CN108628351B - Microfluidic droplet generation device - Google Patents
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Abstract
The invention discloses a micro-fluidic liquid drop generating device which is high in adjusting speed, low in cost and small in proportion of unqualified liquid drops. The micro-fluidic liquid drop generating device comprises a micro-fluidic chip, a vibration mechanism, a light detection mechanism, a storage mechanism, a human-computer interaction mechanism and a control mechanism. The micro-fluidic liquid drop generating device combines the automatic feedback and pressure-controlled oscillation adjusting technology, can adaptively adjust the size of the generated liquid drop, can generate the stable liquid drop with higher uniformity, has higher adjusting speed and liquid drop generating speed, does not influence the generation of the liquid drop in the adjusting process, and can be continuously adjusted. Therefore, the quality of the generated liquid drop can be improved and the generation cost of the liquid drop can be reduced by using the microfluidic liquid drop generating device to generate the liquid drop.
Description
Technical Field
The invention relates to the technical field of microfluidic chips, in particular to a microfluidic droplet generation device.
Background
The microfluidic droplet technology is a brand new technology for controlling micro-volume liquid developed on the basis of microfluidics. The liquid drops generated by the technology are micro-reaction units with the volume of nanoliters or even picoliters, and are applied to the fields of protein crystallization, cell analysis, rapid enzyme reaction kinetics research, digital PCR, gene sequencing and the like. The microfluidic droplet platform can rapidly and stably generate droplets with uniform sizes, and compared with the traditional microplate method, the screening flux of the microfluidic droplet technology can be improved by 1000 times, so that the microfluidic droplet technology has great potential to become a next generation ultrahigh flux screening platform.
At present, the generation mode of the liquid drop in the micro-fluidic chip mainly comprises a Y-shaped channel method, a flow focusing method and the like, so that a continuous phase fluid is enabled to 'squeeze' the front edge of a dispersed phase fluid from a cross part, and the front edge of the dispersed phase fluid is enabled to shrink and deform to be unstable, thereby forming the dispersed liquid drop. As shown in fig. 1, the continuous phase and the dispersed phase are sheared in the micro flow channel under the action of the external pressure, and liquid drops are generated at the crossing outlet of the two phases.
The fluid channels in the microfluidic chip are generally narrow, usually in a micrometer or even lower scale, are limited by the influence of processes and environments, and are easily blocked or have large errors in flow channels, so that the same batch of chips have the consequences of large difference in the generated results, even no generation of liquid drops, and the like.
In order to solve the problem, a CCD camera and the like are added at the rear end of the generated liquid drop for detection in the traditional adjusting method, the size of the liquid drop is calculated according to the detection result, and the pressure sources at the continuous phase end and the dispersed phase end are adjusted again. There are a number of problems with this approach. Firstly, the adjustment of the pressure source is liable to lead to improper adjustment, and in some cases (e.g. low viscosity of the continuous phase) no droplets can be formed; meanwhile, the flow rate ratio of the continuous phase to the dispersed phase can be adjusted by adjusting the pressure source, waste of the continuous phase is easily caused, the generation cost of liquid drops is increased when the generation quantity of the liquid drops is large, the speed is high and the cost of the continuous phase is high, and the common adjusting method has slow reaction in adjustment and cannot quickly enable the size of the liquid drops to reach the expected value.
Disclosure of Invention
In view of the above, there is a need for a microfluidic droplet generation device that can be regulated at a faster rate, at a lower cost, and with a smaller fraction of rejected droplets.
