical solutions of the embodiments of this application, rather than limitations on the technical solutions of this application. In the absence of conflict, the embodiments of this application and the technical features in the embodiments can be combined with each other.

[0028] like Figures 1 to 4 As shown, a radioactive hydrogel microsphere preparation apparatus is provided according to a first aspect of the embodiments of this application, including a mixing reactor 1, a heating module 2, a microsphere forming reactor 3, a heat tracing pipeline 4, and an injection needle 5. The mixing reactor 1, heating module 2, microsphere forming reactor 3, heat tracing pipeline 4, and injection needle 5 are all disposed within a glove box 7. The mixing reactor 1 is used to contain a suspension of radioactive nanoparticles and a polymer solution. The bottom of the mixing reactor 1 is provided with an outlet, and a shut-off valve 12 is provided at the outlet. The heating module 2 is used to heat the suspension of radioactive nanoparticles and the polymer solution in the mixing reactor. A radioactive polymer mixture is formed; one end of the heat tracing pipe 4 is connected to the outlet of the shut-off valve; the injection needle 5 is set at the other end of the heat tracing pipe 4 and is located inside the microsphere forming reactor 3; the microsphere forming reactor 3 is used to contain the oil phase medium and can form an oil phase shear flow field, while the injection needle 5 is located below the oil phase liquid surface, and the inner diameter of the injection needle 5 is 15G~32G. When the radioactive polymer mixture is injected into the oil phase through the injection needle 5, the radioactive polymer mixture can be dispersed into hydrogel microsphere embryos under the action of the oil phase shear flow field. Finally, the spherical droplets are cross-linked and solidified to form hydrogel microspheres.

[0029] In this technical solution, the mixing reactor 1 adopts a funnel-cylinder composite structure, with a cylindrical main reaction chamber at the top and a conical funnel shape at the bottom. An outlet is located at the bottom of the funnel, and a shut-off valve is installed at the outlet. The volume of the mixing reactor 1 is 10~200 mL; the semi-cone angle of the funnel is 30°~60° to facilitate the natural collection of the radioactive polymer mixture to the bottom outlet by gravity. The main body of the mixing reactor 1 is made of 316L stainless steel or polytetrafluoroethylene, both of which have excellent corrosion resistance and radiation resistance. The top of the mixing reactor 1 is equipped with a sealing cover, which is connected to the container body by a flange and fitted with a radiation-resistant silicone rubber sealing ring to ensure the integrity of the atmosphere seal inside the glove box is not affected. The sealing cover integrates a first sealing interface for connecting the radioactive nanoparticle suspension supply unit, a second sealing interface for connecting the polymer solution supply unit, a third sealing interface for installing the first stirring unit, and a fourth sealing interface for connecting the inert gas supply unit. If necessary, a fifth sealing interface for adding surfactants can also be provided on the sealing cover. Additionally, a sealing interface for installing a safety pressure relief valve should also be provided on the sealing cover. The heating module 2 heats the radioactive nanoparticle suspension and polymer solution inside the mixing reactor 1, allowing them to diffuse fully and form a homogeneous radioactive polymer mixture.

[0030] Understandably, in response to the problem mentioned in the background art that the microchannel size of microfluidic chips is so small (tens to hundreds of micrometers) that radioactive nanoparticles easily clog the channels, the solution disclosed in this embodiment uses a heating module 2 to heat the radioactive polymer mixture in the mixing reactor 1, so that the polymer solution is in a low-viscosity sol state. At the same time, the radioactive nanoparticle suspension and the polymer solution are fully diffused and form a uniform polymer mixture. The polymer mixture is continuously kept warm during the subsequent transmission through the heated pipeline 4, which can effectively prevent the polymer mixture from cooling and solidifying before reaching the needle, ensuring that the radioactive polymer mixture always has good fluidity. Furthermore, because the inner diameter of the injection needle 5 used is much larger than the microchannel size of the microfluidic chip, the nanoparticles in the radioactive nanoparticle suspension can pass smoothly through the needle without depositing and clogging the inner wall of the needle. Therefore, the radioactive hydrogel microsphere preparation device disclosed in this embodiment can operate stably for a long time in the glove box without clogging, overcoming the technical obstacles of easy clogging and difficult maintenance when preparing microspheres from radioactive nanoparticle suspensions using the microfluidic method.

[0031] In one feasible embodiment, the radioactive hydrogel microsphere preparation device further includes an inert gas supply unit, which is located outside the glove box 7 and is also connected to the interior of the mixing reactor 1. The inert gas supply unit is used to deliver inert gas into the mixing reactor 1 so that the radioactive polymer mixture is forced into the microsphere forming reactor 3 under gas pressure. Both the shut-off valve and the inert gas supply unit are connected to the control system, which is located outside the glove box 7.

[0032] In this technical solution, the inert gas supply unit includes an inert gas source (nitrogen or argon cylinder), a pressure reducing valve, an electro-proportional valve, and a gas pipeline. The gas pipeline is connected to the mixing reactor 1 via a fourth sealed interface. The electro-proportional valve adjusts the pressure with an accuracy of ±0.5 kPa, enabling linear flow control. The output pressure range of the inert gas supply unit is 0~0.3 MPa. The inert gas is filtered and heated before being introduced into the mixing reactor 1. As an alternative, an external peristaltic pump or syringe pump can be used to drive the radioactive polymer mixture. However, using pneumatic drive avoids the presence of moving parts inside the glove box, reducing potential points of failure and the risk of radioactive contamination.

[0033] It can be understood that this embodiment simplifies the internal structure of the glove box 7 by providing an inert gas supply unit connected to its interior outside the glove box 7, and using the inert gas supply unit to provide driving force, replacing the traditional built-in peristaltic pump or injection pump. This reduces the probability of equipment failure and the difficulty of maintenance. At the same time, because the gas pressure of the inert gas supply unit can be precisely adjusted, the flow rate of the radioactive polymer mixture is stable and controllable, which is beneficial for forming microspheres with uniform particle size.

