WO2021147356A1 - 反应装置及其加工方法、栓塞微球的制备设备及其制备方法 - Google Patents

反应装置及其加工方法、栓塞微球的制备设备及其制备方法 Download PDF

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WO2021147356A1
WO2021147356A1 PCT/CN2020/116485 CN2020116485W WO2021147356A1 WO 2021147356 A1 WO2021147356 A1 WO 2021147356A1 CN 2020116485 W CN2020116485 W CN 2020116485W WO 2021147356 A1 WO2021147356 A1 WO 2021147356A1
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dispersed phase
continuous phase
microspheres
tank
phase
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PCT/CN2020/116485
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English (en)
French (fr)
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马亚丹
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苏州恒瑞宏远医疗科技有限公司
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Priority claimed from CN202010072301.0A external-priority patent/CN112569878B/zh
Priority claimed from CN202010722636.2A external-priority patent/CN112569881B/zh
Application filed by 苏州恒瑞宏远医疗科技有限公司 filed Critical 苏州恒瑞宏远医疗科技有限公司
Priority to US17/639,550 priority Critical patent/US20220331769A1/en
Priority to CN202080093565.2A priority patent/CN115038517A/zh
Publication of WO2021147356A1 publication Critical patent/WO2021147356A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0006—Controlling or regulating processes
    • B01J19/0013—Controlling the temperature of the process
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/02—Apparatus characterised by being constructed of material selected for its chemically-resistant properties
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J4/00—Feed or outlet devices; Feed or outlet control devices
    • B01J4/001—Feed or outlet devices as such, e.g. feeding tubes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00788—Three-dimensional assemblies, i.e. the reactor comprising a form other than a stack of plates
    • B01J2219/00792—One or more tube-shaped elements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00851—Additional features
    • B01J2219/00869—Microreactors placed in parallel, on the same or on different supports
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00873—Heat exchange

Definitions

  • the invention relates to the technical field of medical device production, in particular to a reaction device for the production of embolic microspheres and a processing method thereof, a preparation equipment of embolic microspheres, and a preparation method of embolic microspheres.
  • Tumor cancer has become the primary problem that endangers global public health, and about 4 million new cancer patients are newly added every year in my country, and 600-700,000 people are undergoing tumor interventional therapy, which is increasing at a rate of 10-20%.
  • drug-eluting embolization microsphere chemoembolization is emerging as a new embolization technology, which can not only load chemotherapeutics, but also play an embolization effect, so as to achieve continuous treatment of tumors and improve treatment effects.
  • polyvinyl alcohol embolization microspheres for the treatment of tumor diseases is already a very important clinical treatment method.
  • the principle is that the microspheres embolize the blood vessels at the patient's site to cut off the nutritional supply of tumor cells, so that tumor cells cannot get nutrition.
  • the embolic microspheres can be loaded with chemotherapeutic drugs, and the drugs are continuously and slowly released in the blood vessels near the tumor to target the tumor to achieve the therapeutic effect.
  • embolic material products currently on the market, the only product with encapsulated chemotherapeutic drugs is the DC of the British company Biocompatibles American BioSphere And Hengrui Group's
  • the above three embolization microsphere products have greatly improved the defects of traditional embolization materials, and achieved breakthrough therapeutic effects in the clinical treatment of liver cancer and other tumors.
  • the particle size of polyvinyl alcohol embolization microspheres currently available on the market is not uniform, but within a certain range, such as the range of 100-300 ⁇ m, 300-500 ⁇ m, 500-700 ⁇ m, etc.
  • blood vessels of various sizes are distributed around the tumor. The closer to the center of the tumor, the thinner the blood vessels (that is, the presence of blood vessels less than 100um), the better the embolization effect. Therefore, the smaller particle size and more uniform microspheres enable them to enter and get closer to the tumor blood vessels during the clinical embolization process.
  • the current microspheres are prepared by the "one-pot method", and then undergo a sieving process to obtain microsphere products with a target particle size range.
  • the production process has problems such as low efficiency, complicated quality control, high labor intensity, and high cost. Therefore, it is necessary to develop a new type of polyvinyl alcohol embolic microspheres with uniform particle size and its production process to improve production efficiency and precise treatment effects.
  • Patent CN 107418872 A uses a focused and T-shaped droplet microfluidic chip to prepare biological ink microspheres; it includes: a droplet generation module, including a first fluid The inlet, the droplet microfluidic chip and the output port.
  • the droplet microfluidic chip includes a flow channel system.
  • the first fluid inlet and the output port are respectively connected with the flow channel system, and enter the dispersed phase in the flow channel system from the first fluid inlet
  • the fluid forms droplets and outputs the droplets from the output port
  • the collection and manufacturing module includes a collection and manufacturing body, which includes a plurality of collection holes each having an action surface, and the action surfaces of each collection hole are isolated from each other, and the collection holes are used to receive the liquid. Drop onto the action surface and form microspheres based on liquid droplets on the action surface; a movement module, which is drivingly connected with the output port and/or the collecting and manufacturing body, so that each droplet is correspondingly dropped onto the action surface of the collection hole; the control module, Coupled with the droplet generation module and the motion module respectively.
  • This equipment is mainly used to prepare biological ink microspheres with biological activity.
  • the microspheres are layered spherical structures arranged in layers along the radial direction of the microspheres.
  • the particle size is between 5 and 120 ⁇ m.
  • the key is to control the core The number of cells contained in the collagen solution containing cells in the solution.
  • the core of the above technical solution lies in the structural design of the droplet generation module including the microfluidic chip for biological ink and the design of the corresponding collection and manufacturing, movement module and control module.
  • the above-mentioned device cannot be directly applied to the preparation of polyvinyl alcohol embolic microspheres, and the particle size of 5-120 ⁇ m cannot meet the diameter requirements of polyvinyl alcohol embolic microspheres.
  • CN101376093A adopts a coaxial microreactor assembled with tetrafluorocapillary and hollow fiber to prepare monodisperse polymer microspheres; this patent was published in 2009, the technology is relatively backward, and provides technical ideas for subsequent microreactors, but it does not A better supporting process prepares polyethylene embolization microspheres that meet the requirements of today's surgery.
  • CN109793916A adopts microchannel pipelines to prepare polyvinyl alcohol embolic microspheres with uniform particle size.
  • This patent provides a process for preparing polyvinyl alcohol embolic microspheres using microchannel pipelines, but the application does not disclose the corresponding process equipment. There are still deficiencies in industrial applications.
  • microfluidic technology scheme is still mainly in the scientific research stage.
  • the use of a single pipeline or a single chip to prepare uniform particle size microspheres is difficult to scale up.
  • reaction device in the existing embolization microsphere preparation equipment still has the following problems:
  • thermoplastic polymer reaction devices Most of the existing reaction devices are processed by thermoplastic polymers and connected and assembled by bonding technology.
  • the processing and bonding technologies for thermoplastic polymer reaction devices exist in terms of production efficiency, production quality, production accuracy, and method adaptability.
  • the main problem is also the main bottleneck problem of the current batch production of the reaction device.
  • the technical difficulty is mainly manifested in: the bonding needs to solve the connection and sealing problems at the same time, the overall mechanical strength of the reaction device material, the collapse and deformation of the groove, and the mass production. Consistency and other issues. Therefore, there is an urgent need to develop a reaction device that can realize mass production.
  • the present invention provides a reaction device, including a main structure layer and an encapsulation layer, the main structure layer is integrated with a groove of liquid beads, and the encapsulation is stacked on one side of the main structure layer ;
  • the melting temperature of the main structure layer is higher than the melting temperature of the encapsulation layer, and the main structure layer and the encapsulation layer are connected by thermal bonding.
  • the main structure layer and the encapsulation layer are made of the same material.
  • the tank integrated in the main structure layer has a disperse phase feed port, a continuous phase feed port, and a discharge port; the tank is a flow-focused tank or a coaxial tank or a T-shaped tank or Y-shaped groove.
  • the flow-focusing tank includes a main tank, a dispersed phase tank, and two continuous phase tanks, the two continuous phase tanks are symmetrically arranged, and the dispersed phase tank is disposed between the two continuous phase tanks.
  • the two continuous phase tanks and one end of the dispersed phase tank on the same side are connected to and communicated with one end of the main tank, and the other end of the main tank is away from the dispersed phase tank and the continuous phase tank Extend on one side.
  • the diameter ratio of the continuous phase tank, the dispersed phase tank, and the main tank is 1:0.2-1:1-1.5.
  • a continuous phase feed port is provided at one end of the continuous phase tank away from the main tank, and an end of the dispersed phase tank away from the main tank is provided with a dispersed phase feed port, and the main tank is far away
  • a discharge port is provided at one end of the dispersed phase tank and the continuous phase tank.
  • the continuous phase inlet, the dispersed phase inlet, and the outlet pass through the main structure layer, and one end of the continuous phase inlet, the dispersed phase inlet, and the outlet It is sealed by the encapsulation layer.
  • the two continuous phase tanks are communicated with one end away from the main tank and share one continuous phase feed port.
  • the ratio of the diameter of the feed port of the dispersed phase to the diameter of the dispersed phase tank is 1:1-2; the diameter of the feed port of the continuous phase tank is equal to that of the continuous phase tank. The diameter ratio is 1:1-2.
  • the dispersed phase feed port is connected to the dispersed phase tank through a connecting groove, and the diameter of the connecting groove is larger than the diameter of the dispersed phase groove.
  • the connecting groove and the dispersed phase groove are connected in an inclined plane, and the inclination angle of the inclined plane is 30-60°.
  • the inner hole diameter of the discharge port is larger than the outer hole diameter.
  • the discharge port is a stepped hole or a trumpet-shaped hole.
  • a support layer is further included, and the support layer is stacked on the side of the encapsulation layer facing away from the main structure layer.
  • the material thickness ratio of the main structure layer, the encapsulation layer and the support layer is 1:0.05-0.5:1-3.
  • the support layer, the main structure layer, and the encapsulation layer are made of the same material.
  • the main structure layer and the encapsulation layer are made of thermoplastic polymer materials.
  • the main structure layer and the encapsulation layer are made of cycloolefin polymer.
  • the present invention also provides a processing method of a reaction device, which is used for processing the above-mentioned reaction device, and the processing method is:
  • the main structure layer and the encapsulation layer are separately processed by using the same material, and the polymerization degree of the materials is controlled so that the melting temperature of the encapsulation layer obtained by processing is lower than the melting temperature of the main structure layer;
  • the processed main structure layer and the packaging layer are connected by thermal bonding.
  • step S2 further includes: the main structure layer and the encapsulation layer are connected by thermal bonding under vacuum conditions.
  • step S2 further includes: the thermal bonding temperature is lower than the melting temperature of the main structure layer, and higher than or equal to the melting temperature of the encapsulation layer.
  • the thermal bonding temperature differs from the melting temperature of the main structure layer by 0.1-10%.
  • step S2 further includes: the thermal bonding temperature range is 90-160°C.
  • step S2 further includes: the thermal bonding time range is 3-30 min.
  • step S2 further includes: the thermal bonding pressure range is 20-200 kg.
  • the method further includes step S3: connecting the support layer by means of glue connection on the side of the encapsulation layer facing away from the main body layer.
  • step S3 further includes: the adhesive pressure between the support layer and the encapsulation layer is in the range of 1-10 kg.
  • step S3 further includes: the bonding time range between the support layer and the encapsulation layer is 3-30 s.
  • the main structure layer and the encapsulation layer are made of the same material.
  • the overall mechanical strength of the reaction device is improved, and on the other hand, it provides theoretical support for the thermal bonding connection between the two layers. Avoid introducing impurities; the present invention further restricts that the melting temperature of the main structure layer is higher than the melting temperature of the encapsulation layer.
  • the connection function can be realized as long as the thermal bonding temperature reaches the melting temperature of the encapsulation layer.
  • the thermal bonding temperature can also be lower than the melting temperature of the main structure layer, thereby preventing the collapse and deformation of the grooves forming the grooves due to the high thermal bonding temperature during the thermal bonding connection process, which is beneficial to ensure the batch
  • the consistency of production is suitable for mass production.
  • the reaction device provided by the present invention has the advantages of integration, stable structure, high strength, etc., significantly improves the stability of liquid bead generation, and at the same time has the advantages of high production efficiency, good quality, and suitable for mass production. It is suitable for the application of the reaction device in clinical practice. Diagnosis, drug analysis, environmental monitoring, food development and other fields are of great significance.
  • the present invention provides a device for preparing embolic microspheres, which includes a feeding system, a microsphere generating module, and a curing device; the feeding system is connected to the microsphere generating module, and the microsphere generating module is connected to the curing device Wherein the microsphere generating module includes at least one microreactor, and the microreactor adopts the reaction device described above.
  • the microsphere generating module includes a plurality of the microreactors connected in parallel, and the plurality of microreactors are respectively connected to the feeding system and the curing device, and the plurality of microreactors are connected to the feeding system and the curing device.
  • the microreactor is used to generate microspheres of the same or different diameters.
  • the feed system includes a continuous phase feed system and a dispersed phase feed system, and the continuous phase feed system and the dispersed phase feed system are respectively connected to the continuous phase of each of the microreactors.
  • the feed port is connected with the feed port of the dispersed phase.
  • the continuous phase feed system includes a continuous phase feed pump and a continuous phase storage tank connected to each other, and the continuous phase storage tank is in communication with the continuous phase feed port of each of the microreactors. ;
  • the dispersed phase feed system includes a connected dispersed phase feed pump and a dispersed phase storage tank, and the dispersed phase storage tank is in communication with the dispersed phase feed port of each of the microreactors.
  • the continuous phase feed system further 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 further includes a second pressure source device, and the second pressure source device, the dispersed phase feeding pump and the dispersed phase storage tank are connected in sequence.
  • the continuous phase feed pump and the dispersed phase feed pump adopt pumps equipped with flow and pressure control devices.
  • the microreactor further includes a microfluidic chip; the microfluidic chip cooperates with a controller to control the flow rate of the reaction liquid entering the microreactor.
  • the curing device is an ultraviolet curing device or a thermal curing device, both of which include a curing container and a corresponding generating device.
  • the present invention also provides a method for preparing embolic microspheres, which is completed by the above-mentioned equipment, and the specific steps are as follows:
  • the dispersed phase is mainly water-soluble materials, and the material components of the dispersed phase are polyvinyl alcohol and its derivatives, water, crosslinking agent and initiator of the dispersed phase materials. Firstly, the initiator is dissolved in water, then the cross-linking agent is sequentially added, and finally the polyvinyl alcohol and its derivatives are added, stirred evenly, and used as the dispersed phase for later use.
  • the polyvinyl alcohol and its derivatives use polyvinyl alcohol as a base material, and a crosslinkable amino/hydroxy carboxylic acid derivative/sulfonic acid derivative after acylation is used as a modifier.
  • Acrylic acid or its derivative structure can be a cross-linkable polymer of small molecules.
  • the crosslinking agent in the dispersed phase material is acrylate, which specifically includes: sodium acrylate, ammonium acrylate acrylamide, sodium 2-acrylamido-2-methylpropanesulfonate, etc.;
  • the initiators can be divided into peroxy initiators and photoinitiators.
  • Peroxy initiators include potassium persulfate, ammonium persulfate, etc.
  • photoinitiators include benzyls, acyl phosphorous oxides, and the like.
  • the mass ratio of the polyvinyl alcohol and its derivatives water: crosslinking agent: water phase material initiator is 10:1-100:1-10:0.01-0.6;
  • the mobile phase is mainly oil-soluble materials, and its components are organic solvents such as oil phase initiators, indicating active agents, and butyl acetate. Mainly add the oil phase material initiator and the indicating active agent to the ester solvent in sequence, stir evenly, and use it as the mobile phase for later use.
  • the initiator in the phase material is a tertiary amine compound, including tetramethylethylenediamine, triethanolamine, N,N-dimethyl-p-toluidine, etc.;
  • the surfactants are alkanes and aromatic hydrocarbon compounds, including sodium alkylbenzene sulfonate, cellulose acetate, fatty acid sorbitan, etc.;
  • the mass ratio of the oil phase material initiator and surfactant to butyl acetate is 0.1% to 5%.
  • the disperse phase and mobile phase materials rely on the material feeding system to transport materials.
  • a suitable precision pump can be selected as the driving device to make the material stable, continuous, and high-throughput transport to the microspheres Generate modules.
  • the driving device is a precision pump, including a high-precision injection pump, a high-precision constant flow pump, a precision pressure pump, and is equipped with a computer control panel, sensor feedback and other devices.
