A multi-channel microfluidic mixing system, device

Abstract

The application belongs to the field of biological medicine, and relates to a multi-channel micro-fluidic mixing system and a multi-channel micro-fluidic mixing device comprising the system; the system comprises a mixing core component, a secondary mixing component, a conveying component, a power component and a connecting component; the mixing core component is a multi-channel mixing component, which can convey a to-be-mixed solution A to a to-be-mixed solution B and / or C through multiple parallel pipelines for mixing; the secondary mixing component is connected with a liquid outlet end of the mixing core component, and performs secondary mixing on the mixed liquid of the mixing core component; the micro-fluidic mixing system of the application adopts a plurality of capillary arrays arranged on a collection plate, and is used together with a multi-channel base as the mixing core component, and then the mixed liquid after mixing of the mixing core component is subjected to secondary mixing, so that the obtained lipid nanoparticles have excellent performance parameters in particle size, PDI and encapsulation efficiency.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine and relates to a multi-channel microfluidic mixing system and device. Background Technology

[0002] Microfluidics refers to the science and technology involved in processing or manipulating tiny fluids using microchannels. It is an emerging interdisciplinary field involving chemistry, fluid physics, microelectronics, biology, and biomedical engineering. The core structure of existing microfluidic mixing devices typically employs two inlet channels to deliver two solutions in a specific ratio to the core structure of the microfluidic mixing unit for mixing. This core structure can be designed with different flow channel configurations, allowing the flowing liquids to mix through turbulent, laminar, or collisional processes. This enables chemical micro-reactions or the preparation of nanoparticles, such as liposomes, lipid nanoparticles, core-shell nanoparticles, PLGA nanoparticles, micelles, and nanoemulsions, with particle sizes at the nanometer and micrometer levels.

[0003] In existing technologies, the mixing of different fluids within the core structure of a microfluidic mixing component is generally achieved through free diffusion or turbulent mixing as the liquid flows through channels with varying cross-sections or multiple tortuous angles. The efficiency of both free diffusion and turbulent mixing is positively correlated with the contact surface area between the mixed solutions. Due to the small size and limited length of microfluidic mixing structures, two-phase or even multi-phase liquids need to be uniformly mixed within a short time to obtain nanoparticles and their composites with uniform particle size and high encapsulation efficiency. Therefore, in the design of microfluidic mixing structures, to increase the contact surface area between different fluids, the channel diameter is typically at the micrometer level. Good mixing is achieved through optimized design of the mixing channel structure. This method can be used for small-scale sample preparation, but due to its small channel diameter and limited throughput, it cannot meet the needs of large-scale sample preparation or industrial-scale sample production. When the mixing structure remains unchanged, simply increasing the channel diameter results in a low contact surface area between liquids, leading to low mixing efficiency and making complete mixing of two-phase or multiphase solutions impossible. Therefore, to improve mixing efficiency, the structure and length of the mixing channel must be adjusted. However, these changes often result in the adjusted mixing structure failing to reproduce the mixing effect of the original. This is why current microfluidic mixing equipment cannot be linearly scaled up from small-scale to pilot-scale or even industrial-scale equipment. Therefore, existing microfluidic mixing structures and their optimizations are only suitable for laboratory-scale micro-reaction synthesis or nanoparticle preparation, and still cannot meet the needs of large-scale production. Existing microfluidic equipment inevitably encounters problems such as mixing structure blockage, increased fluid pressure, and decreased mixing efficiency during large-scale production, leading to damage to the mixing structure, increased particle size and distribution of the prepared nanoparticles, decreased encapsulation efficiency or drug loading, and even nanoparticle sedimentation and aggregation, failing to meet the requirements of industrial-scale production. Summary of the Invention

[0004] The existing microfluidic mixing devices have the following technical shortcomings: they are only suitable for laboratory-scale micro-reaction synthesis or nano-formulation preparation, and cannot achieve linear scale-up, which is not conducive to industrial-scale production and application.

[0005] The first aspect of this invention provides a multi-channel microfluidic mixing system, comprising a mixing core component, a secondary mixing component, a conveying component, a power component, and a connecting component. The mixing core component is a multi-channel mixing component capable of conveying a solution A to be mixed to a solution B through multiple parallel pipes for mixing. The secondary mixing component is connected to the outlet end of the mixing core component to perform secondary mixing of the liquid in the mixing core component. The conveying component is connected to the mixing core component, the secondary mixing component, and the power component, respectively, allowing the solution to be mixed to reach each component. The power component is connected to the conveying component to provide power for the liquid flow within the multi-channel microfluidic mixing system. The connecting component is a device for connecting any two of the mixing core component, the secondary mixing component, the conveying component, and the power component.

