CN108073743A - The system and method for separation sub-micron nano particle is focused on based on nonNewtonian percolation - Google Patents
The system and method for separation sub-micron nano particle is focused on based on nonNewtonian percolation Download PDFInfo
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- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06F—ELECTRIC DIGITAL DATA PROCESSING
- G06F30/00—Computer-aided design [CAD]
- G06F30/20—Design optimisation, verification or simulation
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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
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- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06F—ELECTRIC DIGITAL DATA PROCESSING
- G06F30/00—Computer-aided design [CAD]
- G06F30/10—Geometric CAD
- G06F30/17—Mechanical parametric or variational design
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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
- 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
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- 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
Abstract
The present invention provides it is a kind of based on nonNewtonian percolation focus on separation sub-micron nano particle system, the system comprises：For conveying the conveying device of the working fluid with non-newtonian flow bulk effect；Microfluidic cell comprising microchannel, the microfluidic cell are connected by pipeline with the conveying device, are separated for the sub-micron nano particle in the working fluid next to conveying device conveying in the microchannel；It is arranged on the fork outlet of the microfluidic cell end, flexible adaptation focuses on or separated demand, the central fascicle of the fork outlet is used to collect the sub-micron nano particle focused on, and the side branch of the fork outlet is used to separate different sub-micron nano particles；The collection device for being used to collect target sub-micron nano particle of the fork outlet is connected respectively.The present invention can flexibly coordinate the design of a variety of devices to realize the focusing of sub-micron nano particles or separation, do not utilize specific immune response, manufacture and easy to operate, convenient parallel.
Description
Technical field
The invention belongs to particle separation technology fields, and separation sub-micron nanometer is focused on more particularly to based on nonNewtonian percolation
The system and manufacturing method of particle.
Background technology
Continuously, separation sub-micron nano particle is efficiently focused in medical treatment, pharmacy, chemistry, biology, high-resolution medicine
Many applications such as imaging and research field are significant.Ultracentrifugation, pore membrane filtering, specificity are widely used in these fields
The methods of immuno absorbence, separates sub-micron nano particle.These separation methods would generally cause the loss of sub-micron nano particle.
Ultracentrifugation needs 105A acceleration of gravity may damage sensitive biological sub-micron nano particle, prepare operation step
Suddenly it is relatively complicated to take and have certain risk.Pore membrane filtering is susceptible to obstruction when handling a large amount of samples, in removal process
In unavoidably have the loss of sub-micron nano particle.Specific immunity absorption is typically the modified specificity antibody in micro-structure
Absorption captures specific sub-micron nano biological particle, it is necessary to which additional flushing process recycles target particles, equally has comparable
Particle loss.These method generally existing capture rates are low, complex for operation step, are easy to cause sample irreversibility destruction etc.
Shortcoming.
Ripe commercialized flow cytometer needs high cost (instrument cost, reagent consumption, skilled operator
Member), it is widely available to limit its.Flow cytometer focuses on sub-micron nano particle using sheath stream, and sheath fluid is by sheath liquid pipe from surrounding
Sample spray orifice is flowed to, is projected after being enclosed in sample periphery from nozzle, sample is limited in by sheath fluid on the central axes of liquid stream.Due to sheath
The a diameter of micron order of liquid pipe, it is difficult to which nano particle is focused into sub-thread pencil.And caused using sub-micron or nano level pipeline
Manufacture difficulty is substantially increased with production cost.
The content of the invention
The technical problem to be solved by the present invention is to provide a kind of focusing separation sub-micron nanometer based on nonNewtonian percolation
The system and method for grain, make separation and focus on sub-micron nano particle operation it is easier, effect is good, while can also avoid pair
The destruction of irreversibility caused by sample.
To solve the above-mentioned problems, the present invention is provided a kind of focused on based on nonNewtonian percolation and separates sub-micron nano particle
System, the system comprises：
For conveying the conveying device of the working fluid with non-newtonian flow bulk effect；
Microfluidic cell comprising microchannel, the microfluidic cell are connected by pipeline with the conveying device, are used
Sub-micron nano particle in the working fluid come to conveying device conveying separates in the microchannel；
The fork outlet of the microfluidic cell end is arranged on, flexible adaptation focuses on or separated demand.The fork
The central fascicle of outlet is used to collect the sub-micron nano particle focused on, and the side branch of the fork outlet is used to separate difference
Sub-micron nano particle；
The collection device for being used to collect target sub-micron nano particle of the fork outlet is connected respectively.
Further, the position of the position of the microchannel sub-micron nano particle and the fork outlet accordingly flowed out
Selection is put by kinetic modelIt determines,
Wherein, vpIt is the velocity of working fluid sub-micron nano particle, FeIt is elastic force vector, μ is working fluid
Dynamic viscosity, ρpIt is the density of particle, a is the diameter of particle, and v is the velocity of working fluid, and ρ is that working fluid is close
Degree, FLIt is inertia force.
Further, the working fluid is with viscoelastic non-newtonian fluid.
Further, the conveying device can utilize impressed pressure, gravity or other physical fields to the conveying of working fluid
It realizes, the sub-micron nano particle is made to be flowed into the microchannel.
