Mixing unit, mixer, micro-fluidic chip and mixing device

Abstract

The utility model provides a mixing unit for promoting liquid mixing, the mixing unit comprises a first inlet channel, a first outlet channel, a mixing channel and at least one turbulent flow cavity, the mixing channel is communicated with the first inlet channel and the first outlet channel and is used for providing a liquid mixing space, and the turbulent flow cavity is communicated with the first inlet channel and the first outlet channel. At least part of the outer wall surface forming the mixing channel is an arc surface tangent to the wall surface forming the first inlet channel or the first outlet channel; the turbulent flow cavity penetrates through the mixing channel, so that fluid in the mixing channel is shunted in the mixing channel under the influence of the turbulent flow cavity. The mixing unit can promote liquid mixing. The utility model further provides a mixer, a micro-fluidic chip, a mixing device and application thereof. The utility model also provides a method for preparing a product by using the micro-fluidic chip or the mixing device.

Description

Technical Field

[0001] The present disclosure relates to the field of microfluidic chips, and in particular to the field of microfluidic chips for liquid mixing. Background Art

[0002] Microfluidic chip technology manipulates and controls nanoliter and microliter-scale fluid samples at the micrometer scale. Compared to conventional, bulky equipment, microfluidics can integrate sample processing, biochemical reactions, separations, and detection operations onto a chip measuring just a few square centimeters. This significantly reduces sample and reagent consumption and improves synthesis or analysis efficiency. Consequently, the technology is widely used in fields such as biomedicine and the chemical industry.

[0003] Mixing reactions of multiple liquids is one of the most common processes in fields such as chemistry, chemical engineering, and biomedicine. Traditional reactors, such as tubular reactors, kettle reactors, and tower reactors, primarily perform mixing reactions on a macroscopic scale on large volumes of fluids. These reactors suffer from drawbacks such as bulk, poor safety, low mass and heat transfer efficiencies, and poor product consistency. Using microfluidic chips, passive micromixers based on specialized geometries and active micromixers using external force fields have been developed.

[0004] In order to improve the efficiency of fluid mixing and reaction in microchannels, it is necessary to provide a microfluidic chip that can efficiently, quickly and continuously achieve mixing and reaction between two fluids, avoid flow dead corners, and improve the fluid mixing effect. Utility Model Content

[0005] An object of the present disclosure is to provide a mixing unit capable of continuously and efficiently achieving mixing and reaction between two fluids.

[0006] To achieve the above-mentioned purpose, the mixing unit includes a first inlet channel, a first outlet channel, a mixing channel and at least one turbulent cavity. The mixing channel is connected to the first inlet channel and the first outlet channel to provide a space for liquid mixing. At least a portion of the outer wall of the mixing channel is an arc surface tangent to the wall forming the first inlet channel or the first outlet channel; the turbulent cavity runs through the mixing channel so that the fluid in the mixing channel is affected by the turbulent cavity and is diverted in the mixing channel.

[0007] In one or more embodiments, the outer wall surface forming the mixing channel is a first arc surface. Preferably, the angle of the first arc surface on the side tangent to the wall surface of the first inlet channel or the first outlet channel is less than or equal to 90°.

[0008] In one or more embodiments, the inner peripheral wall surface forming the flow-turbulating cavity is a second arc surface.

[0009] In one or more embodiments, the outer wall surface forming the mixing channel is a first arc surface, the inner peripheral wall surface forming the flow-turbulating cavity is a second arc surface, and the first arc surface and the second arc surface jointly define a flow channel.

[0010] In one or more embodiments, the turbulent cavity divides the mixing channel into a first flow channel, a second flow channel, an inlet buffer zone and an outlet buffer zone, and the first flow channel and the second flow channel are connected to the first inlet channel via the inlet buffer zone and are connected to the first outlet channel via the outlet buffer zone.

[0011] In one or more embodiments, the first flow channel and the second flow channel are arranged in different planes.

[0012] In one or more embodiments, the width of the first inlet channel or the first outlet channel is a first dimension, the height of the mixing channel is a second dimension, the inner radius of the second arc surface is a third dimension, the outer radius of the first arc surface is a fourth dimension, the first length of the mixing channel in the flow plane is a fifth dimension, and the second length of the mixing channel perpendicular to the first length in the flow plane is a sixth dimension; wherein, within the range allowing fluid to flow, the first dimension, the second dimension, the third dimension and the fourth dimension, the fifth dimension and the sixth dimension are configured to minimize the flow cross-sectional area of ​​the mixing channel, and the fourth dimension is greater than or equal to half of the equivalent hydraulic diameter of the outer contour of the mixing channel, and the equivalent hydraulic diameter = 2×fifth dimension×sixth dimension / (fifth dimension+sixth dimension), that is, the fourth dimension ≥ fifth dimension×sixth dimension / (fifth dimension+sixth dimension).

[0013] In one or more embodiments, the first dimension is a minimum value within a set range;

[0014] The second size is the minimum value within the set range;

[0015] The third size is the maximum value within the set range;

[0016] The fourth size is the maximum value within the set range;

[0017] The fifth dimension is the minimum value within the set range;

[0018] The sixth size is a minimum value within a set range.

[0019] In one or more embodiments, the walls forming the first inlet channel, the first outlet channel, and the mixing channel facing the fluid have protrusions, so that the walls have roughness.

[0020] In one or more embodiments, the first inlet channel and the first outlet channel are arranged parallel and / or perpendicular to each other.

[0021] Another object of the present disclosure is to provide a mixer, comprising a second inlet channel, a second outlet channel and a mixing unit, wherein the second inlet channel and the second outlet channel are connected by a plurality of the mixing units. Preferably, the plurality of the mixing units are connected end to end to form an S-shaped folded structure.

[0022] In one or more embodiments, the first inlet channels and first outlet channels of adjacent mixing units are connected to each other to form a connecting channel connecting the mixing units, and the connecting channel is tapered to increase the flow rate of the fluid flowing from the first inlet channel to the mixing channel.

[0023] Another object of the present disclosure is to provide a microfluidic chip, comprising a liquid inlet, a liquid outlet, a third inlet channel connected to the liquid inlet, and a third outlet channel connected to the liquid outlet, wherein the liquid inlet is used to introduce a fluid to be mixed, and the liquid outlet is used to lead out the mixed fluid, and further comprising at least one mixer, wherein the mixer is used to connect the third inlet channel and the third outlet channel.

[0024] In one or more embodiments, the plane of the third inlet channel forms an angle with the plane of the second inlet channel.

[0025] In one or more embodiments, the microfluidic chip includes multiple liquid inlets and multiple third inlet channels respectively connected to each liquid inlet, each of the third inlet channels is fluidically connected to the second inlet channel, wherein the angle range between adjacent third inlet channels is 0°<a<360°, preferably, the angle takes the maximum value within the set range, and more preferably, the angle range is 45°≤a≤270°.

[0026] Another object of the present disclosure is to provide a mixing device, which includes the above-mentioned microfluidic chip, at least two raw material supply parts, a driving part, a product receiving part and a shell, each of the raw material supply parts is used to store different types of raw materials, and the raw material supply parts are fluidically connected to the liquid inlet of the microfluidic chip; the driving part is used to provide continuous driving force for each of the raw material supply parts to drive each type of raw material into the liquid inlet and maintain continuous flow in the microfluidic chip; the product receiving part is connected to the liquid outlet of the microfluidic chip, and is used to receive the product formed after mixing by the microfluidic chip. Preferably, the shell includes an operating table, and the raw material supply part and the product receiving part are detachably arranged on the operating table. More preferably, the operating table also includes an industrial control screen, which is arranged on the operating table.

[0027] In one or more embodiments, the device further comprises a plurality of raw material delivery pipelines and product output pipelines, each of the raw material delivery pipelines being used to connect the raw material supply section and the liquid inlet, and the product output pipeline being used to connect the liquid outlet and the product receiving section, wherein each of the raw material delivery pipelines comprises an input port, and the product output pipeline comprises an output port, and the input port and the output port are arranged on the operating table, the input port being used to connect with the raw material supply section, and the output port being used to connect with the product receiving section.

[0028] In one or more embodiments, the device further comprises a cleaning section, which is fluidically connected to the microfluidic chip and / or the raw material delivery pipeline and / or the product output pipeline, and is used to clean the microfluidic chip and / or the raw material delivery pipeline and / or the product output pipeline.

[0029] In one or more embodiments, the device further comprises a multi-way connector, wherein the multi-way connector is independently and closably connected to the cleaning section and / or each of the raw material conveying pipelines and / or the product output pipeline.

[0030] In one or more embodiments, the device further comprises a waste liquid portion and a waste liquid pipeline, wherein the waste liquid pipeline is used to connect the waste liquid portion with the liquid outlet, and the waste liquid portion is used to store waste liquid. Preferably, the waste liquid portion is detachably arranged on the operating table.

[0031] In one or more embodiments, the device further comprises a solenoid valve connected to the liquid outlet, the waste liquid pipeline and the product output pipeline, for achieving selective connection between the liquid outlet and the waste liquid pipeline or the product output pipeline. Preferably, the solenoid valve is configured to receive a remote signal to achieve selective switching.

[0032] In one or more embodiments, the mixing device further comprises a diluent supply portion capable of providing a diluent to the product output from the microfluidic chip.

[0033] In one or more embodiments, the microfluidic chip includes multiple mixers, the first mixer is used to mix a part of the raw materials and output a premixed product, and the latter mixer is used to mix the premixed product output by the former mixer with another part of the raw materials or the diluent of the diluent supply part. Preferably, the structure of each mixer can be the same or different.

[0034] In another aspect, the present disclosure also provides a method for preparing a product by mixing multiple fluids using the microfluidic chip or mixing device described in any embodiment of the present disclosure.

[0035] In one or more embodiments, the method includes: allowing multiple fluids to flow from the liquid inlet of the microfluidic chip to the liquid outlet, so that the multiple fluids are mixed in the microfluidic chip to produce a product; or adding multiple fluids to the raw material supply part of the mixing device, providing a driving force through the driving part to drive the multiple fluids to enter the liquid inlet and flow to the liquid outlet, so that the multiple fluids are mixed in the microfluidic chip to produce a product.

[0036] In one or more embodiments, the product is a particle, preferably a nanoparticle, more preferably a lipid nanoparticle.

