Integrated microfluidic mixer and integrated microfluidic mixing device

Abstract

The invention discloses an integrated micro-fluidic mixer which comprises a plurality of mixing channels formed by a plurality of mixing units connected in series, a plurality of mixing channels connected in parallel, a micro-fluidic mixer sample inlet and a micro-fluidic mixer sample outlet, and the mixing units comprise turbulent flow cavities; the mixer sample inlet is communicated with the inlet channels of the plurality of mixing channels through split drainage tubes, and the outlets of the mixing channels are communicated with the mixer sample outlet through the drainage tubes. Liquid enters the mixing channel through the sample inlet of the mixer, mixing is enhanced through the turbulent flow cavities of the multiple stages of mixing units, the high-flux mixing requirement can be met, the production batch is increased, the equipment utilization rate is increased, and the equipment cost for mixing the liquid is reduced.

Description

Technical Field

[0001] This invention relates to the field of microfluidic chips, and more specifically to an integrated microfluidic mixer and an integrated microfluidic mixing device. Background Technology

[0002] Microfluidic chip technology is widely used in chemical and biological fields such as drug preparation, chemical synthesis, and medical testing, enabling rapid and efficient mixing of chemical or biological samples. Microfluidic chips include active and passive types. Active chips use external power to mix liquids within the chip, while passive chips enhance fluid mixing through chip structure to achieve rapid mixing. However, regardless of whether they are active or passive, the vast majority of microfluidic chips currently on the market are designed and manufactured on a planar surface. Due to the inherent characteristics of microfluidic chips, their size is limited, which in turn affects their flow rate. For example, the NxGen chip published on Precision Nanosystems' website has a preparation capacity of 12 liters per hour, and its publicly stated total preparation capacity is 60 liters. The chip uses COP material, which cracks after being soaked in anhydrous ethanol solution for a period of time and then left for several days. This greatly limits the chip's lifespan and number of uses, while anhydrous ethanol is currently a commonly used solvent for preparing mRNA-LNP. US2016 / 019414 disclosed a production flow chart for Pfizer's COVID-19 vaccine BNT162b2, which uses a combination of multiple fluid mixing modules to increase the production volume per unit time, but greatly increases the production cost. Summary of the Invention

[0003] To improve liquid mixing and mixing throughput in microfluidic chips while reducing production costs, it is necessary to provide an integrated microfluidic chip that can efficiently, rapidly, continuously, and with high throughput mixers to achieve mixing of two or more fluids, thereby improving driver power utilization. This also avoids the large footprint and high manufacturing costs associated with combining multiple mixing modules and reduces dead volume in the piping.

[0004] This invention provides an integrated microfluidic mixer that achieves continuous, efficient, and high-throughput promotion of liquid mixing and reaction.

[0005] In a first aspect, the present invention provides an integrated microfluidic mixer and an integrated microfluidic mixing device, comprising: a first liquid inlet, the first liquid inlet being connected to one end of a guide tube, and the other end of the guide tube being connected to a first inlet channel; a second liquid inlet, the second liquid inlet being connected to a second inlet channel; the first inlet being connected to one end of a mixing channel via the second inlet channel; the mixing channel being used to promote the mixing of liquids; the mixing channel including at least one mixing unit; the mixing unit being provided with an outlet channel; and the outlet channel being used to collect the mixed liquids.

[0006] Preferably, each microfluidic mixer includes multiple mixing channels connected in parallel. The multiple mixing channels can be two, three, four or more.

[0007] Preferably, each mixing channel further includes multiple mixing units connected in series; the mixing units can be two, three, four or more. Each mixing unit includes a mixing inlet, one end of which is connected to the first inlet channel and the second inlet channel, and the other end of which is connected to one end of the turbulence cavity; the other end of the turbulence cavity is connected to the mixing outlet. When multiple mixing units are included, the multiple mixing units are connected sequentially. The outlet channel of the first mixing unit is connected to the inlet channel of the second mixing unit; the outlet channel of the second mixing unit is connected to the inlet channel of the third mixing unit; and so on, forming a series of multi-stage mixing units to enhance the mixing effect.

[0008] Preferably, the turbulence cavity mixing channel includes multiple mixing channels with turbulence plates disposed inside.

[0009] Preferably, the cross-sections of the mixing inlet and mixing outlet of the mixing unit can be square, circular, triangular, or other shapes.

[0010] Preferably, the connection between the mixing inlet of the mixing unit and the turbulence cavity is a first arc surface, which is composed of two circular arcs connected together.

[0011] Preferably, the connection between the outlet channel and the turbulence cavity is a second arc surface, which is composed of two connected circular arcs.

[0012] Preferably, the connection between the first arc surface and the second arc surface is a connecting plane, and the length of the connecting plane is greater than or equal to the lateral diameter of the spoiler.

