Micro-channel structure and micro-fluidic chip comprising same

Abstract

The utility model provides a micro-channel structure and a micro-fluidic chip comprising the same, the micro-channel structure comprises a plurality of liquid inlet channels arranged in parallel and a front-end main channel, one ends of the plurality of liquid inlet channels are used for liquid inlet, and the other ends of the plurality of liquid inlet channels intersect and are communicated with the front-end main channel; the micro-channel structure further comprises a mixing channel composed of a plurality of omega-shaped structure channels connected in sequence, one end of the mixing channel is communicated with the end, away from the liquid inlet channel, of the front-end main channel, the other end of the mixing channel is communicated with a liquid outlet channel, and the cross section area of the front-end main channel is not larger than that of the single liquid inlet channel. The mixing channel adopts an omega-shaped structure channel, so that when fluid passes through each curve of the omega-shaped structure channel, the speed difference between fluid layers can generate shearing force, and the interaction between different fluid layers is enhanced; the bending part of the omega-shaped channel forms a vortex, so that the layering phenomenon of the fluid is further broken, the mixing is promoted, and the mixing efficiency is favorably improved.

Description

TECHNICAL FIELD

[0001] The utility model relates to a micro flow channel structure and micro fluidic chip containing same. BACKGROUND

[0002] Micro fluidic technology is a new type of precision particle manufacturing technology, which can produce micro / nano particles with uniform structure and particle size by means of unique fluid properties in microscale environment and a series of microprocessing and microoperation that cannot be completed by conventional methods. At present, this technology has been applied to a series of micro / nano particle drug delivery systems such as liposomes, nanocrystals, nanoparticles and microspheres. One of the cores of micro fluidic technology is micro fluidic chip. By designing the channel of micro fluidic chip, nanoparticles of various sizes can be prepared at different rates.

[0003] The size of nanoparticles will affect their biodistribution in vivo, cell uptake, plasma and tissue gap clearance, and excretion in vivo. Generally, particles smaller than 100 nm can better penetrate biological membranes and enter the interior of cells, while larger particles can be recognized and removed by the immune system. Therefore, for nanodrug delivery systems, in order to achieve good results, the size of nanoparticles must be precisely controlled. Although the existing micro fluidic chip can meet the preparation of nanoparticles below 100 nm in size, in order to make the particle size uniformity of the prepared lipid nanoparticles higher and control the PDI (polydispersity index, which is a parameter used to describe the uniformity of particle size distribution) within a smaller numerical range, the flow rate of the feedstock will be controlled, so it cannot meet the demand of rapid mass production. UTILITY MODEL CONTENT

[0004] The technical problem to be solved by the utility model is to overcome the defects of narrow tolerable flow rate range and low preparation efficiency in the prior art when micro fluidic chip is used to prepare nanoparticles below 100 nm in size, and to provide a micro flow channel structure and micro fluidic chip containing same, which can efficiently prepare nanoparticles.

[0005] The utility model solves the above technical problems by the following technical scheme:

[0006] A micro flow channel structure comprises a plurality of parallelly arranged liquid inlet channels and a front-end main channel, one end of each of the liquid inlet channels is used for liquid inlet, and the other end of each of the liquid inlet channels converges and communicates with the front-end main channel;

[0007] The micro flow channel structure further comprises a mixing channel composed of a plurality of sequentially connected omega-shaped structure channels, one end of the mixing channel communicates with the end of the front-end main channel away from the liquid inlet channels, the other end of the mixing channel is connected with a liquid outlet channel, and the cross-sectional area of the front-end main channel is not greater than the cross-sectional area of each of the liquid inlet channels.

[0008] In an alternative embodiment, the number of Ω-shaped structure channels is 1-100, preferably 1-30, more preferably 1-10.

[0009] In an alternative embodiment, the plurality of liquid inlet channels form an included angle at the intersection, and the included angle between two liquid inlet channels is 0°-180°, preferably 45°-180°, more preferably 60°-180°.

[0010] In an alternative embodiment, the Ω-shaped structure channel comprises a first circular arc-shaped channel and two second circular arc-shaped channels in communication with both ends of the first circular arc-shaped channel, and the centers of the two second circular arc-shaped channels are located on both sides of the Ω-shaped structure channel, respectively.

[0011] In an alternative embodiment, two adjacent Ω-shaped structure channels are arranged in central symmetry or axial symmetry.

[0012] In an alternative embodiment, two adjacent Ω-shaped structure channels are connected by a horizontal transition section.

