A method for preparing hollow non-spherical micro-nanoparticles based on coaxial microreactor

Abstract

The application provides a method for preparing hollow non-spherical micro-nanoparticles based on a coaxial micro-reactor, and belongs to the field of droplet microfluidics and polymer materials. A three-channel coaxial micro-reactor is designed to generate a water-in-oil-in-water (W / O / W) double emulsion. The innermost phase is an alkaline electrolyte aqueous solution, the intermediate oil phase is a polymer solution, and the outermost phase is a surfactant aqueous solution. With the volatilization of the intermediate phase solvent, the double emulsion droplets form hollow non-spherical micro-nanoparticles. The double emulsion is placed in a collection liquid with different electrolyte concentrations, water molecules in the collection liquid penetrate into the innermost phase under the action of osmotic pressure, increase the size of the inner droplets of the double emulsion, and then change the morphology of the outer droplets, so that the non-spherical structure required is presented, and the size of the hollow micro-nanoparticles is controllable. The coaxial micro-channel reactor used in the application adopts a flow focusing structure, which is used for controllable generation of double emulsion to prepare multi-chamber hollow non-spherical micro-nanoparticles.

Description

Technical Field

[0001] This invention belongs to the field of droplet microfluidics and polymer materials, and relates to a method for preparing hollow non-spherical micro-nano particles based on a coaxial microreactor. This invention combines microchannel technology with the principle of emulsion reverse osmosis, using a dual emulsion generated by the microreactor as a template to adjust the size and morphology of the internal droplets through reverse osmosis to prepare hollow non-spherical micro-nano particles with controllable particle size. Background Technology

[0002] Hollow non-spherical micro / nanoparticles refer to core-shell structured non-spherical particles with particle sizes in the micrometer or nanometer range, possessing one or more hollow internal structures and encased in a shell material. Due to their unique core-shell structure, diverse morphologies, and non-spherical characteristics, hollow non-spherical particles have wide applications in drug delivery and controlled release, active substance encapsulation, and micro-biochemical reactions. Particle size and particle size distribution are key factors affecting their performance. Due to their non-spherical structure, there are relatively few methods for preparing hollow non-spherical particles, such as the template method, seed polymerization method, and thin film stretching method. However, these methods have limitations such as poor controllability of size and structure and complex preparation processes. For example, Chinese invention patent CN201310302405.6 discloses a method for preparing non-spherical particles based on seed polymerization, which prepares non-spherical particles of different morphologies through soap-free emulsion polymerization, but suffers from the limitation of a wide particle size distribution in the product. Chinese invention patent CN202511399412.1 discloses a method for preparing non-spherical particles by combining artificial intelligence methods with microfluidic technology, producing monodisperse bullet-shaped and disk-shaped non-spherical particles. However, this method suffers from drawbacks such as high cost and complex process. Droplet microfluidic technology can stably generate monodisperse and controllable droplets, but it is difficult to prepare non-spherical particles simply by using this as a template. Therefore, a method for preparing hollow non-spherical particles that is universal, has mild conditions, wide applicability, and can precisely control the size and structure of the particles is needed. This invention, by combining droplet microfluidic technology and the principle of emulsion reverse osmosis, further adjusts the droplet structure, achieving the controllable preparation of hollow non-spherical micro / nano particles.

[0003] Based on this, the present invention designs and fabricates a three-inlet coaxial microreactor for generating complex droplets, which can stably prepare multi-chamber hollow non-spherical particles. Based on the principle of emulsion reverse osmosis, the electrolyte concentration of the inner and outer phases of the dual emulsion is adjusted, allowing water molecules in the collected liquid to permeate into the inner droplet under the action of osmotic pressure. The expansion of the inner droplet causes the outer droplet to exhibit a non-spherical structure, thereby realizing the preparation of hollow non-spherical particles. Summary of the Invention

[0004] To address the problems existing in the prior art, this invention provides a method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor. This invention designs a three-channel coaxial microreactor capable of generating structurally controllable double emulsions. By adjusting the osmotic pressure of the inner and outer phases of the double emulsion, the volume of the inner aqueous phase is changed, causing the outer droplets to exhibit a non-spherical morphology, thereby preparing multi-chamber hollow non-spherical particles. Based on the principle of emulsion reverse osmosis, the controllable preparation of hollow non-spherical particles is achieved by adjusting the concentration of the electrolyte solution in the collection liquid and the aqueous phase within the double emulsion.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor, the method comprising the following steps: Step 1: A coaxial microreactor is fabricated using four capillary tubes of different sizes, including an inner tube 1, a middle tube 2, a receiving tube 4, and a support tube 3. The inner tube 1, middle tube 2, and receiving tube 4 are each drawn into a tapered end using a laser needle drawing device, and the tips are then polished smooth to form tapered ends. The middle tube 2 has the same inner diameter and wall thickness as the receiving tube 4. Finally, the capillary tubes are ultrasonically cleaned.

[0006] Furthermore, the support tube 3 is a square capillary tube with both ends polished smooth.

[0007] Furthermore, the capillary is made of glass, the inner diameter L1 of the inner tube 1 ranges from 100 to 400 μm, and the wall thickness T1 ranges from 50 to 100 μm; the inner diameter L2 of the intermediate tube 2 and the receiving tube 4 ranges from 300 to 700 μm, and the wall thickness T2 ranges from 200 to 250 μm; the inner side length L3 of the support tube 3 ranges from 800 to 1300 μm, and the wall thickness T3 ranges from 50 to 100 μm, and (L1+2×T1)<L2, (L2+2×T2)<L3.

