Micro-fluidic chip and micro-fluidic equipment comprising same

Abstract

The micro-fluidic chip comprises a micro-fluidic substrate, the surface of the micro-fluidic substrate is provided with a micro-channel structure, the micro-channel structure sequentially comprises a liquid inlet channel, a mixing channel and a liquid outlet channel which are communicated with one another, the mixing channel is sequentially provided with a first-stage mixing channel and a second-stage mixing channel, and the first-stage mixing channel and the second-stage mixing channel are communicated with the liquid outlet channel. The second-stage mixing flow channel comprises a flow dividing channel and a flow converging channel; the flow dividing channel comprises two flow dividing parts which are arranged at an angle, the input ends of the two flow dividing parts communicate with each other, and an inlet of the second-stage mixing flow channel is formed in the communicating position of the flow dividing parts; the confluence channel is in an arc shape, the two input ends of the confluence channel communicate with the output ends of the two flow dividing parts correspondingly, and an outlet of the second-stage mixing flow channel is formed in the most downstream position of the confluence channel. The secondary mixing runners are sequentially arranged on the mixing runner, the scheme that media are mixed in a front face hedging mode after being shunted is provided, the mixing degree is effectively improved according to the medium collision mixing principle, and meanwhile the preparation efficiency is improved.

Description

[0001] This application claims the priority of Chinese patent application No. 202311517177.4, filed on November 14, 2023. This application cites the entire text of the above Chinese patent application. Technical Field

[0002] The present invention relates to the technical field of nano-pharmaceuticals, and in particular to a microfluidic chip and a microfluidic device containing the same and a microfluidic device containing the same. Background Art

[0003] By using microfluidic mixing, lipid solution and mRNA solution are fully and rapidly mixed in a micromixer to form lipid nanoparticles (LNP) with uniform particle size. LNP can improve the solubility of encapsulated drugs, prevent chemical and biological degradation of drugs, reduce drug toxicity and side effects, and enhance drug penetration. Due to its good biocompatibility and low immunogenicity, liposomes are recognized as ideal carriers for small molecule anti-tumor drugs and gene drugs.

[0004] Microfluidic mixing technology is a reliable method for preparing liposomes and is widely used in the field of preparing lipid nanoparticles. At present, the conventional microfluidic chip mixing channel design basically allows the fluid to mix and collide at the interactive interface. For example, the most common "T"-shaped channel chip design achieves fluid mixing by pumping two independent fluids in from both ends of the horizontal direction at the same time, and colliding at the fluid interactive interface, so as to achieve the purpose of mixing the two fluids and pumping them out through a liquid passage perpendicular to the inlet channel. This type of microfluidic chip relies on the internal stress of the fluid to achieve mixing, so the channel size is relatively small and the fluid flow rate is low, resulting in low preparation efficiency, which is not conducive to meeting the needs of efficient preparation. How to improve the preparation efficiency while ensuring the quality of the output lipid nanoparticles has become the focus of design and research and development of technical personnel. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the defect of low efficiency in preparing lipid nanoparticles by microfluidic chips in the prior art, and to provide a microfluidic chip and a microfluidic device containing the same.

[0006] The present invention solves the above technical problems through the following technical solutions:

[0007] A microfluidic chip, comprising a microfluidic substrate, a microfluidic channel structure is arranged on the surface of the microfluidic substrate, and along the flow direction of the medium, the microfluidic channel structure sequentially comprises a liquid inlet channel, a mixing channel and a liquid outlet channel which are connected, and a primary mixing channel and a secondary mixing channel are sequentially arranged on the mixing channel, and the secondary mixing channel comprises a diversion channel and a confluence channel;

[0008] Wherein, the flow diversion channel comprises two flow diversion parts arranged at an angle, the input ends of the two flow diversion parts are connected, and the inlet of the secondary mixing channel is formed at the connecting part of the flow diversion parts;

[0009] The converging channel is arc-shaped, and the two input ends of the converging channel are respectively connected to the output ends of the two flow diversion parts, and the outlet of the secondary mixing channel is formed at the most downstream of the converging channel along the medium flow direction.

