High-throughput microfluidic screening device and screening method

Abstract

The invention discloses a high-flux microfluidic screening device and a screening method, and belongs to the technical field of material synthesis and chemical engineering, the high-flux microfluidic screening device comprises a mixing divider, an injection pump system and a micro-channel reactor which are communicated with the mixing divider, and a distributor communicated with the micro-channel reactor, wherein one injection pump system is used for conveying split phases to the mixing splitter, and at least two injection pump systems are used for conveying reaction materials to the mixing splitter; through cooperation of the mixing divider, the injection pump system, the micro-channel reactor and the distributor, a discrete liquid drop / liquid column sequence is used for replacing traditional continuous liquid flow, the rigid limitation that the retention time is jointly determined by the volume and the flow of the reactor is broken through, and under the condition that the total liquid holdup and the retention time are determined, the flow rate of the micro-channel reactor is increased. The liquid holdup is divided into a plurality of discrete units, the system can complete reaction and screening under different conditions in the same time period, the screening efficiency is remarkably improved, and meanwhile, the consumption of high-value reagents is greatly reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of material synthesis and chemical engineering, in particular to a high-throughput microfluidic screening device and a screening method. BACKGROUND

[0002] Microfluidic synthesis technology, as a new material preparation method, has attracted widespread attention in the field of high-throughput material preparation in recent years due to its ability to precisely control reaction conditions and efficient mass and heat transfer. This technology precisely controls fluid through microchannel structures, and is particularly suitable for the synthesis of micro-nano materials (such as polymer photovoltaic materials, nano drug carriers, etc.), with the advantages of high reaction efficiency and good product uniformity.

[0003] In the prior art, microfluidic high-throughput synthesis systems have made some progress. For example, the patent for invention with publication number CN120001303A proposes a high-throughput fluid synthesis system for organic functional polymer materials. This system generates plug flow or droplets through a microfluidic module to control the molecular weight of polymers, and combines a chip mixing module and a reactor module to achieve precise synthesis. Although this system can improve synthesis efficiency and product quality to some extent, its reaction system still relies on continuous liquid flow mode, and there is an inherent coupling relationship between the holdup volume of the reactor, the flow rate of the fluid, and the residence time. The synthesis conditions of discrete droplets in the same pipeline are consistent, which leads to a bottleneck in further reducing the amount of reagents used and can only achieve high-throughput synthesis, not high-throughput screening. Especially in high-value material reaction systems, the minimum holdup volume of this continuous flow mode limits the significant reduction of reagent consumption, increasing the cost of synthesis condition screening.

[0004] Another utility model patent with publication number CN217120189U provides a high-throughput material synthesis equipment based on a microfluidic chip. This equipment realizes the rapid and parallel preparation of multi-component materials through an injection pump mechanism, a microfluidic chip, and an automatic dispensing system. However, this equipment also uses continuous sampling and reaction methods, and the volume and path length of its reaction unit determine the minimum reaction volume, which cannot break through the constraints of "holdup volume-residence time". When it is necessary to shorten the residence time or reduce the amount of reagents, the system often needs to reduce the flow rate or reduce the size of the reactor to achieve this, but this will sacrifice the throughput or mixing efficiency, leading to low screening efficiency and resource waste.

[0005] In summary, although the existing microfluidic synthesis technology performs well in high-throughput preparation, its reaction mode based on continuous liquid flow is essentially limited by the balance relationship between the liquid holdup, flow rate and residence time of the reactor, making it difficult to further reduce reagent consumption while maintaining high screening efficiency. This is particularly disadvantageous for reaction systems of high-value materials such as noble metal catalysts, special polymer monomers, etc., limiting the promotion of this technology in large-scale screening and cost-sensitive applications.