Further, the microchannel is linear, variable cross-section shape, serpentine or spiral shape；The section shape of the microchannel
Shape is square, rectangle, trapezoidal, triangle or concave-convex font；The ratio of width to height of the microchannel cross section can be any number.
The present invention also provides it is a kind of based on nonNewtonian percolation focus on separation sub-micron nano particle system manufacturing method,
Include the following steps：
A) working fluid with non-newtonian flow bulk effect containing sub-micron nano particle to be separated is prepared；
B) motor behavior during outflow of sub-micron nano particle is tracked under the different flow velocity of the working fluid, with evaluation
Focus on separated effect；
C) designed by the geometric parameter of theoretical model and numerical simulation of optimum microchannel and fork outlet；
D) conveying device, microfluidic cell, fork outlet, collection device are connected by pipeline.
Further, the step a) includes the following steps：
1) fluid containing sub-micron nano particle to be separated is prepared；
2) suitable high molecular polymer is added in the fluid, with non-newtonian flow bulk effect.
Further, the high molecular polymer is artificial synthesized or natural.
The technique effect of the present invention compared with prior art：
The elastic force that the present invention is applied using viscoelastic fluid to being suspended in sub-micron nano particle therein, regulates and controls fluid
The rheological equationm of state and passage design separation sub-micron nano particle.Advantage is a variety of device designs can flexibly be coordinated to realize sub-micro
The focusing or separation of rice nano particle do not utilize specific immune response, manufacture and easy to operate, convenient parallel.Conveying device
The working fluid of sub-micron nano particle containing focusing to be separated is passed through microfluidic cell, can effectively realize particle three
It is focused on dimension space in passage axis, and it is easy to operate, and focusing effect is good；Meanwhile the rheological equationm of state by regulating and controlling fluid
It can effectively realize that various sizes of sub-micron nano particle converges in the different position of microchannel with passage design, micro-fluidic
The fork outlet of cell end flows to different outlets and realizes separation, and easy to operate, separative efficiency is high, not by specific immunity
Reaction；Since the elastic force of the invention applied using fluid flowing nature separates sub-micron nano particle, not by outer
Magnetic field, sound field, thermal field or other physical fields are powered up, therefore can be avoided to sensitive operational fluid (such as blood) and sensitive particles
(such as cell) causes irreversibility to destroy.And microfluidic cell is easily achieved parallel organization, substantially increases separation flux
Expansibility.
Description of the drawings
Fig. 1 is the system structure diagram for 100 nano particles of focusing that the embodiment of the present invention one provides；
Fig. 2 is the flow chart that the present invention is used to make microfluidic cell；
Fig. 3 is the flow chart that the present invention is used to separate sub-micron nanoparticle approach；
Fig. 4 is the effect diagram for 100 nano particles of focusing before focusing that the embodiment of the present invention one provides；
Fig. 5 is the experiment effect schematic diagram for 100 nano particles of focusing after focusing that the embodiment of the present invention one provides；
Fig. 6 is the structure diagram of the system provided by Embodiment 2 of the present invention for being used to focus on DNA molecular；
Fig. 7 is provided by Embodiment 2 of the present invention for focusing on effect diagram of the DNA molecular before focusing；
Fig. 8 is provided by Embodiment 2 of the present invention for focusing on experiment effect schematic diagram of the DNA molecular after focusing；
Fig. 9 is the system structure signal for being used to separate 1000 nanometers and 100 nano particles that the embodiment of the present invention three provides
Figure；
Figure 10 is the effect for 1000 nanometers of separation and 100 nano particles before separation that the embodiment of the present invention three provides
Schematic diagram；
Figure 11 is the experiment for 1000 nanometers of separation and 100 nano particles after isolation that the embodiment of the present invention three provides
Effect diagram；
Figure 12 be the embodiment of the present invention four provide for separating λ-DNA and hematoblastic system structure diagram；
Figure 13 is the effect signal for separation separation λ-DNA and blood platelet before separation that the embodiment of the present invention four provides
Figure；
Figure 14 is the effect signal for separation separation λ-DNA and blood platelet after isolation that the embodiment of the present invention four provides
Figure.
Specific embodiment
The embodiment of the present invention is described in detail below in conjunction with attached drawing.It should be noted that do not conflicting
In the case of, the feature in embodiment and embodiment in the application can be mutually combined.
Embodiment one：
Present embodiments provide separation sub-micron nano particle is focused on based on nonNewtonian percolation be as shown in Figure 1
System, system include：
For conveying the conveying device 1 of the working fluid with non-newtonian flow bulk effect；
Microfluidic cell 2 (document Liu, C. comprising microchannel；Xue,C.；Chen,X.；Shan,L.；Tian,Y.；Hu,
G.Size-Based Separation of Particles and Cells Utilizing Viscoelastic Effects
In Straight Microchannels.Anal.Chem.2015,87,6041-6048.), microfluidic cell 2 by pipeline with
Conveying device 1 is connected, for conveying device 1 conveying come working fluid in sub-micron nano particle in microchannel into
Line focusing；
The fork outlet 3 of 2 end of microfluidic cell is arranged on, the center fork of fork outlet 3 is received for focusing on sub-micron
Rice grain；
The collection device 4 for being used to collect target sub-micron nano particle of connection fork outlet 3.
