Reaction apparatus and method of processing, embolization microsphere preparation device and method of preparation

Abstract

The application provides a reaction device and a processing method thereof, wherein the reaction device comprises a main structure layer and an encapsulation layer, the main structure layer is integrated with a groove of liquid beads, and the encapsulation layer is stacked on one side of the main structure layer; the main structure layer and the encapsulation layer are made of the same material, the melting temperature of the main structure layer is higher than that of the encapsulation layer, and the main structure layer and the encapsulation layer are connected through a thermal bonding mode. The reaction device has the advantages of integration, stable structure, high strength and the like, and significantly improves the stability of liquid bead generation. The application also relates to a preparation equipment and a preparation method of embolization microspheres, and the three systems of a feeding system (1), a microsphere generation module (2) and a solidification device (3) are combined to realize automatic, standardized and controllable production.

Description

Technical Field

[0001] This invention relates to the field of medical device manufacturing technology, specifically to a reaction apparatus and processing method for producing embolic microspheres, equipment for preparing embolic microspheres, and a method for preparing embolic microspheres. Background Technology

[0002] Polyvinyl alcohol embolization microspheres have become an important clinical treatment for tumors. The principle is to embolize blood vessels at the site of the disease by microspheres, cutting off the nutrient supply to tumor cells and causing them to shrink due to lack of nutrition. At the same time, the embolization microspheres can be loaded with chemotherapy drugs, which are continuously and slowly released into the blood vessels near the tumor, targeting the tumor and thus achieving a therapeutic effect.

[0003] Currently, among commercially available embolization materials, only three products can encapsulate chemotherapy drugs: DCBead® from Biocompatibles (UK), Hepasphere® from BioSphere (USA), and CalliSpheres® from Hengrui Group. These three embolization microsphere products have significantly improved upon the shortcomings of traditional embolization materials, achieving breakthrough therapeutic effects in the clinical treatment of liver cancer and other tumors.

[0004] Currently, the particle size of commercially available polyvinyl alcohol (PVA) embolization microspheres is not uniform, but rather falls within a certain range, such as 100-300 μm, 300-500 μm, and 500-700 μm. Research indicates that blood vessels of various sizes are distributed around tumors, with the vessels becoming finer (i.e., smaller than 100 μm) closer to the tumor center, resulting in better embolization. Therefore, smaller, more uniform microspheres allow them to penetrate and get closer to the tumor's blood vessels during clinical embolization. In terms of manufacturing processes, current microspheres are prepared using a "one-pot" method, followed by a sieving process to obtain microspheres within the target particle size range. This process suffers from low efficiency, complex quality control, high labor intensity, and high costs. Therefore, there is a need to develop novel PVA embolization microspheres with uniform particle size and their manufacturing process to improve production efficiency and achieve more precise treatment outcomes.

[0005] There are currently literature and patent reports on the preparation of microspheres with uniform particle size. For example, patent CN107418872A uses a focusing type and T-type droplet microfluidic chip to prepare bio-ink microspheres. It includes: a droplet generation module, including a first fluid inlet, a droplet microfluidic chip and an output port. The droplet microfluidic chip includes a channel system. The first fluid inlet and the output port are respectively connected to the channel system. The dispersed phase fluid entering the channel system from the first fluid inlet forms droplets and is output from the output port; a collection and manufacturing module, including a collection and manufacturing body, which includes multiple collection holes, each with a working surface. The working surfaces of each collection hole are isolated from each other. The collection holes are used to receive droplets onto the working surfaces and form microspheres based on the droplets on the working surfaces; a motion module, drivenly connected to the output port and / or the collection and manufacturing body, so that each droplet is correspondingly dropped onto the working surface of the collection hole; and a control module, coupled to the droplet generation module and the motion module respectively. This equipment is mainly used to prepare bioactive bio-ink microspheres. These microspheres are layered spherical structures arranged radially, with a particle size between 5 and 120 μm. The key is to control the number of cells contained in the collagen solution containing cells in the core fluid.

[0006] The core of the above technical solution lies in the structural design of a droplet generation module, including a microfluidic chip, for bio-ink, as well as the design of corresponding collection, manufacturing, motion, and control modules.

[0007] However, the aforementioned device cannot be directly applied to the preparation of polyvinyl alcohol embolized microspheres, and the particle size of 5-120 μm cannot meet the diameter requirements of polyvinyl alcohol embolized microspheres.

[0008] CN101376093A uses a coaxial microreactor assembled with PTFE capillary tubes and hollow fibers to prepare monodisperse polymer microspheres. This patent was published in 2009 and the technology is relatively outdated. It provided technical ideas for subsequent microreactors, but there is no good supporting process to prepare polyethylene embolization microspheres that meet the requirements of today's surgery.

[0009] CN109793916A describes a process for preparing polyvinyl alcohol embolization microspheres with uniform particle size using microchannel tubing. However, this application does not disclose the corresponding process equipment, and there are still shortcomings in its industrial application.

[0010] The above patents all employ microfluidic technology to control the shearing between the dispersed and continuous phases, thereby regulating the flow rates of the two phases and the droplet formation structure to prepare microspheres of different particle sizes and uniformity.

[0011] The aforementioned microfluidic technology solutions are still mainly in the research and development stage. They use a single tube or a single chip to prepare microspheres with uniform particle size, which is difficult to scale up. Currently, there is no microfluidic production process to prepare microspheres in large quantities, and there is a lack of directly related equipment that can stably, efficiently, and with high throughput prepare microspheres. At the same time, there are problems such as no clear adaptability to the materials used to prepare microspheres, reproducibility of chip processing, large errors in particle size uniformity, uncontrollable microsphere forming, and low efficiency. In particular, it is difficult to meet the batch and standardization requirements for preparing polyvinyl alcohol embolization microspheres for medical use.

[0012] In addition, the reaction apparatus in existing embolic microsphere preparation equipment still has the following problems: Most existing reaction devices utilize thermoplastic polymers and employ bonding technology for connection and assembly. However, the processing and bonding technology for thermoplastic polymer reaction devices faces significant challenges in terms of manufacturing efficiency, quality, precision, and method adaptability. These issues represent the primary bottleneck for the mass production of reaction devices. The technical difficulties lie in: simultaneously addressing connection and sealing issues during bonding; ensuring the overall mechanical strength of the reaction device materials; preventing tank collapse and deformation; and maintaining consistency in mass production. Therefore, there is an urgent need to develop a reaction device capable of mass production. Summary of the Invention

[0013] To address the problems in the background art, the present invention provides a reaction device, including a main structure layer and an encapsulation layer, wherein the main structure layer integrates a tank for liquid droplets, and the encapsulation layer is stacked on one side of the main structure layer; The melting temperature of the main structural layer is higher than that of the encapsulation layer, and the main structural layer and the encapsulation layer are connected by thermal bonding.

[0014] In some embodiments, the main structural layer and the encapsulation layer are made of the same material.

[0015] In some embodiments, the groove integrated within the main structure layer has a dispersed phase inlet, a continuous phase inlet, and an outlet; the groove is a flow focusing type groove, a coaxial type groove, a T-type groove, or a Y-type groove.

[0016] In some embodiments, the flow focusing type groove includes a main groove, a dispersing phase groove and two continuous phase grooves. The two continuous phase grooves are symmetrically arranged, and the dispersing phase groove is arranged between the two continuous phase grooves. One end of the two continuous phase grooves and the dispersing phase groove on the same side is connected to and communicates with one end of the main groove, and the other end of the main groove extends away from the dispersing phase groove and the continuous groove.

[0017] In some embodiments, the diameter ratio of the continuous phase channel, the dispersed phase channel, and the main channel is 1:0.2-1:1-1.5.

[0018] In some embodiments, a continuous phase inlet is provided at the end of the continuous phase tank away from the main tank, a dispersed phase inlet is provided at the end of the dispersed phase tank away from the main tank, and a discharge outlet is provided at the end of the main tank away from both the dispersed phase tank and the continuous phase tank.

[0019] In some embodiments, the continuous phase inlet, the dispersed phase inlet, and the outlet penetrate the main structural layer, and one end of the continuous phase inlet, the dispersed phase inlet, and the outlet is sealed by the encapsulation layer.

[0020] In some embodiments, the ends of the two continuous phase channels away from the main channel are connected and share a continuous phase inlet.

[0021] In some embodiments, the ratio of the diameter of the dispersed phase inlet to the diameter of the dispersed phase tank is 1:1-2; the ratio of the diameter of the continuous phase tank inlet to the diameter of the continuous phase tank is 1:1-2.

[0022] In some embodiments, the dispersed phase inlet is connected to the dispersed phase channel via a connecting groove, and the diameter of the connecting groove is larger than the diameter of the dispersed phase channel.

[0023] In some embodiments, the connection between the connecting groove and the dispersed phase groove is inclined, and the inclination angle of the inclined surface is 30~60°.

[0024] In some embodiments, the inner diameter of the discharge port is larger than the outer diameter. In some embodiments, the discharge port is a stepped or funnel-shaped hole. In some embodiments, a support layer is further included, which is stacked on the encapsulation layer facing away from the main structure layer. On one side.

[0025] In some embodiments, the material thickness ratio of the main structural layer, the encapsulation layer, and the support layer is 1:0.05-0.5:1-3.

[0026] In some embodiments, the support layer, the main structure layer, and the encapsulation layer are made of the same material.

[0027] In some embodiments, the main structural layer and the encapsulation layer are made of thermoplastic polymer materials.

[0028] In some embodiments, the main structural layer and the encapsulation layer are made of cyclic olefin polymers.

[0029] The present invention also provides a method for processing a reaction apparatus, for processing the reaction apparatus as described above, the method being as follows: S1. The main structural layer and the encapsulation layer are processed using the same material, and the degree of polymerization of the material is controlled so that the melting temperature of the encapsulation layer is lower than that of the main structural layer. S2. The processed main structure layer and encapsulation layer are connected by thermal bonding.

[0030] Preferably, step S2 further includes: the main structure layer and the encapsulation layer are connected by thermal bonding under vacuum conditions.

[0031] In some embodiments, step S2 further includes: the thermal bonding temperature is lower than the melting temperature of the main structural layer and higher than or equal to the melting temperature of the encapsulation layer.

[0032] In some embodiments, the thermal bonding temperature differs from the melting temperature of the main structural layer by 0.1-10%.

[0033] In some embodiments, step S2 further includes: the thermal bonding temperature range is 90-160°C.

[0034] In some embodiments, step S2 further includes: the thermal bonding time ranges from 3 to 30 minutes.

[0035] In some embodiments, step S2 further includes: the thermal bonding pressure range is 20-200 kg.

[0036] In some embodiments, step S3 is further included: connecting the support layer to the side of the encapsulation layer opposite to the main body layer by means of adhesive bonding.

