A cross-shaped four-way parallel microfluidic emulsification system and its application

Abstract

This invention discloses a "cross"-shaped four-way parallel microfluidic emulsification system and its application, addressing the problems of difficult maintenance and poor product consistency during parallel scale-up of existing microfluidic emulsification technologies. The system includes a fluid drive and supply module, a fluid distribution module, and an emulsification module composed of multiple independent, detachable "cross"-shaped four-way microfluidic emulsification units connected in parallel. The key feature of each emulsification unit is that the microchannel diameters at the dispersed phase inlet and emulsion outlet are equal (dD=dE), and both are smaller than the microchannel diameter at the continuous phase inlet (dC). This design, combining modular structure and hierarchical flow distribution, significantly improves unit processing consistency, system maintainability, and flow uniformity during parallel scale-up, making it suitable for high-throughput preparation of monodisperse droplets and functional microspheres.

Description

Technical Field This invention relates to the fields of microfluidic technology, precision machining, and chemical process intensification equipment, and extends to the interdisciplinary fields of biomedical materials, separation science, and functional materials preparation. Specifically, it relates to a microfluidic emulsification system for preparing monodisperse droplets and functional microspheres obtained by solidifying or crosslinking these droplets. More specifically, it relates to a microfluidic emulsification unit, a cross-shaped four-way parallel microfluidic emulsification system that supports parallel scale-up and is easy to maintain, and its applications in high-end industries. Background Technology The preparation of monodisperse emulsion droplets using a "cross"-shaped flow-focusing microchannel structure is an advanced emulsification technology. However, as this technology moves from the laboratory to large-scale, continuous industrial production, it still faces two major bottlenecks: (1) Low device reliability and difficult maintenance: Traditional flow-focusing microfluidic devices are usually fabricated on glass, silicon wafers or polymer (such as PDMS, PMMA) substrates using photolithography, etching or molding processes to create an integrated "cross"-shaped microchannel network. Although this integrated design has high integration, it sacrifices maintainability. Micron-level channels have a high risk of clogging when handling high-viscosity, particulate or easily gelled fluids (such as polymer solutions, biological agents). Once any "cross" node or connected microchannel inside the chip is blocked, it is difficult to perform rapid, effective and non-damaging online unblocking and maintenance, which often leads to a decrease in the reliability of the entire chip or even scrapping, increases production costs and hinders continuous operation.

[0001] (2) Poor consistency in parallel scaling: To increase production capacity, it is necessary to connect multiple cross-shaped four-way microfluidic emulsification units in parallel. However, in existing detachable cross-shaped four-way microfluidic emulsification units, the continuous phase microchannel is no smaller than the emulsion microchannel, and the dispersed phase microchannel is no larger than the continuous phase microchannel. This design results in poor consistency of four-way performance between different batches, making processing more difficult and making it difficult to implement the strategy of "increasing the number of units to achieve parallel scaling". The resulting droplet particle size uniformity is poor.

[0002] Therefore, there is an urgent need in this field for a systematic solution whose core emulsification unit must ensure processing consistency and emulsification process stability from the design source, and the entire system must have engineered and easy-to-maintain characteristics in order to simultaneously overcome the challenges of large-scale preparation with "uniform scale-up" and "stable operation". Summary of the Invention (a) Purpose of the invention The present invention aims to overcome the defects in the existing cross-shaped "four-way" microfluidic emulsification technology, such as large batch-to-batch differences in devices, difficult maintenance, and poor particle size uniformity in parallel system products. It provides a "cross-shaped" four-way flow focusing microfluidic emulsification system from the microfluidic emulsification unit structure design to system integration. This microfluidic emulsification system improves batch consistency through a unique microfluidic emulsification unit design, enables rapid maintenance through modular design, and enhances process stability through integrated distribution and control, ultimately providing a reliable device for the large-scale and controllable preparation of monodisperse functional microparticles.