In the present invention, conveying device 1 can be syringe pump, peristaltic pump or others for the conveying to working fluid
With pressure-driven working fluid and the instrument of accurate flow control, gravity or other physical fields can also be utilized to make sub-micron nanometer
Particle is flowed into accurate flow in microchannel.
In the present embodiment, conveying device 1 is syringe pump, needs the sub-micron nano particle focused on work for conveying to contain
Fluid.
The chip of microfluidic cell 2 can be by dimethyl silicone polymer (PDMS), polymethyl methacrylate (PMMA), poly- carbon
Acid esters (PC) makes, and PDMS, PMMA, PC, glass or silicon chip can be used in the bottom sealing-in substrate of microfluidic cell 2.Micro-fluidic list
The manufacturing process of member 2 use the facture of microchip method using Soft lithograph method as the routine of representative, first in sheet glass or
Graphics chip is lithographically derived on monocrystalline silicon piece, is formed by template to realize the transfer of pattern and replicate comprising in plane or curved surface
Sub-micron nano-pattern micro-fluidic chip, more specifically, comprise the following steps, as shown in Figure 2：
It is prepared by step S21, template：Template is prepared with SU-8 photoresists on silicon chip, by Soft lithograph technology in template
The 3-D solid structure of microchannel needed for etching.
Step S22, passage are formed：After liquid PDMS is uniformly mixed with appropriate curing agent, equably it is cast in template.
And cure at a certain temperature by certain time, the chip for obtaining including microchannel is removed from template.
Step S23, chip sealing：With plasma beam by the chip bonding containing microchannel on glass or silicon base,
Using the liquid PDMS of semi-solid preparation as adhesive, seal chip and connect chip outlet and entrance, then toast and reinforced.
Flux is separated to improve, microfluidic cell 2 uses parallel organization, and sets branch in 1 junction of conveying device, often
One branch corresponds to a microfluidic cell 2.The microchannel of microfluidic cell 2 is linear；The cross sectional shape of microchannel is rectangle.
Sub-micron nano particle to be focused on moves in working fluid is subject to flox condition, the shadow of fluid rheology property
It rings.Viscoelastic fluid (a kind of non-newtonian fluid) is allowed to being suspended in particle application elastic force therein to shearing rate smaller part
(predominantly channel center) migration.Under identical flox condition, the sub-micron in common Newtonian fluid (being typically water)
Nano particle does not have visibility point variation by micro-fluidic chip.According to this principle, realized using the viscoplasticity of working fluid
Three-dimensional focal of the sub-micron nano particle in microchannel.To verify the conclusion and carrying out the optimization of parameter, corresponding mould has been done
Draft experiment, as shown in figure 3, comprising the following steps：
Step S1 is prepared and is waited to focus on simulation fluid, the polystyrene fluorescent microsphere comprising a diameter of 100nm；
Step S2 adds in suitable high molecular polymer, with viscoplasticity in fluid is simulated；
Step S3, the focusing of position and micro-fluidic chip when each particle outflow is tracked under different fluid flow rate are imitated
Fruit；
Step S4 passes through the geometric parameter of theoretical model calculation optimization microchannel.
In the present embodiment, for the cross sectional shape of microchannel to be preferably 30 μm wide, height is preferably 4 μm of rectangle.
In step s 2 specifically, adding in the polyethylene oxide (PEO) of mass percent 0.4-1.2% in fluid is simulated
In step s 4, theoretical model is kinetic model, is specially：
Pass through kinetic modelDetermine the position of particle outflow
It puts.
Wherein, vpIt is the velocity of working fluid sub-micron nano particle, FeIt is elastic force vector, μ is working fluid
Dynamic viscosity, ρpIt is the density of particle, a is the diameter of particle, and v is the velocity of working fluid, and ρ is that working fluid is close
Degree, FLIt is inertia force；
Section 1It is related to elastic force, Section 2It is related to viscous force, Section 3It is related to inertia force.
The shadow of the elastic force that motor behavior when particle in simulation fluid is flowed out from outlet is subject to, viscous force and inertia force
It rings.Elastic force is by formulaIt determines, wherein, fe(Wi,xL) be with Wei Senboge numbers (or
De Baiha numbers) and particle in the relevant function in the position of tube section, it is square directly proportional to shearing rate that N is deviator stress.It understands
The smaller position of shearing rate is directed toward in the direction of elastic force, is the center and corner of passage in this example.Inertia force F simultaneouslyLWork
With preventing particle from leaning near wall, therefore particle migrates under the action of elastic force to channel center.Viscous force is by formula FD=3
πaμ(v-vp) determine, the action direction of viscous force and the migratory direction of particle are on the contrary, finally the heart reaches elasticity to particle in the channel
The state of power and sticky dynamic balance.After the microchannel of microfluidic cell 2 is flowed through, the particle simulated in fluid focuses on passage
Center.