[0013] Preferably, the arc angle between the first and second arc surfaces is 0° < α ≤ 90°; the arc radii R1 and R2 of the first arc surface are less than half the width of the spoiler (W / 2), i.e., R1 < W / 2, R2 < W / 2. The arc radii R4 and R5 of the second arc surface are less than half the width of the spoiler (W / 2), i.e., R4 < W / 2, R5 < W / 2. The radii (R1 and R2) of the first arc surface and the second arc surface (R4 and R5) are less than half the width W of the spoiler, i.e., R1 < W / 2, R2 < W / 2, R3 < W / 2, R4 < W / 2. The connection between the first and second arc surfaces is a plane, and the length of the plane (2 × L3) is greater than or equal to the diameter of the spoiler's blocking center (2 × R3), i.e., L3 ≥ R3.

[0014] Preferably, the connection angle between the mixing units is 0° < β < 180°.

[0015] Preferably, the radius R1 of the first arc surface of the hybrid unit (400) is in the range of 1-1.25mm, and the radius R2 is in the range of 0.5-1mm.

[0016] Preferably, the first liquid inlet, the second liquid inlet, and the mixing unit structure can all be assembled from different modules.

[0017] A second aspect of this application provides an integrated microfluidic mixing device, comprising: a microfluidic chip as described above; further comprising: a liquid storage section for storing different types of raw materials, the liquid storage section being connected to the liquid inlet of the microfluidic chip via a pipeline; a driver for providing continuous driving force to each raw material, driving the raw material into the microfluidic chip; a receiving section for receiving the microfluidic chip mixing product, the receiving section being connected to the microfluidic chip outlet via a pipeline; the microfluidic chip outlet being connected to a T-tube via a pipeline for online dilution of the microfluidic chip mixing product, and then pouring the diluted product into the receiving section.

[0018] Preferably, it also includes an operating system for controlling the operation and pause of the device, and recording the operating status and data.

[0019] Preferably, it also includes a pressure gauge for monitoring fluid pressure during device operation.

[0020] Preferably, it also includes a flow meter for monitoring fluid flow during device operation.

[0021] In one or more embodiments, the cross-section of the first inlet, the second inlet, and the guide tube connected to the mixing channel of the microfluidic mixer, as well as the inlet and outlet channels of the mixing unit, the outlet channel of the microfluidic mixer, and the guide tube connected to the outlet channel of the mixing channel and the microfluidic mixer channel can be square, triangular, circular, or other shapes.

[0022] Another object of the present invention is to provide a microfluidic device comprising at least two reservoirs of the aforementioned integrated microfluidic mixer, namely a raw material reservoir and an excipient reservoir, two actuators, a product receiver, and a housing and frame. Each reservoir stores different types of active pharmaceutical ingredients (APIs) or excipient solutions; each reservoir is connected to the inlet of the integrated microfluidic mixer; the actuators provide continuous driving force to each API or excipient solution, allowing liquid to enter the inlet of the integrated microfluidic mixer and maintaining continuous fluid flow within the microfluidic mixer; the product receiver is connected to the outlet of the integrated microfluidic mixer and is used to receive the product formed after mixing by the integrated microfluidic mixer. Preferably, the housing and frame may be equipped with an operating system and a tubing retainer.

[0023] In one or more embodiments, the device further includes multiple delivery lines for raw material or auxiliary solutions and product output lines. The raw material or auxiliary solution delivery lines are used to connect the liquid outlet of the reservoir and the liquid inlet of the driver. The raw material or auxiliary solution delivery lines are also used to connect the liquid outlet of the driver and the liquid inlet of the integrated microfluidic mixer. The product output lines are used to connect the liquid outlet of the integrated microfluidic mixer and the product receiver. The delivery lines and output lines are disposed on the housing or frame.

[0024] In one or more embodiments, the device further includes a pressure sensor, a flow sensor, and an operating system. Each raw material or excipient solution reservoir corresponds to a driver and a pressure sensor. The pressure sensor inlet and driver outlet are connected via a raw material or excipient solution delivery pipeline, and the pressure sensor outlet is connected to the integrated microfluidic mixer inlet via another delivery pipeline. The flow sensor uses ultrasonic principles to monitor the flow rate in the pipeline. The flow sensor is attached to the delivery pipeline of the pressure sensor-microfluidic mixer inlet via an external device. The pressure sensor and flow sensor transmit electrical signals to the operating system, enabling real-time monitoring of pressure and flow rate in the delivery pipeline. The operating system can record driver operating parameters and status, as well as intermittently record fluid pressure and flow rate. The operating system also enables three-level access control, file export, and file immutability, fully complying with pharmaceutical GMP production standards.

[0025] In one or more embodiments, the apparatus further includes a cleaning reservoir containing cleaning fluid, the cleaning reservoir being connected to the raw material or excipient solution delivery pipeline for cleaning the delivery pipeline and / or the driver and / or the pressure sensor and / or the integrated microfluidic mixer and / or the product output pipeline.

