Microfluidic chip and method for preparing droplets

Abstract

The present invention relates to a microfluidic chip, wherein a first syringe needle and a second syringe needle are connected to an alignment box relative to each other and define a first channel, a third syringe needle is connected to the alignment box and defines a second channel leading to the first channel, a first sealing tube and a second sealing tube are respectively and sealingly inserted into opposite ends of the first channel, a first capillary is sealingly inserted into the first sealing tube for installation, and a second capillary is sealingly inserted into the second sealing tube for installation, and by means of elastic alignment of the first sealing tube and the second sealing tube, the tapered tip of the first capillary is coaxially opposite the inner end of the second capillary to provide a droplet generation area. The present invention also relates to a method for preparing droplets using the above-mentioned microfluidic chip. According to the microfluidic chip of the present invention, non-adhesive sealing, coaxial alignment and fixation, and convenient sampling are achieved at a low cost, and it can be disassembled, cleaned, and reused, which will have important application value for the promotion of microfluidic chips and the preparation of microdroplets.

Description

Technical Field

[0001] The present invention relates to a chip, and more particularly to a microfluidic chip and a method for preparing droplets. Background Art

[0002] Microfluidics is the technology for manipulating tiny volumes of liquid within micron-scale chip channels. It enables the production of highly monodisperse microdroplets with highly controllable size and structure. These droplets provide excellent templates for preparing highly monodisperse microparticles with diverse structures and are widely used in drug delivery, bio-templating, cell culture, and microreactors.

[0003] Common droplet preparation microfluidic chips are categorized as flat-plate and capillary. Flat-plate chips are often made of polymers (expensive batch injection molding and low PDMS production efficiency), are not resistant to high temperatures and corrosion from organic solutions, and are difficult to disassemble and assemble, hindering cleaning and reuse. Glass capillary microfluidic chips utilize capillaries as the functional units for droplet generation and collection. Due to glass's exceptional light transmittance, high pressure resistance, biocompatibility, stable surface properties, and resistance to organic solvent corrosion, these chips have become widely used devices for microdroplet preparation.

[0004] Glass capillary microfluidic chip devices usually coaxially nest hollow capillaries of different thicknesses. This coaxially nested microchannel structure can realize the preparation of single emulsion microdroplets or multiple emulsion microdroplets with a core-shell structure. CN106622407A provides a microfluidic chip that uses a glass slide and glass capillaries to form a structure, and uses an adhesive to connect and fix the glass capillaries through a dispensing needle. This assembled microfluidic chip can be constructed by manual operation. Patent documents for coaxial construction of capillaries also include CN102580799A. This technology cuts a microchannel on a glass slide, inserts a glass capillary into the microchannel, and bonds and seals the glass slide and the interface with an adhesive. CN112517096A discloses a method of using 3D printing technology to prepare a chip substrate using materials such as plastic, metal, and polymer, and using a needle platform, a needle device, and a fixture to construct a capillary microfluidic chip.

[0005] The above technical solutions provide methods for coaxially arranging and fixing capillaries, and their common point is modular chip assembly. It should be pointed out that the chip assembly process is manual, which can easily lead to the problem of not being able to ensure precise three-dimensional coaxial arrangement of the capillaries. Secondly, adhesives are used to fix the capillaries and / or seal the microchannels within the chip. These adhesives are not resistant to organic solvents and are prone to leakage. Once the chip is partially blocked or otherwise damaged, the liquid cannot flow normally, causing the chip to be scrapped, seriously reducing the chip's production efficiency and quality. Among the technical contents of the currently disclosed capillary microfluidic chips, most are constructed in a modular splicing manner, including glass capillaries, microchannel structures, sample injection structures, fixing structures, and sealing structures. This construction method involves multiple sealing links, has high requirements for connectors, and cannot avoid the use of adhesives. At the same time, it is difficult to ensure the sealing of the chip. In addition to the coaxial position relationship of the capillaries, the fixation of the capillaries and the sealing of the microchannels have always been technical difficulties of capillary microfluidic chips.

