A microfluidic device and its operation method, application and equipment

Abstract

The present invention provides a microfluidic device and its operation method, application and equipment. The microfluidic device is composed of a chip assembly and an auxiliary fixture. During operation, the first liquid inlet layer, the second liquid inlet layer and the liquid outlet layer are combined with each other, and the slots on the three layers then form a clamping area specifically for fixing the chip assembly. In response to the preparation requirements of nano or micron particles, replacing the first chip or the second chip with a microchannel of the corresponding size can meet different preparation requirements, and the flexibility is high. The liquid inlet on the liquid inlet layer is directly connected to the microchannel of the chip assembly, and the container filled with a two-phase solution can be directly inserted into the liquid inlet to successfully complete the injection. This design eliminates the intermediate connecting components in conventional devices, greatly simplifies the operation steps, and reduces the dead volume of the device, thereby improving the preparation efficiency and accuracy.

Description

Technical Field

[0001] The present invention belongs to the field of microfluidics technology, and in particular relates to a microfluidics device and an operating method thereof. Background Art

[0002] Microfluidic chips utilize advanced microfluidics technology to integrate complex biochemical reactions and analytical steps onto micron-scale chips, allowing automated systems to complete the entire experimental process. With their low-loss, high-level integration, and precise fluid manipulation capabilities, these chips are finding widespread application in fields such as biomedicine, medical cosmetology, environmental protection, the chemical industry, and cosmetics, demonstrating enormous commercial potential.

[0003] During operation, existing microfluidic chips require the sample injection line to be connected to the chip. One end of the sample injection line is connected to the chip interface, while the other end needs to be connected to the sample injection device. Since frequent plugging and unplugging operations are required when changing samples, this not only easily leads to leakage and damage to the chip, reducing its reuse rate, but also brings a lot of trouble during the connection and operation process. What's more, at the interface between the pipeline and the chip, due to possible incomplete fit, tiny gaps are often formed. These gaps become part of the dead volume. The dead volume filled in the pipeline affects the accuracy and completeness of the micro-synthesis, making it difficult to successfully achieve high-precision micro-synthesis tasks. Summary of the Invention

[0004] In response to the problems existing in the microfluidic devices in the prior art, the present invention provides a microfluidic device and an operating method thereof, wherein the microfluidic device includes a chip assembly and an auxiliary fixture. During operation, when the first liquid inlet layer, the second liquid inlet layer and the liquid outlet layer are enclosed with each other, the slots on the three layers also enclose to form a clamping space for installing the chip assembly. According to the specific needs of nano- or micron-particle preparation, it is only necessary to replace the first chip or the second chip with a microchannel of the corresponding size to easily adapt to different preparation requirements. The liquid inlets on the two liquid inlet layers can be directly connected to the microchannels on the chip assembly, so that the container containing the two-phase solution can be directly and seamlessly inserted into the liquid inlet, thereby completing the liquid filling process. This design eliminates the intermediate connecting components and cumbersome connection steps of the traditional device, greatly simplifying the operation process. The replacement of samples is easier, while the dead volume of the device is reduced, and the preparation efficiency and accuracy are improved.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] A microfluidic device comprises: a chip assembly and an auxiliary fixture, the chip assembly comprises a first chip and a second chip, the first chip and the second chip are both provided with a microchannel, and two liquid phase inlets and a liquid phase outlet connected to the microchannel, the microchannel on the first chip is used to prepare micron particles, and the microchannel on the second chip is used to prepare nanoparticles; the auxiliary fixture comprises a first liquid inlet layer plate, a second liquid inlet layer plate and a liquid outlet layer plate, the first liquid inlet layer plate, the second liquid inlet layer plate and the liquid outlet layer plate are each provided with a card slot, when the first liquid inlet layer plate, the second liquid inlet layer plate and the liquid outlet layer plate are enclosed, the three card slots enclose a clamping space; the first chip and the second chip can be selectively installed in the clamping space; the first liquid inlet layer plate, the second liquid inlet layer plate and the liquid outlet layer plate are respectively provided with a first liquid inlet, a second liquid inlet and a liquid outlet, the first liquid inlet and the second liquid inlet are respectively connected to the two liquid phase inlets of the chip assembly, and the liquid outlet is connected to the liquid phase outlet.

[0007] In some embodiments, the microchannel includes: a first liquid inlet microchannel, a second liquid inlet microchannel and a liquid outlet microchannel that intersect at one point; the first liquid inlet microchannel and the second liquid inlet microchannel are respectively connected to the two liquid phase inlets; the liquid outlet microchannel is connected to the liquid phase outlet.

[0008] In some embodiments, the microchannels of the first chip and the second chip are T-shaped structures; the liquid outlet microchannel of the second chip is a fishbone structure, or an asymmetric multi-ring mixed structure.

[0009] In some embodiments, on the first chip, the T-shaped structure is: the angle at the intersection of the first liquid inlet microchannel and the second liquid inlet microchannel is 90 degrees; a curved section is provided on the liquid outlet microchannel; or, on the second chip, the T-shaped structure is: the angle at the intersection of the first liquid inlet microchannel and the second liquid inlet microchannel is 180 degrees; the liquid outlet microchannel is perpendicular to the first liquid inlet microchannel and the second liquid inlet microchannel; or, on the second chip, the fishbone structure is: the liquid outlet microchannel is a plurality of S-shaped curved channels connected in sequence, and the S-shaped curved channels are provided with periodically arranged fishbone-shaped grooves; or, on the second chip, the asymmetric multi-circular ring mixed structure is: a plurality of circular channels are provided on the liquid outlet microchannel; and the plurality of circular channels are staggered in the extension direction of the liquid outlet microchannel.

[0010] In some embodiments, the width and height of the microchannels of the first chip and the second chip are both 10 to 1000 μm.

