CN117398892A - Microfluidic chip and microfluidic device comprising same - Google Patents

Abstract

The invention discloses a microfluidic chip and microfluidic equipment comprising the same, which comprises a microfluidic substrate, wherein a micro-channel structure is arranged on the surface of the microfluidic substrate, the micro-channel structure sequentially comprises a liquid inlet channel, a mixing channel and a liquid outlet channel which are communicated, 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; the split flow channel comprises two split flow parts which are arranged in an angle way, the input ends of the two split flow parts are communicated, and the inlet of the secondary mixing flow channel is formed at the communication position of the split flow parts; the converging channel is arc-shaped, two input ends of the converging channel are respectively communicated with output ends of the two flow dividing parts, and an outlet of the secondary mixing flow channel is formed at the most downstream part of the converging channel. Through set gradually the second grade mixing flow way on mixing flow way, provide one kind and make the scheme that the medium shunted back front side is to the punching mode mixed, utilize the principle of medium collision mixing, effectively improve the degree of mixing, promote preparation efficiency simultaneously.

Description

Microfluidic chip and microfluidic device comprising same

Technical Field

The invention relates to the technical field of nano pharmacy, in particular to a microfluidic chip, a microfluidic device containing the microfluidic chip and a microfluidic device containing the microfluidic chip.

Background

By adopting a microfluidic mixing method, lipid solution and mRNA solution are fully and rapidly mixed in a micromixer to form Lipid Nano Particles (LNP) with uniform particle size, the LNP can improve the solubility of encapsulated drugs, prevent the drugs from being chemically and biologically degraded, reduce the toxic and side effects of the drugs, enhance the penetrability of the drugs and the like. Because of its good biocompatibility and low immunogenicity, liposomes are recognized as ideal carriers for small molecule antitumor drugs and gene drugs.

As a method for reliably preparing liposome, the microfluidic mixing technology is widely used in the field of preparing lipid nanoparticles. The conventional microfluidic chip mixing flow channel design at present basically enables fluid to be mixed and collided at an interaction interface, such as the most common T-shaped flow channel chip design, and two independent fluids are pumped in from two ends in the horizontal direction at the same time and collided at the fluid interaction interface to realize fluid mixing, so that the purpose of mixing the two fluids and pumping out the two fluids through a liquid channel perpendicular to an inlet flow channel is realized. The microfluidic chip realizes mixing by means of internal stress of fluid, so that the size of a flow channel is relatively small, the flow velocity of the fluid is low, the preparation efficiency is low, and the high-efficiency preparation requirement is not met. How to improve the preparation efficiency while guaranteeing the quality of the produced lipid nano particles becomes an important point for the design and development of technicians.

Disclosure of Invention

The invention aims to overcome the defect of low efficiency of preparing lipid nano particles by a microfluidic chip in the prior art, and provides the microfluidic chip.

The invention solves the technical problems by the following technical scheme:

the microfluidic chip comprises a microfluidic substrate, wherein a micro-channel structure is arranged on the surface of the microfluidic substrate, the micro-channel structure sequentially comprises a liquid inlet channel, a mixing channel and a liquid outlet channel which are communicated with each other along the flow direction of a medium, 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;

the two-stage mixing flow channel comprises two flow dividing parts which are arranged in an angle way, wherein the input ends of the two flow dividing parts are communicated, and the inlet of the two-stage mixing flow channel is formed at the communication position of the flow dividing parts;

the converging channel is arc-shaped, two input ends of the converging channel are respectively communicated with the output ends of the two flow dividing parts, and an outlet of the secondary mixing flow channel is formed at the most downstream part of the converging channel along the medium flowing direction.

According to the micro-fluidic chip, the primary mixing flow channel and the secondary mixing flow channel are arranged in the mixing flow channel of the micro-flow channel structure, the medium flowing through the primary mixing flow channel is divided into two paths by the diversion channel of the secondary mixing flow channel through the continuous arrangement of the primary mixing flow channel and the secondary mixing flow channel, and the two paths of medium are collected into one path by the arc-shaped converging channel of the secondary mixing flow channel. The scheme of mixing by the front opposite-impact mode after medium diversion effectively improves the mixing degree by utilizing the principle of medium collision mixing.