In addition, as shown in figure 4, for the present embodiment confocal fluorescence nano particle entrance Overlay figure, such as Fig. 5 institutes
Show, focus on Overlay figure of the nano particle after focusing for the present embodiment, drawn by observing, analyzing, focusing to be separated
The working fluid of nano particle is passed through microfluidic cell 2, can effectively realize that nano particle focuses on passage on three dimensions
On axis, and it is easy to operate, and focusing effect is good.
Embodiment two：
The present embodiment proposes the system and method for focusing on DNA molecular.
The system that sub-micron nano particle is focused on based on nonNewtonian percolation as shown in Figure 6 is present embodiments provided, is
System includes：
For conveying the conveying device 1 of the working fluid with non-newtonian flow bulk effect；
Microfluidic cell 2 comprising microchannel, microfluidic cell 2 is connected by pipeline with conveying device 1, for defeated
The sub-micron nano particle in the working fluid that conveying comes of device 1 is sent to be separated in microchannel；
2 end of microfluidic cell fork outlet 3 is arranged on, the central fascicle of fork outlet 3 focuses on sub-micron for collecting
Nano particle；
The collection device 4 for being used to collect target sub-micron nano particle of 3 central fascicles of connection fork outlet.
In the present invention, conveying of the conveying device 1 to working fluid can be syringe pump, peristaltic pump or others to press
The instrument of power driving working fluid and accurate flow control can also utilize gravity or other physical fields to make DNA molecular accurately
It is flowed into microchannel.Conveying device 1 is to drive working fluid that can be controlled with any by syringe pump in the present embodiment
The type of drive of flow, for conveying DNA molecular to be focused on；Working fluid is the EDTA solution containing DNA molecular in this example,
Flowing in microchannel simultaneously adjusts flow velocity of this working fluid in microchannel.
The chip of microfluidic cell 2 can be made by PDMS, PMMA, PC, and the bottom sealing-in substrate of microfluidic cell 2 can be used
PDMS, PMMA, PC, glass or silicon chip.The manufacturing process of microfluidic cell 2 uses the conventional miniflow using Soft lithograph method as representative
Chip manufacture method is controlled, graphics chip is lithographically derived on sheet glass or monocrystalline silicon piece first, pattern is realized by template
Transfer and replicating formed comprising plane or micron or the micro-fluidic chip of nano-pattern on curved surface, more specifically, such as Fig. 2 institutes
Show, comprise the following steps：
It is prepared by step S21, template：Template is prepared with SU-8 photoresists on silicon chip, by Soft lithograph technology in template
The 3-D solid structure of microchannel needed for etching.
Step S22, passage are formed：After liquid PDMS is uniformly mixed with appropriate curing agent, equably it is cast in template.
And cure at a certain temperature by certain time, the chip for obtaining including microchannel is removed from template.
Step S23, chip sealing：With plasma beam by the chip bonding containing microchannel on glass or silicon base,
Using the liquid PDMS of semi-solid preparation as adhesive, seal chip and connect chip outlet and entrance, then toast and reinforced.
To improve flux, microfluidic cell 2 uses parallel organization, and is that 1 junction of conveying device sets branch, each
Branch corresponds to a microfluidic cell 2.The microchannel of microfluidic cell 2 is linear；The cross sectional shape of microchannel is rectangle.
It is influenced when DNA molecular flows in microchannel be subject to flox condition, fluid properties, to verify the conclusion and carrying out
The optimization of parameter, as shown in figure 3, having done corresponding simulated experiment.
Step S1 is prepared and is waited to focus on the working fluid for including DNA；
Step S2 adds in suitable high molecular polymer, with viscoplasticity in working fluid；
Step S3 observes spatial distribution when DNA molecular flows out to assess micro-fluidic chip under different fluid flow rate
Focusing effect；
Step S4 passes through the geometric parameter of theoretical model calculation optimization microchannel.
In the present embodiment, for the cross sectional shape of microchannel to be preferably 30 μm wide, height is preferably 4 μm of rectangle.
In step s 2 specifically, adding in the polyethylene oxide of mass percent 0.4%-1.2% in fluid is simulated
(PEO)
In step s 4, theoretical model is kinetic model, is specially：
Kinetic model can be passed throughDetermine DNA molecular
Movement,
Here the DNA molecular in solution is modeled as the radius of gyration as RgSphere.Wherein, vDIt is DNA in working fluid
The velocity of molecule, FeIt is elastic force, μ is the dynamic viscosity of working fluid, ρDIt is the density of DNA molecular, v is workflow
The velocity of body, ρ are working fluid density, and g is acceleration of gravity, FLIt is inertia force；
Section 1It is related to elastic force, Section 2It is related to viscous force, Section 3It is related to inertia force.DNA molecular from outlet flow out when motor behavior mainly with suffered elastic force, viscous force
And inertia force.Viscous force is by formula FD=6 π Rgμ(v-vD) determine.Elastic force is by formulaReally
It is fixed, wherein, fe(Wi,xL) it is relevant in the position of channel cross-section with Wei Senboge numbers (or De Baiha numbers) and DNA molecular
Function, N are the square directly proportional of deviator stress and shearing rate.Understand that the smaller position of shearing rate is directed toward in the direction of elastic force, this
It is the center and corner of passage in example.Inertia force FLEffect prevent DNA molecular from leaning near wall, therefore DNA molecular is in bullet
Property power under the action of to channel center migrate.
