CN115957836A - Multifunctional micro-channel array liquid drop generator and using method thereof - Google Patents

Abstract

The invention discloses a multifunctional micro-channel array liquid drop generator, which comprises a sample barrel body, wherein the middle part of the sample barrel body is provided with a water phase channel which penetrates through the sample barrel body from top to bottom, and the water phase channel is used for containing a water phase or used as a water phase inlet; the upper end face of the chip is in bonded connection with the bottom face of the sample barrel body and surrounds the periphery of the chip, a plurality of micro-channel arrays are carved on the periphery of the chip, a solution main flow channel which is matched and communicated with the water phase channel is formed in the middle of the chip, and a plurality of solution auxiliary flow channels which are evenly distributed are formed in the periphery of the circular solution main flow channel in an outward dispersing mode. The invention can realize the high-flux accurate preparation method of uniform liquid drops by means of hand-held injection, injection by an injection pump or batch centrifugation, overcomes the problem of higher cost of the existing liquid drop generating device and a control instrument thereof, can generate liquid drops anytime and anywhere with high flux, can also carry out a large number of parallel experiments, and meets the requirements of different application scenes.

Description

Multifunctional micro-channel array liquid drop generator and using method thereof

Technical Field

The invention relates to a liquid drop generating technology, in particular to a multifunctional micro-channel array liquid drop generator and a using method thereof.

Background

The stable and uniform water-in-oil droplet microreactor (water-in-oil droplet microreactor) has wide application prospect in the biomedical fields of single cell sequencing, molecular diagnosis, hydrogel microsphere synthesis and the like. Microfluidic technology is a versatile method of forming uniform droplets by controlling the movement of fluids in microchannels. However, the existing microfluidic chip usually needs to be additionally provided with expensive and heavy auxiliary equipment and a complex operation mode, so that the use cost and the labor cost are increased, and the application scenarios are limited. Therefore, a simple and convenient multifunctional liquid drop generation method needs to be developed, so that the cost is reduced, and the use requirements of different application scenes are met.

Therefore, the auxiliary equipment matched with the liquid drop generator in the prior art is expensive, the use environment is limited, and the technical requirements of use under different scenes cannot be met.

Disclosure of Invention

It is an object of the present invention to provide a multi-functional micro-channel array droplet generator and a method of using the same to solve the above-mentioned problems of the background art.

In order to achieve the purpose, the invention provides the following technical scheme: a multi-functional microchannel array droplet generator, comprising:

the sample barrel body is provided with a water phase channel which penetrates through the middle part of the sample barrel body from top to bottom, and the water phase channel is used for containing a water phase or used as a water phase inlet;

the chip, its up end with bonding connection between the bottom surface of sample staving encircles the periphery of chip is carved with a plurality of microchannel array, the middle part of chip set up with the solution sprue of aqueous phase channel adaptation intercommunication, the periphery of solution sprue is outwards dispersed and is seted up the solution of a plurality of even arrangement and assists the runner.

Preferably, the microchannel array comprises lugs surrounding the periphery of the chip and arranged at intervals in sequence, wherein the lugs are adjacent at will, a microchannel is formed between the lugs, the tail end of the microchannel is in a horn shape, and the horn mouth of the microchannel is arranged outwards.

Preferably, the upper end of the bump is higher than the upper end face of the chip, a clamping block is arranged at each corner of six edges of the chip, a clamping groove is formed in the bottom face of the sample barrel body corresponding to the clamping block, and the clamping block is clamped in the clamping groove to realize connection;

the micro-channel and the bottom surface of the sample barrel body form a gap for dispersing the water phase in the sample solution into the oil phase.

Preferably, the chip is made of silicon, the chip is of a hexagonal prism structure formed by surrounding six edges, each solution auxiliary flow channel is arranged in the middle of each edge, a convergence groove for converging and flowing sample solution is formed between each solution auxiliary flow channel and the rear end face of each bump, and the convergence groove is communicated with the solution auxiliary flow channels;

the sample barrel body is made of plastic and is of a hexagonal prism structure, and the sample barrel body is matched with the chip in shape.

Preferably, a water phase cup for containing the sample solution is arranged in the water phase channel.

Preferably, the chip adopts a gradient emulsification principle, and the size of generated liquid drops is matched with the shape and the size of the micro-channel.