Compared with the scheme that the medium is extruded into a narrow runner and the pressure generated by extruding into the narrow runner is utilized for mixing in the prior art, the runner size of the scheme is relatively improved to possibly meet the mixing requirement, and the preparation efficiency can be improved while the quality of the produced lipid nano particles is ensured.

Meanwhile, as the converging channel of the secondary mixing flow channel is arc-shaped, the flow velocity of the medium flowing in the converging channel is relatively uniform, the medium is not easy to block, and the cleaning difficulty is reduced.

Preferably, the mixing flow channel comprises a plurality of secondary mixing flow channels, along the medium flowing direction, the inlet of the first secondary mixing flow channel is communicated with the outlet of the first secondary mixing flow channel, the inlets of the rest secondary mixing flow channels are communicated with the outlet of the previous secondary mixing flow channel, and the outlet of the last secondary mixing flow channel is communicated with the liquid outlet flow channel.

A plurality of secondary mixing flow passages are sequentially arranged on the mixing flow passages, so that the mixing effect is further improved.

Preferably, the number of the secondary mixing flow passages is 3 or more.

The medium mixing degree can be further improved by sequentially flowing through a plurality of secondary mixing flow channels, and the lower limit of the set mixing structure is controlled to ensure the mixing effect.

Preferably, the number of the secondary mixing flow passages is less than or equal to 10.

For the mixing structure with more than 10 mixing structures arranged continuously, the number of the secondary mixing flow channels is further increased, and the mixing effect is improved only to a limited extent. By controlling the upper limit of the set secondary mixing flow channel, unnecessary processing difficulty is avoided due to excessive setting of the secondary mixing flow channel.

Preferably, the liquid inlet channel further comprises a first liquid inlet channel and a second liquid inlet channel, the first liquid inlet channel is provided with a first liquid inlet for allowing the first liquid to enter the micro-channel structure, and the second liquid inlet channel is provided with a second liquid inlet for allowing the second liquid to enter the micro-channel structure;

the output ends of the first liquid inlet flow channel and the second liquid inlet flow channel are communicated with the mixing flow channel;

the included angle between the two first liquid inlet channels and the second liquid inlet channels ranges from 120 degrees to 170 degrees.

Through setting the contained angle between first inlet channel and the second inlet channel to 120 or more to improve the relative striking dynamics of first liquid and the second liquid of entering first inlet channel and second inlet channel respectively in the intercommunication department, further improve the mixing effect.

Meanwhile, the included angle between the first liquid inlet flow channel and the second liquid inlet flow channel is set to be 170 degrees or less, so that the situation that flowing media on the side with relatively large flow rate flow back to the liquid inlet flow channel on the side with relatively small flow rate due to the fact that the directions between the first liquid inlet flow channel and the second liquid inlet flow channel are too opposite is avoided.

Preferably, the primary mixing flow channel is obliquely arranged towards one side of the liquid inlet flow channel with high liquid inlet flow rate;

or, the primary mixing runner is arranged along an angular bisector of the first liquid inlet runner and the second liquid inlet runner.

The primary mixing flow channel is inclined towards one side of the liquid inlet flow channel with relatively high liquid inlet flow rate, so that the flow direction change angle of the medium flowing into the primary mixing flow channel through the liquid inlet flow channel is improved, the vortex of the medium with high flow rate at the position is further improved, and the mixing degree is improved.

Preferably, at the connection position of the outlet of the secondary mixing flow channel and the liquid outlet flow channel, the liquid outlet flow channel is arc-shaped.

The liquid outlet channel is arranged in an arc-shaped channel shape at the joint of the outlet of the secondary mixing channel and the liquid outlet channel, so that the resistance of a medium in the process of flowing into the liquid outlet channel from the secondary mixing channel is increased, the medium is prevented from flowing too fast at the joint, and the mixing effect is improved.

Preferably, the liquid outlet channel is in an arc shape with unchanged curvature between the outlet of the secondary mixing channel and the liquid outlet of the liquid outlet channel.

Through this structure setting, make the liquid outlet channel wholly be the arc that the camber is unchangeable to the technology degree of difficulty when reducing the processing liquid outlet channel.