[0003] (II) Technical Solution To achieve the above object, the present invention provides the following technical solution: A microfluidic emulsification system with a "cross-shaped" four-way parallel structure, characterized by comprising: a fluid driving and supply module, a microfluidic emulsification module, and a fluid distribution module; the microfluidic emulsification module is connected to the fluid driving and supply module through the fluid distribution module.

[0004] The core of the microfluidic emulsification module includes a plurality of parallel "cross-shaped" four-way microfluidic emulsification units. This "cross-shaped" four-way serves as a flow focusing microfluidic emulsification unit. Each four-way is an independent mechanical element, having a dispersed phase inlet, two symmetrically arranged continuous phase inlets, an emulsion outlet, and a cylindrical microchannel connecting each inlet / outlet and intersecting at the geometric center.

[0005] Among them, the internal structure of the "cross-shaped" four-way microfluidic emulsification unit satisfies: a) Microchannel diameter relationship: The diameter (dD) of the microchannel connected to the dispersed phase inlet is the same as the diameter (dE) of the microchannel connected to the emulsion outlet, and both are smaller than the diameters (dC) of the microchannels connected to the two continuous phase inlets, that is, it satisfies the relationship: dD = dE < dC. The microchannel is a cylindrical pipe with a uniform diameter.

[0006] b) Geometric configuration: The diameters and lengths of the two continuous phase inlet microchannels are the same, symmetrically distributed on both sides of the dispersed phase inlet microchannel, and their central axes are collinear. This collinear axis and the central axis of the dispersed phase inlet microchannel are designed to be "vertically intersecting"; moreover, the central axis of the dispersed phase inlet microchannel and the collinear axis of the continuous phase inlet microchannels are coplanar (in the same plane). The "coplanar" and "vertically intersecting" refer to the goals to be achieved in design and manufacturing, and small tolerances are allowed in actual processing.

[0007] c) Modular connection interface: Each port (i.e., the dispersed phase inlet, the two continuous phase inlets, and the emulsion outlet) of the "cross-shaped" four-way flow focusing microfluidic emulsification unit is provided with a detachable connection structure, so that this microfluidic unit can be connected to the fluid pipeline system as an independent unit.

[0008] The diameter dD of the dispersed-phase inlet microchannel is between 0.10 mm and 1.00 mm, preferably between 0.15 mm and 0.45 mm.

[0009] The dC is 1.01 to 1.3 times of the dD, preferably 1.05 to 1.15 times.

[0010] This design of dD = dE < dC can ensure the effective focusing ability of the continuous phase on the dispersed phase. Meanwhile, by simplifying the diameter combination, it reduces the processing complexity and tolerance sensitivity, thus improving the consistency of the mass production of the four-way. The coaxial through-hole punching process can be adopted to significantly reduce the processing difficulty. More importantly, even if there is a slight deviation in the coplanarity of the central axes of the dispersed-phase and continuous-phase microchannels due to processing tolerances, the slightly larger continuous-phase microchannel (dC) can provide a tolerance space for the dispersed-phase flow, ensuring its stable injection and effective focusing, and guaranteeing the performance consistency of the mass production unit from the design. Therefore, this "cross"-type four-way unit itself becomes a component suitable for high-volume and high-consistency precision manufacturing, laying a reliable foundation for constructing a large-scale parallel system.

[0011] The material of the flow-focusing microfluidic emulsification unit of the "cross"-type four-way is stainless steel or hard engineering plastics. The stainless steel is selected from 316L or 304 stainless steel, and its microchannel surface is hydrophilic, which is more suitable for preparing oil-in-water (O / W) type droplets. The hard engineering plastics can be selected from one of polyether ether ketone (PEEK), polytetrafluoroethylene (PTFE), polymethyl methacrylate (PMMA), polycarbonate (PC), cycloolefin copolymer (COC) and cycloolefin polymer (COP), preferably PEEK or PTFE. The hydrophobic plastic four-ways such as PEEK and PTFE are more suitable for preparing water-in-oil (W / O) type droplets. The microchannel surface of the stainless steel four-way can also be treated hydrophobically for use in preparing water-in-oil (W / O) type droplets.

