CN109395788A - A kind of intraluminal fluid dripping is for chip apparatus - Google Patents
A kind of intraluminal fluid dripping is for chip apparatus Download PDFInfo
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- CN109395788A CN109395788A CN201811430323.9A CN201811430323A CN109395788A CN 109395788 A CN109395788 A CN 109395788A CN 201811430323 A CN201811430323 A CN 201811430323A CN 109395788 A CN109395788 A CN 109395788A
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- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 124
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 73
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- 238000002360 preparation method Methods 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000004458 analytical method Methods 0.000 claims abstract description 11
- 238000006424 Flood reaction Methods 0.000 claims abstract description 4
- 238000009826 distribution Methods 0.000 claims abstract description 3
- 239000006185 dispersion Substances 0.000 claims description 28
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- 238000003860 storage Methods 0.000 claims description 15
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- 238000010276 construction Methods 0.000 claims description 7
- 238000007789 sealing Methods 0.000 claims description 7
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
- B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
- B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
- B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
- B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/08—Geometry, shape and general structure
- B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
- B01L2300/00—Additional constructional details
- B01L2300/16—Surface properties and coatings
- B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
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- Chemical & Material Sciences (AREA)
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- Dispersion Chemistry (AREA)
- Analytical Chemistry (AREA)
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- Clinical Laboratory Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
Abstract
A kind of intraluminal fluid dripping is for chip apparatus, including reaction tube and drop formation chip, drop formation chip includes reagent inlet and the consistent branch microchannel of multiple dimensional structures being connected with reagent inlet, branch microchannel is parallel with drop formation chip bottom and dissipates distribution outward by chip center, the outlet of branch microchannel is located at drop formation chip side wall outer rim, and it forms spout structure and is prepared for drop, reaction tube drop prepare when in be loaded with continuous phase reagent, and continuous phase reagent sufficiently floods and infiltrates branch microchannel and the spout structure of drop formation chip in entire drop preparation process, disperse phase reagent to load by reagent inlet, it is reached under pressure through branch microchannel and breaks to form drop at spout structure；The present invention improves device and integrates performance, simplifies drop formation process, reduces the cost and complexity of external pressure driving control system, improves drop to greatest extent and prepares frequency, meets the analysis demand of different application.
Description
Technical field
The invention belongs to biochemical microfluidic arts, and in particular to a kind of intraluminal fluid dripping is for chip apparatus.
Background technique
For the biochemical microfluidic analysis such as enzymatic synthesis and its activity analysis, drop digital pcr and cell high flux screening
Field, drop microflow control technique experienced quick development, rank that microlayer model is commonly used as nanoliter or picoliters are even ascended to heaven from
Scatteredization reaction vessel has great advantage in the precision of analysis detection, sensitivity and repeatability.In addition, micro-fluidic
Technology automation, advantage easy of integration, flux is high, can also greatly improve the sensitivity and efficiency of biochemical analysis.Drop is usual
It is made of immiscible continuous phase and dispersion phase reagent, it is mutual using Osima jacoti, Osima excavata between two-phase fluid and interfacial tension etc.
Dispersed phase is separated into the microlayer model unit of discrete nanoliter level and following volumes by effect.
With the development of microflow control technique, the drop preparation method based on microfluid obtains quickly application and development, commonly uses
Structure include T-type, flow focusing (US9500664B2), coaxial stream (CN105771826B) and ladder emulsification (step
The forms such as emulsification).Wherein, drop system can be realized in the control that the method for ladder emulsification is usually only necessary to dispersed phase
It is standby, the parallelization of device and integrated more easily realization.However, the drop for preparing completion in this method is tended in drop system
Standby unit collects around, and influence subsequent droplet stablizes preparation, in document Macromolecular Chemistry&Physics,
Volume 218,2017, page 1600472, " the High-Throughput Step of Alessandro Ofner et al.