[0006] Therefore, there is an urgent need in the art for a new high-throughput preparation scheme that can break through the above limitations, significantly reduce the amount of reaction reagents while maintaining or even improving screening efficiency, thereby meeting the economic and efficient requirements of high-value material systems. SUMMARY

[0007] The purpose of the present application is to provide a high-throughput microfluidic screening device and a screening method to achieve the purpose of significantly reducing the amount of reaction reagents while improving screening efficiency.

[0008] To achieve the above-mentioned purpose, the present application provides the following solutions: A high-throughput microfluidic screening device, comprising a mixing divider, an injection pump system and a microchannel reactor in communication with the mixing divider, and a distributor in communication with the microchannel reactor, wherein one of the injection pump systems is used to deliver a partitioning phase to the mixing divider, and at least two of the injection pump systems are used to deliver reaction materials to the mixing divider.

[0009] Preferably, the injection pump system comprises an injection pump body and a reaction material pipeline or a partitioning phase pipeline connected to the injection pump body, and the reaction material pipeline and the partitioning phase pipeline are both in communication with the mixing divider.

[0010] Preferably, a check valve is provided on each of the reaction material pipeline and the partitioning phase pipeline.

[0011] Preferably, the microchannel reactor is in communication with the mixing divider and the distributor through liquid outlet pipelines provided at both ends, respectively.

[0012] Preferably, it further comprises a heat exchanger, and the microchannel reactor is arranged in the heat exchanger, and the heat exchanger is used for temperature control of the reaction process.

[0013] Preferably, the microchannel reactor is a polytetrafluoroethylene pipe with an inner diameter of 0.5mm to 1.0mm.

[0014] Preferably, the heat exchanger is a constant-temperature oil bath tank or a Peltier temperature control module.

[0015] Preferably, a height-adjustable base is further included, and the mixing divider, the syringe pump system and the micro-channel reactor are located on the base, and the dispenser is located near the base.

[0016] Preferably, the dispenser comprises a control unit, a three-axis moving platform, a needle head arranged above the three-axis moving platform for collecting fluid, a collection container arranged on the three-axis moving platform, and a stepping motor for driving the three-axis moving platform to move, and the control unit is electrically connected with the stepping motor, and is configured to control the collection container to collect samples corresponding to the needle head.

[0017] A high-throughput microfluidic screening method, comprising the following steps: S1: proportioning sample feeding: starting a syringe pump system for conveying reaction materials, and conveying the reaction materials to a mixing divider according to a first target proportioning, at this time, a syringe pump system for conveying a partitioning phase is in a closed state, and a check valve on a partitioning phase pipeline ensures that the reaction materials do not flow back into the partitioning phase pipeline; S2: liquid flow partitioning: when the syringe pump system for conveying the reaction materials is conveyed to a preset target reaction volume, the syringe pump system is closed, and a syringe pump system for conveying the partitioning phase is started, and the partitioning phase is injected into the mixing divider, and the continuous liquid flow in the mixing divider is partitioned and pushed into a micro-channel reactor, at this stage, the check valve on the reaction material pipeline ensures that the reaction materials do not flow back into the reaction material pipeline; S3: proportioning switching and re-feeding: the syringe pump system for conveying the partitioning phase is closed after being pushed to a set time, and then the syringe pump system for conveying the reaction materials is restarted, and the reaction materials are conveyed to the mixing divider according to a second target proportioning, at this time, the total flow rate is kept constant; S4: serial reaction: in the micro-channel reactor, the liquid columns or liquid drops formed by partitioning and having different reaction proportionings serve as independent micro-reactors, and complete chemical reactions in a flowing process; S5: high-throughput dispensing: the sequence of the liquid columns / liquid drops after reaction is dispensed to different specified positions by a dispenser, so that high-throughput preparation and collection of multiple groups of reaction conditions are completed at one time.