Since the present embodiment is to be focused DNA molecular based on elastic force, can avoid causing not DNA molecular
Invertibity is destroyed.
In addition, as shown in fig. 7, focusing on DNA molecular for the present embodiment is focusing on the fluorescence Overlay figure of front entrance, such as figure
Shown in 8, fluorescence Overlay figure of the DNA molecular after focusing is focused on for the present embodiment, is drawn by observing, analyzing, waits to focus on
The working fluid of DNA molecular be passed through microfluidic cell 2, can effectively realize that DNA molecular focuses on passage on three dimensions
On axis, and it is easy to operate, and focusing effect is good, can avoid irreversibility being caused to destroy DNA molecular.
Embodiment three：
The present embodiment proposes the system and method for separating sub-micron nano particle.
It present embodiments provides and is based on what nonNewtonian percolation focused on separation sub-micron nano particle as of fig. 9 shown
System, system include：
For conveying the conveying device 1 of the working fluid with non-newtonian flow bulk effect；
Microfluidic cell 2 comprising microchannel, microfluidic cell 2 is connected by pipeline with conveying device 1, for defeated
The sub-micron nano particle in the working fluid that conveying comes of device 1 is sent to be separated in microchannel；Flux is separated to improve, it is micro-
Flow control unit 2 uses parallel organization；
Be arranged on 2 end of microfluidic cell fork outlet 3, fork outlet 3 central fascicle 31 for separate diameter compared with
Big sub-micron nano particle, the side branch 32 of fork outlet 3 are used to separate the smaller sub-micron nano particle of diameter；
Central fascicle 31 and the collection device for being used to collect target sub-micron nano particle of side branch 32 are connected respectively
4。
Each microfluidic cell 2 also includes sheath fluid entrance 5.Each 2 afterbody of microfluidic cell connection fork outlet 3.Fork
Outlet 3 is comprising Liang Ge branches, and the nano particle of large-size is from the first branch outlet 31, and smaller sub-micron nano particle is from the
Two branch outlets 32 flow out.
The collection device 4 for being used to collect target sub-micron nano particle of branch outlet 31 and 32 is connected respectively
In the present invention, conveying of the conveying device 1 to working fluid can be syringe pump, peristaltic pump or others to press
The instrument of power driving working fluid and accurate flow control can also utilize gravity or other physical fields to make sub-micron nano particle
Accurately it is flowed into microchannel.Conveying device 1 is to drive working fluid by syringe pump in the present embodiment, for conveying sub-micro
Rice nano particle；It is flowing and adjustment of the working fluid containing sub-micron nano particle to be separated in microchannel in this example
Flow velocity of the working fluid in microchannel.
The chip of microfluidic cell 2 can be made by PDMS, PMMA, PC, and the bottom sealing-in substrate of microfluidic cell 2 can be used
PDMS, PMMA, PC, glass or silicon chip.The manufacturing process of microfluidic cell 2 uses the conventional miniflow using Soft lithograph method as representative
Chip manufacture method is controlled, graphics chip is lithographically derived on sheet glass or monocrystalline silicon piece first, pattern is realized by template
Transfer and replicating formed comprising plane or micron or the micro-fluidic chip of nano-pattern on curved surface, more specifically, such as Fig. 2 institutes
Show, comprise the following steps：
It is prepared by step S21, template：Template is prepared with SU-8 photoresists on silicon chip, by Soft lithograph technology in template
The 3-D solid structure of microchannel needed for etching.
Step S22, passage are formed：After liquid PDMS is uniformly mixed with appropriate curing agent, equably it is cast in template.
And cure at a certain temperature by certain time, the chip for obtaining including microchannel is removed from template.
Step S23, chip sealing：With plasma beam by the chip bonding containing microchannel on glass or silicon base,
Using the liquid PDMS of semi-solid preparation as adhesive, seal chip and connect chip outlet and entrance, then toast and reinforced.
It is influenced when fluid comprising sub-micron nano particle flows in microchannel be subject to flox condition, fluid properties.
Flow path and velocity magnitude of the particle of different-diameter in microchannel are different, and in exit, the direction of outflow is also not
With.To verify the conclusion and carry out the optimization of parameter, corresponding simulated experiment has been done, as shown in figure 3, including：
Step S1 prepares the fluid comprising nano particle first, includes the polystyrene of different size (100-1000nm)
Microballoon；
Step S2 adds in suitable high molecular polymer in comprising nanoparticle fluid, with viscoplasticity, simultaneously
With shear-thinning property；
Step S3 tracks position when each sized particles flow out and point of micro-fluidic chip under different fluid flow rate
From effect；
Step S4 passes through the geometric parameter and exit design of theoretical model calculation optimization microchannel.
It is pointed out that in the present embodiment, the cross sectional shape of microchannel is excellent to be preferably 20 μm, a height of 4-100 wide
Elect 50 μm of rectangle as.The cross-sectional width of first branch outlet 41 is 0.8 times of microchannel width, and the second branch outlet 42 is cut
Face width is 0.2 times of microchannel width.