[0034] In one feasible embodiment, the radioactive hydrogel microsphere preparation apparatus further includes: a radioactive nanoparticle suspension supply unit 11, a polymer solution supply unit 8, a first stirring unit 13, and a liquid level sensor; wherein the radioactive nanoparticle suspension supply unit is located outside the glove box 7, and is connected to the interior of the mixing reactor 1; the radioactive nanoparticle suspension supply unit 11 is used to introduce the radioactive nanoparticle suspension into the mixing reactor 1, and is connected to the control system; the polymer solution supply unit 8 is located outside the glove box 7, and is connected to the interior of the mixing reactor 1; the polymer solution supply unit 8 is used to introduce the polymer solution into the mixing reactor 1, and is connected to the control system; the first stirring unit 13 is located inside the mixing reactor 1, and is used to stir the radioactive nanoparticle suspension and the polymer solution to form a radioactive polymer mixture; the first stirring unit is connected to the control system; the liquid level sensor is located on the outer wall of the mixing reactor 1, and is connected to the control system.

[0035] In this technical solution, the radioactive nanoparticle suspension supply unit 11 includes a first storage tank for storing the radioactive nanoparticle suspension, a peristaltic pump, and a first delivery pipeline. The polymer solution supply unit includes a temperature-controlled second storage tank (temperature control accuracy ±0.5℃, temperature range 55~80℃), a peristaltic pump, and a heated or insulated second pipeline. The flow rate of the second peristaltic pump can be set to 0.1~100 mL / min. Both the first and second delivery pipelines are connected to the mixing reactor 1 via a through-chamber interface on the glove box 7, and then to the mixing reactor 1 via a first and second sealing interface, respectively. The first stirring unit uses a mechanical stirring paddle, driven by a motor located outside the mixing reactor 1. The mechanical stirring paddle is installed inside the mixing reactor via a third sealing interface and connected to the output end of the motor. The motor is electrically connected to an external control system, and the rotation speed of the mechanical stirring paddle is controlled at 200~800 rpm. If necessary, the radioactive hydrogel microsphere preparation device also includes a surfactant supply unit. This unit includes a surfactant solution storage tank, a peristaltic pump, and a surfactant delivery pipeline. The surfactant delivery pipeline is connected to the mixing reactor 1 via a through-chamber interface and a fifth sealing interface. This pipeline is used to add surfactants (such as polysorbate-80, sodium dodecyl sulfate, or polyethylene glycol, at a concentration of 0.01%~1.0% w / v) to the mixing reactor 1 when necessary, to aid in the uniform dispersion of radioactive nanoparticles in the polymer solution. A non-contact ultrasonic level gauge or a capacitive level gauge can be selected as the level sensor to monitor the liquid level in the mixing reactor in real time. A safety pressure relief valve is also integrated into the top sealing cap of the mixing reactor 1. When the internal pressure of the mixing reactor 1 exceeds a preset safety threshold (e.g., 0.3 MPa), the safety pressure relief valve automatically opens to release pressure, preventing equipment damage or leakage of radioactive materials due to excessive pressure. Alternatively, the surfactant can be pre-added to the radioactive nanoparticle suspension or polymer solution instead of requiring a separate supply unit.

[0036] It can be understood that this embodiment achieves automated feeding of radioactive nanoparticle suspension and polymer solution through independent and external radioactive nanoparticle suspension supply unit and polymer solution supply unit; liquid level sensor can prevent overfeeding or idling; the first stirring unit and heating module work together to make nanoparticles uniformly dispersed in polymer solution, avoid agglomeration, and provide uniformly dispersed radioactive polymer mixture for subsequent microsphere preparation.

[0037] In one feasible implementation, the heating module 2 is a water bath heating tank, the mixing reactor 1 is placed in the water bath heating tank, and an ultrasonic transducer is also provided in the water bath heating tank. Both the water bath heating tank and the ultrasonic transducer are connected to the control system. The ultrasonic transducer is used to assist in ultrasonic dispersion and degassing of the radioactive polymer mixture.

[0038] In this technical solution, the water bath heating tank is made of stainless steel and filled with deionized water. Heating is done electrically, with a temperature control range of room temperature to 95℃ and a temperature control accuracy of ±1℃. An ultrasonic transducer is installed at the bottom or side wall of the water bath, preferably operating at 40 kHz, with adjustable power (20~100 W). A sealed structure is provided between the water bath and the outlet of the mixing reactor 1, allowing the heat tracing pipeline to exit sealed from the bottom of the water bath.

[0039] It can be understood that the scheme disclosed in this embodiment uses the synergistic effect of water bath heating and ultrasound. When heated, the viscosity of the polymer solution decreases, which is conducive to the diffusion of nanoparticles. At the same time, the microjets and shock waves generated by the ultrasonic cavitation effect effectively disperse the nanoparticle agglomerates and remove the dissolved bubbles in the radioactive polymer mixture. This can effectively prevent the nanoparticles from settling or agglomerating before injection. Therefore, this method can effectively ensure that the suspension containing radioactive nanoparticles diffuses and is uniformly mixed with the polymer solution.

[0040] In one feasible implementation, the inner diameter of the heat tracing pipe 4 is 1.0 mm to 3.0 mm, the temperature range of the heat tracing pipe 4 is 55°C to 75°C, the length of the heat tracing pipe 4 is 0.3 m to 0.5 m, the heat tracing pipe 4 is connected to the control system, the inner diameter of the injection needle 5 is 15 G to 32 G, and the needle is immersed 1 cm to 3 cm below the surface of the oil phase.

[0041] In this technical solution, the heat tracing pipeline 4 is constructed by wrapping a heating sleeve around a polytetrafluoroethylene (PTFE) flexible tube. The heating sleeve can be a silicone heating sleeve and incorporates a PT100 temperature sensor. The heating sleeve is connected to the control system for feedback control, maintaining the temperature of the heat tracing pipeline 4 at a set value (heating temperature can be set to 55~75℃, temperature control accuracy ±1℃, pressure resistance 1.0 MPa). The heat tracing pipeline 4 is connected to the shut-off valve and injection needle using quick-connect or threaded connectors for easy manual replacement within a glove box. The needle immersion depth is preferably 1.5~2.5 cm to reduce heat loss. The injection needle 5 is a stainless steel medical needle with an inner diameter of 15G~32G (approximately 0.16~1.37 mm). The needle tip can be machined into a flat or rounded shape to reduce disturbance to the fluid flow.