[0006] Patents CN113797986A and CN113058669A solve the above problems to a certain extent, but the specially designed assembly parts all have threads and require very high precision, and the cost is relatively high (hundreds of yuan). Summary of the Invention

[0007] In order to solve the problems in the above-mentioned prior art such as difficulty in coaxial alignment of capillaries, unstable device sealing, easy damage of glass capillaries, high processing precision requirements (high cost) of threaded connectors, etc., the present invention provides a microfluidic chip and a method for preparing droplets.

[0008] According to the microfluidic chip of the present invention, it includes an alignment box, a first syringe needle, a second syringe needle, a third syringe needle, a first sealing tube, a second sealing tube, a first capillary and a second capillary, wherein the first syringe needle and the second syringe needle are connected to the alignment box relative to each other and define a first channel, the third syringe needle is connected to the alignment box and defines a second channel leading to the first channel, the first sealing tube and the second sealing tube are respectively sealedly inserted at opposite ends of the first channel, the first capillary is sealedly inserted into the first sealing tube for installation, and the second capillary is sealedly inserted into the second sealing tube for installation, and with the help of elastic alignment of the first sealing tube and the second sealing tube, the tapered tip of the first capillary is coaxially opposite to the inner end of the second capillary to provide a droplet generation area.

[0009] Preferably, the first capillary tube connects the inner cavity of the first syringe needle and the first channel, the second capillary tube connects the first channel and the inner cavity of the second syringe needle, and the tapered tip of the first capillary tube is inserted into the inner end of the second capillary tube just below the second channel.

[0010] Preferably, the alignment box has a box body, a first protruding tube, a second protruding tube and a third protruding tube, the first protruding tube extends from the left side of the box body, the second protruding tube extends from the right side of the box body, the third protruding tube extends from the upper side of the box body, the first syringe needle sleeve is connected to and communicated with the first protruding tube, the second syringe needle sleeve is connected to and communicated with the second protruding tube, and the third syringe needle sleeve is connected to and communicated with the third protruding tube.

[0011] Preferably, the second channel is vertically connected to the middle of the first channel to form a T-shaped internal channel.

[0012] Preferably, the first or second sealing tube is a silicone or rubber tube.

[0013] Preferably, the microfluidic chip includes two alignment boxes, two first syringe needles, two second syringe needles, two third syringe needles, a first capillary and a second capillary, wherein one first syringe needle, one second syringe needle and one third syringe needle are connected to one alignment box to provide a first module, and another first syringe needle, another second syringe needle and another third syringe needle are connected to another alignment box to provide a second module.

[0014] Preferably, the microfluidic chip also includes two first sealing tubes, two second sealing tubes and a connecting tube connecting the first module and the second module, wherein the two first sealing tubes and the two second sealing tubes are respectively sealedly inserted into the opposite ends of the first channels of the first module and the second module, one end of the connecting tube passes through the second syringe needle and the second sealing tube of the first module, is inserted into the first channel and terminates below the second channel, and the other end of the connecting tube passes through the first syringe needle and the first sealing tube of the second module, is inserted into the first channel and terminates below the second channel.

[0015] Preferably, the first capillary tube is installed through the first sealing tube and the second sealing tube of the first module in sequence to connect the inner cavity of the first syringe needle of the first module and the inner cavity of the connecting tube, and the second capillary tube is installed through the second sealing tube and the first sealing tube of the second module in sequence to connect the inner cavity of the second syringe needle of the second module and the inner cavity of the connecting tube.

[0016] According to the method for preparing droplets using the above-mentioned microfluidic chip of the present invention, the inner phase enters the first capillary through the first syringe needle, the outer phase enters the second channel through the third syringe needle, and the droplets generated at the tapered tip of the first capillary are discharged through the second capillary and the second syringe needle.

[0017] Preferably, multiple microfluidic chips are nested to prepare multiple emulsions.

[0018] The microfluidic chip of the present invention can realize sealing, coaxial alignment fixation and convenient sampling by non-adhesive process at low cost, and can be disassembled, cleaned and reused, which will have important application value for the promotion of microfluidic chips and the preparation of microdroplets. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Schematic diagram of the overall structure of a microfluidic chip according to a preferred embodiment of the present invention.