[0037] In some embodiments, step S3 further includes: the adhesive pressure between the support layer and the encapsulation layer is in the range of 1-10 kg.

[0038] In some embodiments, step S3 further includes: the bonding time between the support layer and the encapsulation layer is in the range of 3-30 seconds.

[0039] The reaction apparatus provided by this invention uses the same material for both the main structural layer and the encapsulation layer. This improves the overall mechanical strength of the apparatus and provides theoretical support for the thermal bonding connection between the two layers, while also preventing the introduction of impurities. Furthermore, this invention limits the melting temperature of the main structural layer to be higher than that of the encapsulation layer. During the thermal bonding process, the connection function can be achieved as long as the thermal bonding temperature reaches the melting temperature of the encapsulation layer. At this point, the thermal bonding temperature can also be lower than the melting temperature of the main structural layer, thereby preventing the collapse and deformation of the formed groove due to the high thermal bonding temperature during the thermal bonding process. This helps ensure the consistency of mass production and is suitable for mass production.

[0040] The reaction device provided by the present invention has the advantages of being integrated, structurally stable, and high-strength, which significantly improves the stability of droplet formation. It also has the advantages of high manufacturing efficiency, good quality, and suitability for mass production. It is of great significance for the application of reaction devices in fields such as clinical diagnosis, drug analysis, environmental monitoring, and food development.

[0041] This invention provides an apparatus for preparing embolized microspheres, comprising a feeding system, a microsphere generation module, and a curing device; the feeding system is connected to the microsphere generation module, and the microsphere generation module is connected to the curing device; wherein the microsphere generation module includes at least one microreactor, and the microreactor employs the reaction device described above.

[0042] In some embodiments, the microsphere generation module includes a plurality of microreactors connected in parallel, each of which is connected to the feeding system and the curing device, and the plurality of microreactors are used to generate microspheres of the same or different diameters.

[0043] In some embodiments, the feeding system includes a continuous phase feeding system and a dispersed phase feeding system, which are respectively connected to the continuous phase inlet and the dispersed phase inlet of each of the microreactors.

[0044] In some embodiments, the continuous phase feeding system includes a continuous phase feed pump and a continuous phase storage tank connected together, the continuous phase storage tank being connected to the continuous phase inlet of each of the microreactors; The dispersed phase feeding system includes a dispersed phase feed pump and a dispersed phase storage tank connected together, and the dispersed phase storage tank is connected to the dispersed phase inlet of each of the microreactors.

[0045] In some embodiments, the continuous phase feeding system further includes a first pressure source device, wherein the first pressure source device, the continuous phase feed pump, and the continuous phase storage tank are connected in sequence. The dispersed phase feeding system also includes a second pressure source device, and the second pressure source device, the dispersed phase feed pump, and the dispersed phase storage tank are connected in sequence.

[0046] In some embodiments, the continuous phase feed pump and the dispersed phase feed pump are pumps equipped with flow and pressure control devices.

[0047] In some embodiments, the microreactor further includes a microfluidic chip; the microfluidic chip works in conjunction with a controller to control the flow rate of the reaction liquid entering the microreactor.

[0048] In some embodiments, the curing apparatus is an ultraviolet curing apparatus or a thermal curing apparatus, both of which include a curing container and a corresponding generating device.

[0049] This invention also provides a method for preparing embolic microspheres, wherein the preparation method is performed using the equipment described above, and the specific steps are as follows: (1) The dispersed phase is mainly water-soluble material. The components of the dispersed phase material are polyvinyl alcohol and its derivatives, water, crosslinking agent and dispersed phase material initiator. First, the initiator is dissolved in water, then the crosslinking agent is added in sequence, and finally polyvinyl alcohol and its derivatives are added. The mixture is stirred evenly and used as the dispersed phase for later use.

[0050] The polyvinyl alcohol and its derivatives are prepared by using polyvinyl alcohol as a base material and acylated crosslinkable amino / hydroxyl carboxylic acid derivatives / sulfonic acid derivatives as modifiers to obtain polymers containing crosslinkable small molecules with acrylic acid or its derivative structure.

[0051] The crosslinking agent in the dispersed phase material is an acrylate, specifically including: sodium acrylate, acrylamide ammonium acrylate, sodium 2-acrylamido-2-methylpropanesulfonate, etc. The initiators can be divided into peroxide initiators and photoinitiators. Peroxide initiators include potassium persulfate, ammonium persulfate, etc., while photoinitiators include benzoyl derivatives, acylphosphide oxides, etc.

[0052] The mass ratio of polyvinyl alcohol and its derivatives: water: crosslinking agent: aqueous phase material initiator is 10:1-100:1-10:0.01-0.6; (2) The mobile phase is mainly composed of oil-soluble materials, and its components are oil-phase initiator, surfactant, butyl acetate and other organic solvents. The oil-phase material initiator and surfactant are added to the ester solvent in sequence and stirred evenly to prepare the mobile phase.

[0053] The initiator in the phase material is a tertiary amine compound, including tetramethylethylenediamine, triethanolamine, N,N-dimethyl-p-toluidine, etc. The surfactant is an alkane or aromatic hydrocarbon compound, including sodium alkylbenzene sulfonate, cellulose acetate, and fatty acid sorbitan, etc. The initiator and surfactant in the oil phase materials each account for 0.1%-5% of the mass of butyl acetate.

[0054] (3) The dispersed phase and the mobile phase materials are transported by the material feeding system. According to their own fluid properties and feed rate, a suitable precision pump can be selected as the driving device to ensure that the materials are transported stably, continuously and in high throughput to the microsphere generation module.

[0055] The driving device is a precision pump, including a high-precision injection pump, a high-precision constant flow pump, and a precision pressure pump, and is also equipped with a computer control panel, sensor feedback and other devices.

[0056] The precision pump controls the material flow rate to be 0.1-500 μL / min for the dispersed phase and 100-50000 μL / min for the mobile phase. (4) The microsphere generation module mainly adopts chip-type, microtube-type and other microreactor devices. After the material is transported to the microreactor device, the structure, material and operating parameters of the microfluidic chip are adjusted so that the dispersed phase forms monodisperse microspheres under the action of the shear force of the mobile phase, thereby achieving the preparation of microspheres with uniform particle size. The size of the microspheres can be controlled from 20 to 1400 μm and the particle size uniformity is <10%.

[0057] The chip and microtube-type microreactor structure is a flow focusing type, coaxial type, T-type or Y-type structure, etc., and its inner diameter of the tube is 20-2000μm; The microreactor is preferably made of high polymer materials such as COP, COC, PTFE, and ABS, which have excellent properties such as corrosion resistance, superhydrophobicity, and high transparency. The microreactor preparation method adopts processes such as 3D printing, CNC, and injection molding, which has the advantages of mass production, high reproducibility, and low price, thus providing a guarantee for the high-throughput production process of microspheres with uniform particle size. (5) After the uniformly sized microspheres are generated, they are transported to the curing device for further internal cross-linking, completing the collection and post-processing of the microspheres. Both curing methods can rapidly cross-link polymer microspheres, improving product stability. At the same time, they provide more selectivity for the materials used to prepare the microspheres, effectively increasing the cross-linking methods and speed of the microspheres, and further increasing the simplicity and selectivity of the polyvinyl alcohol embolization microsphere production process.

[0058] The curing device can be selected from two modes: thermal curing and photocuring. Depending on the nature of the initiator in the polyvinyl alcohol material, if it is a chemical initiator, a thermal curing device is selected; if the initiator is a photoinitiator, a photocuring device is selected. The thermosetting device adopts a jacketed reaction bottle device and is kept warm by a circulating temperature control device. The curing temperature is 40-80℃ and the curing time is 1-6h. It can achieve the dual functions of enrichment and pre-curing. At the same time, the reaction time can be controlled by the discharge speed to achieve product uniformity. The photocuring device uses a coiled tube, which has advantages such as high transparency and high light absorption. The prepared microspheres flow continuously in the tube and are cured by real-time light irradiation with a high-intensity ultraviolet lamp with an irradiation wavelength of 200-500nm and an irradiation time of 2-1000s, so that the polymer microspheres are fully cured, achieving rapid, efficient and safe preparation of embolization microspheres with uniform particle size.

[0059] Furthermore, the present invention uses a PLC controller or a control cabinet in the prior art to control the equipment; the controller or control cabinet controls the flow electronic pump / feed pump in the feeding system, controls the possible mobile phase / dispersed phase pressure vessel, and controls the temperature and pressure in the microsphere generation module and curing device.

[0060] In the aforementioned control system, the microsphere generation module includes several parallel microreactors. The control system includes fault-tolerant settings, so that when a microreactor fails, the control system can automatically cut off the circuit of that microreactor without affecting other circuits or subsequent reaction processes.

[0061] The microreactor in the microsphere generation module selects materials and molding methods according to reaction requirements, and selects different pipe inner diameters. The flow rate is controlled by the chip to prepare microspheres with uniform particle size.

[0062] Furthermore, during the reaction process, the particle size of the polyvinyl alcohol embolization microspheres is controlled by controlling the inlet inner diameter of the microsphere generation module corresponding to the dispersed phase and the flow rate ratio of the dispersed phase to the mobile phase.

[0063] When the inner diameter of the dispersed phase pipe is 20±10μm and the inner diameter of the mobile phase pipe is 20±10μm, and the injection flow rate of the dispersed phase material is controlled at 0.1-2μL / min and the injection flow rate of the mobile phase material is controlled at 400±200μL / min, the particle size of the prepared polyvinyl alcohol embolization microspheres is 20±10μm, and a more optimal scheme is 2±5μm.

[0064] When the inner diameter of the dispersed phase pipe is 60±10μm and the inner diameter of the mobile phase pipe is 90±50μm, and the injection flow rate of the dispersed phase material is controlled at 2±1μL / min and the injection flow rate of the mobile phase material is controlled at 200±100μL / min, the particle size of the prepared polyvinyl alcohol embolization microspheres is 40±20μm, and a more optimal scheme is 40±10μm.

[0065] When the inner diameter of the dispersed phase pipe is 100±20μm and the inner diameter of the mobile phase pipe is 300±150μm, and the injection flow rate of the dispersed phase material is controlled at 5±2μL / min and the injection flow rate of the mobile phase material is controlled at 800±300μL / min, the particle size of the prepared polyvinyl alcohol embolization microspheres is 100±25μm, and a more optimal scheme is 100±10μm.

[0066] When the inner diameter of the dispersed phase pipe is 100±20μm and the inner diameter of the mobile phase pipe is 300±150μm, and the injection flow rate of the dispersed phase material is controlled at 5±2μL / min and the injection flow rate of the mobile phase material is controlled at 500±200μL / min, the particle size of the prepared polyvinyl alcohol embolization microspheres is 250±50μm, and a more optimal scheme is 250±20μm.