The invention also discloses a use method of the multifunctional micro-channel array liquid drop generator, and the multifunctional micro-channel array liquid drop generator comprises the following steps:

immersing the chip part of the liquid drop generator into a centrifugal tube containing an oil phase;

adding a sample solution serving as a water phase into the water phase channel;

will through pressure generation device water phase among the water phase passageway is crowded into in the chip, the water phase is along the solution mainstream way of chip outwards spread each solution and is assisted the runner to assist the runner through the solution and spread to the microchannel array, later through the microchannel array in dispersing the oil phase in the centrifuging tube, produce the liquid drop.

Preferably, the pressure generating device is a micro-syringe, the outlet end of the micro-syringe is connected with the water phase channel by holding the micro-syringe, and the water phase is squeezed into the chip by the pressure generated by injection and is dispersed into the oil phase to generate liquid drops.

Preferably, the pressure generating device is an injection pump and a microinjector, the injection pump is connected with the microinjector, the outlet end of the microinjector is connected with the water phase channel, and the water phase is extruded into the chip and dispersed into the oil phase to generate liquid drops by the pressure generated by the injection pump on the microinjector.

Preferably, the pressure generating device is a centrifuge, the centrifuge is provided with a plurality of installation slots which are uniformly distributed, the chip is immersed in a centrifugal tube containing oil to form a droplet generating device, a water phase is added through a water phase channel, the droplet generating device is placed into the installation slots in batches, the centrifuge is started, and the water phase is thrown into the oil phase through centrifugal force of the centrifuge to generate droplets in batches.

Compared with the prior art, the liquid drop generator is simple and efficient, the method for realizing high-flux accurate preparation of uniform liquid drops by means of handheld injection, injection by an injection pump or batch centrifugation overcomes the problem of higher cost of the existing liquid drop generator and a control instrument thereof, liquid drops can be generated at any time and any place, liquid drops can be generated at high flux, a large number of parallel experiments can be carried out, the requirements of different application scenes are met, the uniformity of the sizes of the generated liquid drop particles can be ensured, and the CV value of the sizes of the liquid drop particles can be effectively improved.

Drawings

FIG. 1 is a schematic diagram of a chip in a drop generator according to the present invention;

FIG. 2 is a schematic diagram of a sample barrel structure of a droplet generator according to the present invention;

FIG. 3 is a schematic diagram of a drop generator according to the present invention;

FIG. 4 is a schematic view of the installation structure of the centrifugal tube of the present invention in the droplet generation process;

FIG. 5 is a schematic view of the mounting structure of the water cup and centrifuge tube of the present invention in the formation of droplets;

FIG. 6 is a schematic diagram of a first embodiment of the present invention in which a micro-syringe is held by hand to squeeze a droplet;

FIG. 7 is a schematic diagram of a second embodiment of the present invention illustrating the formation of droplets by syringe pump extrusion;

FIG. 8 is a schematic view showing a structure of forming liquid droplets by centrifugal force of a centrifugal pump according to a third embodiment of the present invention;

FIG. 9 shows the droplet patterns generated by hand-held injection by different experimenters in the first embodiment;

FIG. 10 is a second embodiment of the droplet formation produced at different flow rates;

FIG. 11 shows the morphology of droplets produced with the proviso that a different oil phase is used in the second embodiment;

FIG. 12 shows the droplet morphology produced at different centrifugation rates in the third example.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Referring to fig. 1 to 3, the invention provides a multifunctional micro-channel array droplet generator, which comprises a sample barrel body 2 and a chip 1, wherein the sample barrel body 2 is preferably made of plastic and has a hexagonal prism structure, a water phase channel 4 penetrating up and down is formed in the middle of the sample barrel body 2, the water phase channel 4 can be used for containing a water phase or used as a water phase inlet after being bonded with the chip 1, and the droplet generator has higher integration level.

In another embodiment, referring to fig. 5, a water phase cup 8 for containing a sample solution can be installed in the water phase channel 4, that is, the water phase cup is inserted into the water phase channel 4, an outer rim 801 protrudes outwards from the upper end of the water phase cup 8, and the diameter of the outer rim 801 is larger than that of the water phase channel 4, so that when the water phase cup 8 is inserted into the water phase channel 4, the outer rim 801 plays a role of limiting the position of the water phase cup 8, and simultaneously, the water phase cup 8 can be prevented from falling into the water phase channel 4. The sample solution can also be called as water phase, and then can be assembled with a standard injector port through the water phase cup 8, and the sample solution has the characteristics and innovation points of portability, high integration level and high matching height with a common injector and a centrifuge tube in a laboratory.