[0013] In an alternative embodiment, the radius of curvature of the second circular arc-shaped channel is 100-3000 μm, preferably 200-2000 μm, more preferably 300-1500 μm;

[0014] and / or, the radius of curvature of the first circular arc-shaped channel is 100-3000 μm, preferably 200-2000 μm, more preferably 400-1800 μm;

[0015] and / or, the channel width of the mixing channel is 10-1500 μm, preferably 100-1000 μm, more preferably 100-800 μm;

[0016] and / or, the channel depth of the mixing channel is 10-1500 μm, preferably 100-1000 μm, more preferably 100-800 μm;

[0017] and / or, the distance between the centers of the first circular arc-shaped channels of two adjacent Ω-shaped structure channels in the horizontal direction is 200-10000 μm, preferably 500-8000 μm, more preferably 1000-6000 μm;

[0018] and / or, the center angle α formed by the center of the first circular arc-shaped channel and the centers of the two second circular arc-shaped channels is in the range of 4°-180°, preferably 60°-120°, more preferably 60°-100°.

[0019] In an alternative embodiment, the ratio of the minimum cross-sectional area of the inlet channel to the cross-sectional area of the front main channel is (1-5) : 1, preferably (1-3) : 1, and more preferably (1-2) : 1.

[0020] In an alternative embodiment, the width of the inlet channel is 10-1000 μm, preferably 50-900 μm, and more preferably 100-800 μm;

[0021] and / or, the depth of the inlet channel is 10-1000 μm, preferably 100-900 μm, and more preferably 100-800 μm;

[0022] and / or, the length of the inlet channel is 10-40 mm, preferably 15-30 mm, and more preferably 18-28 mm;

[0023] and / or, the width of the front main channel is 10-1000 μm, preferably 50-800 μm, and more preferably 100-600 μm;

[0024] and / or, the depth of the front main channel is 10-1000 μm, preferably 50-800 μm, and more preferably 100-800 μm;

[0025] and / or, the length of the front main channel is 100-5000 μm, preferably 200-4000 μm, and more preferably 400-3000 μm.

[0026] In an alternative embodiment, the width of the outlet channel is 10-1000 μm, preferably 50-900 μm, and more preferably 100-800 μm;

[0027] and / or, the depth of the outlet channel is 10-1000 μm, preferably 100-900 μm, and more preferably 100-800 μm;

[0028] and / or, the length of the outlet channel is 0.01-10 cm, preferably 0.1-5 cm, and more preferably 0.3-3 cm.

[0029] In an alternative embodiment, the end of the outlet channel that is in communication with the mixing channel is linear, and the end of the outlet channel that is distal to the mixing channel is curved;

[0030] The ratio of the length of the linear outlet channel to the arc length of the curved outlet channel is (0.1-5) : 1, preferably (0.3-3) : 1, and more preferably (0.5-2) : 1.

[0031] And / or, the angle between the axis of the straight liquid outlet channel and the tangent of the outer edge of the curved liquid outlet channel is 0-90°, preferably 10-80°, more preferably 20-60°.

[0032] In an alternative embodiment, the shape of the liquid outlet channel is only linear or curved.

[0033] The utility model also provides a micro -fluidic chip, the micro -fluidic chip includes the base plate, be equipped with the micro -fluid path structure as the above on the base plate.

[0034] Preferably, the micro -fluidic chip includes the cover plate, the cover plate is located in the side of the base plate with the micro -fluid path structure, the cover plate is equipped with the liquid inlet and the liquid outlet.

[0035] Preferably, the material of the cover plate and the base plate can be the commonly used micro -fluidic chip material, for example, one or more of metal, glass, quartz, ceramic, silicon, hastelloy or high polymer polymer. Among them, the metal can be stainless steel;The high polymer polymer can be polymethyl methacrylate (PMMA), polycarbonate (PC), polystyrene (PS), polypropylene (PP), polyethylene (PE), polyamide (PI), polydimethylsiloxane (PDMS), polyterephthalic acid (PET), polyvinyl chloride (PVC), photoresist, polyester (TPE), polyethylene glycol diacrylate (PEGDA), perfluorinated compound, polyurethane (PU), cyclic olefin copolymer (COC), cyclic olefin polymer (COP), wherein the photoresist can be SU-8 photoresist, and the perfluorinated compound can be one or more of polyperfluoroethylene (PFEP), perfluoroalkoxy (PFA) and perfluoropolyether (PFPE).

[0036] Preferably, the number of micro -fluid path structures on each micro -fluidic chip can be one or more.

[0037] In some preferred embodiments, the number of micro -fluid path structures on each micro -fluidic chip is 2 or more, and the micro -fluid path structure adopts a staggered design, which not only realizes the effective use of space, but also reduces the cost of micro -fluidic chip and improves the utilization rate.

[0038] In actual application, a plurality of micro -fluidic chips can be integrated in series and / or parallel according to the use and batch requirements.