[0067] When the inner diameter of the dispersed phase pipe is 250±130μm and the inner diameter of the mobile phase pipe is 500±200μm, and the injection flow rate of the dispersed phase material is controlled at 20±5μL / min and the injection flow rate of the mobile phase material is controlled at 2000±500μL / min, the particle size of the prepared polyvinyl alcohol embolization microspheres is 500±50μm, and a more optimal scheme is 500±20μm.

[0068] When the inner diameter of the dispersed phase pipe is 800±300μm and the inner diameter of the mobile phase pipe is 1000±500μm, and the injection flow rate of the dispersed phase material is controlled at 50±20μL / min and the injection flow rate of the mobile phase material is controlled at 800±200μL / min, the particle size of the prepared polyvinyl alcohol embolization microspheres is 800±80μm, and a more optimal scheme is 800±50μm.

[0069] When the inner diameter of the dispersed phase pipe is 800±400μm and the inner diameter of the mobile phase pipe is 2000±1000μm; the injection flow rate of the dispersed phase material is controlled at 50±20μL / min and the injection flow rate of the mobile phase material is controlled at 5000±2500μL / min; the particle size of the prepared polyvinyl alcohol embolization microspheres is 1200±100μm, and a more preferred scheme is 1200±50μm.

[0070] When the inner diameter of the dispersed phase pipe is 100±20μm and the inner diameter of the mobile phase pipe is 100±50μm; the injection flow rate of the dispersed phase material is controlled at 5±2μL / min and the injection flow rate of the mobile phase material is controlled at 500±300μL / min; the particle size of the prepared polyvinyl alcohol embolization microspheres is 100±25μm, and a more preferred scheme is 100±10μm.

[0071] When the inner diameter of the dispersed phase pipe is 80±10μm and the inner diameter of the mobile phase pipe is 100±20μm; the injection flow rate of the dispersed phase material is controlled at 5±1μL / min and the injection flow rate of the mobile phase material is controlled at 300±100μL / min; the particle size of the prepared polyvinyl alcohol embolization microspheres is 80±25μm.

[0072] When the inner diameter of the mobile phase pipe is 1500±500μm and the inner diameter of the dispersed phase pipe is 500±200μm; the injection flow rate of the dispersed phase material is controlled at 10-500μL / min and the injection flow rate of the dispersed phase material is controlled at 1000-50000μL / min; the particle size of the prepared polyvinyl alcohol embolization microspheres is 500-1400μm.

[0073] The embolization microsphere production process provided by this invention mainly includes three major systems: a material feeding system, a microsphere generation module, and a curing device. It also covers scale-up process equipment for stable, efficient, and high-throughput microsphere preparation.

[0074] The material feeding system in this invention is divided into dispersed phase material feeding and mobile phase material feeding. According to their respective chemical and fluid properties, appropriate precision pumps are selected as driving devices to be used in combination for two-phase materials, which can meet the sampling requirements of polymer materials, water-soluble materials and organic phase materials with different properties. The microsphere generation module in this invention uses microreactor devices such as chip type and microtube type. Its structure can be focused type, T type, coaxial type, etc. By adjusting the structure and operating parameters of the microfluidic chip, the dispersed phase can form an oil-in-water structure or a water-in-oil structure under the action of mutual shear force between the mobile phase, so as to achieve precise control of microsphere size. Microspheres with uniform particle size are prepared by cross-linking and curing.

[0075] This invention provides two curing devices: thermosetting and photosetting. Both curing methods have the advantages of fast response time and high degree of cross-linking, which effectively improve product stability and provide more choices for the production process of microspheres with uniform particle size.

[0076] The beneficial effects of this invention are as follows: This invention uses microchannels and a unique water-in-oil structure to induce cross-linking polymerization of the polymer molecules contained within the liquid droplets on the surface of the droplets, ultimately forming tightly cross-linked, regularly shaped spherical microspheres. This invention represents a complete process for preparing polyvinyl alcohol embolized microspheres with uniform particle size, rather than just a single component such as microchannels. The effect achieved is not merely the formation of liquid droplets, but rather the cross-linking polymerization within the channels to form microspheres with uniform particle size.

[0077] This invention provides a continuous and automated method for preparing polyvinyl alcohol embolization microspheres with controllable size and uniform particle size, encompassing a systematic equipment and corresponding production process for stable and efficient microsphere preparation. Attached Figure Description

[0078] The above and other features and advantages of the present invention will become clearer from the following detailed description, taken in conjunction with the accompanying drawings, wherein: Figure 1 This is a schematic flowchart of the processing method for the reaction apparatus provided in Example 2; Figure 2 This is a schematic diagram of the equipment for preparing embolic microspheres provided in Example 3; Figure 3 This is a schematic diagram of the equipment for preparing embolic microspheres provided in Example 4; Figure 4 A schematic diagram of 40±20μm polyvinyl alcohol embolization microspheres; Figure 5 A schematic diagram of 100±25μm polyvinyl alcohol embolization microspheres; Figure 6 A schematic diagram of 250±50μm polyvinyl alcohol embolization microspheres; Figure 7 A schematic diagram of 500±50μm polyvinyl alcohol embolization microspheres; Figure 8 A schematic diagram of 800±80μm polyvinyl alcohol embolization microspheres; Figure 9 A schematic diagram of 1200±100μm polyvinyl alcohol embolization microspheres; Figure 10 A schematic diagram of 100±25μm polyvinyl alcohol embolized microspheres. Detailed Implementation

[0079] Referring to the accompanying drawings illustrating embodiments of the invention, the invention will be described in more detail below. However, the invention can be implemented in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are presented to achieve a full and complete disclosure and to enable those skilled in the art to fully understand the scope of the invention. In these drawings, the dimensions and relative dimensions of layers and regions may be enlarged for clarity.

[0080] It should be noted that all directional indications (such as up, down, left, right, front, back, etc.) in the embodiments of the present invention are only used to explain the relative positional relationship and movement of each component in a certain specific posture (as shown in the figure). If the specific posture changes, the directional indication will also change accordingly.

[0081] Example 1 The present invention provides a reaction device, including a main structure layer and an encapsulation layer. The main structure layer has integrated grooves, and the encapsulation layer is stacked on one side of the main structure layer. The melting temperature of the main structure layer is higher than that of the encapsulation layer, and the main structure layer and the encapsulation layer are connected by thermal bonding.

[0082] This invention further specifies that the melting temperature of the main structural layer is higher than that of the encapsulation layer. During the thermal bonding process, the connection function can be achieved as long as the thermal bonding temperature reaches the melting temperature of the encapsulation layer. At this point, the thermal bonding temperature can also be lower than the melting temperature of the main structural layer, thereby preventing the collapse and deformation of the formed grooves due to high thermal bonding temperatures during the thermal bonding process. This helps ensure consistency in mass production and is suitable for mass production. In this embodiment, the main structural layer and the encapsulation layer are made of the same material. Here, the same material refers to a thermoplastic polymer material prepared by polymerization of the same type of monomer. By controlling the monomer ratio and parameters, polymer materials with different molecular weights or degrees of polymerization can be prepared, belonging to the same material but with different melting temperatures.

[0083] The reaction apparatus provided in this embodiment uses the same material for both the main structural layer and the encapsulation layer. This not only improves the overall mechanical strength of the reaction apparatus but also provides theoretical support for the thermal bonding connection between the two layers and avoids the introduction of impurities.

[0084] The reaction device provided by the present invention has the advantages of being integrated, structurally stable, and high-strength, which significantly improves the stability of droplet formation. It also has the advantages of high manufacturing efficiency, good quality, and suitability for mass production. It is of great significance for the application of reaction devices in fields such as clinical diagnosis, drug analysis, environmental monitoring, and food development.

[0085] In this embodiment, the integrated troughs within the main structure layer include a dispersed phase trough and a continuous phase trough. The continuous phase trough and the dispersed phase trough are connected to the same end of the main trough. The continuous phase trough has a continuous phase inlet, the dispersed phase trough has a dispersed phase inlet, and the main trough has a discharge outlet. The trough can be a flow focusing type trough, a coaxial type trough, a T-type trough, or a Y-type trough. There are no restrictions here, and it can be adjusted according to specific needs.

[0086] This embodiment takes the integration of a flow-focusing groove within the main structural layer as an example for further explanation. Specifically, the flow-focusing groove includes a main groove, a dispersed phase groove, and two continuous phase grooves. The continuous phase grooves are symmetrically arranged, and the dispersed phase groove is located between the continuous phase grooves. One end of each of the continuous phase grooves, the continuous phase groove, and the dispersed phase groove is connected to and communicates with one end of the main groove on the same side, and the other end of the main groove extends away from the continuous phase grooves, the continuous phase grooves, and the dispersed phase groove.

[0087] Furthermore, a continuous phase inlet is provided at the end of each of the two continuous phase tanks furthest from the main tank, and a dispersed phase inlet is provided at the end of the dispersed phase tank furthest from the main tank. An outlet is provided at the end of the main tank furthest from both the continuous and dispersed phase tanks. Liquid enters the continuous and dispersed phase tanks respectively through the continuous and dispersed phase inlets and, at their junction with the main tank, is stably formed into droplets under shear force, which are then output through the outlet of the main tank. The design of the continuous phase inlet, dispersed phase inlet, and outlet enables the introduction and removal of fluid within the reaction apparatus, fulfilling functions such as fluid sampling and tank cleaning.

[0088] Furthermore, the ends of the two continuous phase tanks furthest from the main tank are connected and share a single continuous phase inlet. This design increases the symmetry of the two continuous phase tanks, making the fluid distribution more uniform and improving the stability of the microspheres generated by the flow focusing reactor. On the other hand, it optimizes the structure, reduces the number of inlets, improves the overall structural rationality of the device, and reduces the use of required pipelines and adapters. Of course, in other embodiments, the ends of the two continuous phase tanks furthest from the main tank may not be connected, and each end may be provided with an independent continuous phase inlet. Adjustments can be made according to specific needs, and no restrictions are imposed here.

[0089] In this embodiment, the ratio of the diameter of the dispersed phase inlet to the diameter of the dispersed phase tank is 1:1-2, and the ratio of the diameter of the continuous phase inlet to the diameter of the continuous phase tank is 1:1-2. This embodiment ensures that the material completely enters the tank and there is no dead volume of liquid by limiting the diameter of the inlet to be smaller than the diameter of the tank.

[0090] Furthermore, the continuous phase inlet, dispersed phase inlet, and outlet penetrate the main structural layer, and one end of the continuous phase inlet, dispersed phase inlet, and outlet facing the encapsulation layer is sealed by the encapsulation layer, while the other end enables material inlet and outlet.