[0008] Step 2: Assemble four capillaries to obtain a coaxial microreactor, and determine the outermost phase inlet, intermediate phase inlet, innermost phase inlet, and outlet. Specifically: The support tube 3 is placed in the middle of the substrate and simply fixed at both ends with glue. The right end of the middle tube 2 is a tapered end, which is inserted from the left end of the support tube 3, adjusted to be coaxial with the support tube 3, and simply fixed with quick-drying glue. The position where the left end of the support tube 3 connects to the middle tube 2 is the outermost phase inlet, and the left end of the middle tube 2 is the intermediate phase inlet. The intermediate phase inlet is connected to the first fluid conduit, and the connection between the left end of the middle tube 2 and the first fluid conduit is fixed with glue. An opening is machined in the first fluid conduit 8-12 mm to the left of the connection point for the second fluid conduit to pass through.

[0009] The right end of the inner tube 1 is a tapered nozzle, similar to a needle nozzle. It is inserted from the left end of the middle tube 2 and nested coaxially with the middle tube 2. Its position is adjusted so that the tapered nozzle of the inner tube 1 is to the left of the tapered nozzle of the middle tube 2. The left port of the inner tube 1 serves as the innermost phase inlet, which is connected to the second fluid pipeline. The connection between the left port of the inner tube 1 and the second fluid pipeline is fixed with glue.

[0010] The left end of the receiving tube 4 is a tapered nozzle, which is inserted from the right end of the support tube 3. The tips of the intermediate tube 2 and the receiving tube 4 are placed opposite each other, and the end face size of the tapered nozzle of the intermediate tube 2 is smaller than that of the receiving tube 4. The receiving tube 4 is coaxial with the intermediate tube 2 and the inner tube 1. The right end of the receiving tube 4 is connected to a third fluid pipeline as an outlet, and the connection between the right end of the receiving tube 4 and the third fluid pipeline is fixed with glue.

[0011] The inner tube 1 is placed coaxially inside the middle tube 2, and the middle tube 2 and the receiving tube 4 are placed inside the support tube 3, with the four tubes coaxial; the tips of the middle tube 2 and the receiving tube 4 are placed opposite each other.

[0012] Furthermore, the fluid piping is made of materials including connecting pipes and conversion interfaces. The connecting pipes are made of glass or polymer. The conversion interfaces are made of polymer or metal.

[0013] Step 3: Seal all connections between the four capillaries and the fluid lines with adhesive to ensure the microreactor's airtightness, ultimately obtaining a three-channel coaxial microreactor. After the adhesive has dried and cured for 24-48 hours, introduce the outermost phase, intermediate phase, and innermost phase into the outermost phase inlet, intermediate phase inlet, and innermost phase inlet, respectively.

[0014] Furthermore, before injection, a syringe is used to inject water to check whether the three-channel coaxial microreactor has any leakage or blockage. Once the check is completed, the experiment can be carried out.

[0015] Step 4: Connect the three fluid inlets of the coaxial microreactor to the syringe on the microfluidic injection pump using connecting tubes, and control the liquid flow rate by adjusting the flow pump. Connect the outlet of the three-channel coaxial microchannel to the sample vial using connecting tubes. Simultaneously, introduce a surfactant aqueous solution into the outermost phase inlet, a polymer oil solution into the intermediate phase inlet, and an electrolyte aqueous solution into the innermost phase inlet. After introducing the three liquids, a first flow focusing region is formed between the right port of the inner tube 1 and the right port of the intermediate tube 2. At this time, the innermost phase and the intermediate phase mix to form a water-in-oil structure. A second flow focusing region is formed between the right port of the intermediate tube 2 and the left port of the receiving tube 4. The water-in-oil structure mixes with the outermost phase, thereby forming a water-in-oil (W / O / W) double emulsion structure in the receiving tube 4. The first and second flow focusing regions form a dual flow focusing structure.

[0016] Wait 3 to 5 minutes for the dual emulsion to stabilize before starting collection. The innermost layer of the dual emulsion is an aqueous phase, the middle layer is an oil phase formed by the polymer solution, and the outermost layer is an aqueous phase.

[0017] Furthermore, the dual emulsion includes a binuclear dual emulsion, a trinuclear dual emulsion, or a tetranuclear dual emulsion.

[0018] Furthermore, the flow rate of the outermost phase is 150 ~ 450 μL / min; the flow rate of the intermediate phase is 350 ~ 450 μL / min; and the flow rate of the innermost phase is 120 ~ 170 μL / min. By adjusting the three-phase flow rates, a binuclear biemulsion, a trinuclear biemulsion, or a tetranuclear biemulsion can be obtained.

[0019] Furthermore, the surfactant aqueous solution is obtained by dissolving the surfactant in water, with a concentration of 1-3 wt%; the polymer oil solution is obtained by dissolving the polymer in a solvent, with a concentration of 5-20 mg / mL; the electrolyte aqueous solution is obtained by dissolving two types of electrolytes in water, one being a neutral electrolyte with a concentration of 2-9 wt% and the other being an alkaline electrolyte with a concentration of 0.3-1 wt%.

[0020] Furthermore, the surfactant includes polyvinyl alcohol or polysorbate. The polymer includes polylactic acid-glycolic acid copolymer or polyglycolic acid. The solvent used to dissolve the polymer is required to be volatile and includes dichloromethane, ethyl acetate, or chloroform. The neutral electrolyte includes sodium chloride or potassium chloride. The alkaline electrolyte includes sodium carbonate or sodium bicarbonate.