Preferably, the included angle between the two diversion parts ranges from 30 degrees to 120 degrees.

Through this contained angle scope setting, improve the reposition of redundant personnel effect.

Preferably, the flow channel width of the micro flow channel structure is in the range of 0.2-0.4 mm;

preferably, the depth of the micro-channel structure is in the range of 0.2-0.4 mm.

The lower limit size is controlled to be more than or equal to 0.2mm by controlling the lower limit of the width and depth of the runner of the micro-runner structure, so that the size of the runner is ensured, and the preparation efficiency is improved.

The upper limit size is controlled to be less than or equal to 0.4mm by controlling the upper limit of the width and the depth of the runner of the micro-runner structure, so that the preparation quality of the lipid nano particles is prevented from being influenced due to the overlarge size of the runner.

A microfluidic device comprising a microfluidic chip as described above.

According to the microfluidic device, by adopting the microfluidic chip, two paths of media entering the microfluidic chip are oppositely flushed in the collecting process, so that the mixing efficiency is improved. Compared with the scheme that the medium is extruded into a narrow runner and the pressure generated by extruding into the narrow runner is utilized for mixing in the prior art, the runner size of the scheme is relatively improved to possibly meet the mixing requirement, and the preparation efficiency can be improved while the quality of the produced lipid nano particles is ensured. Meanwhile, as the converging channel of the secondary mixing flow channel is arc-shaped, the flow velocity of the medium flowing in the converging channel is relatively uniform, the medium is not easy to block, and the cleaning difficulty is reduced.

The invention has the positive progress effects that:

(1) Through setting gradually first order mixing runner and second grade mixing runner on the mixing runner of micro-fluidic base plate, utilize the runner structure setting of second grade mixing runner, make the medium mix through the mode of reposition of redundant personnel earlier and then facing towards in the second grade mixing runner, utilize this kind of principle that makes medium collision mix, effectively improve medium mixing degree.

(2) Compared with the prior art, the scheme of mixing by extruding the medium into the narrow flow channel and utilizing the pressure generated by extruding into the narrow flow channel can realize mixing by means of opposite impact, and compared with the prior art, the size of the flow channel is increased to meet the mixing requirement, so that the preparation efficiency can be improved while the quality of the produced lipid nano particles is ensured.

(3) Because the converging channel of the secondary mixing flow channel is arc-shaped, the flow velocity of the medium flowing in the converging channel is relatively uniform, the medium is not easy to block, and the cleaning difficulty is reduced.

Drawings

Fig. 1 is a perspective view of a microfluidic substrate according to embodiment 1 of the present invention.

Fig. 2 is a specific layout diagram (one) of a micro flow channel structure of a micro flow control substrate in embodiment 1 of the present invention.

Fig. 3 is a partial enlarged view of a portion B in fig. 2.

Fig. 4 is a specific layout diagram (ii) of a micro flow channel structure of a micro flow control substrate according to embodiment 1 of the present invention.

Fig. 5 is a specific layout diagram of a micro flow channel structure of a micro flow control substrate according to embodiment 2 of the present invention.

Reference numerals illustrate:

microfluidic substrate 1, surface 1a

Micro flow channel structure 11

Inlet flow channel 111, first inlet flow channel 1111, first inlet 1111a, second inlet flow channel 1112, second inlet 1112a

Mixing runner 112

Liquid outlet 113, liquid outlet 113a

Primary mixing runner 114

Two-stage mixing channel 115, inlet 115a, outlet 115b

Split 1151

Confluence channel 1152

Chip cover plate 2

Direction of flow A of the medium

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention.

Example 1

As shown in fig. 1, the present embodiment provides a microfluidic chip, which is applied to a microfluidic device and includes a microfluidic substrate 1 and a chip cover plate 2, wherein a micro flow channel structure 11 is provided on a surface 1a of the microfluidic substrate 1, and the chip cover plate 2 is covered on the surface 1a of the microfluidic substrate 1 to form a channel for medium flow. As shown in fig. 2, the medium to be mixed enters the micro flow channel structure 11 from the first liquid inlet 1111a on the left side and the second liquid inlet 1112a on the right side of the micro flow control substrate 1, respectively, and is output from the liquid outlet 113a at the end of the micro flow channel structure 11 after being sufficiently mixed.