A micro-fluidic liquid drop generating device comprises a micro-fluidic chip, a vibration mechanism, a light detection mechanism, a storage mechanism, a human-computer interaction mechanism and a control mechanism; wherein,
the micro-fluidic chip is provided with a continuous phase input flow channel, a disperse phase input flow channel and an output flow channel, the continuous phase input flow channel and the output flow channel are communicated with the disperse phase input flow channel, and a disperse phase circulating in the disperse phase input flow channel can be sheared by a continuous phase circulating in the continuous phase input flow channel to form liquid drops which are output from the input flow channel;
the vibration mechanism is connected with the microfluidic chip and is used for driving the microfluidic chip to vibrate;
the optical detection mechanism is used for detecting the size information of the liquid drops in the output flow channel;
the storage mechanism is used for storing or storing the amplitude and/or frequency of the vibration mechanism corresponding to the liquid drops with different sizes and the liquid information of the continuous phase and the dispersed phase;
the human-computer interaction mechanism is used for displaying and inputting the size information of the liquid drops, the amplitude and/or frequency of the vibration mechanism and the liquid information of the continuous phase and the dispersed phase;
the control mechanism is electrically connected with the vibration mechanism, the light detection structure, the storage mechanism and the human-computer interaction mechanism respectively; the control mechanism is used for searching the amplitude and/or frequency of the corresponding vibration mechanism from the storage mechanism according to the size information of the liquid drops input by the man-machine interaction mechanism and the liquid information of the continuous phase and the dispersed phase, controlling the vibration mechanism to adjust the amplitude and/or frequency according to the size information of the liquid drops detected by the light detection mechanism, controlling the storage mechanism to store the adjusted amplitude and/or frequency and the size information of the corresponding liquid drops, or directly storing the amplitude and/or frequency corresponding to the liquid drops with different size information and the liquid information of the continuous phase and the dispersed phase into the storage mechanism.
In one embodiment, the continuous phase input flow channel, the output flow channel and the disperse phase input flow channel are communicated in a cross mode to form a Y shape or a cross shape.
In one embodiment, the vibrating mechanism is in contact with or embedded in the microfluidic chip.
In one embodiment, the vibration mechanism is located above the dispersed phase input flow channel and close to the communication position of the dispersed phase input flow channel and the continuous phase input flow channel, and the distance between the vibration mechanism and the dispersed phase input flow channel is 1-3 mm.
In one embodiment, the vibration mechanism is a piezoelectric ceramic plate.
In one embodiment, the microfluidic chip is provided with an optical detection window corresponding to the output flow channel;
the optical detection mechanism comprises a light source and a photoelectric converter; the light source is used for irradiating the output flow channel at the position of the light detection window; the photoelectric converter is used for detecting an image signal reflecting the state of the liquid drop in the output flow channel at the position of the light detection window, converting the image signal into an electric signal and sending the electric signal to the control mechanism;
the control mechanism converts the electric signals into digital signals to be displayed on the human-computer interaction mechanism.
In one embodiment, the light source is one or more of an LED light source, a laser and a mercury lamp; the photoelectric converter is one or more of CCD, PD and PMT.
In one embodiment, the storage mechanism is a LUT memory.
In one embodiment, the control mechanism is an MCU controller, an FPGA processor, and/or a DSP processor.
In one embodiment, the microfluidic droplet generation device further comprises a pressure supply mechanism for providing external pressure to the continuous phase input flow channel and the dispersed phase input flow channel.
The micro-fluidic liquid drop generating device can adaptively adjust the size of the generated liquid drop by combining the automatic feedback and pressure-controlled oscillation adjusting technology, can generate the stable liquid drop with higher uniformity, has higher adjusting speed and liquid drop generating speed, does not influence the generation of the liquid drop in the adjusting process, and can be continuously adjusted. Therefore, the quality of the generated liquid drop can be improved and the generation cost of the liquid drop can be reduced by using the microfluidic liquid drop generating device to generate the liquid drop.
Drawings
FIG. 1 is a schematic diagram of a conventional microfluidic droplet generation device;
fig. 2 is a schematic structural diagram of a microfluidic droplet generation device according to an embodiment of the present invention.
Detailed Description
To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
It will be understood that when an element is referred to as being "secured to" another element, it can be directly on the other element or intervening elements may also be present. When an element is referred to as being "connected" to another element, it can be directly connected to the other element or intervening elements may also be present.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
As shown in fig. 2, the microfluidic droplet generation apparatus 100 according to an embodiment includes a microfluidic chip 110, a vibration mechanism 120, a light detection mechanism 130, a storage mechanism 140, a human-computer interaction mechanism 150, and a control mechanism 160.