[0010] The microfluidic chip is provided with a primary mixing channel and a secondary mixing channel in the mixing channel of its microchannel structure. The primary mixing channel and the secondary mixing channel are continuously provided, and the medium flowing through the primary mixing channel is divided into two paths by using the diversion channel of the secondary mixing channel, and then the two paths of medium are gathered into one path by using the arc-shaped confluence channel of the secondary mixing channel. This arc-shaped confluence structure makes the two paths of medium collide head-on during the confluence process to improve the mixing efficiency. This scheme of mixing by making the medium collide head-on after diversion uses the principle of medium collision mixing to effectively improve the degree of mixing.

[0011] Compared with the prior art method of squeezing the medium into a relatively narrow channel and using the pressure generated by squeezing into the narrow channel for mixing, the relatively increased channel size of this solution may also meet the mixing requirements, and can improve the preparation efficiency while ensuring the quality of the output lipid nanoparticles.

[0012] At the same time, since the confluence channel of the secondary mixing channel is arc-shaped, the flow velocity of the medium flowing in the confluence channel is relatively uniform and not easy to be blocked, and the difficulty of cleaning is reduced.

[0013] Preferably, the mixing flow channel includes a plurality of the secondary mixing flow channels. Along the medium flow direction, the inlet of the first secondary mixing flow channel is connected to the outlet of the primary mixing flow channel, the inlets of the remaining secondary mixing flow channels are connected to the outlet of the previous secondary mixing flow channel, and the outlet of the last secondary mixing flow channel is connected to the liquid outlet flow channel.

[0014] The mixing effect can be further improved by sequentially arranging a plurality of secondary mixing channels on the mixing channel.

[0015] Preferably, the number of the secondary mixing flow channels is greater than or equal to 3.

[0016] Flowing through multiple secondary mixing channels in sequence can further improve the degree of medium mixing, and the mixing effect can be ensured by controlling the lower limit of the set mixing structure.

[0017] Preferably, the number of the secondary mixing flow channels is less than or equal to ten.

[0018] For continuously setting more than 10 mixing structures, further increasing the number of secondary mixing channels will only have a limited effect on the mixing effect. By controlling the upper limit of the secondary mixing channels, it is possible to avoid setting too many secondary mixing channels to increase unnecessary processing difficulty.

[0019] Preferably, the liquid inlet channel further comprises a first liquid inlet channel and a second liquid inlet channel, the first liquid inlet channel has a first liquid inlet port for supplying a first liquid into the microfluidic channel structure, and the second liquid inlet channel has a second liquid inlet port for supplying a second liquid into the microfluidic channel structure;

[0020] The output ends of the first liquid inlet flow channel and the second liquid inlet flow channel are connected to the mixing flow channel;

[0021] The angle between the two first liquid inlet channels and the second liquid inlet channels ranges from 120° to 170°.

[0022] By setting the included angle between the first liquid inlet channel and the second liquid inlet channel to be greater than or equal to 120°, the relative impact force of the first liquid and the second liquid entering the first liquid inlet channel and the second liquid inlet channel respectively at the connecting point is increased, thereby further improving the mixing effect.

[0023] At the same time, the angle between the first liquid inlet channel and the second liquid inlet channel is set to be less than or equal to 170° to avoid the first liquid inlet channel and the second liquid inlet channel being too opposite in orientation, causing the flow medium on the side with relatively larger flow to flow back into the liquid inlet channel on the side with relatively smaller flow.

[0024] Preferably, the primary mixing channel is arranged obliquely toward a side of the liquid inlet channel where the liquid inlet velocity is large;

[0025] Alternatively, the primary mixing channel is arranged along an angle bisector of the first liquid inlet channel and the second liquid inlet channel.