[0042] Understandably, the inner diameter of the heat tracing pipe 4 in this solution, ranging from 1.0 mm to 3.0 mm, ensures sufficient liquid flow. When the temperature of heat tracing pipe 4 is between 55℃ and 75℃, it is suitable for the sol state of most temperature-sensitive polymers (such as gelatin and GelMA). A pipe length of 0.3 to 0.5 m maintains flexible arrangement while reducing heat loss. Furthermore, the needle inner diameter of 15G to 32G is much larger than the microfluidic channel, significantly reducing the probability of clogging. Even in the rare case of clogging, the quick-connect needle can be quickly replaced by hand inside the glove box without tools, resulting in significantly lower maintenance costs and operational complexity compared to microfluidic chips. The needle is immersed to a certain depth below the oil phase surface, ensuring that the extruded liquid is immediately sheared by the oil phase, forming spherical droplets.

[0043] In one feasible embodiment, the radioactive hydrogel microsphere preparation apparatus further includes: an oil phase supply unit 9, a second stirring unit 14, a cooling / heating unit 15, a crosslinking and shaping unit, an exhaust port, a pressurizing port, and a product outlet valve 16; wherein the oil phase supply unit 9 is located outside the glove box 7, is connected to the microsphere forming reactor 3, and is used to supply oil to the microsphere forming reactor 3, and is connected to the control system; the second stirring unit 14 is located inside the microsphere forming reactor 3, and is used to drive the oil phase to form an oil phase shear flow field, and is connected to the control system, and the radioactive polymer mixture is injected through an injection needle. When injected into the molding reactor 3, a hydrogel microsphere preform is formed under the action of the oil phase shear flow field. A cooling / heating unit 15 is installed in the microsphere molding reactor 3, which controls the oil phase temperature. The cooling / heating unit is connected to the control system. A crosslinking and shaping unit is installed in the microsphere molding reactor 3, which crosslinks and shapes the formed hydrogel microsphere preform to form hydrogel microspheres. The crosslinking and shaping unit is connected to the control system. The crosslinking and shaping unit can be any one or more of the following: a photocrosslinking unit, a crosslinking agent / cleaning liquid supply unit connected to the inside of the microsphere molding reactor 3, or a physical crosslinking unit. The physical crosslinking unit is the cooling / heating unit 15. An exhaust port is installed in the microsphere molding reactor 3 and connected to the exhaust system inside the glove box 7. A pressurization port is connected to a pressurization pump via a through-chamber interface. The pressurization pump is connected to the control system. A product outlet valve 16 is installed at the outlet of the microsphere molding reactor 3 and connected to the control system.

[0044] In this technical solution, the microsphere molding reactor 3 is a cylindrical sealed container with a volume of 50~500 mL, made of 316L stainless steel. The outer wall of the microsphere molding reactor 3 is equipped with a lead equivalent radiation shielding layer (0.5~2 mm Pb). The oil phase supply unit includes an oil phase storage tank, a peristaltic pump, and an oil phase delivery pipeline. The oil phase can be dimethyl silicone oil, mineral oil, vegetable oil, or liquid paraffin, with a viscosity range of 100~10000 cSt. The second stirring unit can be a magnetic stir bar (PTFE coated) or an external magnetic stirrer. The magnetic stirrer is connected to the control system, and the rotation speed of the magnetic stirrer is 100~3000 rpm. The cooling / heating unit can be a semiconductor cooling / heating module (Peltier element), with an operating temperature range of -10~60℃, temperature control accuracy of ±1℃, and response time of <5 min. In addition to controlling the oil phase temperature, the semiconductor cooling / heating module can also be used for physical crosslinking (cooling curing). In addition, to adapt to different polymer systems, the microsphere molding reactor 3 is also equipped with a crosslinking agent addition interface. The external crosslinking agent / cleaning liquid supply unit is connected to the microsphere molding reactor 3 through the chamber interface and the crosslinking agent addition interface. The crosslinking agent / cleaning liquid supply unit includes a storage tank for storing crosslinking additives or cleaning liquid, a peristaltic pump, and corresponding delivery pipelines. The microsphere molding reactor 3 is also equipped with a UV curing lamp group 10 for photocrosslinking. The crosslinking agent / cleaning liquid supply unit and the UV curing lamp group 10 are both connected to the control system. Therefore, after the microspheres are molded, the crosslinking additives or corresponding cleaning liquids can be automatically added according to the program without manual operation. Therefore, after the hydrogel microsphere embryo is formed, one or more cross-linking and fixation methods can be selected, such as: low-temperature physical cross-linking (cooling to 0~15℃ using a semiconductor cooling / heating module); chemical cross-linking, i.e., injecting 5% calcium chloride, 0.1~1% glutaraldehyde, etc., into the microsphere forming reactor 3 through a cross-linking agent / cleaning solution supply unit connected to the cross-linking agent addition interface; photocross-linking unit, i.e., installing a UV curing lamp group on the inner side of the top of the microsphere forming reactor 3, with a wavelength of 310~405 nm and a power of 20~200 mW / cm², and turning on the UV curing lamp group through the control unit to perform photocross-linking and curing. In addition, deionized water, phosphate buffer, etc., can also be introduced into the microsphere forming reactor 3 through the cross-linking agent / cleaning solution supply unit.

[0045] It can be understood that, in response to the technical problem in the background technology where the microchannel size of microfluidic chips easily clogs the channels with radioactive nanoparticle suspensions, this embodiment uses an oil phase shear flow field to completely replace the microchannel shear to achieve microsphere molding; the oil phase supply unit automatically injects a set volume of oil phase into the microsphere molding reactor 3 under the command of the control system, and the second stirring unit (such as a magnetic stir bar in conjunction with an external magnetic stirrer) operates at a flow rate of 100~3000... The high-speed rotation of the oil phase, driven by a rotational speed of rpm, creates a stable and controllable shear flow field within the reactor. When the radioactive polymer mixture is injected into this flow field through an injection needle 5 with an inner diameter of 15G~32G (its size is much larger than the microchannels of the microfluidic chip), the liquid flow is dispersed into spherical droplets under shear force, fundamentally avoiding blockage caused by narrow channels. The cooling / heating unit (such as a semiconductor cooling / heating module) adjusts the oil phase temperature in real time, controlling the oil phase viscosity to optimize the shearing effect and providing conditions for subsequent physical crosslinking. The exhaust port connects to the filter exhaust system inside the glove box, releasing excess gas in the reactor during oil phase injection, stirring, and crosslinking agent addition to prevent positive pressure buildup from affecting the stability of the shear flow field and the liquid exiting the needle. To prevent interference, the product outlet valve automatically opens after the microspheres solidify, sealing and pressurizing the mixture of microspheres and oil phase to the microsphere collection unit 6. As for the specific cross-linking and shaping method of the hydrogel microsphere embryo (low-temperature physical cross-linking, chemical cross-linking, or photocross-linking), a suitable known method can be selected according to the selected polymer system (gelatin, GelMA, sodium alginate, etc.), which is automatically executed by the cross-linking and shaping unit. The innovation of this embodiment lies not in the cross-linking method itself, but in integrating functions such as oil phase supply, shear flow field construction, temperature control, exhaust pressure relief, and product output into a system that can be remotely and automatically operated in a glove box. This allows operators to complete the preparation of radioactive microspheres without frequent operation in the glove box, significantly reducing the risk of radiation exposure and the difficulty of operation.