In step s 2 specifically, adding in the polyethylene oxide that mass percent is 0.2%-1.2% in fluid is simulated
(PEO)。
In step s 4, theoretical model is kinetic model, is specially：
Pass through kinetic modelDetermine that each size sub-micron is received
The position of rice grain outflow,
Wherein, vpIt is the velocity of particle in working fluid, FeIt is elastic force, μ is the dynamic viscosity of working fluid,
ρpIt is the density of particle, a is the diameter of particle, and v is the velocity of working fluid, and ρ is working fluid density, and g is that gravity adds
Speed, FLIt is inertia force；
Section 1It is related to elastic force, Section 2It is related to viscous force, Section 3It is related to inertia force.With separated sub-micron nano particle from outlet flow out when motor behavior mainly with it is suffered
Elastic force, viscous force, inertia force.Viscous force is by formula FD=3 π a μ (v-vp) determine.Elastic force is by formulaIt determines, wherein, fe(Wi,xL) it is to exist with Wei Senboge numbers (or De Baiha numbers) and particle
The relevant function in position of tube section, N are the square directly proportional of deviator stress and shearing rate.It understands that the direction of elastic force is directed toward to cut
The smaller position of rate is cut, is the center and corner of passage in this example.Inertia force FLEffect prevent particle from leaning near wall, bullet
Property power make particle to channel center migrate.Particle diameter is bigger, and suffered elastic force and viscous force are bigger, the variation journey of elastic force
Degree more than viscous force variation degree (|Fd|∝Rg), therefore particle diameter is bigger, the shadow that elastic force moves it
Sound is more important, and the speed migrated to channel center is faster.It follows that when carrying out nano particle separation, it is relatively large in diameter
1000nm particles are moved to after microfluidic cell 2 near channel center.And the smaller 100nm particle entrapments of diameter are attached in wall surface
Closely.As shown in Figure 9, the first branch outlet 31 will be collected into 1000nm particles, and the second branch outlet 32 will be collected into 100nm
Grain.
It is the fluorescent effect figure of the present embodiment separating nano-particles entrance before separation in addition, as shown in Figure 10, such as Figure 11
It is shown, the fluorescent effect figure of sub-micron nano particle after isolation is separated for the present embodiment, is drawn, passed through by observing, analyzing
The rheological equationm of state and passage design for regulating and controlling fluid can effectively realize that various sizes of sub-micron nano particle converges in microchannel
Different position, flow to different outlet in the fork outlet 3 of microfluidic cell end and realize separation, easy to operate, separation effect
Rate is high, not by specific immune response.
Example IV：
The present embodiment is proposed for separations of DNA molecules and hematoblastic system and method.
Present embodiments provide separation sub-micron nano particle is focused on based on nonNewtonian percolation be as shown in Figure 12
System, system include：
For conveying the conveying device 1 of the working fluid with non-newtonian flow bulk effect；
Microfluidic cell 2 comprising microchannel, microfluidic cell 2 is connected by pipeline with conveying device 1, for defeated
The sub-micron nano particle in the working fluid that conveying comes of device 1 is sent to be separated in microchannel；
It is arranged on 32 and first side branch 31 of central fascicle, the second side of the fork outlet 3 of 2 end of microfluidic cell
Branch 33, for separating the smaller DNA molecular of particle, the first side branch 31, the second side branch 33 are used for central fascicle 32
Separate the larger blood platelet of particle；
Connect respectively central fascicle 32, the first side branch 31, the second side branch 33 for collecting DNA molecular and blood
The collection device 4 of platelet.
Flux is separated to improve, microfluidic cell 3 uses parallel organization, including being used for non-newtonian flow bulk effect working fluid
Conveying device 1；
Microfluidic cell 2 comprising multiple branch parallels, microfluidic cell 2 are connected by pipeline with conveying device 1, are used
Sub-micron nano particle in the working fluid come to the conveying of conveying device 1 separates in microchannel；
Each 2 afterbody of microfluidic cell connection fork outlet 3.Fork outlet 3 includes three branches, and the blood of large-size is small
Plate is flowed out from the first side branch 31, the second side branch 33, and smaller DNA molecular is flowed out from central fascicle 32.
In the present invention, conveying device 1, the conveying to working fluid can be syringe pump, peristaltic pump or others to press
The instrument of power driving working fluid and accurate flow control can also utilize gravity or other physical fields to make sub-micron nano particle
Accurately it is flowed into microchannel.Conveying device 1 is to drive working fluid by syringe pump in the present embodiment, is treated point for conveying
From biologic grain；Working fluid is containing DNA molecular and hematoblastic PBS solution in this example, and the flowing in microchannel is simultaneously
Adjust flow velocity of this working fluid in microchannel.
The chip of microfluidic cell 2 can be made by PDMS, PMMA, PC, and the bottom sealing-in substrate of microfluidic cell 2 can be used
PDMS, PMMA, PC, glass or silicon chip.The manufacturing process of microfluidic cell 2 uses the conventional miniflow using Soft lithograph method as representative
Chip manufacture method is controlled, graphics chip is lithographically derived on sheet glass or monocrystalline silicon piece first, pattern is realized by template
Transfer and replicating formed comprising plane or micron or the micro-fluidic chip of nano-pattern on curved surface, more specifically, including with
Lower step, as shown in Figure 2：
It is prepared by step S21, template：Template is prepared with SU-8 photoresists on silicon chip, by Soft lithograph technology in template
The 3-D solid structure of microchannel needed for etching.