[0026] In one or more embodiments, the device further includes a multi-port connector, which is connected to the cleaning storage tank and / or the raw material or excipient solution delivery pipeline, and the delivery pipeline is equipped with a clamp valve, which can be opened to keep the pipeline unobstructed during cleaning and closed to disconnect the pipeline when cleaning is not required.

[0027] In one or more embodiments, the device further includes a diversion valve, a waste liquid collector, and a waste liquid pipeline. The diversion valve is connected to the outlet of the integrated microfluidic mixer, and is then connected to the diversion valve-waste liquid collector and the diversion valve-product receiver via the waste liquid pipeline and product output pipeline, respectively. This allows waste liquid generated during the preparation stage, early stage of product preparation, late stage of product preparation, or during cleaning of the pipeline to be collected in the waste liquid collector. During product preparation and production, the diversion valve state is switched to collect the mixed liquid generated by the integrated microfluidic mixer into the product receiver.

[0028] In one or more embodiments, the device further includes a dilution module comprising a diluent reservoir, a driver, and a diluent delivery line, the dilution module being capable of providing a diluent solution from the product output from the integrated microfluidic mixer.

[0029] The present invention also provides a method for mixing multiple fluids to prepare a product using a microfluidic mixer or microfluidic device according to any embodiment of the present invention.

[0030] In one or more embodiments, the method includes: allowing multiple fluids to flow into and out of the microfluidic mixer from the inlet, thereby mixing the multiple fluids in the microfluidic mixer to obtain a product.

[0031] In one or more embodiments, the product is a particle, preferably a nanoparticle, and more preferably a lipid nanoparticle.

[0032] In one or more embodiments, the method includes the steps of a solution of particulate material and / or a solution of target molecules in the microfluidic mixer or microfluidic device.

[0033] In one or more embodiments, the particulate material includes a lipid material or a polymer material.

[0034] In one or more embodiments, the molecular solution of the target is a small molecule compound, a nucleic acid, preferably a nucleic acid.

[0035] In one or more embodiments, the method includes: flowing an organic solution of lipid molecules and an aqueous solution of nucleic acids into the inlet of the microfluidic mixer and flowing towards the outlet, respectively, so that the organic solution and the aqueous solution are mixed in the microfluidic mixer to obtain a particulate solution.

[0036] In one or more embodiments, the organic solution is an ethanol solution, preferably anhydrous ethanol.

[0037] In one or more embodiments, the aqueous solution is a buffer solution.

[0038] In one or more embodiments, the method further includes mixing the prepared particulate solution with a diluent to obtain a diluted particulate solution.

[0039] In one or more embodiments, the diluent is water, citrate buffer, tromethorphan buffer, phosphate buffer, and acetate buffer.

[0040] In one or more embodiments, the method further includes the steps of ultrafiltration, purification, and equilibration of the particulate solution.

[0041] In one or more embodiments, the method includes:

[0042] 1) A lipid ethanol solution is obtained by mixing cationic lipids, accessory lipids, cholesterol, or polyethylene glycol-modified phospholipids in a certain molar ratio and dissolving them in ethanol; mRNA is dissolved in acetate buffer to obtain an aqueous mRNA solution.

[0043] 2) The lipid ethanol solution and the mRNA aqueous solution are fed into the two inlet channels of the microfluidic chip or mixing device at a certain volume ratio and flow out from the outlet channel to obtain a lipid nanoparticle solution.

[0044] In one or more embodiments, the method further includes:

[0045] 3) Diluent dilution: Dilute the lipid nanoparticles with a diluent to reduce the ethanol content in the solution and enhance the stability of the lipid nanoparticle solution.

[0046] 4) Ultrafiltration purification to remove ethanol and salt solution from the lipid nanoparticle solution.

[0047] 5) Equilibration: Add a cryoprotectant (sucrose-PBS solution, trehalose-PBS solution, sucrose-TBS solution, or trehalose-TBS solution) to the ultrafiltration-purified lipid nanoparticle solution and dilute to the target concentration.

[0048] 6) The lipid nanoparticles were filtered through a 0.22 μm sterile filter to obtain the lipid nanoparticle formulation.

[0049] Another aspect of the present invention provides the application of the microfluidic mixer or mixing device described in any embodiment of the present invention in the preparation of products. Preferably, the product is a particle or a pharmaceutical composition; more preferably, the product is lipid nanoparticles.

[0050] The mixing channel structure of the present invention is simple and easy to manufacture. The number of mixing channels can be increased or decreased according to production batch requirements and driver performance. The integrated chip method provided by the present invention can ensure that the pressure of the inlet channel of each mixing channel is consistent, so that the quality of the mixing product of each mixing channel is uniform. The mixing unit of the present invention realizes the diversion and integration of fluids in the mixing channel, effectively adjusts the fluid flow direction and flow rate, promotes the mixing disturbance between liquids, and promotes the mixing between liquids.