[0046] In one feasible embodiment, the radioactive hydrogel microsphere preparation device further includes: a microsphere filtration and collection unit 6 and a waste liquid collection unit; wherein the microsphere filtration and collection unit 6 is connected to the product outlet valve, the microsphere filtration and collection unit 6 is used to filter and retain hydrogel microspheres, and the waste liquid collection unit is located outside the glove box 7 and is connected to the microsphere filtration and collection unit 6.

[0047] In this technical solution, the microsphere filtration and collection unit 6 includes a filter column and a microsphere collection bottle connected in series with the product outlet valve. The filter membrane on the filter column is replaceable, and the pore size of the filter membrane is 10~200 μm. The waste liquid collection unit is a waste liquid collection tank with a shielding layer on the outside and equipped with a radiation dose rate monitoring device for real-time monitoring of the radioactivity level of the waste liquid. The filter column, microsphere collection bottle, and connecting pipelines are all made of sterilizable or disposable materials, and all interfaces are quick-connect sealing structures to allow for manual replacement of the filter membrane or collection bottle inside a glove box.

[0048] Understandably, this embodiment connects the microsphere filtration and collection unit in series with the product outlet valve, completing the filtration, cleaning, and collection process within the glove box in a fully enclosed manner. Simultaneously, the waste liquid is automatically diverted to an outer, shielded waste liquid collection tank, and radiation dose is monitored in real time, completely eliminating the risk of operators directly contacting radioactive waste liquid. The replaceable filter membrane design allows for flexible selection of pore size (10~200 μm) based on the target microsphere particle size, and the quick-connect sealing structure facilitates manual operation within the glove box, solving the problem of difficulty in cleaning and replacing clogged microfluidic chips. The shielding layer of the waste liquid collection tank and the radiation monitoring device further ensure safety during waste liquid storage and disposal, achieving a fully enclosed, radioactively safe operation chain from microsphere molding to product collection and waste liquid treatment.

[0049] According to a second aspect of the embodiments of this application, a method for preparing radioactive hydrogel microspheres is provided, comprising the following steps: S1. Preparation of radioactive nanoparticle suspension (can be completed in the glove box or pre-prepared in the heated chamber before being introduced into the glove box): Radionuclide-labeled nanoparticles (such as 177Lu-labeled iron oxide nanoparticles, 90Y-labeled yttrium phosphate nanoparticles, and 188Re-labeled metal-organic framework nanoparticles) were dispersed in deionized water or buffer solution and ultrasonically dispersed for 10–30 min to prepare a radionuclide nanoparticle suspension with a nanoparticle concentration of 0.1–50 mg / mL. If necessary, surfactants (such as polysorbate-80, sodium dodecyl sulfate, and polyethylene glycol) were added to assist dispersion with a surfactant concentration of 0.01–1.0% (w / v). The resulting suspension was pumped into the mixing reactor 1 inside the glove box through the transom interface using a peristaltic pump or manual injection. The radionuclide-labeled nanoparticles are one or more of the following: radionuclide-labeled iron oxide nanoparticles, gold nanoparticles, calcium carbonate nanoparticles, calcium phosphate nanoparticles, metal-organic framework (MOF) nanoparticles, mesoporous silica nanoparticles, or polymer nanoparticles; the radionuclides include, but are not limited to, one or more of 177Lu, 90Y, 188Re, 186Re, 131I, 64Cu, 89Zr, 225Ac, and 223Ra. S2. Preparation and introduction of polymer solutions: Outside the glove box, a thermosensitive or crosslinkable water-soluble polymer is dissolved in deionized water or buffer solution to prepare a polymer solution with a concentration of 2%~20% (w / v). The preferred polymer types are gelatin (Type A or Type B), methacrylamide gelatin (GelMA), sodium alginate, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), or one or more of their composite systems. After the polymer solution is heated and stirred at 55~80℃ until completely dissolved, it is transferred to a constant temperature storage tank (maintained at 55~80℃) and pumped into the mixing reactor 1 inside the glove box through a heated or insulated second pipe and a passage interface using an external peristaltic pump. The feed flow rate is 1~50 mL / min. The volume ratio of the polymer solution to the radioactive nanoparticle suspension is 10:1~1:1 (v / v). The water-soluble polymers include one or more of gelatin, methacrylamide gelatin (GelMA), sodium alginate, chitosan, hydroxypropyl methylcellulose, hyaluronic acid and its derivatives, polyvinyl alcohol, and polyethylene glycol diacrylate (PEGDA). S3. Mixed dispersion of radioactive nanoparticle suspension and polymer solution: After the radioactive nanoparticle suspension and the polymer solution are simultaneously contained in the mixing reactor 1, the first stirring unit is started through the control system, with the rotation speed set to 200~800 rpm; at the same time, the heating function of the water bath heating tank and the ultrasonic transducer are activated, with the water bath temperature set to 45~75℃ and the ultrasonic power set to 20~100 W; under the synergistic effect of heating and mechanical stirring, the polymer is fully dissolved and forms a low viscosity state, and the polymer solution and radioactive nanoparticles are uniformly mixed; ultrasonic dispersion is carried out for 30~60 minutes to ensure that the nanoparticles are uniformly dispersed in the polymer solution, forming a uniform radioactive polymer mixture; during the dispersion process, the shut-off valve is kept closed to prevent the solution from flowing out prematurely; if necessary, an appropriate amount of surfactant can be added from the outside through the addition interface to further assist the dispersion of nanoparticles.