[0037] In one or more embodiments, the method comprises the step of mixing a solution of particulate material and a solution of a molecule of interest in the microfluidic chip or mixing device.

[0038] In one or more embodiments, the particulate material comprises lipid molecules or high molecular weight polymers.

[0039] In one or more embodiments, the molecule of interest is a nucleic acid.

[0040] In one or more embodiments, the method includes: respectively allowing an organic solution of lipid molecules and an aqueous solution of nucleic acids to flow from the liquid inlet of the microfluidic chip and toward the liquid outlet, so that the organic solution and the aqueous solution are mixed in the microfluidic chip to produce a particle solution; or respectively adding the organic solution of lipid molecules and the aqueous solution of nucleic acids to a raw material supply part of a mixing device, providing a driving force through a driving part to drive the organic solution and the aqueous solution to enter the liquid inlet and flow toward the liquid outlet, so that the organic solution and the aqueous solution are mixed in the microfluidic chip to produce a particle solution.

[0041] In one or more embodiments, the organic solution is an alcohol solution, preferably an ethanol solution.

[0042] In one or more embodiments, the aqueous solution is a buffered solution.

[0043] In one or more embodiments, the method further comprises mixing the prepared particle solution with a diluent to obtain a diluted particle solution.

[0044] In one or more embodiments, the diluent is a buffer.

[0045] In one or more embodiments, the method further comprises the steps of equilibrating, diluting or purifying the lipid mixture.

[0046] In one or more embodiments, the method comprises:

[0047] (1) Cationic lipid, helper lipid, cholesterol or cholesterol derivative, and polymer-conjugated lipid are mixed in a certain molar ratio and dissolved in ethanol to obtain an ethanol lipid solution; mRNA is dissolved in citric acid buffer to obtain an mRNA aqueous solution,

[0048] (2) The ethanol lipid solution and the mRNA aqueous solution are respectively introduced into the two liquid inlets of the microfluidic chip or mixing device at a certain volume ratio and flow out from the liquid outlet to obtain a lipid nanoparticle solution.

[0049] In one or more embodiments, the method further comprises:

[0050] (3) Dialysis solution replacement, remove ethanol and use buffer (such as DPBS) to adjust the volume.

[0051] (4) The lipid nanoparticles were filtered through a 0.22 μm sterile filter to obtain a lipid nanoparticle preparation.

[0052] In another aspect, the present disclosure further provides the use of the microfluidic chip or mixing device described in any embodiment of the present disclosure in preparing a product. Preferably, the product is a particle or a pharmaceutical composition; more preferably, the product is a lipid nanoparticle.

[0053] The mixing unit disclosed herein achieves fluid diversion and integration by means of a turbulent cavity running through the mixing channel, effectively adjusting the flow direction and flow velocity of the fluid, thereby promoting mixing disturbance between the liquids and effectively promoting mixing between the two liquids; by setting an arc surface tangent to the wall forming the first inlet channel or the first outlet channel, it can avoid the generation of flow dead corners in the mixing channel, ensuring the smoothness and continuity of the fluid operation; it can also form a buffer zone, reduce the accumulation of fluid, and achieve a better liquid mixing effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] The above and other features, properties and advantages of the present disclosure will become more apparent from the following description in conjunction with the accompanying drawings and embodiments, in which:

[0055] Figure 1 is a schematic diagram of an embodiment of a microfluidic chip;

[0056] Figure 2 is a schematic diagram of another embodiment of a microfluidic chip;

[0057] Figure 3 is a schematic diagram of one embodiment of a mixer;

[0058] Figure 4 is a schematic diagram of another embodiment of a mixer;

[0059] Figure 5 It is an enlarged view of the mixer;

[0060] Figure 6 yes Figure 5 Top view at point A in the middle;

[0061] Figure 7A 、 7B 7C is a schematic diagram of the structure of the hybrid unit in three third sizes;

[0062] Figure 8A 、 8B 8C is a schematic diagram of the structure of the hybrid unit under three fourth sizes;

[0063] Figure 9A 、 9B 9C is a schematic diagram of the structure of the hybrid unit under three sixth sizes;

[0064] Figure 10A 、 10B 10C, 10D, 10E, and 10F are schematic diagrams of six types of spoiler cavity shapes;

[0065] Figure 11 is a comparative diagram of liquid mixing efficiency under different second sizes;

[0066] Figure 12 It is a comparative diagram of liquid mixing efficiency under different inner circle radii;

[0067] Figure 13 It is a comparative diagram of liquid mixing efficiency under different outer circle radii;

[0068] Figure 14 It is a comparative diagram of liquid mixing efficiency under different sixth dimensions;

[0069] Figure 15 Schematic diagram comparing the liquid mixing efficiency when the first flow channel and the second flow channel are set in the same plane and in different planes;

[0070] Figure 16A This is a schematic diagram comparing the liquid mixing efficiency of adjacent third inlet channels at different angle settings under the total flow rate of a mixing channel;

[0071] Figure 16B This is a schematic diagram comparing the liquid mixing efficiency of adjacent third inlet channels at different angles under the total flow rate of another mixing channel;

[0072] Figure 17 is a simplified structural diagram of an embodiment of a mixing device;

[0073] Figure 18A is a simplified structural diagram of another embodiment of a mixing device;

[0074] Figure 18Bis a simplified structural diagram of yet another embodiment of a mixing device;

[0075] Figure 19 is a schematic diagram of one embodiment of an operating station.

[0076] Description of Reference Numerals

[0077] 10. Mixing unit 500, third outlet channel

[0078] 11. First inlet channel 50, microfluidic chip

[0079] 12. First outlet channel 51, raw material supply unit

[0080] 13. Mixing channel 52, driving unit

[0081] 14. Branch channel 53, product receiving part

[0082] 15. Turbine cavity 54, outer shell

[0083] 100, mixer 55, operating table

[0084] 101, second entrance channel 56, input port

[0085] 102, second outlet channel 57, raw material delivery pipeline

[0086] 130, turning section 58, product output pipeline

[0087] 131, first flow channel 59, industrial control screen

[0088] 132, second flow channel 60, cleaning unit

[0089] 133, inlet buffer 61, waste liquid section

[0090] 134, outlet buffer 62, multi-way connector

[0091] 139, first arc surface 66, waste liquid pipeline

[0092] 151, second arc surface 67, diluent supply portion

[0093] 200, liquid inlet 81, solenoid valve

[0094] 300, liquid outlet 501, first mixer

[0095] 400, third inlet channel 502, second mixer DETAILED DESCRIPTION

[0096] The present disclosure is further described below in conjunction with specific embodiments and accompanying drawings. More details are set forth in the following description to facilitate a full understanding of the present disclosure. However, the present disclosure can obviously be implemented in a variety of other ways different from those described herein. Those skilled in the art can make similar generalizations and deductions based on actual application situations without violating the connotation of the present disclosure. Therefore, the scope of protection of the present disclosure should not be limited by the content of this specific embodiment. It should be noted that these and subsequent drawings are only for example and are not drawn according to the conditions of equal scale, and should not be used to limit the scope of protection actually claimed by the present disclosure.

[0097] It should be noted that the following introduction uses words such as "first" and "second" to limit components, which is only for the convenience of distinguishing the corresponding components. Unless otherwise stated, the above words have no special meaning and do not represent the primary and secondary, and therefore cannot be understood as limiting the scope of protection of this application.

[0098] like Figure 1 and Figure 2 As shown, the microfluidic chip 50 includes a liquid inlet 200, a liquid outlet 300, a third inlet channel 400 connected to the liquid inlet, and a third outlet channel 500 connected to the liquid outlet 300. The liquid inlet 200 is used to introduce the liquid to be mixed, and the liquid outlet 300 is used to lead out the mixed fluid. The microfluidic chip also includes a mixer 100 (100') for connecting the third inlet channel 400 and the third outlet channel 500. The mixer 100 (100') is used to promote liquid mixing.

[0099] Continue to combine Figure 3 and Figure 4 As shown, the mixer 100 (100') includes a second inlet channel 101 and a second outlet channel 102, which are connected by a plurality of mixing units 10 (10'). Preferably, the plurality of mixing units 10 (10') are connected end to end to form an S-shaped folded structure.

[0100] The second inlet channel 101 of the mixer 100 is used to introduce liquid from the third inlet channel 400, and the second outlet channel 102 is used to discharge the mixed liquid after flowing through the mixer 100 (100') to the third outlet channel 500. By arranging multiple mixing units 10 (10') into an S-shaped folded structure connected end to end, the flow path can be maximized within a limited microscale space, effectively extending the fluid flow path length, improving the mixing effect, saving space, and improving manufacturing economy.

[0101] The microfluidic chip includes at least one mixer 100 (100'), for example, two mixers 100 (100') connected in series, with the second outlet channel 102 of the first mixer connected to the second inlet channel 101 of the second mixer. The structures of the two mixers 100 (100') can be the same or different.

[0102] Figure 1 An XYZ coordinate system is shown in the following figures. In this document, unless otherwise specified, the X direction refers to the axial direction of the second inlet channel 101, the Y direction refers to the direction perpendicular to the X direction on the XOY plane where the fluid flows in, and the Z direction refers to the height direction perpendicular to both the X and Y directions.

[0103] exist Figure 1 and Figure 2 In the illustrated embodiment, the microfluidic chip includes a plurality of liquid inlets 200 and a plurality of third inlet channels 400 respectively connected to the liquid inlets 200 , and each third inlet channel 400 is fluidically connected to the second inlet channel 101 .

[0104] The liquid inlet 200 and the third inlet channel 400 include but are not limited to two. In other embodiments, the number of the liquid inlet 200 and the third inlet channel 400 can be increased or decreased by the staff according to specific injection requirements.

[0105] The included angle a between adjacent third inlet channels 400 is in the range of 0°<a<360°. Figure 1 Two independent liquid inlets 200 are shown, and each liquid inlet 200 is independently connected to the third inlet channel 400. The third inlet channels 400 form an angle a between them, and the range of the angle a is 0°<a<360°.

[0106] In a preferred embodiment, the angle a is the maximum value within a set range. The set range is determined according to the specific chip size and the position of the liquid inlet, and the angle a is preferably the maximum value within the range. Figure 16A and 16B The effect comparison chart shown is attached. Figure 16A A comparison chart of the mixing efficiency at six angles, 270°, 180°, 135°, 90°, 60°, and 20°, is shown when the total flow rate of the mixing channel is 2 ml / min.