[0051] The objects, advantages, and features of the present invention will become more apparent to those skilled in the art from the following detailed description of specific embodiments of the invention in conjunction with the accompanying drawings. Attached Figure Description

[0052] The following sections will describe some specific embodiments of the invention in detail by way of example and not limitation, with reference to the accompanying drawings. The same reference numerals in the drawings denote the same or similar parts or portions. Those skilled in the art should understand that these drawings are not necessarily drawn to scale. In the drawings:

[0053] Figure 1a This is a cross-sectional view of an integrated microfluidic mixer with two inlets located on the same side. Figure 1b This is a cross-sectional view of an integrated microfluidic mixer with two inlets located on both sides.

[0054] Figure 2 This is a simplified planar schematic diagram of the two fluid mixing channels of an integrated microfluidic mixer.

[0055] Figure 3 This is a part diagram of a microfluidic mixer with four fluid mixing channels according to an embodiment of the present invention.

[0056] Figure 4 This is an assembly diagram of an integrated microfluidic mixer (4 fluid mixing channels) according to an embodiment of the present invention.

[0057] Figure 5a , 5b 5c are schematic diagrams of the structure of 6, 5, and 4 mixed units at the square entrance, respectively.

[0058] Figure 6 This is a schematic diagram of the structure of the four hybrid units with a circular inlet.

[0059] Figure 7 This is a dimensioning diagram of the mixed channel in an embodiment of the present invention.

[0060] Figure 8 This is a comparison chart of the flow rate results of the aqueous phase and oil phase in the embodiments of the present invention.

[0061] Figure 9 This is a comparison chart of the R2 radius research results in the embodiments of the present invention.

[0062] Figure 10 This is a comparison chart of the R1 radius research results in the embodiments of the present invention.

[0063] Figure 11 This is a comparison chart of the R3 radius research results in the embodiments of the present invention.

[0064] Figure 12 This is a comparison chart of the L3 length research results in the embodiments of the present invention.

[0065] Figure 13a , 13b Figures 1 and 13c are wireframe diagrams of microfluidic mixers with 4, 6, and 8 mixing channels, respectively.

[0066] Figure 14 These are conceptual diagrams of integrated microfluidic mixers with 2 and 4 mixing channels.

[0067] Figure 15 is a schematic diagram of the microfluidic device.

[0068] 100 First liquid inlet

[0069] 110 diversion tube

[0070] 200 Second Inlet

[0071] 210 First Entrance Passage

[0072] 220 Second Entrance Channel

[0073] 300 Mixed Channels

[0074] 500 Exit Channel

[0075] 600 connecting tubing

[0076] 700 liquid outlet

[0077] 400 hybrid unit

[0078] 410 Mixed Inlet

[0079] 420 Turbulent Cavity

[0080] 430 Mixed Export

[0081] 401 First Arc

[0082] 402 connecting plane

[0083] 403 Second Arc

[0084] 404 spoiler

[0085] R1 is the radius of the first arc surface.

[0086] R2 is the radius of the second arc of the first arc.

[0087] The circular radius of the R3 spoiler

[0088] R4 is the radius of the first arc surface of the second arc surface.

[0089] R5 second arc radius

[0090] L1 is the length from the entrance of the mixing channel to the center of the first mixing unit blocking circle.

[0091] L2 is the length from the center of the first mixing unit's blocking circle to the center of the second mixing unit's blocking circle.

[0092] L3 is half the length of the plane connecting the first and second arc surfaces.

[0093] L4 is the length from the center of the last mixing unit blocking circle in the mixing channel to the outlet of the mixing channel.

[0094] 10, 11, 12 Cleaning fluid reservoir

[0095] 21 Raw material storage tank

[0096] 22 Auxiliary Material Storage Tank

[0097] 23 Diluent Reservoir

[0098] 24 Waste Liquid Collector

[0099] 25 Product Receiver

[0100] 30 Four-way Valve

[0101] 31 Three-way

[0102] 33 Dispenser Valve

[0103] 41 drives

[0104] 42 pressure sensors

[0105] 43 Flow Sensor

[0106] 44 Microfluidic Mixer Detailed Implementation

[0107] The present invention will be further described below with reference to specific embodiments and accompanying drawings. More details are set forth in the following description to provide a thorough understanding of the invention. However, the invention can be implemented in many other ways different from those described herein. Those skilled in the art can make similar extensions and derivations based on actual circumstances without departing from the spirit of the invention. Therefore, the scope of protection of the invention should not be limited by the content of these specific embodiments. It should be noted that the accompanying drawings are merely illustrative and are not drawn to scale, and should not be construed as limiting the actual scope of protection claimed by the invention.