[0091] In this embodiment, the diameter ratio of the continuous phase tank, the dispersed phase tank, and the main tank is 1:(0.2-1):(1-1.5); for example, the diameter of the continuous phase tank is 50-1200 μm, the diameter of the dispersed phase tank is 50-1000 μm, and the diameter of the main tank is 50-1500 μm. This embodiment uses the above-mentioned size limitation to facilitate the preparation of a wider range of droplets, while better conforming to the fluid design ratio, possessing maximum shear force, and being able to shear the corresponding range of droplets with the least amount of fluid, while controlling a wider range of ratios; the specific ratio values ​​and their specific values ​​can be selected according to specific needs, and are not limited here.

[0092] In this embodiment, the dispersed phase inlet is connected to the dispersed phase tank via a connecting groove, and the diameter of the connecting groove is larger than the diameter of the dispersed phase tank. The larger diameter of the connecting groove reduces the inertial impact force of the fluid, providing a buffering effect and allowing the fluid to enter the dispersed phase tank smoothly, thereby improving the stability and continuity of droplet formation. Of course, the connecting groove can be omitted in other embodiments, and adjustments can be made according to specific needs; no restrictions are placed here.

[0093] Furthermore, the connection between the connecting groove and the dispersion tank is an inclined plane, and the inclination angle A of the inclined plane is 30-60°. The setting of the inclined plane serves as a buffer for the fluid, enabling it to enter the dispersion tank quickly, and also reduces the existence of dead volume, allowing the fluid to quickly replace the other side at a certain angle. The specific value of the inclination angle can be adjusted according to specific needs and is not limited here.

[0094] In this embodiment, the outer diameter of the discharge port is larger than the inner diameter. This design helps to stabilize the release of fluid pressure and increases the mechanical strength of the reaction device. Specifically, this can be achieved by designing the discharge port as a stepped or funnel-shaped orifice, etc., without limitation.

[0095] Furthermore, the ratio of the minimum aperture of the discharge port to the diameter of the main channel is 1-1.5:1. When the fluid movement direction changes, the droplets will collide, merge, or break up. This ratio allows the droplets to change with the fluid in a gradient, the channel to be enlarged step by step, and the droplets to shorten the distance slowly in the fluid movement without colliding or breaking up, thereby effectively improving the stability of the entire system.

[0096] In this embodiment, the reaction device further includes a support layer, which is stacked on the side of the encapsulation layer facing away from the main structure layer. The thickness of the support layer is greater than the thickness of the encapsulation layer and the main structure layer to ensure its mechanical strength. Of course, in other embodiments, the thickness of the support layer may be less than or equal to the thickness of the encapsulation layer and the main structure layer; this is not limited here and can be adjusted according to specific circumstances. The support layer is mainly used for positioning and clamping the reaction device with the fixture when it is subsequently held by the fixture. Of course, in other embodiments, the support layer may be omitted or the support layer and the encapsulation layer may be combined into one; this can be adjusted according to specific needs and is not limited here.

[0097] Preferably, the support layer, main structural layer, and encapsulation layer are made of the same material, which helps to increase the overall mechanical strength. Of course, in other embodiments, the support layer may be made of different materials than the main structural layer and encapsulation layer; this is not a limitation. The support layer is connected to the main structural layer by adhesive bonding. The type of adhesive can be double-sided tape, photosensitive adhesive, solvent adhesive, etc., and there is no limitation here. It can be selected according to specific needs. Adhesive bonding has the advantages of simple bonding method, low cost and no need for heating. Of course, other bonding methods can be selected as needed in other embodiments, and there is no limitation here.

[0098] In this embodiment, the material thickness ratio of the main structural layer, encapsulation layer, and support layer is 1:(0.05-0.5):(1-3). This ratio limits the overall mechanical strength, providing strong support for the reaction device during installation and preventing breakage. Furthermore, the encapsulation layer is thinner than the main structural layer, ensuring rapid heat transfer during the bonding process, quickly reaching thermal equilibrium, and achieving higher bonding strength. Additionally, the flatness of the main structural layer, encapsulation layer, and support layer is less than 0.01 mm to ensure a tight and secure connection between them.

[0099] In this embodiment, the main structural layer and the encapsulation layer are made of thermoplastic polymer materials. The same type of thermoplastic polymer materials contain different degrees of polymerization, which gives them different melting temperatures. The thermoplastic polymer materials include polymers such as polymethyl methacrylate, polycarbonate, and cyclic olefin polymers. The surface of the reaction device can be treated with hydrophobic or hydrophilic coatings to meet the production needs of different types of microspheres.

[0100] The preferred main structural layer and encapsulation layer 1 are made of cyclic olefin polymers. This material has a wide glass transition temperature (i.e., melting temperature) ranging from 90°C to 160°C, which allows for the selection of different degrees of polymerization of thermoplastic polymer materials for the main structural layer and encapsulation layer, further distinguishing their melting temperatures.

[0101] Example 2 This invention provides a processing method for a reaction apparatus, such as... Figure 1 As shown, this is the reaction apparatus used to process the reaction described in Example 1.

[0102] The specific processing method of the reaction device is as follows: S1, using the same material, the main structural layer and the encapsulation layer described in Example 1 are processed separately, and the material is controlled... The degree of polymerization results in the melting temperature of the encapsulation layer being lower than that of the main structural layer. S2. The processed main structural layer and encapsulation layer are connected by thermal bonding. Connecting the main structural layer and encapsulation layer by thermal bonding under vacuum conditions helps to avoid the introduction of impurities.

[0103] The thermal bonding temperature is lower than the melting temperature of the main structural layer and higher than or equal to the melting temperature of the encapsulation layer, so as to ensure that the encapsulation layer melts to achieve the encapsulation effect while avoiding the collapse or deformation of the groove in the main structural layer.

[0104] The thermal bonding temperature differs from the melting temperature of the main structural layer by 0.1-10%. The thermal bonding temperature melts the encapsulation layer and then bonds it to the main structural layer. By controlling the melting temperature difference of the main structural layer, the compatibility temperature range with the encapsulation layer is increased, enabling the encapsulation layer to bond quickly to the main structural layer. If the temperature difference is too large, weak adhesion and low bonding strength may occur. Therefore, the thermal bonding temperature difference between the thermal bonding temperature and the melting temperature of the main structural layer is controlled within the range of 0.1-10%.

[0105] The heat bonding temperature range is 90-160℃, the heat bonding time range is 3-30 minutes, and the heat bonding pressure range is 20-200 kg. The range of bonding parameters is determined by factors such as material properties and thickness ratio. The bonding pressure, time, and temperature play a decisive role; excessive pressure can easily lead to groove collapse, deformation, energy waste, and low efficiency, while insufficient pressure can result in low bonding strength, poor adhesion, and a high number of defective products. The temperature, time, and pressure of the heat bonding process are all crucial factors in the overall process. The pressure can be selected according to specific needs. For example, the bonding pressure is 60 kg, the temperature is 130℃, and the bonding time is 10 min. There are no restrictions here.

[0106] In this embodiment, when a support layer is provided on the side of the encapsulation layer facing away from the main structure layer, the support layer and the encapsulation layer are connected by adhesive bonding.

[0107] The bonding pressure between the support layer and the encapsulation layer ranges from 1 to 10 kg, and the bonding time ranges from 3 to 30 seconds. The bonding time and pressure during processing can be selected according to specific needs; for example, a bonding pressure range of 3 kg and a bonding time of 5 seconds are not limited here.

[0108] Example 3 Reference Figure 2 This invention provides an apparatus for preparing embolic microspheres, comprising a feeding system 1, a microsphere generation module 2, and a curing device 3. The feeding system 1 is connected to the microsphere generation module 2, and the microsphere generation module 2 is connected to the curing device 3. The feeding system 1 supplies material to the microsphere generation module 2, where the material reacts to generate droplets. After processing by the curing device 3, embolic microspheres with uniform particle size are obtained. The apparatus for preparing embolic microspheres provided by this invention can be used to prepare polyvinyl alcohol embolic microspheres, and can also be used to prepare other types of microspheres, without limitation. The apparatus for preparing embolic microspheres provided by this invention mainly comprises three major systems: a material feeding system, a microsphere generation module, and a curing device, and also covers a scaled-up process for stable, efficient, and high-throughput microsphere preparation.

[0109] In this embodiment, the microsphere generation module 2 includes at least one microreactor, which adopts the reaction device described in Embodiment 1. Furthermore, the microsphere generation module 2 includes multiple microreactors connected in parallel, each connected to the feeding system 1 and the curing device 3 respectively; the parallel operation of multiple microreactors enables mass production, while also providing advantages such as independence and anti-interference capabilities.

[0110] The number of microreactors can be one or more. Figure 2 The eight shown can also be other numbers; there are no restrictions here, and adjustments can be made according to specific circumstances.

[0111] Multiple microreactors can be used to generate microspheres of the same or different diameters. The inner diameter of the channel used to generate droplets in the microreactor is 20-2000 μm. Specifically, by controlling the diameter of the tank used to generate droplets in the microreactor and the operating parameters of the liquid inside, it is possible to prepare microspheres of different sizes with uniform particle size. The size of the microspheres can be controlled from 20-1400 μm, and the particle size uniformity is <10%. This is not a limitation and can be adjusted according to specific needs.

[0112] In this embodiment, the microreactor also includes a microfluidic chip, which works with a controller to control the flow rate of the reaction liquid entering the microreactor, thereby controlling the particle size of the microspheres by controlling the flow rate.

[0113] The microsphere generation module in this invention can adopt microreactors such as chip type and microtube type. Its structure can be a focusing type, T-type, coaxial type, etc. By adjusting the structure and operating parameters of the microfluidic chip, the dispersed phase material can form an oil-in-water structure or a water-in-oil structure under the action of mutual shear force between the continuous phase material, so as to achieve precise control of microsphere size and prepare microspheres with uniform particle size through cross-linking and curing.

[0114] In this embodiment, the feeding system includes a continuous phase feeding system 11 for feeding oil-phase materials and a dispersed phase feeding system 12 for feeding aqueous-phase materials. The continuous phase feeding system 11 is connected to the continuous phase inlet of each microreactor, and the dispersed phase feeding system 12 is connected to the dispersed phase inlet of each microreactor. The material feeding system in this invention is divided into dispersed phase material feeding and mobile phase material feeding. Appropriate precision pumps are selected as driving devices based on their respective chemical and fluid properties, and the system is used in combination for two-phase materials to meet the feeding requirements of polymeric materials, water-soluble materials, and organic phase materials with different properties. Furthermore, the continuous phase feeding system 11 includes a first pressure source device 111, a continuous phase feed pump 112, and a continuous phase storage tank 113 connected in sequence. The continuous phase storage tank 113 is connected to the continuous phase inlet of each microreactor. The continuous phase storage tank 113 is used to store oil phase materials. The first pressure source device 111 is used to provide pressure to the continuous phase feed pump 112. The continuous phase feed pump 112 is used to push the material in the continuous phase storage tank 113 through the pipeline to the continuous phase inlet of each microreactor, thereby realizing the feeding of oil phase materials.