[0020] Figure 2 yes Figure 1 Exploded view of the microfluidic chip.

[0021] Figure 3 yes Figure 2 A perspective view of the alignment box.

[0022] Figure 4 yes Figure 2 Cross-sectional view of the alignment box.

[0023] Figure 5 yes Figure 1 Cross-sectional view of the microfluidic chip.

[0024] Figure 6 Corresponding to Figure 5 Showing the working mechanism of the microfluidic chip.

[0025] Figure 7 is a microscopic image of the obtained droplet.

[0026] Figure 8 is the obtained droplet diameter distribution histogram.

[0027] Figure 9 The diameters of the droplets produced at different flow rates are shown.

[0028] Figure 10 FIG. 4 is a schematic diagram of the overall structure of a microfluidic chip according to another preferred embodiment of the present invention.

[0029] Figure 11 yes Figure 10 A cross-sectional view of the microfluidic chip is shown, illustrating its mechanism of action. DETAILED DESCRIPTION

[0030] The preferred embodiments of the present invention are given below in conjunction with the accompanying drawings and described in detail.

[0031] like Figure 1-Figure 2As shown, a microfluidic chip according to a preferred embodiment of the present invention includes an alignment box 1, a first syringe needle 2, a second syringe needle 3 and a third syringe needle 4, wherein the alignment box 1 is a core module, which has a box body 11, a first convex tube 12, a second convex tube 13 and a third convex tube 14, the first convex tube 12 extends from the left side of the box body 11, the second convex tube 13 extends from the right side of the box body 11, and the third convex tube 14 extends from the upper side of the box body 11, the first syringe needle 2 is sleeved on the first convex tube 12 and connected thereto, the second syringe needle 3 is sleeved on the second convex tube 13 and connected thereto, and the third syringe needle 4 is sleeved on the third convex tube 14 and connected thereto.

[0032] It should be understood that the material of the alignment box 1 is not limited and it can be formed by 3D printing, machining or injection molding. The preferred material is plastic, cured resin or metal.

[0033] like Figure 3-Figure 4 As shown, the first and second protruding tubes 12, 13 are positioned opposite each other and, together with the housing 11, define a first, linear channel 15. The third protruding tube 14 and the housing 11 define a second channel 16, with the first and second channels 15 and 16 vertically connected. In this embodiment, the second channel 16 connects from above to the middle of the first channel 15, forming an inverted T-shaped internal channel. In this embodiment, the inner diameter of the inverted T-shaped internal channel is 3 mm.

[0034] Back to Figure 2 According to a preferred embodiment of the present invention, the microfluidic chip further comprises a first sealing tube 5, a second sealing tube 6, a first capillary 7 and a second capillary 8, Figure 5 The first sealing tube 5 and the second sealing tube 6 are respectively inserted into opposite ends of the first channel 15. The first capillary 7 is inserted into the first sealing tube 5 to connect the inner cavity of the first syringe needle 2 with the first channel 15. The second capillary 8 is inserted into the second sealing tube 6 to connect the first channel 15 with the inner cavity of the second syringe needle 3. The tapered tip of the first capillary 7 is inserted into the inner end of the second capillary 8 directly below the second channel 16. In this embodiment, the inner diameter of the sealing tubes 5 and 6 is 0.1 mm smaller than the outer diameter of the capillaries 7 and 8, thereby achieving a seamless seal through an interference fit. In this embodiment, the first capillary 7 is drawn using a needle puller. The tapered tip at the front end facilitates the preparation of microdroplets. The preferred inner diameter of the tip is 10 μm to 200 μm.