  • the material flow rate controlled by the precision pump is 0.1-500 ⁇ L/min for the dispersed phase and 100-50000 ⁇ L/min for the mobile phase;
  • the microsphere generation module mainly adopts chip type, microtube type and other microreactor devices. After the materials are transported to the microreactor device, the structure, materials, and operating parameters of the microfluidic chip are adjusted to make the dispersed phase flow Under the action of phase shearing force, monodisperse microspheres are formed, thereby achieving the preparation of uniform particle size microspheres.
  • the size of the microspheres can be adjusted between 20-1400um and the particle size uniformity is less than 10%.
  • the structure of the chip and microtube type microreactor is a flow focusing type, a coaxial type, a T type or a Y type structure, etc., and the inner diameter of the pipeline is 20-2000 ⁇ m;
  • the microreactor is preferably high polymer materials such as COP, COC, PTFE, ABS, etc., which have excellent properties such as corrosion resistance, superhydrophobicity, and high transparency;
  • the preparation method of the microreactor adopts 3D printing, numerical control CNC, injection molding and other processes, has the advantages of mass production, high reproducibility, and low price, and provides a guarantee for the high-throughput production process of uniform particle size microspheres;
  • microspheres with uniform particle size are generated, they are transported to the curing device, and the internal crosslinking of the microspheres is further carried out to complete the collection and post-treatment process of the microspheres.
  • Both curing methods can quickly crosslink the polymer microspheres to improve product stability. At the same time, it provides more selectivity for the materials for preparing the microspheres, effectively increases the crosslinking mode and speed of the microspheres, and further increases the simplicity and selectivity of the production process of the polyvinyl alcohol embolized microspheres.
  • the curing device can choose two modes of thermal curing and light curing. According to the nature of the initiator in the polyvinyl alcohol material, if it is a chemical initiator, select a thermal curing device, and if the initiator is a photoinitiator, select a light curing device;
  • the thermal curing device adopts a sandwich reaction flask device, which is insulated by a circulating temperature control device, the curing temperature is 40-80°C, and the curing time is 1-6h, which can achieve the dual-function effect of enrichment and pre-curing, and can be controlled by the discharge speed. Its reaction time can reach the uniformity of the product;
  • the light curing device adopts a coiled tube device, and the pipeline has the advantages of high transparency and high light absorption rate.
  • the prepared microspheres are continuously flowed in the pipeline and cured by real-time light irradiation through a high-intensity ultraviolet lamp.
  • the irradiation wavelength is 200 -500nm, illumination time 2-1000s, make the polymer microspheres fully solidify, and realize fast, efficient and safe preparation of embolic microspheres with uniform particle size.
  • 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 feed system, and controls the mobile phase/dispersed phase that may exist Pressure vessel, and control the temperature and pressure in the microsphere generating module and curing device.
  • the microsphere generating module includes several parallel microreactors, and the control system includes fault-tolerant settings. When a certain microreactor fails, the control system can automatically cut off the line where the microreactor is located. And the subsequent reaction process.
  • the microreactor in the microsphere generating module selects materials and molding methods according to reaction requirements, and selects different pipeline inner diameters, and controls the flow rate through a chip to prepare microspheres with uniform particle diameters.
  • the particle size of the polyvinyl alcohol embolization microspheres is controlled by controlling the inner diameter of the inlet of the microsphere generating module corresponding to the dispersed phase and the flow and the flow rate ratio of the dispersed phase and the mobile phase.
  • the injection flow rate of the dispersed phase material is controlled to be 0.1-2 ⁇ L/min, and the injection flow rate of the mobile phase material is 400 ⁇ 200 ⁇ L/min.
  • the particle size of the vinyl alcohol embolization microspheres is 20 ⁇ 10 ⁇ m, and the better solution is 2 ⁇ 5 ⁇ m.
  • the injection flow rate of the dispersed phase material is controlled to 2 ⁇ 1 ⁇ L/min, and the injection flow rate of the mobile phase material is 200 ⁇ 100 ⁇ L/min.
  • the particle size of the vinyl alcohol embolization microspheres is 40 ⁇ 20 ⁇ m, and the better solution is 40 ⁇ 10 ⁇ m.
  • the inner diameter of the dispersed phase pipeline is 100 ⁇ 20 ⁇ m
  • the inner diameter of the mobile phase pipeline is 300 ⁇ 150 ⁇ m
  • the injection flow rate of the dispersed phase material is controlled to 5 ⁇ 2 ⁇ L/min
  • the injection flow rate of the mobile phase material is 800 ⁇ 300 ⁇ L/min
  • prepared polyethylene The particle size of the alcohol embolization microspheres is 100 ⁇ 25 ⁇ m, and the better solution is 100 ⁇ 10 ⁇ m.
  • the inner diameter of the dispersed phase pipeline is 100 ⁇ 20 ⁇ m
  • the inner diameter of the mobile phase pipeline is 300 ⁇ 150 ⁇ m
  • the injection flow rate of the dispersed phase material is controlled to 5 ⁇ 2 ⁇ L/min
  • the injection flow rate of the mobile phase material is 500 ⁇ 200 ⁇ L/min
  • prepared polyethylene The particle size of the alcohol embolization microspheres is 250 ⁇ 50 ⁇ m, and the better solution is 250 ⁇ 20 ⁇ m.
  • the inner diameter of the dispersed phase pipeline is 250 ⁇ 130 ⁇ m
  • the inner diameter of the mobile phase pipeline is 500 ⁇ 200 ⁇ m
  • the injection flow rate of the dispersed phase material is controlled to 20 ⁇ 5 ⁇ L/min
  • the injection flow rate of the mobile phase material is 2000 ⁇ 500 ⁇ L/min
  • prepared polyethylene The particle size of the alcohol embolization microspheres is 500 ⁇ 50 ⁇ m, and the better solution is 500 ⁇ 20 ⁇ m.
  • the inner diameter of the dispersed phase pipe is 800 ⁇ 300 ⁇ m
  • the inner diameter of the mobile phase pipe is 1000 ⁇ 500 ⁇ m
  • the injection flow rate of the dispersed phase material is controlled to 50 ⁇ 20 ⁇ L/min
  • the injection flow rate of the mobile phase material is 800 ⁇ 200 ⁇ L/min
  • prepared polyethylene The particle size of the alcohol embolization microspheres is 800 ⁇ 80 ⁇ m, and the better solution is 800 ⁇ 50 ⁇ m.
  • the inner diameter of the dispersed phase pipeline is 800 ⁇ 400 ⁇ m
  • the inner diameter of the mobile phase pipeline is 2000 ⁇ 1000 ⁇ m
  • the injection flow rate of the dispersed phase material is controlled to 50 ⁇ 20 ⁇ L/min, and the injection flow rate of the mobile phase material is 5000 ⁇ 2500 ⁇ L/min
  • prepared polyethylene The particle size of the alcohol embolization microspheres is 1200 ⁇ 100 ⁇ m, and the better solution is 1200 ⁇ 50 ⁇ m.
  • the inner diameter of the dispersed phase pipe is 100 ⁇ 20 ⁇ m
  • the inner diameter of the mobile phase pipe is 100 ⁇ 50 ⁇ m
  • the injection flow rate of the dispersed phase material is controlled to 5 ⁇ 2 ⁇ L/min, and the injection flow rate of the mobile phase material is 500 ⁇ 300 ⁇ L/min
  • prepared polyethylene The particle size of the alcohol embolization microspheres is 100 ⁇ 25 ⁇ m, and the better solution is 100 ⁇ 10 ⁇ m.
  • the inner diameter of the dispersed phase pipe is 80 ⁇ 10 ⁇ m
  • the inner diameter of the mobile phase pipe is 100 ⁇ 20 ⁇ m
  • the injection flow rate of the dispersed phase material is controlled to 5 ⁇ 1 ⁇ L/min, and the injection flow rate of the mobile phase material is 300 ⁇ 100 ⁇ L/min
  • prepared polyethylene The particle size of the alcohol embolization microspheres is 80 ⁇ 25 ⁇ m.
  • the inner diameter of the mobile phase pipeline is 1500 ⁇ 500 ⁇ m
  • the inner diameter of the dispersed phase pipeline is 500 ⁇ 200 ⁇ m
  • the injection flow rate of the dispersed phase material is controlled to be 10-500 ⁇ L/min, and the injection flow rate of the dispersed phase material is 1000-50000 ⁇ L/min
  • prepared polyethylene The particle size of the alcohol embolization microspheres is 500-1400 ⁇ m.
  • the embolization microsphere production process mainly includes three major systems: a material feeding system, a microsphere generation module, and a curing device, and at the same time covers the amplification process equipment for stable, efficient, and high-throughput preparation of microspheres.
  • the material feeding system in the present invention is divided into disperse phase material feeding and mobile phase material feeding. According to the respective chemical and fluid properties, a suitable precision pump is selected as the driving device, and it is used as a two-phase material to adapt to different properties of polymers. Sampling requirements for materials, water-soluble materials, and organic phase materials;
  • the microsphere generating module in the present invention adopts chip type, microtube type and other microreactor devices, and its structure can be focus type, T type, coaxial and other structures.
  • the dispersed phase Under the action of the mutual shearing force of the mobile phase, the dispersed phase can form a water-in-oil structure or an oil-in-water structure to achieve precise control of the size of the microspheres, and the uniform particle size microspheres are prepared through cross-linking and solidification.
  • the invention provides two curing devices of thermal curing and light curing.
  • the two curing methods have the advantages of fast response time, high degree of crosslinking, etc., effectively improve product stability, and provide more selectivity for the production process of uniform particle size microspheres.
  • the present invention adopts microchannel pipelines, through the unique structure of water-in-oil, and initiates the cross-linking polymerization of the polymer molecules contained in the liquid bead on the surface of the liquid bead, and finally forms a tightly cross-linked and regular shape.
  • Round microspheres what the present invention represents is a complete preparation process of polyvinyl alcohol embolic microspheres with uniform particle size, not just a certain part such as a microchannel pipeline, and the effect achieved is not only the formation of liquid beads, Instead, it is cross-linked and polymerized in the channel to form microspheres with uniform particle size.
  • the invention can provide a continuous and automatic preparation of polyvinyl alcohol embolized microspheres with a controllable size and uniform particle size, covering a systematic equipment and corresponding production process for stable and efficient preparation of microspheres.
  • FIG. 1 is a schematic flow chart of the processing method of the reaction device provided in Embodiment 2;
  • Example 2 is a schematic diagram of the structure of the device for preparing embolic microspheres provided in Example 3;
  • Example 3 is a schematic diagram of the structure of the device for preparing embolic microspheres provided in Example 4.
  • Figure 4 is a schematic diagram of 40 ⁇ 20 ⁇ m polyvinyl alcohol embolization microspheres
  • Figure 5 is a schematic diagram of 100 ⁇ 25 ⁇ m polyvinyl alcohol embolization microspheres
  • Figure 6 is a schematic diagram of 250 ⁇ 50 ⁇ m polyvinyl alcohol embolization microspheres
  • Figure 7 is a schematic diagram of 500 ⁇ 50 ⁇ m polyvinyl alcohol embolization microspheres
  • Figure 8 is a schematic diagram of 800 ⁇ 80 ⁇ m polyvinyl alcohol embolization microspheres
  • Figure 9 is a schematic diagram of 1200 ⁇ 100 ⁇ m polyvinyl alcohol embolization microspheres
  • Figure 10 is a schematic diagram of 100 ⁇ 25 ⁇ m polyvinyl alcohol embolization microspheres.
  • the invention provides a reaction device comprising a main structure layer and an encapsulation layer.
  • the main structure layer is integrated with a groove, and the package is stacked on one side of the main structure layer; wherein the melting temperature of the main structure layer is higher than that of the encapsulation layer Temperature, the main structure layer and the encapsulation layer are connected by thermal bonding.
  • the present invention further restricts that the melting temperature of the main structure layer is higher than the melting temperature of the encapsulation layer.
  • the thermal bonding connection process as long as the thermal bonding temperature reaches the melting temperature of the encapsulation layer, the connection function can be realized.
  • the thermal bonding The temperature can also be lower than the melting temperature of the main structure layer, so as to prevent the collapse and deformation of the groove forming groove due to the high thermal bonding temperature during the thermal bonding process, which is beneficial to ensure the consistency of mass production , Suitable for mass production.
  • the main structure layer and the encapsulation layer are made of the same material, and the same material mentioned here is a thermoplastic polymer material prepared based on the same type of monomer through polymerization reaction.
  • the volume ratio and parameters are used to prepare polymer materials with different molecular weights or degrees of polymerization, which belong to the same material but have different melting temperatures.
  • the main structure layer and the encapsulation layer are made of the same material.
  • the overall mechanical strength of the reaction device is improved, and on the other hand, it provides theoretical support for the thermal bonding connection between the two layers. Can avoid the introduction of impurities.
  • the reaction device provided by the present invention has the advantages of integration, stable structure, high strength, etc., significantly improves the stability of liquid bead generation, and at the same time has the advantages of high production efficiency, good quality, and suitability for mass production. It is suitable for the application of the reaction device in clinical practice. Diagnosis, drug analysis, environmental monitoring, food development and other fields are of great significance.
  • the tank integrated in the main structure layer includes a dispersed phase tank and a continuous phase tank.
  • the continuous phase tank and the dispersed phase tank are connected to the same end of the main tank.
  • the continuous phase tank has a continuous phase feed port,
  • the phase tank has a disperse phase feed port, and the main tank has a discharge port;
  • the tank can be a flow focus type tank, a coaxial type tank, a T-shaped groove or a Y-shaped groove. There is no restriction here, and it can be adjusted according to specific needs. .
  • the flow focusing groove integrated in the main structure layer is taken as an example for further description.
  • the flow-focusing type tank includes a main tank, a dispersed phase tank and two continuous phase tanks.
  • the continuous phase tank and the continuous phase tank are symmetrically arranged, and the dispersed phase tank is arranged between the continuous phase tank and the continuous phase tank; the continuous phase tank, One end of the continuous phase tank and the dispersed phase tank on the same side is connected to and communicated with one end of the main tank, and the other end of the main tank extends to the side away from the continuous phase tank, the continuous phase tank, and the dispersed phase tank.
  • the two continuous phase tanks are provided with a continuous phase feed port at one end away from the main tank
  • the dispersed phase tank is provided with a dispersed phase feed port at one end away from the main tank
  • the main tank is provided with an outlet port at one end away from the dispersed phase tank and the continuous phase tank.
  • ⁇ Material mouth The liquid enters the continuous phase tank and the dispersed phase tank from the continuous phase feed port and the dispersed phase feed port respectively, and stably generates liquid beads under the action of shearing force at the junction of the main tank and passes through the discharge port of the main tank.
  • Output The setting of the continuous phase feed inlet, the dispersed phase feed inlet, and the feed outlet realizes the introduction and export of fluid in the reaction device, and completes the functions of fluid sampling and tank cleaning.
  • the two continuous phase tanks are connected at one end away from the main tank and share a continuous phase feed port.
  • This design increases the symmetry of the two continuous phase tanks on the one hand, makes the fluid more evenly distributed, and improves the flow-focused reaction device.
  • the stability of the generated microspheres on the other hand, optimize the structure, reduce the number of feed ports, improve the structural rationality of the overall device, and reduce the use of required pipelines and adapters; of course, in other embodiments, two continuous phase tanks
  • the end far away from the main tank may also be disconnected, and the ends are respectively provided with independent continuous phase feed ports, which can be adjusted according to specific needs, and there is no restriction here.
  • the ratio of the diameter of the dispersed phase feed port to the diameter of the dispersed phase tank is 1:1-2, and the ratio of the diameter of the continuous phase feed port to the diameter of the continuous phase tank is 1:1-2.
  • the diameter of the feed inlet directly smaller than the groove it is ensured that the material completely enters the inside of the groove without liquid dead volume.
  • the continuous phase inlet, the dispersed phase inlet, and the outlet penetrate the main structure layer, and the continuous phase inlet, the dispersed phase inlet, and the outlet facing the encapsulation layer are sealed by the encapsulation layer.
  • One end realizes feeding and discharging.
  • 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 50-1200um, and the diameter of the dispersed phase tank is 50-1000um, the diameter of the main groove is 50-1500um;
  • this embodiment uses the above-mentioned size limitation to facilitate the preparation of a wider range of droplets, and at the same time it is more in line with the fluid design ratio, has the largest shear force, and can use the least fluid
  • the droplets in the corresponding range are cut, while the control ratio range is wider; among them, the specific ratio value and respective specific values can be selected according to specific needs, and there is no limitation here.