[0018] The present application has the following technical effects relative to the prior art: The present application replaces the traditional continuous liquid flow with discrete droplet / liquid column sequences, breaking the rigid restriction that "residence time is determined by the reactor volume and flow rate"; in the case of a total liquid holdup and residence time, the liquid holdup can be split into n discrete units, and n different conditions can be reacted and screened in the same time period, and the screening efficiency is n times that of the original; at the same time, since the minimum liquid holdup restriction of the traditional microreactor is overcome, the volume of each reaction unit (droplet / liquid column) can be made very small; for the same screening flux, the total amount of reaction reagents can be reduced to 1 / n of the traditional continuous flow mode. This means a great saving in cost for reaction systems using noble metal catalysts, expensive monomers or biological materials, and has significant industrial application value. BRIEF DESCRIPTION OF DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed in the embodiments. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor.

[0020] Figure 1 is a structural schematic diagram of the present application; Figure 2 is a detailed internal structure diagram of the mixing divider of the present application; Figure 3 is a sequence state schematic diagram of the column / droplet in the microchannel reactor of the present application; Figure 4 is a working process schematic diagram of the distributor of the present application; Figure 5 is a flowchart of the high-throughput preparation method of the present application; 1, injection pump system; 2, mixing divider; 3, check valve; 4, microchannel reactor; 5, distributor; 21, reactant pipeline; 22, partitioning phase pipeline; 23, liquid outlet pipeline; 51, collection container; 52, stepper motor; 53, three-axis moving platform. DETAILED DESCRIPTION

[0021] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only some embodiments of the present application, not all embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0022] The application aims to provide a high-throughput microfluidic screening device and a screening method, so as to improve the screening efficiency and significantly reduce the amount of reaction reagents.

[0023] In order to make the above-mentioned purposes, characteristics and advantages of the application more obvious and easy to understand, the application will be further described in detail below in combination with the drawings and specific embodiments.

[0024] Reference Figures 1 to 2 The application provides a high-throughput microfluidic screening device, which comprises a mixing divider 2, an injection pump system 1 and a microchannel reactor 4 in communication with the mixing divider 2, and a distributor 5 in communication with the microchannel reactor 4, wherein one injection pump system 1 is used for conveying a partitioning phase to the mixing divider 2, and at least two injection pump systems 1 are used for conveying reaction materials to the mixing divider 2; the application replaces the traditional continuous liquid flow with discrete droplet / cylinder sequences through the cooperation of the mixing divider 2, the injection pump system 1, the microchannel reactor 4 and the distributor 5, so as to break the rigid restriction that the residence time is determined by the reactor volume and the flow rate; in the case that the total liquid holding capacity and the residence time are determined, the liquid holding capacity can be split into n discrete units, and the reactions and screening under n different conditions can be completed in the same time period, so that the screening efficiency is improved to n times of the original; meanwhile, since the limitation of the minimum liquid holding capacity of the traditional microreactor is overcome, the volume of each reaction unit (droplet / cylinder) can be made very small; for the same screening throughput, the total amount of reaction reagents can be reduced to 1 / n of the traditional continuous flow mode. This means great cost savings for the reaction system using noble metal catalysts, expensive monomers or biological materials, and has significant industrial application value.

[0025] Reference Figure 2 The injection pump system 1 comprises an injection pump body and a reaction material pipeline 21 or a partitioning phase pipeline 22 connected with the injection pump body, and the reaction material pipeline 21 and the partitioning phase pipeline 22 are in communication with the mixing divider 2; wherein the mixing divider 2 is a multi-channel microfluidic connector, which is internally integrated with a multi-channel mixing structure, is used for preliminarily mixing different reaction materials, and realizes the partitioning of the continuous liquid flow by means of the injected partitioning phase (such as inert gas, immiscible fluid, etc.) to form discrete liquid cylinders or droplets.

[0026] Reference Figure 2 The reaction material pipeline 21 and the partitioning phase pipeline 22 are both provided with check valves 3.