[0108] As shown in Figure 1 and Figure 2As shown, the integrated microfluidic mixer includes a first inlet 100, a second inlet 200, and an outlet 700; a first mixing channel inlet 210; a guide tube 110 connecting the first inlet 100 and the first mixing channel inlet; a second inlet channel 220 connected to the second inlet 200; a mixing channel 300; a mixing channel outlet channel 500; and a guide tube 600 connecting the integrated microfluidic mixer outlet 700 and the mixing channel outlet channel. The first inlet 100 and the second inlet 200 are used to introduce the liquid to be mixed. The guide tube 110 diverts the liquid from the inlet 100 to the mixing channel inlet, where it mixes with the liquid from the second inlet 200 after being diverted through the second inlet channel 220. The mixture is then collected through the connecting tube 600 and flows out of the integrated microfluidic mixer outlet 700.

[0109] Example 1:

[0110] Figure 3 This demonstrates a method for manufacturing microfluidic mixers by fabricating them in segments and then assembling them into a complete mixer. Figure 4 ). Figure 3 a is the inlet of the integrated microfluidic mixer; Figure 3 b is a restrictive gasket for the integrated microfluidic mixer, used to secure parts 3d, 3e, and 3f in the diagram; Figure 3 c is a gasket for the integrated microfluidic mixer, used before the flow channel section and the barrier to prevent liquid leakage; Figure 3 d represents the blocking section of the integrated microfluidic mixer, used to split and agitate the liquid; Figure 3 e represents the integrated microfluidic mixer channel segment used for fluid flow and mixing; Figure 3 f represents the end of the fluid channel segment, which is the outlet channel of the mixing channel; Figure 3 g is a gasket at the end of the channel section (f) and the collection section (h) to prevent liquid leakage; Figure 3 h represents the collection section of the microfluidic mixer, the outlet of the integrated microfluidic mixer. For example... Figure 4 As shown, the components are assembled according to the aab(cdc)-eb(cdc)-eb(cdc)-eb(cdc)-f-(g)h module, and the components are assembled together by threads. Each mixing channel 300 includes 4 mixing units 400, forming an integrated microfluidic mixer with 4 mixing channels 300 (b(cdc) indicates that components c and d are inside component b).

[0111] Example 2:

[0112] The simulation design was conducted using COMSOL Multiphysics 6.0. A three-dimensional model was employed, utilizing turbulent k-ε flow and rarefied mass transport models. The fluid model was incompressible, the turbulence model was RANS, the study type was steady-state, the transport mechanism was convection, and the multiphysics field was reactive flow-rare mass. The mixing effect was evaluated using the method described in Li Zixiao's paper, "Analysis of Factors Affecting the Mixing Effect of Mixers in Microfluidic Chips."

[0113]

[0114] Where Ci represents the ethanol concentration in the statistical region; N represents the number of points being counted in the statistical region; M represents the ethanol concentration at the inlet of the mixing ethanol channel. When M = 0.5, it indicates that the two fluids are not mixed at all; when M = 0, it indicates that the two fluids are completely and uniformly mixed. Therefore, the M value can be regarded as the mixing effect in the experiment.

[0115] The inlet shape is shown in Figure 5. The mixing channel inlet can be square, circular, or any other arbitrary shape. The experimental results are shown in Table 1.

[0116] Table 1. Simulation results of different hybrid channel inlet shapes

[0117]

[0118] Simulation results show that square and circular inlets have no significant impact on the mixing effect. For the same size, the cross-sectional area of ​​the square inlet is smaller than that of the circular inlet, resulting in greater fluid resistance. The pressure value of the square inlet is relatively larger in the simulation.

[0119] Example 3:

[0120] Figure 2 , Figure 6 , Figure 7 As shown, the first arc surface 401 of the mixing unit 400 is composed of two arcs with radii of R1 and R2 respectively. The spoiler 404 in the mixing unit 400 is circular with a radius of R3. Half the length of the connecting plane 402 between the first arc surface 401 and the second arc surface 403 of the mixing unit 400 is L3. The distance from the center of the circular mixing unit at the tail end to the outlet is L4.

[0121] Figure 7 As shown, the pressure monitoring points at the two inlets of the mixing channel 300 are 1 and 2, the fluid mixing point is 3, the circular front end of the turbulence cavity 420 of the first mixing unit is 4, and the circular front end of the turbulence cavity of the second mixing unit is 5.

[0122] The 300-dimensional mixing channel was simulated using COMSOL Multiphysics 6.0. A two-dimensional model was used, employing turbulent k-ε flow and a rarefied mass transport model. The study type was steady-state. The mixing effect was evaluated as cited in the above references.

[0123] With L1 = 4.5 mm, L2 = 5 mm, L3 = R1 = R3 = 0.5 mm, L4 = 3.5 mm, R2 = 1 mm, and a channel size of 1 mm, the mixing effect of different ethanol and water flow rates in the mixing channel and the pressure values ​​at each pressure point were simulated. The simulation data are shown in Table 2 below:

[0124] Table 2: Comparison of Flow Rate Study Results for Aqueous and Oil Phases

[0125]

[0126] The results are as follows Figure 8 As shown, the optimal mixing effect is achieved when the water phase velocity is 0.2 m / s and the oil phase velocity is 0.1 m / s. The mixing effect improves with the increase of the number of mixing units, but approaches its limit when the number of mixing units is 3-4. The lowest pressure values ​​are found at each pressure point in the mixing channel when the water phase:oil phase ratio is 2:1.