Emulsification for the Production of Functional Materials Using a Glass
A kind of high-throughput ladder emulsification chip apparatus of glass baseplate is described in Microfluidic Device ", it is continuous by controlling
The flow wash of phase reagent drives drop to be detached from drop preparation unit, solves the problems, such as that drop is assembled in drop preparation unit, but
Which again increases the complexity of chip apparatus, still need to be transferred to progress subsequent reactions in reaction tube after drop preparation.It is Chinese special
Sharp (Publication No. CN105413772B) provides a kind of mono-/multi- component drop preparation facilities based on integrated micro-channels, including
Discrete phase input system and drop formation system, but drop preparation facilities described in the patent needs multiple component connections, it is difficult
It is minimized with realization device, the discrete phase outlet that drop preparation unit is made of microchannel plastic film mating splint and backing plate connects
Head is constituted, and is formed series of parallel arrangement and is exported downward integrated micro-channels, and drop size, which is limited by the structure, to be difficult to decrease,
And it is only applicable to discrete phase density and is prepared greater than the drop of continuous phase density.
Therefore, there is also defects with integrated aspect in device miniaturization for the drop preparation method of conventional ladder emulsification, need
Complicated fluid means and chip is wanted to design the large scale preparation to realize droplet.
Summary of the invention
In order to overcome the disadvantages of the above prior art, it is an object of the invention to propose a kind of intraluminal fluid dripping for chip dress
Set, improve device integrate performance while, simplify drop formation process, reduce external pressure driving control system cost with
Complexity improves drop to greatest extent and prepares frequency, reduces droplet transfer step and can directly complete subsequent reactions in pipe
Analysis, reagent system (especially dispersed phase) volume are adjusted in a big way, can satisfy the analysis of different application
Demand promotes drop microflow control technique in the development and application of biochemical analysis field.
In order to achieve the above object, the technical scheme adopted by the invention is as follows:
A kind of intraluminal fluid dripping is for chip apparatus, the drop formation chip 2 assembled including reaction tube 1 and therewith, and drop is raw
The consistent branch microchannel 4 of multiple dimensional structures for including reagent inlet 3 at chip 2 and being connected with reagent inlet 3, branch are micro- logical
Road 4 is parallel with 2 bottom of drop formation chip and dissipates distribution outward by chip center, and the outlet of branch microchannel 4 is located at drop
2 side wall outer rim of chip is generated, and forms spout structure 5 and is prepared for drop；
There are gaps between the spout structure 5 and reaction tube 7；
The reaction tube 1 is loaded with continuous phase reagent 8, and continuous phase in entire drop preparation process when prepared by drop
Reagent 8 sufficiently floods and infiltrates branch microchannel 4 and the spout structure 5 of drop formation chip 2, and dispersion phase reagent 9 passes through reagent
Entrance 3 loads, and reaches through branch microchannel 4 broken to form drop 6 at spout structure 5 under pressure, drop 6 formed after because
The density variation of continuous phase reagent 8 and dispersion phase reagent 9 is rapidly separated spout structure 5.
The reagent inlet 3 of the drop formation chip 2 reserves liquid storage cavity configuration 302, first turns reagent when prepared by drop
It moves on in liquid storage cavity configuration 302, then applies the positive pressure persistently controlled to reagent inlet 3 and complete fluid driving and drop system
It is standby.
The sealing of the branch microchannel 4 is completed by slab construction 10, and slab construction 10 is located at 2 bottom of drop formation chip
Portion, slab construction 10 are processed integrally by way of bonding with drop formation chip 2, and branch microchannel 4 is processed in bonding face
Any one side structure on, or on structure on two sides process and by alignment complete microchannel sealing.
The branch microchannel 4 is straight channel or curved shape runner, and microchannel cross-section is round, semicircle, square
Shape or other polygons, 4 length of branch microchannel are 0.5~15mm.
The spout structure 5 is round, rectangle or other polygons；The size of rectangle is wide 5~500um, high by 2~
50um。
For chip apparatus, completely or only branch microchannel 4 and spout structure 5 pass through hydrophobe to the intraluminal fluid dripping
Surface treatment；The method of surface treatment includes directly coating, chemical deposition and chemical reaction modification.
The drop formation chip 2, which is assembled with reaction tube 1 by one-to-one mode, to be applied in combination, i.e. drop formation core
Piece 2 with it is single, 2,4,8,24, the combining form of 48 or 96 pass through the anti-of connecting board structure connection with corresponding
Should the assembly of pipe 1 use, single, 2,4,8,24,48 or 96 and the examination of more dispersed phases can be completed parallel
It is prepared by the drop of agent.