[0050] S4. Preparation of the reactor for heat tracing and microsphere molding: Before the mixing and dispersion are completed, the oil phase solution is pumped into the microsphere forming reactor 3 through an external oil phase supply unit. The volume of the oil phase is 60% to 80% of the volume of the microsphere forming reactor. The oil phase solution is one or more of dimethyl silicone oil, mineral oil, vegetable oil or liquid paraffin, with a viscosity range of 100 to 10000 cSt. The external magnetic stirrer is started and the stirring speed is set to 500 to 2000 rpm to build a stable oil phase shear flow field. During the microsphere forming stage, the oil phase temperature is maintained at a suitable range of 30 to 40°C through an external semiconductor cooling / heating module. At the same time, it is confirmed that the temperature of the heating pipe 4 has been stabilized at 55 to 75°C and the needle at the end of the pipe has been correctly immersed 1 to 3 cm below the surface of the oil phase. S5. Thermal injection-shear molding for preparing hydrogel microsphere preforms: After the mixing and dispersion step is completed, clean inert gas (nitrogen) is slowly introduced into the top of the mixing reactor 1 through the inert gas supply unit connected to the control system. At the same time, the shut-off valve is opened, and the radioactive polymer mixture in the mixing reactor 1 is pumped out of the needle at a uniform speed through the heated pipeline 4 using the gas pressure. At this time, the gas pressure is controlled within the range of 0.01~0.20 MPa to adjust the flow rate (equivalent flow rate: 0.1~20 mL / min). The needle inner diameter is selected as 15G~32G, preferably 20G~30G. The heated low-viscosity radioactive polymer composite solution is continuously pumped out from the needle. Under the shear force generated by the high-speed rotating oil phase, the liquid flow is sheared and dispersed to form spherical droplets. After the droplets leave the needle tip, they remain spherical in the oil phase to form radioactive hydrogel microsphere embryos. During this process, the microsphere particle size can be controlled by adjusting the gas driving pressure (liquid flow rate), the oil phase stirring speed, and the needle inner diameter. S6. Cross-linking and shaping of radioactive hydrogel microspheres: Depending on the polymer system used, one or more of the following crosslinking methods may be employed: (a) Low-temperature physical crosslinking: suitable for thermosensitive polymer systems such as gelatin; after the hydrogel microsphere embryo is formed and stabilized, the temperature of the oil phase is reduced to 0~10℃ by controlling the semiconductor cooling / heating module and maintained for 30~60 min, so that the microspheres are physically gelled and solidified at low temperature. (b) Chemical crosslinking: Applicable to chemically crosslinkable systems such as sodium alginate, gelatin, and chitosan; After the hydrogel microsphere embryo is formed and stabilized, the gas pressure drive is stopped or reduced, and the crosslinking agent solution (such as 5% calcium chloride solution, 0.1~1% glutaraldehyde solution, EDC / NHS crosslinking liquid, etc.) is added from the top interface of the microsphere forming reactor 3 through the external crosslinking agent / cleaning liquid supply unit. The volume of the crosslinking agent is 5%~20% (v / v) of the oil phase volume. The reaction is carried out under stirring conditions for 30~120 min to achieve chemical crosslinking and shaping. (c) Photocrosslinking: Applicable to photocurable polymer systems such as GelMA; after the hydrogel microsphere preform is formed and stabilized, the UV lamp group (wavelength 365~405 nm, power 20~200 mW / cm²) at the top of the microsphere molding reactor 3 is activated and irradiated for 10~60 s. The free radical crosslinking reaction is initiated by the photoinitiator (such as LAP or Irgacure 2959, concentration 0.1~0.5%w / v, pre-added to the polymer solution) to make the microspheres quickly solidify and shape. S7. Collection and purification of hydrogel microspheres (the entire process is carried out in a glove box with closed tubing): After cross-linking and shaping are completed, oil phase stirring is stopped. An equal volume of deionized water or phosphate buffer (PBS, pH 7.4) is added to the microsphere forming reactor 3 through the external cross-linking agent / cleaning solution supply unit. The microspheres are gently stirred to transfer from the oil phase to the aqueous phase. The product outlet valve at the bottom of the microsphere forming reactor 3 is opened through the control system, and the pressurization pump is turned on to use air pressure to pressurize the mixture of microspheres and liquid phase to the microsphere filtration and collection unit 6. The filter column (the pore size of the filter membrane is selected according to the target microsphere particle size, such as 10~200 μm) is used to filter and retain the microspheres. The waste liquid (residual oil phase) flows into the waste liquid collection tank after filtration. Then, the microspheres are washed sequentially with petroleum ether (2 times × 20 mL), deionized water (3 times × 20 mL), and PBS buffer (1 time × 10 mL). The washing solutions are all collected into the waste liquid tank. After washing, an appropriate amount of PBS buffer is added to the filter column to elute the microspheres and collect them in the collection bottle, completing the collection of radioactive hydrogel microspheres.

[0051] Example 1 (Cold Experiment): Preparation of Non-Radioactive Gelatin Microspheres This embodiment uses a non-radioactive LuCl3 solution for simulation, and is used to detect the morphology and particle size distribution of microspheres.