Specifically, as shown in fig. 2, the micro flow channel structure 11 sequentially includes a liquid inlet channel 111, a mixing channel 112 and a liquid outlet channel 113, which are communicated with each other along a medium flowing direction, where the liquid inlet channel 111 is specifically divided into a first liquid inlet channel 1111 and a second liquid inlet channel 1112, and an output end thereof is communicated with an input end of the mixing channel 112.

In this embodiment, the water phase is injected into the micro-channel structure 11 from the first liquid inlet 1111a of the first liquid inlet channel 1111 on the left side, the oil phase is injected into the micro-channel structure 11 from the second liquid inlet 1112a of the second liquid inlet channel 1112 on the right side, and is mixed together at the input end of the mixing channel 112, flows to the liquid outlet channel 113 of the micro-channel structure 11 through the mixing channel 112, and finally leaves the micro-fluidic chip from the liquid outlet 113 b.

In particular, in the present embodiment, as shown in fig. 2 and 3, the mixing flow path 112 includes a primary mixing flow path 114 and a plurality of secondary mixing flow paths 115 that are disposed in sequence, wherein each of the secondary mixing flow paths 115 includes a split flow path and a confluence path 1152 that are disposed in sequence along the medium flow direction a. Wherein, as shown in fig. 3, the split channel includes two split portions 1151 arranged at an angle, the input ends of the two split portions 1151 are communicated, and the inlet 115a of the secondary mixing runner 115 is formed at the communication position of the split portions 1151. And the confluence channel 1152 is arc-shaped, two input ends of the confluence channel 1152 are respectively communicated with output ends of the two split portions 1151, and an outlet 115b of the secondary mixing channel 115 is formed at a most downstream of the confluence channel 1152.

As can be seen from fig. 3, by providing the secondary mixing flow channel 115 with the diversion channel and the confluence channel 1152, the flow channel shape of the secondary mixing flow channel 115 is approximately "drop-shaped", and in fig. 3, the flow path of the medium in the secondary mixing flow channel 115 in the present embodiment is shown by the dotted arrow, after the medium enters the secondary mixing flow channel 115 through the primary mixing flow channel 114, the medium is split by the two splitting parts 1151, then enters the confluence channel 1152 at a tangential angle, and is guided by the arc-shaped channel to "collide front" at the outlet 115b of the secondary mixing flow channel 115.

Through setting up second grade mixing runner 115 on mixing runner 112, divide into two-way through the reposition of redundant personnel passageway of second grade mixing runner 115 with the medium that flows through mixing runner 112, two-way medium is assembled into one way through curved confluence channel 1152, through curved confluence structure for two-way medium openly dashes in the export 115b department of second grade mixing runner 115, in order to improve mixing efficiency. The scheme of mixing by the front opposite-impact mode after medium diversion effectively improves the mixing degree by utilizing the principle of medium collision mixing. Compared with the scheme that the medium is extruded into a narrow runner and the pressure generated by extruding into the narrow runner is utilized for mixing in the prior art, the runner size of the scheme is relatively improved to possibly meet the mixing requirement, and the preparation efficiency can be improved while the quality of the produced lipid nano particles is ensured. In this scheme, the runner width of the micro-runner structure 11 is 0.4mm, and the runner depth is 0.3mm, which are both greater than the runner widths and depths of other micro-runner structures 11 in the prior art, so that more media can be injected in unit time, and the preparation efficiency is improved.

Among them, regarding the optional range of the flow channel width and depth of the micro flow channel structure 11 in this embodiment, it is preferable to control between 0.2 and 0.4 mm. Wherein, the lower limit size is controlled to be more than or equal to 0.2mm so as to ensure the size of the flow channel and improve the preparation efficiency. The upper limit of the size is controlled to 0.4mm or less, and the upper limit of the width and depth of the lipid nanoparticle is controlled to 0.4mm or less because the upper limit of the size is controlled to 0.45mm or less based on the results of the T-mix collision test.

In addition, for the micro-channel structure 11 provided by the scheme, the flow velocity of the medium flowing in the arc-shaped converging channel is relatively uniform, and the medium is not easy to block, so that the cleaning difficulty is reduced.