[0011] In some embodiments, a first liquid inlet channel, a second liquid inlet channel, and a liquid outlet channel are respectively provided in the first liquid inlet layer plate, the second liquid inlet layer plate, and the liquid outlet layer plate; a first liquid outlet hole, a second liquid outlet hole, and a liquid outlet hole are respectively provided in the slot of the first liquid inlet layer plate, the slot of the second liquid inlet layer plate, and the slot of the liquid outlet layer plate; the first liquid inlet, the first liquid inlet channel, the first liquid outlet hole, and one of the liquid phase inlets of the chip assembly are connected in sequence; the second liquid inlet, the second liquid inlet channel, the second liquid outlet hole, and the other liquid phase inlet of the chip assembly are connected in sequence; the liquid phase outlet, the liquid outlet hole, the liquid outlet channel, and the liquid outlet are connected in sequence.

[0012] In some embodiments, the microfluidic device further includes a plurality of sealing rings, which are provided at the contact point between the first liquid outlet and one of the liquid phase inlets of the chip assembly, at the contact point between the second liquid outlet and another liquid phase inlet of the chip assembly, and at the contact point between the liquid phase outlet and the liquid outlet.

[0013] In some embodiments, the microfluidic device further comprises: a plurality of positioning pins and positioning holes, wherein the contact surface between the first liquid inlet layer and the second liquid inlet layer, the contact surface between the first liquid inlet layer and the liquid outlet layer, and the contact surface between the second liquid inlet layer and the liquid outlet layer are all provided with the corresponding positioning pins and positioning holes; and / or,

[0014] The microfluidic device also includes: a plurality of screws, screw holes for the screws to pass through, and threaded holes that are screwed together with the screws. The first liquid inlet layer plate and the second liquid inlet layer plate, the first liquid inlet layer plate and the liquid outlet layer plate, and the second liquid inlet layer plate and the liquid outlet layer plate are all provided with corresponding screw holes and threaded holes. The screws can pass through the screw holes and be screwed into the threaded holes to connect and fix the first liquid inlet layer plate, the second liquid inlet layer plate and the liquid outlet layer plate in pairs; the positions of the screw holes and the threaded holes are adjustable.

[0015] In some embodiments, the first liquid inlet and the second liquid inlet are female Luer threaded connectors, or pagoda connectors, or threaded connectors; and / or the chip component is made of polymethyl methacrylate, or cycloolefin copolymer, or polycarbonate, or glass, or quartz, or silicon wafer; and / or the first liquid inlet layer plate, the second liquid inlet layer plate, and the liquid outlet layer plate are made of SUS304, or SUS316L, or Hastelloy.

[0016] The present invention also provides an operating method for a microfluidic device, using the above-mentioned microfluidic device, the steps including: according to the particle specification requirements to be prepared, installing the corresponding first chip or second chip in the clamping space, respectively passing the two-phase solution into the two liquid phase inlets on the chip assembly from the first liquid inlet and the second liquid inlet, the two-phase solution mixing and reacting in the microchannel, and the generated nanoparticles or micron particles are discharged from the liquid phase outlet.

[0017] The present invention also provides an application of the microfluidic device, wherein the microfluidic device is used for preparing nanoparticles and micron particles.

[0018] The present invention also provides a microfluidic device, comprising the above-mentioned microfluidic device.

[0019] Compared with the prior art, the microfluidic device and the operating method provided by the present invention have the following beneficial effects:

[0020] 1. In the microfluidic device provided by the present invention, a clamping space is formed by the slots on the two liquid inlet and outlet plates. The chip assembly is placed in the clamping space, and a container such as a syringe filled with a two-phase solution can be directly inserted into the liquid inlet on the liquid inlet plate, directly connecting to the microchannels on the chip assembly. This reduces intermediate connecting components, reduces dead volume, avoids the risk of leakage, and eliminates the need for complex connection steps, making operation simpler and faster.

[0021] 2. According to different particle preparation requirements, the device can quickly adapt to the preparation process of nanoparticles and micron particles by simply replacing the first chip and the second chip, thereby improving the flexibility and adaptability of the experiment;

[0022] 3. The auxiliary fixture provided by the present invention realizes the precise alignment and combination of the three layers through the positioning component, and then uses the fastening function of the screws to tightly fix the three layers together to build a stable and compact overall structure. In this structure, the liquid phase channel inside the layer is perfectly connected with the microchannel of the chip component, ensuring high efficiency of fluid transmission and optimizing the overall space configuration. Thanks to this sophisticated design, the space utilization rate is high and the filling volume of the overall structure is small. In addition, the disassembly and installation design of the auxiliary fixture fully considers the convenience of operation. The operation is simple and intuitive, and can be completed quickly without relying on professional tools, which shortens the preparation time before the experiment;

[0023] 4. The material of the chip component provided by the present invention can be a high molecular polymer such as polymethyl methacrylate, or an inorganic material such as polycarbonate, to ensure excellent chemical stability and durability. The auxiliary fixture is made of materials such as SUS304, ensuring that the entire device can still exhibit excellent corrosion resistance when facing strong organic reagents and strong acid and alkali environments, thereby ensuring the long-term stable operation of the device and the reliability of the experimental results. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] The present invention will be further described below with reference to the accompanying drawings and examples.

[0025] Figure 1 A schematic structural diagram of the microfluidic device provided by the present invention;

[0026] Figure 2 An exploded view of the microfluidic device provided by the present invention;

[0027] Figure 3 A cross-sectional view of the microfluidic device provided by the present invention;

[0028] Figure 4 A schematic structural diagram of the first chip provided by the present invention;

[0029] Figure 5 A schematic structural diagram of the second chip provided by the present invention;

[0030] Figure 6 A schematic structural diagram of another embodiment of the second chip provided by the present invention;

[0031] Figure 7 A schematic structural diagram of another embodiment of the second chip provided by the present invention;

[0032] Figure 8 The particle size test results of the nanoparticles prepared in Example 5 of the present invention are as follows;

[0033] Figure 9 This is a quality comparison chart between the nanoparticles synthesized in Example 6 of the present invention and the nanoparticles synthesized in a conventional chip;

[0034] Figure 10 This is the test result of the nanoparticle size prepared in Example 6 of the present invention.