[0035] In particular, the sealing tubes 5 and 6 are highly elastic tubes, such as silicone or rubber tubes, which are positioned between the alignment box 1 and the capillaries 7 and 8 to achieve a seal between the two. It should be understood that silicone or rubber tubes are commercially available products with excellent elasticity, and their inner and outer diameters are precisely coaxial. The sealing tubes 5 and 6 are automatically sealed by inserting and assembling them into the first channel 15 so that their outer diameters match the inner diameter of the first channel 15. The axes of the sealing tubes 5 and 6 are correspondingly concentrically arranged. When the capillaries 7 and 8 are inserted into the sealing tubes 5 and 6, they are subjected to the squeezing force of the silicone or rubber tubes. The consistent wall thickness results in consistent pressure, and the capillaries 7 and 8 automatically assume the axial position, eliminating the need for various adhesives and threaded parts. In other words, the capillaries 7 and 8 are automatically coaxial after assembly.

[0036] It should be understood that the syringe needles 2, 3, and 4 are commercially available products and can be made of plastic or metal. Figure 5 The syringe needles 2, 3, and 4 include a fixedly connected needle 21 and a connector 22, wherein the needle 21 is a thin head and the connector 22 is a flared structure. The connector 22 is directly sleeved on the connecting tubes 12, 13, and 14 of the alignment box 1 (see Figure 2 ) can be conveniently and reliably assembled, achieving a seal between the alignment cartridge 1 and the syringe needles 2, 3, and 4 in a simple and efficient manner. In this embodiment, the inner diameter of the needle 21 is larger than the outer diameter of the capillaries 7 and 8, ensuring that the capillaries 7 and 8 can be inserted into the needle 21 without colliding with the needle 21 and causing damage to the capillaries 7 and 8 during installation. Connecting the needles 21 of the syringe needles 2, 3, and 4 to external piping allows the microfluidic chip to communicate with the external environment. Because the needle 21 is relatively sturdy and reliable, connecting it to the external piping protects the fragile capillaries 7 and 8 contained within it.

[0037] It should be understood that the capillaries 7, 8 do not need to be tightly connected to the needle 21, and the capillaries 7, 8 do not have to be inserted into the needle 21. It is also possible for them to be inserted only into the inside of the connector 22. Because the outlets of the syringe needles 2, 3, 4 are sealed by the sealing tubes 5, 6, the inner cavities of the syringe needles 2, 3, 4 can only be connected to the first channel 15 through the capillaries 7, 8.

[0038] The specific use of the microfluidic chip according to this embodiment is briefly introduced below.

[0039] like Figure 6 As shown, the internal phase (e.g., water) first enters the inner cavity of the first syringe needle 2, then enters the first channel 15 through the first capillary 7, and the external phase (e.g., oil) first enters the inner cavity of the third syringe needle 4, and then enters the second channel 16. In particular, the bottom end of the second channel 16 faces the tapered tip of the first capillary 7 to provide a droplet generation area. The generated droplets enter the inner cavity of the second syringe needle 3 through the second capillary 8, and are then discharged through the second syringe needle 3.

[0040] Example 1

[0041] In order to demonstrate the performance of the microfluidic chip according to the present invention, pure water (internal phase) and mineral oil mixed with 3% surfactant Abil EM90 (external phase) were used to produce an oil-in-water emulsion. The oil phase was concentrated through a second capillary 8 opposite to the first capillary 7, and the coaxial relationship was verified from the microscopic images obtained from the optical microscope.

[0042] In this example, the tip of the first capillary 7 has a size of 30 μm, and the corresponding size of the second capillary 8 is 200 μm. This distance can be easily adjusted by stretching the capillary. When the internal and external phase flow rates are maintained at 20 μL / min and 300 μL / min, respectively, a large number of 0.43 nL droplets with a consistent size distribution (CV 5%) are rapidly prepared at a high generation frequency of 636 Hz. Figure 7 and Figure 8 No significant agglomeration was observed for more than 24 hours after production. This indicates that the present invention can generate uniform and stable droplets, demonstrating reliable effectiveness.

