CN110215938A - A kind of micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent and preparation method thereof - Google Patents
A kind of micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent and preparation method thereof Download PDFInfo
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Abstract
The invention discloses micro-fluidic sorting chips of the spiral acoustic bulk wave of a kind of all-transparent and preparation method thereof.Under centrifugal force and acoustic radiation force double action, according to the density of different cells, volume and compression ratio are realized to target cell without modification, harmless successful sorting.This device using laser cutting and cheesing techniques, prepares the micro- channel for meeting standing wave Production conditions by cheap glass, and blank glass and glass with the micro- channel of spiral are bonded together by thermal bonding method, form sealed chamber.All-transparent acoustic bulk wave micro-fluidic chip prepared by the present invention, it is easy to operate, it is low in cost, and be conducive to the sorting to samples such as circulating tumor cell, fetal nucleated red blood, particles.This equipment sorts cell, and no modification is not damaged, does not influence the activity of cell, is conducive to further detect the cell after sorting, clinically there is very big application space.
Description
Technical field
The invention belongs to micro-total analysis system field, in particular to a kind of micro-fluidic sorting core of the spiral acoustic bulk wave of all-transparent
Piece and preparation method thereof.
Background technique
Print pretreatment, reaction, separation, detection etc. are integrated on the chip of one piece of micro-meter scale by micro-fluidic chip, are had
There is the features such as integrated level is high, and reagent consumption is few, low manufacture cost, analysis efficiency is high, is shown in fields such as physics, chemistry, biologies
Good application prospect.There are many kinds of traditional micro-fluidic chips, can be based on size, magnetic and antigen-antibody specificity
In conjunction with sorting.But there is also many problems in clinical application for these micro-fluidic chips.For example, using the micro- of filter membrane structure
Fluidic chip will cause that the efficiency of separation is very low because of the overlapping of part cell size, furthermore in the process of processing patient's blood sample
In, other impurity in blood can block filter membrane.Using the micro-fluidic chip of magnetic sorting, magnetic particle is easy to reunite, it is difficult to go
Except extra magnetic particle, its application in terms of medicine is also limited to a certain extent.Utilize the specificity knot of antigen-antibody
It closes, capture purity and efficiency can be improved, but after capture, antigen-antibody can not be separated, a series of modification and release are right
The activity of cell can have a huge impact.But the shortcomings that micro-fluidic chip is that flux is relatively low, is not able to satisfy sometimes clinically
The demand of mass disposal sample.
The it is proposed of sound tweezer technology considerably increases the flux of sample, and particle or cell are manipulated using sound wave.Pass through piezoelectricity
The piezoelectric effect of material generates the ultrasonic wave of 0.1~10MHz, adjusts acoustic signals by signal generator and power amplifier,
Two column are added in that acoustic resonance is intracavitary to form stable standing-wave sound field by the ultrasonic laminated that same sound source generates.In acoustic radiation power
Under effect, different particles or cell generate different displacements, to achieve the purpose that sorting.
Currently, in the preparation of bulk wave device, the method for generalling use dry and wet etching is prepared on the monosilicon
Micro- channel, then by the way of anode linkage by glass together with wafer bonding, finally stick PZT piezoelectricity in silicon wafer bottom
Potsherd, to form acoustic bulk wave chip.This bulk wave chip, complex process, consumptive material is expensive, to equipment (thermal evaporation instrument, inductance
Coupled plasma equipment, anode linkage instrument) it is more demanding, because device is opaque, experimental result is observed under the microscope to be compared
It is difficult.Spiral channel can sort cell using centrifugal force merely, but cannot be enriched with.
Summary of the invention
For current micro-fluidic chip the medicine diagnosing and treating early period the problem of, the present invention is intended to provide a kind of
It is low in cost, micro-fluidic sorting chip of the spiral acoustic bulk wave of the simple all-transparent of preparation process and preparation method thereof.Institute of the present invention
The micro-fluidic chip of preparation is assembled using the sheet glass of all-transparent, lower cost for material, and assembling equipment requirement is low, greatly
Reduce production cost, can be used for sorting cell without modification, under reactive conditions that are not damaged, not influencing cell, be conducive to point
Cell after choosing further detects.