[0039] The positive progress effect of the utility model is that:

[0040] (1) The utility model discloses, mixed passageway adopts the Ω type structure passageway, and the mixing of fluid mainly depends on the interaction of shearing action and flow stratification, when the fluid passes through the Ω type structure passageway every bend, the velocity difference between fluid layer can produce shearing force, and the interaction between different fluid layers is enhanced, simultaneously, the curved portion of the Ω type structure passageway forms vortex, further breaks the stratification phenomenon of fluid, promotes mixing, in addition, the complex flow path and longer residence time of the Ω type passageway also help to improve the mixing efficiency.

[0041] Multiple Ω type structure passageways are arranged in the mixed passageway, allow fluid to carry out continuous circulation in the mixed passageway, reduce the dead zone and stagnation area of flow, and when the fluid flows in the Ω type structure passageway, the fluid direction will change constantly, help to improve the mixing efficiency.

[0042] (2) The utility model discloses, the cross section area of front end main passageway is set to be not greater than the cross section area of single liquid inlet passageway, make fluid speed increase when entering the front end main passageway from liquid inlet passageway, thereby make the speed of fluid entering the mixed passageway increase, greatly improve the mixing efficiency of fluid. BRIEF DESCRIPTION OF DRAWINGS

[0043] Figure 1 It is the schematic diagram of micro flow path structure of the utility model.

[0044] Figure 2 It is the structure schematic diagram of Ω type structure passageway in the utility model. Figure 1

[0045] Figure 3 It is the position schematic diagram of adjacent two Ω type structure passageways in the utility model. Figure 1

[0046] It is the distribution schematic diagram of micro flow path structure on a micro fluidic chip in the utility model. Figure 4

[0047] It is the size and PDI data diagram of lipid nano particle measured by dynamic light scattering method in embodiment 2. Figure 5

[0048] BRIEF DESCRIPTION OF DRAWINGS

[0049] Liquid inlet passageway 100, front end main passageway 200, mixed passageway 300, Ω type structure passageway 310, first circular arc passageway 311, second circular arc passageway 312, liquid outlet passageway 400, liquid inlet 500, liquid outlet 600, base plate 700. DETAILED DESCRIPTION

[0050] The utility model is described in detail below with a preferred embodiment, and the utility model is more clearly and completely illustrated by combining with the drawings.

[0051] Reference​​Figures 1-4 The utility model discloses a microfluidic chip, which comprises a plurality of liquid inlet channels 100 and a front-end main channel 200, one end of the liquid inlet channels 100 is used for liquid inlet, and the other end of the liquid inlet channels 100 is connected with the front-end main channel 200. The microfluidic structure further comprises a mixing channel 300 composed of a plurality of Ω-shaped structure channels 310 connected in sequence, one end of the mixing channel 300 is connected with the front-end main channel 200 away from the liquid inlet channel 100, the other end of the mixing channel 300 is connected with a liquid outlet channel 400, and the cross-sectional area of the front-end main channel 200 is not greater than the cross-sectional area of a single liquid inlet channel 100. The adjacent two Ω-shaped structure channels 310 are arranged in a central symmetry. The front end of each liquid inlet channel 100 is provided with a liquid inlet port 500, and the end of the liquid outlet channel 400 is provided with a liquid outlet port 600. The adjacent two Ω-shaped structure channels are connected through a horizontal transition section.

[0052] The number of the Ω-shaped structure channels 310 is 1-100, preferably 1-30, and more preferably 1-10.

[0053] The plurality of liquid inlet channels form an included angle at the intersection point, and the included angle between the two liquid inlet channels is 0°-180°, preferably 45°-180°, and more preferably 60°-180°.

[0054] The Ω-shaped structure channel 310 comprises a first circular-arc channel 311 and two second circular-arc channels 312 connected with both ends of the first circular-arc channel 311, and the centers of the two second circular-arc channels 312 are located on both sides of the Ω-shaped structure channel 310.

[0055] The curvature radius of the second circular-arc channel 312 is 100-3000 μm, preferably 200-2000 μm, and more preferably 300-1500 μm.

[0056] The curvature radius of the first circular-arc channel 311 is 100-3000 μm, preferably 200-2000 μm, and more preferably 300-1500 μm.

[0057] The channel width of the mixing channel 300 is 10-1500 μm, preferably 100-1000 μm, and more preferably 100-800 μm.

[0058] The channel depth of the mixing channel 300 is 10-1500 μm, preferably 100-1000 μm, and more preferably 100-800 μm.

[0059] And / or, the distance L between the centers of the first circular arc-shaped channels 311 of two adjacent Ω-shaped structure channels 310 in the horizontal direction is 200-10000 μm, preferably 500-8000 μm, and more preferably 1000-6000 μm.