[0107] Attachment Figure 16BThis chart compares mixing efficiency at six angles a (a) of 270°, 180°, 135°, 90°, 60°, and 20°, when the total flow rate in the mixing channel is 4 ml / min. The vertical axis, mixing efficiency, is a dimensionless value that represents the mixing effect; higher mixing efficiency values ​​indicate better mixing. The horizontal axis represents the length of the fluid flowing through the mixing unit. As the number of mixing units increases, the length of the fluid flowing through the mixing channel increases, indicating a longer mixing time.

[0108] exist Figure 1 In the embodiment shown, the angle a is about 90°. Figure 16A and 16B The comparison results shown in FIG. 4 show that the larger the angle a is, the better the mixing effect is. Therefore, within a certain setting range, the angle a is preferably set to the maximum value. The larger the angle is, the better the mixing effect between the liquids is.

[0109] In one embodiment, the angle a is in the range of 45°≤a≤270°. By setting a certain angle, the component velocities of the two liquids in two dimensions after entering the second inlet channel 101 can be changed, thereby promoting the mixing of the liquids.

[0110] In order to further promote the mixing between the two liquids, in one embodiment, the plane where the third inlet channel 400 is located forms an angle with the plane where the second inlet channel 101 is located, so that the third inlet channel 400 is configured to be able to deliver the incoming liquid into the mixer 100 at a certain angle, for example, delivering liquid to the second inlet channel 101 at an inclination angle of 10°, 15°, etc.

[0111] As reference Figure 1 As shown in the coordinate axis diagram, the second inlet channel 101 is parallel to the XOY plane, and the third inlet channel 400 is arranged at an angle, such as 10° or 15°, with the XOY plane to deliver the liquids to be mixed obliquely into the second inlet channel 101. By setting a certain angle, the flow rate of the two liquids entering the second inlet channel 101 can be increased, thereby enhancing the impact of the two liquids after converging, promoting mutual disturbance between the two liquids, and enhancing the mixing effect of the flow.

[0112] In one embodiment, the first inlet channels 11 and the first outlet channels 12 of adjacent mixing units 10 are connected to each other to form a connecting channel connecting the mixing units 10. The connecting channel is tapered to increase the flow rate of the fluid flowing from the first inlet channel 11 to the mixing channel 13. The tapered channel is formed at the connection between adjacent mixing units 10. The pressure and flow rate of the fluid are increased after flowing through the tapered channel, thereby effectively increasing the flow rate entering the next mixing unit 10 and enhancing the liquid mixing effect.

[0113] The following combination Figures 4 to 6The mixing unit 10 is now described. The mixing unit 10 includes a first inlet channel 11, a first outlet channel 12, a mixing channel 13, and at least one turbulent cavity 15. The mixing channel 13 connects the first inlet channel 11 and the first outlet channel 12, providing a space for liquid mixing. At least a portion of the outer wall of the mixing channel 13 is an arcuate surface tangent to the wall forming the first inlet channel 11 or the first outlet channel 12. The turbulent cavity 15 extends through the mixing channel 13, so that the fluid in the mixing channel 13 is affected by the turbulent cavity 15 and is diverted within the mixing channel 13.

[0114] Under the interference of the flow-turbulating cavity 15, the mixing channel 13 is divided by the flow-turbulating cavity 15, thereby being able to divert the fluid transported by the first inlet channel 11 and transport the liquid obtained by integrating the diverted liquid to the first outlet channel 12. By configuring at least a portion of the outer wall surface forming the mixing channel 13 as an arc surface tangent to the wall surface forming the first inlet channel 11 or the first outlet channel 12, continuous fluid passage can be achieved, avoiding fluid accumulation and the formation of dead corners, further ensuring the continuity and smoothness of fluid flow, and further promoting the addition of centrifugal force to the fluid when it flows out of the bend 130, thereby increasing the flow rate and achieving a better liquid mixing effect.

[0115] Those skilled in the art will appreciate that the flow-turbulating cavity 15 includes, but is not limited to, the shapes defined in the above embodiments, and other shapes that can divert the fluid are applicable to the present disclosure.

[0116] As in Figure 10A In the embodiment shown, the mixing channel 13 is divided into multiple groups of channels by providing multiple flow-disturbing cavities 15' to promote the disturbance of the liquid; or three flow-disturbing cavities are provided in a triangular arrangement to change the mixing channel 13 from three flow channels to two flow channels and then to one flow channel. Figure 10B and Figure 10C In the embodiment shown, by providing a flow-disturbing cavity 15" having an elliptical cross section, the original flow path of the fluid is effectively changed, and the flow direction and flow rate of the fluid in the X and Y directions are changed to promote mixing between the liquids. Figure 10D and 10E In the embodiment shown, the inner wall surface forming the flow-disturbing cavity is a flat surface, and the flow-disturbing cavity has a triangular cross section or a square cross section; or as in Figure 10F In the embodiment shown, the inner wall surface forming the flow-turbulating cavity is an irregular wall surface, such as a water drop-shaped cross section, which can also achieve the effect of dispersing the fluid flow path and promoting liquid mixing.

[0117] The above structures can divert the fluid, promote the reversal of the liquid, change the liquid flow rate, and finally integrate it through the first outlet channel 12, thereby promoting mixing between liquid laminar flows and improving the mixing effect of the liquid.

[0118] In one embodiment, the outer wall surface forming the mixing channel 13 is a first curved surface 139. Preferably, the angle of the first curved surface 139 on the side tangent to the wall surface of the first inlet channel 11 or the first outlet channel 12 is less than or equal to 90°, so that the first curved surface 139 can form a buffer zone when tangent to the wall surface forming the first inlet channel 11 or the first outlet channel 12. Specifically, relative to the flow-disturbing cavity 15, the outer wall surface forming the mixing channel 13 has two sides. The angle of the first curved surface on the side tangent to the wall surface of the first inlet channel 11 or the first outlet channel 12 is set to less than or equal to 90°, thereby forming a buffer zone for fluid entry.

[0119] Further, combined Figure 6 As shown, the turbulent cavity 15 divides the mixing channel 13 into a first flow channel 131, a second flow channel 132, an inlet buffer zone 133 and an outlet buffer zone 134. The first flow channel 131 and the second flow channel 132 are connected to the first inlet channel 11 via the inlet buffer zone 133, and are connected to the first outlet channel 12 via the outlet buffer zone 134.

[0120] By directly setting a buffer zone in the mixing channel 13, it is possible to prevent the liquid flowing in from the first inlet channel 11 from being directly diverted at the mixing channel 13, causing a reverse impact on the incoming flow and interfering with the liquid delivery effect; it is possible to prevent the fluid from gathering at the first outlet channel 12 to form accumulated liquid after flowing out of the first flow channel 131 and the second flow channel 132, thereby ensuring smooth fluid flow.

[0121] In one embodiment, the inner wall surface of the flow-turbulating cavity 15 is a second arc surface 151. By setting the inner wall surface of the flow-turbulating cavity 15 to a arc surface, accumulation of liquid and dead corners can be avoided, thereby achieving smooth flow of liquid.

[0122] In one embodiment, the outer wall surface forming the mixing channel 13 is a first arc surface 139, and the inner wall surface forming the turbulent cavity 15 is a second arc surface 151. The first arc surface 139 and the second arc surface 151 together define a flow channel. Figure 5 As shown in the first flow channel 131 and the second flow channel 132, it can be understood that the flow channel can be a concentric ring, that is, the first arc surface 139 and the second arc surface 151 are concentric circles, so that the first flow channel 131 and the second flow channel 132 are fan rings; or it can be an eccentric ring, the first arc surface 139 and the second arc surface 151 are not eccentric, in which case the flow channel is irregular, such as 7A to 9CThe first curved surface 139 and the second curved surface 151 define a flow channel, which can provide an arc-shaped barrier for the fluid during the fluid diversion process to change the flow direction and flow rate of the fluid in two dimensions. The centrifugal force from the arc-shaped flow channel can also be applied to the fluid, further promoting fluid mixing by applying another external force to the fluid. The arc-shaped structure can effectively reduce the generation of fluid dead corners.

[0123] The first flow channel 131 and the second flow channel 132 are not limited to the above structures. In another embodiment, as shown in the attached Figure 10B and Figure 10C As shown in FIG, when the flow-turbulating cavity 15 is an elliptical cylinder, the first flow channel 131 and the second flow channel 132 are structures with different inner arc radii and outer arc radii. Figure 10B The design shown allows for an extended bypass path, with Figure 10C The design shown can increase the turning radius of the diverted fluid during rectification, increase the impact force of the fluid during turning, and enhance the mixing effect of the fluid.

[0124] In order to further promote the mixing of the liquids, in another embodiment of the mixing channel 13, the mixing unit is configured as follows Figure 4 In the example shown, the first flow channel 131 and the second flow channel 132 are not arranged on the same plane. Figure 4 Schematic coordinate axes illustrate the exemplary embodiment.

[0125] The third inlet channel 400, the second inlet channel 101, and the first inlet channel 11 all transport fluids on the XOY plane. The first channel 131 and the second channel 132 of the mixing channel 13 are arranged on different XOY planes at different heights, that is, at different Z coordinates, to form a height difference. After the fluid flows into the first inlet channel 11, it is blocked and diverted by the disturbance cavity 15. However, when flowing through the first and second channels 131, 132 at different heights, it is further diverted in the Z direction, achieving three-dimensional fluid flow, thereby changing the fluid's three-dimensional velocity distribution and further enhancing the disturbance and mixing effects. After being diverted by the first and second channels 131, 132, the fluid flows to the first outlet channel 12 and then merges. It continues to flow through the diversion channel 14 in the third dimension to further mix.

[0126] Attachment Figure 15 A schematic diagram comparing the liquid mixing efficiency when the first flow channel and the second flow channel are set on the same plane and on different planes is given. Figure 5 The first flow channel and the second flow channel are located in the same plane, and the triangle points represent the liquid mixing efficiency. Figure 4The first flow channel and the second flow channel are shown to be located on different planes. By comparison, it can be seen that the mixing efficiency can be significantly increased by arranging the first flow channel 131 and the second flow channel 132 on different planes.