  • the disperse phase feed port is connected to the dispersed phase tank through the connecting groove, and the diameter of the connecting groove is larger than the diameter of the dispersed phase groove; the diameter of the connecting groove is larger than the diameter of the dispersed phase groove, which can reduce the inertial impact force of the fluid. Play a buffer effect, make the fluid smoothly enter the dispersed phase tank, thereby improving the stability and continuity of droplet generation.
  • the setting of the connecting groove can also be omitted, and it can be adjusted according to specific needs, and there is no limitation here.
  • the connecting groove and the dispersed phase groove are connected in an inclined plane, and the inclined angle A of the inclined plane is 30-60°.
  • the arrangement of the inclined plane on the one hand has a buffering effect on the fluid and can quickly enter the dispersed phase groove, and on the other hand, On the one hand, the dead volume is reduced, and the fluid can be quickly replaced at a certain angle; on the other hand, the specific value of the inclination angle can be adjusted according to specific needs, and there is no limitation here.
  • the outer diameter of the discharge port is larger than the inner diameter. This design helps the fluid pressure to be released stably, and can further increase the mechanical strength of the reaction device. Specifically, it can be realized by designing the discharge port as a stepped hole or a trumpet-shaped hole, etc., which is not limited here.
  • the ratio of the minimum aperture of the discharge port to the diameter of the main groove is 1-1.5:1; for the conversion of the fluid movement direction, the droplets will collide, fuse or break, and this ratio can make the droplets move along with the fluid. Gradient conversion, the channel gradually enlarges, the droplet slowly shortens the distance in the fluid movement without colliding or breaking, thereby effectively improving the stability of the entire system.
  • the reaction device further includes a support layer, the support layer is placed on the side of the encapsulation layer facing away from the main structure layer, and 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.
  • the thickness of the support layer can also be less than or equal to the thickness of the encapsulation layer and the main structure. It is not limited here and can be adjusted according to the specific situation; the support layer is mainly used when the subsequent reaction device is clamped by the clamp. , The support layer cooperates with the clamp to realize positioning and clamping.
  • the support layer can also be omitted or the support layer and the encapsulation layer can be combined into one, which can be adjusted according to specific needs, and there is no limitation here.
  • the preferred support layer, the main structure layer, and the encapsulation layer are made of the same material, which is beneficial to increase the overall mechanical strength.
  • the support layer can also be made of different materials from the main structure layer and the encapsulation layer, which is not limited here.
  • the support layer is connected to the main structure layer by glue connection.
  • the glue type can be double-sided adhesive, photosensitive glue, solvent glue, etc. There is no restriction here, and it can be selected according to specific needs; the glue connection method has The bonding method is simple, low cost, and does not require heating. Of course, in other embodiments, other connection methods can also be selected according to needs, and there is no limitation here.
  • the ratio of the material thickness of the main structure layer, the encapsulation layer and the support layer is 1:(0.05-0.5):(1-3). It has strong supporting force during installation and will not crack.
  • the thickness of the encapsulation layer is lower than that of the main structure layer, which mainly ensures rapid heat transfer during the bonding process, quickly reaches thermal equilibrium, and achieves high bonding strength).
  • the flatness of the main structure layer, the encapsulation layer and the support layer is less than 0.01 mm to ensure a tight and firm connection between each other.
  • the main structure layer and the encapsulation layer are made of thermoplastic polymer materials, and the same type of thermoplastic polymer materials contain different degrees of polymerization, so that they have different melting temperatures; thermoplastic polymer materials include polymethyl methacrylate, poly Carbonate, cyclic olefin polymer and other polymers can be treated with hydrophobic or hydrophilic coating on the surface of the reaction device to meet the production needs of different types of microspheres.
  • the preferred main structure layer and encapsulation layer 1 are made of cycloolefin polymer, which has a wide range of glass transition temperature (ie melting temperature) from 90°C to 160°C, which facilitates the selection of the main structure layer and the encapsulation layer.
  • glass transition temperature ie melting temperature
  • the different degrees of polymerization of thermoplastic polymer materials further distinguish the melting temperatures of the two.
  • the present invention provides a method for processing a reaction device, as shown in FIG. 1, for processing the reaction device described in Example 1.
  • the processing method of the reaction device is specifically as follows:
  • the main structure layer and the encapsulation layer described in Example 1 are separately processed from the same material, and the polymerization degree of the material is controlled so that the melting temperature of the encapsulation layer obtained by processing is lower than the melting temperature of the main structure layer;
  • the processed main structure layer and the packaging layer are connected by thermal bonding.
  • the main structure layer and the encapsulation layer are connected by thermal bonding under vacuum conditions, which is beneficial to avoid the introduction of impurities.
  • the thermal bonding temperature is lower than the melting temperature of the main structure layer and higher than or equal to the melting temperature of the encapsulation layer to ensure that the encapsulation layer is melted to achieve the encapsulation effect while avoiding the collapse of the groove in the main structure layer. Or deformed.
  • the difference between the thermal bonding temperature and the melting temperature of the main structure layer is 0.1-10%; the thermal bonding temperature melts the encapsulation layer and then bonds with the main structure layer.
  • the temperature difference with the encapsulation layer is improved.
  • the compatible temperature range enables the encapsulation layer to quickly bond with the main structure layer. If the temperature difference is too large, it is easy to cause unstable adhesion and low bonding strength. Therefore, the thermal bonding temperature and the melting temperature difference of the main structure layer are controlled In the range of 0.1-10%.
  • the thermal bonding temperature range is 90-160°C
  • the thermal bonding time range is 3-30min
  • the thermal bonding pressure range is 20-200kg.
  • the bonding parameter range is determined according to factors such as the nature of the material and the thickness ratio. , The bonding pressure, time, and temperature all play a decisive role. If it is too large, it will easily cause the collapse, deformation, energy waste, and low efficiency of the groove. If it is too low, it will cause low bonding strength, low adhesion, and low efficiency. There are more products and other issues; the temperature, time and pressure of thermal bonding during processing can be selected according to specific needs. For example, the bonding pressure is 60kg, the temperature is 130°C, and the bonding time is 10min. There is no restriction here. .
  • the support layer and the packaging layer are connected by glue connection.
  • the bonding pressure between the support layer and the encapsulation layer is in the range of 1-10kg, and the bonding time is in the range of 3-30s.
  • the gluing time and pressure during the processing can be selected according to specific needs.
  • the bonding pressure range is 3kg, and the bonding time is 5s, which is not limited here.
  • the present invention provides a device for preparing embolic microspheres, including a feeding system 1, a microsphere generating module 2 and a curing device 3; the feeding system 1 is connected to the microsphere generating module 2, and the microsphere generating module 2 Connected to the curing device 3, the feeding system 1 is used to provide materials to the microsphere generating module 2, and the materials are reacted in the microsphere generating module 2 to generate droplets. After being processed by the curing device 3, embolic microspheres with uniform particle size are obtained.
  • the device for preparing embolic microspheres provided by the present invention can be used to prepare polyvinyl alcohol embolic microspheres, and can also be used to prepare other types of microspheres, which is not limited here.
  • the embolization microsphere preparation equipment mainly includes three major systems: a material feeding system, a microsphere generation module, and a curing device, and also covers a stable, high-efficiency, and high-throughput amplification process equipment for preparing microspheres.
  • the microsphere generating module 2 includes at least one microreactor, and the microreactor uses the reaction device described in Example 1. Further, the microsphere generating module 2 includes a plurality of microreactors connected in parallel, and the plurality of microreactors are respectively connected to the feeding system 1 and the curing device 3; the plurality of microreactors are operated in parallel to realize mass production. At the same time, multiple microreactors have the advantages of independence and anti-interference.
  • the number of microreactors can be one, eight as shown in FIG. 2, or other numbers, which are not limited here, and can be adjusted according to specific conditions.
  • microreactors can be used to generate microspheres of the same or different diameters, and the inner diameter of the channel for generating droplets in the microreactor is 20-2000 ⁇ m; specifically, it can be used to generate droplets by controlling the microreactor.
  • the diameter of the tank, the operating parameters of the liquid in it and other factors can achieve the preparation of uniform particle size microspheres of different sizes.
  • the size of the microspheres can be adjusted between 20-1400um and the particle size uniformity is less than 10%. Adjust according to specific needs.
  • the microreactor further includes a microfluidic chip, and the microfluidic chip cooperates with the controller to control the flow rate of the reaction liquid entering the microreactor, so as to control the particle size of the microspheres by controlling the flow rate.
  • the microsphere generating module in the present invention can adopt chip type, microtube type and other microreactors, and its structure can be focus type, T type, coaxial and other structures.
  • the dispersed phase materials can form a water-in-oil structure or an oil-in-water structure under the mutual shearing force of the continuous phase materials to achieve precise control of the size of the microspheres, and the uniform particle size microspheres are prepared through cross-linking and solidification.
  • the feeding system includes a continuous phase feeding system 11 for feeding oil phase materials and a dispersed phase feeding system 12 for feeding water phase materials; the continuous phase feeding system 11 and each microreactor The continuous phase feed ports are respectively connected, and the dispersed phase feed system 12 is connected to the dispersed phase feed ports of each microreactor respectively.
  • the material feeding system in the present invention is divided into disperse phase material feeding and mobile phase material feeding. According to the respective chemical and fluid properties, a suitable precision pump is selected as the driving device, and it is used as a two-phase material to adapt to different properties of polymers. Sampling requirements for materials, water-soluble materials, and organic phase materials;
  • the continuous phase feed 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 feed of each microreactor.
  • the feed ports are connected separately; 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, and the continuous phase feed pump 112 is used to push the continuous phase storage tank
  • the material in 113 is conveyed to the continuous phase feed port of each micro-reactor through the pipeline, so as to realize the feed of oil phase material.
  • the dispersed phase feeding system 12 includes a second pressure source device 121, a dispersed phase feeding 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 respectively ;
  • the dispersed phase storage tank 123 is used to store water phase materials, the second pressure source device 121 is used to provide pressure to the dispersed phase feed pump 122, and the dispersed phase feed pump 122 is used to push the materials in the dispersed phase storage tank 123 through
  • the pipeline is conveyed to the disperse phase feed port of each microreactor, so as to realize the feed of the water phase material.
  • the continuous phase feed pump 112 and the dispersed phase feed pump 122 are both pressure pumps and need to be used with a pressure source device.
  • the continuous phase storage tank 113 and the dispersed phase storage tank 123 are pressed into the material by pressure. Inside the microreactor.
  • first pressure source device 111 and the second pressure source device 121 may specifically be devices such as nitrogen cylinders, gas compressors, etc., which are not limited here, and can be selected according to specific needs.
  • 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 that the flow and pressure of the feed can be controlled.
  • the dispersed phase is preferably controlled.
  • the flow rate is 0.1-500 ⁇ L/min, and the continuous phase flow rate is 100-50000 ⁇ L/min, so that the materials can be transported to each microreactor stably, continuously and with high flux.
  • the continuous phase feed pump 112 and the dispersed phase feed pump 122 can specifically be selected as a precision pressure pump, a high precision injection pump, a high precision constant flow pump, and the like.
  • the precision pressure pump has a range of 0-4bar and an accuracy of 0.01%-0.2%. It can be purchased from domestic and foreign suppliers, such as Suzhou Wenhao, Dolomite, etc.; the high-precision injection pump has a variety of working modes to adapt to different fields It has high control accuracy and wide linear speed range.
  • Its flow range can be 0.001 ⁇ L/h-50mL/min, which can be purchased from domestic and foreign suppliers, such as Baodinglan Grid Co., Ltd., Shanghai Spectral Analysis and Detection Technology, etc.; high-precision constant-flow pumps have high pressure and head, and the conveying material does not contact the outside world, and its accuracy is 0.01-1000mL/min, which can be purchased from domestic and foreign suppliers , Such as Baoding Lange Co., Ltd., Shanghai Precision Instruments and other companies.
  • the discharge port of each microreactor is connected to the curing device 3, and the droplets generated by each microreactor are transported to the curing device 3 for curing, thereby obtaining embolic microspheres.
  • the curing device 3 is an ultraviolet curing device or a thermal curing device, etc., both of which include a curing container and a corresponding generating device.
  • the invention provides two curing devices of thermal curing and light curing. The two curing methods have the advantages of fast response time, high degree of crosslinking, etc., effectively improve product stability, and provide more selectivity for the production process of uniform particle size microspheres.
  • the initiator in the polyvinyl alcohol material is a chemical initiator, it is a thermal curing device.
  • the thermal curing device is a double-layer reaction flask, mechanical stirring and constant temperature water bath. Part of the composition, the reaction process is mechanically stirred to make the fluid uniform, and the constant temperature water bath provides energy conduction, reaches the thermal curing reaction conditions, and finally realizes the enrichment and cross-linking reaction of the product.
  • the initiator in the polyvinyl alcohol material is a photoinitiator, it is a photocuring device.
  • the photocuring device is irradiated with an ultraviolet light source with an intensity of 10-1000W.
  • the generated microspheres are formed by ultraviolet initiation polymerization in the pipeline to achieve the product Cross-linking polymerization. Both curing methods can quickly crosslink the polymer microspheres, improve product stability, and effectively increase the molding method and speed of the microspheres, and increase the simplicity of the production process of polyvinyl alcohol embolized microspheres.
  • two curing methods thermal curing and light curing, are simultaneously used for curing; but in other embodiments, only one curing method may be used, for example, only thermal curing (see Figure 3), or only use light curing, which is subject to actual needs, and will not be repeated here.
  • the assembly of the modules of the embolic microsphere preparation equipment is based on plastic pipe fittings, metal pipes, threaded sleeves, washers, adapters and other accessories to connect, so that the sleeves and metal pipes with external threads can be connected to the chip,
  • the microtubes get a high-tight interface, and the liquid is transported by plastic pipe fittings, such as PTFE pipes with an inner diameter of 100-3200um and PEEK pipes with an inner diameter of 100-3200um.
  • the pipes have good flexibility, smoothness, and non-toxicity. , Provide guarantee for the connection of the whole process.
  • the invention adopts micro-channel pipelines, through the unique structure of water-in-oil, and initiates the cross-linking polymerization of the polymer molecules contained in the liquid bead on the surface of the liquid bead, and finally forms tightly cross-linked, regular-shaped round microspheres;
  • the invention represents a complete set of equipment for the preparation of embolic microspheres, not just a certain component such as a microchannel pipeline, and the effect achieved is not only to form liquid beads, but to cross-link and polymerize in the channel to form particles.
  • the invention can provide a continuous and automatic preparation of polyvinyl alcohol embolized microspheres with a controllable size and uniform particle size, covering a systematic equipment and corresponding production process for stable and efficient preparation of microspheres.
  • This embodiment is an adjustment made on the basis of the third embodiment.
  • the continuous phase feed system 11 includes a directly connected continuous phase feed pump 112 and a continuous phase storage tank 113
  • the dispersed phase feed system 12 includes a directly connected The dispersed phase feed pump 122 and the dispersed phase storage tank 123.
  • the continuous phase feed pump 112 and the dispersed phase feed pump 122 adopt a non-pressure type pump structure, such as a suction type pump structure, which is directly arranged in the continuous phase storage tank 113 and the dispersed phase storage tank 123 and It is sufficient to connect the micro-reactor to the pipeline, as shown in Figure 3.
  • a non-pressure type pump structure such as a suction type pump structure
  • Embodiment 3 For other structures of the device for preparing embolic microspheres in this embodiment, reference can be made to the description in Embodiment 3, which is not limited here.
  • the present invention provides a preparation method of embolic microspheres, which is specifically illustrated by taking the preparation of polyvinyl alcohol embolic microspheres as an example.
  • a precision pressure pump is used to transport materials, the microreactor is a focused chip, and the inner diameter of the dispersed phase pipe is 20 ⁇ 10 ⁇ m, and the inner diameter of the mobile phase pipe is 20 ⁇ 10 ⁇ m.
  • Device setup add the prepared dispersed phase and mobile phase materials to the liquid storage bottle, connect the pressure control module, air source, computer control panel, pipeline and other devices, first start the initialization device to verify whether the liquid storage bottle has The gas is exposed, confirming its excellent air tightness.
  • a plurality of micro-reactors (for example, 8 in Figure 2) are arranged in parallel in sequence, and their pipelines are connected to the discharge port pipelines through adapters.
  • the outlet pipelines of the micro-reactors are connected to the curing device, and the curing
  • the device adopts a thermal curing method and is connected to a constant temperature heating cycle device.
  • the homogeneous microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone respectively, dried in vacuum, and then swelled to obtain polyethylene plug microspheres with uniform particle size.