[0115] The dispersed phase feeding system 12 includes a second pressure source device 121, a dispersed phase feed pump 122, and a dispersed phase storage tank 123 connected in sequence. The dispersed phase storage tank 123 is connected to the dispersed phase inlet of each microreactor. The dispersed phase storage tank 123 is used to store aqueous phase materials. The second pressure source device 121 is used to provide pressure to the dispersed phase feed pump 122. The dispersed phase feed pump 122 is used to push the material in the dispersed phase storage tank 123 through the pipeline to the dispersed phase inlet of each microreactor, thereby realizing the feeding of aqueous phase materials.

[0116] In this embodiment, both the continuous phase feed pump 112 and the dispersed phase feed pump 122 are pressure pumps that need to be used in conjunction with a pressure source device to pressurize the materials stored in the continuous phase storage tank 113 and the dispersed phase storage tank 123 into the microreactor.

[0117] Furthermore, the first pressure source device 111 and the second pressure source device 121 can be nitrogen cylinders, gas compressors, or other devices. There are no restrictions here, and they can be selected according to specific needs.

[0118] Furthermore, the continuous phase feed pump 112 and the dispersed phase feed pump 122 preferably adopt a pump structure with pressure and flow control devices, so as to control the flow rate and pressure of the feed. In this embodiment, the dispersed phase flow rate is preferably controlled to be 0.1-500 μL / min and the continuous phase flow rate is 100-50000 μL / min, so as to ensure that the material is stably, continuously and in high throughput delivered to each microreactor.

[0119] The continuous phase feed pump 112 and dispersed phase feed pump 122 can be specifically selected from precision pressure pumps, high-precision syringe pumps, and high-precision constant flow pumps. Precision pressure pumps have a flow range of 0-4 bar and an accuracy of 0.01%-0.2%, and can be purchased from domestic and international suppliers, such as Suzhou Wenhao and Dolomite (USA). High-precision syringe pumps have multiple operating modes to adapt to the needs of various applications in different fields. They possess ultra-high control accuracy and a wide linear velocity range, with a flow rate range selectable from 0.001 μL / h to 50 mL / min. They can also be purchased from domestic and international suppliers, such as Baoding Lange Co., Ltd. and Shanghai Spectrum Analysis and Testing Technology Co., Ltd. High-precision constant flow pumps have high pressure and head, and the transported material does not come into contact with the outside environment. Their accuracy is 0.01-1000 mL / min, and they can also be purchased from domestic and international suppliers, such as Baoding Lange Co., Ltd. and Shanghai Precision Instruments Co., Ltd.

[0120] In this embodiment, the outlet of each microreactor is connected to the curing device 3. The droplets generated by each microreactor are transported to the curing device 3 for curing, thereby obtaining embolic microspheres. The curing device 3 is either an ultraviolet curing device or a thermosetting device. The invention provides two curing devices: thermosetting and photosetting. Both curing methods offer advantages such as fast response time and high cross-linking degree, effectively improving product stability and providing more options for the production process of microspheres with uniform particle size.

[0121] To further illustrate, taking the preparation of polyvinyl alcohol embolized microspheres as an example, if the initiator in the polyvinyl alcohol material is a chemical initiator, then it is a thermosetting device. The thermosetting device consists of three parts: a double-layer reaction bottle, a mechanical stirrer, and a constant temperature water bath. The reaction process is carried out by mechanically stirring the fluid evenly, and the constant temperature water bath provides energy conduction to achieve the thermosetting reaction conditions, ultimately realizing the enrichment and cross-linking reaction of the product.

[0122] If the initiator in the polyvinyl alcohol (PVA) material is a photoinitiator, then a photocuring device is used. This device employs an ultraviolet (UV) light source with an intensity of 10-1000W for irradiation. The generated microspheres undergo UV-initiated polymerization in the pipeline, achieving cross-linking polymerization of the product. Both curing methods can rapidly cross-link polymer microspheres, improving product stability. Simultaneously, they effectively increase the molding methods and speed of microspheres, and simplify the production process of PVA embolization microspheres.

[0123] In this embodiment, as Figure 2 As shown, both thermal curing and photocuring are used simultaneously for curing; however, in other embodiments, only one curing method may be used, such as only thermal curing (see...). Figure 3 (as shown), or simply use light curing, depending on the actual needs, which will not be elaborated here.

[0124] Furthermore, the assembly of each module of the embolization microsphere preparation equipment is based on the connection of accessories such as plastic tubing, metal tubing, threaded sleeves, gaskets, and adapters. This allows the threaded sleeves and metal tubing to achieve a highly tight interface with the chip and microtube. At the same time, the liquid is transported by plastic tubing, such as PTFE tubing with an inner diameter of 100-3200um or PEEK tubing with an inner diameter of 100-3200um. This tubing has advantages such as good flexibility, smooth surface, and non-toxicity, which ensures the connection of the entire process.

[0125] The equipment for preparing embolic microspheres provided by this invention has the following advantages: This invention employs microchannels and utilizes a unique water-in-oil structure to initiate cross-linking polymerization of the polymer molecules contained within the liquid droplets on the surface of the droplets, ultimately forming tightly cross-linked, regularly shaped spherical microspheres. This invention represents a complete set of equipment for preparing embolic microspheres, not just a single component such as microchannels. The effect achieved is not merely the formation of liquid droplets, but rather the cross-linking polymerization within the channels to form microspheres with uniform particle size. This invention provides a continuous and automated method for preparing polyvinyl alcohol embolic microspheres with controllable size and uniform particle size, encompassing a systematic equipment and corresponding production process for stable and efficient microsphere preparation.

[0126] Example 4 This embodiment is an adjustment based on embodiment 3. Specifically, as follows: Figure 3 As shown in the figure, in this embodiment, the continuous phase feeding system 11 includes a continuous phase feed pump 112 and a continuous phase storage tank 113 that are directly connected, and the dispersed phase feeding system 12 includes a dispersed phase feed pump 122 and a dispersed phase storage tank 123 that are directly connected.

[0127] In this embodiment, the continuous phase feed pump 112 and the dispersed phase feed pump 122 adopt a non-pressure pump structure, such as a suction type pump structure. They can be directly installed on the pipelines connecting the continuous phase storage tank 113 and the dispersed phase storage tank 123 to the microreactor. Figure 3 As shown in the image.

[0128] In this embodiment, the other structures of the equipment for preparing embolized microspheres can be referred to the description in Example 3, and are not limited here.

[0129] Example 5 This invention provides a method for preparing embolization microspheres, specifically using the preparation of polyvinyl alcohol embolization microspheres as an example.

[0130] This embodiment uses a precision pressure pump to transport materials. The microreactor is a focusing chip with an inner diameter of 20±10μm for both the dispersed phase and the mobile phase. The specific steps are as follows: (1) Preparation of dispersed phase material: Weigh 0.4g of potassium persulfate and add 100g of water, stir magnetically to dissolve, slowly add 10g of sodium acrylate, stir evenly, then add 10g of polyvinyl alcohol derivative, stir evenly, and use as dispersed phase material for later use.

[0131] (2) Preparation of mobile phase material: Add 10g of fatty acid sorbitan surfactant to 1000mL of ethyl acetate solution, then add 10mL of triethanolamine, stir evenly, and use it as mobile phase material for later use.

[0132] (3) Device Assembly: Add the prepared dispersed and mobile phase materials to the storage bottle, connect the pressure control module, gas source, computer control panel, pipelines, etc., and first start the initialization device to verify whether there is gas leakage in the storage bottle and confirm its excellent airtightness. Connect multiple microreactors (e.g., Figure 2 The eight reactors are arranged in parallel, and their pipelines are connected to the outlet pipelines via adapters. The outlet pipeline of the microreactor is connected to the curing device, which adopts a thermal curing method and is connected to a constant temperature heating and circulation device.

[0133] (4) Preparation of uniformly sized microspheres: The dispersed phase pressure switch is activated to deliver the dispersed phase material to the chip pipeline. At the same time, the mobile phase pressure switch is activated to rapidly deliver the mobile phase material to the microreactor pipeline. By adjusting the pressure and flow rate relationship, the injection flow rate of the dispersed phase material is controlled at 0.1-2 μL / min, and the injection flow rate of the mobile phase material is controlled at 400±200 μL / min. At the chip focusing crossroads, the dispersed phase material is sheared into small droplets by the oil mobile phase material, forming a water-in-oil structure. The material is then delivered to the curing device and stirred and cured at 80℃ for 2 hours. The uniformly sized microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone, respectively, vacuum dried, and then swollen to obtain polyethylene embolization microspheres with uniform particle size.

[0134] (5) Particle size analysis: The microspheres have a uniform particle size distribution and a high yield, which can be used for mass production. The prepared polyvinyl alcohol embolization microspheres have a particle size of 20±10μm, and the optimal solution is 20±5μm, which meets the requirement of uniform particle size.

[0135] Example 6 This invention provides a method for preparing embolization microspheres, specifically using the preparation of polyvinyl alcohol embolization microspheres as an example.

[0136] This embodiment uses a precision pressure pump to transport materials. The microreactor is a focusing chip with a dispersed phase channel inner diameter of 60±10μm and a mobile phase channel inner diameter of 90±50μm. The specific steps are as follows: (1) Preparation of dispersed phase material: Weigh 0.4g of potassium persulfate and add 100g of water, stir magnetically to dissolve, slowly add 10g of sodium acrylate, stir evenly, then add 10g of polyvinyl alcohol derivative, stir evenly, and use as dispersed phase material for later use.

[0137] (2) Preparation of mobile phase material: Add 10g of fatty acid sorbitan surfactant to 1000mL of butyl acetate solution, then add 10mL of triethanolamine, stir evenly, and use it as mobile phase material for later use.

[0138] (3) Device assembly: Add the prepared dispersed phase and mobile phase materials to the storage bottle, connect the pressure control module, gas source, computer control panel, pipelines, etc., and first start the initialization device to verify whether there is gas leakage in the storage bottle and confirm its excellent airtightness. Arrange multiple microreactors in parallel in sequence, and connect their pipelines to the outlet pipelines through adapters. The outlet pipelines of the microreactors are connected to the curing device, which adopts the thermosetting method and is connected to the constant temperature heating circulation device.