[0035] The meanings of the symbols in the accompanying drawings are as follows:

[0036] 100—chip assembly; 101—first liquid phase inlet; 102—first liquid inlet microchannel; 103—second liquid phase inlet; 104—second liquid inlet microchannel; 105—liquid phase outlet; 106—liquid outlet microchannel; 107—first chip; 108—second chip; 109—fishbone-shaped slot; 110—annular channel;

[0037] 200—first liquid inlet plate; 201—first liquid inlet; 202—first liquid inlet channel;

[0038] 300—second liquid inlet plate; 301—second liquid inlet; 302—second liquid inlet channel;

[0039] 400—liquid outlet plate; 401—liquid outlet; 402—liquid outlet channel;

[0040] 500—sealing ring; 600—locating pin; 601—locating hole; 700—screw; 701—screw hole; 702—threaded hole. DETAILED DESCRIPTION

[0041] The present invention is further explained in detail below in conjunction with the drawings and descriptions of specific embodiments. However, the descriptions including the embodiments below are only intended to enable ordinary technicians in the technical field to which the present invention belongs to more clearly understand the principles and essence of the present invention, and are not intended to limit the present invention in any form.

[0042] Example 1

[0043] like Figure 1 As shown, the present invention provides a microfluidic device including: a chip assembly 100 and an auxiliary fixture.

[0044] Among them, the chip assembly 100 includes a first chip 107 and a second chip 108. The first chip 107 and the second chip 108 are both provided with microchannels, as well as two liquid phase inlets and a liquid phase outlet 105 connecting the microchannels. The two liquid phase inlets are a first liquid phase inlet 101 and a second liquid phase inlet 103. The microchannels on the first chip 107 are used to prepare micron particles, and the microchannels on the second chip 108 are used to prepare nanoparticles.

[0045] The width and height of the microchannels of the first chip 107 and the second chip 108 are both 10 to 1000 μm.

[0046] The above-mentioned auxiliary fixture includes a first liquid inlet layer plate 200, a second liquid inlet layer plate 300 and a liquid outlet layer plate 400. The first liquid inlet layer plate 200, the second liquid inlet layer plate 300 and the liquid outlet layer plate 400 are each provided with a card slot. When the first liquid inlet layer plate 200, the second liquid inlet layer plate 300 and the liquid outlet layer plate 400 are combined, the three card slots also correspond to form a clamping space. According to the specification requirements of the prepared particles, the first chip 107 or the second chip 108 can be selectively installed in the clamping space.

[0047] A first liquid inlet 201, a second liquid inlet 301, and a liquid outlet 401 are provided on the first liquid inlet layer 200, the second liquid inlet layer 300, and the liquid outlet layer 400, respectively. The first liquid inlet 201 and the second liquid inlet 301 are connected to the two liquid-phase inlets of the chip assembly 100, respectively, while the liquid outlet 401 is connected to the liquid-phase outlet 105. The device containing the two-phase solution is directly connected to the liquid inlets on the liquid inlet layer, directly inputting the sample into the microchannel of the chip assembly 100, eliminating the intermediate pipeline of the conventional connection and reducing dead volume. Taking the first chip 107 as an example, the first liquid inlet 201 on the first liquid inlet layer plate 200 is connected to the first liquid phase inlet 101 on the first chip 107, the second liquid inlet 301 on the second liquid inlet layer plate 300 is connected to the second liquid phase inlet 103, and the liquid outlet 401 on the liquid outlet layer plate 400 is connected to the liquid phase outlet 105 on the first chip 107. The two-phase solution is introduced into the microchannel through the first liquid inlet 201 and the second liquid inlet 301 respectively, and then enters the microchannel through the first liquid phase inlet 101 and the second liquid phase inlet 103, mixes and reacts in the microchannel, and the generated micron particles are discharged from the liquid phase outlet 105 of the first chip 107, and finally collected at the liquid outlet 401 of the liquid outlet layer plate 400.

[0048] Furthermore, the liquid inlet and liquid outlet 401 provided on the three layers are not on the same side as the card slot, that is: a card slot is provided on one side of the first liquid inlet layer 200, and a first liquid inlet 201 is provided on a side adjacent to the side where the card slot is provided; similarly, a card slot is provided on one side of the second liquid inlet layer 300, and a second liquid inlet 301 is provided on a side adjacent to the side where the card slot is provided; a card slot is provided on one side of the liquid outlet layer 400, and a liquid outlet 401 is provided on a side adjacent to the side where the card slot is provided.

[0049] The shape of the liquid outlet 401 is preferably conical, and the apex of the cone is away from the side surface of the liquid outlet layer 400 where the liquid outlet 401 is located.

[0050] Furthermore, an observation window is provided in the clamping space to facilitate observation by operators.

[0051] In some embodiments, the first liquid inlet 201 and the second liquid inlet 301 are female Luer threaded connectors, or pagoda connectors, or threaded connectors. Preferably, the female Luer threaded connector allows a syringe to be directly inserted into the liquid inlet for injection, and the female Luer threaded connector can also be directly connected to a pipeline and other injection equipment.

[0052] In the prior art, the main materials used in microfluidic chips are soft silicone materials (such as PDMS polydimethylsiloxane) and organic thermoplastic materials (such as COC). Among them, PDMS material has the advantages of low cost, good biocompatibility, chemical inertness, and easy processing and use. However, PDMS chips are not resistant to high pressure. Using a clamp to lock the chip can easily cause the PDMS flow channel to be squeezed and deformed, affecting the liquid holding capacity of the chip design. In addition, PDMS materials are not resistant to strong acids and alkalis, as well as treatments such as ether, chlorinated organic solvents, and aromatic solvents. Although COC materials are resistant to acids and alkalis, they cannot be used with ketones, ethers, chlorinated solvents, and aromatic solvents. These organic solvents are necessary for the synthesis of micron and nanoparticles and the synthesis of functional material microspheres. These defects limit the application of materials such as PDMS and COC in the field of microfluidics, especially in the field of nanoparticles and functional material microspheres.