[0127] exist Figure 4 In the illustrated embodiment, the first flow channel 131 and the second flow channel 132, which are diagonally distributed with respect to each other, are respectively arranged on different planes. It can be further understood that, in another embodiment, the mixing channel 13 may also include multiple layers of flow channels at different heights on the Z axis, each layer of flow channels including the first flow channel 131 and the second flow channel 132. After the fluid is fed into the mixing channel 13 through the first inlet channel 11, it is diverted through the diversion channel 14 and fed into the first flow channel 131 and the second flow channel 132, which are located at different heights distributed along the Z axis, to achieve, for example, four-way or six-way branching, and finally converge at the first outlet channel 12, completing the diversion and mixing process; or in another embodiment, the first flow channel 131 and the second flow channel 132 are respectively higher and lower than the XY plane where the first inlet channel 11 is located, so that after flowing out of the first inlet channel 11, the fluid flows upward and downward, respectively, thereby causing a change in the component velocity in the third dimension.

[0128] Those skilled in the art will appreciate that the mixing channel may be provided with different structures at different heights along the Z axis, and any structure that can increase the flow of the fluid in the third dimension outside the original flow plane may be applied to the present disclosure.

[0129] In one embodiment, the walls of the first inlet channel 11, the first outlet channel 12, and the mixing channel 13 facing the fluid have projections to create a rough surface. By increasing the roughness of the walls to increase flow resistance, the disturbance effect within the laminar flow can be further enhanced, promoting mixing.

[0130] The following combination Figure 6 、 7A to 9C The design dimensions of the mixing unit 10 are described.

[0131] Figure 6 The top view of the mixing unit 10 on the XOY plane is shown. The turning portion 130 is an arc-shaped structure. The mixing unit 10 has a cylindrical flow-turbulating cavity 15. The first arc surface 139 and the second arc surface 151 define a flow channel.

[0132] The width of the first inlet channel 11 or the first outlet channel 12 of the mixing unit 10 along the X direction is the first dimension W1. The inner radius and outer radius of the first flow channel 131 and the second flow channel 132 are the third dimension R1 and the fourth dimension R2 respectively. Figure 5 As shown, the height of the mixing channel 13 in the Z direction is the second dimension H.

[0133] The first length of the mixing channel 13 in the flow plane XOY is the fifth dimension W2, and the second length perpendicular to the first length in the flow plane is the sixth dimension L. Specifically, Figure 6 As shown, the fifth dimension W2 is the length of the mixing channel 13 along the Y direction, and the sixth dimension L is the length of the mixing channel 13 along the X direction.

[0134] Within the range allowing fluid to flow, the first dimension W1, the second dimension H, the third dimension R1, the fourth dimension R2, the fifth dimension W2, and the sixth dimension L are configured to minimize the flow cross-sectional area of ​​the mixing channel 13. The flow cross-sectional area herein refers to the cross-sectional area of ​​the first flow channel 131 and the second flow channel 132, for example, the flow cross-sectional area located on the YOZ or XOZ plane.

[0135] The cross-sectional area range that allows the fluid to flow is determined by the staff according to the specific requirements of the mixed liquid. For example, in the preparation of the mixture, the minimum flow cross-sectional area is about 100 to 1000 μm 2 It is understood that the flow cross-sectional area range allowing the fluid to flow can also have various ranges according to different test requirements.

[0136] In one embodiment, in order to set the flow cross-sectional area of ​​the mixing channel 13 as small as possible, the first dimension W1 is the minimum value within the set range; the second dimension H is the minimum value within the set range; the third dimension R1 is the maximum value within the set range; the fourth dimension R2 is the maximum value within the set range; the fifth dimension W2 is the minimum value within the set range; and the sixth dimension L is the minimum value within the set range.

[0137] Specifically, Figure 11 A comparison of mixing effects at three different heights H is shown. Triangular points represent the mixing efficiency when the second dimension H is 0.25 mm, circular points represent the mixing efficiency when H is 0.5 mm, and diamond points represent the mixing efficiency when H is 1 mm. In this case, the first dimension W1, representing the flow path width of the first inlet channel 11 or the first outlet channel 12, is 0.5 mm, the fifth dimension W2 is 1.5 mm, and the sixth dimension L is 1.5 mm. The inner radius R1 and outer radius R2 of the first flow channel 131 and the second flow channel 132 are 0.375 and 0.75 mm, respectively.

[0138] according to Figure 11 As can be seen from the comparison chart, mixing efficiency increases as height H decreases. This is because a lower depth H narrows the flow channel, thereby reducing the cross-sectional area. Therefore, the height of the first inlet channel 11, first outlet channel 12, and mixing channel 13 along the Z-axis is the minimum value within the preferred setting range of 10 to 1000 μm for the second dimension H, to achieve better liquid mixing.

[0139] 7A to 7C Schematic diagrams of mixing units 10 with different inner circle radii R1 are shown. 7A to 7C As shown, the third dimensions R1', R1", and R1'" are 0.25 mm, 0.375 mm, and 0.5 mm, respectively. At this time, the height of the first inlet channel 11, the first outlet channel 12, and the mixing channel 13 along the Z-axis direction is the second dimension H of 0.25 mm, indicating that the first dimension W1 of the flow path width of the first inlet channel 11 or the first outlet channel 12 is 0.5 mm, the fifth dimension W2 is 1.5 mm, the sixth dimension L is 1.5 mm, and the outer radius R2 of the first flow channel 131 and the second flow channel 132 is 0.75 mm.

[0140] The mixing effect comparison chart can be referred to Figure 12 As shown, Figure 12 The vertical axis represents mixing efficiency; larger values ​​indicate better surface mixing. The horizontal axis represents the number of mixing cells through which the fluid flows, i.e., the number of separating and combining micro-cells. As the number of mixing cells increases, the surface fluid mixing time increases. Triangles represent mixing efficiency when R1 is 0.25 mm, circles when 0.375 mm, and diamonds when 0.5 mm.

[0141] according to Figure 12 The mixing results shown show that, at the same flow rate, the mixing effect improves as the inner radius R1 increases. This is because increasing the third dimension R1 reduces the cross-sectional area of ​​the mixing channel 13 in the YOZ plane, thereby increasing the flow rate and the influence of the channel sidewall on the unit flow. Therefore, within the setting range of the third dimension R1, the maximum value of the third dimension R1 is preferably selected to improve the mixing effect. In one embodiment, the setting range of the third dimension R1 is 10 to 1500 μm.

[0142] Figures 8A to 8C A schematic diagram of a mixing unit 10 having a fourth size R2 with different outer radius is shown. Specifically, Figures 8A to 8C A schematic diagram shows fourth dimensions R2', R2", and R2'" of 0.5 mm, 0.75 mm, and 1 mm, respectively. In this case, the third dimension R1 is 0.375 mm, and the height of the first inlet channel 11, the first outlet channel 12, and the mixing channel 13 along the Z-axis direction is the second dimension H of 0.25 mm, indicating that the flow path width W1 of the first inlet channel 11 or the first outlet channel 12 is 0.5 mm. The fifth dimension W2 is 1.5 mm, and the sixth dimension L is 1.5 mm.

[0143] The mixing effect comparison chart can be referred to Figure 13As shown, the triangular points represent the mixing efficiency when R2 is 0.5 mm, the circular points represent the mixing efficiency when R2 is 0.75 mm, and the diamond points represent the mixing efficiency when R2 is 1 mm. According to the comparison results, it can be seen that as the outer radius increases, the mixing effect of the liquid is successively enhanced. It can be understood that, at the same flow rate, by increasing the fourth dimension R2, the cross-sectional area of ​​the mixing channel 13 becomes smaller, thereby increasing the flow rate and also increasing the influence of the channel side wall on the unit fluid. Therefore, in one embodiment, within the setting range of the fourth dimension R2 of 10 to 1500 μm, the fourth dimension R2 is preferably the maximum value within the setting range to improve the mixing effect.

[0144] Figures 9A to 9C A schematic diagram of three mixing units 10 obtained using three different sixth dimensions L is shown. At this time, the sixth dimensions L', L", and L'' are 1.25 mm, 1.5 mm, and 1.75 mm, respectively. The height of the first inlet channel 11, the first outlet channel 12, and the mixing channel 13 along the Z-axis direction is a second dimension H of 0.25 mm, indicating that the first dimension W1 of the flow path width of the first inlet channel 11 or the first outlet channel 12 is 0.5 mm, the fifth dimension W2 is 1.5 mm, and the inner circle radius R1 and outer circle radius R2 of the first flow channel 131 and the second flow channel 132 are 0.375 mm and 0.75 mm.

[0145] The mixing effect comparison chart can be referred to Figure 14 As shown, the triangular points represent the mixing efficiency when L is 1.25 mm, the circular points represent the mixing efficiency when L is 1.5 mm, and the diamond points represent the mixing efficiency when L is 1.75 mm.

[0146] according to Figure 14 The mixing results show that, under the same flow rate, as the sixth dimension L increases, the mixing effect becomes worse. Figure 9A As can be seen, when L is minimum, the cross-sectional area of ​​mixing channel 13 decreases, thereby increasing the flow rate and the influence of the channel sidewall on the unit flow. When L is maximum, the cross-sectional area of ​​mixing channel 13 increases, and the mixing effect deteriorates. Therefore, the sixth dimension is preferably set to the minimum value within the range of 20 to 3000 μm.

[0147] It is understood that the flow cross-sectional area can also be adjusted by adjusting the fifth dimension W2. A larger fifth dimension W2 decreases the cross-sectional area of ​​the mixing channel 13, thus facilitating liquid mixing. A smaller fifth dimension W2 increases the cross-sectional area of ​​the mixing channel 13, hindering liquid mixing. Therefore, the fifth dimension is preferably set to the maximum value within the range of 20-3000 μm.

[0148] Based on the principle of minimizing the cross-sectional area, it can be understood that the first dimension W1 is the width of the first inlet channel 11 or the first outlet channel 12. The smaller the first dimension W1, the faster the fluid enters the first outlet channel 12 at the same flow rate, and the better the mixing effect. The first dimension W1 is preferably set in the range of 10 to 1000 μm.

[0149] It should be noted that when the flow cross-sectional area is designed to be smaller, the flow resistance will increase accordingly. Therefore, the driving force of the liquid conveying power device needs to be increased to ensure that the fluid flows smoothly through the mixer.