[0139] (4) Preparation of uniformly sized microspheres: The dispersed phase pressure switch is activated to deliver the dispersed phase material to the chip pipeline. At the same time, the mobile phase pressure switch is activated to rapidly deliver the mobile phase material to the chip pipeline. By adjusting the pressure and flow rate relationship, the injection flow rate of the dispersed phase material is controlled at 2±1 μL / min, and the injection flow rate of the mobile phase material is controlled at 200±100 μL / min. At the chip focusing crossroads, the dispersed phase material is sheared into small droplets by the oil mobile phase material, forming a water-in-oil structure. It is then delivered to the curing device and stirred and cured at 80℃ for 2 hours. The uniformly sized microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone, respectively, vacuum dried, and then swollen to obtain polyethylene embolization microspheres with uniform particle size.

[0140] (5) Particle size analysis: such as Figure 4 As shown, the microspheres exhibit uniform particle size distribution and high yield, enabling mass production. The prepared polyvinyl alcohol embolization microspheres have a particle size of 40±20μm, with a more optimal size of 40±10μm, meeting the requirement of uniform particle size.

[0141] Example 7 This invention provides a method for preparing embolization microspheres, specifically using the preparation of polyvinyl alcohol embolization microspheres as an example.

[0142] This embodiment uses a precision pressure pump and an injection pump to deliver materials. The microreactor is a focusing chip with a dispersed phase channel inner diameter of 100±20μm and a mobile phase channel inner diameter of 300±150μm. By controlling the flow rates of the dispersed and mobile phases, microspheres with uniform particle size are prepared. The specific steps are as follows: (1) Preparation of dispersed phase material: Weigh 0.4g of ammonium persulfate and add 60g of water, stir magnetically to dissolve, slowly add 8g of sodium 2-acrylamido-2-methylpropanesulfonate, stir evenly, then add 10g of polyvinyl alcohol derivative, stir evenly, and use as dispersed phase material for later use.

[0143] (2) Preparation of mobile phase material: Add 10g of fatty acid sorbitan surfactant to 1000mL of butyl acetate solution, then add 8mL of tetramethylethylenediamine, stir evenly, and use it as mobile phase material for later use.

[0144] (3) Assembly of the device: Turn on the injection pump and automatically suck the prepared dispersed phase into the injection pump; connect the control module of the precision pressure pump, put the oil phase material into the storage pipe, connect the two discharge pipes to the chip pipes, arrange the four chips in parallel in sequence, and connect their pipes to the discharge port pipes through adapters. Connect the chip outlet pipes to the curing device, which adopts the thermal curing method and is connected to the constant temperature heating circulation device.

[0145] (4) Preparation of uniformly sized microspheres: Set the injection pump parameters to an injection flow rate of 5±2 μL / min and the pressure pump parameters to an injection flow rate of 800±300 μL / min. Turn on the injection pump to push the dispersed phase material into the chip pipeline, and simultaneously turn on the precision pressure pump to rapidly deliver the mobile phase material into the chip pipeline. At the chip focusing crossroads, the dispersed phase material is sheared into small droplets by the oil mobile phase material, forming a water-in-oil structure. Continue to deliver to the curing device and stir and cure at 60℃ for 3 hours. Cool the uniformly sized microspheres to room temperature, wash with butyl acetate, ethyl acetate, and acetone respectively, vacuum dry, and then swell to obtain polyethylene embolization microspheres with uniform particle size.

[0146] (5) Particle size analysis: such as Figure 5 As shown, the microspheres exhibit uniform particle size distribution and high yield, enabling mass production. The prepared polyvinyl alcohol embolization microspheres have a particle size of 100±25μm, with a more optimal size of 100±10μm, meeting the requirement of uniform particle size.

[0147] Example 8 This invention provides a method for preparing embolization microspheres, specifically using the preparation of polyvinyl alcohol embolization microspheres as an example.

[0148] This embodiment uses a precision injection pump and a constant flow pump to deliver materials. The microsphere generation device is a focusing chip with an inner diameter of 100±20μm for the dispersed phase channel and 300±150μm for the mobile phase channel. Figure 3 As shown, the specific steps are as follows: (1) Preparation of dispersed phase material: Weigh 0.4g of ammonium persulfate and add 60g of water, stir magnetically to dissolve, slowly add 8g of sodium 2-acrylamido-2-methylpropanesulfonate, stir evenly, then add 10g of polyvinyl alcohol derivative, stir evenly, and use as dispersed phase material for later use.

[0149] (2) Preparation of mobile phase material: Add 10g of fatty acid sorbitan surfactant to 1000mL of butyl acetate solution, then add 8mL of tetramethylethylenediamine, stir evenly, and use it as mobile phase material for later use.

[0150] (3) Assembly of the device: Turn on the injection pump and automatically suck the prepared dispersed phase into the injection pump; insert the feed line of the precision constant flow pump into the prepared mobile phase material, connect the two discharge lines to the chip lines, arrange the four chips in parallel in sequence, and connect their lines to the discharge port lines through adapters. Connect the chip outlet lines to the curing device, which adopts the thermal curing method and is connected to the constant temperature heating circulation device.

[0151] (4) Preparation of uniform particle size microspheres: Set the injection pump parameters to an injection flow rate of 5±2 μL / min, and set the constant flow pump parameters to an injection flow rate of 500±200 μL / min. Turn on the injection pump to push the dispersed phase material into the chip pipeline, and simultaneously turn on the precision constant flow pump to rapidly deliver the mobile phase material into the chip pipeline. At the chip focusing crossroads, the dispersed phase material is sheared into small droplets by the oil mobile phase material, forming an oil-in-water structure, and continues to be delivered to the curing device, where it is stirred at 60°C. Curing time was 3 hours. The uniform microspheres were cooled to room temperature, washed with butyl acetate, ethyl acetate and acetone respectively, dried under vacuum, and then swollen to obtain polyethylene embolization microspheres with uniform particle size.

[0152] (5) Particle size analysis: such as Figure 6 As shown, the prepared polyvinyl alcohol embolization microspheres have a particle size of 250±50μm, and a more preferred size is 250±20μm, which meets the requirement of uniform particle size.

[0153] Example 9 This invention provides a method for preparing embolization microspheres, specifically using the preparation of polyvinyl alcohol embolization microspheres as an example.

[0154] This embodiment uses a precision injection pump and a constant flow pump to deliver materials. The microsphere generation device is a 3D-printed cross-shaped pipeline with an inner diameter of 250±130μm for the dispersed phase pipeline and an inner diameter of 500±200μm for the mobile phase pipeline. The specific steps are as follows: (1) Preparation of dispersed phase material: Weigh 0.4g of potassium persulfate and add 100g of water, stir magnetically to dissolve, slowly add 8g of sodium 2-acrylamido-2-methylpropanesulfonate, stir evenly, then add 10g of polyvinyl alcohol derivative, stir evenly, and use as dispersed phase material for later use.

[0155] (2) Preparation of mobile phase material: Add 10g of cellulose acetate surfactant to 1000mL of butyl acetate solution, then add 5mL of N,N-dimethylamine, stir evenly, and use it as mobile phase material for later use.

[0156] (3) Assembly of the device: Turn on the injection pump and automatically suck the prepared dispersed phase into the injection pump; insert the feed line of the precision constant flow pump into the prepared mobile phase material, connect the two discharge lines to the corresponding chip lines respectively, connect the cross-shaped lines to the discharge port lines through adapters, and connect the chip outlet line to the curing device. The curing device adopts the thermal curing method and is connected to the constant temperature heating circulation device.

[0157] (4) Preparation of uniform microspheres: Set the injection pump parameters to an injection flow rate of 20±5 μL / min and the constant flow pump parameters to an injection flow rate of 2000±500 μL / min. Turn on the injection pump to push the dispersed phase material into the chip tubing, and simultaneously turn on the precision constant flow pump to rapidly deliver the mobile phase material into the cross-shaped tubing. At the center of the cross, the dispersed phase material is sheared into small droplets by the oil mobile phase material, forming a water-in-oil structure. Continue to deliver to the curing device and stir and cure at 60℃ for 3 hours. Cool the uniform microspheres to room temperature, wash with butyl acetate, ethyl acetate, and acetone respectively, vacuum dry, and then swell to obtain polyethylene embolization microspheres with uniform particle size.

[0158] (5) Particle size analysis: such as Figure 7 As shown, the prepared polyvinyl alcohol embolization microspheres have a particle size of 500±50μm, and a more preferred size is 500±20μm, which meets the requirement of uniform particle size.

[0159] Example 10 This invention provides a method for preparing embolization microspheres, specifically using the preparation of polyvinyl alcohol embolization microspheres as an example.

[0160] This embodiment uses a precision pressure pump to deliver materials. The microsphere generation device is a T-shaped chip with an inner diameter of 800±300μm for the dispersed phase pipe and 1000±500μm for the mobile phase pipe. A photocuring device is used. The specific steps are as follows: (1) Preparation of dispersed phase material: Weigh 0.15g of 2,4,6-trimethylbenzoyl-diphenylphosphine oxide and add 80g of water. Stir magnetically to dissolve. Slowly add 10g of sodium 2-acrylamido-2-methylpropanesulfonate and stir until uniform. Then add 10g of polyvinyl alcohol derivative and stir until uniform. This is used as the dispersed phase material for later use.

[0161] (2) Preparation of mobile phase material: Add 20g of cellulose acetate surfactant to 2000mL of butyl acetate solution and stir evenly to prepare the mobile phase material.

[0162] (3) Device assembly: Add the prepared dispersed phase and mobile phase materials to the storage bottle, connect the pressure control module, gas source, computer control panel, pipelines, etc., and first start the initialization device to confirm its excellent airtightness. Arrange multiple chips in parallel in sequence, and connect their pipelines to the outlet pipelines through adapters. Connect the chip outlet pipelines to the curing device, which is a light curing device connected to a UV lamp.

[0163] (4) Preparation of uniformly sized microspheres: The dispersed phase pressure switch is activated to deliver the dispersed phase material to the chip pipeline. At the same time, the mobile phase pressure switch is activated to quickly deliver the mobile phase material to the chip pipeline. By adjusting the pressure and flow rate relationship, the injection flow rate of the dispersed phase material is controlled at 50±20μL / min and 800±200μL / min. At the T-shaped part of the chip, the dispersed phase material is sheared into liquid droplets by the oil mobile phase material, forming a water-in-oil structure. The ultraviolet lamp device is turned on with a power of 400W. While the microspheres are running in the coil, the ultraviolet lamp simultaneously performs surface photocuring. The photocuring time is 40s, and the microspheres are rapidly cross-linked to prepare the product. The product is then washed with butyl acetate, ethyl acetate, and acetone, vacuum dried, and then swollen to obtain polyethylene embolization microspheres with uniform particle size.