[0053] The selection of materials resistant to acids, alkalis, and strong organic solvents for the manufacture of microfluidic chips is an urgent problem in the industry. Therefore, another inventive aspect of the present invention is that the chip assembly 100 is made of a polymer such as polymethyl methacrylate or cycloolefin copolymer, or an inorganic material such as polycarbonate, glass, quartz, or silicon wafer. Chip assembly 100 made of these materials is resistant to the destructive effects of strong organic reagents, strong acids, and strong bases on its structure and performance.

[0054] In some embodiments, the first liquid inlet layer plate 200 , the second liquid inlet layer plate 300 , and the liquid outlet layer plate 400 are made of SUS304, SUS316L, or Hastelloy.

[0055] In some embodiments, the present invention provides a specific structure of the chip assembly 100: the microchannels on the first chip 107 and the second chip 108 include: a first liquid inlet microchannel 102, a second liquid inlet microchannel 104 and a liquid outlet microchannel 106 that intersect at one point.

[0056] The first liquid inlet microchannel 102 and the second liquid inlet microchannel 104 are respectively connected to the two liquid phase inlets (the first liquid phase inlet 101 and the second liquid phase inlet 103), and the liquid outlet microchannel 106 is connected to the liquid phase outlet 105. The two-phase solutions flowing in from the two liquid phase inlets are mixed at the intersection and flow toward the liquid outlet microchannel 106. In this process, micron / nanoparticles are generated and finally discharged from the liquid phase outlet 105.

[0057] In some embodiments, the microchannel on the first chip 107 for preparing micronized particles is a T-shaped structure.

[0058] Further, such as Figure 4As shown, the T-shaped structure on the first chip 107 is as follows: the angle between the first liquid inlet microchannel 102 and the second liquid inlet microchannel 104 at the intersection is 90°, and a curved section is provided on the liquid outlet microchannel 106 .

[0059] In some embodiments, the liquid outlet microchannel 106 on the second chip 108 for preparing nanoparticles is a fishbone structure, or an asymmetric multi-ring mixed structure, or other mixed structure settings.

[0060] Further, such as Figure 5 As shown, the fishbone structure on the second chip 108 is as follows: the liquid outlet microchannel 106 is a plurality of S-shaped curved channels connected in sequence, and periodically arranged fishbone-shaped slots 109 are provided in the S-shaped curved channels.

[0061] Further, such as Figure 6 As shown, the asymmetric multi-circular mixing structure on the second chip 108 is as follows: a plurality of circular channels 110 are provided on the liquid outlet microchannel 106, and in the extension direction of the liquid outlet microchannel 106, the plurality of circular channels 110 are arranged in a staggered manner. Preferably, the plurality of circular channels are arranged at equal distances.

[0062] In addition, the liquid outlet microchannel 106 on the second chip 108 can also adopt a conventional Tesla structure, which includes several arc channels and straight channels. A circular arc channel and a straight channel correspond one to one and are assembled into a fluid channel. Several fluid channels are connected in sequence to form a fluid channel of the Tesla structure.

[0063] In some embodiments, the microchannel on the second chip 108 for preparing nanoparticles may also be a T-shaped structure.

[0064] Preferably, Figures 4 to 6 On the first chip and the second chip shown, the first liquid inlet microchannel 102 and the second liquid inlet microchannel 104 are both formed by connecting a horizontally arranged channel and an inclined arranged channel.

[0065] like Figure 7 As shown, the T-shaped structure on the second chip 108 is as follows: the angle at the intersection of the first liquid inlet microchannel 102 and the second liquid inlet microchannel 104 is 180 degrees, and the liquid outlet microchannel 106 is perpendicular to the first liquid inlet microchannel 102 and the second liquid inlet microchannel 104.

[0066] In summary, given the structural differences in the microchannel structures between the first and second chips, in actual operation, the appropriate chip can be selected to meet the needs of different particle preparations. Furthermore, by adjusting key parameters such as liquid flow rate, reactant concentration, and reaction time, precise control of the target particle size can be achieved.

[0067] The first liquid inlet microchannel 102 and the second liquid inlet microchannel 104 are respectively connected to the two liquid phase inlets, that is, the first liquid phase inlet 101 on the chip component 100 is connected to the first liquid inlet 201 on the first liquid inlet layer 200 through the first liquid inlet microchannel 102, and the second liquid phase inlet 103 on the chip component 100 is connected to the second liquid inlet 301 on the second liquid inlet layer 300 through the second liquid inlet microchannel 104. The two-phase solution input from the first liquid inlet 201 and the second liquid inlet 301 enters the microchannel on the chip component 100 through the first liquid inlet microchannel 102 and the second liquid inlet microchannel 104 respectively.

[0068] In some embodiments, a first liquid inlet channel 202 , a second liquid inlet channel 302 , and a liquid outlet channel 402 are respectively provided in the first liquid inlet layer plate 200 , the second liquid inlet layer plate 300 , and the liquid outlet layer plate 400 .

[0069] A first liquid outlet hole, a second liquid outlet hole and a liquid outlet hole are respectively provided in the slot of the first liquid inlet layer plate 200 , the slot of the second liquid inlet layer plate 300 and the slot of the liquid outlet layer plate 400 .