[0127] With L1 = 4.5mm, L2 = 5mm, L3 = R1 = R3 = 0.5mm, L4 = 3.5mm, channel size 1mm, water phase = 0.2m / s, oil phase = 0.1m / s, the mixing effect of the mixing channel and the pressure values ​​at each pressure point were simulated when the radius of R2 was 0.25mm, 0.5mm, and 1mm, respectively. The simulation data are shown in Table 3 below:

[0128] Table 3: Comparison of R² radius research results

[0129]

[0130] The results are as follows Figure 9 As shown, under the same flow rate, different R2 radii have no significant impact on the mixing effect. The mixing effect improves with the increase of the number of mixing units, reaching a limit when the number of mixing units is 3 to 4. The pressure values ​​at all points are lowest when the R2 radius is 0.5 to 1 mm. Therefore, the preferred R2 radius is 0.5 to 1 mm.

[0131] With L1 = 4.5mm, L2 = 5mm, L3 = R3 = 0.5mm, L4 = 3.5mm, channel size 1mm, R2 = 1mm, water phase = 0.2m / s, oil phase = 0.1m / s, the mixing effect of the mixing channel and the pressure values ​​at each pressure point were simulated when R1 radius was 0.5mm, 0.75mm, and 1.25mm respectively. The simulation data are shown in Table 4 below:

[0132] Table 4: Comparison of R1 radius research results

[0133]

[0134] The results are as follows Figure 10 As shown, under the same flow rate, different R1 radii have no significant impact on the mixing effect. The mixing effect improves with the increase of the number of mixing units, reaching a limit when the number of mixing units is 3 to 4. The pressure values ​​at all points are lowest when the R1 radius is 1.25 mm. Therefore, the preferred R1 radius is 1.25 mm.

[0135] With L1 = 4.5mm, L2 = 5.5mm, L3 = 0.8mm, L4 = 3.5mm, channel size 1mm, R1 = R2 = 1mm, water phase = 0.2m / s, oil phase = 0.1m / s, the mixing effect of the mixing channel and the pressure values ​​at each pressure point were simulated when the radius of R3 was 0.4mm, 0.5mm, and 0.6mm, respectively. The simulation data are shown in Table 5 below:

[0136] Table 5: Comparison of R3 radius research results

[0137]

[0138] The results are as follows Figure 11 As shown, under the same flow rate, different R3 radii have no significant impact on the mixing effect. The mixing effect improves with the increase of the number of mixing units, reaching a limit when the number of mixing units is 3. The pressure values ​​at all points are lowest when the R3 radius is 0.4 mm. Therefore, the preferred R3 radius is 0.4 mm.

[0139] With L1 = 4.5mm, L2 = 5mm, R3 = 0.5mm, L4 = 3.5mm, channel size 1mm, R1 = R2 = 1mm, water phase = 0.2m / s, oil phase = 0.1m / s, the mixing effect and pressure values ​​at each pressure point of the mixing channel were simulated when the length of L3 was 0.65mm, 0.7mm, and 0.8mm, respectively. The simulation data are shown in Table 6 below:

[0140] Table 6: Comparison of L3 Length Study Results

[0141]

[0142] The results are as follows Figure 12 As shown, at the same flow rate, different L3 lengths have no significant impact on the mixing effect. The mixing effect improves with increasing number of mixing units, reaching a limit when the number of mixing units is 3. The L3 length has no significant effect on each pressure point.

[0143] Example 4

[0144] The simulation was designed using COMSOL Multiphysics 6.0. A three-dimensional model was employed, utilizing turbulent k-ε flow and rarefaction transport models. The fluid model was incompressible, the turbulence model was RANS, the study type was steady-state, the transport mechanism was convection, and the multiphysics field was reactive flow-rare substance. The influence of different flow channels and mixing units on the mixing effect was simulated. The pressures at the two inlets and mixing channels, as well as the mixing effect at the tail end of each mixing channel, were measured. Perspective views of the integrated microfluidic mixer with 4, 6, and 8 mixing channels are shown in Figure 13. The internal mixing channels of the integrated microfluidic mixer with 2 and 4 mixing channels are shown in Figure 13. Figure 14 .

[0145] When two internal mixing channels are selected, the simulation calculation data for each of the four mixing units in each channel are shown in Table 7:

[0146] Table 7: Simulation results for 2 mixing channels, 4 mixing units per channel

[0147]

[0148] When four internal mixing channels are selected, the simulation calculation data for each channel with 2 to 4 mixing units are shown in Table 8:

[0149] Table 8: Simulation results for 4 mixing channels, with 2–4 mixing units per channel.