[0006] Furthermore, the multi-channel hybrid component includes a capillary array assembly plate and a multi-channel base;

[0007] Furthermore, the capillary array assembly plate includes an assembly plate and capillaries connected to the assembly plate; wherein one end of the capillary is connected to the assembly plate, and the inner lumen of the capillary passes through the assembly plate;

[0008] Furthermore, the multi-channel base includes a hybrid channel that matches the capillary array assembly plate;

[0009] Furthermore, the multi-channel base includes a sample inlet channel communicating with the mixing channel;

[0010] Furthermore, the injection channel includes a left injection channel and a right injection channel;

[0011] Furthermore, the multi-channel base has a mixing channel that matches the capillary array assembly plate, wherein the matching is the matching of the capillary extending into the mixing channel;

[0012] Furthermore, the secondary mixing component is a channel of a certain length;

[0013] Furthermore, in the secondary mixing component, the channel is a straight channel or a curved channel;

[0014] Furthermore, in the secondary mixing component, the length of the channel is 1cm to 100m;

[0015] Furthermore, the curved channel includes one or more combinations of spiral curved channels, figure-eight curved channels, S-shaped curved channels, Z-shaped curved channels, Tesla hybrid structure channels, and Ω hybrid structure channels;

[0016] Furthermore, the bending radius of the curved channel is 0.5mm to 20cm;

[0017] Furthermore, the capillary array assembly plate has capillary arrays arranged in one or more of the following patterns: circular, square, elliptical, triangular, hexagonal, pentagonal, trapezoidal, star-shaped, or random.

[0018] Furthermore, the number of capillaries is 2 to 100;

[0019] Furthermore, the outer diameter of the capillary is 0.05 mm to 10 mm;

[0020] Furthermore, the outer diameter of the capillary is 0.1 mm to 5 mm;

[0021] Furthermore, the inner diameter of the capillary is 0.01–5 mm;

[0022] Furthermore, the inner diameter of the capillary is 0.1–3 mm;

[0023] Furthermore, the assembly plate is one of the following shapes: cylindrical, elliptical, square, trapezoidal, hexagonal, pentagonal, triangular, star-shaped, or irregular.

[0024] Furthermore, the assembly plate is cylindrical; the diameter of the circle is 1–100 mm;

[0025] Furthermore, the assembly plate is cylindrical; the diameter of the circle is 1–30 mm;

[0026] Furthermore, the capillaries are preferably 7 to 50 in number; most preferably 7 to 31 in number.

[0027] Furthermore, the length of the capillary is 10–100 mm; preferably 15–21 mm.

[0028] Furthermore, the connection between the mixing core component and the conveying component is achieved through a groove on the mixing core component;

[0029] Furthermore, the connection between the hybrid core component and the conveying component is that the groove on the multi-channel base is connected to the conveying component through a connecting component;

[0030] Furthermore, the conveying component is a pipe, preferably a circular pipe;

[0031] Furthermore, the connecting component is one or more of a compression fitting, a threaded fitting, and a straight-insertion fitting;

[0032] Furthermore, the power component is a device that provides flow power to the liquid within the system;

[0033] Furthermore, the power component is a pump or compressed gas, preferably a plunger pump;

[0034] In a specific embodiment of the present invention, there are 7 capillaries;

[0035] In another specific embodiment of the present invention, there are 13 capillaries;

[0036] In another specific embodiment of the present invention, there are 19 capillaries;

[0037] In another specific embodiment of the present invention, there are 31 capillaries;

[0038] In a specific embodiment of the present invention, the length of the capillary is 15 mm;

[0039] In another specific embodiment of the present invention, the length of the capillary is 21 mm;

[0040] In a specific embodiment of the present invention, the outer diameter of the capillary is 0.3 mm;

[0041] In another specific embodiment of the present invention, the outer diameter of the capillary is 0.5 mm;

[0042] In a specific embodiment of the present invention, the inner diameter of the capillary is 0.1 mm;

[0043] In another specific embodiment of the present invention, the inner diameter of the capillary is 0.2 mm;

[0044] In another specific embodiment of the present invention, the inner diameter of the capillary is 0.3 mm;

[0045] In a specific embodiment of the present invention, the collecting plate is cylindrical; the diameter of the circle is 8mm;

[0046] In a specific embodiment of the present invention, the upper side of the multi-channel base includes an upper sample inlet groove, the left and right sides of the multi-channel base respectively include a left sample inlet groove and a right sample inlet groove, and the lower side of the multi-channel base includes a mixing and discharging groove; the upper sample inlet groove and the mixing and discharging groove are connected by a mixing channel; the left sample inlet groove and the right sample inlet groove are connected to the mixing channel through the left sample inlet channel and the right sample inlet channel respectively.

[0047] Furthermore, the size of the upper sample inlet groove is not less than the size of the capillary array collection plate;

[0048] Furthermore, the mixing channel is square, polygonal, or cylindrical; preferably cylindrical.

[0049] Furthermore, the length of the mixing channel is 20–1000 mm; preferably 20–100 mm.

[0050] Furthermore, the diameter of the mixing channel is 1–100 mm; preferably 1–10 mm.