  • Particle size analysis The particle size distribution of the microspheres is uniform, and the output is high, which can realize mass production.
  • the prepared polyvinyl alcohol embolic microspheres have a particle size of 20 ⁇ 10 ⁇ m, and a better solution is 20 ⁇ 5 ⁇ m, which meets the requirement of uniform particle size.
  • the present invention provides a preparation method of embolic microspheres, which is specifically illustrated by taking the preparation of polyvinyl alcohol embolic microspheres as an example.
  • a precision pressure pump is used to transport materials, and the microreactor is a focused chip, the inner diameter of the dispersed phase pipe is 60 ⁇ 10 ⁇ m, and the inner diameter of the mobile phase pipe is 90 ⁇ 50 ⁇ m. Specific steps are as follows:
  • the homogeneous microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone respectively, dried in vacuum, and then swelled to obtain polyethylene plug microspheres with uniform particle size.
  • Particle size analysis As shown in Figure 4, the particle size distribution of the microspheres is uniform, and the output is high, which can realize mass production.
  • the prepared polyvinyl alcohol embolic microspheres have a particle size of 40 ⁇ 20 ⁇ m, and a better solution is 40 ⁇ 10 ⁇ m, which meets the requirement of uniform particle size.
  • the present invention provides a preparation method of embolic microspheres, which is specifically illustrated by taking the preparation of polyvinyl alcohol embolic microspheres as an example.
  • a precision pressure pump and a syringe pump are used to transport materials.
  • the microreactor is a focused chip.
  • the inner diameter of the dispersed phase pipe is 100 ⁇ 20 ⁇ m and the inner diameter of the mobile phase pipe is 300 ⁇ 150 ⁇ m.
  • the granules are prepared by controlling the flow rate of the dispersed phase and the mobile phase. The specific steps for uniform diameter microspheres are as follows:
  • the homogeneous microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone respectively, dried in vacuum, and then swelled to obtain polyethylene plug microspheres with uniform particle size.
  • Particle size analysis As shown in Figure 5, the particle size distribution of the microspheres is uniform, and the output is high, which can realize mass production.
  • the prepared polyvinyl alcohol embolic microspheres have a particle size of 100 ⁇ 25 ⁇ m, and a better solution is 100 ⁇ 10 ⁇ m, which meets the requirement of uniform particle size.
  • the present invention provides a preparation method of embolic microspheres, which is specifically illustrated by taking the preparation of polyvinyl alcohol embolic microspheres as an example.
  • a precision injection pump and a constant flow pump are used to transport materials.
  • the microsphere generating device is a focused chip, and the inner diameter of the dispersed phase pipeline is 100 ⁇ 20 ⁇ m, and the inner diameter of the mobile phase pipeline is 300 ⁇ 150 ⁇ m.
  • the specific steps are as follows:
  • the homogeneous microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone respectively, dried in vacuum, and then swelled to obtain polyethylene plug microspheres with uniform particle size.
  • the present invention provides a preparation method of embolic microspheres, which is specifically illustrated by taking the preparation of polyvinyl alcohol embolic microspheres as an example.
  • a precision syringe pump and a constant flow pump are used to transport materials.
  • the microsphere generating device is a 3D printed cross-shaped pipeline.
  • the inner diameter of the dispersed phase pipeline is 250 ⁇ 130 ⁇ m and the inner diameter of the mobile phase pipeline is 500 ⁇ 200 ⁇ m.
  • dispersed phase materials weigh 0.4g potassium persulfate into 100g water, magnetically stir to dissolve, slowly add 8g 2-acrylamido-2-methylpropanesulfonate sodium, stir evenly, and then add 10g poly Vinyl alcohol derivatives, stir evenly, and use them as dispersed phase materials for later use.
  • the homogeneous microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone respectively, dried in vacuum, and then swelled to obtain polyethylene plug microspheres with uniform particle size.
  • the present invention provides a preparation method of embolic microspheres, which is specifically illustrated by taking the preparation of polyvinyl alcohol embolic microspheres as an example.
  • a precision pressure pump is used to transport materials
  • the microsphere generating device is a T-chip
  • the inner diameter of the dispersed phase pipe is 800 ⁇ 300 ⁇ m
  • the inner diameter of the mobile phase pipe is 1000 ⁇ 500 ⁇ m
  • the light curing device is used.
  • the light curing time is 40s, and the microspheres are quickly cross-linked to prepare the product. Then use butyl acetate and ethyl acetate respectively. , Acetone washing, vacuum drying, and then swelling to obtain polyethylene plug microspheres with uniform particle size.
  • Particle size analysis As shown in Figure 8, the particle size distribution of the microspheres is uniform, the output is high, and the curing time is short, which can realize mass production.
  • the prepared polyvinyl alcohol embolic microspheres have a particle size of 800 ⁇ 80 ⁇ m, and a better solution is 800 ⁇ 50 ⁇ m, which meets the requirement of uniform particle size.
  • the present invention provides a preparation method of embolic microspheres, which is specifically illustrated by taking the preparation of polyvinyl alcohol embolic microspheres as an example.
  • a precision pressure pump is used to transport materials
  • the microsphere generating device is a T-type chip
  • the inner diameter of the dispersed phase pipeline is 800 ⁇ 400 ⁇ m
  • the inner diameter of the mobile phase pipeline is 2000 ⁇ 1000 ⁇ m.
  • microspheres When the microspheres are pre-aged in the coil to prevent collision and fusion from entering the curing device, they will continue to be transported to the curing device and stirred and solidified at 80°C for 4 hours.
  • the homogeneous microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone respectively, dried in vacuum, and then swelled to obtain polyethylene plug microspheres with uniform particle size.
  • Particle size analysis As shown in Figure 9, the particle size distribution of the microspheres is uniform, and the output is high, which can realize mass production.
  • the prepared polyvinyl alcohol embolic microspheres have a particle size of 1200 ⁇ 100 ⁇ m, and a more optimal solution is 1200 ⁇ 50 ⁇ m, which meets the requirement of uniform particle size.
  • the present invention provides a preparation method of embolic microspheres, which is specifically illustrated by taking the preparation of polyvinyl alcohol embolic microspheres as an example.
  • a precision pressure pump is used to transport materials
  • the microsphere generating device is a focused chip
  • the inner diameter of the dispersed phase pipe is 100 ⁇ 20 ⁇ m
  • the inner diameter of the mobile phase pipe is 100 ⁇ 50 ⁇ m
  • a light curing device is used. Specific steps are as follows:
  • the light curing time is 60s.
  • the microspheres are quickly cross-linked to prepare the product, and then use butyl acetate and ethyl acetate respectively. , Acetone washing, vacuum drying, and then swelling to obtain polyethylene plug microspheres with uniform particle size.
  • Particle size analysis As shown in Figure 10, the particle size distribution of the microspheres is uniform, while the output is high, and the curing time is short, which can realize batch and rapid production.
  • the prepared polyvinyl alcohol embolic microspheres have a particle size of 100 ⁇ 25 ⁇ m, and a better solution is 100 ⁇ 10 ⁇ m, which meets the requirement of uniform particle size.