[0021] Step 5: Place the double emulsion collected in receiving tube 4 into the collecting liquid. The solvent in the oil phase of the double emulsion will evaporate naturally, forming hollow non-spherical micro-nano particles.

[0022] Furthermore, the collecting liquid is a mixture of water and electrolyte. By adjusting the concentration of the electrolyte in the collecting liquid, the osmotic pressure environment of the dual emulsion is altered, resulting in hollow, non-spherical micro / nano particles with controllable size. The concentration of the electrolyte ranges from 1 to 10 wt%.

[0023] Furthermore, the electrolyte includes sodium chloride or potassium chloride.

[0024] Compared with existing microreactors, the present invention has the following advantages: (1) The microreactor designed in this invention adopts a dual-flow focusing structure, which can generate a stable monodisperse water-in-oil-in-water double emulsion within the microreactor, thereby generating hollow non-spherical particles. The reactor material has low cost, clear structure and function, stable chemical properties, and can be directly observed during operation. It can be used to prepare hollow non-spherical particles of various materials.

[0025] (2) This invention is based on the principle of emulsion reverse osmosis. Two emulsions are placed in aqueous solutions with different electrolyte concentrations to change the osmotic pressure environment of the two emulsions. Water molecules migrate through the intermediate oil phase under the influence of the electrolyte concentration difference between the droplets in the two emulsions and the collected solution until osmotic pressure equilibrium is reached. This changes the size of the droplets in the two emulsions and causes the outer droplets to form a non-spherical structure. Without complex equipment and techniques, the size of hollow non-spherical micro / nano particles with controllable dimensions can be prepared.

[0026] (3) Combining droplet microfluidics and emulsion reverse osmosis, multinuclear dual emulsions, such as binuclear and trinuclear emulsions, were generated in a three-channel coaxial microreactor by adjusting the flow rates and types of the three-phase fluids (outermost, intermediate, and innermost phases). When placed under different osmotic pressure environments, hollow non-spherical micro-nano particles with controllable particle size and different numbers of chambers can be successfully prepared. Attached Figure Description

[0027] Figure 1 Here are schematic diagrams and actual images of a coaxial microreactor: Figure 1 (a) in the diagram is a schematic diagram of the microreactor structure; Figure 1 (b) in the image is a physical diagram of the microreactor; Figure 1 (c) is a microscopic image of the dual-flow focusing structure inside the microreactor; Figure 1 Image (d) in the image is a capillary image used to assemble the microreactor.

[0028] Figure 2 This is a schematic diagram of the experimental procedure.

[0029] Figure 3 For different electrolyte concentrations in the collected liquid ( C W2 Microscopic images of the initial, stable, and double-chambered hollow non-spherical particles of the binuclear biemulsion: Figure 2 (a) C W2 = 1 wt% Figure 2 (b) C W2 = 3 wt% Figure 2 (c) C W2 =8 wt% Figure 2 (d) C W2 = 10 wt%.

[0030] Figure 4 In different C W2 The equivalent diameter of the initial state, stable state, and hollow non-spherical particles of the binary double emulsion.

[0031] Figure 5 Microscopic images of the formation processes of binuclear, trinuclear, and tetranuclear double emulsions, as well as multinuclear double emulsion droplets and multi-chamber hollow non-spherical particles, under different types and flow rates of three-phase fluids: Figure 5 (a) in the text represents a binucleated double emulsion; Figure 5 (b) in the text is a trinuclear dual emulsion; Figure 5 (c) in the text is a tetranuclear dual emulsion.

[0032] In the diagram: 1 Inner tube; 2 Intermediate tube; 3 Support tube; 4 Receiving tube; 5 Microscope; 6 Computer; 7 Sample bottle. Detailed Implementation

[0033] The present invention will be further described below with reference to specific embodiments.

[0034] Example 1 (Dual-core dual-emulsion) The steps for preparing dual-core dual-emulsion and dual-chamber hollow non-spherical particles using the coaxial microreactor in this embodiment are as follows: Step 1: A microreactor is fabricated using four capillary tubes of different sizes, including an inner tube 1, a middle tube 2, a receiving tube 4, and a support tube 3. The inner tube 1, middle tube 2, and receiving tube 4 are each drawn into a tapered end using a laser needle drawing device, and the tips are then polished smooth to form tapered ends. The middle tube 2 has the same inner diameter and wall thickness as the receiving tube 4. Finally, the capillary tubes are ultrasonically cleaned.

[0035] In this embodiment, the support tube 3 is a square capillary tube with both ends polished smooth.

[0036] In this embodiment, the capillary is made of glass, the inner tube 1 has an inner diameter of 300 μm and a wall thickness of 75 μm, the middle tube 2 and the receiving tube 4 have an inner diameter of 580 μm and a wall thickness of 210 μm, and the support tube 3 has an inner side length of 1100 μm and a wall thickness of 75 μm.

[0037] Step 2: Assemble four capillaries to obtain a microreactor, and determine the outermost phase inlet, intermediate phase inlet, innermost phase inlet, and outlet. Specifically: The support tube 3 is placed in the middle of the substrate and simply fixed at both ends with glue. The right end of the middle tube 2 is a tapered end, which is inserted from the left end of the support tube 3. It is adjusted to be coaxial with the support tube 3 and simply fixed with quick-drying glue. The position where the left end of the support tube 3 connects to the middle tube 2 is the outermost phase inlet, and the left end of the middle tube 2 is the intermediate phase inlet. The intermediate phase inlet is connected to the first fluid conduit, and the connection between the left end of the middle tube 2 and the first fluid conduit is fixed with glue. An opening is machined 10 mm to the left of the connection point in the first fluid conduit for the second fluid conduit to pass through.