[0051] Furthermore, the left and right injection channels are cylindrical;

[0052] Furthermore, the diameters of the left and right injection channels are 1–20 mm;

[0053] Furthermore, the distance between the left and right injection channels and the upper injection groove is less than the length of the capillary tube;

[0054] In a specific embodiment of the present invention, the upper sample inlet groove is circular;

[0055] In a specific embodiment of the present invention, the left sample inlet groove, the right sample inlet groove, and the mixing and discharging groove are circular;

[0056] A second aspect of the present invention provides a multi-channel microfluidic mixing device that includes or uses the multi-channel microfluidic mixing system of the first aspect of the present invention;

[0057] Furthermore, the multi-channel microfluidic mixing device includes a capillary array assembly plate, a multi-channel base, a delivery pipeline, a plunger pump, and a secondary mixing channel, as defined above;

[0058] Furthermore, the multi-channel microfluidic mixing device also includes a control system; the control system is a terminal control system.

[0059] Furthermore, the terminal is an intelligent interactive terminal;

[0060] Furthermore, the intelligent interactive terminal includes a computer terminal, a mobile phone terminal, and a PLC terminal;

[0061] In a specific embodiment of the present invention, the multi-channel microfluidic mixing device includes a multi-channel microfluidic mixing system for mixing and preparing two liquids;

[0062] Furthermore, the two liquids include any two of the following: aqueous phase liquid, lipid phase liquid, and water-lipid mixture;

[0063] Furthermore, the two liquids include an aqueous phase liquid and a lipid phase liquid, a lipid phase liquid and a lipid phase liquid, and an aqueous phase liquid and an aqueous phase liquid;

[0064] Furthermore, the mixing equipment includes mixing equipment in the biological field and mixing equipment in the chemical field;

[0065] Furthermore, the mixing equipment in the biological field includes mixing equipment for preparing lipid nanoparticles, mixing equipment for preparing liposome nanomedicines, mixing equipment for preparing micelles, mixing equipment for preparing nanoemulsions, mixing equipment for preparing nanospheres, and mixing equipment for preparing lipid polymers.

[0066] Furthermore, the mixing equipment in the chemical field includes mixing equipment for the preparation of chemical nanoparticles, mixing equipment for the preparation of chemical molecules, and mixing equipment for chemical post-processing;

[0067] In a specific embodiment of the present invention, the terminal refers to a device or program used to interact with a computer system or network. It acts as a bridge between the user and the computer, enabling the user to communicate and operate the computer through input and output.

[0068] In a specific embodiment of the present invention, the PC terminal is a device used to connect to a computer system and provide input and output functions.

[0069] In a specific embodiment of the present invention, the mixing device in the chemical field is a continuous flow microchannel reactor.

[0070] The beneficial effects of this invention are as follows:

[0071] The microfluidic mixing system of this invention uses multiple capillaries arranged in an array on a collection plate to disperse the solution A to be mixed into multiple liquid streams, which are then injected into the solution B to be mixed flowing through the mixing channel to improve mixing efficiency. Combined with the secondary mixing channel of this invention, thorough mixing of the solutions can be achieved. The technical solution provided by this invention can linearly scale up the core mixing component while maintaining a consistent contact surface area between the mixed solutions. Lipid nanoparticles with excellent particle size, PDI, and encapsulation efficiency can be prepared at a total mixing flow rate of 50–600 mL / min. Compared with existing microfluidic technologies, it has significantly superior effects in high-flow-rate sample preparation and linear scale-up. Attached Figure Description

[0072] Figure 1 This is a schematic diagram of the multi-channel microfluidic hybrid system of the present invention;

[0073] Figure 2 A front sectional view of the multichannel mixing component of a multichannel microfluidic mixing system;

[0074] Figure 3 A schematic front view of a capillary array assembly plate for a multi-channel hybrid component;

[0075] Figure 4 A top view of the capillary array assembly plate structure for a multi-channel hybrid component;

[0076] Figure 5 A bottom view of the capillary array assembly plate structure of the multi-channel hybrid component;

[0077] Figure 6 This is a partial sectional view of the main view of the capillary array assembly plate structure of the multi-channel hybrid component.

[0078] Figure 7 A front sectional view of the multi-channel base of the multi-channel hybrid component;

[0079] Figure 8 A left-side schematic diagram of the multi-channel base for a multi-channel hybrid component;

[0080] Figure 9 A top view of the multi-channel base of the multi-channel hybrid component;

[0081] Figure 10 A front sectional view of the capillary array assembly plate and the multi-channel base in conjunction.

[0082] Figure 11 A schematic diagram of liquid flow when a capillary array assembly plate is used in conjunction with a multi-channel base.