[0070] Specifically:

[0071] Combine Figure 1-7 As shown, the first liquid inlet 201, the first liquid inlet channel 202, the first liquid outlet hole and one of the liquid phase inlets of the chip component 100 (i.e., the first liquid phase inlet 101) are connected in sequence, and the liquid phase solution input from the first liquid inlet 201 of the first liquid inlet layer 200 flows into the first liquid inlet channel 202, and then flows through the first liquid outlet hole and the first liquid phase inlet on the chip component 100 in sequence before entering the first liquid inlet microchannel 102.

[0072] The second liquid inlet 301, the second liquid inlet channel 302, the second liquid outlet and another liquid phase inlet (i.e., the second liquid phase inlet 103) of the chip component 100 are connected in sequence. Another liquid phase solution input from the second liquid inlet 301 of the second liquid inlet layer 300 flows into the second liquid inlet channel 302, and then flows through the second liquid outlet and the second liquid phase inlet on the chip component 100 in sequence before entering the second liquid inlet microchannel 104.

[0073] The liquid outlet microchannel 106 , the liquid phase outlet 105 , the liquid outlet hole of the liquid outlet layer 400 , the liquid outlet channel 402 and the liquid outlet 401 on the chip assembly 100 are connected in sequence.

[0074] The particle solution generated by mixing the two liquid phase solutions in the first liquid inlet microchannel 102 and the second liquid inlet microchannel 104 at the intersection flows into the liquid outlet microchannel 106, flows through the liquid phase outlet 105 of the liquid outlet microchannel 106, the liquid outlet hole of the chip component 100, enters the liquid outlet channel 402 in the liquid outlet layer plate 400, and is finally discharged from the liquid outlet 401.

[0075] In some embodiments, in order to improve the sealing effect of the microfluidic device, the present invention further provides a plurality of sealing rings 500. The first liquid inlet plate 200, the second liquid inlet plate 300, and the liquid outlet plate 400 are sealed at their respective connections with the chip assembly 100 by the sealing rings 500. Specifically:

[0076] Sealing rings 500 are provided at the contact point between the first liquid outlet hole on the first liquid inlet layer plate 200 and one of the liquid phase inlets of the chip assembly 100, at the contact point between the second liquid outlet hole on the second liquid inlet layer plate 300 and another liquid phase inlet of the chip assembly 100, and at the contact point between the liquid phase outlet 105 and the liquid outlet hole on the liquid outlet layer plate 400.

[0077] More specific:

[0078] On the first liquid inlet layer plate 200 , a sealing ring 500 receiving groove is provided at the card groove where the outer edge of the first liquid outlet hole is located. The sealing ring 500 is installed in the sealing ring 500 receiving groove to seal the joint between the first liquid outlet hole and the first liquid phase inlet 101 on the chip assembly 100 .

[0079] Similarly, on the first liquid inlet plate 200, a sealing ring 500 receiving groove is provided at the groove where the outer edge of the second liquid outlet hole is located; on the liquid outlet plate 400, a sealing ring 500 receiving groove is also provided at the groove where the outer edge of the liquid outlet hole is located.

[0080] Preferably, the sealing ring 500 is made of one of silicone, nitrile, fluorinated rubber, perfluoroelastomer (FFKM) or polytetrafluoroethylene (PTFE).

[0081] In some embodiments, the present invention further provides a device for assisting the enclosure of three layers, including a plurality of detachable positioning pins 600 and positioning holes 601 .

[0082] Positioning pins 600 and positioning holes 601 are respectively provided on the contact surface of the first liquid inlet layer 200 and the second liquid inlet layer 300, the contact surface of the first liquid inlet layer 200 and the liquid outlet layer 400, and the contact surface of the second liquid inlet layer 300 and the liquid outlet layer 400, and the positions of the positioning pins 600 and the positioning holes 601 are adjustable.

[0083] Figure 2The figure shows one arrangement of the positioning pins 600 and positioning holes 601. Two symmetrical positioning holes 601 are provided on the first liquid inlet layer 200, and two corresponding positioning pins 600 are provided on the contact surface between the second liquid inlet layer 300 and the first liquid inlet layer 200. By inserting the two positioning pins 600 into the positioning holes 601, the first liquid inlet layer 200 and the second liquid inlet layer 300 are docked. The position of the positioning pins 600 and positioning holes 601 is adjustable, meaning that the positioning holes 601 can also be provided on the second liquid inlet layer 300, and the positioning pins 600 can be provided on the contact surface between the first liquid inlet layer 200 and the second liquid inlet layer 300. Similarly, the arrangement of the positioning pins 600 and the positioning holes 601 on the contact surfaces of the first liquid inlet layer 200 and the liquid outlet layer 400, as well as the arrangement of the positioning pins 600 and the positioning holes 601 on the contact surfaces of the second liquid inlet layer 300 and the liquid outlet layer 400 are also the same as the arrangement structures on the above-mentioned first liquid inlet layer 200 and the second liquid inlet layer 300, and will not be repeated here.

[0084] Furthermore, the present invention also provides a fixing device for fixing three layers after being enclosed, and the fixing assembly also includes: a plurality of screws 700, screw holes 701 for the screws 700 to pass through, and threaded holes 702 for screwing with the screws 700.

[0085] Threaded holes 702 and screw holes 701 are respectively provided on the first liquid inlet layer 200 and the second liquid inlet layer 300, on the first liquid inlet layer 200 and the liquid outlet layer 400, and on the second liquid inlet layer 300 and the liquid outlet layer 400. The screw 700 can pass through the screw hole 701 and be screwed into the threaded hole 702 to connect and fix the first liquid inlet layer 200, the second liquid inlet layer 300 and the liquid outlet layer 400 in pairs, that is, the first liquid inlet layer 200 and the second liquid inlet layer 300 are connected and fixed, the first liquid inlet layer 200 and the liquid outlet layer 400 are connected and fixed, and the second liquid inlet layer 300 and the liquid outlet layer 400 are connected and fixed.