Bonding between the up end of chip 1 and the bottom surface of sample staving 2 is connected, the periphery that encircles chip 1 is carved with a plurality of microchannel array, the solution sprue 31 that communicates with 4 adaptations of water phase channel is seted up at the middle part of chip 1, sample solution flows into in the solution sprue 3 through water phase channel 4, the solution that a plurality of was evenly arranged is assisted runner 31 to outwards dispersing in the periphery of circular shape solution sprue 3, sample solution passes through sprue 3 and toward outside the dispersion flow each solution is assisted in the runner 31.

Wherein, the microchannel array is including encircleing 1 the periphery of chip is interval arrangement's lug 5 in proper order, arbitrary adjacent two form microchannel 6 between the lug 5, microchannel 6 is used for supplying sample solution to flow in and form the liquid drop that generates through microchannel 6, and microchannel 6's end is the loudspeaker form, and microchannel 6's horn mouth outwards sets up. The shape and the size of the micro-channel 6 determine the size of generated liquid drop particles, the uniformity of the size of the liquid drop can be effectively ensured, and further the CV value of the size of the liquid drop particles is effectively improved.

The upper end of the bump 5 is higher than the upper end face of the chip 1, the corners of the periphery of the chip 1 are provided with fixture blocks 71, the bottom face of the sample barrel body 2 is provided with clamping grooves corresponding to the fixture blocks 71, and the fixture blocks 71 are clamped in the clamping grooves to realize connection; since the upper end surface of the bump 5 is higher than the upper end surface of the chip 1 by a certain distance, after the chip 1 and the sample barrel 2 are connected, the micro-channel 6 and the bottom surface of the sample barrel 2 form a gap for dispersing the water phase in the sample solution into the oil phase, i.e. a channel for forming liquid drops by reaction.

In the invention, the chip 1 is made of silicon, the chip 1 is a hexagonal prism structure formed by enclosing six edges 7, the shape of the sample barrel body 2 is matched with that of the chip 1, each solution auxiliary flow passage 31 is arranged in the middle of each edge 7, a converging groove 32 for converging and flowing a sample solution is formed between each solution auxiliary flow passage 31 and the rear end face of the bump 5, and the converging groove 32 is communicated with the solution auxiliary flow passages 31, so that the sample solution flows into the converging groove 32 in a centralized manner through each solution auxiliary flow passage 31 and flows into the micro-channels 6 through the converging groove 32 respectively to form smooth flow of a water phase.

The design of the liquid drop generator of the device is based on a step emulsification principle, is a preparation method for spontaneously forming liquid drops by inducing Laplace pressure difference through a geometric shape, is mainly driven by interfacial tension instead of a high-energy shearing stress system, and theoretically has the characteristics of low shearing, insensitivity to flow, simple structure and easiness in integration because the size of the liquid drops is independent of the flow rates of a continuous phase and a disperse phase. The liquid drop generator of the device can generate liquid drops with uniform particles under the conditions of different pressures, different speeds and the like.

Referring to fig. 4-8, the present invention also discloses a method for using a multifunctional micro-channel array droplet generator, which uses the multifunctional micro-channel array droplet generator described above, and comprises the following steps:

immersing part of a chip 1 of the drop generator into a centrifugal tube 9 filled with an oil phase, wherein the preferable volume of the centrifugal tube is 1.5ml;

adding a sample solution as an aqueous phase into the aqueous phase channel 4;

the water phase in the water phase channel 4 is squeezed into the chip 1 by the pressure generating device, the water phase is diffused to each auxiliary flow channel 31 along the main flow channel 3 of the chip, and is diffused to each micro-channel 6 of the micro-channel array through the auxiliary flow channel 31, and then is dispersed to the oil phase in the centrifugal tube 9 through the micro-channel array, and liquid drops are generated under the pressure of the pressure generating device.

The pressure generating device can be flexibly selected according to the requirement, is suitable for various environments and can generate liquid drops with basically consistent sizes under the action of various extrusion forces.

Referring to fig. 6, the pressure generating device is a micro-syringe 81, in the using process, the chip 1 and other structures are immersed in a centrifuge tube 9 containing oil, the micro-syringe 81 is held by hand, the outlet end of the micro-syringe 81 is connected with a water phase channel 4, the water phase is squeezed into the chip 1 by the pressure generated by injection, sequentially passes through a main flow channel 3, an auxiliary flow channel 31, a converging tank 32 and a micro-channel 6, and is dispersed into the oil phase through the micro-channel 6 to generate liquid drops.

The greatest innovation of using the hand-held micro-injector 81 is that the liquid drop can be stably generated in a hand-held manner, no cumbersome auxiliary equipment (such as a syringe pump) is needed, the liquid drop is not needed to be generated in a fixed scene, and the use cost is reduced.