The microfluidic chip 110 has a continuous phase input channel 112, a dispersed phase input channel 114, and an output channel 116. The continuous phase input channel 112 and the output channel 116 are both connected to the dispersed phase input channel 114, and the dispersed phase flowing through the dispersed phase input channel 114 can be cut by the continuous phase flowing through the continuous phase input channel 112 to form liquid droplets, and the liquid droplets are output from the input channel 116.
In this embodiment, the continuous phase input channel 112 in the microfluidic chip 110 is cross-connected with the dispersed phase input channel 114 and the output channel 116 to form a cross structure, and has two continuous phase input ports (or liquid storage ports), one dispersed phase input port (or liquid storage port) and one output port, which are respectively used for the input of the continuous phase and the dispersed phase and the output of the generated droplets. The material of the microfluidic chip 110 may be any transparent material such as COC, PMMA, PC, etc. It is understood that in other embodiments, the shape of the microfluidic chip 110 is not limited thereto, and may be a microchannel having another shape such as a Y-shape.
Further, in the present embodiment, the microfluidic chip 110 further has a pressure supply mechanism for supplying external pressure to the continuous phase input flow channel 112 and the dispersed phase input flow channel 114. The continuous and dispersed phases flow into the respective input channels under external pressure, and the dispersed phase is sheared by the continuous phase in the channels to form droplets. The pressure supply mechanism can be a device capable of providing pressure, such as an injection pump, a constant pressure pump and/or an air compressor. The pressure may be either negative or positive.
The droplets generated in the microfluidic chip 110 may be in a water-in-oil mode, an oil-in-water mode, or a multi-layer encapsulation mode. One or more surfactants may be added to the continuous and/or dispersed phase for enhancing the stability of the droplets.
The vibration mechanism 120 is connected to the microfluidic chip 110 for driving the microfluidic chip 110 to vibrate. In the present embodiment, the vibration mechanism 120 is preferably located above the disperse phase input channel 114 and near the position where the disperse phase input channel 114 communicates with the continuous phase input channel 112. The distance between the vibrating mechanism 120 and the dispersed phase input channel 114 is 1-3 mm. The vibration mechanism 120 may be in contact with the microfluidic chip 110 or embedded in the microfluidic chip 110. The vibration mechanism is a piezoelectric ceramic piece or other modules which change the vibration frequency and/or amplitude according to the frequency and/or amplitude of the electric signal.
The optical detection mechanism 130 is used to detect the size information of the droplets in the output channel 116.
In the present embodiment, the microfluidic chip 110 is provided with a light detection window corresponding to the output channel 116. The light detection mechanism 130 includes a light source 132 and a photoelectric converter 134. The light source 132 is used to illuminate the output flow channel 116 at the location of the light detection window. The light from the light source 132 may be directed through an optical fiber or directly onto the output runner 116. The photoelectric converter 134 is used for detecting an image signal reflecting the state of the liquid droplet in the output channel 116 at the position of the light detection window, converting the image signal into an electric signal and sending the electric signal to the control mechanism 160, and the control mechanism 160 converts the electric signal into a digital signal and displays the digital signal on the human-computer interaction mechanism 150. The photoelectric converter 134 may acquire a corresponding image signal through an optical fiber or direct imaging. The image signal may be a one-dimensional signal or a two-dimensional signal.
Further, in the present embodiment, the light source 132 may be, but is not limited to, one or more of an LED light source, a laser, and a mercury lamp. The photoelectric converter 134 may be, but is not limited to, one or more of a CCD, a PD, and a PMT. The light detection mechanism 130 of the present embodiment may further include an electronic shutter, a filter, and the like.
The storage mechanism 140 stores or is used to store the amplitude and/or frequency of the vibration mechanism 120, and the liquid information of the continuous and dispersed phases for different sized droplets.