[0150] The mixing unit 10 described above can achieve fluid diversion and change the direction and velocity of the original flow by providing a turbulent cavity 15 that runs through the mixing channel 13, thereby significantly enhancing fluid disturbance and promoting mixing between the two liquids. In addition, the walls of the first inlet channel 11 and the first outlet channel 12 are arranged to be tangent to at least a portion of the outer wall of the mixing channel 13, respectively, so as to achieve structural fluidity, thereby enabling continuous and efficient mixing and transportation of liquids. To achieve this purpose, the fourth dimension R2 is set to be greater than or equal to half of the equivalent hydraulic diameter of the outer contour of the mixing channel 13, and the equivalent hydraulic diameter = 2×W2×L / (W2+L), that is, R2 ≥ W2×L / (W2+L).

[0151] In order to maintain a continuous barrier to the fluid, a plurality of mixing units 10 are connected to form a mixer 100 .

[0152] Back to Figure 5 , the first inlet channel 11 of one mixing unit 10 sends the liquid from the second inlet channel 101 into the mixing channel 13. After the first liquid is diverted and mixed through the mixing channel 13, it flows out of the first outlet channel 12 and continues to flow through the first inlet channel 11' of the next mixing unit 10', enters the mixing channel 13' for diversion, and continues to flow out of the first outlet channel 12', realizing a cyclic alternating diversion and integration process. In this cyclic alternating diversion and integration process, the liquid is cyclically alternating to change the flow direction and speed of the fluid. The fluid is continuously separated, merged, and the flow direction is continuously changed, thereby promoting the mixing effect between different liquids. By setting the first curved surface and the second curved surface, the flow dead corner in the mixing channel is avoided, and the smooth flow of the fluid is guaranteed. In addition, by setting the first curved surface to be tangent to the wall of the first inlet channel or the first outlet channel, the continuity of the fluid flow can be further guaranteed, the accumulation of the fluid can be reduced, and a better liquid mixing effect can be achieved.

[0153] In one embodiment, the flow directions of the first inlet channel 11 and the first outlet channel 12 of each mixing unit 10 are parallel and / or perpendicular to each other.

[0154] like Figure 5The embodiment shown adopts both parallel and vertical settings, thereby configuring multiple mixing units 10 into a folded shape, which can achieve folding of the flow channel in a limited space, thereby extending the flow distance of the liquid, promoting the mixing effect of the liquid and improving economy.

[0155] The distribution structure of the mixing unit 10 in the mixer 100 includes but is not limited to the above-mentioned embodiments. For example, in other embodiments, the flow directions of the first inlet channel 11 and the first outlet channel 12 of at least part of the mixing unit 10 can also be set to a structure that is both vertical or both parallel.

[0156] By configuring different numbers of mixing units 10 with parallel or vertical structures, the number of bends and the length-to-width ratio of the folded structure can be changed, allowing the mixer 100 to meet actual fluid flow and mixing requirements. For example, by setting the flow directions of the first inlet channels 11 and the first outlet channels 12 of multiple mixing units 10 to be parallel, the multiple mixing units 10 are configured in a straight line, which can effectively save materials and costs while meeting the fluid mixing requirements. The selection of the above structure is determined by the staff based on the specific chip size and the specific mixing effect required, and will not be repeated here.

[0157] Connecting multiple mixing units end-to-end to form a mixer enables the alternating flow of fluids, which then merges and diverges. This continuously applies disturbances to the different liquids, changing the flow direction and dimensional velocity of the fluids, further enhancing the mixing effect. In this diverging and combining microchannel system, the linear velocity and flow direction of the fluids can be continuously changed, significantly improving the mixing efficiency between the fluids.

[0158] In conjunction with the above introduction to the microfluidic chip, we can also understand a mixing device for mixing at least two substances to form a product. In some embodiments, the device can be used to prepare a drug, which is formed by mixing at least two raw materials.

[0159] The mixing device combines Figures 17 to 18B The device shown is a simplified diagram, which includes the above-mentioned microfluidic chip 50, at least two raw material supply parts 51, a driving part 52, a product receiving part 53 and a housing 54.

[0160] Each raw material supply unit 51 is used to store different types of raw materials. The raw material supply units 51 are fluidically connected to the liquid inlet 200 of the microfluidic chip 50. The driving unit 52 is used to provide continuous driving force for each raw material supply unit 51 to drive various types of raw materials into the liquid inlet 200 and maintain continuous flow in the microfluidic chip 50.

[0161] like Figure 18A and 18BTwo raw material supply parts 51 and 51 ′ respectively filled with different raw materials and driving parts 52 and 52 ′ respectively connected to the two raw material supply parts 51 and 51 ′ are shown. Through the extraction of the driving parts 52 and 52 ′, the two raw material supply parts 51 and 51 ′ transport the raw materials to the liquid inlet 200.

[0162] In one embodiment, the driving unit 52 is a plurality of double plunger pumps, each of which is independently connected to each raw material supply unit 51. The double plunger pump structure has two plunger pump units. The plunger pump unit on one side outputs liquid while the plunger pump unit on the other side inhales liquid. The two plunger pump units continuously switch operations, thereby enabling continuous output of raw materials. In another embodiment, the driving unit 52 can also be a peristaltic pump, an electromagnetic pump, or a centrifugal pump, etc. It will be understood by those skilled in the art that any pump body capable of achieving a driving effect is applicable to the present disclosure.

[0163] In one embodiment, Figure 18B As shown, the mixing device further includes a diluent supply unit 67, which provides diluent to dilute the product output by the microfluidic chip. The diluent supply unit 67 can be fluidically connected to the liquid outlet 300 of the microfluidic chip 50. Furthermore, the diluent supply unit 67 is openably and closably connected to the product output pipeline 58 via a multi-way connector outside the microfluidic chip 50.

[0164] The product receiving portion 53 is connected to the liquid outlet 300 of the microfluidic chip 50 and is used to receive the product formed after mixing by the microfluidic chip 50. The housing 54 includes an operating table 55, on which the raw material supply portion 51 and the product receiving portion 53 are detachably mounted.

[0165] In one embodiment, the device also includes a plurality of raw material delivery pipelines 57 and product output pipelines 58, each raw material delivery pipeline 57 is used to connect the raw material supply part 51 and the liquid inlet 200, and the product output pipeline 58 is used to connect the liquid outlet 300 and the product receiving part 53, wherein each raw material delivery pipeline 57 includes an input port 56, and the product output pipeline 58 includes an output port, and the input port 56 and the output port are arranged on the operating table 55, the input port 56 is used to connect with the raw material supply part 51, and the output port is used to connect with the product receiving part 53.

[0166] Specifically, the raw material delivery pipe 57 is connected to the liquid inlet 200 to deliver the raw material into the microfluidic chip 50; the liquid outlet 300 delivers the prepared product into the product output pipe 58 through the chip outlet pipe 82 until it enters the product receiving part 53.

[0167] In addition, by providing openings on the operating platform 55 on the raw material delivery pipe 57 and the product output pipe 58, replacement, installation and removal of the raw material supply part 51 and the product receiving part 53 are facilitated.

[0168] In one embodiment, the raw material supply part 51 and the product receiving part 53 are in the shape of bottles or cans, which further facilitates replacement.

[0169] In one embodiment, the device also includes a cleaning section 60, which is fluidically connected to the microfluidic chip 50 and / or the raw material delivery pipeline 57 and / or the product output pipeline 58, and is used to clean the microfluidic chip 50 and / or the raw material delivery pipeline 57 and / or the product output pipeline 58.

[0170] In one embodiment, the device further comprises a multi-way connector 62 , which is independently and closably connected to the cleaning section 60 and / or each raw material delivery pipeline 57 and / or the product output pipeline 58 .

[0171] Reference Figures 17 to 18B As shown, by adjusting the multi-way connector, the cleaning liquid can selectively clean each raw material delivery pipeline 57 and each product output pipeline 58.

[0172] In one embodiment, the device further includes a waste liquid portion 61 and a waste liquid pipeline 66 . The waste liquid pipeline 66 connects the waste liquid portion 61 with the liquid outlet 300 . The waste liquid portion 61 is used to store waste liquid.

[0173] Waste liquid may be generated at the beginning and / or preparation and / or end stages of preparing the mixed product on the microfluidic chip, and the waste liquid portion 61 is used to store the waste liquid.

[0174] Similar to the raw material supply section 51 and the product receiving section 53 , the waste liquid section 61 is detachably disposed on the operating table 55 to facilitate easy replacement, installation, and removal of the waste liquid section.

[0175] Based on the above embodiment, the device also includes a solenoid valve connected to the liquid outlet 300, the waste liquid pipeline 66 and the product output pipeline 58, for achieving selective communication between the liquid outlet 300 and the waste liquid pipeline 66 and the product output pipeline 58.

[0176] Preferably, the solenoid valve 81 is configured to receive a remote signal to achieve selective switching. For example, the solenoid valve 81 is controlled by the host computer software to switch the flow pipe, thereby achieving selective collection of products or waste liquids.

[0177] In one embodiment, the operating table 55 further includes an industrial control screen 59, which is provided on the operating table 55. The industrial control screen 59 can display basic parameters such as flow rate and time, as well as functional parameters such as waste discharge and cleaning. Preferably, the industrial control screen 59 has a touch function to facilitate the staff to adjust the parameters.

[0178] In one embodiment, the mixing device further includes a temperature control system for heating the area of ​​the raw material supply unit 51 and / or the microfluidic chip 50 and / or the product receiving unit 53 to increase or decrease the temperature of the liquid in the raw material supply unit 51 and / or the microfluidic chip 50 and / or the product receiving unit 53, so that the temperature is controlled within a range of 0 to 65° C. By providing a temperature control system, the ambient temperature can be adjusted to promote liquid mixing and enhance the mixing effect.

[0179] In one embodiment, combined Figure 18B It is understood that the microfluidic chip includes multiple mixers, the first mixer is used to mix some types of raw materials from the partial raw material supply part 51 and output a premixed product, and each subsequent mixer is used to mix the premixed product output by the previous mixer with another type of raw material from another part of the raw material supply part 51 or the diluent in the diluent supply part 67.

