Automatic liquid separation device and method based on digital micro-fluidic chip

Abstract

The invention discloses an automatic liquid separation device and method based on a digital micro-fluidic chip. The device comprises an injection system consisting of a multi-channel injection pump and a catheter; a reagent storage module; and a liquid separation interface board. The multi-channel injection pump is controlled by the peripheral control module to push the reagents from the reagent storage module to the liquid separation interface plate through a catheter according to a preset sequence, and volume distribution and quantification are completed in the liquid separation interface plate. The invention has the advantages of compact structure and high quantitative precision, and is suitable for miniaturized and portable application scenarios.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to the field of microfluidics and automated pipetting technology, in particular, to an automatic dispensing device and method based on a digital microfluidic chip. BACKGROUND

[0002] Microfluidic chips aim to integrate sampling, dilution, reaction, separation, detection and other operations on the chip; among them, the digital microfluidic chip with droplets as the operation unit can independently generate, mix and split microliter / nanoliter droplets, has high parallel processing efficiency and can effectively reduce cross contamination. DMF is based on the principle of dielectric wetting, and the contact angle of the droplet is adjusted by an external electric field to realize droplet manipulation. The contact angle changes with the voltage and has a saturation phenomenon.

[0003] Existing fully automatic pipetting workstations mostly rely on three-dimensional mechanical arms and pipetting tips, and although the throughput is high, the volume is large, the cost and maintenance pressure are large, and it is difficult to be used in limited space scenes such as on-site instant detection.

[0004] Therefore, one or more methods are needed to solve the above problems.

[0005] It should be noted that the information disclosed in the above background section is only used to strengthen the understanding of the background of the present disclosure, and therefore can include information that does not constitute prior art known to those of ordinary skill in the art. SUMMARY

[0006] The purpose of the present disclosure is to provide an automatic dispensing device and method based on a digital microfluidic chip, which is aimed at complex reaction process scenarios to achieve automatic quantitative liquid injection, automatic injection of different reaction reagents, and to at least partially overcome one or more problems caused by limitations and defects of related technologies.

[0007] To achieve the above purpose, the first aspect of the present disclosure provides an automatic dispensing device based on a digital microfluidic chip, comprising:

[0008] An injection system comprising a multi-channel injection pump and a plurality of conduits in communication therewith for driving the sequential injection of a plurality of reagents;

[0009] A reagent storage module for storing a plurality of biochemical reaction reagents;

[0010] A dispensing interface plate in communication with the conduits, having a microchannel structure inside for volume distribution and quantification;

[0011] The multi-channel injection pump, under the control of the peripheral control module, pushes the reagents from the reagent storage module to the dispensing interface plate through the conduits in a predetermined order, and completes volume distribution and quantification in the dispensing interface plate.

[0012] Further, the conduit is detachably connected with the pump connector at the end of the injection pump through the quick connector, and connected with the reagent bottle at the end of the reagent bottle through the micro connector, and a multi-channel electromagnetic valve is arranged at the end of the conduit to realize selection and switching of different channels.

[0013] Further, the reagent storage module comprises a low-temperature reagent group and a normal-temperature reagent group, and is maintained at a constant low temperature and a constant normal temperature by a temperature control module respectively.

[0014] Further, the liquid distribution interface plate is a three-layer structure, comprising: an upper cover plate provided with a reagent bottle matching jack; a film layer located in the middle and used for realizing liquid on-off control; and a channel layer engraved with a micro channel used for quantification, wherein a quantification section used for realizing accurate quantification is arranged on the channel layer, and the volume of the quantification section is determined by the geometric size of the channel.

[0015] Further, the channel layer comprises at least two kinds of quantification channels with different volumes to adapt to the quantification injection requirements of different reagents.

[0016] Further, the valve seat of the film layer and the channel layer cooperates to form a passive micro valve structure driven by external liquid phase pressure, which is used for on-off switching and quantification control of the micro channel.

[0017] Further, a connecting structure is further included for connecting the liquid outlet of the liquid distribution interface plate with an external reaction unit, and the external reaction unit is a digital microfluidic chip; when the connecting structure cooperates with the continuous phase of the immiscible oil phase, a micro droplet can be formed at the output end and injected into the chip.