In the present embodiment, the storage unit 140 is preferably an LUT memory. The LUT memory may be a non-volatile readable and writable memory or other readable and writable memory capable of retaining data from loss in a power-off state. The LUT memory can quickly and accurately find the required storage information, and can conveniently store the information to be stored in the storage mechanism 140.
The human-computer interaction mechanism 150 is used to display and input droplet size information, amplitude and/or frequency of the vibration mechanism 120, and liquid information for the continuous and dispersed phases. The human-computer interaction mechanism 150 may be one or a combination of several tools with information input and output functions, such as a PC, a touch screen input display device, and a keyboard.
The control mechanism 160 is electrically connected to the vibration mechanism 120, the light detection mechanism 130, the storage mechanism 140, and the human-computer interaction mechanism 150, respectively. The control mechanism 160 is used for searching the amplitude and/or frequency of the corresponding vibration mechanism 120 from the storage mechanism 140 according to the size information of the droplets and the liquid information of the continuous phase and the dispersed phase input by the human-computer interaction mechanism 150, controlling the vibration mechanism 120 to adjust the amplitude and/or frequency according to the size information of the droplets detected by the light detection mechanism 130, controlling the storage mechanism 140 to store the adjusted amplitude and/or frequency and the size information of the corresponding droplets, or directly storing the amplitude and/or frequency corresponding to the droplets with different size information and the liquid information of the continuous phase and the dispersed phase into the storage mechanism 140.
The control mechanism 160 is an MCU controller, an FPGA processor and/or a DSP processor for processing the signal reflecting the state of the droplet entering from the light detection mechanism 130 to obtain droplet size information and other information and/or commands.
Specifically, the control mechanism 160 searches the relation between the corresponding droplet size and the input information in the storage mechanism 140 according to the information, obtains the amplitude and/or frequency of the electric signal for driving the vibration mechanism 120 and adjusts the amplitude and frequency of the electric signal, feeds back the information to the control mechanism 160 by monitoring the droplet size generated in the output channel 116, the control mechanism 160 controls the human-computer interaction mechanism 150 to display the information generated by the current droplet, records the relation between the parameters such as the amplitude and/or frequency of the electric signal for driving the vibration mechanism 120 and the continuous phase and/or dispersed phase components and the droplet size, compares the information with the information stored in the storage mechanism 140, and if the corresponding information is not searched or the information of the droplet size is not consistent with the searched droplet size information, the relevant information in the storage means 140 is updated and the control means 160 compares the detected droplet size with the desired size and changes the amplitude and/or frequency of the electrical signal driving the vibration means 120 in accordance with the comparison to achieve the purpose of changing the droplet size.
Parameters such as the composition of the continuous phase and/or the dispersed phase, the vibration frequency and/or the amplitude parameter of the vibration mechanism 120, and the corresponding droplet size information are written into the storage mechanism 140 at the time of device initialization or at the time of subsequent experiments. When the device is initialized, parameters such as the components of the continuous phase and/or the dispersed phase are changed, the vibration frequency and/or amplitude of the vibration mechanism 120 are adjusted, the size of the correspondingly generated droplet is recorded, the corresponding relation between the size of the droplet and the relevant parameters is recorded, the corresponding relation is written into the storage mechanism 140, or the storage mechanism 140 is kept empty, and the information is recorded into the storage mechanism 140 in the subsequent test.
The process of generating droplets by the microfluidic droplet generation device 100 of the present invention will be further described with reference to specific examples.
Examples
When the micro-fluidic chip is manufactured, the piezoelectric ceramic sheet is embedded into the micro-fluidic chip and is positioned between an inlet of the dispersed phase input flow channel and an intersection of the continuous phase input flow channel and close to the intersection. The piezoelectric ceramic piece is positioned above the disperse phase input flow channel in the chip and keeps a distance of 1-3 mm with the disperse phase input flow channel. The piezoelectric ceramic piece is connected with the main control module through an electrode.