Chip prepared by the present invention is made of transparent material.Glass is prepared by laser processing meets half-wave lint-long integer
Micro-channels again, the two-sided lithium niobate monocrystal for being coated with tin-doped indium oxide (ITO) conductive membrane layer are viscous as piezoelectric material
The bottom of acoustic resonant cavity is affixed on as sound wave generator, and draws two copper wire as signal input lead on two sides.Full impregnated
Bright device is conducive to be observed the separating effect of the samples such as circulating tumor cell, fetal nucleated red blood and particle.It is general
The application of logical glass, is also greatly reduced device cost while easily operated.The piezoelectric material of different frequency corresponds to different depths
The channel of degree also corresponds to different flux, can be according to clinical demand, the quickly and easily parameter of adjusting device.Using laser
It is integrated to be easy to implement large-scale device to prepare chip for processing.The spiral acoustic bulk wave micro-fluidic chip of all-transparent can be used for
Sort cell, cell is not damaged without modification in assorting room, does not influence the activity of cell, be conducive to the cell after sorting into
The further detection of row.The standing wave resonance chamber that piezoelectric material generates, can be such that target cell concentrates at node, all targets
Cell concentrates in same level, convenient for being collected to the cell of sorting, has on following clinical medicine very big
Application space.
Technical solution provided by the invention is as follows:
A kind of micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent, the acoustic resonant cavity stacked by sheet glass and piezoresistive material
Material is constituted, and structure is as follows:
(1) acoustic resonant cavity is stacked by two blocks of sheet glass and is formed；
(2) the upper layer sheet glass of the acoustic resonant cavity is machined with micron order helical channel for circulating tumor cell, tire
The sorting of the samples such as youngster's erythroblast, particle is also provided with the hole location being connected to channel as inlet and outlet；
(3) lower layer's sheet glass structural integrity of the acoustic resonant cavity is used for the encapsulation of resonant cavity；
(4) the two-sided conductive film that is coated with of the piezoelectric material is pasted on acoustic resonant cavity bottom, and draws two on two sides
Copper wire is as signal input lead.
Specifically, the channel of the upper layer sheet glass of acoustic resonant cavity is formed by laser processing in above-mentioned steps (1), channel
Depth meets the integral multiple of half-wavelength.
Specifically, the use of the resonance frequency of piezoelectric material is 3.8MHz, 500 μm of helical channel width, corresponding depth is
200μm。
Sealing-in is carried out with the method for Muffle furnace temperature-gradient method specifically, being bonded in advance between above-mentioned sheet glass using low temperature.
Specifically, above-mentioned channel is helical form in the plane of sheet glass.Channel is two circle helixes, outermost bung flange
Diameter is 20mm.Spiral channel is compared to straight flute road, it is possible to reduce short grained diffusion further increases the efficiency of separation.?
In spiral channel, cell can be sorted merely, but cannot be enriched with and sound field combination using centrifugal force, sorting
Particle or cell can be enriched with simultaneously, improve the efficiency and purity of sorting.
Specifically, the inlet and outlet in above-mentioned steps (2) is connected in container by crossover sub.Preferably, conversion connects
Head is Peek biology adapter, and bonding at the punching of Peek biology adapter and glass exit is got up with epoxy resin.
Specifically, piezoelectric material is the two-sided lithium niobate for being coated with tin-doped indium oxide conductive membrane layer in above-mentioned steps (4)
Monocrystalline.
Specifically, above-mentioned lithium niobate monocrystal is cut with a thickness of 1mm, 36 ° of Y, monocrystalline resonance frequency is 3.8MHz.