[0027] Reference Figure 3The micro-channel reactor 4 is in communication with the mixing segmenter 2 and the distributor 5 through the liquid outlet pipes 2323 arranged at both ends, respectively; the micro-channel reactor 4 is used for providing a reaction channel and a required residence time for the segmented liquid column / drop; it can be a simple pipe structure, or can be integrated with a complex mixing unit such as a spiral or a snake-shaped one to enhance mass transfer; further, the micro-channel reactor 4 can be a polytetrafluoroethylene pipe with an inner diameter of 0.5 mm to 1.0 mm, and the total length can be determined according to the target reaction residence time (for example, 1-30 minutes).

[0028] Further, the heat exchanger is a constant-temperature oil bath or a Peltier temperature control module, which can accurately control the reaction temperature at any set value between room temperature and 150°C, with a control accuracy of ±0.5°C.

[0029] Reference Figure 1 Further, a height-adjustable base is included, and the mixing segmenter 2, the injection pump system 1 and the micro-channel reactor 4 are located on the base, and the distributor 5 is located near the base, which aims to ensure that the liquid column / drop sequence after the reaction can smoothly enter the distributor 5.

[0030] Reference Figure 4 The distributor 5 includes a control unit, a three-axis moving platform 53, a needle arranged above the three-axis moving platform 53 for collecting fluid, a standard 100-hole microplate 51 arranged above the three-axis moving platform 53 as an arrayed collection container 51, and a stepping motor 52 for driving the three-axis moving platform 53 to move, the control unit is electrically connected with the stepping motor 52, and the control unit is electrically connected with the stepping motor 52, which can programmably control the needle above any specified hole position on the microplate to collect samples.

[0031] Reference Figure 5 Taking screening of an optimal ratio of catalysts as an example; the following steps are included: S1: first ratio sample injection; the injection pump system 1 for conveying the reaction material is started, and the reaction material is conveyed to the mixing segmenter 2 at a constant flow rate of 0.2 mL / min according to a first ratio of catalyst precursor (for example, A:B = 9:1), at this time, the injection pump system 1 for conveying the segmentation phase is in a closed state, and this process lasts for 10 seconds; S2: first liquid flow segmentation; the injection pump system 1 for conveying the reaction material is closed, and at the same time, the injection pump system 1 for conveying the segmentation phase is immediately started, and nitrogen is injected at a flow rate of 0.1 mL / min, lasting for 5 seconds. This operation pushes the material of the first ratio in the mixing segmenter 2 into the micro-channel reactor 4, and forms an independent liquid column separated by nitrogen; S3: second ratio switching and re-injection; the injection pump system 1 for delivering the segmented phase is closed; then the injection pump system 1 for delivering the reactant is restarted, keeping the total flow rate at 0.2 mL / min, but switching the ratio of the materials to the second one (e.g. A:B = 8:2); after 10 seconds of delivery, the step S2 is repeated, and nitrogen is injected to form a second independent liquid column; this cycle is repeated to form a series of liquid columns with different catalyst ratios in the micro-channel reactor 4 (the state of which can be referred to Figure 2 S4: series reaction; the liquid column series formed above flows forward in the micro-channel reactor 4, and the whole reactor is placed in a heat exchanger at 70°C; each liquid column acts as an independent micro-reactor, and the synthesis reaction of the catalyst is completed during the flow, with a residence time of about 15 minutes; S5: high-throughput distribution; the liquid column series after the reaction flows out of the micro-channel reactor 4 and enters the distributor 5; the control unit controls the stepper motor 52 to drive the micro-well plate to move according to the preset program; when the first liquid column (corresponding to A:B = 9:1) flows out, the needle moves above the A1 well of the micro-well plate to collect; when the second liquid column (corresponding to A:B = 8:2) flows out, the needle moves above the A2 well to collect; and so on; finally, all the catalyst samples with different ratios are automatically and accurately distributed to different well positions of the micro-well plate, and a high-throughput screening experiment is completed.