[0052] S1. Preparation of radioactive nanoparticle suspension: 1. Preparation of non-radioactive nanoparticle suspensions: In a heated chamber, LuCl3 solution was mixed with polydopamine-coated iron oxide nanoparticles (approximately 100 nm in diameter, 10 mg) in pH 5.5 ammonium acetate buffer (0.4 mol / L, 2 mL), and reacted at 95 °C for 30 min to achieve Lu ion chelation. The reacted iron oxide nanoparticles were then dispersed in 2 mL of deionized water, and Tween-80 (final concentration 0.1%, w / v) was added. The mixture was ultrasonically dispersed for 10 min to prepare a radioactive nanoparticle suspension. The suspension was then pumped into the mixing reactor inside the glove box via a syringe through the port inlet. S2. Preparation and introduction of polymer solution: Outside the glove box, 10.0 g of gelatin (Gelatin Type A, 250 Bloom, Sigma-Aldrich) was added to 100 mL of deionized water and heated and stirred in a 60°C water bath for 30 min until completely dissolved, preparing a 10% (w / v) gelatin solution; the solution was then transferred to a constant temperature storage tank (60°C) and pumped into the mixing reactor 1 inside the glove box at a flow rate of 10 mL / min through a heated pipeline (pipeline temperature 60°C) using an external peristaltic pump; S3, Mixed Dispersion: The magnetic stirrer is started by the control system, and the speed is set to 400 rpm; the heating function of the water bath heating tank and the ultrasonic transducer are started, the water bath temperature is set to 60℃, and the ultrasonic power is set to 60 W; the mixture is stirred and ultrasonicated for 30 minutes to uniformly disperse the Lu-loaded iron oxide nanoparticles in the gelatin solution; the electromagnetic shut-off valve is kept closed throughout the process. S4. Preparation of the microsphere molding reactor: 300 mL of dimethyl silicone oil (viscosity 500 cSt) was injected into the microsphere molding reactor 3 via an external oil phase supply unit pump; the external magnetic stirrer was set to 1000 rpm to create an oil phase shear flow field; the external semiconductor cooling / heating module was activated to lower the oil phase temperature and maintain it at 35°C; it was confirmed that the temperature of the heat tracing pipeline had stabilized at 60°C and that the 25G flat-head needle at the end of the pipeline had been immersed about 2 cm below the surface of the oil phase. S5, Thermal Injection Molding – Shear Molding: After dispersion, nitrogen gas is introduced into the top of the mixing reactor through an inert gas supply unit connected to the control system, and the pressure is slowly increased to 0.05 MPa. At the same time, the electromagnetic shut-off valve is opened, and the radioactive gelatin composite solution is continuously pumped out through a heated pipeline from a 25G needle (with an inner diameter of about 0.26 mm) under pneumatic pressure, at a flow rate of about 2 mL / min. After the heated low-viscosity gelatin composite solution enters the 5°C oil phase through the needle, it is sheared into spherical droplets under the shear force generated by the high-speed rotating oil phase. After the droplets leave the needle tip, they remain spherical in the oil phase and form microsphere ligands. Pumping continues for about 10 min. After all the solution in the mixing reactor has been pumped out, the electromagnetic shut-off valve is closed and the gas supply is stopped. S6. Low-temperature physical cross-linking and setting: Maintain the oil phase at 5℃ and the stirring state at 1000 rpm, and continue physical cross-linking for 30 min to allow the gelatin microspheres to fully gel, solidify and shape at low temperature, forming stable radioactive hydrogel microspheres. S7. Microsphere Collection and Purification: Stop stirring the oil phase; add an equal volume of deionized water (300 mL) to the microsphere forming reactor 3 through the external supply system, and gently mix to disperse the microspheres into the aqueous phase; open the product outlet valve at the bottom of the microsphere forming reactor 3, and use 0.02 MPa air pressure to press the microsphere / liquid phase mixture into the microsphere filtration and collection unit 6 (filter membrane pore size 100 μm); the filter column filters and retains the microspheres, and the waste liquid is collected into the waste liquid tank through the waste liquid pipeline; wash the microspheres sequentially with petroleum ether (3 times × 20 mL) and deionized water (3 times × 20 mL); finally, elute the microspheres into the collection bottle with PBS buffer (10 mL) to complete the collection of radioactive hydrogel microspheres.

[0053] like Figure 5 An optical microscope image of the non-radioactive gelatin microspheres prepared in Example 1 of this invention; Figure 6 This is a SEM image of the non-hydrophobic gel microspheres prepared in Example 1 of the present invention.

[0054] Example 2: Preparation of radioactive hydrogel microspheres with different particle sizes by adjusting parameters The preparation method in this embodiment is basically the same as that in Example 1. Radioactive hydrogel microspheres of different particle sizes are prepared by changing the gas pressure driving pressure, oil phase stirring speed, and needle inner diameter. The specific parameters are as follows: S1~S3: Same as Example 1.

[0055] S4~S5 variation parameters: (a) Small particle size group: In step S4, the speed of the magnetic stirrer was adjusted to 1500 rpm, and in step S5, the air pressure was adjusted to 0.02 MPa. The needle was replaced with a 32G needle (with an inner diameter of about 0.11 mm). The average particle size of the prepared microspheres was about 30 ± 12 μm. Figure 7 Light microscopy images of the prepared radioactive hydrogel microspheres (small particle size group). (b) Medium particle size group: Step S4 is the same as in Example 1, the magnetic stirrer speed is 1000 rpm, the air pressure in step S5 is 0.05 MPa, the needle is adjusted to a 28G needle, and the average particle size of the prepared microspheres is about 100±25 μm. Figure 8 Light microscopy images of the prepared radioactive hydrogel microspheres (medium particle size group). (c) Large particle size group: In step S4, the speed of the magnetic stirrer was adjusted to 500 rpm, and in step S5, the air pressure was adjusted to 0.10 MPa. The needle was replaced with an 18G needle (with an inner diameter of approximately 0.84 mm). The average particle size of the prepared microspheres was approximately 300 ± 60 μm. Figure 9 Light microscopic images of the prepared radioactive hydrogel microspheres (large particle size group).

[0056] S6~S7: Same as Example 1.

[0057] The results of this embodiment show that by adjusting the gas pressure driving pressure, the oil phase stirring speed, and the needle inner diameter, the particle size of the radioactive hydrogel microspheres can be effectively controlled, achieving controllable preparation within the range of 30~300 μm, and meeting the particle size requirements of different clinical applications.

[0058] Example 3: Preparation and radioactivity detection of gelatin microspheres supported on 90γ-yttrium phosphate nanoparticles This embodiment uses the radioactive nuclide 90Y and detects its radioactivity using a liquid scintillation counter; it includes the following steps: S1. In a glove box, take 1 mL of 90YCl3 solution (activity 500 mCi / mL), add 1 mL of 0.1 M Na3PO4 solution, stir at room temperature for 10 min to generate 90YPO4 nanoparticle precipitate; centrifuge at 10000 rpm for 5 min, discard the supernatant, wash twice with sterile water; finally, resuspend the precipitate in 0.5 mL of sterile water, sonicate for 5 min to obtain 90YPO4 nanoparticle suspension; S2~S7: Same as Example 1.

[0059] Determination of radioactivity in microspheres: Take a certain amount (e.g., 0.1 g) of wet microspheres, add 1 mL of concentrated nitric acid and heat to digest. After cooling, transfer to a liquid scintillation counter bottle, add 10 mL of scintillation fluid, and determine the total activity using a liquid scintillation counter. Figure 10 The image shows the activity spectrum of the 90Y radioactive microspheres prepared in this embodiment.