In this embodiment, along the medium flowing direction a, 6 secondary mixing channels 115 are disposed on the mixing channel 112, and each secondary mixing channel 115 is 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. The mixing effect is further enhanced by flowing the medium sequentially through the plurality of secondary mixing channels 115.

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 the secondary mixing channels 115 should not be too small, and it is not less than 3. Meanwhile, the number of the secondary mixing flow channels 115 should not be too large, and when more than 10 secondary mixing flow channels 115 are continuously arranged, the number of the secondary mixing flow channels 115 is further increased, and the improvement of the mixing effect is limited, so that the number of the secondary mixing flow channels 115 should be less than or equal to 10 in order to avoid the excessive arrangement of the secondary mixing flow channels 115 and the unnecessary increase of the processing difficulty.

As shown in fig. 3, for the split channel of the secondary mixing channel 115, in order to improve the splitting effect, the angle α between the two split portions 1151 is selected to be between 30 ° and 120 °, for example, in this embodiment, the angle α between the two split portions 1151 is 60 °.

In addition, as shown in fig. 3, at the junction of the primary mixing flow channel 114 and the inlet 115a of the secondary mixing flow channel 115, the flow channel extending direction of the primary mixing flow channel 114 is the same as the flow channel extending direction of one of the split portions 1151. In particular, in the present embodiment, the flow channel extending direction of the primary mixing flow channel 114 is the same as the flow channel extending direction of the flow dividing portion 1151 located at the left side, and by controlling the inflow angle between the primary mixing flow channel 114 and the inlet 115a of the secondary mixing flow channel 115, the reverse flow of the medium flowing from the primary mixing flow channel 114 into the secondary mixing flow channel 115 is avoided by using the reverse flow prevention principle of the tesla valve.

Of course, in other embodiments, the flow path extending direction of the primary mixing flow path 114 may be located between the angular bisector C of the two split portions 1151 and the flow path extending direction of one of the split portions 1151, that is, the primary mixing flow path 114 is inclined with respect to the angular bisector C of the two split portions 1151, so as to avoid the medium from flowing back there by using the anti-backflow principle of the tesla valve.

As shown in fig. 4, in the present embodiment, the included angle β between the first liquid inlet channel 1111 and the second liquid inlet channel 1112 is 150 °, and by this angle setting, the water phase and the oil phase entering the first liquid inlet channel 1111 and the second liquid inlet channel 1112 respectively can generate relatively large impact force at the communicating position of the two, so as to improve the primary mixing effect between the water phase and the oil phase. Of course, in other embodiments, the angle β between the first and second inlet channels 1111, 1112 may range between 120 ° and 170 °. Wherein, through setting up the contained angle beta between first inlet channel 1111 and the second inlet channel 1112 to be more than or equal to 120 to guarantee the dynamics of the relative striking between the aqueous phase oil phase, improve the mixing effect. Meanwhile, the included angle β between the first inlet flow channel 1111 and the second inlet flow channel 1112 is set to 170 ° or less, so as to avoid that the directions of the first inlet flow channel 1111 and the second inlet flow channel 1112 are too opposite, and the medium on the side with relatively large flow rate is caused to flow back into the inlet flow channel on the side with relatively small flow rate.

In this embodiment, the medium entering the first inlet 1111a side is defined as an aqueous phase, and the medium entering the second inlet 1112a side is defined as an oil phase, which is used only for illustration to facilitate explanation of the difference between the positions of the first inlet fluid channel 1111 and the second inlet fluid channel 1112, and in other embodiments, the medium entering the first inlet fluid channel 1111 and the second inlet fluid channel 1112 may be the same or different, and the specific type of the medium entering the inlet fluid channel 111 may refer to the prior art scheme and will not be described herein.