[0026] By making the primary mixing channel tilt toward the side of the liquid inlet channel with a relatively large liquid flow rate, the flow direction change angle of the medium when it flows into the primary mixing channel through the liquid inlet channel is increased, thereby increasing the vortex of the medium with a larger flow rate at this location and improving the degree of mixing.

[0027] Preferably, at the connection between the outlet of the secondary mixing channel and the liquid outlet channel, the liquid outlet channel is arc-shaped.

[0028] By setting the outlet flow channel in an arc shape at the connection between the outlet of the secondary mixing flow channel and the outlet flow channel, the resistance of the medium in the process of flowing from the secondary mixing flow channel into the outlet flow channel is increased, avoiding the medium from flowing too fast at this point and improving the mixing effect.

[0029] Preferably, between the outlet of the secondary mixing channel and the liquid outlet of the liquid outlet channel, the liquid outlet channel is in an arc shape with a constant curvature.

[0030] Through this structural arrangement, the liquid outlet flow channel is made to be an arc with a constant curvature as a whole, so as to reduce the process difficulty when machining the liquid outlet flow channel.

[0031] Preferably, the angle between the two diversion portions ranges from 30° to 120°.

[0032] By setting the angle range, the diversion effect is improved.

[0033] Preferably, the channel width of the microchannel structure is in the range of 0.2 to 0.4 mm;

[0034] Preferably, the channel depth of the microchannel structure is in the range of 0.2-0.4 mm.

[0035] By controlling the lower limit of the channel width and depth of the microchannel structure, the lower limit size is controlled to be greater than or equal to 0.2 mm to ensure the channel size and improve the preparation efficiency.

[0036] By controlling the upper limit of the channel width and depth of the microchannel structure, the upper limit size is controlled to be less than or equal to 0.4 mm to avoid the channel size being too large and affecting the preparation quality of lipid nanoparticles.

[0037] A microfluidic device comprises the microfluidic chip mentioned above.

[0038] This microfluidic device, by adopting this microfluidic chip, allows the two media entering the microfluidic chip to collide head-on during the convergence process to improve the mixing efficiency. Compared with the prior art solution of squeezing the medium into a relatively narrow flow channel and using the pressure generated by squeezing into the narrow flow channel for mixing, the relatively increased flow channel size of this solution may also meet the mixing requirements, and can improve the preparation efficiency while ensuring the quality of the lipid nanoparticles produced. At the same time, since the confluence channel of the secondary mixing flow channel is arc-shaped, the flow velocity of the medium flowing in the confluence channel is relatively uniform and not easy to be blocked, and the cleaning difficulty is reduced.

[0039] The positive and progressive effects of the present invention are:

[0040] (1) A primary mixing channel and a secondary mixing channel are sequentially arranged on the mixing channel of the microfluidic substrate, and the channel structure of the secondary mixing channel is used to allow the medium to be mixed in the secondary mixing channel by first splitting the flow and then confronting each other. This principle of medium collision and mixing is used to effectively improve the degree of medium mixing.

[0041] (2) Compared with the prior art method of mixing by squeezing the medium into a relatively narrow channel and utilizing the pressure generated by squeezing into the narrow channel, the present invention achieves mixing by hedging. Compared with the prior art, increasing the channel size can also meet the mixing requirements. Therefore, it can improve the preparation efficiency while ensuring the quality of the lipid nanoparticles produced.

[0042] (3) Since the confluence channel of the secondary mixing channel is arc-shaped, the flow velocity of the medium in the confluence channel is relatively uniform and not easy to be blocked, so the cleaning difficulty is reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 It is a three-dimensional diagram of the microfluidic substrate of Example 1 of the present invention.

[0044] Figure 2 FIG1 is a specific layout diagram of the microfluidic structure of the microfluidic substrate of Example 1 of the present invention.

[0045] Figure 3 for Figure 2 A partial enlarged view of part B.

[0046] Figure 4 FIG. 2 is a specific layout diagram of the microfluidic structure of the microfluidic substrate of Example 1 of the present invention.