[0012] The microfluidic emulsification module includes multiple such "cross"-type four-way microfluidic emulsification units, and a fluid distribution module connected between the fluid driving and supply module and these microfluidic emulsification units. The fluid distribution module is used to distribute a fluid to multiple parallel units, and its core is to include at least one flow splitter. In some embodiments, it can be a single-stage "1 to M" (M is equal to the total number of units) flow splitter; in the preferred embodiment, for a more uniform distribution, it is composed of cascaded multi-stage flow splitters (adapters), where at least one stage of the flow splitter adopts a "1 to N" structure (i.e., 1 inlet and N outlets, where N is an integer greater than or equal to 2, preferably an even number), to achieve a gradual and uniform distribution of the fluid.

[0013] The fluid driving and supplying module includes a liquid storage device for storing the dispersed-phase fluid and the continuous-phase fluid, and a driving system for precisely delivering the fluid, such as a high-precision injection pump, a piston pump, a pressure pump, or a closed-loop control system of a gear pump with a flow meter, etc.

[0014] (III) Beneficial effects 1. Easy to maintain and reliable in operation: Each four-way microfluidic emulsification unit is an independent module, connected through a detachable interface. If any microfluidic emulsification unit is blocked or damaged, it can be quickly replaced or cleaned individually without discarding the core components; solving the problem of "local failure, overall scrapping" of traditional microfluidic chips, improving the online rate and service life of the equipment, reducing the maintenance cost, and meeting the requirements of continuous production.

[0015] 2. Laying a foundation for linear amplification: The "dD = dE<dC" path design optimizes the processing friendliness and consistency. For the four-way microfluidic emulsification unit adopting this design, the consistency of the droplet sizes prepared between batches is significantly improved, making it possible to linearly amplify the production capacity by simply increasing the number of units, which helps to obtain highly monodisperse droplets in large-scale preparation.

[0016] 3. Wide application prospects: The high-quality monodisperse microparticles that can be prepared based on this system are the core materials in many high-end fields, and the applications can cover the biomedical field (such as medical aesthetic filling microspheres, drug controlled-release carriers, vascular embolization microspheres), the separation science field (such as high-performance chromatographic separation media), the advanced materials field (such as photonic crystals, light scattering elements, standard particles), etc., with significant economic value and social benefits. Description of the drawings Figure 1 It is a schematic structural diagram of the "cross" - shaped four-way microfluidic emulsification unit of the present invention Among them, 1 is the dispersed-phase microchannel, 2 and 3 are the continuous-phase microchannels, 4 is the emulsion microchannel; dD = dE<dC.

[0017] Figure 2 It is a microscope image of the droplets prepared by the "cross" - shaped four-way microfluidic unit Figure 3 It is a schematic diagram of a microfluidic emulsification module composed of 64 four-way microfluidic units connected in parallel in a "1 to 4" type hierarchical shunt form.

[0018] Figure 4 It is a diagram of a "1 to 8" shunt Specific implementation manners Next, the present invention will be further described in combination with the drawings and embodiments. These embodiments are used to explain the present invention rather than limit the scope of the present invention.