[0032] The principles and implementation manners of the present application are described by using specific examples in the present application; the above examples are only used to help understand the method of the present application and its core idea; meanwhile, for those skilled in the art, according to the idea of the present application, the specific implementation manners and application ranges will be changed. In conclusion, the content of the present specification should not be understood as a limitation of the present application.​

Claims

1. A high-throughput microfluidic screening device, characterized in that, The device includes a mixer divider, an injection pump system and a microchannel reactor connected to the mixer divider, and a distributor connected to the microchannel reactor, wherein one of the injection pump systems is used to deliver a divided phase to the mixer divider, and at least two of the injection pump systems are used to deliver reactants to the mixer divider.

2. The high-throughput microfluidic screening device according to claim 1, characterized in that, The injection pump system includes an injection pump body and a reactant pipeline or a phase separation pipeline connected to the injection pump body. Both the reactant pipeline and the phase separation pipeline are connected to the mixing and dividing device.

3. The high-throughput microfluidic screening device according to claim 1, characterized in that, Both the reactant pipeline and the phase separation pipeline are equipped with check valves.

4. The high-throughput microfluidic screening device according to claim 1, characterized in that, The microchannel reactor is connected to the mixing divider and the distributor via liquid outlet pipes at both ends.

5. The high-throughput microfluidic screening device according to claim 4, characterized in that, It also includes the heat exchanger, in which the microchannel reactor is disposed, and the heat exchanger is used for temperature control of the reaction process.

6. The high-throughput microfluidic screening device according to claim 5, characterized in that, The microchannel reactor is a polytetrafluoroethylene tube with an inner diameter of 0.5 mm to 1.0 mm.

7. The high-throughput microfluidic screening device according to claim 6, characterized in that, The heat exchanger is a constant temperature oil bath or a Peltier temperature control module.

8. The high-throughput microfluidic screening device according to claim 1, characterized in that, It also includes a height-adjustable base, on which the mixing divider, injection pump system and microchannel reactor are located, and the dispenser is located near the base.

9. The high-throughput microfluidic screening device according to claim 1, characterized in that, The dispenser includes a control unit, a three-axis moving platform, a needle for collecting fluid disposed above the three-axis moving platform, a collection container disposed on the three-axis moving platform, and a stepper motor for driving the three-axis moving platform to move. The control unit is electrically connected to the stepper motor and is used to control the collection container to collect samples corresponding to the needle.

10. A high-throughput microfluidic screening method, characterized in that, The high-throughput microfluidic screening device according to any one of claims 1 to 7 includes the following steps: S1: Proportional injection: Start the injection pump system for delivering the reactants and deliver the reactants to the mixer divider according to the first target proportion. At this time, the injection pump system for delivering the divided phase is in the off state, and the check valve on the divided phase pipeline ensures that the reactants do not flow back into the divided phase pipeline. S2: Liquid flow segmentation: When the injection pump system used to transport the reactants reaches the preset target reaction volume, it is shut down. At the same time, the injection pump system used to transport the segmented phase is turned on and the segmented phase is injected into the mixer-segmenter. The continuous liquid flow in the mixer-segmenter is segmented and pushed into the microchannel reactor. During this stage, the check valve on the reactant pipeline ensures that the reactants do not flow back into the reactant pipeline. S3: Ratio switching and re-injection: The syringe pump system used to deliver the split phase is shut down after the set time is reached, and then the syringe pump system used to deliver the reactants is restarted. The second target ratio delivers the reactants to the mixer and splitter, and the total flow rate remains constant at this time. S4: Series reaction: In a microchannel reactor, liquid columns or droplets that are segmented and have different reaction ratios are used as independent microreactors to complete chemical reactions during the flow process; S5: High-throughput distribution: The liquid column / droplet sequence after the reaction is distributed to different designated locations via a distributor, thereby completing the high-throughput preparation and collection of multiple reaction conditions at once.

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