Step S22, passage are formed：After liquid PDMS is uniformly mixed with appropriate curing agent, equably it is cast in template.
And cure at a certain temperature by certain time, the chip for obtaining including microchannel is removed from template.
Step S23, chip sealing：With plasma beam by the chip bonding containing microchannel on glass or silicon base,
Using the liquid PDMS of semi-solid preparation as adhesive, seal chip and connect chip outlet and entrance, then toast and reinforced.
Flux is separated to improve, microfluidic cell 2 and fork outlet 3 are 1 junction of conveying device using parallel organization
Branch is set, and each branch corresponds to a microfluidic cell 2；Each microfluidic cell 2 corresponds to a fork outlet 3.
Working fluid is subject to what is interacted between fluid driving forces, flox condition, biologic grain when being flowed in microchannel
It influences, therefore, the flow path and velocity magnitude of various sizes of biologic grain are different, in the direction of exit outflow
It is different.To verify the conclusion and carrying out the optimization of parameter, corresponding simulated experiment is done, as shown in figure 3, including following step
Suddenly：
Step S1 prepares simulation fluid to be separated first, includes the polystyrene microsphere of different size (100nm-2 μm)
Simulate DNA molecular and blood platelet；
Step S2 adds in suitable high molecular polymer, with viscoplasticity and shear thinning in fluid is simulated
Matter；
Step S3, position and micro-fluidic core when observation DNA molecular and blood platelet flow out under different fluid flow rate
The separating effect of piece；
Step S4 passes through the geometric parameter and exit design of theoretical model calculation optimization microchannel.
It is pointed out that in the present embodiment, the microchannel of microfluidic cell 2 is of a straight line type, the section of microchannel
Shape is 10-60 μm wide, is preferably 30 μm, 2-5 μm high, is preferably 4 μm of rectangle.
The cross-sectional width of first side branch 31 is 0.3 times of microchannel width, the cross-sectional width of the 3rd side branch 33
For 0.3 times of microchannel width, the cross-sectional width of central fascicle 32 is 0.4 times of microchannel width.
In step s 2 specifically, adding in the polyethylene glycol oxide that mass percent is 0.2%-1.2% in fluid is simulated
(PEO)。
In step s 4, theoretical model is kinetic model, is specially：
Pass through kinetic modelDetermine that DNA molecular and blood are small
The outlet port of plate, wherein, vpIt is DNA molecular or hematoblastic velocity, F in working fluideIt is elastic force, μ is workflow
The dynamic viscosity of body, ρpIt is DNA molecular or hematoblastic density, a is DNA molecular or hematoblastic diameter, and v is working fluid
Velocity, ρ is working fluid density, and g is acceleration of gravity, FLIt is inertia force；
Section 1It is related to elastic force, Section 2It is related to viscous force, Section 3It is related to inertia force.Motor behavior when DNA molecular to be separated or blood platelet are flowed out from outlet mainly with it is suffered
Elastic force, viscous force, inertia force.Viscous force is by formula FD=3 π a μ (v-vp) determine.Elastic force is by formulaIt determines, wherein, fe(Wi,xL) it is to exist with Wei Senboge numbers (or De Baiha numbers) and cell
The relevant function in position of tube section, N are the square directly proportional of deviator stress and shearing rate.It understands that the direction of elastic force is directed toward to cut
The smaller position of rate is cut, is the center and corner of passage in this example.Inertia force FLEffect prevent DNA molecular or blood platelet from
By near wall.
DNA molecular will be moved to channel center in the presence of a tensile force.And blood platelet is since size and passage are close, to logical
There is strong influence in road inner periphery flow field, and the direction of its suffered elastic force is caused to be directed toward wall surface, simultaneously because inertia force effect is not
Balance can be reached between wall surface and channel center by near wall, blood platelet.It follows that carrying out DNA molecular and blood platelet
During separation, blood platelet is relatively large in diameter after microfluidic cell 2, is moved to channel center both sides.And the smaller DNA molecular of diameter moves
It moves among passage.As shown in Figure 12, the first side branch 31 and the 3rd side branch 33 will be collected into blood platelet, center point
Branch 32 will be collected into DNA molecular.
Since the present embodiment is that the DNA molecular in blood and blood platelet are separated based on elastic force, can keep away
Exempt from irreversibility to be caused to destroy DNA molecular and blood platelet.
It is the Overlay of the present embodiment separations of DNA molecules and blood platelet entrance before separation in addition, as shown in figure 13
Figure is the Overlay figure of the present embodiment separations of DNA molecules and blood platelet after isolation, by observing, analyzing as shown in figure 14
It draws, can effectively realize that DNA molecular and blood platelet converge in microchannel by the rheological equationm of state and passage design that regulate and control fluid
Different position, flow to different outlet in the fork outlet 3 of microfluidic cell end and realize separation, easy to operate, separation effect
Rate is high, not by specific immune response；Also effectively avoiding simultaneously causes irreversibility to break DNA molecular and blood platelet
It is bad.