[0086] During the assembly of the three layers, the positioning pins 600 and positioning holes 601 mainly play a positioning role, while the screw holes 701, threaded holes 702 and screws 700 cooperate with each other to fix the assembled three layers to prevent the chip assembly 100 from shifting in the clamping position.

[0087] like Figure 2As shown, taking the docking combination of the first liquid inlet layer 200 and the second liquid inlet layer 300 as an example, a screw hole 701 and two positioning holes 601 are set on the first liquid inlet layer 200, and a threaded hole 702 and two positioning pins 600 are set on the second liquid inlet layer 300. When the two layers are docked, the positioning pins 600 on the second liquid inlet layer 300 are first aligned with the positioning holes 601 on the first liquid inlet layer 200 and inserted for positioning. The bolts pass through the threaded holes 702 on the first liquid inlet layer 200 and are screwed into the threaded holes 702 on the second liquid inlet layer 300 to fix the first liquid inlet layer 200 and the second liquid inlet layer 300 together.

[0088] Preferably, on the contact surface between the first liquid inlet plate 200 and the second liquid inlet plate 300, two positioning holes 601 are symmetrically arranged on either side of the screw hole 701, and on the contact surface between the second liquid inlet plate 300 and the first liquid inlet plate 200, two positioning pins 600 are symmetrically arranged on either side of the threaded hole 702. When the positions of the threaded holes 702 and the screw holes 701, and the positioning pins 600 and the positioning holes 601 are swapped, the corresponding configuration adjustment is the same as the above arrangement.

[0089] Two screw holes 701 and two positioning pins 600 are provided on the liquid outlet layer 400. Correspondingly, a threaded hole 702 and a positioning hole 601 are respectively provided on the first liquid inlet layer 200 and the second liquid inlet layer 300. The threaded hole 702 and the positioning hole 601 are arranged on the same side. The two positioning pins 600 are respectively inserted into the two positioning holes 601. Then, the two screws 700 are respectively inserted into the two screw holes 701 and screwed together with the threaded holes 702 on the first liquid inlet layer 200 and the second liquid inlet layer 300 to fix the first liquid inlet layer 200, the second liquid inlet layer 300 and the liquid outlet layer 400. The three card slots provided thereon are also enclosed to form a clamping space.

[0090] Preferably, the bolts are hexagonal bolts, and the threaded holes 702 are hexagonal threaded holes 702 .

[0091] Example 2

[0092] Based on Example 1, the present invention further provides a method for operating a microfluidic device, using the above-mentioned microfluidic device, the steps comprising:

[0093] According to the particle specifications to be prepared, the corresponding first chip 107 or second chip 108 is installed in the clamping space. The first chip 107 can be used for the preparation of micron particles, such as alginate microspheres, PVA microspheres, PLGA microspheres, etc., and the second chip 108 can be used for the preparation of nanoparticles, such as liposome nanoparticles, PLGA nanoparticles, PCL nanoparticles, etc.

[0094] After the chip assembly 100 is placed, the syringes filled with the two-phase solution are respectively inserted into the female Luer threaded connectors at the first liquid inlet 201 and the second liquid inlet 301. The two-phase solution is introduced into the two liquid phase inlets on the chip assembly 100 from the first liquid inlet channel 202 and the second liquid inlet channel 302, and is collected at one place from the first liquid inlet microchannel 102 and the second liquid inlet microchannel 104 for mixing. The generated nanoparticles or micron particles flow into the liquid outlet microchannel 106, enter the liquid outlet channel 402 of the liquid outlet layer 400 from the liquid phase outlet 105, and are finally discharged from the liquid outlet 401 on the liquid outlet layer 400 for collection.

[0095] Example 3

[0096] Based on the above embodiment, the present invention further provides an application of the above microfluidic device, which can be used to prepare nanoparticles and micron particles, and the first chip 107 and the second chip 108 can be replaced according to the particle size requirements of the prepared particles.

[0097] Example 4

[0098] On the basis of the above embodiments, the present invention further provides a microfluidic device, comprising the above microfluidic device, and further comprising: a reaction chamber for accommodating the microfluidic device.

[0099] Furthermore, the microfluidic device also includes: a process monitoring system, such as a flow meter and a pressure gauge, etc., for adjusting flow rate, pressure, etc.

[0100] The microfluidic device also includes: detection and analysis systems, such as microscopes, micro-area spectrometers, impedance meters, QCM-D, etc., which are used to obtain multi-dimensional information and help screen and analyze results.

[0101] The operation method of the microfluidic device and the particle production results provided by the present invention are described below with reference to specific examples.

[0102] The following explanations of the terms involved in the following embodiments are as follows:

[0103] Total flow rate: refers to the sum of the flow rates of the organic phase and the aqueous phase.

[0104] Flow rate ratio: refers to the flow rate ratio of the organic phase to the aqueous phase.

[0105] Pre-waste liquid: refers to the waste liquid that needs to be discarded during the initial stage of nanoparticle synthesis using microfluidic technology.

[0106] Particle size: refers to the average particle diameter of nanoparticles.

[0107] PDI: Polydispersity index, polydispersity index, reflects the uniformity of particle size.

[0108] The instruments used in the following examples are as follows:

[0109] Synthesis: Intelligent Nanoparticle Synthesizer (NP-S2), Shanghai Pengzan Biotechnology Co., Ltd.

[0110] Detection: Malvern dynamic light scattering nanoparticle size analyzer, Malvern Panalytical.

[0111] Example 5

[0112] This example is intended to demonstrate the versatility of the microfluidic device and its feasibility in the synthesis of lipid nanoparticles, and should not be construed as limiting the application function of the present invention.

[0113] (1) Reagent selection:

[0114] PLGA (50:50) was weighed, dissolved in acetonitrile, and filtered through a 0.22 μm filter membrane before use.

[0115] The prepared PVA aqueous solution was filtered through a 0.22 μm filter membrane and set aside for use.