[0083] Figure 12 A schematic diagram of a multichannel microfluidic mixing device that includes a multichannel microfluidic mixing system;

[0084] Figure 13 A specific embodiment of a capillary array assembly plate for multi-channel hybrid components;

[0085] Figure 14 Another specific implementation of the capillary array assembly plate for multi-channel hybrid components;

[0086] Figure 15 Another specific implementation of the capillary array assembly plate for multi-channel hybrid components;

[0087] Figure 16 Another specific implementation of the capillary array assembly plate for multi-channel hybrid components;

[0088] Figure 17 Another specific implementation of the capillary array assembly plate for multi-channel hybrid components;

[0089] Figure 18 Another specific implementation of the capillary array assembly plate for multi-channel hybrid components;

[0090] Figure 19 A schematic diagram of a commercially available Myanna chip;

[0091] In the diagram: 1. Collector plate; 2. Capillary tube; 3. Inner cavity; 4. Multi-channel base; 5. Mixing channel; 6. Upper injection groove; 7. Left injection groove; 8. Right injection groove; 9. Mixing and exiting groove; 10. Left injection channel; 11. Right injection channel; 12. Direction of the capillary array collector plate placed in the multi-channel base; 13. Schematic direction of liquid inlet for solution A to be mixed; 14. Schematic direction of liquid outlet for mixing; 15. Schematic direction of liquid inlet for solution B to be mixed; 16. Schematic direction of liquid inlet for solution B or C to be mixed; 17. Stainless steel pipe; 18. T-joint; 19. Spiral tube; 20. Precision stainless steel pump for solution A to be mixed; 21. Precision stainless steel pump for solution B to be mixed; 22. Compression fitting; 23. Threaded fitting; 24. Straight fitting; 25. Solution B to be mixed; 26. Solution A to be mixed; 27. Mixed solution. Detailed Implementation

[0092] The present invention will now be described in further detail with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be noted that, for ease of description, only the parts relevant to the present invention are shown in the accompanying drawings.

[0093] It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined with each other. The technical solution of this invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0094] Unless otherwise stated, the exemplary embodiments / exemplifications shown are to be understood as providing exemplary features of various details that provide ways in which the technical concept of the invention can be implemented in practice. Therefore, unless otherwise stated, the features of the various embodiments / exemplifications may be additionally combined, separated, interchanged and / or rearranged without departing from the technical concept of the invention.

[0095] The use of crosshairs and / or shading in the accompanying drawings is generally used to clarify the boundaries between adjacent components. Thus, unless otherwise stated, the presence or absence of crosshairs or shading does not convey or indicate any preference or requirement for the specific material, material properties, dimensions, proportions, commonalities between the illustrated components, or any other characteristics, properties, etc., of the components. Furthermore, in the accompanying drawings, the dimensions and relative dimensions of components may be exaggerated for clarity and / or descriptive purposes. When exemplary embodiments can be implemented differently, a specific process sequence may be performed in a different order than that described. For example, two consecutively described processes may be performed substantially simultaneously or in the reverse order of their description. Furthermore, the same reference numerals denote the same components.

[0096] When a component is referred to as being "on" or "above" another component, "connected to" or "joined to" another component, the component may be directly on, directly connected to, or directly joined to the other component, or there may be intermediate components. However, when a component is referred to as being "directly on" another component, "directly connected to," or "directly joined to" another component, there are no intermediate components. Therefore, the term "connection" can refer to a physical connection, an electrical connection, etc., and may or may not have intermediate components.

[0097] For descriptive purposes, the present invention may use spatial relative terms such as “below,” “under,” “below,” “down,” “above,” “above,” “higher,” and “side (e.g., in a “sidewall”)” to describe the relationship between one component and another component as shown in the accompanying drawings. In addition to the orientations depicted in the drawings, the spatial relative terms are also intended to encompass different orientations of the device during use, operation, and / or manufacture. For example, if the device in the drawings is flipped, a component described as “below” or “under” another component or feature would subsequently be positioned “above” said other component or feature. Thus, the exemplary term “below” can encompass both “above” and “below” orientations. Furthermore, the device may be otherwise positioned (e.g., rotated 90 degrees or in other orientations), thus interpreting the spatial relative descriptive terms used herein accordingly.

[0098] The terminology used herein is for the purpose of describing particular embodiments and is not intended to be restrictive. As used herein, unless the context clearly indicates otherwise, the singular forms “a” and “the” are intended to include the plural forms as well. Furthermore, when the terms “comprising” and / or “including” and variations thereof are used in this specification, it indicates the presence of the stated features, integrals, steps, operations, parts, components, and / or groups thereof, but does not exclude the presence or addition of one or more other features, integrals, steps, operations, parts, components, and / or groups thereof. It should also be noted that, as used herein, the terms “substantially,” “about,” and other similar terms are used as approximate terms rather than as terms of degree, thus allowing them to account for inherent deviations in measurements, calculated values, and / or provided values ​​that would be recognized by one of ordinary skill in the art.

[0099] Unless otherwise specified, the detection methods used in this invention are based on common methods disclosed in the prior art.

[0100] The specific implementation of this invention is as follows:

[0101] like Figure 1 As shown, Figure 1This is a schematic diagram of the multi-channel microfluidic mixing system of the present invention; the solutions to be mixed A and B or C are powered by the power component and transported into the mixing core component via the transport component connected between the components. The mixture is mixed to obtain lipid nanoparticle liquid, which then enters the secondary mixing component for secondary mixing to obtain lipid nanoparticle solution.