[0018] Further, the same pump channel of the multi-channel injection pump can be sequentially connected with a plurality of reagent bottle interfaces through the multi-channel electromagnetic valve, so that sequential quantification and mixing of a plurality of reagents can be completed without changing the physical connection.

[0019] Further, the liquid distribution interface plate is connected with a waste liquid pool to reset the quantification section and realize accurate volume by over-injection and drainage.

[0020] The second aspect of the present application provides a method for automatically distributing liquid by using the automatic liquid distribution device, comprising:

[0021] S1 connecting a plurality of reagent bottles of reagents to the liquid distribution interface plate and connecting with the conduit of the multi-channel injection pump;

[0022] S2 controlling the injection pump and the multi-channel electromagnetic valve to make the target reagent flow to the waste liquid, so that the predetermined quantification channel of the liquid distribution interface plate is filled and volumed;

[0023] S3 closing the corresponding channel and injecting an oil phase immiscible with the reagent to push the quantification reagent to the connecting structure;

[0024] S4 repeats steps S2 to S3 on multiple reagents in a preset order to obtain a target proportioned liquid or mixed system;

[0025] S5 injects the proportioned liquid into the digital microfluidic chip through the connecting structure.

[0026] The present disclosure includes a multi-channel syringe pump, a reagent storage module, and a dispensing interface plate. The multi-channel syringe pump and the conduit realize flow path switching, and the automatic injection of multiple reagents can be completed without a large mechanical arm. The structure is compact and easy to maintain, and is suitable for small and portable application scenarios. The dispensing interface plate is provided with a micro-channel structure, which can realize high-precision quantitative distribution of microliters to nanoliters. Combined with the stable propulsion of the syringe pump, repeatable volume distribution and accurate volume can be realized.

[0027] It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and cannot limit the present disclosure. BRIEF DESCRIPTION OF DRAWINGS

[0028] The above and other features and advantages of the present disclosure will become more apparent by describing in detail its example embodiments with reference to the attached drawings.

[0029] Figure 1 A structural schematic diagram of an automatic dispensing device based on a digital microfluidic chip is shown according to an example embodiment of the present disclosure;

[0030] Figure 2 And 3 A structural schematic diagram of a dispensing interface plate is shown according to an example embodiment of the present disclosure;

[0031] Figure 4 A schematic diagram of single-channel quantitative principle of a dispensing interface plate is shown according to an example embodiment of the present disclosure. DETAILED DESCRIPTION

[0032] Example embodiments will now be described more fully with reference to the accompanying drawings. However, example embodiments can be implemented in various forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that the present disclosure will be thorough and complete, and will fully convey the concept of example embodiments to those skilled in the art. Like reference numerals refer to like elements throughout the drawings, and a repeated description thereof will be omitted.

[0033] Furthermore, the described features, structures, or characteristics can be combined in any suitable manner in one or more embodiments. Numerous specific details are provided in the following description to give a thorough understanding of embodiments of this disclosure. However, those skilled in the art will recognize that the technical solutions of this disclosure can be practiced without one or more of the specific details described, or other methods, components, materials, apparatuses, steps, etc., can be employed. In other instances, well-known structures, methods, apparatuses, implementations, materials, or operations are not shown or described in detail to avoid obscuring various aspects of this disclosure.

[0034] The block diagrams shown in the accompanying drawings are merely functional entities and do not necessarily correspond to physically independent entities. That is, these functional entities can be implemented in software, or in one or more software-hardened modules, or in different network and / or processor devices and / or microcontroller devices.

[0035] In this example embodiment, as Figure 1 As shown, the present invention provides an automatic liquid dispensing device based on a digital microfluidic chip, comprising:

[0036] An injection system, comprising a multi-channel injection pump 1 and multiple catheters 2 connected thereto, for driving the sequential injection of multiple reagents;

[0037] The reagent storage module is used to store various biochemical reaction reagents;

[0038] The liquid separation interface plate 7 is connected to the conduit 2 and has a microchannel structure inside for volume distribution and quantitative measurement.