Another object of the present invention is to provide the preparation methods of above-mentioned sorting chip, comprising the following steps:
(1) design template
The parameter of micro- channel is adjusted according to theoretical calculation；Resonance frequency using monocrystalline is 3.8MHz, spiral goove road width
500 μm of degree, corresponding depth are 200 μm；Channel is two circle helixes.Preferably, two five semicircles of helix are enclosed to form, most
The diameter of outside bung flange is 20mm, and from big to small, diameter of a circle is followed successively by 20mm, 19mm, 18mm, 17mm, 16mm；
(2) glass is processed
The glass of two block sizes is cut, one of for processing channel, another piece for encapsulating；Preferably, sheet glass
With a thickness of 1mm；
For processing the sheet glass of channel, according to template size, is prepared using laser processing and meet half-wavelength integral multiple
Micro-channels, then punched, as injection port and outlet；
(3) integrated device
Two blocks of sheet glass are packaged by the method for thermal bonding, form the chamber of sealing；
(4) resonant cavity is constructed
Meet the trench bottom of half-wavelength integral multiple in depth, by the lithium niobate monocrystal with piezoelectric effect of certain size
It is pasted onto bottom, two sides extraction wire is driven using power amplifier.
Fig. 1-3 shows the structure of the micro-fluidic chip of offer of the invention.
The present invention also provides the micro-fluidic sorting chip of the spiral acoustic bulk wave of above-mentioned all-transparent without modification, it is not damaged,
The application in the cell sorting of cell activity condition is not influenced.
The principle of micro-fluidic chip sorting cell is centrifugal force and acoustic radiation force collective effect, and fluid dynamics sorting is root
It goes to compete with inertia force according to Dien pulling force, causes various sizes of particle distribution in different equilbrium positions, to keep circulation swollen
Oncocyte, leucocyte, blood platelet sorting are come.The effect of acoustic radiation force, so that sorted various cells are further enriched with,
To improve the efficiency and purity of sorting.
Fig. 4 (a) is the stress diagram of cell in chip channel only under the action of the centrifugal force, and Fig. 4 (b) is only to be centrifuged
To the theoretical schematic diagram of different cell sortings under power effect；
The principle of fluid dynamics separation is Dien pulling force of the fall out effect on particle in curved microfluidic channel
It goes to compete with inertia force, causes various sizes of particle distribution in different equilbrium positions.The neutrality to suspend in the channel of curve
Particle will be subjected to the inertia force being made of gradient shearforce and wall effect effect.Gradient shearforce is generated by speed parabola
And it is related with its shear rate gradient, direction is pointing directly at wall by curve microchannel center；Wall effect is by near wall
What the asymmetric wake-up of particle induced, and have the tendency that pushing particle to far from wall.The competition of two kinds of effects the result is that grain
Son concentrates on specific equilbrium position.Inertia force effect migrates particle the heart and between the walls in the channel, and theoretical prediction can table
It states are as follows:
FL=fL(Re, xL)·ρU2a4/Dh 2 (1)
Here, coefficient fLIt is reynolds number Re (Re=ρ UDh/ μ) and position x of the particle in channel cross sectionL(in channel
The distance of the heart) function.U is the maximum speed in microchannel, and ρ and μ respectively indicate the Dynamic Viscosity of density and fluid, DhIt is micro-
The driving force diameter (four times of channel cross-sections are divided by perimeter) in channel, a is particle diameter.According to formula, particle size is to cross force
It has significant effect, this is the basic mechanism for obviously distinguishing different sized particles equilbrium positions.It therefore can be different by size
Circulating tumor cell, packet cell, blood platelet are separated.
Fig. 5 is micro-fluidic chip provided by the invention only under acoustic radiation force effect to the simulation effect picture of cell sorting；
Wherein, Fig. 5 (a) sound field overall diagram；Fig. 5 (b) sound field slice map；Fig. 5 (c) sound pressure level；Fig. 5 (d) acoustic pressure grade pet chip
Figure；
Cell stress size is related with cell radius, density and compressible coefficient, and the size of specific acoustic radiation force can
To be indicated with following formula.
The size of acoustic radiation force can be indicated with publicity above.In the volume that wherein Vc is particle, P0 is acoustic pressure size, is
It is defined by formula above.The density of medium and particle uses ρ respectivelycAnd ρwTwo parameters indicate that the corresponding compressed coefficient is βwWith
βc.As φ > 0, particle is moved towards nodal point；As φ < 0, particle is moved towards antinodal point.To which circulating tumor is thin
Born of the same parents, leucocyte and blood platelet are enriched on different level.