[0116] (2) Reagent preparation:

[0117] The reagents were adjusted to appropriate concentrations for later use. PLGA was diluted to 5 mg / ml using acetonitrile, and the PVA aqueous solution was diluted to 2% using ultrapure water.

[0118] (3) Installation of microfluidic device

[0119] When preparing nanoparticles, a second chip 108 is selected and the microfluidic device is assembled according to the above method, wherein: the first liquid inlet 201 and the second liquid inlet 301 both use a 1 / 4-28 threaded connector to Luer port injection connection component, and the chip assembly 100 flow channel uses an asymmetric multi-ring hybrid structure. First, the second chip 108 is cleaned and then loaded into the clamping space formed by the first liquid inlet layer plate 200, the second liquid inlet layer plate 300 and the liquid outlet layer plate 400.

[0120] (4) Nanoparticle synthesis

[0121] The syringe adapters are properly mounted on the two injection ports, and the liquid inlet channels in the two liquid inlet layers and the second chip 108 are cleaned and pre-filled with acetonitrile and ultrapure water.

[0122] After cleaning, the syringe is replaced and the syringe adapter is properly loaded. The syringe with the Luer thread port draws the reagent, is inserted into the syringe adapter channel, and is connected to the microfluidic device through the Luer port.

[0123] (5) Set experimental parameters:

[0124] Total flow rate: 20 ml / min, flow rate ratio: PLGA: water = 1:3, pre-waste liquid 0.6 ml, product 0.6 ml.

[0125] The collected product was diluted with ultrapure water at a ratio of 1:9 to prepare 1 ml for later use.

[0126] (6) Result detection

[0127] Pipette 1 ml of the nanoparticles obtained in the previous step and transfer them into a Malvern cuvette (DTS0012). Load the cuvette properly according to the instrument's specifications.

[0128] Adjust the instrument's test parameters. Select Liposome (RI = 1.450, Absorption = 0.001) for "Material" and "Water" (Temperature = 25°C, Viscosity = 0.8872 cP, RI = 1.330) for "Dispersant." Set the "Temperature" setting to 25°C and the equilibration time to 60 seconds. Under "Measurement," select "Auto" under "Advanced" to allow the instrument to determine the test duration.

[0129] (7) Results

[0130] PLGA nanoparticles with an average particle size of <100 nm and PDI <0.2 can be synthesized, such as Figure 8 shown.

[0131] Example 6

[0132] This example is intended to demonstrate the versatility of the microfluidic device and its feasibility in the synthesis of lipid nanoparticles, and should not be construed as limiting the application function of the present invention.

[0133] (1) Reagent selection:

[0134] Compound phospholipid test kit (FL-S16-001), Shanghai Pengzan Biotechnology Co., Ltd., including:

[0135] Compound lecithin (DLin-MC3-DMA:Cholesterol:DSPC:PEG-2000-DMG=50:38.5:10:1.5, mol:mol)

[0136] Citric acid buffer (pH = 4.0)

[0137] (2) Reagent preparation:

[0138] Adjust the reagents to appropriate concentrations for later use. Dilute the compound lecithin with ethanol and the citric acid buffer with ultrapure water. The final concentration of the compound lecithin is 12 mM, and the concentration of the citric acid buffer is 50 mM.

[0139] (3) Installation of microfluidic device

[0140] Select the second chip 108, and assemble the microfluidic device according to the above method, wherein: the first liquid inlet 201 and the second liquid inlet 301 both use 1 / 4-28 threaded connector to Luer port injection connection components, wherein: the glass chip assembly 100 flow channel uses an asymmetric multi-ring mixing structure, clean the second chip 108, and then load it into the clamping space formed by the first liquid inlet layer plate 200, the second liquid inlet layer plate 300 and the liquid outlet layer plate 400.

[0141] (4) Nanoparticle synthesis

[0142] The syringe adapters are properly mounted on the two injection ports, and 100% anhydrous ethanol and 50 mM citric acid buffer are drawn in at a flow rate ratio of 1:3 to flush the liquid inlet channels in the two liquid inlet layers and the second chip 108 .

[0143] After cleaning, the syringe is replaced and the syringe adapter is properly loaded. The syringe with the Luer thread port draws the reagent, is inserted into the syringe adapter channel, and is connected to the microfluidic device through the Luer port.

[0144] (5) Set experimental parameters:

[0145] Total flow rate: 20 ml / min, flow rate ratio: lipid: water = 1:3, pre-waste liquid 0.6 ml, product 0.6 ml.

[0146] The collected product was diluted with ultrapure water at a ratio of 1:9 to prepare 1 ml for later use.

[0147] (6) Result detection

[0148] Pipette 1 ml of the nanoparticles obtained in the previous step and transfer them into a Malvern cuvette (DTS0012). Load the cuvette properly according to the instrument's specifications.

[0149] Adjust the instrument's test parameters. Select Liposome (RI = 1.450, Absorption = 0.001) in "Material" and "Water" (Temperature = 25°C, Viscosity = 0.8872 cP, RI = 1.330) in "Dispersant." Set the "Temperature" setting to 25°C and the equilibration time to 60 seconds. Under "Measurement," select "Auto" in "Advanced" to allow the instrument to determine the test duration.

[0150] (7) Results

[0151] like Figure 9 and 10 As shown, lipid nanoparticles with an average particle size of <50nm and a PDI of <0.1 can be synthesized. Under the same synthesis parameters, the results of this chip are similar to those of traditional lipid nanoparticle synthesis chips.

[0152] The ideal embodiment of the present invention is inspiration. Through the above description, relevant personnel can make various changes and modifications without departing from the scope of the technical idea of ​​this invention.

