Micro-fluidic chip and micro-fluidic equipment comprising same

Abstract

The micro-fluidic chip comprises a micro-fluidic substrate, a micro-channel structure is arranged on the surface of the micro-fluidic substrate, the micro-channel structure sequentially comprises a liquid inlet channel, a mixing channel and a liquid outlet channel which are communicated with one another, a first-stage mixing channel and a second-stage mixing channel are sequentially arranged on the 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 priority to Chinese patent application No. 202311517177.4, filed on November 14, 2023. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

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

[0003] By using microfluidic mixing, lipid solutions and mRNA solutions are thoroughly and rapidly mixed in a micromixer to form lipid nanoparticles (LNPs) of uniform size. LNPs 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 their excellent 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. The current conventional microfluidic chip mixing channel design basically allows fluids 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 causing collisions at the fluid interaction interface, thereby achieving 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 for technical personnel. Utility Model Content

[0005] The technical problem to be solved by the utility model 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 utility model solves the above technical problems through the following technical solutions:

[0007] A microfluidic chip, comprising a microfluidic substrate, wherein a microfluidic channel structure is provided on the surface of the microfluidic substrate. Along the flow direction of the medium, the microfluidic channel structure sequentially comprises an inlet channel, a mixing channel, and an outlet channel that are interconnected. A primary mixing channel and a secondary mixing channel are sequentially provided on the mixing channel. The secondary mixing channel comprises a diversion channel and a confluence channel.

[0008] The diversion channel includes two diversion parts arranged at an angle, the input ends of the two diversion parts are connected, and the inlet of the secondary mixing channel is formed at the connecting part of the 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 diversion parts. The outlet of the secondary mixing channel is formed at the most downstream of the converging channel along the medium flow direction.

[0010] This microfluidic chip is constructed by disposing a primary mixing channel and a secondary mixing channel within the mixing channel of its microfluidic structure. Through the continuous arrangement of the primary and secondary mixing channels, the secondary mixing channel's diversion channel is used to divide the medium flowing through the primary mixing channel into two paths. The two media are then brought together into one path through the curved converging channel of the secondary mixing channel. This curved converging structure allows the two media to collide head-on during the converging process, improving mixing efficiency. This solution of mixing the media by directing them into a direct collision after diversion utilizes the principle of media collision mixing to effectively improve the degree of mixing.

[0011] Compared with the existing technology 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, which 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 flow direction of the medium, 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] By sequentially arranging multiple secondary mixing channels on the mixing channel, the mixing effect can be further improved.

[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 channels is less than or equal to 10.

[0018] For continuous configurations of 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 unnecessary processing difficulties caused by excessive secondary mixing channels.

[0019] Preferably, the liquid inlet channel further comprises a first liquid inlet channel and a second liquid inlet channel, the first liquid inlet channel having a first liquid inlet for supplying a first liquid into the microfluidic channel structure, and the second liquid inlet channel having a second liquid inlet 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 included 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 connection 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 greater;

[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 tilting the primary mixing channel toward the side of the liquid inlet channel with a relatively high 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 higher 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 liquid outlet flow channel, the resistance of the medium in the process of flowing from the secondary mixing flow channel into the liquid 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 in an arc shape with a constant curvature as a whole, thereby reducing the difficulty in processing 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 above-mentioned microfluidic chip.

[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, thereby improving the mixing efficiency. Compared with the existing 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, because the confluence channel of the secondary mixing channel is arc-shaped, the flow rate of the medium flowing in the confluence channel is relatively uniform and not easy to be blocked, and the difficulty of cleaning is reduced.

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

[0040] (1) By sequentially setting a primary mixing channel and a secondary mixing channel on the mixing channel of the microfluidic substrate, and utilizing the channel structure of the secondary mixing channel, the medium is mixed in the secondary mixing channel by first diversion and then frontal collision. By utilizing this principle of collision and mixing of the medium, the degree of medium mixing is effectively improved.

[0041] (2) Compared with the existing technology that squeezes the medium into a relatively narrow flow channel and uses the pressure generated by squeezing into the narrow flow channel to achieve mixing, this solution achieves mixing by hedging. Compared with the existing technology, increasing the flow channel size can also meet the mixing requirements. Therefore, it can improve the preparation efficiency while ensuring the quality of the output lipid nanoparticles.