[0060] And / or, the center angle α formed by the centers of the first circular arc-shaped channel and the centers of the two second circular arc-shaped channels ranges from 4° to 180°, preferably from 60° to 120°, and more preferably from 60° to 100°.

[0061] The ratio of the minimum cross-sectional area of the liquid inlet channel to the cross-sectional area of the front-end main channel 200 is (1-5) : 1, preferably (1-3) : 1, and more preferably (1-2) : 1.

[0062] The width of the liquid inlet channel is 10-1000 μm, preferably 50-900 μm, and more preferably 100-800 μm.

[0063] And / or, the depth of the liquid inlet channel is 10-1000 μm, preferably 100-900 μm, and more preferably 100-800 μm.

[0064] And / or, the length of the liquid inlet channel is 10-40 mm, preferably 15-30 mm, and more preferably 18-28 mm.

[0065] And / or, the width of the front-end main channel 200 is 10-1000 μm, preferably 50-800 μm, and more preferably 100-600 μm.

[0066] And / or, the depth of the front-end main channel 200 is 10-1000 μm, preferably 50-800 μm, and more preferably 100-800 μm.

[0067] And / or, the length of the front-end main channel 200 is 100-5000 μm, preferably 200-4000 μm, and more preferably 400-3000 μm.

[0068] The width of the liquid outlet channel 400 is 10-1000 μm, preferably 50-900 μm, and more preferably 100-800 μm.

[0069] And / or, the depth of the liquid outlet channel 400 is 10-1000 μm, preferably 100-900 μm, and more preferably 100-800 μm.

[0070] And / or, the length of the liquid outlet channel 400 is 0.01-10 cm, preferably 0.1-5 cm, and more preferably 0.3-3 cm.

[0071] The straight-line-shaped end of the liquid outlet channel 400 is connected with the mixing channel 300, and the curved-shaped end of the liquid outlet channel 400 is away from the mixing channel 300; the ratio of the length of the straight-line-shaped liquid outlet channel 400 to the arc length of the curved-shaped liquid outlet channel 400 is (0.1-5) : 1, preferably (0.3-3) : 1, and more preferably (0.5-2) : 1.

[0072] The angle between the axis of the straight-line-shaped liquid outlet channel 400 and the tangent of the outer edge of the curved-shaped liquid outlet channel 400 is 0-90°, preferably 10-80°, and more preferably 20-60°.

[0073] In an alternative embodiment, the shape of the liquid outlet channel 400 is only straight-line-shaped or curved-shaped.

[0074] The utility model discloses still a kind of microfluidic chip, microfluidic chip includes substrate 700, substrate 700 is equipped with above-mentioned microfluid channel structure.

[0075] The microfluidic chip further includes a cover plate, which is disposed on the side of the substrate 700 having the microfluid channel structure. The cover plate has a liquid inlet 500 and a liquid outlet 600.

[0076] The cover plate and the substrate 700 can be made of common microfluidic chip materials, such as one or more of metal, glass, quartz, ceramic, silicon, hastelloy, or high polymer. The metal can be stainless steel. The high polymer can be polymethyl methacrylate (PMMA), polycarbonate (PC), polystyrene (PS), polypropylene (PP), polyethylene (PE), polyamide (PI), polydimethylsiloxane (PDMS), polyethylene terephthalate (PET), polyvinyl chloride (PVC), photoresist, polyester (TPE), polyethylene glycol diacrylate (PEGDA), perfluorinated compound, polyurethane (PU), cyclic olefin copolymer (COC), or cyclic olefin polymer (COP). The photoresist can be SU-8 photoresist. The perfluorinated compound can be one or more of polyperfluoroethyl propylene (PFEP), perfluoroalkoxy (PFA), and perfluoropolyether (PFPE).

[0077] The number of microfluid channel structures on each microfluidic chip can be one or more.

[0078] In some embodiments, the number of microfluid channel structures on each microfluidic chip is two or more, as shown in FIG. 2B. The microfluid channel structures can be designed in a staggered manner, which not only achieves efficient use of space, but also reduces the cost of the microfluidic chip and improves the utilization rate. Figure 4

[0079] In actual application, multiple microfluidic chips can be integrated in series and / or in parallel according to the use and batch requirements. ​