[0102] Example 1: Multi-channel microfluidic mixing device

[0103] The multi-channel microfluidic mixing device in this embodiment adopts... Figure 1 The multi-channel microfluidic mixing system shown in this invention comprises a capillary array assembly plate and a multi-channel base (e.g., ...). Figure 2 As shown), the capillary array collecting plate includes a cylindrical collecting plate 1 and capillary tubes 2 perpendicularly connected to one side of the collecting plate 1; the inner cavity 3 of the capillary tubes passes through the collecting plate 1 to the other side of the collecting plate (as shown). Figures 3-6 (as shown);

[0104] like Figures 3-6 , Figure 13 The capillary array collection plate shown is a cylinder with a diameter of 8 mm and a thickness of 1.2 mm. There are 7 capillaries arranged in a circle. The capillary length is 15 mm, the outer diameter is 0.3 mm, and the capillary wall thickness is 0.1 mm. The inner cavity 3 of the capillary passes through the collection plate 1 to the other side of the collection plate.

[0105] like Figures 7-9 As shown, the multi-channel base has a total length of 53mm. The upper side includes an upper sample inlet groove 6 with a diameter of 8.5mm. The left and right sides of the multi-channel base respectively include a left sample inlet groove 7 and a right sample inlet groove 8 with diameters of 6.3mm. The lower side of the multi-channel base includes a mixing and exiting groove 9 with a diameter of 8.5mm. The upper sample inlet groove 6 and the mixing and exiting groove 9 are connected by a mixing channel 5 with a diameter of 2.1mm and a length of 43mm. The left sample inlet groove 7 and the right sample inlet groove 8 are connected to the mixing channel 5 through a left sample inlet channel 10 and a right sample inlet channel 11 with diameters of 2mm, respectively. In this embodiment, the upper sample inlet groove 6, the left sample inlet groove 7, the right sample inlet groove 8, and the mixing and exiting groove 9 are circular.

[0106] like Figure 10 As shown in Figure 12, the capillary of the capillary array assembly plate is placed downwards into the upper sample inlet groove of the matching multichannel base;

[0107] In practical use, such as Figure 11As shown, the capillary enters the mixing channel and is located at the upper part of the mixing channel; each solution to be mixed is powered by the Jingrui stainless steel pump of the power component and transported into the mixing core component through the stainless steel pipe of the conveying component; the schematic direction 13 for the inlet of solution A is that solution A is introduced from the upper sample inlet groove 6 including the capillary array collection plate; the schematic direction 15 for the inlet of solution B and the schematic direction 16 for the inlet of solution B or C are shown, solution B or C is introduced from the left and right sample inlet pipes of the multi-channel base, and contact mixing occurs in the mixing channel 5 of the multi-channel base. While solution A diffuses laterally, it moves downward together with solution B or C, flowing through the entire mixing channel. During the flow through the mixing channel, lipid nanoparticles are formed, and the mixture containing lipid nanoparticles flows out from the outlet of the multi-channel base, as shown. Figure 11 The mixed sample output direction shown is 14;

[0108] like Figure 12 As shown, this is a multi-channel microfluidic mixing device incorporating the multi-channel microfluidic mixing system of the present invention. Solution A 26 to be mixed is powered by the stainless steel pump 20 and transported through a stainless steel pipe to the upper injection groove. Solution A passes through the upper end of the capillary array assembly plate within the upper injection groove, and then enters the mixing channel 5 through the capillary cavity; solution B... Powered by the stainless steel pump 21, the solution to be mixed (B) enters the mixing channel from the left and right sides of the multi-channel base via the stainless steel pipe and the tee 18, respectively, through the left and right inlet channels. Solution A begins to contact solution B at the capillary outlet. As solution A diffuses laterally into solution B, it moves downwards along with solution B, flowing through the entire mixing channel. During this flow, the lipid components in solution A encapsulate the mRNA in solution B, forming lipid nanoparticle liquid. The lipid nanoparticle liquid enters the spiral pipe 19 from the stainless steel pipe connected to the mixing outlet groove for secondary mixing, yielding the lipid nanoparticles described in this invention. In this mixing device, the upper inlet groove, the mixing outlet groove, and the stainless steel pipe are connected via a compression fitting 22; the left and right inlet grooves are connected to the stainless steel pipe via threaded fittings 23; and the tee is connected to the stainless steel pipe via a straight-insertion fitting 24.

[0109] In other embodiments of the present invention, similar operations are employed, using different capillary array collection plates, such as... Figures 14-18 Lipid nanoparticles were prepared using capillary array plates with different inner diameters (13, 19, and 31 capillaries, and capillary lengths of 15 mm and 21 mm).

[0110] The specific parameters are as follows:

[0111] Figure 14The capillary array assembly plate has 13 capillaries arranged in a circular pattern; the length of the capillary 2 is 15mm, the outer diameter is 0.3mm, and the wall thickness of the capillary is 0.1mm.

[0112] Figure 15 The capillary array assembly plate has 19 capillaries arranged in a circular pattern; the capillary 2 has a length of 15mm, an outer diameter of 0.3mm, and a wall thickness of 0.1mm.