[0047] Figure 5 This is a specific layout diagram of the microfluidic structure of the microfluidic substrate of Example 2 of the present invention.

[0048] Description of reference numerals:

[0049] Microfluidic substrate 1, surface 1a

[0050] Microfluidic structure 11

[0051] Liquid inlet channel 111, first liquid inlet channel 1111, first liquid inlet port 1111a, second liquid inlet channel 1112, second liquid inlet port 1112a

[0052] Mixing channel 112

[0053] Liquid outlet channel 113, liquid outlet 113a

[0054] Primary mixing channel 114

[0055] Secondary mixing channel 115, inlet 115a, outlet 115b

[0056] Diversion section 1151

[0057] Confluence channel 1152

[0058] Chip cover 2

[0059] Medium flow direction A DETAILED DESCRIPTION

[0060] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples.

[0061] Example 1

[0062] like Figure 1 As shown, this embodiment provides a microfluidic chip, which is used in a microfluidic device, and includes a microfluidic substrate 1 and a chip cover 2, wherein a microfluidic channel structure 11 is provided on the surface 1a of the microfluidic substrate 1, and the chip cover 2 is covered on the surface 1a of the microfluidic substrate 1 to form a channel for medium flow. Figure 2 As shown, the medium to be mixed enters the microfluidic structure 11 from the first liquid inlet 1111a on the left side and the second liquid inlet 1112a on the right side of the microfluidic substrate 1, and is output from the liquid outlet 113a at the end of the microfluidic structure 11 after being fully mixed.

[0063] Specifically, Figure 2 As shown, the microfluidic structure 11 includes a liquid inlet channel 111, a mixing channel 112 and a liquid outlet channel 113 which are connected in sequence along the medium flow direction. The liquid inlet channel 111 is specifically divided into a first liquid inlet channel 1111 and a second liquid inlet channel 1112, and its output end is connected to the input end of the mixing channel 112.

[0064] In this embodiment, the water phase is injected into the microfluidic structure 11 from the first liquid inlet port 1111a of the first liquid inlet channel 1111 on the left, and the oil phase is injected into the microfluidic structure 11 from the second liquid inlet port 1112a of the second liquid inlet channel 1112 on the right, and converges and mixes at the input end of the mixing channel 112, and then flows to the liquid outlet channel 113 of the microfluidic structure 11 through the mixing channel 112, and finally leaves the microfluidic chip from the liquid outlet 113b.

[0065] Specifically in this embodiment, Figure 2 and Figure 3 As shown, the mixing channel 112 includes a primary mixing channel 114 and a plurality of secondary mixing channels 115 arranged in sequence, wherein the secondary mixing channels 115 each include a flow dividing channel and a flow converging channel 1152 arranged in sequence along the medium flow direction A. Figure 3As shown, the flow diversion channel includes two flow diversion parts 1151 arranged at an angle, the input ends of the two flow diversion parts 1151 are connected, and the inlet 115a of the secondary mixing channel 115 is formed at the connecting part of the flow diversion parts 1151. The converging channel 1152 is arc-shaped, and the two input ends of the converging channel 1152 are respectively connected to the output ends of the two flow diversion parts 1151, and the outlet 115b of the secondary mixing channel 115 is formed at the most downstream of the converging channel 1152.

[0066] Among them, from Figure 3 It can be seen that by providing the secondary mixing channel 115 with the diversion channel and the confluence channel 1152, the flow channel shape of the secondary mixing channel 115 is roughly "water drop shape". Figure 3 The dotted arrows in the figure show the flow path of the medium in the secondary mixing channel 115 in this embodiment. After the medium enters the secondary mixing channel 115 through the primary mixing channel 114, it is diverted by two diversion parts 1151, and then enters the confluence channel 1152 at a tangential angle, and is guided by the arc channel to "collide head-on" at the outlet 115b of the secondary mixing channel 115.