In the present invention, the quantity of micro-fluidic focusing/separative element and micro-fluidic chip is not limited to, can be according to required for specific
Focusing/separation flux set；The microchannel of micro-fluidic chip is also not limited to straight channel or double-spiral structure, can be according to tool
The focusing that body needs/separation adds in or is changed to bending, single-screw or serpentine structure；The cross sectional shape of microchannel is not limited to square
Shape or square, trapezoidal, triangle or other shapes.
This technology can be used in the numerous areas such as biology, medicine and industry.For example, hematoblastic presence can disturb peripheral blood
The PCR quantitative analyses of cell mitochondrial DNA, separation blood platelet are of great significance to the accuracy for improving PCR with DNA molecular.
Excretion body is the small double-layer of lipoid membrane structure that can be secreted by most cells, and a diameter of 30-150nm carries intracellular biological
Bioactive molecule, so as to change other cell functions, becomes medical diagnosis on disease treatment and the research of accurate medical development in intercellular trafficking
Hot spot.The Separation ＆ Purification of excretion body are the foundation stones of its research, outside primarily discrete excretion body and larger-sized ordinary cells
The impurity such as vesica (200-2000nm).In terms of environment, it can efficiently remove sub-micron nano particle in water and pathogen is direct
Determine the quality of water process.
The foregoing is only a preferred embodiment of the present invention, is not intended to limit the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should all be included in the protection scope of the present invention.
Claims (9)
1. the system of separation sub-micron nano particle is focused on based on nonNewtonian percolation, which is characterized in that the system comprises：
For conveying the conveying device of the working fluid with non-newtonian flow bulk effect；
Microfluidic cell comprising microchannel, the microfluidic cell are connected by pipeline with the conveying device, for pair
Sub-micron nano particle in the working fluid that the conveying device conveying comes is focused separation in the microchannel；
The fork outlet of the microfluidic cell end is arranged on, flexible adaptation focuses on or separated demand, the fork outlet
Central fascicle for collecting the sub-micron nano particle focused on, the side branch of the fork outlet is for separating different Asias
Micron/nano particle；
The collection device for being used to collect target sub-micron nano particle of the fork outlet is connected respectively.
2. the system of separation sub-micron nano particle is focused on based on nonNewtonian percolation as described in claim 1, it is characterised in that：
The position of the position of the microchannel sub-micron nano particle and the fork outlet accordingly flowed out is selected by moving
Mechanical modelIt determines,
Wherein, vpIt is the velocity of working fluid sub-micron nano particle, FeIt is elastic force vector, μ is the dynamic of working fluid
Mechanics viscosity, ρpIt is the density of particle, a is the diameter of particle, and v is the velocity of working fluid, and ρ is working fluid density, FL
It is inertia force.
3. the system of separation sub-micron nano particle is focused on based on nonNewtonian percolation as claimed in claim 2, it is characterised in that：
The working fluid is with viscoelastic non-newtonian fluid.
4. the system of separation sub-micron nano particle is focused on based on nonNewtonian percolation as claimed in claim 3, it is characterised in that：
The conveying device can utilize impressed pressure, gravity or other physical fields to realize the conveying of working fluid, make described
Sub-micron nano particle is flowed into the microchannel.
5. the system of separation sub-micron nano particle is focused on based on nonNewtonian percolation as claimed in claim 4, it is characterised in that：
The microfluidic cell is also associated with sheath fluid entrance.
6. the system of separation sub-micron nano particle is focused on based on nonNewtonian percolation as claimed in claim 5, it is characterised in that：
The microchannel is linear, variable cross-section shape, serpentine or spiral shape；The cross sectional shape of the microchannel for square,
Rectangle, trapezoidal, triangle or concave-convex font；The ratio of width to height of the microchannel cross section can be any number.
7. a kind of manufacturer for the system for focusing on separation sub-micron nano particle based on nonNewtonian percolation as described in claim 1
Method, which is characterized in that include the following steps：
A) working fluid with non-newtonian flow bulk effect containing sub-micron nano particle to be separated is prepared；
B) motor behavior during outflow of sub-micron nano particle is tracked under the different flow velocity of the working fluid, is focused on evaluating
Separated effect；
C) designed by the geometric parameter of theoretical model and numerical simulation of optimum microchannel and fork outlet；
D) conveying device, microfluidic cell, fork outlet, collection device are connected by pipeline.
8. manufacturing method as claimed in claim 7, which is characterized in that the step a) includes the following steps：
1) fluid containing sub-micron nano particle to be separated is prepared；
2) suitable high molecular polymer is added in the fluid, with non-newtonian flow bulk effect.
9. manufacturing method as claimed in claim 8, it is characterised in that：
The high molecular polymer is artificial synthesized or natural.
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| CN110465339A (en) * | 2019-09-03 | 2019-11-19 | 浙江大学 | A method of it flowing solid two-phase and transports middle particle positioning |
| CN110935238A (en) * | 2019-12-05 | 2020-03-31 | 西安交通大学 | Micro-nano particle enrichment device based on coupling of variable cross-section microchannel and viscoelastic fluid |
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