[0039] Under the control of the peripheral control module, the multi-channel injection pump 1 pushes the reagent from the reagent storage module through the conduit 2 to the dispensing interface plate 7 in a preset sequence, and completes the volume distribution and quantification in the dispensing interface plate 7.

[0040] This example of an automated dispensing device includes a multi-channel syringe pump, a reagent storage module, and a dispensing interface plate. The multi-channel syringe pump and tubing enable flow path switching, allowing for automated dispensing of multiple reagents without the need for a large robotic arm. Its compact structure and easy maintenance make it suitable for miniaturized and portable applications. The dispensing interface plate features a microchannel structure, enabling high-precision quantitative dispensing from microliters to nanoliters. Combined with the stable propulsion of the syringe pump, repeatable volume dispensing and precise volume determination are achieved.

[0041] In one embodiment of the present invention, the catheter 2 is detachably connected to the pump connector 3 at the injection pump end via a quick-connect connector 3, and connected to the reagent bottle end via a micro connector 4. A multi-channel solenoid valve is provided at the end of the catheter 2 to allow for the selection and switching of different channels. The same pump channel of the multi-channel injection pump 1 can be sequentially connected to multiple reagent bottle interfaces via the multi-channel solenoid valve, thereby enabling the sequential quantitative mixing of multiple reagents without changing the physical connections.

[0042] In one embodiment of the present invention, the reagent storage module includes a low-temperature reagent group 5 and a room-temperature reagent group 6, which are respectively maintained at a constant low temperature and a constant room temperature by a temperature control module. The reagent bottles in the low-temperature reagent group 5 store reagents that require low-temperature storage during the biochemical reaction. The reagent bottles in the room-temperature reagent group 6 store reagents that require room-temperature storage during the biochemical reaction.

[0043] In one embodiment of the present invention, such as Figure 2 and 3 As shown, the dispensing interface plate 7 has a three-layer structure, including: a top cover plate 11 with an insertion hole adapted to the reagent bottle; a thin film layer 12 located in the middle for liquid flow control; and a channel layer 13 etched with microchannels for quantitative dispensing. The channel layer 13 has a quantitative segment for precise dispensing, the volume of which is determined by the geometry of the channel. In this example, the channel layer 13 has circularly etched channels on the substrate, allowing for quantitative dispensing within the channels. The liquid flows through different channels under the drive of the injection system. The channel layer 13 contains at least two different volumes of quantitative channels to accommodate the quantitative injection requirements of different reagents.

[0044] In one embodiment of the present invention, the valve seat of the thin film layer 12 and the channel layer 13 cooperate to form a passive microvalve structure driven by external liquid phase pressure, which is used to switch the microchannel on and off and to quantitatively control it.

[0045] In one embodiment of the present invention, the automatic liquid dispensing device further includes a connecting structure 8 for connecting the outlet of the liquid dispensing interface plate 7 to an external reaction unit, wherein the external reaction unit is a digital microfluidic chip 10. When the connecting structure 8 continuously interacts with an immiscible oil phase, it can form microdroplets at the output end and inject them into the chip 10. The digital microfluidic chip 10 is used to drive the movement of the microdroplets. After the reagent is quantitatively dispensed by the liquid dispensing interface plate 7 under the action of the injection system, it is injected into the digital microfluidic chip 10 through the connecting structure 8 to form microdroplets. The digital microfluidic chip 10 then completes the subsequent on-chip biochemical reaction process.

[0046] In one embodiment of the present invention, the liquid separation interface plate 7 is connected to the waste liquid tank so as to reset the quantitative segment and achieve precise volume determination by over-injection and drainage.

[0047] A second aspect of the present invention provides a method for automatic liquid separation using the above-described automatic liquid separation device, comprising:

[0048] S1 connects reagent bottles containing multiple reagents to the dispensing interface plate and is connected to the tubing of a multi-channel syringe pump;

[0049] S2 controls the injection pump and the multi-channel solenoid valve to allow the target reagent to flow excessively to the waste liquid, thereby filling and fixing the volume of the predetermined quantitative channel of the dispensing interface plate.