[0067] By setting a secondary mixing channel 115 on the mixing channel 112, the medium flowing through the mixing channel 112 is divided into two paths through the shunt channel of the secondary mixing channel 115, and then the two paths of medium are gathered into one path through the arc-shaped confluence channel 1152, and the two paths of medium are made to face each other at the outlet 115b of the secondary mixing channel 115 through the arc-shaped confluence structure, so as to improve the mixing efficiency. This scheme of mixing by frontal collision after the medium is shunted, effectively improves the degree of mixing by using the principle of medium collision mixing. Compared with the scheme in the prior art of squeezing the medium into a relatively narrow channel and mixing by using the pressure generated by squeezing into the narrow channel, the relative improvement of the channel size of this scheme may also meet the mixing requirements, and can improve the preparation efficiency while ensuring the quality of the lipid nanoparticles produced. Specifically in this scheme, the channel width of the microchannel structure 11 is 0.4mm, and the channel depth is 0.3mm, which are both greater than the channel width and depth of other microchannel structures 11 in the prior art, so that more medium can be injected per unit time, thereby improving the preparation efficiency.

[0068] Among them, regarding the optional range of the channel width and depth of the microfluidic structure 11 in this solution, it is preferably controlled between 0.2 and 0.4 mm. Among them, the lower limit size is controlled to be greater than or equal to 0.2 mm to ensure the channel size and improve the preparation efficiency. The upper limit size is controlled to be less than or equal to 0.4 mm, which refers to the results of the T-mix collision experiment. The width and depth dimensions are below 0.45 mm to form qualified lipid nanoparticles, so the upper limit of the depth and height is controlled at 0.4 mm and below.

[0069] In addition, for the microchannel structure 11 provided in the present solution, since the flow velocity of the medium flowing in the arc-shaped confluence channel is relatively uniform and not easily blocked, the cleaning difficulty is reduced.

[0070] In this embodiment, along the medium flow direction A, 6 secondary mixing channels 115 are arranged on the mixing channel 112, and each secondary mixing channel 115 is connected end to end, that is, the inlet 115a of the first secondary mixing channel 115 is connected to the outlet of the primary mixing channel 114, the inlet 115a of the remaining secondary mixing channels 115 is connected to the outlet 115b of the previous secondary mixing channel 115, and the outlet 115b of the last secondary mixing channel 115 is connected to the liquid outlet channel 113. By making the medium flow through multiple secondary mixing channels 115 in sequence, the mixing effect is further improved.

[0071] Of course, in other embodiments, other numbers of secondary mixing channels 115 may be provided on the mixing channel 112 to achieve the same purpose of improving the mixing effect. Among them, in order to ensure the mixing effect, the number of secondary mixing channels 115 should not be too small, and should be greater than or equal to 3. At the same time, the number of secondary mixing channels 115 should not be too large. When more than 10 secondary mixing channels 115 are provided in succession, the subsequent increase in the number of secondary mixing channels 115 will have limited effect on the improvement of the mixing effect. Therefore, in order to avoid unnecessary processing difficulty caused by too many secondary mixing channels 115, the number of secondary mixing channels 115 should be less than or equal to 10.

[0072] like Figure 3 As shown, for the diversion channel of the secondary mixing channel 115, in order to improve the diversion effect, the angle α between the two diversion parts 1151 is selected in the range of 30°~120°. For example, in this embodiment, the angle α between the two diversion parts 1151 is 60°.

[0073] In addition, if Figure 3 As shown, at the connection between the inlet 115a of the primary mixing flow channel 114 and the secondary mixing flow channel 115, the flow channel extension direction of the primary mixing flow channel 114 is the same as the flow channel extension direction of one of the flow diversion parts 1151. Specifically in this embodiment, the flow channel extension direction of the primary mixing flow channel 114 is the same as the flow channel extension direction of the flow diversion part 1151 located on the left side, and the inflow angle between the primary mixing flow channel 114 and the inlet 115a of the secondary mixing flow channel 115 is controlled to utilize the anti-backflow principle of the Tesla valve at this location to avoid backflow when the medium flows from the primary mixing flow channel 114 into the secondary mixing flow channel 115.