As shown in fig. 4, in the present embodiment, the first inlet channel 1111 on the left side is used for injecting the water phase, and the second inlet channel 1112 on the right side is used for injecting the oil phase, and 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 embodiment, in order to generate a larger vortex of the water phase having a relatively large flow velocity when the water phase enters the mixing flow channel 112, the mixing flow channel 112 is inclined toward the left first inlet flow channel 1111, so that the flow direction change angle of the water phase flowing into the mixing flow channel 112 through the left first inlet flow channel 1111 is increased, and the purpose of increasing the vortex of the water phase thereat is achieved. By increasing the turbulence of the water phase where the flow velocity is relatively high, the degree of mixing of the medium can be increased. Of course, in other embodiments, if the flow rate of the oil phase is relatively high, the first inlet channel 111 may be inclined toward the inlet channel 111 side where the oil phase is located.

In addition, as shown in fig. 4, 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 curved, for example, in the present embodiment, the liquid outlet channel 113 is curved to the left. The arc-shaped bent flow passage structure can increase the resistance of the medium in the process of flowing into the liquid outlet flow passage 113 from the secondary mixing flow passage 115, avoid the too fast flow velocity of the medium at the position and improve the mixing effect. More preferably, in this embodiment, the whole section of the liquid outlet channel 113 is arc-shaped and has the same curvature between the outlet 115b of the secondary mixing channel 115 and the liquid outlet 113a of the micro-channel structure 11, and this arc-shaped structure with the same curvature can reduce the difficulty of processing the liquid channel. In particular, in the present embodiment, the curvature of the liquid outlet channel 113 is r9.6mm.

The microfluidic chip improves the mixing efficiency by arranging the secondary mixing flow channel 115 with a substantially 'drop shape' and utilizing the mode of mutual collision of media, and the mixing purpose is realized without controlling the size of the flow channel as in the prior art. Therefore, the micro-fluidic chip provided by the scheme can improve the output efficiency on the premise of meeting the mixing effect and the output quality by increasing the size of the flow channel, and specific experimental data are as follows:

(1) The experimental steps are as follows: for the microfluidic chip provided in this example, the left side was connected to a 10ml syringe, the inside of the syringe was a water phase, the right side was connected to a 10ml syringe, the inside of the syringe was an oil phase, the microfluidic chip was placed on a primary mixer, the flow rate (the flow rate ratio of the left side to the right side was set to 3:1) and the amount to be discarded before and after (0.5 ml was discarded before and 0.3ml was discarded after) were set, and the size and uniformity (PDI) of the particle size of the lipid nanoparticle was measured by a laser particle sizer after the lipid nanoparticle was prepared. What needs to be explicitly stated is: in this experiment, the aqueous phase contained no mRNA, i.e., the oil phase was mixed with pure water to form lipid nanoparticles without mRNA coating.

(2) The size and uniformity data of the lipid nanoparticle particle size at different injection flow rates are as follows:

as can be seen from comparing the data of experiment serial numbers 1-5, for the microfluidic chip provided by the scheme, when the mixing flow rate is 18 ml/min-24 ml/min, the size and uniformity of the particle size of the prepared lipid nanoparticle are high, and the preparation requirement is met. The mixing flow rate in the above table refers to the flow rate in the mixing flow channel after the oil phase and the water phase are collisional mixed.

Other microfluidic chips in the prior art can generally prepare qualified lipid nanoparticles at a flow rate of 12ml/min, and if the flow rate is further increased, blockage can occur due to the limitation of the size of a flow channel, and even the chip is damaged due to blockage. The micro-fluidic chip provided by the scheme can prepare qualified lipid nano particles at the flow rate of 18 ml/min-24 ml/min, and the preparation efficiency is obviously improved compared with other micro-fluidic chips in the prior art.

Meanwhile, experiments prove that the micro-fluidic chip provided by the scheme is adopted, the particle size of the lipid nano particles gradually reduces along with the rising of the mixing flow rate, and when the mixing flow rate reaches or exceeds 24ml/min, the particle size of the lipid nano particles is minimum, and the uniformity of the particle size of the prepared lipid nano particles is highest (namely the PDI value is minimum).

In other embodiments, the aqueous phase may also be a solution containing mRNA, and the mRNA-containing aqueous phase and the oil phase are mixed within the microfluidic chip to form mRNA-coated lipid nanoparticles. By applying the microfluidic chip provided by the scheme to other product lines and observing the properties of the prepared lipid nanoparticles containing mRNA, the method can be used for finding: under the influence of factors that the particle size and uniformity of the lipid nano particles prepared by adopting the microfluidic chip meet the requirements, the encapsulation rate of the prepared lipid nano particles on mRNA can be stabilized to be more than 90%, which is higher than that of the prior art, wherein 80% is generally used as a qualified evaluation standard.