[0043] It should be understood that by adjusting the size of the tapered tip of the first capillary 7, the size of the generated droplets can be adjusted accordingly. For example, the smaller the size of the tapered tip, the smaller the droplets. When the tip size is fixed, the size of the generated droplets can be adjusted by adjusting the flow rate / flow ratio of the inner and outer phases. For example, the greater the flow rate of the outer phase, the smaller the droplets, and the greater the flow rate of the inner phase, the larger the droplets. Figure 9 As shown in FIG. 1 , by changing the flow rate ratio of the inner dispersed phase (Qd) to the outer continuous phase (Qc), the change in the diameter of the droplets can be clearly seen. Accordingly, the present invention can control the diameter of the droplets as needed and has wide applicability.

[0044] like Figure 10 As shown, a microfluidic chip according to another preferred embodiment of the present invention includes two alignment cartridges 1, 10, two first syringe needles 2, 20, two second syringe needles 3, 30, and two third syringe needles 4, 40. The left first syringe needle 2 is connected to and communicates with the left side of the left alignment cartridge 1, the left second syringe needle 3 is connected to and communicates with the right side of the left alignment cartridge 1, and the left third syringe needle 4 is connected to and communicates with the left alignment cartridge 1 from the top, thereby providing a first module. The right first syringe needle 20 is connected to and communicates with the left side of the right alignment cartridge 10, the right second syringe needle 30 is connected to and communicates with the right side of the right alignment cartridge 10, and the right third syringe needle 40 is connected to and communicates with the right alignment cartridge 10 from the top, thereby providing a second module.

[0045] like Figure 11As shown, the microfluidic chip according to another preferred embodiment of the present invention also includes a connecting tube 9 connecting the first module and the second module, the left end of which passes through the left second syringe needle 3 and the second sealing tube 6 of the first module and is inserted into the first channel 15 and terminates below the second channel 16, and the right end of which passes through the right first syringe needle 20 and the first sealing tube 50 of the second module and is inserted into the first channel 15 and terminates below the second channel 16.

[0046] In particular, the first capillary 7 of this embodiment is installed through the first sealing tube 5 and the second sealing tube 6 of the first module in sequence to connect the inner cavity of the left first syringe needle 2 and the inner cavity of the connecting tube 9, and the second capillary 8 is installed through the second sealing tube 60 and the first sealing tube 50 of the second module in sequence to connect the inner cavity of the right second syringe needle 20 and the inner cavity of the connecting tube 9.

[0047] The specific use of the microfluidic chip according to this embodiment is briefly introduced below.

[0048] like Figure 11 As shown, the internal phase (e.g., water) first enters the lumen of the left first syringe needle 2, then enters the lumen of the connecting tube 9 through the first capillary 7. The first external phase (e.g., oil) first enters the lumen of the left third syringe needle 4, then enters the lumen of the connecting tube 9 through the second channel 16 of the first module. The second external phase (e.g., oil) first enters the lumen of the right third syringe needle 40, then enters the lumen of the connecting tube 9 through the second channel 16 of the second module. In particular, the tapered tip of the first capillary 7 provides a droplet generation region. The generated droplets enter the lumen of the right second syringe needle 30 through the second capillary 8, and are then discharged through the right second syringe needle 30.

[0049] It should be understood that if the second external phase is the same as the first external phase, then this embodiment can form smaller droplets than the previous embodiment. If the first external phase is replaced with an intermediate phase such as oil and the second external phase is provided as an external phase such as water, then a double-layer droplet will be generated.

[0050] Thus, the microfluidic chip according to the present invention can be further nested in multiple layers to prepare multiple emulsions. For example, two modules can form a double emulsion, and three modules can form a triple emulsion, as long as the corresponding capillaries are treated with hydrophobic or oleophobic treatment.

[0051] The microfluidic chip of the present invention is easily connected to a sample injection device using a syringe needle, which effectively protects fragile glass capillaries. It is also inexpensive to manufacture and readily available, and all components can be assembled and disassembled in under two minutes. In other words, the present invention provides a reconfigurable, modular microfluidic chip that can be freely assembled and disassembled as needed, combined, and reused after cleaning, reducing costs.