[0153] The technical scope of this invention is not limited to the contents of the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A microfluidic device, characterized in that: include: Chip assembly and auxiliary fixtures, The chip assembly includes a first chip and a second chip, each of the first chip and the second chip is provided with a microchannel, and two liquid phase inlets and a liquid phase outlet connected to the microchannel, the microchannel on the first chip is used to prepare micron particles, and the microchannel on the second chip is used to prepare nanoparticles; The auxiliary fixture includes a first liquid inlet plate, a second liquid inlet plate and a liquid outlet plate, and each of the first liquid inlet plate, the second liquid inlet plate and the liquid outlet plate is provided with a slot. When the first liquid inlet layer plate, the second liquid inlet layer plate and the liquid outlet layer plate are enclosed, the three clamping slots enclose a clamping space; The first chip and the second chip are selectively mounted in the clamping space; The first liquid inlet, the second liquid inlet and the liquid outlet are respectively provided with a first liquid inlet and a second liquid outlet. The first liquid inlet and the second liquid inlet are respectively connected to the two liquid phase inlets of the chip assembly, and the liquid outlet is connected to the liquid phase outlet.

2. The microfluidic device according to claim 1, wherein The microchannel comprises: a first liquid inlet microchannel, a second liquid inlet microchannel and a liquid outlet microchannel which intersect at one point; The first liquid inlet microchannel and the second liquid inlet microchannel are respectively connected to the two liquid phase inlets; The liquid outlet microchannel is communicated with the liquid phase outlet.

3. The microfluidic device according to claim 2, wherein The microchannels of the first chip and the second chip are T-shaped structures; The liquid outlet microchannel of the second chip is a fishbone structure or an asymmetric multi-ring mixed structure.

4. The microfluidic device according to claim 3, characterized in that On the first chip, the T-shaped structure is as follows: the angle between the first liquid inlet microchannel and the second liquid inlet microchannel at the intersection is 90 degrees; the liquid outlet microchannel is provided with a curved section; or, On the second chip, the T-shaped structure is as follows: the angle between the first liquid inlet microchannel and the second liquid inlet microchannel at the intersection is 180 degrees; The liquid outlet microchannel is perpendicular to the first liquid inlet microchannel and the second liquid inlet microchannel; or, On the second chip, the fishbone structure is: the liquid outlet microchannel is a plurality of sequentially connected S-shaped curved channels, and the S-shaped curved channels are provided with periodically arranged fishbone-shaped slots; or, On the second chip, the asymmetric multi-circular ring mixing structure is as follows: a plurality of circular ring channels are provided on the liquid outlet microchannel; In the extension direction of the liquid outlet microchannel, a plurality of the annular channels are arranged in a staggered manner.

5. The microfluidic device according to any one of claims 1 to 4, characterized in that: The width and height of the microchannels of the first chip and the second chip are both 10 to 1000 μm.

6. The microfluidic device according to claim 1, wherein A first liquid inlet channel, a second liquid inlet channel and a liquid outlet channel are respectively provided in the first liquid inlet layer plate, the second liquid inlet layer plate and the liquid outlet layer plate; A first liquid outlet hole, a second liquid outlet hole and a liquid outlet hole are respectively provided in the slot of the first liquid inlet layer plate, the slot of the second liquid inlet layer plate and the slot of the liquid outlet layer plate; The first liquid inlet, the first liquid inlet channel, the first liquid outlet, and one of the liquid phase inlets of the chip assembly are connected in sequence; The second liquid inlet, the second liquid inlet channel, the second liquid outlet and the other liquid phase inlet of the chip assembly are connected in sequence; The liquid phase outlet, the liquid outlet hole, the liquid outlet channel and the liquid outlet are connected in sequence.

7. The microfluidic device according to claim 6, characterized in that It also includes several sealing rings, The sealing ring is provided at the contact point between the first liquid outlet and one of the liquid phase inlets of the chip assembly, the contact point between the second liquid outlet and another liquid phase inlet of the chip assembly, and the contact point between the liquid phase outlet and the liquid outlet.

8. The microfluidic device according to claim 1, 6 or 7, wherein: Also includes: including a number of positioning pins and positioning holes, The contact surfaces of the first liquid inlet layer plate and the second liquid inlet layer plate, the contact surfaces of the first liquid inlet layer plate and the liquid outlet layer plate, and the contact surfaces of the second liquid inlet layer plate and the liquid outlet layer plate are all provided with the matching positioning pins and positioning holes; and / or, It also includes: a plurality of screws, screw holes for the screws to pass through, and threaded holes for screwing with the screws. The first liquid inlet layer plate and the second liquid inlet layer plate, the first liquid inlet layer plate and the liquid outlet layer plate, and the second liquid inlet layer plate and the liquid outlet layer plate are all provided with corresponding screw holes and threaded holes, and the screws can pass through the screw holes and be screwed into the threaded holes to connect and fix the first liquid inlet layer plate, the second liquid inlet layer plate and the liquid outlet layer plate in pairs; The positions of the screw hole and the threaded hole are adjustable.

9. The microfluidic device according to claim 1, wherein: The first liquid inlet and the second liquid inlet are female Luer thread connectors, or pagoda connectors, or thread connectors; and / or, The chip component is made of polymethyl methacrylate, cycloolefin copolymer, polycarbonate, glass, quartz, or silicon wafer; and / or, The first liquid inlet layer plate, the second liquid inlet layer plate and the liquid outlet layer plate are made of SUS304, SUS316L or Hastelloy.

10. A method for operating a microfluidic device, characterized in that: Using the microfluidic device according to any one of claims 1 to 9, the steps include: According to the particle specification requirements to be prepared, the corresponding first chip or second chip is installed in the clamping space, and the two-phase solution is respectively introduced into the two liquid phase inlets on the chip assembly from the first liquid inlet and the second liquid inlet. The two-phase solution mixes and reacts in the microchannel, and the generated nanoparticles or micron particles are discharged from the liquid phase outlet.

11. A microfluidic device, characterized in that: The microfluidic device comprises any one of claims 1 to 9.

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