[0074] Of course, in other embodiments, the flow channel extension direction of the first-stage mixing flow channel 114 may also be located between the angular bisector C of the two diversion portions 1151 and the flow channel extension direction of one of the diversion portions 1151, that is, the first-stage mixing flow channel 114 is inclined relative to the angular bisector C of the two diversion portions 1151, so as to also utilize the anti-backflow principle of the Tesla valve to avoid backflow of the medium at this location.

[0075] Specific as Figure 4 As shown, in this embodiment, the angle β between the first liquid inlet flow channel 1111 and the second liquid inlet flow channel 1112 is 150°. By setting this angle, the water phase and the oil phase entering the first liquid inlet flow channel 1111 and the second liquid inlet flow channel 1112 respectively can generate a relatively large impact force at the connection point between the two, so as to improve the effect of preliminary mixing between the water phase and the oil phase. Of course, in other embodiments, the angle β between the first liquid inlet flow channel 1111 and the second liquid inlet flow channel 1112 can range from 120° to 170°. Among them, by setting the angle β between the first liquid inlet flow channel 1111 and the second liquid inlet flow channel 1112 to be greater than or equal to 120°, the relative impact force between the water phase and the oil phase is guaranteed, thereby improving the mixing effect. At the same time, the angle β between the first liquid inlet channel 1111 and the second liquid inlet channel 1112 is set to be less than or equal to 170° to avoid the first liquid inlet channel 1111 and the second liquid inlet channel 1112 being too opposite in orientation, causing the medium on the side with relatively larger flow to flow back into the liquid inlet channel on the side with relatively smaller flow.

[0076] Among them, in this embodiment, the medium entering the first liquid inlet 1111a side is defined as an aqueous phase, and the medium entering the second liquid inlet 1112a side is defined as an oil phase. Its role is only used for illustration to facilitate the explanation of the position difference between the first liquid inlet channel 1111 and the second liquid inlet channel 1112. In other embodiments, the media entering the first liquid inlet channel 1111 and the second liquid inlet channel 1112 respectively can be the same or different. The specific type of medium entering the liquid inlet channel 111 can refer to the existing technical solutions and will not be repeated here.

[0077] like Figure 4As shown, in this embodiment, the first liquid inlet flow channel 1111 located on the left side is used to inject the water phase, and the second liquid inlet flow channel 1112 located on the right side is used to inject the oil phase. The flow rate of the water phase is greater than that of the oil phase, and the flow rate ratio of the two is about 3:1. Therefore, in this solution, in order to make the water phase with a relatively large flow rate generate a larger vortex when entering the mixing flow channel 112, the mixing flow channel 112 is tilted toward the first liquid inlet flow channel 1111 on the left side, so that the flow direction change angle of the water phase when it flows into the mixing flow channel 112 through the first liquid inlet flow channel 1111 on the left side is increased, so as to achieve the purpose of increasing the vortex of the water phase at this location. By increasing the vortex of the water phase with a relatively large flow rate at this location, the mixing degree of the medium can be improved. Of course, in other embodiments, if the flow rate of the oil phase is relatively large, the first liquid inlet flow channel 111 can also be tilted toward the side of the liquid inlet flow channel 111 where the oil phase is located.

[0078] In addition, if Figure 4 As shown, at the connection between the outlet 115b of the secondary mixing channel 115 and the liquid outlet channel 113, the liquid outlet channel 113 is arc-shaped. For example, in the present embodiment, the liquid outlet channel 113 is curved to the left. This arc-shaped curved channel structure can increase the resistance of the medium in the process of flowing from the secondary mixing channel 115 into the liquid outlet channel 113, avoid the medium flowing too fast at this place, and improve the mixing effect. More preferably, in the present embodiment, between the outlet 115b of the secondary mixing channel 115 and the liquid outlet 113a of the microchannel structure 11, the entire liquid outlet channel 113 is arc-shaped, and the curvature is maintained at the same arc. This arc-shaped structure maintaining the same curvature can reduce the difficulty of processing the channel. Specifically in the present embodiment, the curvature of the liquid outlet channel 113 is R9.6mm.