[0180] For example, a first mixer 501 is connected to two raw material supply sections 51, receiving and mixing two types of raw materials. After mixing, it outputs a premixed liquid, which flows into a second mixer 502. Simultaneously, the second mixer is connected to another raw material supply section 51, mixing the premixed liquid with other raw materials provided by a third raw material supply section 51 to form a product. The resulting product can be diluted with a diluent provided by a diluent supply section 67, forming a final output product that is then input into the product receiving section 53. It is understood that the number of mixers can be increased based on actual mixing needs, with each subsequent mixer being used to mix the premixed product formed by the preceding mixer with another type of raw material or diluent. Under the settings, the diluent and one or more of the multiple raw material liquid channels can be selectively activated according to user needs; the number of mixers can also be selected based on the application scenario. The above-described device enables uniform and controllable synthesis and preparation of products, has a high degree of automation, and can achieve continuous output of products efficiently and conveniently.

[0181] By using the apparatus of the present disclosure (including mixers, microfluidic chips, and mixing devices), uniform and rapid mixing of various liquids can be achieved. Therefore, using the apparatus of the present disclosure, particles (such as nanoparticles) can be prepared by mixing particulate materials and molecules of interest, and the uniformity of the particles is better. Therefore, in some embodiments, the present disclosure provides a method for preparing particles using the mixer, microfluidic chip, or mixing device of the present disclosure, which involves mixing, balancing, diluting, and purifying a solution of the particulate material and a solution of the molecule of interest. On the other hand, the present disclosure provides the use of the apparatus of the present disclosure (including mixers, microfluidic chips, and mixing devices) in the preparation of particles or pharmaceutical compositions.

[0182] particles

[0183] The particles disclosed herein are mainly composed of particulate materials, in which molecules of interest may also be encapsulated. In some embodiments, the molecules of interest are nucleic acid molecules (including RNA or DNA), and the particulate material is a material for delivering nucleic acid molecules to animal cells. A variety of materials are suitable for producing such particles. The delivery materials of interest are: (i) lipid molecules, and (ii) non-toxic and biodegradable polymers that can form microparticles. When transmitted through lipid nanoparticles, the molecules of interest are encapsulated therein; when transmitted through polymer microparticles, the molecules of interest can be in the form of encapsulation or adsorption. These particles are molded in the mixer, microfluidic chip and mixing device disclosed herein and made into any shape, such as a sphere. The particles disclosed herein can be used as components of pharmaceutical compositions for the treatment, prevention or immunization of various diseases. These compositions also include typical pharmaceutically acceptable excipients in addition to the particles, as described in Remington: The Science and Practice of Pharmacy. 20th edition.

[0184] lipid nanoparticles

[0185] Amphipathic lipid molecules can form a monolayer or bilayer to wrap the kernel containing molecules of interest (e.g., nucleic acid molecules) in an aqueous environment to become lipid particles, such as liposomes or lipid nanoparticles. " Lipid nanoparticles " (LNP) as described herein refers to particles (e.g., 1-1000 nm) with at least one nanometer size. Lipid nanoparticles can be included in preparations for delivering active agents or therapeutic agents (e.g., nucleic acids) to target sites (e.g., cells, tissues (e.g., diseased tissues such as tumor tissue), organs). The lipids forming lipid nanoparticles include one or more cationic lipid molecules, one or more auxiliary lipid molecules, one or more cholesterol or cholesterol derivatives and / or one or more polymer-conjugated lipid molecules. The auxiliary lipid molecule can be one or more neutral lipid molecules. The molecules of interest can be encapsulated in the lipid portion of the lipid nanoparticle or in the aqueous space encapsulated by some or all of the lipid portions of the lipid nanoparticles to protect them from enzymatic degradation, or other undesirable effects induced by the mechanism of the host organism or cells, such as adverse immune responses, can not be produced.

[0186] As used herein, "lipids" refer to a group of organic compounds that include, but are not limited to, esters of fatty acids and are generally characterized by being poorly soluble in water but soluble in many organic solvents. They are generally divided into at least three categories: (1) "simple lipids," which include fats and oils as well as waxes; (2) "complex lipids," which include phospholipids and glycolipids; and (3) "derivative lipids," such as steroids. Non-limiting examples of steroids include cholesterol, etc. Lipids can be purchased commercially or synthesized according to techniques known in the art.

[0187] "Cationic lipid" refers to a lipid with a positive ion polar head and is a complex lipid. Cationic lipids that can be used in the present disclosure include: dioleoyltrimethylamine propane (DOTAP), 1,2-distearoyloxy-N,N-dimethyl-3-aminopropane (DSDMA), 1,2-dioleoxy-N,N-dimethyl-3-aminopropane (DODMA), 1,2-dilinoleoyloxy-N,N-dimethyl-3-aminopropane (DLinDMA), 1,2-dilinoleoyloxy-N,N-dimethyl-3-aminopropane (DLenDMA). Cationic lipids can bind to negatively charged nucleic acids.

[0188] The "cholesterol derivative" may be a cholesterol derivative known in the art for use in preparing liposomes. Exemplary cholesterol derivatives include commonly used cholesterol, CAS: 57-88-5.

[0189] As used herein, a "polymer-conjugated lipid" refers to a molecule comprising a lipid portion and a polymer portion. An example of a polymer-conjugated lipid is a polyethylene glycol (PEG)-containing lipid. The term "PEGylated lipid" refers to a lipid whose hydrophobic portion has been PEGylated. This modification can increase stability and prevent nonspecific adsorption of lipid particles. For example, the lipid can be conjugated to PEG using the techniques disclosed in WO2005 / 121348. PEGs of various lengths are available, such as 0.5-8 kDa. PEGylated lipids are known in the art and include 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoylglycerol (PEG-DMG), PEG-DAG (diacylglycerol), PEG-PE (phosphatidylethanolamine), PEG-S-DAG, PEG-DSPE (distearoylphosphatidylethanolamine), PEG-cer (ceramide), and PEG dialkoxypropylcarbamate. In a preferred embodiment of the present disclosure, the polymer-conjugated lipid is PEG2000-DMG.

[0190] "Neutral lipids" as described herein refer to lipid substances that exist in the form of uncharged or neutral zwitterions at a selected pH. At physiological pH, such lipids include, but are not limited to, phosphatidylcholines such as 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), phosphatidylethanolamines such as 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), sphingomyelin (SM) and ceramides. Neutral lipids can be synthetic or naturally derived.

[0191] The particles of the composition containing a plurality of lipid nanoparticles of different diameters (whether or not comprising nucleic acid molecules) ideally have a diameter in the range of 30-220 nm. In the composition obtained using the disclosed apparatus, the average diameter of the lipid nanoparticles can be from about 30 nm to about 150 nm, from about 40 nm to about 150 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, from about 70 nm to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 nm to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or from about 30 nm to about 150 nm. The lipid nanoparticles are preferably about 100 nm, about 200 nm, about 35 nm, about 40 nm, about 45 nm, about 50 nm, about 55 nm, about 60 nm, about 65 nm, about 70 nm, about 75 nm, about 80 nm, about 85 nm, about 90 nm, about 95 nm, about 100 nm, about 105 nm, about 110 nm, about 115 nm, about 120 nm, about 125 nm, about 130 nm, about 135 nm, about 140 nm, about 145 nm or about 150 nm, and the lipid nanoparticles are substantially non-toxic. In addition, in the composition obtained by the device of the present disclosure, the polydispersity index of the diameter does not exceed 0.2, preferably does not exceed 0.16 or 0.14, and more preferably does not exceed 0.07.

[0192] Lipid nanoparticles containing nucleic acids and methods for preparing the same are known in the art, for example, see CN102712935A or related patents, the entire disclosure of which is incorporated herein by reference in its entirety for all purposes. Specifically, a method for preparing lipid nanoparticles using the disclosed apparatus comprises: introducing an organic solution of lipids and an aqueous solution of nucleic acids into a liquid inlet of a mixer or microfluidic chip described herein and flowing them toward a liquid outlet, respectively, to mix the organic solution and the aqueous solution in the apparatus. The method further comprises balancing, diluting, and purifying the lipid mixture.

[0193] For example, cationic lipid molecules, auxiliary lipid molecules, cholesterol or cholesterol derivatives and polymers (such as PEG2000) conjugated lipid molecules are mixed in a certain molar ratio and dissolved in an alcohol (such as ethanol) to obtain a lipid alcohol solution. RNA is dissolved in a buffer solution (such as a citric acid buffer) to obtain a nucleic acid (such as RNA) aqueous solution. By using the microfluidic chip herein to mix the lipid alcohol solution and the nucleic acid aqueous solution in a certain volume ratio, this includes flowing the lipid alcohol solution and the nucleic acid aqueous solution into the two liquid inlets of the microfluidic chip or mixing device in a certain volume ratio, and flowing out from the liquid outlet to obtain a lipid nanoparticle solution. Dialysis is performed to replace the liquid, remove the alcohol and use PBS to make the volume constant. Finally, the lipid nanoparticles are filtered through a 0.22 μm sterile filter to obtain a lipid nanoparticle preparation.

[0194] The molar ratio of the cationic lipid molecule, the helper lipid molecule, the cholesterol or cholesterol derivative, and the polymer-conjugated lipid molecule in the alcohol solution is 5-60:5-60:5-50:1-10, preferably 40-60:5-20:30-50:0.5-5, and more preferably 45-55:8-12:35-45:1-2. In one or more embodiments, the lipid comprises DlinDMA (e.g., DLin-MC3-DMA), DSPC, cholesterol, and DMG (e.g., PEG2000-DMG) in a ratio of 50:10:38.5:1.5. In one or more embodiments, the lipid comprises SM102, DSPC, cholesterol, and DMG (e.g., PEG2000-DMG) in a ratio of 50:10:38.5:1.5. In one or more embodiments, the lipids include ALC-0315, DSPC, cholesterol, and ALC-0159 in a ratio of 46.3:9.4:42.7:1.6.

[0195] The volume ratio (flow rate ratio) of the alcohol solution to the buffer solution is 1 / 1-1 / 10, for example, 1 / 1-1 / 5. The total flow rate of the alcohol solution and the buffer solution is 1-100 ml / min, for example, 1-30 ml / min. Preferably, the volume ratio of the alcohol solution to the buffer solution is 1 / 2-1 / 4, and the total flow rate is 5-15 ml / min.