Assuming that the LUT in the storage means has been experimentally measured and recorded with data as shown in table 1 below, it is now necessary to generate droplets having a diameter of 55 μm, and by looking up a table in the LUT, matching information such as continuous phase composition, viscosity, dispersed phase composition, viscosity, etc., and obtaining vibration frequency information corresponding to droplet diameters of 50 to 60 μm stored in the table, the droplet change of 10 μm at that scale, the frequency change of about 10kHz, and scaling the ratio, the vibration frequency required for the 55 μm droplet is obtained at about 25 kHz. The control mechanism adjusts the vibration frequency to be 25kHz, liquid drops are generated, and the diameter of the generated liquid drops is obtained through feedback of the optical detection mechanism. According to different conditions of the diameter, the control mechanism automatically carries out the following treatment:
1. if the diameter of the generated droplet is found to be within an acceptable error range (e.g., 0.5 μm) from the expected value, no subsequent processing is performed.
2. If the generated liquid drop and the expected error are found to be out of a tolerable range but between 50 and 60 mu m, increasing the vibration frequency by 1kHz and reducing the vibration frequency by 1 mu m according to the calculated scale, and correspondingly increasing or reducing the vibration frequency until the generated liquid drop and the expected value are within an acceptable error range.
3. If the diameter of the generated liquid drop is not within the range of 50-60 mu m, the abnormal condition is shown after the system is electrified to work, for example, the flow channel of the microfluidic chip is blocked or the difference between the chip and the chip used when the LUT table is initialized is too large due to poor process, the data in the LUT table are inaccurate, the data in the LUT table are cleared, two vibration frequencies (which can be selected according to experience) are selected to generate the liquid drop according to the relation that the frequency is larger and the liquid drop is smaller, the corresponding liquid drop size is respectively obtained, and the liquid drop size is recorded in the LUT table. The vibration frequency is then readjusted according to the protocol described in cases 1 and 2 until the resulting drop diameter deviates from the desired value by an acceptable margin of error.
Table 1LUT storage example
The microfluidic droplet generation device 100 can adaptively adjust the size of generated droplets by combining an automatic feedback and pressure-controlled oscillation adjustment technology, can generate stable droplets with high uniformity, has high adjustment speed and droplet generation speed, does not influence the generation of droplets in the adjustment process, and can be continuously adjusted. Therefore, the quality of the generated liquid drop can be improved and the generation cost of the liquid drop can be reduced by using the microfluidic liquid drop generating device to generate the liquid drop.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (9)
1. A micro-fluidic liquid drop generating device is characterized by comprising a micro-fluidic chip, a vibrating mechanism, a light detection mechanism, a storage mechanism, a human-computer interaction mechanism and a control mechanism; wherein,
the micro-fluidic chip is provided with a continuous phase input flow channel, a disperse phase input flow channel and an output flow channel, the continuous phase input flow channel and the output flow channel are communicated with the disperse phase input flow channel, a disperse phase circulating in the disperse phase input flow channel can be sheared by a continuous phase circulating in the continuous phase input flow channel to form liquid drops to be output from the input flow channel, and the continuous phase input flow channel, the output flow channel and the disperse phase input flow channel are communicated in a crossed mode to form a Y shape or a cross shape;
the vibration mechanism is connected with the microfluidic chip to drive the microfluidic chip to vibrate, the vibration mechanism is in contact with the microfluidic chip or is embedded in the microfluidic chip, the vibration mechanism is located above the disperse phase input flow channel and close to the communication position of the disperse phase input flow channel and the continuous phase input flow channel, and the distance between the vibration mechanism and the disperse phase input flow channel is 1-3 mm;
the optical detection mechanism is used for detecting the size information of the liquid drops in the output flow channel;
the storage mechanism is used for storing or storing the amplitude and/or frequency of the vibration mechanism corresponding to the liquid drops with different sizes and the liquid information of the continuous phase and the dispersed phase;
the human-computer interaction mechanism is used for displaying and inputting the size information of the liquid drops, the amplitude and/or frequency of the vibration mechanism and the liquid information of the continuous phase and the dispersed phase;
the control mechanism is electrically connected with the vibration mechanism, the light detection structure, the storage mechanism and the human-computer interaction mechanism respectively; the control mechanism is used for searching the amplitude and/or frequency of the corresponding vibration mechanism from the storage mechanism according to the size information of the liquid drops input by the man-machine interaction mechanism and the liquid information of the continuous phase and the dispersed phase, controlling the vibration mechanism to adjust the amplitude and/or frequency according to the size information of the liquid drops detected by the light detection mechanism, controlling the storage mechanism to store the adjusted amplitude and/or frequency and the size information of the corresponding liquid drops, or directly storing the amplitude and/or frequency corresponding to the liquid drops with different size information and the liquid information of the continuous phase and the dispersed phase into the storage mechanism.