  • the present invention provides a preparation method of embolic microspheres, which is specifically illustrated by taking the preparation of polyvinyl alcohol embolic microspheres as an example.
  • a precision pressure pump is used to transport materials, and the microsphere generating device is a focused chip.
  • the inner diameter of the dispersed phase pipe is 80 ⁇ 10 ⁇ m and the inner diameter of the mobile phase pipe is 100 ⁇ 20 ⁇ m. Specific steps are as follows:
  • the light curing time is 1s, and the surface of the microspheres is cross-linked, and then collected in the flask , After 12h, start the thermal curing device, stir and cure at 60°C for 3h.
  • the homogeneous microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone respectively, dried in vacuum, and then swelled to obtain polyethylene plug microspheres with uniform particle size.
  • Particle size analysis The particle size distribution of the microspheres is uniform, and the molding process of the microspheres can be controlled to realize batch and controllable production.
  • the prepared polyvinyl alcohol plug microspheres have a particle size of 80 ⁇ 25 ⁇ m, and a more optimal solution is 80 ⁇ 10 ⁇ m, which meets the requirement of uniform particle size.
  • the present invention provides a preparation method of embolic microspheres, which is specifically illustrated by taking the preparation of polyvinyl alcohol embolic microspheres as an example.
  • the microsphere generating device is a coaxial microtube, with an inner diameter of the dispersed phase pipeline of 1500 ⁇ 500 ⁇ m and an inner diameter of the mobile phase pipeline of 500 ⁇ 200 ⁇ m. Specific steps are as follows:
  • the homogeneous microspheres are cooled to room temperature, washed with butyl acetate, ethyl acetate, and acetone respectively, dried in vacuum, and then swelled to obtain polyethylene plug microspheres with uniform particle size.
  • the prepared polyvinyl alcohol plug microspheres have a particle size of 500-1400 ⁇ m, which meets the requirement of uniform particle size.

Abstract

本发明提供了反应装置及其加工方法，其中反应装置包括主体结构层和封装层，主体结构层集成有液珠的槽，封装层叠置于所述主体结构层的一侧；主体结构层与封装层采用同种材料制成，且主体结构层的熔融温度高于封装层的熔融温度，主体结构层与封装层通过热键合方式连接。本发明反应装置具有一体化、结构稳定、强度高等优点，显著提升液珠生成的稳定性。本发明还涉及栓塞微球的制备设备及其制备方法，其通过进料系统（1）、微球生成模块（2）、固化装置（3）三大系统结合实现了自动化、标准化、可控化生产。

Description

反应装置及其加工方法、栓塞微球的制备设备及其制备方法 技术领域
本发明涉及医疗器械生产技术领域，具体涉及栓塞微球生产的反应装置及其加工方法、栓塞微球的制备设备及栓塞微球的制备方法。
背景技术
肿瘤性癌症已经成为危害全球公共健康的首要问题，而我国每年新增的肿瘤患者约400万人，有60-70万人进行肿瘤介入治疗，并以10-20％速率增加。随着微创技术的发展，药物洗脱栓塞微球化疗栓塞术作为新型栓塞技术正在兴起，不仅能够负载化疗药，又能起到栓塞作用，从而实现对肿瘤的持续治疗，提升治疗效果。
聚乙烯醇栓塞微球用于肿瘤疾病的治疗已经是非常重要的临床治疗手段，其原理是通过微球栓塞病患部位的血管，切断肿瘤细胞的营养供应，使肿瘤细胞因得不到营养而萎缩，同时，栓塞微球可以负载化疗药，在肿瘤附近血管处持续缓慢释放药物，靶向治疗肿瘤，进而达到治疗的作用。
目前上市的栓塞材料产品中，具有包载化疗药物的产品只有英国Biocompatibles公司的DC
Figure PCTCN2020116485-appb-000001
美国BioSphere公司的
Figure PCTCN2020116485-appb-000002
以及恒瑞集团旗下的
Figure PCTCN2020116485-appb-000003
以上三种栓塞微球产品已经大大改善了传统栓塞材料的缺陷，在肝癌等肿瘤临床治疗过程中，取得了突破性的治疗效果。
目前市场供应的聚乙烯醇栓塞微球产品粒径并不均一，而是在一定范围内，比如100-300μm、300-500μm、500-700μm等范围。根据研究表明，肿瘤四周分布着各种尺寸的血管，越接近肿瘤中心，血管越细(即存在小于100um的血管)，栓塞效果越好。因此，更小粒径、更均匀的微球，使其在临床栓塞过程中能够进入、且更接近肿瘤血管中。同时在生产工艺方面，当前微球采用“一锅法”制备，再经过分筛工序获得目标粒径范围的微球产品。该生产工艺存在效率低、质控复杂、劳动强度大、成本高等问题。因此需要开发新型粒径均一的聚乙烯醇栓塞微球及其生产工艺，以提高生产效率及精准化治疗效果。
目前已有制备粒径均一微球的文献与专利报道，例如专利CN 107418872 A采用聚焦型、T型液滴微流控芯片制备生物墨汁微球；其包括：液滴生成模块，包括第一流体入口、液滴微流控芯片和输出端口，液滴微流控芯片包括流道系，第一流体入口和输出端口分别与流道系连通，从第一流体入口进入流道系内的分散相流体形成液滴并从输出端口输出液滴；收集制造模块，包括收集制造主体，收集制造主体包括各自具有作用表面的多个收集孔，各收集孔的作用表面彼此隔离，收集孔用于接收液滴至作用表面并在作用表面上基于液滴形成微球；运动模块，与输出端口和/或收集制造主体驱动连接，以使各液滴对应地滴至收集孔的作用表面上；控制模块，与液滴生成模块和运动模块分别耦合。该设备主要用于制备具有生物活性 的生物墨汁微球，该微球为沿微球的径向分层设置的分层球状结构，其粒径为5-120μm之间，其关键在于控制核芯液中包含细胞的胶原溶液中所含细胞个数。
上述技术方案的核心在于针对生物墨汁用包括微流控芯片的液滴生成模块结构设计及相应的收集制造、运动模块和控制模块的设计。
但上述该装置并不能够直接应用于聚乙烯醇栓塞微球的制备，且5-120μm的粒径也不能够满足聚乙烯醇栓塞微球的直径要求。
CN101376093A采用四氟毛细管与中空纤维组装的共轴微反应器，能够制备单分散聚合物微球；该专利公开于2009年，技术较为落后，为之后的微反应器提供了技术思路，但并没有比较好的配套工艺制备满足当今手术要求的聚乙烯栓塞微球。
CN109793916A采用微通道管路制备粒径均一的聚乙烯醇栓塞微球，该专利提供了一种采用微通道管路制备聚乙烯醇栓塞微球的工艺，但该申请没有公开相应的工艺设备，在工业化应用上仍存在欠缺之处。
以上专利都是采用微流控技术使分散相与连续相的相互剪切，调控两相流速大小及液滴生成结构，制备不同粒径大小及均一性微球。
上述微流控技术方案仍主要处于科研研究阶段，使用单个管路或者单芯片制备粒径均一微球，存在工艺放大化难，目前仍无微流控生产工艺制备大量微球，缺乏可稳定、高效、高通量制备微球的直接相关设备，同时对制备微球的材料无明确适应性、芯片加工重复性、粒径均一度误差较大、微球成型情况不可控、效率低等问题，特别是难以满足制备医疗所需的聚乙烯醇栓塞微球的批量、标准化需求。
另外，针对现有栓塞微球的制备设备中的反应装置还存在以下问题：
现有反应装置大都采用热塑性聚合物加工，并采用键合技术进行连接组装，但是对于热塑性聚合物反应装置的加工与键合技术在制作效率、制作质量、制作精度、方法的适应性等方面存在主要问题，也是目前反应装置批量化实现生产的主要瓶颈问题，其技术难度主要表现在：键合需要同时解决连接与密封问题、反应装置材质的整体机械强度、槽塌陷与变形、批量化生产的一致性等问题。因此急需开发一种可实现批量化生产的反应装置。
发明内容
针对背景技术中的问题，本发明提供了一种反应装置，包括主体结构层和封装层，所述主体结构层集成有液珠的槽，所述封装层叠置于所述主体结构层的一侧；
其中，所述主体结构层的熔融温度高于所述封装层的熔融温度，所述主体结构层与所述封装层通过热键合方式连接。
在一些实施例中，所述主体结构层与所述封装层采用同种材料制成。
在一些实施例中，所述主体结构层内集成的槽具有分散相进料口、连续相进料口和出料口；所述槽为流动聚焦型槽或同轴型槽或T型槽或Y型槽。
在一些实施例中，所述流动聚焦型槽包括有主槽、分散相槽和两连续相槽，两所述连续相槽对称设置，所述分散相槽设置在两所述连续相槽之间；两所述连续相槽、所述分散相槽同一侧的一端均连接到所述主槽的一端上并与之连通，所述主槽的另一端向远离所述分散相槽、连续相槽一侧延伸。
在一些实施例中，所述连续相槽、分散相槽、主槽的直径比例为1∶0.2-1∶1-1.5。
在一些实施例中，所述连续相槽远离所述主槽的一端设置连续相进料口，所述分散相槽远离所述主槽的一端设置有分散相进料口，所述主槽远离所述分散相槽、连续相槽的一端设置有出料口。
在一些实施例中，所述连续相进料口、分散相进料口、出料口贯穿所述主体结构层，且所述连续相进料口、分散相进料口、出料口的一端通过所述封装层密封。
在一些实施例中，两所述连续相槽远离所述主槽的一端相连通并共用一个所述连续相进料口。
在一些实施例中，所述分散相在槽进料口的直径与所述分散相槽的直径比例为1：1-2；所述连续相槽进料口的直径与所述连续相槽的直径比例为1：1-2。
在一些实施例中，所述分散相进料口通过连接槽与所述分散相槽连通，且所述连接槽的直径大于所述分散相槽的直径。
在一些实施例中，所述连接槽与所述分散相槽连接处呈斜面连接，且该斜面的倾斜角度为30～60°。
在一些实施例中，所述出料口内侧孔径大于外侧孔径。
在一些实施例中，所述出料口为一阶梯孔或喇叭形孔。
在一些实施例中，还包括有支持层，所述支持层叠置于所述封装层背向所述主体结构层的一侧上。
在一些实施例中，所述主体结构层、封装层与支持层的材料厚度比例为1：0.05-0.5：1-3。
在一些实施例中，所述支持层与所述主体结构层、所述封装层采用同种材料制成。
在一些实施例中，所述主体结构层与所述封装层采用热塑性聚合物材料。
在一些实施例中，所述主体结构层与所述封装层采用环烯烃聚合物。
本发明还提供了一种反应装置的加工方法，用于加工如上所述的反应装置，加工方法为：
S1、采用同种材料分别加工出所述主体结构层和封装层，并通过控制材料的聚合度，使得加工获得的所述封装层的熔融温度低于所述主体结构层的熔融温度；
S2、加工好的所述主体结构层和封装层通过热键合方式进行连接。
较佳地，步骤S2进一步包括：所述主体结构层和封装层在真空条件下通过热键合方式进行连接。
在一些实施例中，步骤S2进一步包括：热键合温度低于所述主体结构层的熔融温度，且高于或等于所述封装层的熔融温度。
在一些实施例中，所述热键合温度与所述主体结构层的熔融温度相差0.1-10％。
在一些实施例中，步骤S2进一步包括：热键合温度范围为90-160℃。
在一些实施例中，步骤S2进一步包括：热键合时间范围为3-30min。
在一些实施例中，步骤S2进一步包括：热键合连压力范围为20-200kg。
在一些实施例中，还包括步骤S3：在所述封装层背向所述主体层的一侧上通过胶连接的方式连接支撑层。
在一些实施例中，步骤S3进一步包括:所述支持层与所述封装层之间的粘合压力范围为1-10kg。
在一些实施例中，步骤S3进一步包括:所述支持层与所述封装层之间的粘合时间范围为3-30s。
本发明提供的反应装置，主体结构层和封装层采用同种材料制成，一方面提高了反应装置的整体机械强度，另一方面为两层之间的热键合连接提供理论支持，还可避免引入杂质；本发明进一步的限定了主体结构层的熔融温度高于封装层的熔融温度，在热键合连接过程中只要热键合温度达到封装层的熔融温度即可实现连接的功能，此时热键合温度还可实现低于主体结构层的熔融温度，从而防止在热键合连接过程中由于热键合温度高导致其内的形成槽的槽塌陷、变形的问题，有利于保证批量生产的一致性，适用于批量生产。
本发明的提供的反应装置，具有一体化、结构稳定、强度高等优点，显著提升液珠生成的稳定性，同时具备制作效率高、质量好、适合批量化生产等优点，对于反应装置应用在临床诊断、药物分析、环境监测、食品开发等领域具有重大意义。
本发明提供了一种栓塞微球的制备设备，包括进料系统、微球生成模块和固化装置；所述进料系统与微球生成模块连接，所述微球生成模块与所述固化装置连接；其中所述微球生成模块包括有至少一个微反应器，所述微反应器采用如上所述的反应装置。
在一些实施例中，所述微球生成模块包括有多个并联的所述微反应器，多个所述微反应器均分别与所述进料系统和所述固化装置连接，多个所述微反应器用于生成相同或不同直径的微球。
在一些实施例中，所述进料系统包括有连续相进料系统和分散相进料系统，所述连续相进料系统和分散相进料系统分别与各所述微反应器的连续相进料口和分散相进料口连通。
在一些实施例中，所述连续相进料系统包括有相连的连续相进料泵和连续相储料罐，所述连续相储料罐与各所述微反应器的连续相进料口连通；
所述分散相进料系统包括相连的分散相进料泵和分散相储料罐，所述分散相储料罐与各所述微反应器的分散相进料口连通。
在一些实施例中，所述连续相进料系统还包括有第一压力源装置，所述第一压力源装置、连续相进料泵、连续相储料罐顺序连接；
所述分散相进料系统还包括有第二压力源装置，所述第二压力源装置、分散相进料泵和分散相储料罐顺序连接。
在一些实施例中，所述连续相进料泵、所述分散相进料泵采用配备有带有流量、压力控制装置的泵。
在一些实施例中，所述微反应器还包括微流控芯片；所述微流控芯片配合控制器控制进入所述微反应器的反应液流速。
在一些实施例中，所述固化装置为紫外光固化装置或热固化装置，均包括固化容器及相应的发生装置。
本发明还提供了一种栓塞微球的制备方法，所述的制备方法由如上所述的设备完成，具体步骤如下：
(1)分散相主要为水溶性物料，分散相物料组分为聚乙烯醇及其衍生物、水、交联剂和分散相物料引发剂。首先将引发剂溶解于水中，再依次加入交联剂，最后加入聚乙烯醇及其衍生物，搅拌均匀，作为分散相备用。
所述聚乙烯醇及其衍生物采用聚乙烯醇为基材，以酰化后可交联的氨基/羟基的羧酸衍生物/磺酸衍生物为改性剂，进行改性后制得含有丙烯酸或其衍生物结构的可交联小分子的聚合物。
所述分散相物料中的交联剂为丙烯酸盐，具体包括：丙烯酸钠、丙烯酸丙烯酰胺铵盐、2-丙烯酰胺基-2-甲基丙磺酸钠等；
所述引发剂可分为过氧类引发剂和光引发剂，过氧类引发剂包括过硫酸钾、过硫酸铵等，光引发剂包括苯偶酰类、酰基磷氧化物等。
所述述聚乙烯醇及其衍生物:水:交联剂:水相物料引发剂质量比为10:1-100:1-10:0.01-0.6；
(2)流动相主要为油溶性物料，其组分为油相引发剂、表明活性剂、乙酸丁酯等有机溶剂。主要将油相物料引发剂、表明活性剂依次加入到酯类溶剂中，搅拌均匀，作为流动相备用。
所述相物料中的引发剂为叔胺类化合物，包括四甲基乙二胺、三乙醇胺、N,N-二甲基对甲苯胺等；
所述表面活性剂为烷烃类、芳香烃类化合物，包括烷基苯磺酸钠、醋酸纤维素、脂肪酸山梨坦等；
所述油相物料引发剂和表面活性剂占乙酸丁酯的质量比均为0.1％-5％。
(3)分散相与流动相物料依靠物料进料系统进行输送物料，根据自身流体性质及进料量可选择合适的精密泵作为驱动装置，使物料稳定、连续、高通量的输送至微球生成模块。
所述驱动装置为精密泵，包括高精度注射泵、高精度恒流泵、精密压力泵，同时配置电脑操控面板、传感器反馈等装置。
所述精密泵控制物料流速为分散相流速为0.1-500μL/min，流动相流速为100-50000μL/min；