[0196] The processes of balancing, diluting, and purifying the lipid mixture are well known in the art and include, but are not limited to, dialysis, dilution, and filtration. For example, the diluent is a buffer solution; the dialysis is performed using 50 volumes of PBS (pH = 7.2-7.4) for 4 hours; and the filtration is performed using a 0.22 μm microporous filter membrane.

[0197] Polymeric microparticles

[0198] The disclosed apparatus can also be used to form microparticles using various polymers for encapsulating or adsorbing nucleic acids. Substantially nontoxic or biodegradable polymers are preferred. Useful polymers are also sterilizable to allow for pharmaceutical-grade formulations. Suitable nontoxic and biodegradable polymers include, but are not limited to, poly(α-hydroxy acids), polyhydroxybutyric acid, polylactones (including polycaprolactone), polydioxanone, polyvalerolactone, polyorthoesters, polyanhydrides, polycyanoacrylates, tyrosine-derived polycarbonates, or polyesteramides, and combinations thereof. Microparticles preferably have a diameter in the range of 0.02 μm to 8 μm. In a composition comprising microparticles of varying diameters, at least 80% by number have a diameter in the range of 0.03-7 μm. Techniques for preparing suitable microparticles are well known in the art, for example, in "Polymers in Drug Delivery," edited by Uchegbu et al., CRC Press, 2006. Exemplarily, a method for preparing polymeric microparticles comprises the step of mixing a polymer and a nucleic acid of interest using the disclosed apparatus.

[0199] Molecules of interest

[0200] Molecules of interest are typically active agents or therapeutic agents, including nucleic acid molecules. "Nucleic acid" or "nucleic acid molecule" as described herein refers to a polymer containing at least two deoxyribonucleotides or ribonucleotides in single-stranded or double-stranded form, including DNA, RNA, and hybrids thereof. DNA can be in the form of an antisense molecule, plasmid DNA, cDNA, PCR product, or vector. RNA can be in the form of small hairpin RNA (shRNA), messenger RNA (mRNA), antisense RNA, small interfering RNA (siRNA), microRNA (miRNA), multivalent RNA, Dicer substrate RNA, or viral RNA (vRNA), and combinations thereof. Nucleic acid molecules that can be encapsulated by the particles of the present invention include, but are not limited to, DNA that can be transcribed to form protein-encoding RNA molecules or inhibitory RNA molecules, protein-encoding RNA molecules or inhibitory RNA molecules (e.g., siRNA, miRNA), ribozymes, and aptamers. After the particles are administered in vivo, the nucleic acid molecules are released from the particles and transcribed and / or translated within the cell, thereby providing DNA, RNA, or protein in situ. The nucleic acid molecules may contain modified nucleic acid bases. The proteins include immunogens.

[0201] An "effective amount" or "therapeutically effective amount" of a molecule of interest, such as a therapeutic nucleic acid, is an amount sufficient to produce the desired effect, such as an increase or inhibition of target sequence expression compared to normal expression levels detected in the absence of the nucleic acid.

[0202] The amount of nucleic acid per particle can vary, depending on the nature of the particle used. Typically, a particle can contain 1-500 nucleic acid molecules. For lipid nanoparticles, the typical number of nucleic acid molecules is <50 per particle. For polymeric microparticles, the number of RNA molecules depends on the particle diameter and is typically <50, or 50-200 per particle. The nucleic acid molecules in the particle can be the same or different and can have the same or different lengths.

[0203] Methods for preparing nucleic acid molecules are well known in the art, see for example Sambrook et al. (2001) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press.

[0204] Example 1

[0205] (1) DLin-MC3-DMA (abbreviated as MC3, Aivitao (Shanghai) Pharmaceutical Technology Co., Ltd.), DSPC (Aivitao (Shanghai) Pharmaceutical Technology Co., Ltd.), cholesterol (Aivitao (Shanghai) Pharmaceutical Technology Co., Ltd.), and PEG2000-DMG (Aivitao (Shanghai) Pharmaceutical Technology Co., Ltd.) were mixed and dissolved in anhydrous ethanol at a molar ratio of 50:10:38.5:1.5. eGFP-mRNA was dissolved in a citric acid buffer solution (10 mmol / L) at pH = 4.0. (2) 0.6 ml of ethanol solution and 1.8 ml of citric acid solution were respectively loaded into 2 ml syringes; each syringe was connected to the two liquid inlets 200 of the chip 50 through a catheter; the solution in the syringe was pumped into the chip through the catheter by a syringe pump for mixing. Alternatively, the ethanol solution and the citric acid solution were respectively loaded into the two raw material supply parts 51 of the mixing device, and the driving part provided a driving force to transport the solution to the liquid inlet 200 of the microfluidic chip 50 and mix it in the chip. (3) The flow rate ratio of ethanol to citric acid solution was 1 / 3, and the total flow rate was 12 ml / min. The obtained mixed solution was placed in a dialysis bag and dialyzed against 50 volumes of PBS (pH = 7.2-7.4) for 4 h. Filtered with a 0.22 μm microporous filter membrane before use. The size and polydispersity index of lipid nanoparticles were determined by dynamic light scattering. The encapsulation efficiency of lipid nanoparticles was determined using the Quant it Ribogreen RNA quantification kit (ThermoFisher Scientific, UK) according to the manufacturer's instructions. The test results are shown in Table 1.

[0206] Example 2

[0207] (1) SM-102 (Xiamen Sinobond Biotechnology Co., Ltd.), DSPC (Aiweituo (Shanghai) Pharmaceutical Technology Co., Ltd.), cholesterol (Aiweituo (Shanghai) Pharmaceutical Technology Co., Ltd.), and PEG2000-DMG (Aiweituo (Shanghai) Pharmaceutical Technology Co., Ltd.) were mixed and dissolved in anhydrous ethanol at a molar ratio of 50:10:38.5:1.5. eGFP-mRNA was dissolved in a citric acid buffer solution (10 mmol / L) at pH = 4.0. (2) 0.6 ml of ethanol solution and 1.8 ml of citric acid solution were loaded into 2 ml syringes respectively; each syringe was connected to the two liquid inlets 200 of the chip 50 through a catheter; the solution in the syringe was pumped into the chip through the catheter by a syringe pump for mixing. Alternatively, the ethanol solution and the citric acid solution were respectively loaded into the two raw material supply parts 51 of the mixing device, and the driving part provided a driving force to transport the solution to the liquid inlet 200 of the microfluidic chip 50 and mix it in the chip. (3) The flow rate ratio of ethanol to citric acid solution was 1 / 3, and the total flow rate was 12 ml / min. The obtained mixed solution was placed in a dialysis bag and dialyzed against 50 volumes of PBS (pH = 7.2-7.4) for 4 h. Filtered with a 0.22 μm microporous filter membrane before use. The size and polydispersity index of lipid nanoparticles were determined by dynamic light scattering. The encapsulation efficiency of lipid nanoparticles was determined using the Quant it Ribogreen RNA quantification kit (Thermo Fisher Scientific, UK) according to the manufacturer's instructions. The test results are shown in Table 1.

[0208] Example 3

[0209] (1) ALC-0315 (Xiamen Sinobon Biotechnology Co., Ltd.), DSPC (Aiweituo (Shanghai) Pharmaceutical Technology Co., Ltd.), cholesterol (Aiweituo (Shanghai) Pharmaceutical Technology Co., Ltd.), and ALC-0159 (Xiamen Sinobon Biotechnology Co., Ltd.) were mixed and dissolved in anhydrous ethanol at a molar ratio of 46.3:9.4:42.7:1.6. eGFP-mRNA was dissolved in a citric acid buffer solution (10 mmol / L) at pH = 4.0. (2) 0.6 ml of ethanol solution and 1.8 ml of citric acid solution were respectively loaded into 2 ml syringes; each syringe was connected to the two liquid inlets 200 of the chip 50 through a catheter. The solution in the syringe was pumped into the chip through the catheter by a syringe pump for mixing. Alternatively, the ethanol solution and the citric acid solution were respectively loaded into the two raw material supply parts 51 of the mixing device, and the driving part provided a driving force to transport the solution to the liquid inlet 200 of the microfluidic chip 50 and mix it in the chip. (3) The flow rate ratio of ethanol to citric acid solution was 1 / 3, and the total flow rate was 12 ml / min. The obtained mixed solution was placed in a dialysis bag and dialyzed against 50 volumes of PBS (pH = 7.2-7.4) for 4 h. Filtered with a 0.22 μm microporous filter membrane before use. The size and polydispersity index of lipid nanoparticles were determined by dynamic light scattering. The encapsulation efficiency of lipid nanoparticles was determined using the Quant it Ribogreen RNA quantification kit (Thermo Fisher Scientific, UK) according to the manufacturer's instructions. The test results are shown in Table 1.

[0210] The chips used in Examples 1-3 are Figure 1 The chip shown.

[0211] Comparative Examples 1-3

[0212] The difference from Example 1-3 is that the chip used is an SHM chip (purchased from Maianna (Shanghai) Instrument Technology Co., Ltd.).

[0213] The lipid nanoparticle samples from the above examples were used in a cell transfection experiment. DC2.4 cells were used as the experimental subjects, with 200 ng of mRNA added for every 2 x 105 cells. The main steps involved were as follows:

[0214] 1) DC2.4 Cell Recovery: Remove frozen DC2.4 cells from a -80°C freezer and immediately thaw in a 37°C water bath. After thawing, add cells to prewarmed culture medium and centrifuge at 1200 rpm for 5 min. Discard the supernatant and resuspend the recovered DC2.4 cells in an appropriate amount of DMEM medium containing 10% FBS. Place cells in a 37°C, 5% CO2 incubator for activation.

[0215] 2) According to the experimental requirements, DC2.4 cells were plated in 24-well plates for cell transfection one day in advance. The cell number and cell viability were recorded by cell counting. 2×10 5 Take the cell suspension from each cell, add a certain volume of DMEM culture medium containing 10% FBS and mix evenly, add 1 mL to each well for subsequent transfection experiments.

[0216] 3) After 24 hours, gently remove the culture medium with a pipette 30 minutes in advance, add 1 mL of DPBS to each well for washing, then aspirate the medium. Then add 300 μL of serum-free Opti-MEM medium to each well for subsequent transfection experiments.