[0038] The right end of the inner tube 1 is a tapered nozzle, similar to a needle nozzle. It is inserted from the left end of the middle tube 2 and nested coaxially with the middle tube 2. Its position is adjusted so that the tapered nozzle of the inner tube 1 is to the left of the tapered nozzle of the middle tube 2. The left port of the inner tube 1 serves as the innermost phase inlet, which is connected to the second fluid pipeline. The connection between the left port of the inner tube 1 and the second fluid pipeline is fixed with glue.

[0039] The left end of the receiving tube 4 is a tapered nozzle, which is inserted from the right end of the support tube 3. The tips of the intermediate tube 2 and the receiving tube 4 are placed opposite each other, and the end face size of the tapered nozzle of the intermediate tube 2 is smaller than that of the receiving tube 4. The receiving tube 4 is coaxial with the intermediate tube 2 and the inner tube 1. The right end of the receiving tube 4 is connected to a third fluid pipeline as an outlet, and the connection between the right end of the receiving tube 4 and the third fluid pipeline is fixed with glue.

[0040] The inner tube 1 is placed coaxially inside the middle tube 2, and the middle tube 2 and the receiving tube 4 are placed inside the support tube 3, with the four tubes coaxial; the tips of the middle tube 2 and the receiving tube 4 are placed opposite each other.

[0041] In this embodiment, the fluid conduit is made of connecting pipes and conversion interfaces. The connecting pipe is made of polytetrafluoroethylene (PTFE), a high-molecular polymer, and the conversion interface is made of a metal injection needle.

[0042] Step 3: Seal all connections between the four capillary tubes and the fluid lines with glue to ensure the microreactor's airtightness, ultimately obtaining a three-channel coaxial microreactor, such as... Figure 1 As shown. After the adhesive has dried and cured for 30 hours, the outermost phase, intermediate phase, and innermost phase are introduced into the outermost phase inlet, intermediate phase inlet, and innermost phase inlet, respectively.

[0043] In this embodiment, before injection, a syringe is used to inject water to check whether there is leakage or blockage in the three-channel coaxial microreactor. Once the check is completed, the experiment can be carried out.

[0044] Step 4: Connect the three fluid inlets of the coaxial microreactor to the syringe on the microfluidic injection pump using connecting tubes, and control the liquid phase flow rate by adjusting the flow pump. Connect the outlet of the three-channel coaxial microchannel to the sample vial using connecting tubes. Simultaneously, introduce a surfactant aqueous solution into the outermost phase inlet, a polymer oil phase solution into the intermediate phase, and an electrolyte aqueous solution into the innermost phase. After introducing the three liquids, a first flow focusing region is formed between the right port of the inner tube 1 and the right port of the intermediate tube 2. At this point, the innermost phase mixes with the intermediate phase to form a water-in-oil structure. A second flow focusing region is formed between the right port of the intermediate tube 2 and the left port of the receiving tube 4. The water-in-oil structure mixes with the outermost phase, thereby forming a W / O / W double emulsion structure in the receiving tube 4. The first and second flow focusing regions constitute a dual flow focusing structure.

[0045] Wait 4 minutes for the double emulsion to stabilize before collecting. The experimental procedure is as follows: Figure 2 As shown. The innermost layer of the dual emulsion is an aqueous phase, the middle layer is an oil phase formed by the polymer solution, and the outermost layer is an aqueous phase.

[0046] In this embodiment, the flow rate of the outermost phase is 450 μL / min; the flow rate of the intermediate phase is 450 μL / min; and the flow rate of the innermost phase is 130 μL / min, resulting in a binuclear double emulsion.

[0047] In this embodiment, the surfactant aqueous solution is obtained by dissolving polyvinyl alcohol (PVA) in water at a concentration of 2 wt%; the polymer oil solution is obtained by dissolving polylactic acid-glycolic acid copolymer (PLGA) in dichloromethane (DCM) at a concentration of 10 mg / mL; and the electrolyte aqueous solution is obtained by dissolving two electrolytes in water: sodium chloride at a concentration of 4 wt% and sodium carbonate at a concentration of 0.6 wt%.

[0048] Step 5: Place the binuclear biemulsion collected by receiving tube 4 into collection solutions with different electrolyte concentrations. The solvent in the oil phase of the biemulsion will evaporate naturally, forming bicavated hollow non-spherical micro-nano particles.

[0049] In this embodiment, the dual-core dual-emulsion is placed in four collection bottles, and the collection liquids in the collection bottles are 1, 3, 8 and 10 wt% sodium chloride aqueous solutions, respectively. Figure 3 This study displays microscopic images of binuclear dual-emulsion droplets in their initial state upon entering collection solutions of different concentrations, their stable state upon reaching osmotic pressure equilibrium within the collection solution, and the binuclear hollow non-spherical particles after solvent evaporation. The effect of collection solution concentration on the size of the binuclear dual-emulsion is measured using the average inner diameter of the two inner droplets as the equivalent diameter. The particle size changes in the three states are shown below. Figure 4 As shown, when the sodium chloride concentration in the collected liquid is greater than that in the aqueous phase of the double emulsion, the size of the inner droplets decreases, and the size of the double-chambered hollow non-spherical particles decreases accordingly; when the sodium chloride concentration in the collected liquid is less than that in the aqueous phase of the double emulsion, the size of the inner droplets increases, and the size of the double-chambered hollow non-spherical particles increases accordingly. Finally, binuclear hollow non-spherical particles with an equivalent diameter ranging from 180 to 340 μm are obtained.