A kind of intraluminal fluid dripping for chip apparatus operating method, comprising the following steps:
The first step is ready for the continuous phase reagent 8 and dispersion phase reagent 9 of drop preparation, takes out reaction tube 1 and drop
Generate chip 2 and the rubber pad 12 for sealing drop formation chip 2；
Continuous phase reagent 8 is added with pipettor cooperation disposable tip in second step, fixed reaction tube 1 in reaction tube 1；
Drop formation chip 2 is put into reaction tube 1 and assembles by third step, and continuous phase reagent 8 will be in capillary after standing
The branch's fluid channel 4 and spout structure 5 of drop formation chip 2 are sufficiently flooded and infiltrated under power effect；
4th step draws the liquid storage that dispersion phase reagent 9 is loaded into drop formation chip 2 with pipettor cooperation disposable tip
In cavity configuration 302；Drop preparation as carried out multiple samples simultaneously, replaces disposable tip and repeats above-mentioned sample-adding；
5th step covers rubber pad 12 in 2 upper surface of drop formation chip, and fixed rubber pad 12 simultaneously makes on rubber pad 12
Venthole alignment liquid storage cavity configuration 302 center；
6th step loads the positive pressure of continued for constant to reagent inlet 3, has been prepared by set time or monitoring drop
Pressure jump after terminates drop preparation process；Disperse phase reagent 9 and reaches spout knot through branch microchannel 4 under pressure
At structure 5, drop 6 is broken to form under the collective effect of fluid dynamic, two-phase interface tension, gravity and buoyancy；Due to dispersed phase
The density variation of reagent 9 and continuous phase reagent 8, drop 6 will be disengaged from spout structure 5.
Rubber pad 12 and drop formation chip 2 are removed, the lotion prepared in reaction tube 1 is obtained, it can be directly in reaction tube 1
Interior progress subsequent reactions and analysis.
Compared to existing drop preparation method and device, the invention has the following advantages that
(1) intraluminal fluid dripping of the present invention is located at drop formation core for the spout structure 5 of realization drop formation in chip apparatus
The side wall outer rim of piece 2, in conjunction with continuous phase reagent 8 and dispersion 9 density variation of phase reagent, drop 6 can be detached from rapidly spout structure
5, flowing of the transfer of drop 6 independent of continuous phase reagent 8 reduces the complexity of control system and reduces continuous phase examination
The consumption of agent 8.Compared with the prior art, continuous phase density is more than or less than all achievable drop system when dispersion phase reagent density
It is standby, it is less to the limitation of continuous phase reagent 8 and dispersion phase reagent 9, expand the application range that drop prepares chip apparatus.
(2) for intraluminal fluid dripping of the present invention in chip apparatus, 6 diameter of drop depends on branch's fluid channel 4 and spout
The microscopic dimensions of structure 5, therefore the size of drop 6 is more controllable.Meanwhile by adjusting branch's fluid channel 4 and spout structure 5
The change of liquid-drop diameter, the macrostructures such as reaction tube 1 and reagent inlet 3 and system drive control group can be realized in microscopic dimensions
Part can customize the liquid drop microfluidic system of " set of system, plurality of specifications " substantially all without adjustment according to experiment demand, this
The cost of analysis detection will be effectively reduced and expands its scope of application.
(3) intraluminal fluid dripping of the present invention only need to disposably load suitable continuous phase reagent 8 for chip apparatus in use
Effectively infiltration spout structure 5 can carry out subsequent drop preparation, and with progress prepared by drop, manage interior amount of reagent and increase,
Spout structure 5 is infiltrated always in continuous phase reagent 8, sustainable to carry out extensive drop preparation.Therefore, for same specification
Chip apparatus, the consumption without increasing continuous phase reagent 8 can adjust in a big way dispersion phase reagent 9 volume and liquid
Quantity is dripped, can be improved the accounting of dispersed phase reagent system in emulsion system, meets the lotion preparation of different biochemical analysis fields
Demand has good compatibility and scalability.
(4) compared to the prior art, intraluminal fluid dripping of the present invention completes drop for chip apparatus directly in reaction tube
Preparation, no reagent residual and dead volume, nearly all dispersion phase reagent 9 can generate the drop 6 of size uniformity, can directly into
The reaction and analytic process of row next step reduce the transfer step of drop 6, avoid droplets from 6 fusions and loss, improve the collection of system
Cheng Du and working efficiency.