[0150]

[0151]

[0152] Simulation results show that as the number of mixing channels increases, the pressure at the two inlets also increases, but the pressure is still much lower than 1 bar (1 bar = 10). 5 The manufacturer KNAUER provides a 1000ml / min plunger pump with a maximum pressure of 50bar, indicating that the plunger pump can meet the fluid power requirements of multi-fluid channel multi-mixing units.

[0153] Example 5

[0154] Based on the above description of microfluidic mixers, a microfluidic mixing device can also be described for mixing at least two substances to form a mixture. This microfluidic mixing device can also be used to prepare drugs formed by mixing at least two solutions.

[0155] A simplified structural diagram of the microfluidic mixing device is shown below. Figure 15a , Figure 15b as well as Figure 15cAs shown, it includes a microfluidic mixer 44, a raw material reservoir 21, an auxiliary material reservoir 22, a driver 41, a pressure sensor 42, a flow sensor 43, and a product receiver 25.

[0156] like Figure 15a As shown, the raw material reservoir 21 can be used to store the active pharmaceutical ingredient solution or RNA or DNA solution, and the excipient reservoir 22 can be used to store the polymer solution. Both the raw material reservoir 21 and the excipient reservoir 22 are connected to the inlet of the microfluidic mixer. The driver 41 provides a continuous driving force to the raw material reservoir 21 and the excipient reservoir 22, driving the solution into the inlet and maintaining continuous flow within the microfluidic mixer 44. Each reservoir outlet has a clamp valve 30 to control the opening and closing of the pipeline; it is opened when in use and closed when not in use to prevent loss of solution due to gravity or evaporation. The product output from the microfluidic mixer 44 passes through the separator valve 33, which allows defective products caused by unstable input of the solution in the early and late stages of the preparation process to be input into the waste liquid collector 24, while the good product is input into the product receiver 25.

[0157] like Figure 15b As shown, the mixing device also includes a diluent reservoir 23, which is equipped with a driver 41, a pressure sensor 42, and a flow sensor 43. The diluent reservoir 23 is used to provide diluent to dilute the mixture output from the microfluidic mixer 44. The diluent reservoir 23 can be connected to the outlet of the microfluidic mixer 44 via a three-way valve 31, and then the other end is connected to a dispensing valve 33.

[0158] like Figure 15c As shown, the mixing device also includes cleaning solution reservoirs 10, 11, and 12, which are respectively filled with sodium hydroxide solution, sodium acetate solution, or water for injection and anhydrous ethanol. Each cleaning solution reservoir outlet has a pinch valve to control the opening and closing of the pipeline. The outlets of reservoirs 10, 11, and 12 are connected via a four-way valve 30, and then via a three-way valve 31 to the front end of the actuator 41 corresponding to the active pharmaceutical ingredient reservoir 21, excipient reservoir 22, and diluent reservoir 23. Before using the equipment or after preparation, the four-way valve 30 can be used to open cleaning solution reservoirs 10, 11, or 12, respectively, using the actuators to power the flow of cleaning solution into the pipeline and microfluidic mixer 44, and then into waste liquid collector 24.

[0159] The active pharmaceutical ingredient reservoir and the product receiver can be in the form of a bottle, can, or bag.

[0160] When the raw material reservoir, product receiver, diluent reservoir, and cleaning agent reservoir are bag-shaped, the bag outlet is a CPC quick connector for easy connection and replacement.

[0161] The auxiliary material storage container can be in the form of a bag, can, or bottle.

[0162] Preferably, the microfluidic mixing device further includes a temperature control system for heating the raw material reservoir 21 and / or the auxiliary material reservoir 22 and / or the microfluidic mixer 44 and / or the product receiver 25. The temperature of the raw material reservoir 21 and / or the auxiliary material reservoir 22 and / or the microfluidic mixer 44 and / or the product receiver 25 is controlled between room temperature and 65°C. The temperature control system enhances solution dissolution, prevents substances from precipitating from the solution, and enhances the mixing effect of the solution in the microfluidic mixer.

[0163] Preferably, the microfluidic mixing device also includes a control system, which contains flow and pressure calibration software for the driver 41, as well as a parameter setting system for the manufacturing process. Before manufacturing, the driver 41 needs to be calibrated using the control system and externally measured flow and pressure sensors to ensure the accuracy of the parameters set during production. The control system controls the flow rate of the driver 41 during production through parameter settings. Simultaneously, the control system can receive data from the flow sensor 43 and pressure sensor 42, providing real-time feedback on the flow rate generated by the driver 41 during production, enhancing production monitoring, and ensuring consistent product quality throughout the production process. The control system can periodically record the generated data to form a production log file for easy export and review analysis of the production process. Furthermore, the control system meets the requirements of pharmaceutical GMP production equipment, featuring three-level access control and unmodifiable files.

[0164] This invention also provides a method for manufacturing a microfluidic mixer:

[0165] In one embodiment, the present invention provides a machining method for a microfluidic mixer. Software simulation shows that slight changes in the length of L3 do not affect the mixing effect of the mixing channel. Therefore, this length variation can be used to divide the entire microfluidic mixer into multiple segments for precision machining (e.g., ...). Figure 3 After being processed into individual parts, the parts are joined together using thin gaskets to prevent liquid leakage. Once assembled, they form a complete microfluidic mixer. Figure 4 ).