[0050] In this embodiment, the formation process of the binuclear double emulsion, the stable state of the binuclear double emulsion when the collection liquid is 3 wt% sodium chloride, and the microscopic images of the double-chambered hollow non-spherical particles formed therefrom are shown below. Figure 5 As shown in (a).

[0051] In this embodiment, an electrolyte concentration difference is created between the collected liquid and the droplets within the dual emulsion by altering the electrolyte concentration concentration. Based on the principle of emulsion reverse osmosis, water molecules in the inner droplets permeate out under the osmotic pressure generated by the electrolyte concentration difference, or water molecules in the collected liquid permeate into the inner droplets, causing the dual emulsion to exhibit the desired non-spherical structure and adjusting its size. Ultimately, this achieves the preparation of size-controllable binuclear hollow non-spherical particles.

[0052] Example 2 (Tri-core Dual Emulsion) The steps for preparing trinuclear dual emulsions and three-chamber hollow non-spherical particles using the coaxial microreactor in this embodiment are as follows: Step 1: A microreactor is fabricated using four capillary tubes of different sizes, including an inner tube 1, a middle tube 2, a receiving tube 4, and a support tube 3. The inner tube 1, middle tube 2, and receiving tube 4 are each drawn into a tapered end using a laser needle drawing device, and the tips are then polished smooth to form tapered ends. The middle tube 2 has the same inner diameter and wall thickness as the receiving tube 4. Finally, the capillary tubes are ultrasonically cleaned.

[0053] In this embodiment, the support tube 3 is a square capillary tube with both ends polished smooth.

[0054] In this embodiment, the capillary is made of glass, the inner tube 1 has an inner diameter of 100 μm and a wall thickness of 50 μm, the middle tube 2 and the receiving tube 4 have an inner diameter of 300 μm and a wall thickness of 200 μm, and the support tube 3 has an inner side length of 800 μm and a wall thickness of 50 μm.

[0055] Step 2: Assemble four capillaries to obtain a microreactor, and determine the outermost phase inlet, intermediate phase inlet, innermost phase inlet, and outlet. Specifically: The support tube 3 is placed in the middle of the substrate and simply fixed at both ends with glue. The right end of the middle tube 2 is a tapered end, which is inserted from the left end of the support tube 3, adjusted to be coaxial with the support tube 3, and simply fixed with quick-drying glue. The position where the left end of the support tube 3 connects to the middle tube 2 is the outermost phase inlet, and the left end of the middle tube 2 is the intermediate phase inlet. The intermediate phase inlet is connected to the first fluid conduit, and the connection between the left end of the middle tube 2 and the first fluid conduit is fixed with glue. An opening is machined 8 mm to the left of the connection point in the first fluid conduit for the second fluid conduit to pass through.

[0056] The right end of the inner tube 1 is a tapered nozzle, similar to a needle nozzle. It is inserted from the left end of the middle tube 2 and nested coaxially with the middle tube 2. Its position is adjusted so that the tapered nozzle of the inner tube 1 is to the left of the tapered nozzle of the middle tube 2. The left port of the inner tube 1 serves as the innermost phase inlet, which is connected to the second fluid pipeline. The connection between the left port of the inner tube 1 and the second fluid pipeline is fixed with glue.

[0057] The left end of the receiving tube 4 is a tapered nozzle, which is inserted from the right end of the support tube 3. The tips of the intermediate tube 2 and the receiving tube 4 are placed opposite each other, and the end face size of the tapered nozzle of the intermediate tube 2 is smaller than that of the receiving tube 4. The receiving tube 4 is coaxial with the intermediate tube 2 and the inner tube 1. The right end of the receiving tube 4 is connected to a third fluid pipeline as an outlet, and the connection between the right end of the receiving tube 4 and the third fluid pipeline is fixed with glue.

[0058] The inner tube 1 is placed coaxially inside the middle tube 2, and the middle tube 2 and the receiving tube 4 are placed inside the support tube 3, with the four tubes coaxial; the tips of the middle tube 2 and the receiving tube 4 are placed opposite each other.

[0059] In this embodiment, the fluid conduit is made of a connecting tube and a conversion interface. The connecting tube is a glass fiber tube made of glass, and the conversion interface is an injection needle made of a polymer.

[0060] Step 3: Seal all connections between the four capillaries and the fluid lines with adhesive to ensure the microreactor's airtightness, ultimately obtaining a three-channel coaxial microreactor. After the adhesive has dried and cured for 24 hours, introduce the outermost phase, intermediate phase, and innermost phase into the outermost phase inlet, intermediate phase inlet, and innermost phase inlet, respectively.

[0061] In this embodiment, before injection, a syringe is used to inject water to check whether there is leakage or blockage in the three-channel coaxial microreactor. Once the check is completed, the experiment can be carried out.

[0062] Step 4: Connect the three fluid inlets of the coaxial microreactor to the syringe on the microfluidic injection pump using connecting tubes, and control the liquid phase flow rate by adjusting the flow pump. Connect the outlet of the three-channel coaxial microchannel to the sample vial using connecting tubes. Simultaneously, introduce a surfactant aqueous solution into the outermost phase inlet, a polymer oil phase solution into the intermediate phase, and an electrolyte aqueous solution into the innermost phase. After introducing the three liquids, a first flow focusing region is formed between the right port of the inner tube 1 and the right port of the intermediate tube 2. At this point, the innermost phase mixes with the intermediate phase to form a water-in-oil structure. A second flow focusing region is formed between the right port of the intermediate tube 2 and the left port of the receiving tube 4. The water-in-oil structure mixes with the outermost phase, thereby forming a W / O / W double emulsion structure in the receiving tube 4. The first and second flow focusing regions constitute a dual flow focusing structure.