[0113] Figure 16 The capillary array assembly plate has 31 capillaries arranged in a circular pattern; the capillary 2 has a length of 15mm, an outer diameter of 0.3mm, and a wall thickness of 0.1mm.

[0114] Figure 17 The capillary array assembly plate has 13 capillaries arranged in a circle; the length of the capillary 2 is 15mm, the outer diameter is 0.5mm, and the wall thickness of the capillary is 0.1mm.

[0115] Figure 18 The capillary array assembly plate has 13 capillaries arranged in a circle; the length of capillary 2 is 21mm, the outer diameter is 0.3mm, and the capillary wall thickness is 0.1mm.

[0116] Example 2

[0117] Using Example 1 Figure 13 (Serial Number 1) Figure 14 (Serial No. 2) Figure 15 (Serial No. 3) Figure 16 (Serial No. 4) Figure 17 (Serial No. 5) Figure 18 The capillary array assembly plate (6) is used in conjunction with a matching multichannel base to prepare lipid nanoparticles. The particle size, PDI, and encapsulation efficiency of the prepared lipid nanoparticles are detected and compared with those prepared by commercially available microfluidic devices in the prior art.

[0118] In this embodiment, solution A to be mixed is a lipid solution, and solution B to be mixed is an aqueous solution. The specific operation is as follows:

[0119] The lipid solution was an ethanol solution containing SM102, CHOL, DSPC, and DMG-PEG2000, with the concentrations of SM102 (18 mg / mL), CHOL (7.55 mg / mL), DSPC (4.01 mg / mL), and DMG-PEG2000 (1.91 mg / mL). The aqueous solution was a 500 mmol / L PBS buffer containing 0.5 mg / mL mRNA.

[0120] The lipid solution enters the mixing channel from the upper injection groove through the capillary lumen of the capillary array plate, while the aqueous solution enters the mixing channel from the left and right injection grooves through the left and right injection channels. The lipid solution begins to contact the aqueous solution at the capillary outlet, and while diffusing laterally, it moves downward together with the aqueous solution, flowing through the entire mixing channel. The lipid components in the lipid solution encapsulate the mRNA in the aqueous solution to form lipid nanoparticles. Throughout the process, the total flow rate of the lipid solution and the aqueous solution is 50 mL / min, 80 mL / min, 100 mL / min, 120 mL / min, 240 mL / min, 300 mL / min, 360 mL / min, and 600 mL / min (the flow rate ratio of the aqueous solution to the lipid solution is 3:1). The lipid nanoparticle liquid flowing out of the mixing outlet groove is collected.

[0121] Compared to the Myanna chip (serial number 7) in commercially available microfluidic devices, the hybrid core structure of the commercially available Myanna chip is as follows: Figure 19 As shown, the structure is a typical multi-angle tortuous path mixing channel structure in the prior art; the lipid phase solution and the aqueous phase solution enter from the left and right inlets respectively, mix and contact in the multi-angle tortuous path mixing channel, and the lipid nanoparticle liquid is collected from the mixing channel outlet, with other conditions being the same as above.

[0122] The collected lipid nanoparticles were analyzed for particle size, PDI, and encapsulation efficiency. The results are shown in Tables 1 to 3 below.

[0123] Table 1 Particle size (nm) detection data

[0124] Serial Number 1 65.48 60.51 60.23 58.8 58.49 56.13 55.71 57.56 Serial Number 2 76.12 76.33 73.76 72.68 72.55 68.01 67.92 67.67 Serial Number 3 68.72 69.01 69.95 68.86 68.70 67.32 67.33 66.98 Serial Number 4 71.77 69.56 69.35 69.76 68.33 67.92 63.24 65.33 Serial Number 5 85.23 85.89 85.18 83.97 81.56 81.55 80.36 80.63 Serial Number 6 87.57 87.11 87.03 87.15 85.34 85.13 84.33 85.34 Serial Number 7 73.22 72.89 70.88 88.34 - - - -

[0125] Table 1 shows the particle size measurement data of lipid nanoparticles prepared by mixing lipid solution and aqueous solution using the multi-channel microfluidic mixing device of the present invention. As can be seen from Table 1, at a flow rate of 50–600 mL / min, the particle size fluctuation of the lipid nanoparticles obtained by mixing using the multi-channel microfluidic mixing device of the present invention is small; when the number of capillaries is 7–13 (numbers 1–4), the particle size of the obtained lipid nanoparticles is between 55–70 nm; when the number of capillaries is 19–31 (numbers 5 and 6), the particle size of the obtained lipid nanoparticles is between 80–90 nm.

[0126] In item 7, lipid nanoparticles were prepared by mixing using a commercially available microfluidic device, Myanna chip. At a flow rate of 50–100 mL / min, the particle size of the prepared lipid nanoparticles was between 70 and 75 nm. At a flow rate of 120 mL / min, the particle size of the prepared lipid nanoparticles increased to 88.34 nm. At a flow rate greater than 120 mL / min, the mixing preparation of lipid nanoparticles failed due to damage to the chip structure caused by high liquid pressure.