(4)微球生成模块主要采用芯片型、微管型等微反应器装置，物料经过输送至微反应器装置后，通过调控微流控芯片结构、材料、运行参数等，使分散相在流动相剪切力作用下，形成单分散微珠，从而达到制备粒径均一微球，其微球大小可在20-1400um调控，粒径均一度<10％。
所述芯片与微管型微反应器结构为流动聚焦型、同轴型、T型或Y型结构等，其管路内径为20-2000μm；
所述微反应器优选COP、COC、PTFE、ABS等高聚合物材料，具有耐腐蚀性、超疏水性、透明度高等优异性质；
所述微反应器制备方法采用3D打印、数控CNC、注塑成型等工艺，具有批量化生产、重现性高、价格低廉等优势，为粒径均一微球高通量生产工艺提供保证；
(5)粒径均一微球生成后被输送至固化装置，进一步进行微球的内部交联，完成微球的收集与后处理工艺。两种固化方式都能快速交联聚合物微球，提高产品稳定性。同时为对制备微球的材料提供更多的选择性，有效增加微球的交联方式与速度，进一步增加聚乙烯醇栓塞微球生产工艺的简便性、选择性。
所述固化装置可选择热固化与光固化两种模式，根据聚乙烯醇物料中引发剂性质，若为化学引发剂则选择热固化装置，引发剂为光引发剂则选择光固化装置；
所述热固化装置采用夹层反应瓶装置，通过循环控温装置进行保温，固化温度40-80℃，固化时间1-6h，可达到富集与预固化双功能效果，同时可通过出料速度控制其反应时间，达到产品的均一性；
所述光固化装置采用盘管装置，其管路具有透明度高、光吸收率高等优点，将制备的微球在管路里连续化流动并通过高强度紫外灯进行实时光照固化，其照射波长200-500nm，光照时间2-1000s，使聚合物微球充分固化，实现快速、高效、安全制备粒径均一栓塞微球。
进一步地，本发明采用PLC控制器或现有技术中的控制柜对设备进行控制；控制器或控制柜控制进料系统中的流量电子泵/进料泵，控制可能存在的流动相/分散相压力容器，并且控制微球生成模块和固化装置中的温度和压力。
在上述控制系统中，微球生成模块包括若干个并联的微反应器，控制系统中包括容错设置，当某一个微反应器出现故障，控制系统能够自动切断该微反应器所在线路，不对其他线路和后序的反应流程造成影响。
所述微球生成模块中的微反应器根据反应需要选择材料和成型方式，并选择不同的管路内径，通过芯片控制其流速以制备粒径均一的微球。
进一步地，在反应过程中，通过控制分散相与流动相对应的微球生成模块的入口内径与分散相与流动相的流速比，来控制聚乙烯醇栓塞微球的粒径。
当分散相管道内径20±10μm，流动相管道内径20±10μm；控制分散相物料的进样流速为0.1-2μL/min，流动相物料的进样流速为400±200μL/min，其制备的聚乙烯醇栓塞微球粒径为20±10μm，更优的方案为2±5μm。
当分散相管道内径60±10μm，流动相管道内径90±50μm；控制分散相物料的进样流速为2±1μL/min，流动相物料的进样流速为200±100μL/min，其制备的聚乙烯醇栓塞微球粒径为40±20μm，更优的方案为40±10μm。
当分散相管道内径100±20μm，流动相管道内径300±150μm；控制分散相物料的进样流速为5±2μL/min，流动相物料的进样流速为800±300μL/min，制备的聚乙烯醇栓塞微球粒径为100±25μm，更优的方案为100±10μm。
当分散相管道内径100±20μm，流动相管道内径300±150μm；控制分散相物料的进样流速为5±2μL/min，流动相物料的进样流速为500±200μL/min，制备的聚乙烯醇栓塞微球粒径为250±50μm，更优的方案为250±20μm。
当分散相管道内径250±130μm，流动相管道内径500±200μm；控制分散相物料的进样流速为20±5μL/min，流动相物料的进样流速为2000±500μL/min，制备的聚乙烯醇栓塞微球粒径为500±50μm，更优的方案为500±20μm。
当分散相管道内径800±300μm，流动相管道内径1000±500μm；控制分散相物料的进样流速为50±20μL/min，流动相物料的进样流速为800±200μL/min，制备的聚乙烯醇栓塞微球粒径为800±80μm，更优的方案为800±50μm。
当分散相管道内径800±400μm，流动相管道内径2000±1000μm；控制分散相物料的进样流速为50±20μL/min，流动相物料的进样流速为5000±2500μL/min；制备的聚乙烯醇栓塞微球粒径为1200±100μm，更优的方案为1200±50μm。
当分散相管道内径100±20μm，流动相管道内径100±50μm；控制分散相物料的进样流速为5±2μL/min，流动相物料的进样流速为500±300μL/min；制备的聚乙烯醇栓塞微球粒径为100±25μm，更优的方案为100±10μm。
当分散相管道内径80±10μm，流动相管道内径100±20μm；控制分散相物料的进样流速为5±1μL/min，流动相物料的进样流速为300±100μL/min；制备的聚乙烯醇栓塞微球粒径为80±25μm。
当流动相管道内径1500±500μm，分散相管道内径500±200μm；控制分散相物料的进样流速为10-500μL/min，分散相物料的进样流速为1000-50000μL/min；制备的聚乙烯醇栓塞微球粒径为500-1400μm。
本发明提供的栓塞微球生产工艺，其主要包含物料进料系统、微球生成模块、固化装置三大系统，同时涵盖稳定、高效、高通量制备微球的放大化工艺设备。
本发明中的物料进料系统分为分散相物料进料与流动相物料进料，根据各自化学及流体性质选择合适的精密泵作为驱动装置，作为两相物料搭配使用，适应不同性质的高分子物料、水溶性物料、有机相物料的进样要求；
本发明中的微球生成模块采用芯片型、微管型等微反应器装置，其结构可为聚焦型、T型、同轴等多种结构，通过调控微流控芯片结构及运行参数，使分散相在流动相相互剪切力作用下，可形成油包水结构或者水包油结构，达到精准控制微球尺寸，通过交联固化制备出粒径均一微球。
本发明提供热固化与光固化两种固化装置，两种固化方式具备响应时间快、交联程度高等优点，有效提高产品稳定性，对粒径均一微球生产工艺提供更多选择性。
本发明的有益效果：本发明采用微通道管路，通过油包水的独特结构，通过在液珠表面引发液珠内所包含聚合分子的交联聚合，最终形成交联紧密的，形状规则的圆形微球；本发明所代表的是一整套粒径均一聚乙烯醇栓塞微球的制备工艺，而不仅仅是微通道管路等某一部件，达到的效果也不仅仅是形成液珠，而是要在通道内交联聚合，形成粒径均一的微球。
本发明可提供一种连续化、自动化制备大小可控、粒径均一的聚乙烯醇栓塞微球，涵盖稳定、高效制备微球的系统化设备及相应的生产工艺。
附图说明
结合附图，通过下文的述详细说明，可更清楚地理解本发明的上述及其他特征和优点，其中：
图1为实施例2中提供的反应装置的加工方法的流程示意图；
图2为实施例3中提供的栓塞微球的制备设备的结构示意图；
图3为实施例4中提供的栓塞微球的制备设备的结构示意图；
图4为40±20μm聚乙烯醇栓塞微球的示意图；
图5为100±25μm聚乙烯醇栓塞微球的示意图；
图6为250±50μm聚乙烯醇栓塞微球的示意图；
图7为500±50μm聚乙烯醇栓塞微球的示意图；
图8为800±80μm聚乙烯醇栓塞微球的示意图；
图9为1200±100μm聚乙烯醇栓塞微球的示意图；
图10为100±25μm聚乙烯醇栓塞微球的示意图。
具体实施方式
参见示出本发明实施例的附图，下文将更详细地描述本发明。然而，本发明可以以许多不同形式实现，并且不应解释为受在此提出之实施例的限制。相反，提出这些实施例是为了达成充分及完整公开，并且使本技术领域的技术人员完全了解本发明的范围。这些附图中，为清楚起见，可能放大了层及区域的尺寸及相对尺寸。
需要说明，本发明实施例中所有方向性指示(诸如上、下、左、右、前、后……)仅用于解释在某一特定姿态(如附图所示)下各部件之间的相对位置关系、运动情况等，如果该特定姿态发生改变时，则该方向性指示也相应地随之改变。
实施例1
本发明提供了一种反应装置，包括主体结构层和封装层，主体结构层集成有槽，封装层叠置于主体结构层的一侧；其中，且主体结构层的熔融温度高于封装层的熔融温度，主体结构层与封装层通过热键合方式连接。
本发明进一步的限定了主体结构层的熔融温度高于封装层的熔融温度，在热键合连接过程中只要热键合温度达到封装层的熔融温度即可实现连接的功能，此时热键合温度还可实现低于主体结构层的熔融温度，从而防止在热键合连接过程中由于热键合温度高导致其内的形成槽的槽塌陷、变形的问题，有利于保证批量生产的一致性，适用于批量生产。
在本实施例中，主体结构层与封装层采用同种材料制成，其中，该处所讲的同种材料为基于同一类型单体经过聚合反应制备的热塑型聚合物材料，通过控制单体比例与参数，制备不同分子量或者聚合度的高分子材料，归属于同一种材料，但具有不同的熔融温度。
本实施例提供的反应装置，主体结构层和封装层采用同种材料制成，一方面提高了反应装置的整体机械强度，另一方面为两层之间的热键合连接提供理论支持，还可避免引入杂质。
本发明的提供的反应装置，具有一体化、结构稳定、强度高等优点，显著提升液珠生成的稳定性，同时具备制作效率高、质量好、适合批量化生产等优点，对于反应装置应用在临床诊断、药物分析、环境监测、食品开发等领域具有重大意义。
在本实施例中，主体结构层内集成的槽包括有分散相槽、连续相槽，连续相槽、分散相槽连接到主槽的同一端上，连续相槽具有连续相进料口，分散相槽具有分散相进料口，主槽具有出料口；槽为可以为流动聚焦型槽或同轴型槽或T型槽或Y型槽，此处不做限制，可根据具体需要进行调整。
本实施例以主体结构层内集成有流动聚焦型槽为例作进一步的说明。
具体的，流动聚焦型槽包括有主槽、分散相槽和两连续相槽，连续相槽、连续相槽对称设置，分散相槽设置在连续相槽、连续相槽之间；连续相槽、连续相槽、分散相槽同一侧的一端均连接到主槽的一端上并与之连通，主槽的另一端向远离连续相槽、连续相槽、分散相槽一侧延伸。
进一步的，两连续相槽远离主槽的一端设置连续相进料口，分散相槽远离主槽的一端设置有分散相进料口，主槽远离分散相槽、连续相槽的一端设置有出料口。液体自连续相进料口、分散相进料口分别进入到连续相槽、分散相槽内并在其与主槽交汇处在剪切力的作用下稳定生成液珠经由主槽的出料口输出。连续相进料口、分散相进料口、出料口的设置实现了流体在反应装置中的引入和导出，完成流体进样、槽清洗等功能。
进一步的，两连续相槽远离主槽的一端相连通并共用一个连续相进料口，这样设计一方面增加两个连续相槽的对称性，使流体更加均匀分布，更加提高流动聚焦型反应装置生成微球的稳定性，另一方面进行结构优化，降低进料口数量，提高整体装置的结构合理性，减少所需管路、转接头的使用；当然，在其他实施例中两连续相槽远离主槽的一端也可不连通，其端部分别设置有独立的连续相进料口，根据具体需要进行调整，此处不做限制。
在本实施例中，分散相进料口的直径与分散相槽的直径比例为1：1-2，连续相进料口的直径与连续相槽的直径比例为1：1-2，本实施例通过限定进料口的直接小于槽的直径，保证物料完全进入槽内部，无液体死体积存在。
进一步的，连续相进料口、分散相进料口、出料口贯穿主体结构层，且连续相进料口、分散相进料口、出料口朝向封装层的一端通过封装层密封，另一端实现进出料。
在本实施中，连续相槽、分散相槽、主槽的直径比例为1∶(0.2-1)∶(1-1.5)；例如，连续相槽直径为50-1200um，分散相槽的直径为50-1000um，主槽的直径为50-1500um；本实施例通过上述尺寸的限定，以便于制备较宽范围的液滴，同时更符合流体设计比例，具备最大剪切力，能够以最少的流体剪切相应范围的液滴，同时调控比例范围较宽；其中，具体比例值、以及各自的具体取值可根据具体需要进行选择，此处不做限制。
在本实施例中，分散相进料口通过连接槽与分散相槽连通，且连接槽的直径大于分散相槽的直径；连接槽直径大于分散相槽的直径，能够降低流体的惯性冲击力，起到缓冲效果，使流体平稳进入分散相槽，从而提高液滴生成的稳定性及持续性。当然在其他实施例中也可省略连接槽的设置，可根据具体需要进行调整，此处不做限制。
进一步的，连接槽与分散相槽连接处呈斜面连接，且该斜面的倾斜角度A为30-60°，该斜面的设置一方面对流体起到缓冲作用，能够快速进入分散相槽中，另一方面减少死体积存在，以一定角度使流体快速更换另一方面的；其中，倾斜角度的具体取值可根据具体需要进行调整，此处不做限制。
在本实施例中，出料口外侧孔径大于内侧孔径，这样设计有助于流体压力稳定释放，更能增加反应装置的机械强度。具体的，可通过将出料口设计为一阶梯孔或喇叭形孔等形式来实现，此处不做限制。
进一步的，出料口的最小孔径与主槽的直径比例为1-1.5∶1；对于流体运动方向的转换，会对液滴产生碰撞融合或者打碎，该比例能够使液滴随着流体有梯度的转换，通道逐级放大，液滴在流体运动中缓慢的缩短距离而不产生碰撞或者打碎，进而有效的提高整个系统稳定性。
在本实施例中，该反应装置还包括有支持层，支持层叠置于封装层背向主体结构层的一侧上，支持层的厚度大于封装层、主体结构层的厚度，以保证其机械强度，当然在其他实施例中支撑层的厚度也可小于或者等于封装层、主体结构的厚度，此处不做限制，可根据具体情况进行调整；支持层主要用于后续反应装置被夹具夹持时，支持层与夹具配合实现定位夹紧。当然在其他实施例中，也可省略支持层或者支持层与封装层合二为一，可根据具体需要进行调整，此处不做限制。
其中，优选的支持层与主体结构层、封装层采用同种材料制成，有利于增加整体机械强度。当然，在其他实施例中支持层也可与主体结构层、封装层采用不同的材料制成，此处不足限制
其中，支持层采用胶连接方式实现与主体结构层的连接，其胶类型可选择双面胶、光敏胶、溶剂胶等，此处不做限制，可根据具体需要进行选择；胶连接的方式具有粘合法简单、成本低、无需加热等优点，当然在其他实施例中也可根据需要选择其他连接方式，此处不做限制。
在本实施例中，主体结构层、封装层与支持层的材料厚度比例为1：(0.05-0.5)：(1-3)，上述比例的限定，一方面增加整体机械强度，使反应装置在安装时候具有较强的支撑力，不会产生破裂，另一方面封装层厚度低于主体结构层，主要保证键合过程快速传热，快速到达热平衡，达到较高的键合强度)。进一步的，主体结构层、封装层与支持层的平整度低于0.01mm，以保证相互之间的紧密牢固连接。
在本实施例中，主体结构层与封装层采用热塑性聚合物材料，同一类热塑性聚合物材料含有不同聚合度，使其具有不同的熔融温度；热塑性聚合物材料包括聚甲基丙烯酸甲酯、聚碳酸酯、环烯烃聚合物等聚合物，可进行反应装置表面疏水或者亲水化涂层处理，以应对不同类型微球的生产需求。
其中，优选的主体结构层与封装层1采用环烯烃聚合物，该材料具有从90℃-160℃较宽范围的玻璃化转变温度(即熔融温度)，从而有利于主体结构层与封装层选择热塑性聚合物材料的不同聚合度，进一步区分开两者的熔融温度。
实施例2
本发明提供了一种反应装置的加工方法，如图1所示，用于加工实施例1中所述的反应装置。
该反应装置的加工方法具体为：
S1、采用同种材料分别加工出实施例1中所述的主体结构层和封装层，并通过控制材料的聚合度，使得加工获得的封装层的熔融温度低于主体结构层的熔融温度；
S2、加工好的主体结构层和封装层通过热键合方式进行连接。
其中，主体结构层和封装层在真空条件下通过热键合方式进行连接，有利于避免杂质的引入。
其中，热键合温度低于主体结构层的熔融温度，且高于或等于封装层的熔融温度，以保证在使得封装层融化达到封装效果的同时，又避免了主体结构层内的槽的塌陷或变形。
其中，热键合温度与主体结构层的熔融温度相差0.1-10％；热键合温度使封装层熔融，进而与主体结构层键合，通过控制主体结构层的熔融温度差，提高与封装层的相容温度区间，使封装层快速与主体结构层键合，如果温差过大，易发生粘连不牢靠，键合强度低等现象，因此将热键合温度与主体结构层的熔融温度差控制在0.1-10％范围内。
其中，热键合温度范围为90-160℃，热键合时间范围为3～30min，热键合连压力范围为20-200kg，根据材料的性质、厚度的比例等因素决定键合的参数范围，键合的压力、时间、温度都是起到决定性作用，过大容易造成槽的塌陷、变形、能源浪费、效率低等不好影响，过低易造成键合强度低、粘连不高、次品较多等问题；加工过程中热键合的温度、时间以及 压力均可根据具体需要进行选择，例如键合的压力为60kg、温度为130℃、键合时间为10min，此处不做限制。
在本实施例中，当封装层背向主体结构层的一侧上还设置有支持层时，支持层与封装层之间采用胶连接的方式进行连接。
其中，支持层与封装层之间的粘合压力范围为1-10kg，粘合时间范围为3-30s。加工过程中胶合的时间以及压力均可根据具体需要进行选择，例如粘合的压力范围3kg，粘合时间为5s，此处不做限制。
实施例3
参照图2，本发明提供了一种栓塞微球的制备设备，包括进料系统1、微球生成模块2和固化装置3；进料系统1与微球生成模块2连接，微球生成模块2与固化装置3连接，进料系统1用于向微球生成模块2提供物料，物料在微球生成模块2内反应生成滴液，经固化装置3处理后获得粒径均一的栓塞微球。本发明提供的栓塞微球的制备设备可用于制备聚乙烯醇栓塞微球，也可以用于制备其他类型的微球，此处不做限制。本发明提供的栓塞微球的制备设备，其主要包含物料进料系统、微球生成模块、固化装置三大系统，同时涵盖稳定、高效、高通量制备微球的放大化工艺设备。
在本实施例中，微球生成模块2包括有至少一个微反应器，微反应器采用实施例1中所述的反应装置。进一步的，微球生成模块2包括有多个并联的微反应器，多个微反应器均分别与进料系统1和固化装置3连接；多个微反应器并联运行，可实现批量化生产，同时多个微反应器具备独立性、抗干扰性等优点。
其中，微反应器的设置数量可以为一个，也可为图2中所示的八个，也可为其他数量，此处不作限制，可根据具体情况进行调整。
其中，多个微反应器的可以用于生成相同或不同直径的微球，微反应器内用于生成滴液的通道内径为20-2000μm；具体可以通过控制微反应器内用于生成滴液的槽的直径、其内液体的运行参数等因素，达到制备不同尺寸的粒径均一微球，其微球大小可在20-1400um调控，粒径均一度<10％，此处不足限制，可根据具体需要进行调整。