(5) intraluminal fluid dripping of the present invention is simple and reliable for structure for chip apparatus, and precise injection molding or silicon micromachined work can be used
Skill batch machining, reaction tube 1 can also often be substituted with centrifuge tube by laboratory, can be effectively reduced chip apparatus cost, also guarantee
The versatility of subsequent analysis platform.
Detailed description of the invention
Fig. 1 is three dimensional structure diagram of the intraluminal fluid dripping in the embodiment of the present invention 1 based on centrifuge tube for chip apparatus.
Fig. 2-1 is top view of the intraluminal fluid dripping in the embodiment of the present invention 1 based on centrifuge tube for chip apparatus；Fig. 2-2
It is the sectional view along A-A of Fig. 2-1.
Fig. 3 is that the three dimensional structure diagram of drop formation chip and chip bottom branch are micro- logical in the embodiment of the present invention 1
The partial enlarged view in road.
Fig. 4-1 is the schematic diagram of chip apparatus drop preparation process in the embodiment of the present invention 1, disperses phase reagent density at this time
Less than discrete phase reagent density；Fig. 4-2 is the schematic diagram of chip apparatus drop preparation process in the embodiment of the present invention 1, this time-division
Dephasing reagent density is greater than discrete phase reagent density.
Fig. 5 is the intraluminal fluid dripping of eight union forms in embodiment 2 for the three dimensional structure diagram of chip apparatus.
In Fig. 6-1 embodiment of the present invention 2 the intraluminal fluid dripping of eight union forms for chip apparatus top view；Fig. 6-2 is
The B-B direction cross-sectional view of Fig. 6-1.
Fig. 7 is operating process of the intraluminal fluid dripping of the present invention for chip apparatus.
Fig. 8 is the liquid-drop diameter and capillary number (Ca) relational graph of the chip apparatus preparation of different dimensional structures.
When Fig. 9-1 is that dispersion phase density is less than continuous phase reagent density, the standby experiment schematic diagram of intraluminal fluid dripping of the present invention；
When Fig. 9-2 is that dispersion phase density is greater than continuous phase reagent density, the standby experiment schematic diagram of intraluminal fluid dripping of the present invention.
Figure 10 is experimental observation effect of the intraluminal fluid dripping of the present invention for chip apparatus, wherein figure (a) is intraluminal fluid drop life
Bright field imaging before being tested at chip apparatus；Scheme (b), (c), the micro- sight that (d) is chip apparatus intraluminal fluid drop preparation process
Mapping.
Specific embodiment
It elaborates below with reference to drawings and examples to the present invention.
Embodiment 1, referring to Fig.1, Fig. 2-1, Fig. 2-2, Fig. 3, Fig. 4-1, Fig. 4-2, a kind of intraluminal fluid dripping for chip apparatus,
The drop formation chip 2 assembled including reaction tube 1 and therewith, reaction tube 1 using laboratory often with centrifuge tube or PCR pipe, both
Cooperate drop formation chip 2 to complete drop formation, the container that drop is collected with reacted is also functioned as, below with the centrifuge tube of 0.5mL
For；The drop formation chip 2 is stepped cylinder shape structure, is prepared after assembling with reaction tube 1 for drop；Described
The consistent branch microchannel 4 of multiple dimensional structures that there is drop formation chip 2 reagent inlet 3 to be connected with reagent inlet 3, branch
Microchannel 4 is parallel with 2 bottom of drop formation chip and is distributed by chip center's outward radial, and the outlet of branch microchannel 4 is located at
2 side wall outer rim of drop formation chip simultaneously forms spout structure 5, prepares for drop；The drop formation chip 2 relies on chip
External boss structure 202 forms coaxial clearance fit with reaction tube 1, guarantees the positioning of drop formation chip 2, ensures simultaneously
Spacing is kept between spout structure 5 and reaction tube 7.
Referring to Fig. 4-1 and Fig. 4-2, the drop formation chip 2, which is assembled with reaction tube 1 by one-to-one mode, to be combined
It uses.After assembly, drop formation chip 2 gos deep into reaction tube 1, keeps the gap 0.5~1mm with reaction tube 7, ensure that
When 100 μ l reagent is at most added, drop 6 and continuous phase reagent 8 do not overflow reaction tube 1.