Referring to fig. 9, different experimenters produce liquid drops in a handheld injection mode, the liquid drops are uniform in size, different personnel have small errors, the operation is simple, any student can use the liquid drops to operate, the operation is clear at a glance, professional training is not needed, and the application scene is expanded to a great extent.

Referring to fig. 7, the pressure generating means is a syringe pump 82 used in conjunction with a micro syringe 81, and the syringe pump 82 is connected to the micro syringe 81, in which case pressure is automatically applied to the micro syringe 81 by the syringe pump 82 without providing a pressure source by hand.

The outlet end of the micro-injector 81 is connected with the water phase channel 4, the water phase is extruded into the chip 1 through the pressure generated by the injection pump 82 on the micro-injector 81, passes through the main channel 3, the auxiliary channel 31, the merging groove 32 and the micro-channel 6 in sequence, and is dispersed into the oil phase 91 in the centrifuge tube 9 through the micro-channel 6 to generate liquid drops.

The biggest innovation point of the embodiment is that power sources do not need to be provided manually, the automatic operation is realized, the intellectualization is improved, the liquid drops can be continuously generated at high flux, and the generation rate of the liquid drops can reach dozens of mL/h.

Referring to fig. 10, it can be seen that the injection by the injection pump 82 can produce droplets continuously at high throughput, and at lower flow rates (less than 1000 μ l/hr), the size of the droplets is more uniform, and when the flow rate is increased, the size of the droplets is slightly increased and the size uniformity is slightly decreased. It should be noted that the flux of forming droplets can be further increased by increasing the number of internal aqueous phase channels of the chip 1, which satisfies the demand for mass production of droplets in industry.

In addition, the dispersed phase is compatible with both mineral oil and fluorinated oil, as shown in fig. 11, and when 7500 fluorinated oil is used as the dispersed phase, the uniformity of the droplets can be ensured.

Referring to fig. 8, the pressure generating device is a centrifuge 83, a plurality of installation slots 84 are uniformly arranged on the centrifuge 83, the installation slots 84 are used for being inserted into the packaged droplet generating device, the chip 1 is immersed into the centrifuge tube 9 containing oil to form the droplet generating device, a water phase is added through the water phase channel 4, the droplet generating device is placed into the installation slots 84 in batches, the centrifuge 83 is started, the water phase is thrown into the oil phase 91 through the centrifugal force of the centrifuge 83 to generate droplets in batches, the specific liquid flow direction still passes through the main flow channel 3, the auxiliary flow channel 31, the merging slot 32 and the micro channel 6 in sequence, and is dispersed into the oil phase 91 in the centrifuge tube 9 through the micro channel 6 to generate droplets.

The largest innovation point of the embodiment is that the existing centrifugal machine in a laboratory can be used for producing liquid drops, and a matching device is not required to be additionally purchased, so that the use cost is saved; in addition, can carry out the experiment through centrifuge in batches, practice thrift time cost and human cost, improve the efficiency of production.

The liquid drops can be simultaneously produced in large quantities by a centrifugal liquid drop production mode, as shown in figure 12, when the centrifugal speed is 100-200 g, only 1 minute of centrifugation is needed, and 30 mu L of water phase can completely generate the liquid drops, and the liquid drops can be ensured to have good uniformity and stability.

In the above three embodiments, the same applies if the water phase cup 8 is filled in the water phase passage 4.

In conclusion, the invention discloses a simple and efficient method for realizing high-flux accurate preparation of uniform liquid drops by means of handheld injection, injection by an injection pump or batch centrifugation, which overcomes the problem of higher cost of the conventional liquid drop generating device and matched instruments thereof, can generate liquid drops at any time and any place, can generate liquid drops at high flux quickly, can also carry out a large number of parallel experiments, meets the requirements of different application scenes, and has practical application value in the aspect of molecular diagnosis; meanwhile, the invention has the characteristics of ensuring the uniformity of the size of the generated liquid drop particles and effectively improving the CV value of the size of the liquid drop particles.

In the description of the present invention, it should be noted that the terms "upper", "lower", "front", "rear", "inner", "outer", and the like indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience of description and simplification of description, but do not indicate or imply that the referred device or element must have a specific orientation, be constructed in a specific orientation, and be operated, and thus, should not be construed as limiting the present invention.

In the description of the present invention, it should be noted that, unless otherwise explicitly specified or limited, the terms "mounted," "connected," and "connected" are to be construed broadly, e.g., as meaning either a fixed connection, a removable connection, or an integral connection; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The specific meaning of the above terms in the present invention can be understood by those of ordinary skill in the art through specific situations.