[0060] In summary, Example 3 successfully prepared... 90 The gelatin microspheres supported on YPO4 nanoparticles have uniform particle size (approximately 150–200 μm) and a radioactivity recovery rate >90%. This demonstrates that the apparatus and method of this invention are also applicable to... 90 Pure β nuclides such as Y and in-situ synthesized nanoparticle systems.

[0061] Compared with the prior art, the radioactive hydrogel microsphere preparation apparatus and method provided by the present invention have the following beneficial effects: (1) It has strong robustness and effectively solves the problem of microchannel blockage. This invention employs a thermally controlled injection-shear molding principle. The inner diameter of the injection needle is 15G~32G (approximately 0.16~1.37mm), which is much larger than the microchannel size of microfluidic chips (tens to hundreds of micrometers). This allows nanoparticle aggregates in the radioactive nanoparticle suspension to pass through smoothly without easily depositing and clogging the inner wall of the needle. At the same time, the heating module and the heat tracing pipeline work together to keep the polymer mixture in a low-viscosity sol state (45~80℃), effectively reducing the risk of clogging.

[0062] (2) External air pressure driven, the device is simple and reliable This invention employs an inert gas supply unit located outside the glove box as the drive source, replacing the traditional built-in peristaltic pump or syringe pump. This eliminates the need for moving parts inside the glove box, significantly reducing the probability of equipment failure and the risk of radioactive contamination. The gas pressure is linearly adjusted (0~0.3 MPa, accuracy ±0.5 kPa) via a precision electro-proportional valve, ensuring stable and controllable flow rate. This achieves injection accuracy comparable to a micro-syringe pump, meeting the requirements for uniform microsphere size.

[0063] (3) Fully enclosed process, high radiation protection safety In this invention, all operations, including mixing, heating, conveying, injection, shearing and molding, cross-linking and curing, cleaning and filtration, and product collection of the radioactive nanoparticle suspension and polymer solution, are completed within a sealed container and pipeline inside a shielded glove box. The radioactive material remains under controlled conditions at all times, with no open operation steps. Waste liquid (residual oil phase, cleaning fluid) automatically flows through a sealed pipeline into an outer shielded waste liquid collection tank equipped with a radiation dose rate monitoring device. This completely eliminates the risk of operators coming into contact with radioactive aerosols, liquid splashes, and waste liquid, significantly reducing external radiation dose and facilitating centralized management and disposal of radioactive waste.

[0064] (4) Remote automated control with very few operating steps inside the glove box. This invention utilizes a control system (PLC or industrial computer) located outside the glove box to remotely and automatically control the heating and stirring of the mixing reactor, ultrasonic-assisted dispersion, shut-off valve switching, inert gas supply pressure, heating pipeline temperature, oil phase supply and stirring of the microsphere molding reactor, cooling / heating unit, crosslinking and shaping unit (crosslinking agent addition, UV lamp assembly), and product outlet valve. Operators only need to complete material loading and pipeline connection before preparation (1-2 glove operations), eliminating the need for repeated intervention during the preparation process. This significantly reduces the difficulty of operation within the glove box and the radiation exposure time, making it particularly suitable for the rapid and standardized preparation of short-half-life nuclides.

[0065] (5) Multi-mode cross-linking integration, with a wide range of material applications The microsphere molding reactor of this invention integrates three crosslinking and curing methods: ① low-temperature physical crosslinking (cooled to 0~15℃ via a semiconductor cooling / heating module, suitable for temperature-sensitive polymers such as gelatin); ② chemical crosslinking (automatically injected with crosslinking agents such as calcium chloride and glutaraldehyde via a crosslinking agent addition interface, suitable for sodium alginate, chitosan, etc.); ③ photocrosslinking (irradiated by a UV curing lamp, suitable for photocurable polymers such as GelMA). Users can flexibly select the crosslinking mode according to the selected polymer system without changing equipment, achieving multi-purpose functionality and broad material versatility.

[0066] (6) The particle size can be adjusted over a wide range to meet different clinical needs. In this invention, the particle size of the hydrogel microspheres can be controlled independently or in combination by three parameters: ① inert gas driving pressure (0.01~0.20 MPa, affecting the liquid flow rate); ② oil phase stirring speed (100~3000 rpm, affecting the shear force); ③ injection needle inner diameter (15G~32G). The synergistic adjustment of these parameters allows for controllable adjustment of the microsphere particle size within the range of 30~300 μm (Example 2 confirms 30~300 μm), meeting the differentiated needs for microsphere size in various clinical scenarios such as interventional embolization therapy for tumors, internal radiotherapy, and particle implantation.

[0067] (7) High integration and small space occupied in the glove box The present invention features a compact, integrated design for its mixing reactor (funnel-cylinder composite structure), water bath ultrasonic heating tank, heat tracing pipeline, microsphere molding reactor, and microsphere filtration and collection unit. The entire unit occupies approximately 30cm × 40cm of internal space within the glove box, making it suitable for installation and operation within a standard shielded glove box (typically with an internal width of approximately 60~80cm). It does not encroach on other experimental spaces and is easy to promote and use in existing radiopharmaceutical laboratories.

[0068] In this invention, the terms "first," "second," and "third" are used for descriptive purposes only and should not be construed as indicating or implying relative importance; the term "multiple" refers to two or more unless otherwise explicitly defined. The terms "install," "connect," "link," and "fix" should be interpreted broadly. For example, "connect" can be a fixed connection, a detachable connection, or an integral connection; "link" can be a direct connection or an indirect connection through an intermediate medium. Those skilled in the art can understand the specific meaning of the above terms in this invention according to the specific circumstances.

[0069] In the description of this invention, it should be understood that the terms "upper," "lower," "left," "right," "front," "rear," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the device or unit referred to must have a specific orientation or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on this invention.