在本实施例中，微反应器还包括有微流控芯片，微流控芯片配合控制器控制进入微反应器的反应液流速，从而来通过控制流速来控制微球的粒径。
本发明中的微球生成模块可采用芯片型、微管型等微反应器，其结构可为聚焦型、T型、同轴等多种结构，通过调控微流控芯片结构及运行参数，使分散相物料在连续相物料相互剪切力作用下，可形成油包水结构或者水包油结构，达到精准控制微球尺寸，通过交联固化制备出粒径均一微球。
在本实施例中，进料系统包括有用于进油相物料的连续相进料系统11和用于进水相物料的分散相进料系统12；连续相进料系统11与各微反应器的连续相进料口分别连接，分散相进料系统12与各微反应器的分散相进料口分别连接。本发明中的物料进料系统分为分散相物料进料与流动相物料进料，根据各自化学及流体性质选择合适的精密泵作为驱动装置，作为两相物料搭配使用，适应不同性质的高分子物料、水溶性物料、有机相物料的进样要求；
进一步的，连续相进料系统11包括有顺序相连的第一压力源装置111、连续相进料泵112和连续相储料罐113，连续相储料罐113与各微反应器的连续相进料口分别连接；连续相储料罐113用于储存油相物料，第一压力源装置111用于向连续相进料泵112提供压力，连续相进料泵112用于推动连续相储料罐113内物料通过管路输送给各为微反应器的连续相进料口，从而实现油相物料的进料。
分散相进料系统12包括顺序相连的第二压力源装置121、分散相进料泵122和分散相储料罐123，分散相储料罐123与各微反应器的分散相进料口分别连接；分散相储料罐123用于储存水相物料，第二压力源装置121用于向分散相进料泵122提供压力，分散相进料泵122用于推动分散相储料罐123内物料通过管路输送给各为微反应器的分散相进料口，从而实现水相物料的进料。
在本实施例中连续相进料泵112和分散相进料泵122均为压力泵需要配合压力源装置使用将连续相储料罐113、分散相储料罐123内储料通过压力压入到微反应器内。
进一步的，第一压力源装置111、第二压力源装置121具体可以为氮气瓶、气体压缩机等装置，此处不做限制，可根据具体需要进行选择。
进一步的，连续相进料泵112、分散相进料泵122优选的采用带有压力、流量控制装置的泵结构，从而能能够控制进料的流量、压力，本实施例中优选的控制分散相流速为0.1-500μL/min，连续相流速为100-50000μL/min，以便于使得物料稳定、连续、高通量的输送至各微反应器中。
连续相进料泵112、分散相进料泵122具体可以选用精密压力泵、高精度注射泵、高精度恒流泵等结构。精密压力泵其量程0-4bar、精度0.01％-0.2％，可从国内外供应商进行采购，例如苏州纹颢、美国Dolomite等公司；高精度注射泵具备多种工作模式使其能够适应不同领域中各式各样应用的需求，本身拥有超高的控制精度和较宽的线速度范围，其流量范围可选0.001μL/h-50mL/min，可从国内外供应商进行采购，例如保定兰格有限公司、上海谱质分析检测技术等公司；高精度恒流泵具备较高的压力和扬程，而且输送物质不与外界接触，其精度0.01-1000mL/min，可从国内外供应商进行采购，例如保定兰格有限公司、上海精密仪器等公司。
在本实施例中，各微反应器的出料口均与固化装置3连通，各微反应器生成的滴液输送到固化装置3中进行固化，从而获得栓塞微球。其中，固化装置3为紫外光固化装置或热固化装 置等，均包括固化容器及相应的发生装置。本发明提供热固化与光固化两种固化装置，两种固化方式具备响应时间快、交联程度高等优点，有效提高产品稳定性，对粒径均一微球生产工艺提供更多选择性。
以制备聚乙烯醇栓塞微球为例作进一步的说明，聚乙烯醇物料中引发剂若为化学引发剂则为热固化装置，其热固化装置为双层反应瓶、机械搅拌与恒温水浴槽三部分组成，其反应过程通过机械方式使流体搅拌均匀，恒温水浴槽提供能量传导，达到热固化反应条件，最终实现产品的富集及交联反应。
聚乙烯醇物料中引发剂若为光引发剂则为光固化装置，其光固化装置采用紫外光源进行照射，强度10-1000W，生成的微球在管路中经过紫外引发聚合成型，实现产品的交联聚合。两种固化方式都能快速交联聚合物微球，提高产品稳定性，同时有效增加微球的成型方式与速度，增加聚乙烯醇栓塞微球生产工艺的简便性。
在本实施例中，如图2所示，同时采用热固化和光固化两种固化方式同时进行固化处理；但在其他实施例中，可以仅采用一种固化方式，例如只采用热固化(参见图3所示)，或者仅采用光固化，具体以实际需要为准，在此不再赘述。
此外，所述栓塞微球的制备设备的各模块的组装基于塑料管件、金属管、螺纹套管、垫圈、转接头等配件进行连接，使带有外螺纹的套管、金属管能与芯片、微管获得高紧密的接口，同时液体依靠塑料管件进行流体输送，例如内径为100-3200um的PTFE管、内径100-3200um PEEK管，该管件具备良好的柔韧性、表明光滑度、非毒性等优点，为整套工艺的连接提供保证。
本发明提供的栓塞微球的制备设备具有以下优点：
本发明采用微通道管路，通过油包水的独特结构，通过在液珠表面引发液珠内所包含聚合分子的交联聚合，最终形成交联紧密的，形状规则的圆形微球；本发明所代表的是一整套栓塞微球的制备设备，而不仅仅是微通道管路等某一部件，达到的效果也不仅仅是形成液珠，而是要在通道内交联聚合，形成粒径均一的微球。本发明可提供一种连续化、自动化制备大小可控、粒径均一的聚乙烯醇栓塞微球，涵盖稳定、高效制备微球的系统化设备及相应的生产工艺。
实施例4
本实施例是在实施例3的基础上进行的调整。
具体的，如图3中所示，在本实施例中，连续相进料系统11包括直接相连的连续相进料泵112和连续相储料罐113，分散相进料系统12包括直接相连的分散相进料泵122和分散相储料罐123。
本实施例中连续相进料泵112和分散相进料泵122采用非压力型泵结构，例如抽吸类型的泵结构，其直接设置在连续相储料罐113和分散相储料罐123与微反应器连通的管路上即可，如图3中所示。
本实施例中栓塞微球的制备设备的其他结构均可参照实施例3中的描述，此处不作限制。
实施例5
本发明提供了一种栓塞微球的制备方法，具体以制备聚乙烯醇栓塞微球为例做具体说明。
本实施例采用精密压力泵输送物料，微反应器为聚焦型芯片，其分散相管道内径20±10μm，流动相管道内径20±10μm。具体步骤如下：
(1)分散相物料的配制：称取0.4g过硫酸钾加入100g水，磁力搅拌溶解，缓慢滴加10g丙烯酸钠，搅拌均匀，再加入10g聚乙烯醇衍生物，搅拌均匀，作为分散相物料备用。
(2)流动相物料的配制：将10g脂肪酸山梨坦表面活性剂加入到1000mL乙酸乙酯溶液中，再加入10mL三乙醇胺，搅拌均匀，作为流动相物料备用。
(3)装置组建：将配制的分散相与流动相物料加入至储液瓶中，连接压力控制模块、气源、电脑控制面板、管路等装置，首先启动初始化装置，验证储液瓶是否有气体露出，确认其优良的气密性。将多个微反应器(例如图2中的8个)依次并联排布，其管路分别与出料口管路通过转接头连接，微反应器的出口管路与固化装置相连通，其固化装置采用热固化方式，连接恒温加热循环装置。
(4)粒径均一微球制备：启动分散相压力开关，将分散相物料输送至芯片管路，同时启动流动相压力开关，将流动相物料快速输送至微反应器的管路，通过调控压力与流速关系，控制分散相物料的进样流速为0.1-2μL/min，流动相物料的进样流速为400±200μL/min，在芯片聚焦型十字路口处，分散相物料被油流动相物料剪切成小液珠，形成油包水结构，继续输送至固化装置，在80℃下搅拌固化2h。将均一微球冷却至室温，分别用乙酸丁酯、乙酸乙酯、丙酮洗涤，真空干燥，再溶胀，即得粒径均一的聚乙烯栓塞微球。
(5)粒径分析：微球粒径分布均一，同时产量较高，可实现批量化生产。其制备的聚乙烯醇栓塞微球粒径为20±10μm，更优的方案为20±5μm，符合粒径均一的要求。
实施例6
本发明提供了一种栓塞微球的制备方法，具体以制备聚乙烯醇栓塞微球为例做具体说明。
本实施例采用精密压力泵输送物料，微反应器为聚焦型芯片，其分散相管道内径60±10μm，流动相管道内径90±50μm。具体步骤如下：
(1)分散相物料的配制：称取0.4g过硫酸钾加入100g水，磁力搅拌溶解，缓慢滴加10g丙烯酸钠，搅拌均匀，再加入10g聚乙烯醇衍生物，搅拌均匀，作为分散相物料备用。
(2)流动相物料的配制：将10g脂肪酸山梨坦表面活性剂加入到1000mL乙酸丁酯溶液中，再加入10mL三乙醇胺，搅拌均匀，作为流动相物料备用。
(3)装置组建：将配制的分散相与流动相物料加入至储液瓶中，连接压力控制模块、气源、电脑控制面板、管路等装置，首先启动初始化装置，验证储液瓶是否有气体露出，确认其优良的气密性。将多个微反应器依次并联排布，其管路分别于出料口管路通过转接头连接，微反应器的出口管路与固化装置相连通，其固化装置采用热固化方式，连接恒温加热循环装置。
(4)粒径均一微球制备：启动分散相压力开关，将分散相物料输送至芯片管路，同时启动流动相压力开关，将流动相物料快速输送至芯片管路，通过调控压力与流速关系，控制分散相物料的进样流速为2±1μL/min，流动相物料的进样流速为200±100μL/min，在芯片聚焦型十字路口处，分散相物料被油流动相物料剪切成小液珠，形成油包水结构，继续输送至固化装置，在80℃下搅拌固化2h。将均一微球冷却至室温，分别用乙酸丁酯、乙酸乙酯、丙酮洗涤，真空干燥，再溶胀，即得粒径均一的聚乙烯栓塞微球。
(5)粒径分析：如图4所示，微球粒径分布均一，同时产量较高，可实现批量化生产。其制备的聚乙烯醇栓塞微球粒径为40±20μm，更优的方案为40±10μm，符合粒径均一的要求。
实施例7
本发明提供了一种栓塞微球的制备方法，具体以制备聚乙烯醇栓塞微球为例做具体说明。
本实施例采用精密压力泵与注射泵输送物料，微反应器为聚焦型芯片，其分散相管道内径100±20μm，流动相管道内径300±150μm，通过控制分散相与流动相流速，制备出粒径均一微球具体步骤如下：
(1)分散相物料的配制：称取0.4g过硫酸铵加入60g水，磁力搅拌溶解，缓慢滴加8g 2-丙烯酰胺基-2-甲基丙磺酸钠，搅拌均匀，再加入10g聚乙烯醇衍生物，搅拌均匀，作为分散相物料备用。
(2)流动相物料的配制：将10g脂肪酸山梨坦表面活性剂加入到1000mL乙酸丁酯溶液中，再加入8mL四甲基乙二胺，搅拌均匀，作为流动相物料备用。
(3)装置组建：打开注射泵，将配制的分散相自动吸入注射泵；将精密压力泵的控制模块连接，油相物料放入储料管中，两个出料管路与芯片管路对应相连接，将4个芯片依次并联排布，其管路分别与出料口管路通过转接头连接，芯片出口管路与固化装置相连通，其固化装置采用热固化方式，连接恒温加热循环装置。
(4)粒径均一微球制备：设置注射泵参数，设定进样流速为5±2μL/min，分设置压力泵参数，设定进样流速为800±300μL/min。打开注射泵，将分散相物料推送至芯片管路，同时打开精密压力泵，将流动相物料快速输送至芯片管路，在芯片聚焦型十字路口处，分散相物料被油流动相物料剪切成小液珠，形成油包水结构，继续输送至固化装置，在60℃下搅拌固化3h。将均一微球冷却至室温，分别用乙酸丁酯、乙酸乙酯、丙酮洗涤，真空干燥，再溶胀，即得粒径均一的聚乙烯栓塞微球。
(5)粒径分析：如图5所示，微球粒径分布均一，同时产量较高，可实现批量化生产。其制备的聚乙烯醇栓塞微球粒径为100±25μm，更优的方案为100±10μm，符合粒径均一的要求。
实施例8
本发明提供了一种栓塞微球的制备方法，具体以制备聚乙烯醇栓塞微球为例做具体说明。
本实施例采用精密注射泵与恒流泵输送物料，微球生成装置为聚焦型芯片，其分散相管道内径100±20μm，流动相管道内径300±150μm。如图3所示，具体步骤如下：
(1)分散相物料的配制：称取0.4g过硫酸铵加入60g水，磁力搅拌溶解，缓慢滴加8g 2-丙烯酰胺基-2-甲基丙磺酸钠，搅拌均匀，再加入10g聚乙烯醇衍生物，搅拌均匀，作为分散相物料备用。
(2)流动相物料的配制：将10g脂肪酸山梨坦表面活性剂加入到1000mL乙酸丁酯溶液中，再加入8mL四甲基乙二胺，搅拌均匀，作为流动相物料备用。
(3)装置组建：打开注射泵，将配制的分散相自动吸入注射泵；将精密恒流泵的进料管路插入配制好的流动相物料中，两个出料管路与芯片管路对应相连接，将4个芯片依次并联排布，其管路分别与出料口管路通过转接头连接，芯片出口管路与固化装置相连通，其固化装置采用热固化方式，连接恒温加热循环装置。
(4)粒径均一微球制备：设置注射泵参数，设定进样流速为5±2μL/min，分设置恒流泵参数，设定进样流速为500±200μL/min。打开注射泵，将分散相物料推送至芯片管路，同时打开精密恒流泵，将流动相物料快速输送至芯片管路，在芯片聚焦型十字路口处，分散相物料被油流动相物料剪切成小液珠，形成油包水结构，继续输送至固化装置，在60℃下搅拌 固化3h。将均一微球冷却至室温，分别用乙酸丁酯、乙酸乙酯、丙酮洗涤，真空干燥，再溶胀，即得粒径均一的聚乙烯栓塞微球。
(5)粒径分析：如图6所示，制备的聚乙烯醇栓塞微球粒径为250±50μm，更优的方案为250±20μm，符合粒径均一的要求。
实施例9
本发明提供了一种栓塞微球的制备方法，具体以制备聚乙烯醇栓塞微球为例做具体说明。
本实施例采用精密注射泵与恒流泵输送物料，微球生成装置为3D打印十字型管路，其分散相管道内径250±130μm，流动相管道内径500±200μm，具体步骤如下：
(1)分散相物料的配制：称取0.4g过硫酸钾加入100g水，磁力搅拌溶解，缓慢滴加8g 2-丙烯酰胺基-2-甲基丙磺酸钠，搅拌均匀，再加入10g聚乙烯醇衍生物，搅拌均匀，作为分散相物料备用。
(2)流动相物料的配制：将10g醋酸纤维素表面活性剂加入到1000mL乙酸丁酯溶液中，再加入5mL N,N-二甲苯胺，搅拌均匀，作为流动相物料备用。
(3)装置组建：打开注射泵，将配制的分散相自动吸入注射泵；将精密恒流泵的进料管路插入配制好的流动相物料中，两个出料管路分别与芯片管路对应相连接，将十字型管路分别与出料口管路通过转接头连接，芯片出口管路与固化装置相连通，其固化装置采用热固化方式，连接恒温加热循环装置。
(4)粒径均一微球制备：设置注射泵参数，设定进样流速为20±5μL/min，分设置恒流泵参数，设定进样流速为2000±500μL/min。打开注射泵，将分散相物料推送至芯片管路，同时打开精密恒流泵，将流动相物料快速输送至十字型管路，在十字型中心处，分散相物料被油流动相物料剪切成小液珠，形成油包水结构，继续输送至固化装置，在60℃下搅拌固化3h。将均一微球冷却至室温，分别用乙酸丁酯、乙酸乙酯、丙酮洗涤，真空干燥，再溶胀，即得粒径均一的聚乙烯栓塞微球。
(5)粒径分析：如图7所示，制备的聚乙烯醇栓塞微球粒径为500±50μm，更优的方案为500±20μm，符合粒径均一的要求。
实施例10
本发明提供了一种栓塞微球的制备方法，具体以制备聚乙烯醇栓塞微球为例做具体说明。
本实施例采用精密压力泵输送物料，微球生成装置为T型芯片，其分散相管道内径800±300μm，流动相管道内径1000±500μm，采用光固化装置，具体步骤如下：
(1)分散相物料的配制：称取0.15g 2,4,6-三甲基苯甲酰基-二苯基氧化膦加入80g水，磁力搅拌溶解，缓慢滴加10g 2-丙烯酰胺基-2-甲基丙磺酸钠，搅拌均匀，再加入10g聚乙烯醇衍生物，搅拌均匀，作为分散相物料备用。
(2)流动相物料的配制：将20g醋酸纤维素表面活性剂加入到2000mL乙酸丁酯溶液中，搅拌均匀，作为流动相物料备用。
(3)装置组建：将配制的分散相与流动相物料加入至储液瓶中，连接压力控制模块、气源、电脑控制面板、管路等装置，首先启动初始化装置，确认其优良的气密性。将多个芯片依次并联排布，其管路分别于出料口管路通过转接头连接，芯片出口管路与固化装置相连通，其固化装置采用光固化装置，连接UV灯。
(4)粒径均一微球制备：启动分散相压力开关，将分散相物料输送至芯片管路，同时启动流动相压力开关，将流动相物料快速输送至芯片管路，通过调控压力与流速关系，控制分散相物料的进样流速为50±20μL/min，分散相物料的进样流速为800±200μL/min，在芯片T型处，分散相物料被油流动相物料剪切成液珠，形成油包水结构。打开紫外灯装置，功率400W，当微球在盘管中运行，紫外灯同时进行表面光固化，其光固化时间40s，微球快速交联，制备出产品，再分别用乙酸丁酯、乙酸乙酯、丙酮洗涤，真空干燥，再溶胀，即得粒径均一的聚乙烯栓塞微球。
(5)粒径分析：如图8所示，微球粒径分布均一，同时产量较高，固化时间较短，可实现批量化生产。其制备的聚乙烯醇栓塞微球粒径为800±80μm，更优的方案为800±50μm，符合粒径均一的要求。
实施例11
本发明提供了一种栓塞微球的制备方法，具体以制备聚乙烯醇栓塞微球为例做具体说明。
本实施例采用精密压力泵输送物料，微球生成装置为T型芯片，其分散相管道内径800±400μm，流动相管道内径2000±1000μm。具体步骤如下：
(1)分散相物料的配制：称取0.4g过硫酸钾加入50g水，磁力搅拌溶解，缓慢滴加10g 2-丙烯酰胺基-2-甲基丙磺酸钠，搅拌均匀，再加入10g聚乙烯醇衍生物，搅拌均匀，作为分散相物料备用。
(2)流动相物料的配制：将10g醋酸纤维素表面活性剂加入到1000mL乙酸丁酯溶液中，再加入10mL四甲基乙二胺，搅拌均匀，作为流动相物料备用。
(3)装置组建：将配制的分散相与流动相物料加入至储液瓶中，连接压力控制模块、气源、电脑控制面板、管路等装置，首先启动初始化装置，验证储液瓶是否有气体露出，确认其优良的气密性。将T型芯片依次并联排布，其管路分别于出料口管路通过转接头连接，芯片出口管路与固化装置相连通，其固化装置同时采用盘管预固化与热固化方式，连接恒温加热循环装置。
(4)粒径均一微球制备：启动分散相压力开关，将分散相物料输送至芯片管路，同时启动流动相压力开关，将流动相物料快速输送至芯片管路，通过调控压力与流速关系，控制分散相物料的进样流速为50±20μL/min，流动相物料的进样流速为5000±2500μL/min，在芯片聚焦型十字路口处，分散相物料被油流动相物料剪切成液珠，形成油包水结构，当其微球在盘管预老化，防止进入固化装置碰撞融合，继续输送至固化装置，在80℃下搅拌固化4h。将均一微球冷却至室温，分别用乙酸丁酯、乙酸乙酯、丙酮洗涤，真空干燥，再溶胀，即得粒径均一的聚乙烯栓塞微球。