[0127] The data above shows that, compared with the existing commercially available Myanna chips, the multi-channel microfluidic mixing device of the present invention can prepare lipid nanoparticles by mixing lipid solutions and aqueous solutions at a flow rate greater than 120 mL / min. The prepared lipid nanoparticles have small particle size fluctuations, which is conducive to the industrial-scale production application.

[0128] Table 2 PDI test data

[0129] Serial Number 1 0.149 0.137 0.136 0.116 0.119 0.123 0.119 0.120 Serial Number 2 0.129 0.134 0.129 0.119 0.129 0.124 0.118 0.118 Serial Number 3 0.137 0.141 0.131 0.128 0.104 0.120 0.106 0.110 Serial Number 4 0.152 0.157 0.151 0.158 0.142 0.153 0.137 0.138 Serial Number 5 0.157 0.158 0.164 0.149 0.150 0.162 0.128 0.128 Serial Number 6 0.158 0.153 0.159 0.145 0.149 0.159 0.135 0.136 Serial Number 7 0.158 0.153 0.160 0.189 - - - -

[0130] Table 2 shows the PDI measurement data of lipid nanoparticles prepared by mixing lipid solution and aqueous solution using the multi-channel microfluidic mixing device of the present invention. As can be seen from Table 2, at flow rates of 50–600 mL / min, the PDI values ​​of the lipid nanoparticles obtained by mixing using the multi-channel microfluidic mixing device of the present invention fluctuate within a reasonable range. When the number of capillaries is 7–13 (numbers 1–3), the PDI values ​​of the obtained lipid nanoparticles are between 0.1 and 0.15; when the number of capillaries is 19–31 (numbers 5–6), the PDI values ​​of the obtained lipid nanoparticles are between 0.12 and 0.17.

[0131] When the number of capillaries in sequence 4 is 13 and the inner diameter of the capillaries is 0.3 mm, the PDI value of the lipid nanoparticles obtained is significantly increased compared with that in sequence 3 (13 capillaries and an inner diameter of 0.1 mm).

[0132] In item 7, lipid nanoparticles were prepared by mixing using commercially available Myanna chips. At a flow rate of 50–100 mL / min, the PDI value of the prepared lipid nanoparticles was between 0.15 and 0.16. At a flow rate of 120 mL / min, the PDI value of the prepared lipid nanoparticles increased to 0.189. At a flow rate greater than 120 mL / min, the mixing preparation of lipid nanoparticles failed due to damage to the chip structure caused by high liquid pressure.

[0133] The data above demonstrate that, compared to existing commercially available microfluidic devices such as the Myanna chip, the multi-channel microfluidic mixing device of this invention can prepare lipid nanoparticles by mixing lipid solutions and aqueous solutions at flow rates greater than 120 mL / min. The prepared lipid nanoparticles exhibit low PDI fluctuation and excellent polymer dispersibility. In particular, the capillary array assembly plate with a capillary inner diameter of 0.1 mm achieves PDI values ​​of 0.1–0.13 for lipid nanoparticles at flow rates greater than 240 mL / min, exhibiting significantly superior polymer dispersibility. This is beneficial for large-scale industrial production applications.

[0134] Table 3 Encapsulation efficiency (%) test data

[0135] Serial Number 1 90.12 90.18 93.34 93.97 95.84 95.49 95.94 95.35 Serial Number 2 90.75 90.17 90.09 90.67 95.72 96.03 96.25 95.86 Serial Number 3 90.53 90.67 91.05 92.69 93.89 95.22 96.10 96.00 Serial Number 4 91.34 92.43 92.78 94.09 93.98 95.26 96.31 96.89 Serial Number 5 89.98 89.89 90.56 90.32 91.12 91.09 91.23 92.00 Serial Number 6 89.86 89.78 89.88 90.43 91.34 91.78 91.34 91.45 Serial Number 7 91.12 91.78 87.45 81.65 - - - -

[0136] Table 3 shows the encapsulation efficiency measurement data of lipid nanoparticles prepared by mixing lipid solution and aqueous solution using the multi-channel microfluidic mixing device of the present invention. As can be seen from Table 3, at a flow rate of 50–600 mL / min, the encapsulation efficiency of lipid nanoparticles obtained by mixing using the multi-channel microfluidic mixing device of the present invention is greater than 89%; especially for items 1–4 (7–13 capillaries), the encapsulation efficiency of lipid nanoparticles obtained at a high flow rate of 300–600 mL / min is greater than 95%; for items 5–6 (19–31 capillaries), the encapsulation efficiency of lipid nanoparticles obtained is between 89% and 92%.

[0137] In item 7, lipid nanoparticles were prepared by mixing using a commercially available microfluidic Myanna chip. At a flow rate of 50–100 mL / min, the encapsulation efficiency of the prepared lipid nanoparticles was between 81% and 92%. At a flow rate of 120 mL / min, the PDI encapsulation efficiency of the prepared lipid nanoparticles decreased to 81.65%. At a flow rate greater than 120 mL / min, the mixing preparation of lipid nanoparticles failed due to damage to the chip structure caused by high liquid pressure.