[0080] Example 1

[0081] In the embodiment, the microfluidic chip has two liquid inlet channels 100, the included angle of the two liquid inlet channels at the intersection is 60°, the central angle α of the center of the first circular arc channel and the center of the two second circular arc channels is 90°, the mixing channel 300 is composed of six Ω-shaped structure channels 310, adjacent two of the six Ω-shaped structure channels 310 are centrally symmetric, one end of the liquid outlet channel 400 connected with the mixing channel 300 is linear, and the other end of the liquid outlet channel 400 away from the mixing channel 300 is curved. The curvature radius of the second circular arc channel is 500 μm; the curvature radius of the first circular arc channel is 600 μm; the width of the mixing channel is 200 μm; the depth of the mixing channel is 300 μm; the horizontal distance between the centers of the first circular arc channels of the adjacent two Ω-shaped structure channels is 2000 μm; the width of the liquid inlet channel is 300 μm; the depth of the liquid inlet channel is 300 μm; the length of the liquid inlet channel is 20 mm; the width of the front end main channel is 200 μm; the depth of the front end main channel is 300 μm; and the length of the front end main channel is 1000 μm.

[0082] In order to test the effect of the microfluidic chip, the following preparation method is used to prepare the lipid nanoparticles:

[0083] (1) DLin-MC3-DMA (1,2-dilinoleyloxy-3-dimethylaminopropane), DSPC (distearoylphosphatidylcholine), cholesterol, and DMG-PEG2000 (1,2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol 2000) are prepared into an ethanol solution with a total concentration of 10 mM as an organic phase according to a molar ratio of 46.3:9.4:42.7:1.6, and 50 mM citric acid buffer with a pH value of 4.0 is used as an aqueous phase;

[0084] (2) The organic phase and the aqueous phase are injected into the microfluidic chip through the injection pump at a flow rate ratio of 1:1, 1:2, 1:3, 1:4, 1:5, and 1:6, and a total flow rate of 12 mL / min, to prepare a lipid nanoparticle solution;

[0085] (3) The lipid nanoparticle solution is dialyzed in PBS buffer overnight to obtain the lipid nanoparticles.

[0086] (4) The size and PDI of the lipid nanoparticles are measured by dynamic light scattering method, and the measured results are shown in Table 1.

[0087] Table 1

[0088]

[0089]

[0090] From the results of the above table, it can be seen that when the flow rate ratio is 1:1, the average particle size of the lipid nanoparticles prepared is larger, which is 711nm±15nm; when the flow rate ratio is 1:2 to 1:6, the average particle size of the lipid nanoparticles prepared is less than 100nm, and the PDI is within 0.15, and the particle size distribution is small; it is shown that the microfluidic chip of the utility model can prepare the lipid nanoparticles with small particle size and uniform size under the flow rate ratio of the organic phase and the aqueous phase ratio of 1:2 to 1:6.

[0091] Example 2

[0092] In the embodiment, the microfluidic chip has two liquid inlet channels 100, the included angle of the two liquid inlet channels at the intersection point is 60°, the central angle α of the center of the first circular arc channel and the center of the two second circular arc channels is 90°, the mixing channel 300 is composed of six Ω-shaped structure channels 310, adjacent two of the six Ω-shaped structure channels 310 are centrally symmetric, one end of the liquid outlet channel 400 connected with the mixing channel 300 is linear, and the other end of the liquid outlet channel 400 away from the mixing channel 300 is curved. The curvature radius of the second circular arc channel is 2000μm; the curvature radius of the first circular arc channel is 2400μm; the width of the mixing channel is 800μm; the depth of the mixing channel is 600μm; the distance between the centers of the first circular arc channels of the adjacent two Ω-shaped structure channels in the horizontal direction is 6500μm; the width of the liquid inlet channel is 800μm; the depth of the liquid inlet channel is 600μm; the length of the liquid inlet channel is 6mm; the width of the front end main channel is 600μm; the depth of the front end main channel is 600μm; and the length of the front end main channel is 1000μm.

[0093] In order to test the tolerable flow rate range of the microfluidic chip of the utility model, the following preparation method is used to prepare the lipid nanoparticles:

[0094] (1) DLin-MC3-DMA, DSPC, cholesterol and DMG-PEG2000 are prepared into an ethanol solution with a total concentration of 10mM as the organic phase according to a molar ratio of 46.3:9.4:42.7:1.6, and 50mM citric acid buffer with a pH value of 4.0 is used as the aqueous phase;

[0095] (2) the organic phase and the aqueous phase are injected into the microfluidic chip through the injection pump at a flow rate ratio of 1:3 and a total flow rate of 2mL / min to 100mL / min, and the lipid nanoparticle solution is prepared;

[0096] (3) Dynamic light scattering method is used to measure the size and PDI of the lipid nanoparticles, and the measured results are shown in Table 1. Figure 5 .