[0052] In summary, the microfluidic chip according to the present invention is easy and reliable to assemble, can be disassembled and cleaned and then reconstructed, and the assembly process does not require adhesives or screw parts; it only has one customized processing part - the "alignment box", and the processing precision requirements are low, and multiple can be used in series; the syringe needle has a wide range of optional ranges, is highly compatible with the injection pipeline, and has a firm and reliable seal; the reagent compatibility is good, and it can be used for microdroplet preparation for various purposes by simply replacing the reagent; the cost is extremely low, at the level of a few yuan.

[0053] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of the present invention. Various modifications are possible. In other words, any simple, equivalent changes and modifications made in accordance with the claims and description of the present invention are within the scope of protection of the patent claims. Anything not fully described in this invention constitutes conventional technology.

Claims

1. A microfluidic chip, characterized in that: The microfluidic chip includes an alignment box, a first syringe needle, a second syringe needle, a third syringe needle, a first sealing tube, a second sealing tube, a first capillary tube and a second capillary tube, wherein the first syringe needle and the second syringe needle are connected to the alignment box relative to each other and define a first channel, the third syringe needle is connected to the alignment box and defines a second channel leading to the first channel, the second channel is vertically connected to the middle of the first channel to form a T-shaped internal channel, the first sealing tube and the second sealing tube are respectively sealed and inserted into the opposite ends of the first channel, the first or second sealing tube is a silicone or rubber tube, and the first capillary tube is sealed and inserted into the first A sealing tube is installed in the sealing tube to connect the inner cavity of the first syringe needle and the first channel. The second capillary is sealingly inserted into the second sealing tube and installed in the inner cavity of the second syringe needle to connect the first channel. The tapered tip of the first capillary is inserted into the inner end of the second capillary directly below the second channel. With the help of the elastic alignment of the first sealing tube and the second sealing tube, the tapered tip of the first capillary is coaxially opposite to the inner end of the second capillary to provide a droplet generation area. The inner phase enters the first capillary through the first syringe needle, and the outer phase enters the second channel through the third syringe needle. Droplets generated in the droplet generation area are discharged through the second capillary and the second syringe needle.

2. The microfluidic chip according to claim 1, characterized in that The alignment box has a box body, a first protruding tube, a second protruding tube and a third protruding tube. The first protruding tube extends from the left side of the box body, the second protruding tube extends from the right side of the box body, and the third protruding tube extends from the upper side of the box body. The first syringe needle sleeve is connected to and communicated with the first protruding tube, the second syringe needle sleeve is connected to and communicated with the second protruding tube, and the third syringe needle sleeve is connected to and communicated with the third protruding tube.

3. The microfluidic chip according to claim 1, characterized in that The microfluidic chip includes two alignment boxes, two first syringe needles, two second syringe needles, two third syringe needles, a first capillary and a second capillary, wherein one first syringe needle, one second syringe needle and one third syringe needle are connected to one alignment box to provide a first module, and another first syringe needle, another second syringe needle and another third syringe needle are connected to another alignment box to provide a second module.

4. The microfluidic chip according to claim 3, characterized in that The microfluidic chip also includes two first sealing tubes, two second sealing tubes and a connecting tube connecting the first module and the second module, wherein the two first sealing tubes and the two second sealing tubes are respectively sealedly inserted into the opposite ends of the first channels of the first module and the second module, one end of the connecting tube passes through the second syringe needle of the first module and the second sealing tube, is inserted into the first channel and terminates below the second channel, and the other end of the connecting tube passes through the first syringe needle of the second module and the first sealing tube, is inserted into the first channel and terminates below the second channel.

5. The microfluidic chip according to claim 4, characterized in that: The first capillary tube is installed through the first sealing tube and the second sealing tube of the first module in sequence to connect the inner cavity of the first syringe needle of the first module and the inner cavity of the connecting tube. The second capillary tube is installed through the second sealing tube and the first sealing tube of the second module in sequence to connect the inner cavity of the second syringe needle of the second module and the inner cavity of the connecting tube.

6. A method for preparing droplets using the microfluidic chip according to any one of claims 1 to 5.

7. The method according to claim 6, characterized in that Multiple microfluidic chips are nested to prepare multiple emulsions.

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