[0019] The "cross"-shaped four-way microfluidic emulsification unit is an independent modular device. Each port (dispersed phase inlet, two continuous phase inlets, and emulsion outlet) is equipped with a detachable connection structure, such as a standard threaded interface. See the schematic diagram. Figure 1 This allows each unit to quickly and reliably connect to or disconnect from the system fluid pipeline via corresponding connectors and pipes, enabling independent maintenance. When a four-way unit in the system becomes blocked or needs cleaning, its corresponding upstream branch valve (if configured) can be closed or the system paused, allowing for individual disassembly, replacement, or unblocking without interrupting other parts of the system. This achieves rapid online or offline maintenance, improving system reliability and continuous production capability. The fluid distribution module can be designed according to the number of parallel units and uniformity requirements. When the number of parallel units is small, a distribution form including a single splitter (e.g., "1 to M", where M is the number of units) can be directly adopted. To achieve highly uniform distribution to dozens, hundreds, or even thousands of microfluidic units, a hierarchical splitting form is preferred. This form consists of cascaded multi-stage splitters forming a tree-like or pyramidal network. Each stage of the splitter preferably adopts a "1 to N" structure (N is preferably an even number). For example, by cascading three stages of "1 to 4" splitters, uniform distribution to 64 units can be achieved (see Example 3). This structure facilitates uniform flow distribution among parallel units. To further ensure flow uniformity, when constructing the system, fluid lines (such as PEEK pipes) connecting the outlet of the same-stage distributor to the inlet of the next stage or to the inlet of each four-way unit should have the same length and inner diameter as much as possible. This minimizes the uneven flow distribution caused by differences in pipe flow resistance, thereby ensuring the consistency of operating conditions for each parallel emulsification unit from both the distribution structure and flow path impedance matching aspects. Example 1 Performance consistency of the "cross" shaped four-way microfluidic emulsification unit 1. Four-way unit fabrication: A batch of 316L stainless steel "cross"-shaped four-way microfluidic emulsification units were fabricated using precision machining technology. Designed nozzle diameters: dD = dE = 0.25 mm, dC = 0.27 mm. The perpendicularity and coplanarity of the central axes of the two continuous phase microchannels and the dispersed phase channel were controlled. Each port of each four-way microfluidic emulsification unit was machined with standard threads.

[0020] 2. Consistency Test: Six of the above four-way microfluidic emulsification units were randomly selected. One of them was used, and its dispersed phase microchannel and continuous phase microchannel were connected to the dispersed phase and continuous phase driven by a high-precision injection pump, respectively, through a PEEK tubing with corresponding threaded connectors. The dispersed phase was a dichloromethane solution of polylactic acid-glycolic acid copolymer (PLGA), and the continuous phase was an aqueous PVA solution. After optimizing the conditions to obtain uniformly sized droplets, the experiment was repeated with the remaining five four-way units under the same conditions to test the droplet size (microscopic image of droplets prepared by one of the four-way units is shown in [reference needed]). Figure 2 ). The relative standard deviation (RSD) of the droplet sizes of 6 groups was calculated to be 7.8%. For comparison, 6 traditional four-way structures with dD = dE = dC = 0.25 mm were taken and tested under the same method, and the RSD of the droplet sizes of 6 groups was as high as 21.9%. The results show that the unit of the present invention is significantly superior to the traditional structure, proving that the design of "dD = dE < dC" can effectively improve the batch-to-batch product consistency.

[0021] Example 2 : Performance Consistency of "Cross" Type Four-Way Microfluidic Emulsification Unit 1. Four-way preparation: Prepare another batch of 316L stainless steel units with the designed inner diameters: dD = dE = 0.15 mm, dC = 0.16 mm. Similarly control the geometric accuracy, and the ports are processed into standard threads.

[0022] 2. Consistency test: Randomly select 6 units and test them according to the method of Example 1. The RSD of the droplet sizes of 6 groups is 6.7%. Compared with 6 traditional four-way structures with dD = dE = dC = 0.15 mm, the RSD is 19.6%. It is proved again the advantage of the design of the present invention in improving batch-to-batch consistency.

[0023] Example 3 : Construction and Application of a Microfluidic Emulsification System with 64 Parallel Four-Way Microfluidic Emulsification Units 1. System construction: Construct a parallel emulsification system with 64 stainless steel four-way units. Use PEEK tubes and matching connectors to construct a shunt network with a three-stage "1-to-4" shunt cascade (schematic diagram is shown in Figure 3 ). Taking the connection of the dispersed phase as an example: The main pipe of the dispersed phase is connected to the inlet of the first-stage "1-to-4", and its four outlets are respectively connected to the inlets of the second-stage "1-to-4". Each outlet of the second stage is then respectively connected to the inlets of the third-stage "1-to-4", and each outlet of the third stage is finally respectively connected to the dispersed phase inlet of a four-way unit, forming a parallel module of "4×4×4 = 64" to achieve uniform shunting of the dispersed phase. The continuous phase adopts a similar hierarchical shunting, and appropriate numbers and structures of shunters can be added appropriately. Connect this emulsification module with a driving pump, a liquid storage device, and an emulsion receiving and curing device to form a complete system.