[0063] Wait 3 minutes for the dual emulsion to stabilize before starting collection. The innermost layer of the dual emulsion is an aqueous phase, the middle layer is an oil phase formed by the polymer solution, and the outermost layer is an aqueous phase.

[0064] In this embodiment, the flow rate of the outermost phase is 150 μL / min; the flow rate of the intermediate phase is 350 μL / min; and the flow rate of the innermost phase is 120 μL / min, resulting in a trinuclear dual emulsion.

[0065] In this embodiment, the surfactant aqueous solution is obtained by dissolving polysorbate in water, with a concentration of 1 wt%; the polymer oil solution is obtained by dissolving polyglycolic acid copolymer in ethyl acetate, with a concentration of 5 mg / mL; and the electrolyte aqueous solution is obtained by dissolving two electrolytes in water, one being potassium chloride with a concentration of 2 wt% and the other being sodium carbonate with a concentration of 0.3 wt%.

[0066] Step 5: Place the trinuclear double emulsion collected in receiving tube 4 into the collecting liquid. The solvent in the oil phase of the double emulsion will evaporate naturally, forming three-chamber hollow non-spherical micro-nano particles. Figure 5 (b) shows the formation process of the trinuclear double emulsion, the stable state of the trinuclear double emulsion in the collection liquid, and the microscopic images of the three-chambered hollow non-spherical particles formed therefrom.

[0067] In this embodiment, the collecting liquid is a 1 wt% potassium chloride aqueous solution.

[0068] In this embodiment, by adjusting the type and flow rate of the three-phase fluid, a trinuclear dual emulsion was controllably generated in a three-channel coaxial microreactor, and hollow non-spherical particles with three chambers were successfully prepared.

[0069] Example 3 (Quadruple-core dual emulsion) The steps for preparing tetranuclear dual emulsions and four-chamber hollow non-spherical particles using the coaxial microreactor in this embodiment are as follows: Step 1: A microreactor is fabricated using four capillary tubes of different sizes, including an inner tube 1, a middle tube 2, a receiving tube 4, and a support tube 3. The inner tube 1, middle tube 2, and receiving tube 4 are each drawn into a tapered end using a laser needle drawing device, and the tips are then polished smooth to form tapered ends. The middle tube 2 has the same inner diameter and wall thickness as the receiving tube 4. Finally, the capillary tubes are ultrasonically cleaned.

[0070] In this embodiment, the support tube 3 is a square capillary tube with both ends polished smooth.

[0071] In this embodiment, the capillary is made of glass, the inner tube 1 has an inner diameter of 400 μm and a wall thickness of 100 μm, the middle tube 2 and the receiving tube 4 have an inner diameter of 700 μm and a wall thickness of 250 μm, and the support tube 3 has an inner side length of 1300 μm and a wall thickness of 100 μm.

[0072] Step 2: Assemble four capillaries to obtain a microreactor, and determine the outermost phase inlet, intermediate phase inlet, innermost phase inlet, and outlet. Specifically: The support tube 3 is placed in the middle of the substrate and simply fixed at both ends with glue. The right end of the middle tube 2 is a tapered end, which is inserted from the left end of the support tube 3, adjusted to be coaxial with the support tube 3, and simply fixed with quick-drying glue. The position where the left end of the support tube 3 connects to the middle tube 2 is the outermost phase inlet, and the left end of the middle tube 2 is the intermediate phase inlet. The intermediate phase inlet is connected to the first fluid conduit, and the connection between the left end of the middle tube 2 and the first fluid conduit is fixed with glue. An opening is machined 12 mm to the left of the connection point in the first fluid conduit for the second fluid conduit to pass through.

[0073] The right end of the inner tube 1 is a tapered nozzle, similar to a needle nozzle. It is inserted from the left end of the middle tube 2 and nested coaxially with the middle tube 2. Its position is adjusted so that the tapered nozzle of the inner tube 1 is to the left of the tapered nozzle of the middle tube 2. The left port of the inner tube 1 serves as the innermost phase inlet, which is connected to the second fluid pipeline. The connection between the left port of the inner tube 1 and the second fluid pipeline is fixed with glue.

[0074] The left end of the receiving tube 4 is a tapered nozzle, which is inserted from the right end of the support tube 3. The tips of the intermediate tube 2 and the receiving tube 4 are placed opposite each other, and the end face size of the tapered nozzle of the intermediate tube 2 is smaller than that of the receiving tube 4. The receiving tube 4 is coaxial with the intermediate tube 2 and the inner tube 1. The right end of the receiving tube 4 is connected to a third fluid pipeline as an outlet, and the connection between the right end of the receiving tube 4 and the third fluid pipeline is fixed with glue.

[0075] The inner tube 1 is placed coaxially inside the middle tube 2, and the middle tube 2 and the receiving tube 4 are placed inside the support tube 3, with the four tubes coaxial; the tips of the middle tube 2 and the receiving tube 4 are placed opposite each other.

[0076] In this embodiment, the fluid conduit is made of a connecting tube and a conversion interface. The connecting tube is a polytetrafluoroethylene (PTFE) tube made of a polymer, and the conversion interface is an injection needle made of a polymer.