[0050] S3 closes the corresponding pathway and injects an oil phase that is immiscible with the reagent, pushing the quantitative reagent to the connection structure;

[0051] S4 repeats steps S2 to S3 with multiple reagents in a preset order to obtain a quantitative liquid or mixed system with the target ratio;

[0052] S5 injects the quantitative liquid into the digital microfluidic chip through the connection structure.

[0053] To enable those skilled in the art to more clearly understand the solution of the present invention, the embodiments of the present invention are described below:

[0054] refer to Figure 4 For the reagent mixing process, reagent bottle interface 1, reagent bottle interface 2, reagent bottle interface 3, reagent bottle interface 4, and reagent bottle interface 5 are respectively connected to the reagent storage module, such as... Figure 2The connection method between the liquid separation interface plate 7 and the low temperature reagent group 5 and the room temperature reagent group 6 is as follows: reagent bottle 1 stores sample 1, reagent bottle 2 stores sample 2, reagent bottle 3 stores sample 3, reagent bottle 4 stores sample 4, and reagent bottle 5 stores oil. Valves 1, 2, and 3 are connected to the same channel of a multi-channel syringe pump. A multi-channel solenoid valve at the end of the tubing controls the channel opening and closing. Waste tanks 1 and 2 are connected to a mixing reagent bottle. The quantitative procedure is as follows: The multi-channel syringe pump is turned on, and the solenoid valve corresponding to valve 1 is activated. The liquid phase passing through the thin film layer will disconnect the corresponding position of valve 1, allowing the liquid to flow to the waste tank. This pushes the multi-channel syringe pump, causing excess sample 1 from reagent bottle 1 to flow into waste tank 1. At this point, the volume of the tubing between reagent bottle 1 and valve 1 is 10 μL. Then, the solenoid valve corresponding to valve 1 is closed, causing the tubing to lose pressure. This opens the channel corresponding to valve 1, driving reagent bottle 5 corresponding to the multi-channel syringe pump to inject 20 μL of oil into the mixing reagent bottle. At this point, valves 2 and 3 are in the open / closed state. The above operation is performed sequentially on reagent bottles 2, 3, and 4. The mixing chamber contains a mixture of four reagents, totaling 40 μL of sample mixture and excess oil. The mixture in the mixing reagent bottle is mixed by pumping the oil in reagent bottle 5. After mixing, valve 2 is opened and valve 3 is closed. The syringe pump pushes excess oil to fill the metering chamber with a 5 μL volume. Then, valve 3 is opened, and the syringe pump pushes 10 μL of oil to allow the 5 μL mixture to completely enter the digital microfluidic chip through the connection structure. Subsequent reaction processes take place within the digital microfluidic chip. This embodiment demonstrates the application of the quantitative logic for excess injection of a certain volume of oil phase and the multi-specification quantitative channels within the interface board. Timing control can achieve sequential metering and mixing of multiple reagents and stable injection into the chip.

[0055] In summary, this invention enables precise and automated dispensing of multiple reagents and on-chip DMF processing with a small volume and low system complexity. It can be applied to front-end liquid supply modules in scenarios such as molecular diagnostics, chemical synthesis, enzyme reactions, and environmental monitoring, meeting the needs of on-site testing and rapid deployment.

[0056] It should be noted that although the steps of the method in this disclosure are described in a specific order in the accompanying drawings, this does not require or imply that the steps must be performed in that specific order, or that all the steps shown must be performed to achieve the desired result. Additional or alternative steps may be omitted, multiple steps may be combined into one step, and / or a step may be broken down into multiple steps.

[0057] Furthermore, the above figures are merely illustrative of the processes included in the method according to exemplary embodiments of the present invention, and are not intended to be limiting. It is readily understood that the processes shown in the above figures do not indicate or limit the temporal order of these processes. Additionally, it is readily understood that these processes may be executed synchronously or asynchronously, for example, in multiple modules.