2. The microfluidic droplet generation apparatus of claim 1, wherein the material of the microfluidic chip is any one of COC, PMMA and PC.
3. The microfluidic droplet generation apparatus of claim 1, wherein the vibration mechanism is a piezoceramic wafer.
4. The microfluidic droplet generation apparatus of claim 1, wherein the microfluidic chip is provided with a light detection window corresponding to the output channel;
the optical detection mechanism comprises a light source and a photoelectric converter; the light source is used for irradiating the output flow channel at the position of the light detection window; the photoelectric converter is used for detecting an image signal reflecting the state of the liquid drop in the output flow channel at the position of the light detection window, converting the image signal into an electric signal and sending the electric signal to the control mechanism;
the control mechanism converts the electric signals into digital signals to be displayed on the human-computer interaction mechanism.
5. The microfluidic droplet generation apparatus of claim 4, wherein the light source is one or more of an LED light source, a laser, and a mercury lamp; the photoelectric converter is one or more of CCD, PD and PMT.
6. The microfluidic droplet generation device of claim 1, wherein the storage mechanism is a LUT memory.
7. The microfluidic droplet generation device of claim 1, wherein the control mechanism is an MCU controller, an FPGA processor, and/or a DSP processor.
8. The microfluidic droplet generation apparatus of any of claims 1-7, further comprising a pressure supply mechanism for providing external pressure to the continuous phase input channel and the dispersed phase input channel.
9. Microfluidic droplet generation device according to claim 8 wherein the pressure supply means is a syringe pump, a constant pressure pump and/or an air compressor.
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| CN110052298A (en) * | 2019-05-09 | 2019-07-26 | 中国计量大学 | A method of vibration pipeline control micro-fluidic chip generates microlayer model |
| KR102382612B1 (en) * | 2020-02-03 | 2022-04-05 | (주)인벤티지랩 | A microparticle producing system which comprises carrying fluid, and a controlling method thereof |
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| CN114308150B (en) * | 2021-12-07 | 2023-01-03 | 中国地质大学（武汉） | Feedback control type double-pulse driving liquid drop generating system and liquid drop generating method |
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| FR2968582B1 (en) * | 2010-12-08 | 2018-05-25 | Commissariat A L'energie Atomique Et Aux Energies Alternatives | METHOD AND DEVICE FOR GENERATING DROPS OF LOW GENERATING SPEED AND MODULAR GRANULOMETRIC SPECTRUM |
| CN103402907B (en) * | 2011-01-17 | 2016-03-23 | 新加坡科技研究局 | Microfluidic droplet generator |
| KR101620154B1 (en) * | 2014-01-16 | 2016-05-12 | 고려대학교 산학협력단 | Apparatus for separating micro-nano scale particle using field-flow fractionation based on acoustic wave |
| CN104571152A (en) * | 2015-01-20 | 2015-04-29 | 哈尔滨工业大学 | Liquid drop micro fluid control closed-loop regulation device based on microvalve |
| CN104888875B (en) * | 2015-07-01 | 2017-03-01 | 北京工业大学 | Based on the movable micro-fluidic chip of the lower wall surface specified location of microchannel |
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