[0097] From the results, it can be seen that when the total flow rate is 4 mL / min to 100 mL / min, the average particle size of the lipid nanoparticles prepared by the microfluidic chip is less than 100 nm, and the PDI is within 0.15, which indicates that the flow rate range applicable to the chip is at least 4 mL / min to 100 mL / min. Figure 5 Examples 3-5

[0098] In Example 3-5, the microfluidic chip has two liquid inlet channels 100, the included angle formed by the two liquid inlet channels at the intersection point is 60°, the central angle α formed by the connection of the center of the first circular arc channel and the center of the two second circular arc channels is 90°, the mixing channel 300 is composed of six Ω-shaped structure channels 310, adjacent two of the six Ω-shaped structure channels 310 are centrally symmetric, one end of the liquid outlet channel 400 connected with the mixing channel 300 is linear, and the other end of the liquid outlet channel 400 away from the mixing channel 300 is curved. The curvature radius of the second circular arc channel is 500 μm; the curvature radius of the first circular arc channel is 600 μm; the width of the mixing channel is 200 μm; the depth of the mixing channel is 300 μm; the distance between the centers of the first circular arc channels of the adjacent two Ω-shaped structure channels in the horizontal direction is 2000 μm; the depth of the liquid inlet channel is 300 μm; the length of the liquid inlet channel is 20 mm; the width of the front end main channel is 200 μm; the depth of the front end main channel is 300 μm; and the length of the front end main channel is 1000 μm. In Example 3, the width of the liquid inlet channel is 200 μm, in Example 4, the width of the liquid inlet channel is 300 μm, and in Example 5, the width of the liquid inlet channel is 600 μm.

[0099] In order to investigate the influence of the width of the liquid inlet channel of the microfluidic chip of the utility model on mixing, the following preparation method is used to prepare the lipid nanoparticles:

[0100] (1) DLin-MC3-DMA, DSPC, cholesterol and DMG-PEG2000 are prepared into an ethanol solution with a total concentration of 10 mM as an organic phase according to a molar ratio of 46.3:9.4:42.7:1.6, and 50 mM citric acid buffer with a pH value of 4.0 is prepared as an aqueous phase.

[0101] (2) The above organic phase and aqueous phase are injected into the microfluidic chip through the injection pump at a flow rate ratio of 1:3 and a total flow rate of 12 mL / min, and a lipid nanoparticle solution is obtained;

[0102]

[0103] ​The width of the inlet channel in the microfluidic chip used in Example 3 is 200 μm.

[0104] The width of the inlet channel in the microfluidic chip used in Example 4 is 300 μm.

[0105] The width of the inlet channel in the microfluidic chip used in Example 5 is 600 μm.

[0106] (3) The lipid nanoparticles were obtained after the above lipid nanoparticle solution was dialyzed overnight in PBS buffer.

[0107] (4) The size and PDI of the lipid nanoparticles were determined by dynamic light scattering method, and the results are shown in Table 3.

[0108] Table 2

[0109] Example Width of inlet channel Particle size PDI Example 3 200 μm 65 nm ± 3 nm 0.15±0.01 Example 4 300 μm 59 nm ± 1 nm 0.08±0.04 Example 5 600 μm 58 nm ± 1 nm 0.07±0.02

[0110] As can be seen from the above table, the average particle size of the lipid nanoparticles prepared in Example 3 is about 65 nm, and the PDI is about 0.15, while the average particle size of the lipid nanoparticles prepared in Examples 4-5 is less than 60 nm, and the PDI is less than 0.15, indicating that the particle size of the lipid nanoparticles prepared in Examples 4-5 is smaller and more uniform.

[0111] Examples 6-8

[0112] In this example, the microfluidic chip has two inlet channels 100 in the microchannel structure, the included angle formed by the two inlet channels at the intersection point is 60°, the central angle α formed by the connection of the center of the first circular arc channel and the center of the two second circular arc channels is 90°, the mixing channel 300 is composed of six Ω-shaped structure channels 310, adjacent two of the six Ω-shaped structure channels 310 are centrally symmetric, one end of the outlet channel 400 connected with the mixing channel 300 is linear, and the other end of the outlet channel 400 away from the mixing channel 300 is curved.

[0113] In Example 6, the radius of curvature of the second circular arc channel is 450 μm; the radius of curvature of the first circular arc channel is 550 μm; the width of the mixing channel is 100 μm; the depth of the mixing channel is 300 μm; the horizontal distance between the centers of the first circular arc channels of the adjacent two Ω-shaped structure channels is 2000 μm; the width of the inlet channel is 300 μm; the depth of the inlet channel is 300 μm; the length of the inlet channel is 20 mm; the width of the front end main channel is 200 μm; the depth of the front end main channel is 300 μm; and the length of the front end main channel is 1000 μm.