[0077] Step 3: Seal all connections between the four capillaries and the fluid lines with adhesive to ensure the microreactor's airtightness, ultimately obtaining a three-channel coaxial microreactor. After the adhesive has dried and cured for 48 hours, introduce the outermost phase, intermediate phase, and innermost phase into the outermost phase inlet, intermediate phase inlet, and innermost phase inlet, respectively.

[0078] In this embodiment, before injection, a syringe is used to inject water to check whether there is leakage or blockage in the three-channel coaxial microreactor. Once the check is completed, the experiment can be carried out.

[0079] Step 4: Connect the three fluid inlets of the coaxial microreactor to the syringe on the microfluidic injection pump using connecting tubes, and control the liquid phase flow rate by adjusting the flow pump. Connect the outlet of the three-channel coaxial microchannel to the sample vial using connecting tubes. Simultaneously, introduce a surfactant aqueous solution into the outermost phase inlet, a polymer oil phase solution into the intermediate phase, and an electrolyte aqueous solution into the innermost phase. After introducing the three liquids, a first flow focusing region is formed between the right port of the inner tube 1 and the right port of the intermediate tube 2. At this point, the innermost phase mixes with the intermediate phase to form a water-in-oil structure. A second flow focusing region is formed between the right port of the intermediate tube 2 and the left port of the receiving tube 4. The water-in-oil structure mixes with the outermost phase, thereby forming a W / O / W double emulsion structure in the receiving tube 4. The first and second flow focusing regions constitute a dual flow focusing structure.

[0080] Wait 5 minutes for the dual emulsion to stabilize before starting collection. The innermost layer of the dual emulsion is an aqueous phase, the middle layer is an oil phase formed by the polymer solution, and the outermost layer is an aqueous phase.

[0081] In this embodiment, the flow rate of the outermost phase is 400 μL / min; the flow rate of the intermediate phase is 400 μL / min; and the flow rate of the innermost phase is 170 μL / min, resulting in a tetranuclear dual emulsion.

[0082] In this embodiment, the surfactant aqueous solution is obtained by dissolving polyvinyl alcohol in water, with a concentration of 3 wt%; the polymer oil solution is obtained by dissolving polylactic acid-glycolic acid copolymer in chloroform, with a concentration of 20 mg / mL; and the electrolyte aqueous solution is obtained by dissolving two electrolytes in water, one being potassium chloride with a concentration of 9 wt% and the other being sodium bicarbonate with a concentration of 1 wt%.

[0083] Step 5: Place the tetranuclear double emulsion collected in receiving tube 4 into the collecting liquid. The solvent in the oil phase of the double emulsion evaporates naturally, forming four-chamber hollow non-spherical micro-nano particles. Figure 5 (c) shows the formation process of the tetranuclear double emulsion, the stable state of the tetranuclear double emulsion in the collection liquid, and the microscopic images of the four-chambered hollow non-spherical particles formed therefrom.

[0084] In this embodiment, the collecting liquid is an 8 wt% potassium chloride aqueous solution.

[0085] In this embodiment, by adjusting the type and flow rate of the three-phase fluid, a tetranuclear double emulsion was controllably generated in a three-channel coaxial microreactor, and hollow non-spherical particles with four chambers were successfully prepared.

[0086] The above embodiments are merely illustrative of the implementation methods of the present invention, but should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the protection scope of the present invention.

Claims

1. A method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor, characterized in that, The method prepares a coaxial microreactor using four capillary tubes of different sizes. The inner tube (1) is coaxially placed inside the middle tube (2), and the middle tube (2) and the receiving tube (4) are placed inside the support tube (3). The four tubes are coaxial. The receiving tube (4) is placed inside the support tube (3), and the tips of the middle tube (2) and the receiving tube (4) are placed opposite each other, forming a three-channel system for generating a water-in-oil-in-water double emulsion. The innermost phase of the three channels is an electrolyte aqueous solution, the middle phase is a polymer oil solution, and the outermost phase is a surfactant aqueous solution. Hollow, non-spherical micro / nano particles are formed by the evaporation of the intermediate phase solvent from the double emulsion droplets. When the double emulsion is placed in a collection solution with different electrolyte concentrations, water molecules permeate from the collection solution into the innermost phase under the action of osmotic pressure, increasing the size of the droplets inside the double emulsion and changing the morphology of the outer droplets to make them exhibit the desired non-spherical structure, thus achieving controllable preparation of hollow micro / nano particles.