Referring to Fig. 3, the reagent inlet 3 includes the liquid storage cavity configuration 302 for reagent storage, liquid storage cavity body structure
302 be a conical cavity, can be used for storing the reagent for being no more than 100 μ L.
Referring to Fig. 3, the bottom of the drop formation chip 2 is a slab construction 10, passes through thermocompression bonding or medium
The modes such as bonding and drop formation chip 2 are processed integrally, for encapsulating branch's fluid channel 4 of drop formation chip bottom, are protected
It demonstrate,proves the size of fluid channel and forms the spout structure 5 for being used for drop formation.
The spout structure 5 is 15~150 μm wide, high 5~25 μm of rectangle, between existing between reaction tube 7
Gap generates and is detached from the requirement of spout structure 5 to meet drop 6；Spout structure 5 is parallel with chip bottom, in drop preparation process
In infiltrated in continuous phase reagent 8 always, can guarantee after drop 6 is formed to lead to because density variation is detached from rapidly spout structure 5
It crosses spout structure 5 and prepares monodisperse microlayer model of the diameter in 15 μm~150 μ ms.
The material of the drop formation chip 2 uses thermosetting property or thermoplastic polyester, such as poly dimethyl silicon
Oxygen alkane (PDMS), polycarbonate (PC), polymethyl methacrylate (PMMA), polypropylene (PP), cyclenes hydrocarbon type copolymer (COC)
Deng；Or inorganic material, such as silicon (Si), glass etc..
For chip apparatus, completely or only branch microchannel 4 and spout structure 5 pass through hydrophobe to the intraluminal fluid dripping
Surface treatment avoids the adherency of dispersion phase reagent 9 so that dispersion phase reagent 9 is greater than 90 ° in the surface contact angle of spout structure 5
With residual, promotes drop 6 to generate and be detached from spout structure 5 rapidly；The method of surface treatment include directly coating, chemical deposition and
Chemical reaction modification.
The working principle of the present embodiment are as follows:
Referring to Fig. 4-1 and Fig. 4-2, reaction tube 1 when prepared by drop in be loaded with continuous phase reagent 8, and continuous phase reagent 8
Sufficiently flood and infiltrate branch microchannel 4 and the spout structure 5 of drop formation chip 2；Disperse phase reagent 9 and passes through reagent inlet 3
It is loaded into liquid storage cavity configuration 302, is reached at spout structure 5 under the positive pressure effect of lasting control through branch microchannel 4
Break to form drop 6；Continuous phase reagent 8 is two kinds of immiscible reagents with dispersion phase reagent 9, and the density of two kinds of reagents is deposited
In difference, density variation is 0.1~1.0g/cm3；According to the density relationship of continuous phase reagent 8 and dispersion phase reagent 9, drop 6 will
The phenomenon that floating to liquid level or sinking to 1 tube bottom of reaction tube is presented in continuous phase reagent 8；As shown in Fig. 4-1, when dispersed phase tries
When the density of agent 9 is less than the density of continuous phase reagent 8, drop 6 floats up to continuous phase liquid level position after generating；As Fig. 4-2 institute
Show, when the density for dispersing phase reagent 9 is greater than the density of continuous phase reagent 8, drop 6 sinks down into tube bottom after generating, do not influence
Subsequent droplet generates.
Embodiment 2, referring to Fig. 5, Fig. 6-1 and Fig. 6-2, a kind of intraluminal fluid dripping is for chip apparatus, including reaction tube 1 and liquid
Drop generates chip 2；To realize the preparation of scale drop and chip apparatus mass production, the reaction tube 1 connects by first
Fishplate bar structure 101 is processed in the form of eight unions, and reaction tube 1 uses flat round type, to reduce continuous phase reagent
Consumption；Meanwhile drop formation chip 2 is made in the form of eight townhouses also by the second connecting board structure 201, and and reaction tube
1 is assembled, and can carry out the drop preparation of 8 groups of dispersed phase reagents 9,2 bottom of drop formation chip and 1 tube bottom of reaction tube simultaneously
Between there is storage of the distance for drop 6 or continuous phase reagent 8.
The reaction tube 1 and drop formation chip 2 is not limited to eight union forms, and drop formation chip 2 can be with list
It is a, 2,4,8,24, the assembly of reaction tube 1 of the combining form of 48 or 96 and the forms such as 8 unions or 96 orifice plates makes
With parallel to complete single, 2,4,8,24, drops preparations of 48 or 96 and more dispersion phase reagents 9.