[0138] The data above demonstrate that, compared to existing commercially available microfluidic Myanna chips, the multi-channel microfluidic mixing device of this invention can prepare lipid nanoparticles by mixing lipid solutions and aqueous solutions at flow rates greater than 120 mL / min. The prepared lipid nanoparticles exhibit excellent encapsulation efficiency, which is beneficial for the encapsulation and delivery of mRNA active components. In particular, at flow rates greater than 240 mL / min, the encapsulation efficiency of the lipid nanoparticles exceeds 95%, exhibiting a significantly superior encapsulation effect. This facilitates large-scale industrial production applications.

[0139] In other specific embodiments of the present invention, when the total liquid flow rate is greater than 600 mL / min during microfluidic mixing, similar beneficial effects as described above are still obtained.

[0140] In other specific embodiments of the present invention, the multi-channel microfluidic mixing device of the present invention is used for the mixing preparation of nucleic acid drugs encapsulated by lipid polymers, the mixing preparation of siRNA, ASO, miRNA, saRNA, or Aptamer encapsulated by LNPs, and when the total liquid flow rate is greater than 100 mL / min during microfluidic mixing, it has similar beneficial effects as described above.

[0141] In other specific embodiments of the present invention, the system of the present invention is used in a continuous flow microchannel reactor to carry out chemical micro-reactions, and has similar beneficial effects as described above.

[0142] In summary, compared with the microfluidic mixing chips or devices disclosed in the prior art, the capillary array assembly plate of the present invention, together with the matching multi-channel base, can perform microfluidic mixing preparation of lipid nanoparticles at a total flow rate of greater than 120 mL / min. The prepared lipid nanoparticles are of stable and reliable quality and can be applied to industrial-scale production in workshops.

Claims

1. A multi-channel microfluidic mixing system, characterized in that: The system includes a mixing core component, a secondary mixing component, a conveying component, a power component, and a connecting component. The mixing core component is a multi-channel mixing component that conveys solution A to be mixed to solution B through multiple parallel pipes for mixing. The multi-channel mixing component includes a capillary array assembly plate and a multi-channel base. The secondary mixing component is connected to the liquid outlet of the mixing core component and performs secondary mixing on the liquid in the mixing core component. The conveying component is connected to the mixing core component, the secondary mixing component, and the power component, respectively, so that the solution to be mixed reaches each component. The power component is connected to the conveying component and provides power for the liquid flow within the multi-channel microfluidic mixing system. The connecting component is a device that connects any two of the mixing core component, the secondary mixing component, the conveying component, and the power component.

2. The system according to claim 1, characterized in that: The capillary array assembly plate includes an assembly plate and capillaries connected to the assembly plate; wherein one end of the capillary is connected to the assembly plate, and the inner cavity of the capillary passes through the assembly plate.

3. The system according to claim 2, characterized in that: The multichannel base includes a mixing channel that matches the capillary array assembly plate, and an injection channel that communicates with the mixing channel.

4. The system according to claim 1, characterized in that: The secondary mixing component is a channel of a certain length; wherein the channel is a straight channel or a curved channel.

5. The system according to claim 1, characterized in that: The connection between the hybrid core component and the conveying component is achieved through a groove on the hybrid core component.

6. The system according to claim 2; characterized in that: The number of capillaries is 2 to 100, and the inner diameter is 0.01 to 5 mm.

7. The system according to claim 3; characterized in that: The matching refers to the matching of the capillary extensions of the capillary array assembly plate into the mixing channel.

8. The system according to claim 5, characterized in that: The connection between the mixing core component and the conveying component is achieved by connecting the groove on the multi-channel base to the conveying component through a connecting component; wherein, the upper side of the multi-channel base includes an upper sample inlet groove, the left and right sides of the multi-channel base respectively include a left sample inlet groove and a right sample inlet groove, and the lower side of the multi-channel base includes a mixing outlet groove; the upper sample inlet groove and the mixing outlet groove are connected by a mixing channel; the left sample inlet groove and the right sample inlet groove are connected to the mixing channel through the left sample inlet channel and the right sample inlet channel respectively.

9. The system according to claim 8, characterized in that: The distance between the left and right injection channels and the upper injection groove is less than the length of the capillary.

10. A multichannel microfluidic mixing device comprising or using the system according to any one of claims 1 to 9; characterized in that: The multi-channel microfluidic mixing device includes a plunger pump, a capillary array assembly plate, a multi-channel base, a delivery pipeline, and a secondary mixing channel.

11. The mixing apparatus according to claim 10, comprising a multi-channel microfluidic mixing system for mixing and preparing two liquids, characterized in that: The two liquids include any two of the following: aqueous phase liquid, lipid phase liquid, and water-lipid mixture.

12. The mixing device according to claim 10, characterized in that: The mixing equipment includes mixing equipment in the biological field and mixing equipment in the chemical field.

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