[0079] The microfluidic chip, by setting a secondary mixing channel 115 that is roughly "water drop-shaped", improves the mixing efficiency by using the collision of media, without the need to control the channel size to achieve the mixing purpose as in the prior art. Therefore, the microfluidic chip provided by this solution can improve the output efficiency by increasing the channel size while satisfying the mixing effect and output quality. The specific experimental data are as follows:

[0080] (1) Experimental steps: A 10 ml syringe is connected to the left side of the microfluidic chip provided in this embodiment, and the syringe contains the water phase. A 10 ml syringe is connected to the right side, and the syringe contains the oil phase. The microfluidic chip is placed on a primary mixer, and the flow rate (the flow rate ratio of the left and right sides is set to 3:1) and the amount to be discarded before and after (0.5 ml is discarded before and 0.3 ml is discarded after). After the lipid nanoparticles are prepared, the size and uniformity (PDI) of the lipid nanoparticles are measured by a laser particle size analyzer. It should be clearly stated that in this experiment, the water phase does not contain mRNA, that is, the oil phase is mixed with pure water to form lipid nanoparticles without mRNA coating.

[0081] (2) The size and uniformity data of lipid nanoparticles at different injection flow rates are as follows:

[0082]

[0083] Comparing the data of Experiment No. 1 to 5, it can be seen that for the microfluidic chip provided in this scheme, when the mixing flow rate is 18ml / min~24ml / min, the particle size and uniformity of the prepared lipid nanoparticles are of high quality and meet the preparation requirements. The mixing flow rate in the above table refers to the flow rate in the mixing channel after the oil phase and the water phase collide and mix.

[0084] Other microfluidic chips in the prior art can usually prepare qualified lipid nanoparticles at a flow rate of 12 ml / min. If the flow rate is further increased, due to the limitation of the flow channel size, blockage will occur, and even the chip will be damaged due to blockage. The microfluidic chip provided in this solution can prepare qualified lipid nanoparticles at a flow rate of 18 ml / min~24 ml / min, and the preparation efficiency is significantly improved compared with other microfluidic chips in the prior art.

[0085] At the same time, through multiple experimental verifications, it can be found that when using the microfluidic chip provided by this scheme, as the mixing flow rate increases, the particle size of the lipid nanoparticles gradually decreases. When the mixing flow rate reaches or exceeds 24 ml / min, the particle size of the lipid nanoparticles is the smallest, and the particle size uniformity of the prepared lipid nanoparticles is the highest (that is, the PDI value is the smallest).

[0086] In other embodiments, the aqueous phase may also be a solution containing mRNA, and the aqueous phase containing mRNA is mixed with the oil phase in the microfluidic chip to form lipid nanoparticles coated with mRNA. By applying the microfluidic chip provided by this scheme to other product lines and observing the properties of the lipid nanoparticles containing mRNA prepared therefrom, it can be found that: under the influence of the factors that the particle size and uniformity of the lipid nanoparticles prepared by the microfluidic chip meet the requirements, the encapsulation rate of the prepared lipid nanoparticles for mRNA can be stabilized at more than 90%, which is higher than the conventional technology which usually uses 80% as a qualified evaluation standard.

[0087] Example 2

[0088] like Figure 5 As shown, this embodiment also provides a microfluidic chip, and the microchannel structure 11 on the microfluidic substrate 1 is substantially the same as that provided in Example 1, and the main difference is that:

[0089] (1) The angle β between the first liquid inlet channel 1111 and the second liquid inlet channel 1112 is 160°. By further increasing the angle between the first liquid inlet channel 1111 and the second liquid inlet channel 1112 on the basis of Example 1, the two media can generate a relatively greater impact force at the connection point, so as to further improve the initial mixing effect.