Example 2

As shown in fig. 5, this embodiment also provides a microfluidic chip, in which the micro flow channel structure 11 on the microfluidic substrate 1 is substantially the same as that provided in embodiment 1, and the main difference is that:

(1) The included angle β between the first inlet flow channel 1111 and the second inlet flow channel 1112 is 160 °, and by further increasing the included angle between the first inlet flow channel 1111 and the second inlet flow channel 1112 on the basis of embodiment 1, the two mediums can generate relatively larger impact force at the connection position, so as to further improve the primary mixing effect.

(2) The primary mixing channel 114 of the mixing channel 112 is located at the angular bisector D of the first inlet channel 1111 and the second inlet channel 1112, and the primary mixing channel 114 is symmetrically disposed with respect to the first inlet channel 1111 and the second inlet channel 1112, so that the injection condition of the water phase from the left side or the right side is kept consistent.

While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the principles and spirit of the invention, but such changes and modifications fall within the scope of the invention.

Claims (10)

1. The microfluidic chip comprises a microfluidic substrate, wherein a micro-channel structure is arranged on the surface of the microfluidic substrate, and the microfluidic chip is characterized in that the micro-channel structure sequentially comprises a liquid inlet channel, a mixed channel and a liquid outlet channel which are communicated with each other along the flow direction of a medium, a primary mixed channel and a secondary mixed channel are sequentially arranged on the mixed channel, and the secondary mixed channel comprises a diversion channel and a confluence channel;

the two-stage mixing flow channel comprises two flow dividing parts which are arranged in an angle way, wherein the input ends of the two flow dividing parts are communicated, and the inlet of the two-stage mixing flow channel is formed at the communication position of the flow dividing parts;

the converging channel is arc-shaped, two input ends of the converging channel are respectively communicated with the output ends of the two flow dividing parts, and an outlet of the secondary mixing flow channel is formed at the most downstream part of the converging channel along the medium flowing direction.

2. The microfluidic chip according to claim 1, wherein the mixing channels comprise a plurality of secondary mixing channels, the inlet of the first secondary mixing channel is communicated with the outlet of the primary mixing channel along the flow direction of the medium, the inlets of the remaining secondary mixing channels are communicated with the outlet of the previous secondary mixing channel, and the outlet of the last secondary mixing channel is communicated with the liquid outlet channel.

3. The microfluidic chip according to claim 2, wherein the number of the secondary mixing channels is 3 or more;

and/or the number of the secondary mixing flow passages is less than or equal to 10.

4. The microfluidic chip of claim 1, wherein said inlet flow channel comprises a first inlet flow channel having a first inlet for a first liquid into said microchannel structure and a second inlet flow channel having a second inlet for a second liquid into said microchannel structure;

the output ends of the first liquid inlet flow channel and the second liquid inlet flow channel are communicated with the mixing flow channel;

the included angle between the first liquid inlet flow channel and the second liquid inlet flow channel ranges from 120 degrees to 170 degrees.

5. The microfluidic chip according to claim 4, wherein the primary mixing channel is arranged obliquely toward one side of the liquid inlet channel where the liquid inlet flow rate is large;

or, the primary mixing runner is arranged along an angular bisector of the first liquid inlet runner and the second liquid inlet runner.

6. The microfluidic chip of claim 1, wherein the fluid outlet channel is arcuate.

7. The microfluidic chip according to claim 6, wherein the liquid outlet channels are curved in an arc direction of the same curvature.

8. The microfluidic chip according to any one of claims 1 to 7, wherein an included angle between two of the split portions ranges from 30 ° to 120 °.

9. The microfluidic chip according to any one of claims 1 to 7, wherein,

the width of the flow channel of the micro-flow channel structure is in the range of 0.2-0.4 mm;

and/or the flow channel depth of the micro flow channel structure is in the range of 0.2-0.4 mm.

10. A microfluidic device comprising a microfluidic chip according to any one of claims 1-9.