[0114] In the embodiment 7: the curvature radius of the second circular arc channel is 500 μm; the curvature radius of the first circular arc channel is 600 μm; the width of the mixing channel is 200 μm; the depth of the mixing channel is 300 μm; the distance between the centers of the first circular arc channels of the two adjacent Ω-shaped structure channels in the horizontal direction is 2000 μm; the width of the liquid inlet channel is 300 μm; the depth of the liquid inlet channel is 300 μm; the length of the liquid inlet channel is 20 mm; the width of the front end main channel is 200 μm; the depth of the front end main channel is 300 μm; and the length of the front end main channel is 1000 μm.

[0115] In the embodiment 8: the curvature radius of the second circular arc channel is 2000 μm; the curvature radius of the first circular arc channel is 2400 μm; the width of the mixing channel is 800 μm; the depth of the mixing channel is 600 μm; the distance between the centers of the first circular arc channels of the two adjacent Ω-shaped structure channels in the horizontal direction is 6500 μm; the width of the liquid inlet channel is 800 μm; the depth of the liquid inlet channel is 600 μm; the length of the liquid inlet channel is 6 mm; the width of the front end main channel is 600 μm; the depth of the front end main channel is 600 μm; and the length of the front end main channel is 1000 μm.

[0116] In order to investigate the influence of the width of the mixing channel 300 in the micro flow channel structure of the utility model on mixing, the following preparation method is adopted to prepare the lipid nanoparticles:

[0117] (1) DLin-MC3-DMA, DSPC, cholesterol and DMG-PEG2000 are prepared into an ethanol solution with a total concentration of 10 mM as an organic phase according to a molar ratio of 46.3:9.4:42.7:1.6, and 50 mM citric acid buffer with a pH value of 4.0 is prepared as an aqueous phase.

[0118] (2) The above organic phase and aqueous phase are respectively injected into the microfluidic chip through the injection pump at a flow rate ratio of 1:3 and a total flow rate of 12 mL / min, and a lipid nanoparticle solution is obtained;

[0119] The width of the Ω-shaped microchannel in the microfluidic chip adopted in the embodiment 6 is 100 μm.

[0120] The width of the Ω-shaped microchannel in the microfluidic chip adopted in the embodiment 7 is 200 μm.

[0121] The width of the Ω-shaped microchannel in the microfluidic chip adopted in the embodiment 8 is 800 μm.

[0122] (3) After the above lipid nanoparticle solution is dialyzed in PBS buffer overnight, a lipid nanoparticle is obtained.

[0123] (4) The size and PDI of the lipid nanoparticles were measured by dynamic light scattering method, and the measured results are listed in Table 3.

[0124] Table 3

[0125]

[0126] From the above table results, it can be seen that the average particle sizes of the lipid nanoparticles prepared in Examples 6-8 are all below 100 nm, and the PDI is less than 0.15, indicating that the particles of Examples 6-8 are good in uniformity. According to the above results, when the width of the mixing channel 300 is increased from 100 μm to 800 μm, the particle sizes of the prepared lipid nanoparticles are basically consistent.

[0127] Example 9

[0128] In order to investigate whether the microfluidic chip of the present application has the ability to stably produce siRNA-loaded lipid nanoparticles, siRNA-loaded lipid nanoparticles were prepared by the following preparation method, and repeated multiple times:

[0129] (1) DLin-MC3-DMA, DSPC, cholesterol, DMG-PEG2000 were prepared into an ethanol solution with a total concentration of 10 mM as an organic phase according to a molar ratio of 46.3:9.4:42.7:1.6, and a certain amount of siRNA was added to a 50 mM citric acid buffer with a pH value of 4.0 as an aqueous phase (N:P ratio is 6);

[0130] (2) The above organic phase and aqueous phase were injected into the microfluidic chip through the injection pump at a flow rate ratio of 1:3, and the total flow rate was 12 mL / min, to obtain a lipid nanoparticle solution;

[0131] (3) After the above lipid nanoparticle solution was dialyzed in PBS buffer overnight, the lipid nanoparticles were obtained.

[0132] (4) The size and PDI of the lipid nanoparticles were measured by dynamic light scattering method, and the encapsulation rate of the lipid nanoparticles was measured by using QuantiTRiboGreen RNA quantitative kit, and the measured results are listed in Table 4.

[0133] Table 4

[0134] Particle size PDI Encapsulation efficiency siRNA-loaded lipid nanoparticle 1 60 nm ± 1 nm 0.09±0.01 93.5％±1.4％ siRNA-loaded lipid nanoparticle 2 62 nm ± 2 nm 0.11±0.03 90.9％±0.6％ siRNA-loaded lipid nanoparticle 3 57 nm ± 1 nm 0.07±0.01 92.0％±1.1％

[0135] From the results of the above table, it can be seen that the average particle size of the siRNA-loaded lipid nanoparticles prepared by the microfluidic chip based on the microfluidic structure is about 60 nm, the PDI is less than 0.15, and the encapsulation rate of siRNA is more than 85%, which indicates that the microfluidic chip based on the microfluidic structure has the ability to repeatedly produce lipid nanoparticles with small and uniform particle size and high encapsulation rate.