[0217] 4) The LNP preparation prepared in the example was diluted with Opti-MEM medium to an mRNA concentration of 1 ug / ml.

[0218] 5) Add 200 μl of the diluted mixture evenly along the top of each well, containing 200 ng of mRNA per well. Incubate the cells in a 37°C, 5% CO2 incubator for activation.

[0219] 6) After 24 hours, the cell viability, EGFP positive rate, and mean fluorescence intensity data were obtained by flow cytometry. The results are shown in Table 1.

[0220] Table 1

[0221]

[0222] It should be noted that the above description uses specific terms to describe the embodiments of the present application, such as "one embodiment," "an embodiment," and / or "some embodiments" to refer to a certain feature, structure, or characteristic associated with at least one embodiment of the present application. It should be emphasized and noted that "one embodiment," "an embodiment," or "an alternative embodiment" mentioned twice or more in different places in this specification does not necessarily refer to the same embodiment. In addition, certain features, structures, or characteristics of one or more embodiments of the present application may be appropriately combined.

[0223] Although the present disclosure is disclosed above with reference to preferred embodiments, this is not intended to limit the present disclosure. Any person skilled in the art may make possible changes and modifications without departing from the spirit and scope of the present disclosure. Therefore, any modifications, equivalent variations, and modifications made to the above embodiments based on the technical essence of the present disclosure without departing from the content of the technical solution of the present disclosure shall fall within the scope of protection defined by the claims of the present disclosure.

Claims

1. A mixing unit (10) for promoting liquid mixing, characterized in that include: First entryway (11); a first outlet channel (12); a mixing channel (13) communicating with the first inlet channel (11) and the first outlet channel (12) and providing a space for liquid mixing, wherein at least a portion of an outer wall surface forming the mixing channel (13) is a curved surface tangent to a wall surface forming the first inlet channel (11) or the first outlet channel (12); At least one turbulent cavity (15), the turbulent cavity (15) passing through the mixing channel (13), so that the fluid in the mixing channel (13) is affected by the turbulent cavity (15) and is diverted in the mixing channel (13).

2. The mixing unit according to claim 1, wherein The outer wall surface forming the mixing channel (13) is a first arc surface (139).

3. The mixing unit according to claim 2, characterized in that The angle of the first arc surface (139) on one side tangent to the wall surface of the first inlet channel (11) or the first outlet channel (12) is less than or equal to 90°.

4. The mixing unit according to claim 1, wherein The inner peripheral wall surface forming the turbulent cavity (15) is a second arc surface (151).

5. The mixing unit according to claim 1, wherein The outer wall surface forming the mixing channel (13) is a first arc surface (139), and the inner peripheral wall surface forming the flow-turbulating cavity (15) is a second arc surface (151). The first arc surface (139) and the second arc surface (151) jointly define a flow channel.

6. The mixing unit according to claim 1, wherein The turbulent cavity (15) divides the mixing channel (13) into a first flow channel (131), a second flow channel (132), an inlet buffer zone (133) and an outlet buffer zone (134); the first flow channel (131) and the second flow channel (132) are connected to the first inlet channel (11) via the inlet buffer zone (133), and are connected to the first outlet channel (12) via the outlet buffer zone (134).

7. The mixing unit according to claim 6, characterized in that The first flow channel (131) and the second flow channel (132) are arranged not on the same plane.

8. The mixing unit according to claim 5, wherein The width of the first inlet channel (11) or the first outlet channel (12) is a first size, The height of the mixing channel (13) is a second dimension, The inner radius of the second arc surface (151) is a third size, and the outer radius of the first arc surface (139) is a fourth size. The first length of the mixing channel (13) in the flow plane is the fifth dimension, A second length of the mixing channel (13) perpendicular to the first length in the flow plane is a sixth dimension; Wherein, within the range allowing fluid to flow, the first size, the second size, the third size, the fourth size, the fifth size and the sixth size are configured to minimize the flow cross-sectional area of ​​the mixing channel (13), and the fourth size is greater than or equal to half of the equivalent hydraulic diameter of the outer contour of the mixing channel (13), and the equivalent hydraulic diameter = 2×fifth size×sixth size / (fifth size+sixth size), that is, the fourth size ≥ fifth size×sixth size / (fifth size+sixth size).

9. The mixing unit according to claim 8, characterized in that The first size is the minimum value within a set range; The second size is the minimum value within the set range; The third size is the maximum value within the set range; The fourth size is the maximum value within the set range; The fifth dimension is the minimum value within the set range; The sixth size is a minimum value within a set range.

10. The mixing unit according to claim 1, wherein The wall surface toward the fluid side forming the first inlet channel (11), the first outlet channel (12) and the mixing channel (13) has convexities so that the wall surface forms roughness.

11. The mixing unit according to claim 1, wherein The first inlet channel (11) and the first outlet channel (12) are arranged parallel and / or perpendicular to each other.

12. A mixer (100), comprising a second inlet channel (101) and a second outlet channel (102), characterized in that: It also comprises the mixing unit (10) according to any one of claims 1 to 11, wherein the second inlet channel (101) and the second outlet channel (102) are connected via a plurality of the mixing units (10).

13. The mixer (100) according to claim 12, characterized in that A plurality of the mixing units (10) are connected end to end to form an S-shaped folded structure.

14. The mixer (100) according to claim 12, characterized in that The first inlet channels (11) and the first outlet channels (12) of adjacent mixing units (10) are connected to each other to form a connecting channel connecting the mixing units (10), and the connecting channel is tapered to increase the flow rate of the fluid flowing from the first inlet channel (11) to the mixing channel (13).

15. A microfluidic chip (50), comprising a liquid inlet (200), a liquid outlet (300), a third inlet channel (400) connected to the liquid inlet (200), and a third outlet channel (500) connected to the liquid outlet (300), wherein the liquid inlet (200) is used to introduce a fluid to be mixed, and the liquid outlet (300) is used to lead out a mixed fluid, characterized in that: Also includes: At least one mixer (100) according to any one of claims 12 to 14, the mixer (100) being used to connect the third inlet channel (400) and the third outlet channel (500).

16. The microfluidic chip (50) according to claim 15, characterized in that The plane where the third inlet channel (400) is located forms an angle with the plane where the second inlet channel (101) is located.

17. The microfluidic chip (50) according to claim 15, characterized in that The microfluidic chip comprises a plurality of liquid inlets (200) and a plurality of third inlet channels (400) respectively connected to the liquid inlets (200), wherein each of the third inlet channels (400) is fluidically connected to the second inlet channel (101). Wherein, the included angle range between adjacent third inlet channels (400) is 0°<a<360°.

18. The microfluidic chip (50) according to claim 17, characterized in that The angle takes the maximum value within the set range.

19. The microfluidic chip (50) according to claim 17, characterized in that: The angle range is 45°≤a≤270°.

20. A mixing device, characterized in that include: The microfluidic chip (50) according to any one of claims 15 to 19; At least two raw material supply parts (51), each of the raw material supply parts (51) is used to store different types of raw materials, and the raw material supply parts (51) are fluidically connected to the liquid inlet (200) of the microfluidic chip (50); A driving unit (52) is used to provide continuous driving force for each of the raw material supply units (51) to drive each type of raw material into the liquid inlet (200) and maintain continuous flow within the microfluidic chip (50); a product receiving portion (53), connected to the liquid outlet (300) of the microfluidic chip (50), for receiving the product formed after mixing by the microfluidic chip (50); and Housing (54).

21. The mixing device according to claim 20, wherein The housing (54) includes an operating table (55), and the raw material supply part (51) and the product receiving part (53) are detachably arranged on the operating table (55).

22. The mixing device according to claim 21, wherein The operating console (55) further includes an industrial control screen (59) which is arranged on the operating console (55).

23. The mixing device according to claim 21, wherein The device further comprises a plurality of raw material delivery pipelines (57) and product output pipelines (58), wherein each of the raw material delivery pipelines (57) is used to connect the raw material supply portion (51) and the liquid inlet (200), and the product output pipeline (58) is used to connect the liquid outlet (300) and the product receiving portion (53). Each of the raw material delivery pipelines (57) includes an input port (56), and each of the product output pipelines (58) includes an output port. The input port (56) and the output port are arranged on the operating table (55). The input port (56) is used to communicate with the raw material supply part (51), and the output port is used to communicate with the product receiving part (53).

24. The mixing device according to claim 23, wherein The device further includes a cleaning section (60), which is fluidically connected to the microfluidic chip (50) and / or the raw material delivery pipeline (57) and / or the product output pipeline (58) for cleaning the microfluidic chip (50) and / or the raw material delivery pipeline (57) and / or the product output pipeline (58).

25. The mixing device according to claim 24, characterized in that The device further comprises a multi-way connector (62), wherein the multi-way connector (62) is independently and closably connected to the cleaning portion (60) and / or each of the raw material delivery pipelines (57) and / or the product output pipeline (58).

26. The mixing device according to claim 23, wherein The device further comprises a waste liquid portion (61) and a waste liquid pipeline (66), wherein the waste liquid pipeline (66) is used to connect the waste liquid portion (61) with the liquid outlet (300), and the waste liquid portion (61) is used to store waste liquid.

27. The mixing device according to claim 26, wherein The waste liquid portion (61) is detachably arranged on the operating table (55).

28. The mixing device according to claim 26 or 27, characterized in that The device further comprises a solenoid valve (81) connected to the liquid outlet (300), the waste liquid pipeline (66) and the product output pipeline (58), for achieving selective communication between the liquid outlet (300) and the waste liquid pipeline (66) or the product output pipeline (58).

29. The mixing device according to claim 28, wherein The solenoid valve (81) is configured to receive a remote signal to achieve selective switching.

30. The mixing device of claim 20, wherein: The mixing device further includes a diluent supply portion (67) capable of providing a diluent to the product output from the microfluidic chip.

31. The mixing device according to claim 30, wherein The microfluidic chip includes a plurality of mixers (100), wherein the first mixer is used to mix a portion of the raw materials from a portion of the raw material supply section (51) and output a premixed product, and each subsequent mixer is used to mix the premixed product output by the preceding mixer with another portion of the raw materials from another portion of the raw material supply section (51) or the diluent from the diluent supply section.

32. The mixing device according to claim 31, wherein The structures of the mixers are the same.

33. The mixing device of claim 31, wherein The structures of the mixers are different.

Images