Fig. 6 is that micro-fluidic chip provided by the invention is only adjusted the distance under acoustic radiation force effect the cell of boundary different location
The simulation effect picture of sorting；Fig. 6 (a) sound field is far from boundary overall diagram；Fig. 6 (b) sound field leans on proximal border overall diagram；Fig. 6 (c) acoustic pressure
Grade is far from boundary overall diagram；Fig. 6 (d) sound pressure level leans on proximal border overall diagram；
In the channel that size meets half-wavelength integral multiple, up and down direction forms standing wave chamber, and countless nodal points is formed
One nodal plane, the cell apart from boundary different location, can be collected at node, thus by cell enrichment.
Fig. 7 be micro-fluidic chip provided by the invention under centrifugal force and acoustic radiation force collective effect to the reason of cell sorting
By schematic diagram.Fig. 7 (a) is without any active force；Only centrifugal force acts on Fig. 7 (b)；Only acoustic radiation force acts on Fig. 7 (c)；Fig. 7 (d) from
Mental and physical efforts and acoustic radiation force collective effect；
(a) without under any active force, all mixing with cells are together.(b) circulating tumor is separated according only to fluid dynamics
Cell, leucocyte, blood platelet, it is found that cell particle concentrates on specific equilbrium position.(c) only acoustic radiation force acts on, cell
Enrichment it can get up on different horizontal planes.(d) under collective effect, cell can be further enriched on specific equilbrium position.
Beneficial effects of the present invention:
1. the material using all-transparent is assembled, optical analysis identification is carried out conducive to efficient, quick, real-time；
2. simple glass replaces traditional monocrystalline silicon piece and high temperature resistant pyrex, production cost is significantly reduced；
3. it is integrated to be easy to implement large-scale device to prepare chip for laser cutting；
4. thermal bonding replaces anode linkage, the requirement to equipment is reduced, and reduces processing cost；
5. overcoming traditional leakage problem with the injection port and outlet of crossover sub connection sample；
6. centrifugal force and acoustic radiation force collective effect sort cell, more efficient；
7. the piezoelectric material of different frequency corresponds to the channel of different depth, different flux is also corresponded to, it can be according to clinic
Demand, the parameter of quick and convenient adjusting device, the problem of overcoming traditional microfluidic chip small throughput；
Micro flow chip prepared by 8. can without modification, it is not damaged and do not influence cell it is active under the conditions of sorting it is thin
Born of the same parents are conducive to further detect the cell after sorting, and the application for being micro-fluidic chip in cell sorting provides one
Kind new approaches；
9. the present invention can be realized the sorting of different cells, as circulating tumor cell, erythroblast, myeloma cell and
Particle etc., is of great significance to life science.
Detailed description of the invention
Fig. 1 is the structural schematic diagram of micro-fluidic chip provided by the invention；
Fig. 2 is the relative position schematic diagram of micro-fluidic chip each section provided by the invention；
Fig. 3 is the dimensional drawing of spiral channel micro-fluidic chip provided by the invention；
Fig. 4 (a) is the stress diagram of cell in chip channel only under the action of the centrifugal force, and Fig. 4 (b) is only to be centrifuged
To the theoretical schematic diagram of different cell sortings under power effect；
Fig. 5 is micro-fluidic chip provided by the invention only under acoustic radiation force effect to the simulation effect picture of cell sorting；
Wherein, Fig. 5 (a) sound field overall diagram；Fig. 5 (b) sound field slice map；Fig. 5 (c) sound pressure level；Fig. 5 (d) sound pressure level slice map；
Fig. 6 is micro-fluidic chip provided by the invention in the thin of boundary different location of only adjusting the distance under acoustic radiation force effect
The simulation effect picture of born of the same parents' sorting；
Fig. 7 be micro-fluidic chip provided by the invention under centrifugal force and acoustic radiation force collective effect to the reason of cell sorting
By schematic diagram 7 (a) without any active force；Only centrifugal force acts on Fig. 7 (b)；Only acoustic radiation force acts on Fig. 7 (c)；Fig. 7 (d) centrifugal force
With acoustic radiation force collective effect；
Appended drawing reference: lithium niobate monocrystal that 1- is two-sided to be coated with tin-doped indium oxide conductive membrane layer (36 ° of Y are cut, with a thickness of
1mm)；2- UV-curable epoxy layer；3- double glazing piece；4- thermal bonding layer；5- injection port；6- outlet.