[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, and the difficulty of cleaning is reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is a three-dimensional diagram of the microfluidic substrate of Example 1 of the present utility model.

[0044] Figure 2 FIG1 is a specific layout diagram of the microchannel structure of the microfluidic substrate of Example 1 of the present utility model (I).

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

[0046] Figure 4 FIG2 is a specific layout diagram of the microfluidic structure of the microfluidic substrate of Example 1 of the present utility model.

[0047] Figure 5 This is a detailed layout diagram of the microchannel structure of the microfluidic substrate of Example 2 of the present utility model.

[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 microchannel 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 discharged from the liquid outlet 113a at the end of the microfluidic structure 11 after being fully mixed.

[0063] Specifically, such as Figure 2 As shown, the microchannel 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 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 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 each of the secondary mixing channels 115 includes a diversion channel and a confluence channel 1152 arranged in sequence along the medium flow direction A. Figure 3As shown, the diversion channel includes two diversion parts 1151 arranged at an angle, the input ends of the two diversion parts 1151 are connected, and the inlet 115a of the secondary mixing channel 115 is formed at the connection point of the 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 diversion parts 1151, and the outlet 115b of the secondary mixing channel 115 is formed at the downstream end 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. It is guided by the arc channel and "collides 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 by the diversion channel of the secondary mixing channel 115, and then the two media are gathered into one path by the arc-shaped confluence channel 1152. Through the arc-shaped confluence structure, the two media are made to collide head-on at the outlet 115b of the secondary mixing channel 115 to improve the mixing efficiency. This solution of mixing by diverting the medium and then facing each other head-on uses the principle of medium collision mixing to effectively improve the degree of mixing. Compared with the solution in the prior art that mixes by squeezing the medium into a relatively narrow channel and using the pressure generated by squeezing into the narrow channel, 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 lipid nanoparticles produced. Specifically in this solution, the channel width of the microchannel structure 11 is 0.4mm and the channel depth is 0.3mm, both of which are larger than the channel width and depth of other microchannel structures 11 in the prior art, so that more media can be injected per unit time, thereby improving the preparation efficiency.

[0068] In this embodiment, the optional range of the channel width and depth of the microfluidic structure 11 is preferably controlled between 0.2 and 0.4 mm. The lower limit 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 is controlled to be less than or equal to 0.4 mm. This is based on the results of the T-mix collision experiment. The width and depth dimensions are less than 0.45 mm to form qualified lipid nanoparticles. Therefore, the upper limit of the depth and height is controlled to 0.4 mm and below.

[0069] In addition, for the microchannel structure 11 provided by this 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, six secondary mixing channels 115 are provided on the mixing channel 112 along the medium flow direction A. The secondary mixing channels 115 are connected end to end, i.e., the inlet 115a of the first secondary mixing channel 115 is connected to the outlet of the primary mixing channel 114, the inlets 115a of the remaining secondary mixing channels 115 are 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 allowing the medium to 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. In order to ensure the mixing effect, the number of secondary mixing channels 115 provided 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 provided should not be too large. When more than 10 secondary mixing channels 115 are provided continuously, 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 excessive 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 junction of the primary mixing channel 114 and the inlet 115a of the secondary mixing channel 115, the flow channel extension direction of the primary mixing channel 114 is the same as the flow channel extension direction of one of the diverter portions 1151. Specifically, in this embodiment, the flow channel extension direction of the primary mixing channel 114 is the same as the flow channel extension direction of the diverter portion 1151 located on the left. By controlling the inflow angle between the primary mixing channel 114 and the inlet 115a of the secondary mixing channel 115, the anti-backflow principle of the Tesla valve is utilized at this location to prevent backflow when the medium flows from the primary mixing channel 114 into the secondary mixing channel 115.

[0074] Of course, in other embodiments, the flow channel extension direction of the first-stage mixing channel 114 can 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 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 the water phase, and the medium entering the second liquid inlet 1112a side is defined as the 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 channel 1111 located on the left is used to inject the water phase, and the second liquid inlet channel 1112 located on the right 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 channel 112, the mixing channel 112 is tilted toward the first liquid inlet channel 1111 on the left, so that the angle of change in the flow direction of the water phase when flowing into the mixing channel 112 through the first liquid inlet channel 1111 on the left is increased, thereby achieving the purpose of enhancing the vortex of the water phase at this location. By enhancing the vortex of the water phase with a relatively large flow rate at this location, the degree of mixing 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 channel 111 can also be tilted toward the side of the liquid inlet 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 this embodiment, the liquid outlet channel 113 bends 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 from flowing too fast at this point, and improve the mixing effect. More preferably, in this 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 remains the same. This arc-shaped structure that maintains the same curvature can reduce the difficulty of processing the channel. Specifically in this embodiment, the curvature of the liquid outlet channel 113 is R9.6mm.