Referring to Fig. 4-1, Fig. 4-2, Fig. 5, Fig. 7, a kind of operating method of intraluminal fluid dripping for chip apparatus, including following step
It is rapid:
The first step is ready for the continuous phase reagent 8 and dispersion phase reagent 9 of drop preparation, takes out reaction tube 1 and drop
Generate chip 2 and the rubber pad 12 for sealing drop formation chip 2；
Continuous phase reagent 8 is added with pipettor cooperation disposable tip in second step, fixed reaction tube 1 in reaction tube 1；
Drop formation chip 2 is put into reaction tube 1 and assembles by third step, and continuous phase reagent 8 will be in capillary after standing
The branch's fluid channel 4 and spout structure 5 of drop formation chip 2 are sufficiently flooded and infiltrated under active force effect；
4th step draws the liquid storage that dispersion phase reagent 9 is loaded into drop formation chip 2 with pipettor cooperation disposable tip
In cavity configuration 302；Drop preparation as carried out multiple samples simultaneously, replaces disposable tip and repeats above-mentioned sample-adding；
5th step covers rubber pad 12 in 2 upper surface of drop formation chip, and fixed rubber pad 12 simultaneously makes on rubber pad 12
Venthole alignment liquid storage cavity configuration 302 center, so as to the air-tight connection of subsequent actuating device of atmospheric pressure；
6th step loads the positive pressure of continued for constant to reagent inlet 3, has been prepared by set time or monitoring drop
Pressure jump after terminates drop preparation process；Disperse phase reagent 9 and reaches spout knot through branch microchannel 4 under pressure
At structure 5, drop 6 is broken to form under the collective effect of fluid dynamic, two-phase interface tension, gravity and buoyancy；Due to dispersed phase
The density variation of reagent 9 and continuous phase reagent 8, drop 6 will be disengaged from spout structure 5, and presents and float in continuous phase reagent 8
Liquid level or the phenomenon that sink to 1 tube bottom of reaction tube, spout structure 5 is infiltrated always in continuous phase reagent 8, does not influence subsequent droplet
6 preparations.
After the completion of six steps, negative pressure can be applied by the reagent inlet 3 to drop formation chip 2, part is superfluous
Continuous phase reagent 8 is transferred out of reaction tube 1 by drop formation chip 2, and integral inverted is reduced under the premise of not influencing emulsion system
The volume for answering system is conducive to the efficiency for improving subsequent reactions process.
Rubber pad 12 and drop formation chip 2 are removed, the lotion prepared in reaction tube 1 is obtained, it can be directly in reaction tube 1
Interior progress subsequent reactions and analysis.
Referring to Fig. 8, Fig. 8 is liquid-drop diameter and capillary number (Ca) relationship prepared by 8 groups of various sizes of branch microchannels 4
Figure, the size (wide × high) of branch microchannel 4 be respectively 26.6um × 10.5um, 47.4um × 10.5um, 56.0um ×
10.5um、69.4um×10.5um、42.8um×14.3um、62.4um×14.3um、77.7um×14.3um、100.7um×
14.3um, liquid-drop diameter D increase with the size of branch microchannel 4 and are increased；For fixed-size branch microchannel 4, scheming
Show that the diameter change of drop in capillary number (Ca) range is relatively small；It can be prepared by the microchannel of above-mentioned 8 packet size
Drop of the diameter within the scope of 35um~70um.By further adjusting the size of branch microchannel 4, chip of the present invention
Device can form diameter in the monodisperse drop of 5um to 500um range, and volume range is about 65fL to 65nL, meet different
The drop of application prepares demand.