[0090] (2) The primary mixing channel 114 of the mixing channel 112 is located at the bisector D of the angle between the first liquid inlet channel 1111 and the second liquid inlet channel 1112. By symmetrically arranging the primary mixing channel 114 relative to the first liquid inlet channel 1111 and the second liquid inlet channel 1112, the operating conditions remain consistent regardless of whether the water phase is injected from the left or right side.

[0091] Although the specific embodiments of the present invention are described above, it should be understood by those skilled in the art that this is only for illustration and the protection scope of the present invention is defined by the appended claims. Those skilled in the art may make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but these changes and modifications all fall within the protection scope of the present invention.

Claims

1. A microfluidic chip, comprising a microfluidic substrate, wherein a microchannel structure is provided on the surface of the microfluidic substrate, characterized in that: Along the medium flow direction, the microchannel structure includes a liquid inlet channel, a mixing channel and a liquid outlet channel which are connected in sequence, and a primary mixing channel and a secondary mixing channel are arranged in sequence on the mixing channel, and the secondary mixing channel includes a diversion channel and a confluence channel; Wherein, the flow diversion channel comprises two flow diversion parts arranged at an angle, the input ends of the two flow diversion parts are connected, and the inlet of the secondary mixing channel is formed at the connecting part of the flow diversion parts; The converging channel is arc-shaped, and the two input ends of the converging channel are respectively connected to the output ends of the two flow diversion parts, and the outlet of the secondary mixing channel is formed at the most downstream of the converging channel along the medium flow direction.

2. The microfluidic chip according to claim 1, characterized in that: The mixing flow channel includes a plurality of secondary mixing flow channels. Along the medium flow direction, the inlet of the first secondary mixing flow channel is connected to the outlet of the primary mixing flow channel, the inlets of the remaining secondary mixing flow channels are connected to the outlet of the previous secondary mixing flow channel, and the outlet of the last secondary mixing flow channel is connected to the liquid outlet flow channel.

3. The microfluidic chip according to claim 2, characterized in that: The number of the secondary mixing flow channels is greater than or equal to 3; And / or, the number of the secondary mixing channels is less than or equal to 10.

4. The microfluidic chip according to claim 1, characterized in that: The liquid inlet channel comprises a first liquid inlet channel and a second liquid inlet channel, the first liquid inlet channel has a first liquid inlet port for supplying a first liquid into the microfluidic channel structure, and the second liquid inlet channel has a second liquid inlet port for supplying a second liquid into the microfluidic channel structure; The output ends of the first liquid inlet flow channel and the second liquid inlet flow channel are connected to the mixing flow channel; The angle between the first liquid inlet channel and the second liquid inlet channel is in the range of 120° to 170°.

5. The microfluidic chip according to claim 4, characterized in that: The primary mixing channel is arranged obliquely toward a side of the liquid inlet channel where the liquid inlet flow rate is large; Alternatively, the primary mixing channel is arranged along an angle bisector of the first liquid inlet channel and the second liquid inlet channel.

6. The microfluidic chip according to claim 1, characterized in that: The liquid outlet channel is arc-shaped.

7. The microfluidic chip according to claim 6, characterized in that: The liquid outlet flow channel is bent along an arc direction with the same curvature.

8. The microfluidic chip according to any one of claims 1 to 7, characterized in that: The angle between the two diversion parts ranges from 30° to 120°.

9. The microfluidic chip according to any one of claims 1 to 7, characterized in that: The channel width of the microchannel structure is in the range of 0.2 to 0.4 mm; And / or, the channel depth of the microchannel structure is in the range of 0.2-0.4 mm.

10. A microfluidic device, characterized in that: A microfluidic chip comprising any one of claims 1 to 9.

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