Specific embodiment
The following further describes the present invention with reference to the drawings, and the contents of the present invention are completely without being limited thereto.
Embodiment 1
The preparation of the micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent
Preparation step is as follows:
1. design template
To guarantee that the different cells of sorting have an apparent line of demarcation, it is ensured that be collected into different outlets different
Sample is sorted, the parameter of micro- channel is adjusted according to theoretical calculation.The resonance frequency of the present embodiment monocrystalline is 3.8MHz, spiral goove
500 μm of road width, corresponding depth is 200 μm；Channel is two circle helixes, and five semicircles form, outermost bung flange it is straight
Diameter is 20mm, and diameter of a circle is followed successively by 20mm, 19mm, 18mm, 17mm, 16mm from big to small.It is white thin according to circulating tumor cell
Born of the same parents and blood platelet power suffered in helical channel are of different sizes, and the displacement in the outlet of trench ends distance is different, we are arranged
Three outlets, to sort circulating tumor cell, leucocyte and blood platelet.Three export and are followed successively by 150 μ with a distance from bifurcation
M, at 300 μm, 500 μm.
2. processing glass
Cut that two block sizes are identical, glass with a thickness of 1mm, one of for processing channel, another piece is used for resonance
The encapsulation of chamber.According to template size, the micro-channels for meeting half-wavelength integral multiple are prepared using laser processing.Monocrystalline it is humorous
Vibration frequency is 3.8MHz, and 500 μm of helical channel width, corresponding depth is 200 μm；Channel is two circle helixes, five semicircles
It forms, the diameter of outermost bung flange is 20mm, and from big to small diameter of a circle is followed successively by 20mm, 19mm, 18mm, 17mm, 16mm.
Fig. 3 shows the structure snd size of helical channel.The piezoelectric material of different frequency corresponds to the channel of different depth, also corresponding different
Flux, can be according to clinical demand, the parameter of quick and convenient adjusting device.It is right on same glass after processing channel
Glass is punched, as injection port and outlet.Injection port is two, and one is blood injection port, another is buffer
Injection port.There are three outlets.Structure is as shown in Figure 2.
3. integrated device
Using an equal amount of complete glass as lower layer's glass, it to be used for package cavity.Upper and lower level sheet glass uses thermal bonding
Method into
Line unit closes, and forms the chamber of sealing.Structure is as depicted in figs. 1 and 2.
Procedure of processing is as follows:
(1) low temperature is bonded in advance
Upper and lower level sheet glass is cleaned, successively cleans 10min with dish washing liquid, tap water rinses 15min, and deionized water rinses five
More than secondary, finally under the flow action of deionized water, two sheet glass are fitted closely.The glass top and bottom posted are dried up,
It is heated on 80 DEG C of baking platforms, sees whether that there are diffraction fringes.If there is diffraction fringe, illustrates that cleaning is not thorough, need to clean again
With regard to sealing, diffraction fringe, then illustrate to clean up if it does not exist, dries continue to heat 2h on platform herein.
(2) high temperature is bonded, 540 DEG C~550 DEG C high intermediate temperature sealings realized between glass and glass
After heating 2h on 80 DEG C of baking platforms, this chip is put into Muffle furnace.Temperature program is as follows:
4. constructing resonant cavity
Meet the trench bottom of half-wavelength integral multiple in depth, by the lithium niobate list with piezoelectric effect of 10mm*10mm
Brilliant (thickness 1mm, 36 ° of Y cut) is bonded in lower layer's sheet glass bottom in the way of epoxy resin ultra-violet curing, and two sides is drawn and led
Line is driven using power amplifier, and target cell is fixed at node by the frequency and size of adjustment signal, is realized same
Separating effect of the kind cell in same level.