Although the preferred embodiments of the present patent have been described in detail, the present patent is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present patent within the knowledge of those skilled in the art.

Claims (10)

1. A multi-functional microchannel array droplet generator, comprising:

the device comprises a sample barrel body (2), wherein a water phase channel (4) which penetrates through the sample barrel body (2) up and down is formed in the middle of the sample barrel body (2), and the water phase channel (4) is used for containing a water phase or used as a water phase inlet;

chip (1), its up end with the bonding is connected between the bottom surface of sample staving (2), encircles the periphery of chip (1) is carved with a plurality of microchannel array, the middle part of chip (1) seted up with solution sprue (3) of water phase channel (4) adaptation intercommunication, the periphery of solution sprue (3) outwards diverges and sets up solution that a plurality of was evenly arranged and assists runner (31).

2. A multi-functional microchannel array droplet generator and method of use thereof as claimed in claim 1, wherein: the microchannel array is including encircleing lug (5) of interval arrangement in proper order of the periphery of chip (1), arbitrary adjacent two form microchannel (6) between lug (5), the end of microchannel (6) is the loudspeaker form, the horn mouth of microchannel (6) sets up outwards.

3. The multifunctional micro-channel array droplet generator of claim 1, wherein the upper end of the bump (5) is higher than the upper end surface of the chip (1), a fixture block (71) is arranged at each corner of six edges of the chip (1), a clamping groove is arranged on the bottom surface of the sample barrel body (2) corresponding to the fixture block (71), and the fixture block (71) is clamped into the clamping groove to realize connection;

the micro-channel (6) and the bottom surface of the sample barrel body (2) form a gap for dispersing the water phase in the sample solution into the oil phase.

4. The multifunctional microchannel array droplet generator of claim 1, wherein the chip (1) is made of silicon, the chip (1) is a hexagonal prism structure formed by enclosing six edges (7), each solution auxiliary channel (31) is arranged in the middle of each edge (7) and forms a merging groove (32) for the sample solution to flow together with the back end surface of the bump (5), and the merging groove (32) is communicated with the solution auxiliary channels (31);

the sample barrel body (2) is made of plastic and is of a hexagonal prism structure, and the sample barrel body (2) is matched with the chip (1) in shape.

5. A multifunctional microchannel array droplet generator as claimed in claim 1 wherein the aqueous phase channel (4) is provided with an aqueous phase cup for holding a sample solution.

6. A multifunctional microchannel array droplet generator as claimed in claim 2 wherein the chip (1) employs the principle of gradient emulsification and the size of the generated droplets is adapted to the shape and size of the microchannels (6).

7. A method of using a multifunctional microchannel array droplet generator, wherein the multifunctional microchannel array droplet generator of any one of claims 1-6 is used, comprising the steps of:

partially immersing a chip (1) of the liquid drop generator into a centrifugal tube (9) filled with an oil phase;

adding the water phase channel (4) into the sample solution as the water phase;

it will to push into through the pressure generation device aqueous phase in the aqueous phase passageway (4) in chip (1), the aqueous phase is along solution mainstream way (3) of chip outdiffusion to each solution and assists runner (31) to assist in the runner (31) through the solution and diffuse to the microchannel array, later disperse through the microchannel array in the oil phase in centrifuging tube (9), produce the liquid drop.

8. The use of a multifunctional microchannel array droplet generator as claimed in claim 7 wherein the pressure generating means is a micro-injector (81) and the outlet end of the micro-injector is connected to the aqueous phase channel (4) by holding the micro-injector, and the pressure generated by injection squeezes the aqueous phase into the chip (1) and disperses it into the oil phase to produce droplets.

9. The use method of the multifunctional microchannel array droplet generator in claim 7, wherein the pressure generating device is a syringe pump (82) and a micro injector (81), the syringe pump (82) is connected with the micro injector (81), the outlet end of the micro injector (81) is connected with the water phase channel (4), and the water phase is squeezed into the chip (1) and dispersed into the oil phase to generate the droplets by the pressure generated by the syringe pump (82) to the micro injector (81).

10. The use method of the multifunctional micro-channel array droplet generator according to claim 7, wherein the pressure generating device is a centrifuge (83), the centrifuge (83) is provided with a plurality of installation grooves (84) which are uniformly distributed, the chip (1) is immersed in a centrifuge tube (9) containing oil to form the droplet generating device, a water phase is added through a water phase channel (4), the droplet generating device is placed in the installation grooves (84) in batches, the centrifuge (83) is started, and the water phase is thrown into the oil phase through centrifugal force of the centrifuge (83) to generate droplets in batches.

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