[0166] In one embodiment, the present invention also utilizes 3D printing technology to manufacture a microfluidic mixer. The present invention uses a 405nm wavelength photocurable elastic photosensitive resin for DLP 3D printing, comprising acrylate, reactive diluent, photoinitiator, leveling agent, dispersant, and polymerization inhibitor. An integrated microfluidic mixer is rapidly manufactured by directly utilizing the photocuring principle of the photosensitive resin.

[0167] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. An integrated microfluidic mixer for promoting liquid mixing, characterized in that, include: A first liquid inlet (100) is connected to one end of a guide pipe (110), and the other end of the guide pipe (110) is connected to a first inlet channel (210); a second liquid inlet (200) is connected to a second inlet channel (220); the first inlet (210) and the second inlet channel (220) are respectively connected to one end of a mixing channel (300); the mixing channel (300) is used to promote the mixing of liquids; the mixing channel (300) includes at least one mixing unit (400); the mixing unit (400) is provided with an outlet channel (500); the outlet channel (500) is used to collect the mixed liquids.

2. The integrated microfluidic mixer according to claim 1, characterized in that, Each microfluidic mixer contains multiple mixing channels (300) connected in parallel.

3. The integrated microfluidic mixer according to claim 2, characterized in that, Each of the mixing channels further includes a plurality of mixing units (400) connected in series; each mixing unit (400) includes a mixing inlet (410), one end of which is connected to the first inlet channel (210) and the second inlet channel (220), and the other end is connected to one end of the turbulence cavity (420); the other end of the turbulence cavity (420) is connected to the mixing outlet (430). When multiple mixing units (400) are included, the multiple mixing units (400) are connected in sequence.

4. The integrated microfluidic mixer according to claim 3, characterized in that, A baffle plate (404) is provided inside the baffle cavity (420).

5. The integrated microfluidic mixer according to claim 4, characterized in that, The mixing inlet (410) and mixing outlet (430) of the mixing unit (400) can have square, circular, triangular or other shapes in cross-section.

6. The integrated microfluidic mixer according to claim 5, characterized in that, The connection between the mixing unit mixing inlet (410) and the turbulence cavity (420) is a first arc surface, which is composed of two circular arcs connected together.

7. The integrated microfluidic mixer according to claim 6, characterized in that, The connection between the mixing outlet (430) and the turbulence cavity (420) is a second arc surface, which is composed of two arcs connected together.

8. The integrated microfluidic mixer according to claim 7, characterized in that, The connection point between the first arc surface and the second arc surface is a connecting plane (402), and the length of the connecting plane (402) is greater than or equal to the lateral diameter of the spoiler (404).

9. The integrated microfluidic mixer according to claim 8, characterized in that, The arc angle between the first arc surface and the second arc surface is 0° < α ≤ 90°; the arc radius R1 and R2 of the first arc surface are less than half the width of the spoiler (W / 2), i.e., R1 < W / 2, R2 < W / 2; the arc radius R4 and R5 of the second arc surface are less than half the width of the spoiler (W / 2), i.e., R4 < W / 2, R5 < W / 2.

10. The integrated microfluidic mixer according to any one of claims 1 to 9, characterized in that, The connection angle between the mixing units is 0° < β < 180°.

11. The integrated microfluidic mixer according to any one of claims 1 to 9, characterized in that, The first arc radius R1 of the hybrid unit (400) ranges from 1 to 1.25 mm, and the value of R2 ranges from 0.5 to 1 mm.

12. The integrated microfluidic mixer according to any one of claims 1 to 9, characterized in that, The first liquid inlet (100), the second liquid inlet (200), and the mixing unit (400) can all be assembled from different modules.

13. An integrated microfluidic mixing device, characterized in that, include: The device includes the microfluidic chip as described in any one of claims 1-12; it further includes: a liquid storage section for storing different types of raw materials, the liquid storage section being connected to the liquid inlet of the microfluidic chip via a pipeline; a driver for providing continuous driving force to each raw material, driving the raw material into the microfluidic chip; and a receiving section for receiving the microfluidic chip mixture, the receiving section being connected to the microfluidic chip outlet via a pipeline; the microfluidic chip outlet is connected to a T-tube via a pipeline for online dilution of the microfluidic chip mixture, and then the diluted product is poured into the receiving section.

14. The integrated microfluidic device as described in claim 13, characterized in that, It also includes an operating system, which controls the device's operation, pauses it, and records its operating status and data.

15. The integrated microfluidic device as described in claim 14, characterized in that, It also includes pressure gauges for monitoring fluid pressure during device operation.

16. The integrated microfluidic device as described in claim 15, characterized in that, It also includes flow meters, used to monitor fluid flow during device operation.

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