[0164] (5) Particle size analysis: such as Figure 8 As shown, the microspheres exhibit uniform particle size distribution, high yield, and short curing time, enabling mass production. The prepared polyvinyl alcohol embolization microspheres have a particle size of 800±80μm, with a more optimal size of 800±50μm, meeting the requirement of uniform particle size.

[0165] Example 11 This invention provides a method for preparing embolization microspheres, specifically using the preparation of polyvinyl alcohol embolization microspheres as an example.

[0166] This embodiment uses a precision pressure pump to transport materials, and the microsphere generating device is a T-shaped chip with an inner diameter of 800±400μm for the dispersed phase pipe and 2000±1000μm for the mobile phase pipe. The specific steps are as follows: (1) Preparation of dispersed phase material: Weigh 0.4g of potassium persulfate and add 50g of water, stir magnetically to dissolve, slowly add 10g of sodium 2-acrylamido-2-methylpropanesulfonate, stir evenly, then add 10g of polyvinyl alcohol derivative, stir evenly, and use as dispersed phase material for later use.

[0167] (2) Preparation of mobile phase material: Add 10g of cellulose acetate surfactant to 1000mL of butyl acetate solution, then add 10mL of tetramethylethylenediamine, stir evenly, and use it as mobile phase material for later use.

[0168] (3) Device assembly: Add the prepared dispersed phase and mobile phase materials to the storage bottle, connect the pressure control module, gas source, computer control panel, pipelines, etc., and first start the initialization device to verify whether there is gas leakage in the storage bottle and confirm its excellent airtightness. Arrange the T-shaped chips in parallel in sequence, and connect their pipelines to the outlet pipelines through adapters. The chip outlet pipeline is connected to the curing device, which adopts both coil pre-curing and heat curing methods and is connected to a constant temperature heating circulation device.

[0169] (4) Preparation of uniform microspheres: The dispersed phase pressure switch is activated to deliver the dispersed phase material to the chip pipeline. At the same time, the mobile phase pressure switch is activated to quickly deliver the mobile phase material to the chip pipeline. By adjusting the pressure and flow rate relationship, the injection flow rate of the dispersed phase material is controlled at 50±20μL / min, and the injection flow rate of the mobile phase material is controlled at 5000±2500μL / min. At the chip focusing crossroads, the dispersed phase material is sheared into liquid droplets by the oil mobile phase material to form a water-in-oil structure. When the microspheres are pre-aged in the coil to prevent collision and fusion in the curing device, they are continued to be delivered to the curing device and stirred and cured at 80℃ for 4h. The uniform microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone respectively, vacuum dried, and then swollen to obtain polyethylene plug microspheres with uniform particle size.

[0170] (5) Particle size analysis: such as Figure 9 As shown, the microspheres exhibit uniform particle size distribution and high yield, enabling mass production. The prepared polyvinyl alcohol embolization microspheres have a particle size of 1200±100μm, with a more optimal size of 1200±50μm, meeting the requirement of uniform particle size.

[0171] Example 12 This invention provides a method for preparing embolization microspheres, specifically using the preparation of polyvinyl alcohol embolization microspheres as an example.

[0172] This embodiment uses a precision pressure pump to deliver materials, and the microsphere generation device is a focusing chip with an inner diameter of 100±20μm for the dispersed phase channel and 100±50μm for the mobile phase channel. A photocuring device is used. The specific steps are as follows: (1) Preparation of dispersed phase material: Weigh 0.2g of phenyl (2,4,6-trimethylbenzoyl) lithium phosphate and add 80g of water. Stir magnetically to dissolve. Slowly add 10g of sodium 2-acrylamido-2-methylpropanesulfonate and stir until uniform. Then add 10g of polyvinyl alcohol derivative and stir until uniform. This will be used as the dispersed phase material for later use.

[0173] (2) Preparation of mobile phase material: Add 20g of cellulose acetate surfactant to 2000mL of butyl acetate solution and stir evenly to prepare the mobile phase material.

[0174] (3) Device assembly: Add the prepared dispersed phase and mobile phase materials to the storage bottle, connect the pressure control module, gas source, computer control panel, pipelines, etc., and first start the initialization device to verify whether there is gas leakage in the storage bottle and confirm its excellent airtightness. Arrange multiple chips in parallel in sequence, and connect their pipelines to the outlet pipelines through adapters. The chip outlet pipeline is connected to the curing device, which is a light curing device connected to a UV lamp.

[0175] (4) Preparation of microspheres with uniform particle size: The dispersed phase pressure switch is activated to deliver the dispersed phase material to the chip pipeline. At the same time, the mobile phase pressure switch is activated to quickly deliver the mobile phase material to the chip pipeline. By adjusting the relationship between pressure and flow rate, the microspheres are controlled. The injection flow rate of the dispersed phase material was 5±2 μL / min, and the injection flow rate of the mobile phase material was 500±300 μL / min. At the chip focusing crossroads, the dispersed phase material was sheared into droplets by the oil-based mobile phase material, forming a water-in-oil structure. The UV lamp was turned on at 1000W. While the microspheres were running in the coil, the UV lamp simultaneously performed surface photocuring for 60 seconds, resulting in rapid cross-linking of the microspheres and the preparation of the product. The product was then washed with butyl acetate, ethyl acetate, and acetone, vacuum dried, and then swollen to obtain polyethylene embolic microspheres with uniform particle size.

[0176] (5) Particle size analysis: such as Figure 10 As shown, the microspheres exhibit uniform particle size distribution, high yield, and short curing time, enabling mass production and rapid deployment. The prepared polyvinyl alcohol embolization microspheres have a particle size of 100±25μm, with a more optimal size of 100±10μm, meeting the requirement of uniform particle size.

[0177] Example 13 This invention provides a method for preparing embolization microspheres, specifically using the preparation of polyvinyl alcohol embolization microspheres as an example.

[0178] This embodiment uses a precision pressure pump to transport materials, and the microsphere generation device is a focusing chip with an inner diameter of 80±10μm for the dispersed phase pipe and 100±20μm for the mobile phase pipe. The specific steps are as follows: (1) Preparation of dispersed phase material: Weigh 0.6g potassium persulfate and 0.1g lithium phenyl (2,4,6-trimethylbenzoyl) phosphate and add 40g water. Stir magnetically to dissolve. Slowly add 6g sodium acrylate sulfonate and stir evenly. Then add 10g polyvinyl alcohol derivative and stir evenly. This will be used as the dispersed phase material for later use.

[0179] (2) Preparation of mobile phase material: Add 10g of cellulose acetate surfactant to 1000mL of ethyl acetate solution, then add 10mL of triethanolamine, stir evenly, and use it as mobile phase material for later use.

[0180] (3) Device assembly: Add the prepared dispersed phase and mobile phase materials to the storage bottle, connect the pressure control module, gas source, computer control panel, pipelines and other devices, and start the device. Arrange 50 chips in parallel in sequence, and connect their pipelines to the outlet pipelines through adapters. Connect the chip outlet pipelines to the curing device, which uses a combination of light pre-curing and heat curing. Connect the UV lamp, constant temperature heating circulation and other devices.

[0181] (4) Preparation of uniform microspheres: The dispersed phase pressure switch is activated to deliver the dispersed phase material to the chip pipeline. At the same time, the mobile phase pressure switch is activated to quickly deliver the mobile phase material to the chip pipeline. By adjusting the pressure and flow rate relationship, the injection flow rate of the dispersed phase material is controlled at 5±1μL / min, and the injection flow rate of the mobile phase material is controlled at 300±100μL / min. At the chip focusing crossroads, the dispersed phase material is sheared into small droplets by the oil mobile phase material, forming a water-in-oil structure. It is then delivered to the photocuring device. While the microspheres are running in the coil, the UV lamp simultaneously performs surface pre-curing. The photocuring time is 1s, and the surface of the microspheres cross-links. Then, they are collected in a flask. After 12 hours, the thermocuring device is activated, and the microspheres are stirred and cured at 60℃ for 3 hours. The uniform microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone, respectively, vacuum dried, and then swollen to obtain polyethylene embolization microspheres with uniform particle size.

[0182] (5) Particle size analysis: The microspheres have a uniform particle size distribution, and the microsphere forming process can be controlled to achieve mass production and controllable production. The prepared polyvinyl alcohol embolization microspheres have a particle size of 80±25μm, and the optimal solution is 80±10μm, which meets the requirement of uniform particle size.

[0183] Example 14 This invention provides a method for preparing embolization microspheres, specifically using the preparation of polyvinyl alcohol embolization microspheres as an example.

[0184] This embodiment uses a precision injection pump and a constant flow pump to deliver materials. The microsphere generation device is a coaxial microtube with an inner diameter of 1500±500μm for the dispersed phase and 500±200μm for the mobile phase. The specific steps are as follows: (1) Preparation of dispersed phase material: Weigh 0.4g of ammonium persulfate and add 60g of water, stir magnetically to dissolve, slowly add 8g of sodium 2-acrylamido-2-methylpropanesulfonate, stir evenly, then add 10g of polyvinyl alcohol derivative, stir evenly, and use as dispersed phase material for later use.

[0185] (2) Preparation of mobile phase material: Add 10g of fatty acid sorbitan surfactant to 1000mL of butyl acetate solution, then add 8mL of tetramethylethylenediamine, stir evenly, and use it as mobile phase material for later use.

[0186] (3) Assembly of the device: Turn on the injection pump and automatically suck the prepared dispersed phase into the injection pump; insert the feed line of the precision constant flow pump into the prepared mobile phase material, connect the two discharge lines to the chip lines, arrange the four chips in parallel in sequence, and connect their lines to the discharge port lines through adapters. Connect the chip outlet lines to the curing device, which adopts the thermal curing method and is connected to the constant temperature heating circulation device.

[0187] (4) Preparation of uniform microspheres: Set the injection pump parameters to an injection flow rate of 10-500 μL / min / min, and set the constant flow pump parameters to an injection flow rate of 1000-50000 μL. Turn on the injection pump to push the dispersed phase material into the chip pipeline, and simultaneously turn on the precision constant flow pump to rapidly deliver the mobile phase material into the chip pipeline. At the chip focusing crossroads, the dispersed phase material is sheared into small droplets by the oil mobile phase material, forming a water-in-oil structure. Continue to deliver to the curing device and stir and cure at 60°C for 10 hours. Cool the uniform microspheres to room temperature, wash with butyl acetate, ethyl acetate, and acetone respectively, vacuum dry, and then swell to obtain polyethylene embolization microspheres with uniform particle size.