[0079] This microfluidic chip, by providing a roughly "teardrop-shaped" secondary mixing channel 115, utilizes the collision of media to improve mixing efficiency, eliminating the need to control channel size to achieve mixing as in the prior art. Therefore, the microfluidic chip provided by this solution can improve output efficiency by increasing channel size while maintaining mixing effectiveness and output quality. Specific experimental data are as follows:

[0080] (1) Experimental steps: For the microfluidic chip provided in this example, a 10 ml syringe containing an aqueous phase was connected to the left side, and a 10 ml syringe containing an oil phase was connected to the right side. The microfluidic chip was placed on a primary mixer, and the flow rate (the flow rate ratio of the left and right sides was set to 3:1) and the amount to be discarded (0.5 ml to be discarded in the front and 0.3 ml to be discarded in the back) were set. After the lipid nanoparticles were prepared, the particle size and uniformity (PDI) of the lipid nanoparticles were measured using a laser particle size analyzer. It should be clarified that in this experiment, the aqueous phase did not contain mRNA, that is, the oil phase was 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 from Experiments 1 to 5, we can see that for the microfluidic chip provided by this protocol, when the mixing flow rate was between 18 ml / min and 24 ml / min, the lipid nanoparticles produced had high particle size and uniformity, meeting the preparation requirements. The mixing flow rate in the table above refers to the flow rate in the mixing channel after the oil and water phases collide and mix.

[0084] Other existing microfluidic chips can typically produce qualified lipid nanoparticles at a flow rate of 12 ml / min. However, increasing the flow rate further can lead to clogging due to channel size limitations, which can even damage the chip. However, the microfluidic chip provided in this solution can produce qualified lipid nanoparticles at flow rates of 18 ml / min to 24 ml / min, significantly improving production efficiency compared to other existing microfluidic chips.

[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 can also be a solution containing mRNA, and the mRNA-containing aqueous phase and the oil phase are mixed within the microfluidic chip to form lipid nanoparticles encapsulated with mRNA. By applying the microfluidic chip provided in this solution to other production lines and observing the properties of the mRNA-containing lipid nanoparticles produced therefrom, it was found that, under the influence of factors such as the particle size and uniformity of the lipid nanoparticles produced using the microfluidic chip meeting the requirements, the mRNA encapsulation efficiency of the lipid nanoparticles produced can be stably above 90%, which is higher than the 80% standard generally used as a passing mark in existing technologies.

[0087] Example 2

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

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

[0090] (2) The primary mixing channel 114 of the mixing channel 112 is located at the angle bisector D 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 specific embodiments of the present invention have been described above, those skilled in the art will appreciate that these are merely illustrative and that the scope of protection 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, and such changes and modifications are intended to fall within the scope of protection 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 that are connected in sequence. A primary mixing channel and a secondary mixing channel are sequentially arranged on the mixing channel. The secondary mixing channel includes a diversion channel and a confluence channel. The diversion channel includes two diversion parts arranged at an angle, the input ends of the two diversion parts are connected, and the inlet of the secondary mixing channel is formed at the connecting part of the 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 diversion parts. 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, wherein The mixing flow channel includes multiple secondary mixing flow channels. Along the flow direction of the medium, the inlet of the first secondary mixing flow channel is connected to the outlet of the first 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, wherein: 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, wherein The liquid inlet channel includes a first liquid inlet channel and a second liquid inlet channel, the first liquid inlet channel has a first liquid inlet for supplying a first liquid into the microfluidic channel structure, and the second liquid inlet channel has a second liquid inlet 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 included 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 the side of the liquid inlet channel where the liquid inlet velocity is greater; 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, wherein The liquid outlet channel is arc-shaped.

7. The microfluidic chip according to claim 6, wherein: 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, wherein: 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, wherein: The flow 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: The microfluidic chip comprises the microfluidic chip according to any one of claims 1 to 9.

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