[0024] 2. Preparation process: Using the above microfluidic emulsification system, polycaprolactone (PCL) microspheres were prepared. The dispersed phase was a dichloromethane solution of 5% (w / v) PCL (Mw≈45 kDa). The continuous phase was an aqueous solution containing 1.8% (w / v) polyvinyl alcohol (PVA, 87 - 89% hydrolysis degree) and 0.1% (w / v) Tween 80. Process parameters: The total flow rate of the dispersed phase was 9.6 mL / h (average 0.15 mL / h per single unit), the total flow rate of the continuous phase was 960 mL / h (average 15 mL / h per single unit), and the total flow rate ratio was 1:100. It was operated in a fume hood at 25 °C, and the PCL microspheres were obtained after removing dichloromethane from the emulsion.

[0025] 3. Product characterization: Tested by a laser diffraction particle size analyzer, the average particle size of the microspheres was 58.3 μm, the coefficient of variation (CV) of the particle size was less than 8.1%, and the particle size distribution was uniform. It was proved that the parallel emulsification system designed based on "dD=dE<dC" could achieve the preparation of uniform microspheres with high throughput.

[0026] Example 4 : Preparation of PLGA microspheres using a microfluidic emulsification system with 64 parallel four-way units The parallel system containing 64 four-way microfluidic emulsification units constructed in Example 3 was used to prepare PLGA microspheres.

[0027] 1. Preparation process: The dispersed phase was a dichloromethane solution of 5% (w / v) PLGA (LA:GA = 75:25, Mw≈30 kDa). The continuous phase was an aqueous solution containing 2% (w / v) polyvinyl alcohol (PVA, 87 - 89% hydrolysis degree) and 0.15% (w / v) Tween 80. The total flow rate of the dispersed phase was 12.8 mL / h (0.20 mL / h per four-way unit), the total flow rate of the continuous phase was 640 mL / h (10 mL / h per four-way emulsification unit), and the total flow rate ratio (continuous phase:dispersed phase) was 50:1. It was continuously operated at room temperature, and the obtained O / W emulsion was introduced into a curing solution containing 3% PVA and gently stirred for 6 hours to volatilize dichloromethane, and PLGA microspheres were formed by curing. After centrifugation, washing with water, and freeze-drying, white powder was obtained.

[0028] 2. Product characterization: The particle size analyzer test showed that the average particle size of the PLGA microspheres was 97.6 μm, showing a single-peak narrow distribution, and CV<7.3%. SEM observation showed that the morphology of the microspheres was regular and the surface was smooth. It was proved that this system was suitable for the preparation of PLGA microspheres.

[0029] Example 5 : Application of PEEK material units in the preparation of W / O type functional emulsions Using PEEK material, a cross-shaped four-way microfluidic emulsification unit (dD=dE=0.30 mm, dC=0.38 mm) was fabricated. An emulsification module containing 16 of these units was constructed, dispersedly connected, first using a 1-to-2 splitter, and then each connected to a 1-to-8 splitter (see...). Figure 4 A two-stage flow splitting method was employed. This method was applied to prepare W / O emulsions encapsulating active ingredients. The continuous phase was silicone oil containing 2.7% (w / v) hydrophobic emulsifier, and the dispersed phase was a buffer salt solution containing a model water-soluble active ingredient. The system operated stably, successfully preparing W / O droplets with uniform particle size (CV < 8.7%) and good encapsulation efficiency. This example demonstrates the application potential of hydrophobic engineering plastic microfluidic units in preparing reverse emulsions. The above embodiments demonstrate the core advantages of the system of the present invention. The system is highly scalable; by increasing the number of stages in the hierarchical flow path, it can theoretically achieve parallel operation of dozens, hundreds, or even thousands of units. The modular design allows for flexible selection of units made of different materials (e.g., hydrophilic stainless steel for O / W, hydrophobic PEEK for W / O) within the same system according to process requirements, and even adjustment of the number of units in different branches, achieving high process adaptability and production flexibility.