[0188] (5) Particle size analysis: The prepared polyvinyl alcohol embolization microspheres have a particle size of 500-1400 μm, which meets the requirement of uniform particle size. Those skilled in the art should understand that the present invention can be implemented in many other specific forms without departing from its spirit or scope. Although embodiments of the invention have been described, it should be understood that the invention should not be limited to these embodiments, and those skilled in the art can make changes and modifications within the spirit and scope of the invention as defined in the appended claims.

Claims

1. A reaction apparatus, characterized in that, It includes a main structure layer and an encapsulation layer, wherein the main structure layer integrates a groove for liquid droplets, and the encapsulation layer is stacked on one side of the main structure layer; The melting temperature of the main structural layer is higher than that of the encapsulation layer. The main structural layer and the encapsulation layer are made of the same material but have different degrees of polymerization; The main structural layer and the encapsulation layer are made of thermoplastic polymer material; Furthermore, the thermoplastic polymer is a cyclic olefin polymer; The groove is a flow-focusing type groove, a coaxial type groove, a T-shaped groove, or a Y-shaped groove. The flow-focusing type groove includes a main groove, a dispersed phase groove, and a continuous phase groove. The diameter ratio of the continuous phase groove, the dispersed phase groove, and the main groove is 1:0.2-1:1-1.

5. The diameter of the continuous phase groove is 50-1200 μm, the diameter of the dispersed phase groove is 50-1000 μm, and the diameter of the main groove is 50-1500 μm. The integrated trough within the main structural layer has a dispersed phase inlet, a continuous phase inlet, and an outlet. The diameter of the dispersed phase inlet is in a ratio of 1:1-2 to the diameter of the dispersed phase trough; the diameter of the continuous phase inlet is in a ratio of 1:1-2 to the diameter of the continuous phase trough; and the minimum aperture of the outlet is in a ratio of 1-1.5:1 to the diameter of the main trough. The dispersed phase inlet is connected to the dispersed phase tank through a connecting groove. The connection between the connecting groove and the dispersed phase tank is an inclined plane with an inclination angle of 30-60°. The reaction apparatus is used for the preparation of polyvinyl alcohol embolization microspheres with uniform particle size; The size of the polyvinyl alcohol embolization microspheres is controlled between 20-1400 μm, and the particle size uniformity is <10%. The reaction apparatus is obtained through a processing method comprising the following steps: S1. The main structural layer and the encapsulation layer are processed using the same material, and the degree of polymerization of the material is controlled so that the melting temperature of the encapsulation layer is lower than that of the main structural layer. S2. The processed main structure layer and encapsulation layer are directly connected by thermal bonding under vacuum conditions; and the thermal bonding temperature is lower than the melting temperature of the main structure layer and higher than the melting temperature of the encapsulation layer.

2. The reaction apparatus according to claim 1, characterized in that, The flow focusing type groove includes a main groove, a dispersing phase groove and two continuous phase grooves, the two continuous phase grooves are symmetrically arranged, and the dispersing phase groove is arranged between the two continuous phase grooves; The two continuous phase slots and the dispersed phase slots are connected to one end of the main slot and communicate with it on the same side. The other end of the main slot extends away from the dispersed phase slot and the continuous phase slot.

3. The reaction apparatus according to claim 2, characterized in that, The continuous phase tank is provided with a continuous phase feed inlet at the end away from the main tank, the dispersed phase tank is provided with a dispersed phase feed inlet at the end away from the main tank, and the main tank is provided with a discharge outlet at the end away from both the dispersed phase tank and the continuous phase tank.

4. The reaction apparatus according to claim 3, characterized in that, The continuous phase inlet, dispersed phase inlet, and outlet penetrate the main structural layer, and one end of the continuous phase inlet, dispersed phase inlet, and outlet is sealed by the encapsulation layer.

5. The reaction apparatus according to claim 3, characterized in that, The two continuous phase channels are connected at the ends away from the main channel and share a continuous phase inlet.

6. The reaction apparatus according to claim 3, characterized in that, The diameter of the connecting groove is larger than the diameter of the dispersing phase groove.

7. The reaction apparatus according to claim 3, characterized in that, The inner diameter of the discharge port is smaller than the outer diameter.

8. The reaction apparatus according to claim 7, characterized in that, The discharge port is a stepped hole or a funnel-shaped hole.

9. The reaction apparatus according to claim 1, characterized in that, It also includes a support layer, which is stacked on the side of the encapsulation layer facing away from the main structure layer.

10. The reaction apparatus according to claim 9, characterized in that, The material thickness ratio of the main structural layer, the encapsulation layer and the support layer is 1:0.05-0.5:1-3.

11. The reaction apparatus according to claim 9, characterized in that, The support layer, the main structure layer, and the encapsulation layer are made of the same material.

12. A method for processing a reaction apparatus, characterized in that, The apparatus is used to process the reaction device according to any one of claims 1-11, and the processing method comprises the following steps: S1. The main structural layer and the encapsulation layer are processed using the same material, and the degree of polymerization of the material is controlled so that the melting temperature of the encapsulation layer is lower than that of the main structural layer. S2. The processed main structure layer and encapsulation layer are directly connected by thermal bonding under vacuum conditions; and the thermal bonding temperature is lower than the melting temperature of the main structure layer and higher than the melting temperature of the encapsulation layer.

13. The processing method of the reaction apparatus according to claim 12, characterized in that, The thermal bonding temperature differs from the melting temperature of the main structural layer by 0.1-10%.

14. The processing method of the reaction apparatus according to claim 12, characterized in that, Step S2 further includes: the thermal bonding temperature range is 90-160℃.

15. The processing method of the reaction apparatus according to claim 12, characterized in that, Step S2 further includes: the thermal bonding time range is 3-30 min.

16. The processing method of the reaction apparatus according to claim 12, characterized in that, Step S2 further includes: the thermal bonding pressure range is 20-200 kg.

17. The processing method of the reaction apparatus according to claim 12, characterized in that, It also includes step S3: connecting the support layer to the side of the encapsulation layer facing away from the main structure layer by means of adhesive bonding.

18. The processing method of the reaction apparatus according to claim 17, characterized in that, Step S3 further includes: the adhesive pressure between the support layer and the encapsulation layer is in the range of 1-10 kg.

19. The processing method of the reaction apparatus according to claim 17, characterized in that, Step S3 further includes: the bonding time between the support layer and the encapsulation layer is in the range of 3-30 seconds.

20. An apparatus for preparing embolic microspheres, characterized in that, It includes a feeding system, a microsphere generation module, and a curing device; the feeding system is connected to the microsphere generation module, and the microsphere generation module is connected to the curing device; wherein the microsphere generation module includes at least one microreactor, and the microreactor adopts the reaction device according to any one of claims 1-11.

21. The apparatus for preparing embolic microspheres according to claim 20, characterized in that, The microsphere generation module includes multiple microreactors connected in parallel. Each of the multiple microreactors is connected to the feeding system and the curing device, and the multiple microreactors are used to generate microspheres of the same or different diameters.

22. The apparatus for preparing embolic microspheres according to claim 20 or 21, characterized in that, The feeding system includes a continuous phase feeding system and a dispersed phase feeding system, which are respectively connected to the continuous phase inlet and the dispersed phase inlet of each microreactor.

23. The apparatus for preparing embolic microspheres according to claim 22, characterized in that, The continuous phase feeding system includes a continuous phase feed pump and a continuous phase storage tank connected together, and the continuous phase storage tank is connected to the continuous phase inlet of each of the microreactors. The dispersed phase feeding system includes a dispersed phase feed pump and a dispersed phase storage tank connected together, and the dispersed phase storage tank is connected to the dispersed phase inlet of each of the microreactors.

24. The apparatus for preparing embolic microspheres according to claim 23, characterized in that, The continuous phase feeding system also includes a first pressure source device, and the first pressure source device, the continuous phase feed pump, and the continuous phase storage tank are connected in sequence. The dispersed phase feeding system also includes a second pressure source device, and the second pressure source device, the dispersed phase feed pump, and the dispersed phase storage tank are connected in sequence.

25. The apparatus for preparing embolic microspheres according to claim 23, characterized in that, The continuous phase feed pump and the dispersed phase feed pump are equipped with pumps with flow and pressure control devices.

26. The apparatus for preparing embolic microspheres according to claim 20, characterized in that, The microreactor also includes a microfluidic chip; the microfluidic chip works with a controller to control the flow rate of the reaction liquid entering the microreactor.

27. The apparatus for preparing embolic microspheres according to claim 20, characterized in that, The curing device is either an ultraviolet curing device or a thermal curing device, both of which include a curing container and a corresponding generating device.

28. A method for preparing embolic microspheres, wherein the preparation method is performed by the equipment described in any one of claims 20-27, characterized in that, In the feeding system, oil phase material is fed into the microreactor through a continuous phase feeding system, and aqueous phase material is fed into the microreactor through a dispersed phase feeding system. In the microreactor channel, the aqueous phase material is sheared into small droplets under the shear force of the oil phase material to form a water-in-oil structure. Finally, after being solidified by a solidification device, polyvinyl alcohol embolized microspheres with uniform particle size are obtained. The size of the polyvinyl alcohol embolization microspheres generated by microreactors of different diameters can be controlled between 20-1400 μm, and the particle size uniformity is <10%.

29. The method for preparing embolic microspheres according to claim 28, characterized in that, The aqueous phase material is polyvinyl alcohol and its derivatives, water, crosslinking agent, and aqueous phase material initiator; the oil phase material is an oil phase material initiator, surfactant, and ester solvent, and the mass ratio of polyvinyl alcohol and its derivatives:water:crosslinking agent:aqueous phase material initiator is 10:1-100:1-10:0.01-0.6; the mass ratio of oil phase material initiator and surfactant to ester solvent is 0.1%-5%.

30. The method for preparing embolic microspheres according to claim 29, characterized in that, The polyvinyl alcohol and its derivatives are prepared by using polyvinyl alcohol as a base material and acylated crosslinkable amino / hydroxyl carboxylic acid derivatives / sulfonic acid derivatives as modifiers to obtain polymers containing crosslinkable small molecules with acrylic acid or its derivative structure.

31. The method for preparing embolic microspheres according to claim 29, characterized in that, The initiator for the aqueous phase material is a peroxide initiator and / or a photoinitiator, specifically including benzoyl or acylphosphide oxides.

32. The method for preparing embolic microspheres according to claim 29, characterized in that, The curing device is an ultraviolet curing device or a thermal curing device; The thermosetting device adopts a jacketed reaction bottle device, and is kept warm by a circulating temperature control device. The curing temperature is 40-80℃ and the curing time is 1-6h. The ultraviolet curing device uses a coil device to continuously flow the prepared microspheres in the pipeline and cure them in real time by high-intensity ultraviolet light with an irradiation wavelength of 200-500nm and an irradiation time of 2-1000s.

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