(5)粒径分析：如图9所示，微球粒径分布均一，同时产量较高，可实现批量化生产。其制备的聚乙烯醇栓塞微球粒径为1200±100μm，更优的方案为1200±50μm，符合粒径均一的要求。
实施例12
本发明提供了一种栓塞微球的制备方法，具体以制备聚乙烯醇栓塞微球为例做具体说明。
本实施例采用精密压力泵输送物料，微球生成装置为聚焦型芯片，其分散相管道内径100±20μm，流动相管道内径100±50μm，采用光固化装置。具体步骤如下：
(1)分散相物料的配制：称取0.2g苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐加入80g水，磁力搅拌溶解，缓慢滴加10g 2-丙烯酰胺基-2-甲基丙磺酸钠，搅拌均匀，再加入10g聚乙烯醇衍生物，搅拌均匀，作为分散相物料备用。
(2)流动相物料的配制：将20g醋酸纤维素表面活性剂加入到2000mL乙酸丁酯溶液中，搅拌均匀，作为流动相物料备用。
(3)装置组建：将配制的分散相与流动相物料加入至储液瓶中，连接压力控制模块、气源、电脑控制面板、管路等装置，首先启动初始化装置，验证储液瓶是否有气体露出，确认其优良的气密性。将多个芯片依次并联排布，其管路分别于出料口管路通过转接头连接，芯片出口管路与固化装置相连通，其固化装置采用光固化装置，连接UV灯。
(4)粒径均一微球制备：启动分散相压力开关，将分散相物料输送至芯片管路，同时启动流动相压力开关，将流动相物料快速输送至芯片管路，通过调控压力与流速关系，控制 分散相物料的进样流速为5±2μL/min，流动相物料的进样流速为500±300μL/min，在芯片聚焦型十字路口处，分散相物料被油流动相物料剪切成液珠，形成油包水结构。打开紫外灯装置，功率1000W，当微球在盘管中运行，紫外灯同时进行表面光固化，其光固化时间60s，微球快速交联，制备出产品，再分别用乙酸丁酯、乙酸乙酯、丙酮洗涤，真空干燥，再溶胀，即得粒径均一的聚乙烯栓塞微球。
(5)粒径分析：如图10所示，微球粒径分布均一，同时产量较高，固化时间较短，可实现批量化、快速化生产。其制备的聚乙烯醇栓塞微球粒径为100±25μm，更优的方案为100±10μm，符合粒径均一的要求。
实施例13
本发明提供了一种栓塞微球的制备方法，具体以制备聚乙烯醇栓塞微球为例做具体说明。
本实施例采用精密压力泵输送物料，微球生成装置为聚焦型芯片，其分散相管道内径80±10μm，流动相管道内径100±20μm。具体步骤如下：
(1)分散相物料的配制：称取0.6g过硫酸钾与0.1g苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐加入40g水，磁力搅拌溶解，缓慢滴加6g丙烯酸磺酸钠，搅拌均匀，再加入10g聚乙烯醇衍生物，搅拌均匀，作为分散相物料备用。
(2)流动相物料的配制：将10g醋酸纤维素表面活性剂加入到1000mL乙酸乙酯溶液中，再加入10mL三乙醇胺，搅拌均匀，作为流动相物料备用。
(3)装置组建：将配制的分散相与流动相物料加入至储液瓶中，连接压力控制模块、气源、电脑控制面板、管路等装置，启动装置。将50个芯片依次并联排布，其管路分别于出料口管路通过转接头连接，芯片出口管路与固化装置相连通，其固化装置采用光预固化再用热固化两种结合方式固化，连接紫外灯、恒温加热循环等装置。
(4)粒径均一微球制备：启动分散相压力开关，将分散相物料输送至芯片管路，同时启动流动相压力开关，将流动相物料快速输送至芯片管路，通过调控压力与流速关系，控制分散相物料的进样流速为5±1μL/min，流动相物料的进样流速为300±100μL/min，在芯片聚焦型十字路口处，分散相物料被油流动相物料剪切成小液珠，形成油包水结构，继续输送至光固化装置，当微球在盘管中运行，紫外灯同时进行表面预固化，其光固化时间1s，微球表面交联，然后收集在烧瓶中，等12h后，启动热固化装置，在60℃下搅拌固化3h。将均一微球冷却至室温，分别用乙酸丁酯、乙酸乙酯、丙酮洗涤，真空干燥，再溶胀，即得粒径均一的聚乙烯栓塞微球。
(5)粒径分析：微球粒径分布均一，操控微球成型过程，可实现批量化、可控化生产。其制备的聚乙烯醇栓塞微球粒径为80±25μm，更优的方案为80±10μm，符合粒径均一的要求。
实施例14
本发明提供了一种栓塞微球的制备方法，具体以制备聚乙烯醇栓塞微球为例做具体说明。
本实施例采用精密注射泵与恒流泵输送物料，微球生成装置为同轴微管，其分散相管道内径1500±500μm，流动相管道内径500±200μm。具体步骤如下：
(1)分散相物料的配制：称取0.4g过硫酸铵加入60g水，磁力搅拌溶解，缓慢滴加8g 2-丙烯酰胺基-2-甲基丙磺酸钠，搅拌均匀，再加入10g聚乙烯醇衍生物，搅拌均匀，作为分散相物料备用。
(2)流动相物料的配制：将10g脂肪酸山梨坦表面活性剂加入到1000mL乙酸丁酯溶液中，再加入8mL四甲基乙二胺，搅拌均匀，作为流动相物料备用。
(3)装置组建：打开注射泵，将配制的分散相自动吸入注射泵；将精密恒流泵的进料管路插入配制好的流动相物料中，两个出料管路与芯片管路对应相连接，将4个芯片依次并联排布，其管路分别与出料口管路通过转接头连接，芯片出口管路与固化装置相连通，其固化装置采用热固化方式，连接恒温加热循环装置。
(4)粒径均一微球制备：设置注射泵参数，设定进样流速为10-500μL/min/min，分设置恒流泵参数，设定进样流速为1000-50000μL。打开注射泵，将分散相物料推送至芯片管路，同时打开精密恒流泵，将流动相物料快速输送至芯片管路，在芯片聚焦型十字路口处，分散相物料被油流动相物料剪切成小液珠，形成油包水结构，继续输送至固化装置，在60℃下搅拌固化10h。将均一微球冷却至室温，分别用乙酸丁酯、乙酸乙酯、丙酮洗涤，真空干燥，再溶胀，即得粒径均一的聚乙烯栓塞微球。
(5)粒径分析：制备的聚乙烯醇栓塞微球粒径为500-1400μm，符合粒径均一的要求。
本技术领域的技术人员应理解，本发明可以以许多其他具体形式实现而不脱离其本身的精神或范围。尽管已描述了本发明的实施案例，应理解本发明不应限制为这些实施例，本技术领域的技术人员可如所附权利要求书界定的本发明的精神和范围之内作出变化和修改。

Claims (44)

  1. 一种反应装置，其特征在于，包括主体结构层和封装层，所述主体结构层集成有液珠的槽，所述封装层叠置于所述主体结构层的一侧；
    其中，所述主体结构层的熔融温度高于所述封装层的熔融温度，所述主体结构层与所述封装层通过热键合方式连接。
  2. 根据权利要求1所述的反应装置，其特征在于，所述主体结构层与所述封装层采用同种材料制成。
  3. 根据权利要求1或2所述的反应装置，其特征在于，所述主体结构层内集成的槽具有分散相进料口、连续相进料口和出料口；所述槽为流动聚焦型槽或同轴型槽或T型槽或Y型槽。
  4. 根据权利要求3所述的反应装置，其特征在于，所述流动聚焦型槽包括有主槽、分散相槽和两连续相槽，两所述连续相槽对称设置，所述分散相槽设置在两所述连续相槽之间；两所述连续相槽、所述分散相槽同一侧的一端均连接到所述主槽的一端上并与之连通，所述主槽的另一端向远离所述分散相槽、连续相槽一侧延伸。
  5. 根据权利要求4所述的反应装置，其特征在于，所述连续相槽、分散相槽、主槽的直径比例为1∶0.2-1∶1-1.5。
  6. 根据权利要求4所述的反应装置，其特征在于，所述连续相槽远离所述主槽的一端设置连续相进料口，所述分散相槽远离所述主槽的一端设置有分散相进料口，所述主槽远离所述分散相槽、连续相槽的一端设置有出料口。
  7. 根据权利要求6所述的反应装置，其特征在于，所述连续相进料口、分散相进料口、出料口贯穿所述主体结构层，且所述连续相进料口、分散相进料口、出料口的一端通过所述封装层密封。
  8. 根据权利要求6所述的反应装置，其特征在于，两所述连续相槽远离所述主槽的一端相连通并共用一个所述连续相进料口。
  9. 根据权利要求6所述的反应装置，其特征在于，所述分散相槽进料口的直径与所述分散相槽的直径比例为1：1-2；所述连续相槽进料口的直径与所述连续相槽的直径比例为1：1-2。
  10. 根据权利要求6所述的反应装置，其特征在于，所述分散相进料口通过连接槽与所述分散相槽连通，且所述连接槽的直径大于所述分散相槽的直径。
  11. 根据权利要求10所述的反应装置，其特征在于，所述连接槽与所述分散相槽连接处呈斜面连接，且该斜面的倾斜角度为30-60°。
  12. 根据权利要求6所述的反应装置，其特征在于，所述出料口内侧孔径小于外侧孔径。
  13. 根据权利要求12所述的反应装置，其特征在于，所述出料口为一阶梯孔或喇叭形孔。
  14. 根据权利要求1所述的反应装置，其特征在于，还包括有支持层，所述支持层叠置于所述封装层背向所述主体结构层的一侧上。
  15. 根据权利要求14所述的反应装置，其特征在于，所述主体结构层、封装层与支持层的材料厚度比例为1：0.05-0.5：1-3。
  16. 根据权利要求14所述的反应装置，其特征在于，所述支持层与所述主体结构层、所述封装层采用同种材料制成。
  17. 根据权利要求1或14所述的反应装置，其特征在于，所述主体结构层与所述封装层采用热塑性聚合物材料。
  18. 根据权利要求17所述的反应装置，其特征在于，所述主体结构层与所述封装层采用环烯烃聚合物。
  19. 一种反应装置的加工方法，其特征在于，用于加工权利要求1-18中任意一项所述的反应装置，加工方法为：
    S1、采用同种材料分别加工出所述主体结构层和封装层，并通过控制材料的聚合度，使得加工获得的所述封装层的熔融温度低于所述主体结构层的熔融温度；
    S2、加工好的所述主体结构层和封装层通过热键合方式进行连接。
  20. 根据权利要求19所述的反应装置的加工方法，其特征在于，步骤S2进一步包括：所述主体结构层和封装层在真空条件下通过热键合方式进行连接。
  21. 根据权利要求19所述的反应装置的加工方法，其特征在于，步骤S2进一步包括：热键合温度低于所述主体结构层的熔融温度，且高于或等于所述封装层的熔融温度。
  22. 根据权利要求21所述的反应装置的加工方法，其特征在于，所述热键合温度与所述主体结构层的熔融温度相差0.1-10％。
  23. 根据权利要求21所述的反应装置的加工方法，其特征在于，步骤S2进一步包括：热键合温度范围为90-160℃。
  24. 根据权利要求19所述的反应装置的加工方法，其特征在于，步骤S2进一步包括：热键合时间范围为3-30min。
  25. 根据权利要求19所述的反应装置的加工方法，其特征在于，步骤S2进一步包括：热键合压力范围为20-200kg。
  26. 根据权利要求19所述的反应装置的加工方法，其特征在于，还包括步骤S3：在所述封装层背向所述主体层的一侧上通过胶连接的方式连接支撑层。
  27. 根据权利要求26所述的反应装置的加工方法，其特征在于，步骤S3进一步包括:所述支持层与所述封装层之间的粘合压力范围为1-10kg。
  28. 根据权利要求26所述的反应装置的加工方法，其特征在于，步骤S3进一步包括:所述支持层与所述封装层之间的粘合时间范围为3-30s。
  29. 一种栓塞微球的制备设备，其特征是，包括进料系统、微球生成模块和固化装置；所述进料系统与微球生成模块连接，所述微球生成模块与所述固化装置连接；其中所述微球生成模块包括有至少一个微反应器，所述微反应器采用权利要求1-18中任意一项所述的反应装置。
  30. 根据权利要求29所述的栓塞微球的制备设备，其特征在于，所述微球生成模块包括有多个并联的所述微反应器，多个所述微反应器均分别与所述进料系统和所述固化装置连接，多个所述微反应器用于生成相同或不同直径的微球。
  31. 根据权利要求29或30所述的栓塞微球的制备设备，其特征在于，所述进料系统包括有连续相进料系统和分散相进料系统，所述连续相进料系统和分散相进料系统分别与各所述微反应器的连续相进料口和分散相进料口连通。
  32. 根据权利要求31所述的栓塞微球的制备设备，其特征在于，所述连续相进料系统包括有相连的连续相进料泵和连续相储料罐，所述连续相储料罐与各所述微反应器的连续相进料口连通；
    所述分散相进料系统包括相连的分散相进料泵和分散相储料罐，所述分散相储料罐与各所述微反应器的分散相进料口连通。
  33. 根据权利要求32所述的栓塞微球的制备设备，其特征在于，所述连续相进料系统还包括有第一压力源装置，所述第一压力源装置、连续相进料泵、连续相储料罐顺序连接；
    所述分散相进料系统还包括有第二压力源装置，所述第二压力源装置、分散相进料泵和分散相储料罐顺序连接。
  34. 根据权利要求32所述的栓塞微球的制备设备，其特征在于，所述连续相进料泵、所述分散相进料泵采用配备有带有流量、压力控制装置的泵。
  35. 根据权利要求29所述的栓塞微球的制备设备，其特征在于，所述微反应器还包括微流控芯片；所述微流控芯片配合控制器控制进入所述微反应器的反应液流速。
  36. 根据权利要求29所述的栓塞微球的制备设备，其特征在于，所述固化装置为紫外光固化装置或热固化装置，均包括固化容器及相应的发生装置。
  37. 一种栓塞微球的制备方法，所述的制备方法由权利要求29至36任一项所述的设备完成，其特征在于，在进料系统中分别通过连续相进料系统进油相物料至微反应器，通过分散相进料系统进水相物料至微反应器；在微反应器通道中将水相物料在油相物料剪切力的作用下，剪切成小液珠，形成油包水的结构，最后通过固化装置固化后得到粒径均一的聚乙烯醇栓塞微球。
  38. 根据权利要求37所述的栓塞微球的制备方法，其特征在于，所述水相物料为聚乙烯醇及其衍生物、水、交联剂和水相物料引发剂；所述油相物料为油相物料引发剂、表面活性剂和溶剂乙酸乙酯、乙酸丁酯等酯类溶剂,所述述聚乙烯醇及其衍生物:水:交联剂:水相物料引发剂质量比为10:1-100:1-10:0.01-0.6；所述油相物料引发剂和表面活性剂占酯类溶剂的质量比均为0.1％-5％。
  39. 根据权利要求38所述的栓塞微球的制备方法，其特征在于，所述聚乙烯醇及其衍生物采用聚乙烯醇为基材，以酰化后可交联的氨基/羟基的羧酸衍生物/磺酸衍生物为改性剂，进行改性后制得含有丙烯酸或其衍生物结构的可交联小分子的聚合物。
  40. 根据权利要求38所述的栓塞微球的制备方法，其特征在于，水相物料引发剂为过氧类引发剂和、或光引发剂，光引发剂具体包括苯偶酰类或酰基磷氧化物。
  41. 根据权利要求37所述的栓塞微球的制备方法，其特征在于，通过不同直径的微反应器控制生成的聚乙烯醇栓塞微球大小可在20-1400um调控，粒径均一度<10％。
  42. 根据权利要求37所述的栓塞微球的制备方法，其特征在于，所述固化装置为紫外光固化装置或热固化装置；
    所述热固化装置采用夹层反应瓶装置，通过循环控温装置进行保温，固化温度40-80℃，固化时间1-6h；
    所述紫外光固化装置采用盘管装置，将制备的微球在管路里连续化流动并通过高强度紫外灯进行实时光照固化，其照射波长200-500nm，光照时间2-1000s。
  43. 根据权利要求37所述的栓塞微球的制备方法，其特征在于，通过进料系统控制分散相和连续相的流速，结合微反应器中对应的分散相和连续相进口内径控制生成的聚乙烯醇栓塞微球的直径大小。
  44. 根据权利要求43所述的栓塞微球的制备方法，其特征在于，当分散相管道内径20±10μm，连续相管道内径20±10μm；控制分散相物料的进样流速为0.1-2μL/min，连续相物料的进样流速为400±200μL/min，其制备的聚乙烯醇栓塞微球粒径为20±10μm；
    当分散相管道内径60±10μm，连续相管道内径90±50μm；控制分散相物料的进样流速为2±1μL/min，连续相物料的进样流速为200±100μL/min，其制备的聚乙烯醇栓塞微球粒径为40±20μm；
    当分散相管道内径100±20μm，连续相管道内径300±150μm；控制分散相物料的进样流速为5±2μL/min，连续相物料的进样流速为800±300μL/min，制备的聚乙烯醇栓塞微球粒径为100±25μm；
    当分散相管道内径100±20μm，连续相管道内径300±150μm；控制分散相物料的进样流速为5±2μL/min，连续相物料的进样流速为500±200μL/min，，制备的聚乙烯醇栓塞微球粒径为250±50μm；
    当分散相管道内径250±130μm，连续相管道内径500±200μm；控制分散相物料的进样流速为20±5μL/min，连续相物料的进样流速为2000±500μL/min，制备的聚乙烯醇栓塞微球粒径为500±50μm；
    当分散相管道内径800±300μm，连续相管道内径1000±500μm；控制分散相物料的进样流速为50±20μL/min，连续相物料的进样流速为800±200μL/min，制备的聚乙烯醇栓塞微球粒径为800±80μm；
    当分散相管道内径800±400μm，连续相管道内径2000±1000μm；控制分散相物料的进样流速为50±20μL/min，连续相物料的进样流速为5000±2500μL/min；制备的聚乙烯醇栓塞微球粒径为1200±100μm；
    当分散相管道内径100±20μm，连续相管道内径100±50μm；控制分散相物料的进样流速为5±2μL/min，连续相物料的进样流速为500±300μL/min；制备的聚乙烯醇栓塞微球粒径为100±25μm；
    当分散相管道内径80±10μm，连续相管道内径100±20μm；控制分散相物料的进样流速为5±1μL/min，连续相物料的进样流速为300±100μL/min；制备的聚乙烯醇栓塞微球粒径为80±25μm；
    当分散相管道内径1500±500μm，连续相管道内径500±200μm；控制分散相物料的进样流速为10-500μL/min，连续相物料的进样流速为1000-50000μL/min；制备的聚乙烯醇栓塞微球粒径为500-1400μm。
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