[0058] Other embodiments of this disclosure will readily occur to those skilled in the art upon consideration of the specification and practice of the invention disclosed herein. This application is intended to cover any variations, uses, or adaptations of this disclosure that follow the general principles of this disclosure and include common knowledge or customary techniques in the art not disclosed herein. The specification and embodiments are to be considered exemplary only, and the true scope and spirit of this disclosure are indicated by the claims.

[0059] It should be understood that this disclosure is not limited to the precise structures described above and shown in the accompanying drawings, and various modifications and changes can be made without departing from its scope. The scope of this disclosure is limited only by the appended claims.

Claims

1. An automatic liquid dispensing device based on a digital microfluidic chip, characterized in that, include: An injection system comprising a multi-channel injection pump and multiple catheters connected thereto, for driving the sequential injection of various reagents; The reagent storage module is used to store various biochemical reaction reagents; The liquid separation interface plate is connected to the conduit and has a microchannel structure inside for volume distribution and quantitative measurement. The multi-channel injection pump, under the control of the peripheral control module, pushes the reagent from the reagent storage module through the conduit to the dispensing interface plate in a preset sequence, and completes the volume distribution and quantification in the dispensing interface plate.

2. The automatic liquid dispensing device according to claim 1, characterized in that, The catheter is detachably connected to the pump connector at the injection pump end via a quick-connect fitting, and to the reagent bottle end via a micro connector. A multi-channel solenoid valve is provided at the end of the catheter to enable selection and switching of different channels.

3. The automatic liquid dispensing device according to claim 1 or 2, characterized in that, The reagent storage module includes a low-temperature reagent group and a room-temperature reagent group, which are respectively maintained at a constant low temperature and a constant room temperature by a temperature control module.

4. The automatic liquid dispensing device according to claim 1, characterized in that, The liquid dispensing interface plate has a three-layer structure, including: a top cover plate with an insertion hole adapted to the reagent bottle; a thin film layer located in the middle for liquid flow control; and a channel layer engraved with microchannels for quantitative measurement, wherein the channel layer is provided with a quantitative segment for accurate quantitative measurement, the volume of which is determined by the geometry of the channel.

5. The automatic liquid dispensing device according to claim 4, characterized in that, The channel layer includes at least two different volumes of quantitative channels to accommodate the quantitative injection requirements of different reagents.

6. The automatic liquid dispensing device according to claim 4 or 5, characterized in that, The thin film layer and the valve seat of the channel layer cooperate to form a passive microvalve structure driven by external liquid phase pressure, which is used to switch the microchannel on and off and to quantitatively control it.

7. The automatic liquid dispensing device according to claim 1, characterized in that, It also includes a connection structure for connecting the outlet of the liquid distribution interface plate to an external reaction unit, which is a digital microfluidic chip; when the connection structure is continuously engaged with an immiscible oil phase, it can form microdroplets at the output end and inject them into the chip.

8. The automatic liquid dispensing device according to claim 2, characterized in that, The same pump channel of the multi-channel syringe pump can be sequentially connected to multiple reagent bottle interfaces through the multi-channel solenoid valve, thereby enabling the sequential quantification and mixing of multiple reagents without changing the physical connections.

9. The automatic liquid dispensing device according to claim 4, characterized in that, The liquid separation interface plate is connected to the waste liquid tank to reset the quantitative section and achieve precise volume determination by overfilling and draining the liquid.

10. A method for automatic liquid separation using the automatic liquid separation device according to any one of claims 1 to 9, characterized in that, include: S1 connects reagent bottles containing multiple reagents to the dispensing interface plate and is connected to the tubing of a multi-channel syringe pump; S2 controls the injection pump and the multi-channel solenoid valve to allow the target reagent to flow excessively to the waste liquid, thereby filling and fixing the volume of the predetermined quantitative channel of the dispensing interface plate. S3 closes the corresponding pathway and injects an oil phase that is immiscible with the reagent, pushing the quantitative reagent to the connection structure; S4 repeats steps S2 to S3 with multiple reagents in a preset order to obtain a quantitative liquid or mixed system with the target ratio; S5 injects the quantitative liquid into the digital microfluidic chip through the connection structure.

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