[0070] In the description of this specification, the terms "one embodiment," "some embodiments," "specific embodiment," etc., refer to a specific feature, structure, material, or characteristic described in connection with that embodiment or example, which is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0071] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A device for preparing radioactive hydrogel microspheres, characterized in that, It includes a mixing reactor, a heating module, a heat tracing pipeline, an injection needle, and a microsphere molding reactor, all of which are housed inside a glove box. The mixing reactor is used to contain a suspension of radioactive nanoparticles and a polymer solution. The mixing reactor has an outlet at the bottom, and a shut-off valve is installed at the outlet. The heating module is used to heat the radioactive nanoparticle suspension and polymer solution in the mixing reactor to form a radioactive polymer mixture. One end of the heat tracing pipeline is connected to the outlet of the shut-off valve, and the heat tracing pipeline is used to keep the radioactive polymer mixture passing through it warm or heat it. The injection needle is located at the other end of the heat tracing pipeline and is situated inside the microsphere forming reactor. The microsphere forming reactor is used to contain the oil phase medium and can form an oil phase shear flow field. The injection needle is located below the oil phase liquid surface. When the radioactive polymer mixture enters the oil phase through the injection needle, the radioactive polymer mixture can form hydrogel microspheres under the action of the oil phase shear flow field.

2. The apparatus for preparing radioactive hydrogel microspheres according to claim 1, characterized in that, Also includes: An inert gas supply unit is provided, located outside the glove box and connected to the mixing reactor. The inert gas supply unit is used to deliver inert gas into the mixing reactor so that the radioactive polymer mixture is forced into the microsphere forming reactor under gas pressure. Both the shut-off valve and the inert gas supply unit are connected to the control system, which is located outside the glove box.

3. The apparatus for preparing radioactive hydrogel microspheres according to claim 1, characterized in that, Also includes: A radioactive nanoparticle suspension supply unit is provided outside the glove box, the radioactive nanoparticle suspension supply unit is connected to the mixing reactor, and the radioactive nanoparticle suspension supply unit is connected to the control system. A polymer solution supply unit is provided outside the glove box, the polymer solution supply unit is connected to the interior of the mixing reactor, and the polymer solution supply unit is connected to the control system. A first stirring unit is disposed within the mixing reactor. The first stirring unit is used to stir the radioactive nanoparticle suspension and the polymer solution to form the radioactive polymer mixture. The first stirring unit is connected to the control system.

4. The apparatus for preparing radioactive hydrogel microspheres according to claim 1, characterized in that, The heating module is a water bath heating tank, and the mixing reactor is placed inside the water bath heating tank. The water bath heating tank also includes: An ultrasonic transducer is provided, and both the water bath heating tank and the ultrasonic transducer are connected to the control system. The ultrasonic transducer is used to assist in ultrasonic dispersion and degassing of the radioactive polymer mixture.

5. The apparatus for preparing radioactive hydrogel microspheres according to claim 1, characterized in that, The inner diameter of the heat tracing pipeline is 1.0 mm to 3.0 mm, the temperature range of the heat tracing pipeline is 55℃ to 75℃, the length of the heat tracing pipeline is 0.3 m to 0.5 m, the heat tracing pipeline is connected to the control system, the inner diameter of the injection needle is 15 G to 32 G, and the needle is immersed 1 cm to 3 cm below the surface of the oil phase.

6. The apparatus for preparing radioactive hydrogel microspheres according to claim 1, characterized in that, Also includes: An oil phase supply unit is provided outside the glove box. The oil phase supply unit passes through the glove box and communicates with the microsphere forming reactor. The oil phase supply unit is also connected to the control system. The second stirring unit is disposed inside the microsphere forming reactor. The second stirring unit is used to drive the oil phase to form an oil phase shear flow field. The second stirring unit is connected to the control system. A refrigeration / heating unit is disposed in the microsphere molding reactor, the microsphere molding reactor is used to control the oil phase temperature, and the refrigeration / heating unit is connected to the control system; A cross-linking and shaping unit is disposed in the microsphere forming reactor, which is used to cross-link and shape the hydrogel microsphere embryo to form the hydrogel microspheres. The cross-linking and shaping unit is connected to the control system. An exhaust port is provided in the microsphere molding reactor and is connected to the exhaust system inside the glove box; A pressurization port is provided in the microsphere molding reactor. The pressurization port is connected to a pressurization pump outside the glove box. The pressurization pump is connected to the control system. The product outlet valve is located at the outlet of the microsphere forming reactor and is connected to the control system.

7. The apparatus for preparing radioactive hydrogel microspheres according to claim 6, characterized in that, Also includes: A microsphere filtration and collection unit is connected to the product outlet valve and is used to filter and retain the hydrogel microspheres. Waste liquid collection unit, which is located outside the glove box and is connected to the microsphere filter collection unit.

8. A method for preparing radioactive hydrogel microspheres, characterized in that, The method for preparing radioactive hydrogel microspheres is applied to the radioactive hydrogel microsphere preparation apparatus as described in any one of claims 1 to 7, and the method for preparing radioactive hydrogel microspheres includes: With the shut-off valve closed, the radioactive nanoparticle suspension is introduced into the mixing reactor, and the polymer solution is introduced into the mixing reactor. The radioactive nanoparticle suspension and the polymer solution are heated by the heating module to keep the polymer solution in a low viscosity state and form the radioactive polymer mixture. An oil phase is introduced into the microsphere forming reactor to form a shear flow field in the oil phase. Then, the shut-off valve is opened to allow the heated radioactive polymer mixture to enter the oil phase through the heat tracing pipeline. The radioactive polymer mixture is continuously output from the needle of the injection needle, and hydrogel microsphere embryos are formed under the action of the shear flow field in the oil phase during output. The hydrogel microsphere embryos are cross-linked and shaped to form the hydrogel microspheres. Collect the hydrogel microspheres.

9. The method for preparing radioactive hydrogel microspheres according to claim 8, characterized in that, After the oil phase is introduced, the second stirring unit is controlled to stir so as to form the oil phase shear flow field; After the shut-off valve is opened, inert gas is simultaneously introduced into the mixing reactor through the inert gas supply unit so that the radioactive polymer mixture is forced into the oil phase under pressure.

10. The method for preparing radioactive hydrogel microspheres according to claim 9, characterized in that, Also includes: After the hydrogel microspheres are formed through cross-linking and shaping, the second stirring unit is controlled to stop stirring. Then, a cleaning solution is added to the microsphere forming reactor to transfer the hydrogel microspheres from the oil phase to the aqueous phase; Open the product outlet valve to pressurize the hydrogel microspheres and liquid mixture to the microsphere filtration and collection unit, where the hydrogel microspheres are collected after filtration and washing.

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