Referring to Fig. 9-1, Fig. 9-2, when preparing drop using chip apparatus of the present invention, dispersion phase reagent 9 is made in pressure
Enter branch microchannel 4 and the generation ladder emulsification at spout structure 5 with lower, the principle is as follows: in low capillary pipe number
Under fluid flow conditions, dispersion phase reagent 9 contacted at spout structure 5 with continuous phase reagent 8 and interfacial tension act under by
Gradually expansion forms hemisphere jut, and fluid internal and external pressure balance, interface profile is in quasi-static lower evolution；According to Young-Laplace side
Journey, as hemisphere jut is grown, internal Laplace pressure Δ P=2 γ/R is gradually reduced.However, by branch microchannel 4
Structure size limitation, dispersing curvature of the phase reagent 8 in branch microchannel 4 has minimum value k*=1/r*；Work as hemisphere jut
When size increases to r* or more, disperse the internal pressure of hemisphere jut at phase reagent 8 and spout structure 5 not in branch microchannel 4
It keeps balancing again；Under the effect of Laplace pressure, additional dispersion phase reagent 8 is driven in hemisphere jut and causes branch
Disperse 8 fluid of phase reagent in microchannel 4 and form constriction, bottleneck is broken under interfacial tension effect, and hemisphere jut separates to be formed
Drop 6；Due to dispersing the density variation of phase reagent 9 and continuous phase reagent 8, drop 6 will be disengaged from the spout structure 5 of chip side wall,
And the phenomenon that floating to liquid level or sinking to 1 tube bottom of reaction tube is presented in continuous phase reagent 8, it avoids droplets from spout structure 5
The aggregation at place does not influence subsequent droplet preparation.
0, Figure 10 is experiment test effect of the intraluminal fluid dripping for chip apparatus referring to Fig.1, uses soft lithographic work in experiment
Skill makes the drop formation chip 2 of PDMS material, and continuous phase reagent 8 is the fluorinated oil containing surfactant, and dispersion phase reagent 9 is
PCR buffer；Wherein, figure (a) illustrates the intraluminal fluid drop before experiment and generates chip apparatus；Figure (b), (c), (d) illustrate core
The intraluminal fluid of sheet devices drips preparation process；Scheming (c) is chip apparatus partial enlargement observed result, it is seen that dispersion phase reagent 9 is through dividing
Branch fluid channel quickly forms drop 6 at spout structure 5, and drop 6, which floats, is detached from spout structure 5, does not influence the system of subsequent droplet
Standby, drop preparation speed is fast, size uniformity；After figure (d) illustrates drop preparation experiment progress a period of time, since density is closed
System, Water-In-Oil (W/O) type drop 6 assemble the preparation, it can be achieved that extensive intraluminal fluid drop on oil phase liquid face upper layer, work well.
Claims (9)
1. a kind of intraluminal fluid dripping is for chip apparatus, it is characterised in that: the drop formation core assembled including reaction tube (1) and therewith
Piece (2), drop formation chip (2) include reagent inlet (3) and be connected with reagent inlet (3) consistent point of multiple dimensional structures
Branch microchannel (4), branch microchannel (4) are parallel with drop formation chip (2) bottom and dissipate distribution outward by chip center, point
The outlet of branch microchannel (4) is located at 2 side wall outer rim of drop formation chip, and forms spout structure (5) and prepare for drop；
There are gaps between the spout structure (5) and reaction tube (7)；
The reaction tube (1) when prepared by drop in be loaded with continuous phase reagent (8), and it is continuous in entire drop preparation process
Phase reagent (8) sufficiently floods and infiltrates branch microchannel (4) and the spout structure (5) of drop formation chip (2), disperses phase reagent
(9) it is loaded by reagent inlet (3), is reached through branch microchannel (4) break to form liquid at spout structure (5) under pressure
It drips (6), because the density variation of continuous phase reagent (8) and dispersion phase reagent (9) is rapidly separated spout structure after drop (6) formation
(5)。
2. a kind of intraluminal fluid dripping according to claim 1 is for chip apparatus, it is characterised in that: the drop formation core
The reagent inlet (3) of piece (2) reserves liquid storage cavity configuration (302), first by agent transfer to liquid storage cavity configuration (302) when prepared by drop
It is interior, then reagent inlet (3) are applied with the positive pressure persistently controlled and completes fluid driving and drop preparation.
3. a kind of intraluminal fluid dripping according to claim 1 is for chip apparatus, it is characterised in that: the branch microchannel
(4) sealing is completed by slab construction (10), and slab construction (10) is located at drop formation chip (2) bottom, slab construction (10)
Integral with drop formation chip (2) processing by way of bonding, branch microchannel (4) are processed in any side of bonding face
In structure, or is processed on structure on two sides and microchannel sealing is completed by alignment.