2. The method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor according to claim 1, characterized in that, The method includes the following steps: Step 1: A coaxial microreactor is prepared based on four capillary tubes of different sizes. The four capillary tubes include an inner tube (1), an intermediate tube (2), a receiving tube (4), and a support tube (3). The inner tube (1), intermediate tube (2), and receiving tube (4) are drawn into tapered openings using a laser needle drawing instrument. The tips are then polished to form tapered openings. The inner diameter and wall thickness of the intermediate tube (2) are the same as those of the receiving tube (4). Finally, the capillary tubes are ultrasonically cleaned. Step 2: Assemble four capillaries to obtain a coaxial microreactor, and determine the outermost phase inlet, intermediate phase inlet, innermost phase inlet, and outlet; specifically: Place the support tube (3) in the middle of the substrate and fix both ends; The right end of the intermediate tube (2) is a tapered end. It is inserted from the left end of the support tube (3) and fixed coaxially with the support tube (3). The position where the left end of the support tube (3) connects with the intermediate tube (2) is used as the outermost phase inlet. The left end of the intermediate tube (2) is used as the intermediate phase inlet. The intermediate phase inlet is connected to the first fluid pipeline. The first fluid pipeline has an opening at a certain distance to the left of the connection point for the second fluid pipeline to pass through. The right end of the inner tube (1) is a tapered end, which is inserted from the left end of the middle tube (2) and nested coaxially with the middle tube (2). The tapered end of the inner tube (1) is to the left of the tapered end of the middle tube (2). The left port of the inner tube (1) serves as the innermost phase inlet and is connected to the second fluid pipeline. The left end of the receiving tube (4) is a tapered end, which is inserted from the right end of the support tube (3). The tips of the intermediate tube (2) and the receiving tube (4) are placed opposite each other, and the end face size of the tapered end of the intermediate tube (2) is smaller than the end face size of the receiving tube (4). The receiving tube (4) is coaxially installed with the intermediate tube (2) and the inner tube (1). The right end of the receiving tube (4) is connected to a third fluid pipeline as an outlet. Step 3: Seal all connections between the four capillaries and the fluid lines to obtain a three-channel coaxial microreactor; Step 4: Connect the three fluid inlets of the coaxial microreactor to the syringe of the microfluidic injection pump and control the liquid flow rate by adjusting the flow pump; connect the outlet of the three-channel coaxial microchannel to the sample vial; at the same time, introduce the surfactant aqueous solution into the outermost phase inlet, the polymer oil solution into the middle phase inlet, and the electrolyte aqueous solution into the innermost phase inlet. After the three-phase liquid is introduced, a first flow focusing region is formed between the right port of the inner tube (1) and the right port of the middle tube (2). At this time, the innermost phase and the middle phase mix to form a water-in-oil structure. A second flow focusing region is formed between the right port of the middle tube (2) and the left port of the receiving tube (4). The water-in-oil structure mixes with the outermost phase, and finally a water-in-oil-in-water double emulsion structure is formed in the receiving tube (4). After a certain period of time, the double emulsion is stably generated and collection begins. Step 5: Place the double emulsion collected by the receiving tube (4) into the collecting liquid. The solvent in the oil phase of the double emulsion will evaporate naturally, forming hollow non-spherical micro-nano particles.

3. The method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor according to claim 2, characterized in that, In the capillary: The support tube (3) is a square capillary tube with both ends polished smooth; The capillary tube is made of glass; The inner diameter L1 of the inner tube (1) ranges from 100 to 400 μm, and the wall thickness T1 ranges from 50 to 100 μm; the inner diameter L2 of the intermediate tube (2) and the receiving tube (4) ranges from 300 to 700 μm, and the wall thickness T2 ranges from 200 to 250 μm; the inner side length L3 of the support tube (3) ranges from 800 to 1300 μm, and the wall thickness T3 ranges from 50 to 100 μm, and (L1+2×T1)<L2, (L2+2×T2)<L3.

4. The method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor according to claim 2, characterized in that, In step 2: The first fluid conduit has an opening machined 8 to 12 mm to the left at the connection point; The fluid pipeline is made of connecting pipes and conversion interfaces; the connecting pipes are made of glass or polymer; the conversion interfaces are made of polymer or metal.

5. The method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor according to claim 2, characterized in that, In step 3, a syringe is used to inject water to check whether the three-channel coaxial microreactor has any leakage or blockage. After the check is completed, step 4 is performed.

6. The method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor according to claim 2, characterized in that, In step 4: The first flow focusing region and the second flow focusing region form a dual flow focusing structure; The innermost layer of the dual emulsion is an aqueous phase, the middle layer is an oil phase formed by a polymer solution, and the outermost layer is an aqueous phase. The dual emulsion includes a binuclear dual emulsion, a trinuclear dual emulsion, or a tetranuclear dual emulsion.

7. The method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor according to claim 2, characterized in that, In step 4: the flow rate of the outermost phase is 150 ~ 450 μL / min; the flow rate of the intermediate phase is 350 ~ 450 μL / min; and the flow rate of the innermost phase is 120 ~ 170 μL / min. By adjusting the three-phase flow rates, a binuclear binuclear emulsion, a trinuclear binuclear emulsion, or a tetranuclear binuclear emulsion can be obtained.

8. The method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor according to claim 2, characterized in that, In step 4: The aqueous solution of the surfactant is obtained by dissolving the surfactant in water, and its concentration is 1 to 3 wt%; the surfactant includes polyvinyl alcohol or polysorbate; The polymer oil phase solution is obtained by dissolving the polymer in a solvent, with a concentration of 5-20 mg / mL; the polymer includes polylactic acid-glycolic acid copolymer or polyglycolic acid; the solvent includes dichloromethane, ethyl acetate or chloroform; The electrolyte aqueous solution is obtained by dissolving two types of electrolytes in water: one is a neutral electrolyte with a concentration of 2-9 wt%; the other is an alkaline electrolyte with a concentration of 0.3-1 wt%. The neutral electrolyte includes sodium chloride or potassium chloride; the alkaline electrolyte includes sodium carbonate or sodium bicarbonate.

9. The method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor according to claim 2, characterized in that, In step 5: The collection liquid is a mixture of water and electrolyte. By adjusting the concentration of electrolyte in the collection liquid, the osmotic pressure environment of the double emulsion is changed, forming hollow non-spherical micro-nano particles with controllable size.

10. A method for preparing hollow non-spherical micro / nanoparticles based on a coaxial microreactor according to claim 2, characterized in that, In step 5: The concentration range of the electrolyte is 1 ~ 10 wt%; The electrolyte includes sodium chloride or potassium chloride.

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