[0136] Although the specific embodiments of the present application are described above, those skilled in the art should understand that this is only an example, the protection scope of the present application is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present application, but these changes and modifications all fall within the protection scope of the present application.

Claims

1. A microfluidic structure, characterized by, The micro-channel structure comprises a plurality of liquid inlet channels and a front-end main channel arranged in parallel, one end of the plurality of liquid inlet channels is used for liquid inlet, and the other end of the plurality of liquid inlet channels converges and communicates with the front-end main channel; The micro-channel structure further comprises a mixing channel composed of a plurality of Ω-shaped structure channels connected in sequence, one end of the mixing channel communicates with the other end of the front-end main channel away from the liquid inlet channel, and the other end of the mixing channel communicates with a liquid outlet channel, and the cross-sectional area of the front-end main channel is not greater than the cross-sectional area of a single liquid inlet channel.

2. The microchannel structure of claim 1, wherein, The Ω-shaped structure channel comprises a first circular arc channel and two second circular arc channels communicating with both ends of the first circular arc channel, and the centers of the two second circular arc channels are located on both sides of the Ω-shaped structure channel, respectively; And / or, adjacent two Ω-shaped structure channels are arranged in central symmetry or axial symmetry; And / or, adjacent two Ω-shaped structure channels are connected through a horizontal transition section.

3. The microchannel structure of claim 2, wherein, The curvature radius of the second circular arc channel is 100-3000 μm; And / or, the curvature radius of the first circular arc channel is 100-3000 μm; And / or, the channel width of the mixing channel is 10-1500 μm; And / or, the channel depth of the mixing channel is 10-1500 μm; And / or, the distance between the centers of the first circular arc channels of adjacent two Ω-shaped structure channels in the horizontal direction is 200-10000 μm; And / or, the central angle α formed by the center of the first circular arc channel and the centers of the two second circular arc channels ranges from 4° to 180°.

4. The microchannel structure of claim 3, wherein The curvature radius of the second circular arc channel is 300-1500 μm; And / or, the curvature radius of the first circular arc channel is 400-1800 μm; And / or, the channel width of the mixing channel is 100-800 μm; And / or, the channel depth of the mixing channel is 100-800 μm; And / or, the distance between the centers of the first circular arc channels of adjacent two Ω-shaped structure channels in the horizontal direction is 1000-6000 μm; And / or, the central angle α formed by the center of the first circular arc channel and the centers of the two second circular arc channels ranges from 60° to 100°.

5. The microchannel structure of any one of claims 1-4, wherein, The ratio of the minimum value of the cross-sectional area of the liquid inlet channel to the cross-sectional area of the front-end main channel is (1-5):

1.

6. The microchannel structure of claim 5, wherein The width of the liquid inlet channel is 10-1000 μm; And / or, the depth of the liquid inlet channel is 10-1000 μm; And / or, the length of the liquid inlet channel is 10-40 mm; And / or, the width of the front-end main channel is 10-1000 μm; And / or, the depth of the front-end main channel is 10-1000 μm; And / or, the length of the front-end main channel is 100-5000 μm.

7. The microchannel structure of claim 6, wherein The width of the liquid inlet channel is 100-800 μm; And / or, the depth of the liquid inlet channel is 100-800 μm; And / or, the length of the liquid inlet channel is 18-28 mm; And / or, the width of the front-end main channel is 100-600 μm; And / or, the depth of the front-end main channel is 100-800 μm; And / or, the length of the front-end main channel is 400-3000 μm.

8. The microchannel structure of claim 1, wherein The width of the liquid outlet channel is 10-1000 μm; And / or, the depth of the liquid outlet channel is 10-1000 μm; And / or, the length of the liquid outlet channel is 0.01-10 cm.

9. The microchannel structure of claim 1, wherein The end of the liquid outlet channel connected with the mixing channel is linear, and the end of the liquid outlet channel away from the mixing channel is curved; The ratio of the length of the linear liquid outlet channel to the arc length of the curved liquid outlet channel is (0.1-5) : 1; And / or, the angle between the axis of the linear liquid outlet channel and the tangent of the outer edge of the curved liquid outlet channel is 0-90°.

10. A microfluidic chip, characterized by, The microfluidic chip comprises a substrate, and the substrate is provided with the microfluid channel structure according to any one of claims 1-9.

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