4. a kind of intraluminal fluid dripping according to claim 1 is for chip apparatus, it is characterised in that: the branch microchannel
It (4) is that perhaps curved shape runner microchannel cross-section is that round, semicircle, rectangle or other polygons, branch are micro- to straight channel
Channel (4) length is 0.5~15mm.
5. a kind of intraluminal fluid dripping according to claim 1 is for chip apparatus, it is characterised in that: the spout structure
It (5) is round, rectangle or other polygons；The size of rectangle is wide 5~500um, high 2~50um.
6. a kind of intraluminal fluid dripping according to claim 1 is for chip apparatus, it is characterised in that: the intraluminal fluid dripping
Completely or only branch microchannel (4) and the surface treatment of spout structure (5) Jing Guo hydrophobe of standby chip apparatus；The side of surface treatment
Method includes directly coating, chemical deposition and chemical reaction modification.
7. a kind of intraluminal fluid dripping according to claim 1 is for chip apparatus, it is characterised in that: the drop formation core
Piece (2) is assembled by one-to-one mode with reaction tube (1) and is applied in combination, i.e., drop formation chip (2) with it is single, 2,4,
8,24,48 or 96 combining forms are assembled with the corresponding reaction tube (1) connected by connecting board structure and are used, energy
It is enough parallel to complete single, 2,4,8,24, drops preparations of 48 or 96 and more dispersion phase reagents.
8. a kind of intraluminal fluid dripping is for the operating method of chip apparatus, which comprises the following steps:
The first step is ready for continuous phase reagent (8) and dispersion phase reagent (9) of drop preparation, takes out reaction tube (1) and liquid
Drop generates chip (2) and the rubber pad (12) for sealing drop formation chip (2)；
Continuous phase reagent is added with pipettor cooperation disposable tip in second step, fixed reaction tube (1) in reaction tube (1)
(8)；
Drop formation chip (2) is put into reaction tube (1) and assembles by third step, and continuous phase reagent (8) will be in hair after standing
Spy sufficiently floods and infiltrates the branch's fluid channel (4) and spout structure (5) of drop formation chip (2) under firmly acting on；
4th step draws the liquid storage that dispersion phase reagent (9) is loaded into drop formation chip (2) with pipettor cooperation disposable tip
In cavity configuration (302)；Drop preparation as carried out multiple samples simultaneously, replaces disposable tip and repeats above-mentioned sample-adding；
5th step covers rubber pad (12) in drop formation chip (2) upper surface, and fixed rubber pad (12) simultaneously make rubber pad
(12) center of venthole alignment liquid storage cavity configuration (302) on；
6th step completes the positive pressure of reagent inlet (3) load continued for constant by set time or monitoring drop preparation
Pressure jump afterwards terminates drop preparation process；Disperse phase reagent (9) and reaches spout through branch microchannel (4) under pressure
At structure (5), drop (6) are broken to form under the collective effect of fluid dynamic, two-phase interface tension, gravity and buoyancy；Due to
Disperse the density variation of phase reagent (9) and continuous phase reagent (8), drop (6) will be disengaged from spout structure (5).
9. a kind of intraluminal fluid dripping according to claim 8 is for the operating method of chip apparatus, it is characterised in that: remove rubber
Rubber mat (12) and drop formation chip (2) obtain the lotion prepared in reaction tube (1), can directly carry out in reaction tube (1)
Subsequent reactions and analysis.
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| CN201811430323.9A CN109395788B (en) | 2018-11-28 | 2018-11-28 | Chip device for preparing liquid drops in tube |
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| CN201811430323.9A CN109395788B (en) | 2018-11-28 | 2018-11-28 | Chip device for preparing liquid drops in tube |
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| CN110813395A (en) * | 2019-11-29 | 2020-02-21 | 南通大学 | Suction head droplet generating device for rapidly preparing micro droplets |
| CN112619719A (en) * | 2020-12-04 | 2021-04-09 | 深圳先进技术研究院 | Droplet generation microdevice for digital PCR |
| CN113956968A (en) * | 2021-10-20 | 2022-01-21 | 西安天隆科技有限公司 | Liquid drop type digital PCR system and analysis method for realizing absolute quantification thereof |
| WO2022048374A1 (en) * | 2020-09-07 | 2022-03-10 | 深圳市亚辉龙生物科技股份有限公司 | Droplet microfluidic chip and microdroplet preparation method |
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