Claims

1. A "cross"-shaped four-way parallel microfluidic emulsification system, characterized in that, include: Fluid drive and supply module, microfluidic emulsification module, and fluid distribution module; The fluid drive and supply module is in fluid communication with the microfluidic emulsification module through the fluid distribution module; The microfluidic emulsification module includes multiple parallel-connected "cross"-shaped four-way microfluidic emulsification units; The microfluidic emulsification unit has a dispersed phase inlet microchannel, two continuous phase inlet microchannels and an emulsion outlet microchannel, and satisfies the following: the microchannel diameter (dD) of the dispersed phase inlet is equal to the microchannel diameter (dE) of the emulsion outlet, and both are smaller than the microchannel diameter (dC) of the continuous phase inlet. In the "cross"-shaped four-way microfluidic emulsification unit, the two continuous phase inlet microchannels have the same diameter and their central axes are collinear, and they intersect perpendicularly with the central axis of the dispersed phase inlet microchannel and are coplanar.

2. The microfluidic emulsification system according to claim 1, characterized in that, The dD and dE are between 0.10 mm and 1.00 mm, and dE and dD are equal; the dC is 1.01 to 1.3 times the dD.

3. The microfluidic emulsification system according to claim 1, characterized in that, The fluid distribution module includes at least one distributor.

4. The microfluidic emulsification system according to any one of claims 1-3, characterized in that, The fluid distribution module is a graded flow distribution module, consisting of multiple cascaded flow distributors.

5. The microfluidic emulsification system according to claim 4, characterized in that, Each stage in the multi-stage splitter has a "1 to N" structure, where N is an integer greater than or equal to 2.

6. The microfluidic emulsification system according to claim 1, characterized in that, Each port of the "cross"-shaped four-way microfluidic emulsification unit is provided with a detachable connection structure, which is a threaded connection structure.

7. The microfluidic emulsification system according to claim 1, characterized in that, The material of the "cross"-shaped four-way microfluidic emulsification unit is selected from stainless steel or engineering plastic; wherein, the stainless steel is 316L or 304 stainless steel; and the engineering plastic is selected from one of polyetheretherketone, polytetrafluoroethylene, polymethyl methacrylate, polycarbonate, cyclic olefin copolymers and cyclic olefin polymers.

8. The microfluidic emulsification system according to claim 7, characterized in that, The engineering plastic is selected from polyetheretherketone or polytetrafluoroethylene.

9. A method for preparing monodisperse emulsion droplets or microspheres obtained by solidifying said emulsion droplets using the microfluidic emulsification system according to any one of claims 1-8, comprising the following steps: 1) Dispersed and continuous phase fluids are provided via a fluid drive and supply module; 2) The dispersed phase and continuous phase fluid are distributed to each parallel "cross" type four-way microfluidic emulsification unit through the fluid distribution module; 3) The dispersed phase fluid enters through the dispersed phase inlet microchannel, and the continuous phase fluid enters through two continuous phase inlet microchannels. The two are emulsified at the intersection of the microchannels through the flow focusing mode to form monodisperse droplets, which are discharged and collected through the emulsion outlet microchannel. 4) If microspheres are to be prepared, the obtained monodisperse droplets are solidified or cross-linked to obtain microspheres.

10. The use of the microfluidic emulsification system according to any one of claims 1-8 in the preparation of medical aesthetic filling microspheres, drug sustained-release carriers, embolization microspheres, separation medium microspheres or light scattering microspheres.

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