Application Example 1
Cell sorting is carried out using micro-fluidic sorting chip prepared by embodiment 1
After taking patient's blood sample, red blood cell is removed using erythrocyte cracked liquid first, then according to the density of different cells,
Volume, compression ratio, under the action of the centrifugal force, radius of the different cells in helical channel is different, and the displacement from exit will
Difference, in addition the presence of standing wave, allogenic cell can be gathered on same nodal plane, so that cell sorting is come out, from inboard to
Outside, corresponding cell are circulating tumor cell, leucocyte and blood platelet.In operating process not to target cell into
Row modification, so not damaged to cell, activity is also just unaffected.
The foregoing is only a preferred embodiment of the present invention, but the scope of protection of the invention be not limited thereto,
Any modification that anyone skilled in the art is made in the technical scope disclosed by the present invention, equivalent replacement and
Improve etc., it should be included within the protection scope of invention.
Claims (10)
1. a kind of micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent, the acoustic resonant cavity and piezoelectric material stacked by sheet glass
It constitutes, it is characterised in that:
(1) acoustic resonant cavity is stacked by two blocks of sheet glass and is formed；
(2) the upper layer sheet glass of the acoustic resonant cavity is machined with micron order helical channel and has for circulating tumor cell, fetus
The sorting of the samples such as nucleated red blood cell, particle is also provided with the hole location being connected to channel as inlet and outlet；
(3) lower layer's sheet glass structural integrity of the acoustic resonant cavity is used for the encapsulation of resonant cavity；
(4) the two-sided conductive film that is coated with of the piezoelectric material is pasted on acoustic resonant cavity bottom, and draws two copper wire on two sides
As signal input lead.
2. the micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent according to claim 1, it is characterised in that: the step
(1) channel of the upper layer sheet glass of acoustic resonant cavity is formed by laser processing in, and channel depth meets the integral multiple of half-wavelength.
3. the micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent according to claim 1, it is characterised in that: use piezoelectricity
The resonance frequency of material is 3.8MHz, and 500 μm of helical channel width, corresponding channel depth is 200 μm.
4. the micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent according to claim 1, it is characterised in that: the glass
It is bonded in advance between piece using low temperature and the method for Muffle furnace temperature-gradient method carries out sealing-in.
5. the micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent according to claim 1, it is characterised in that: the channel
It is helical form in the plane of sheet glass.
6. the micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent according to claim 1, it is characterised in that: the step
(2) inlet and outlet in is connected in container by crossover sub.
7. the micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent according to claim 1, it is characterised in that: the step
(4) piezoelectric material is the two-sided lithium niobate monocrystal for being coated with tin-doped indium oxide conductive membrane layer in.
8. the micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent according to claim 7, it is characterised in that: the niobic acid
Lithium monocrystalline is cut with a thickness of 1mm, 36 ° of Y, and the resonance frequency of monocrystalline is 3.8MHz.
9. a kind of preparation method of the micro-fluidic sorting chip of the spiral acoustic bulk wave of all-transparent described in claim 1, feature exist
In, comprising the following steps:
(1) design template
The parameter of micro- channel is adjusted according to theoretical calculation；Resonance frequency using monocrystalline is 3.8MHz, helical channel width 500
μm, corresponding depth is 200 μm；Channel is two circle helixes；
(2) sheet glass is processed
The glass of two block sizes is cut, one of for processing channel, another piece for encapsulating；
For processing the sheet glass of channel, according to template size, is prepared using laser processing and meet the micro- of half-wavelength integral multiple
Meter level channel, is then punched, as injection port and outlet；
(3) integrated device
Two blocks of sheet glass are packaged by the method for thermal bonding, form the chamber of sealing；
(4) resonant cavity is constructed
Meet the trench bottom of half-wavelength integral multiple in depth, the lithium niobate monocrystal with piezoelectric effect is pasted onto bottom, two
Face extraction wire, is driven using power amplifier.
10. the micro-fluidic sorting chip of the spiral acoustic bulk wave of the described in any item all-transparents of claim 1-8 without modification, it is lossless
Wound, do not influence cell activity condition cell sorting application.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910261467.4A CN110215938B (en) | 2019-04-02 | 2019-04-02 | Full-transparent spiral type acoustic wave micro-fluidic sorting chip and preparation method thereof |
Applications Claiming Priority (1)
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