CN115041245B - Method and device for capturing and separating particles based on ultrahigh frequency bulk acoustic wave acoustic current potential well - Google Patents
Method and device for capturing and separating particles based on ultrahigh frequency bulk acoustic wave acoustic current potential well Download PDFInfo
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- 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
- B01L3/502761—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 specially adapted for handling suspended solids or molecules independently from the bulk fluid flow, e.g. for trapping or sorting beads, for physically stretching molecules
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- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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- H03H3/00—Apparatus or processes specially adapted for the manufacture of impedance networks, resonating circuits, resonators
- H03H3/007—Apparatus or processes specially adapted for the manufacture of impedance networks, resonating circuits, resonators for the manufacture of electromechanical resonators or networks
- H03H3/02—Apparatus or processes specially adapted for the manufacture of impedance networks, resonating circuits, resonators for the manufacture of electromechanical resonators or networks for the manufacture of piezoelectric or electrostrictive resonators or networks
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- B01L2200/10—Integrating sample preparation and analysis in single entity, e.g. lab-on-a-chip concept
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- B01L2300/06—Auxiliary integrated devices, integrated components
- B01L2300/0627—Sensor or part of a sensor is integrated
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- B01L2300/0893—Geometry, shape and general structure having a very large number of wells, microfabricated wells
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- H03—ELECTRONIC CIRCUITRY
- H03H—IMPEDANCE NETWORKS, e.g. RESONANT CIRCUITS; RESONATORS
- H03H3/00—Apparatus or processes specially adapted for the manufacture of impedance networks, resonating circuits, resonators
- H03H3/007—Apparatus or processes specially adapted for the manufacture of impedance networks, resonating circuits, resonators for the manufacture of electromechanical resonators or networks
- H03H3/02—Apparatus or processes specially adapted for the manufacture of impedance networks, resonating circuits, resonators for the manufacture of electromechanical resonators or networks for the manufacture of piezoelectric or electrostrictive resonators or networks
- H03H2003/023—Apparatus or processes specially adapted for the manufacture of impedance networks, resonating circuits, resonators for the manufacture of electromechanical resonators or networks for the manufacture of piezoelectric or electrostrictive resonators or networks the resonators or networks being of the membrane type
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Abstract
The invention discloses a method and a device for capturing and separating particles based on an ultrahigh frequency bulk acoustic wave sound current potential well, comprising a central processing unit, a power source module and a particle separating module, wherein the central processing unit is used for sending instruction information to the power source module; the power adjusting module is used for converting the received instruction information into a power signal; the micro-fluidic chip is positioned above the ultrahigh frequency bulk acoustic wave resonator and used for controlling the sample to directionally pass through the micro-channel; the ultrahigh frequency bulk acoustic resonator is characterized in that a microstructure array is processed on the top electrode, and each microstructure unit in the microstructure array penetrates through the top electrode and the adhesion layer to reach the surface of the piezoelectric layer; high-speed acoustic fluid vortex generated by fluid is excited by the peripheral acoustic pressure field of the microstructure units, so that a stagnation region, namely an acoustic flow potential well field, is created in the middle of the fluid vortex, and particles with different sizes are captured and separated. The method and the device can capture and separate particles with different sizes and materials and have better effect.
Description
Technical Field
The invention belongs to the field of analytical instruments, and particularly relates to a method and a device for capturing and separating particles based on ultrahigh frequency bulk acoustic waves.
Background
With the development of scientific technology, people pay more and more attention to molecules related to biomedicine, and the development of a rapid and simple method for simultaneously detecting multiple biological samples has important significance. Particle manipulation techniques, including particle capture, enrichment, separation, dispersion, patterning techniques, play an important role in the fields of biomedicine, industry, the environment, and the like. Suitable particulate manipulation tools will enable size-based classification and filtering for studies of downstream behavior such as multiplexed diagnostics and drug delivery. There are many methods available to manipulate and separate particles, such as cells or microvesicles, and conventional passive sorting techniques are based on different densities and sizes, such as ultracentrifugation, ultrafiltration, and inertial microfluidics.
Active techniques include electrical, magnetic, optical, acoustical, hydrodynamic, and like manipulation methods. Each method has a specific application range, and the separation resolution of the passive separation technology is low; the application of the electrophoresis technique with strong electric field and heat generation has limitations that it can only work in a solution with specific electric properties; magnetophoresis techniques involve magnetic beads, requiring additional incubation time and elution steps to remove the beads from the separated particles or cells; optical and hydrodynamic techniques damage cells, and surface acoustic wave and acoustophoresis techniques based on standing waves in fluids have been used to separate, extract, and manipulate microparticles and cells.
Chinese patent publication No. CN114112826A discloses an acousto-optic interconnection microfluidic detection system and detection method for fluorescent particles. The detection system includes: the device comprises a micro-fluidic chip, an ultrahigh frequency sound source, a fluorescence detection device and a data analysis device, wherein the micro-fluidic chip is used for controlling a sample to be detected to directionally pass through a micro-channel in the micro-fluidic chip, and the sample to be detected comprises fluorescent particles with at least two sizes: the ultrahigh frequency sound source is used for providing a sound pressure field environment for the sample to be detected in the micro-channel so that fluorescent particles in the sample to be detected can decelerate and pass through the micro-channel in a single row: the fluorescence detection module is used for providing exciting light so that a sample to be detected in the micro-channel emits fluorescence, and is also used for collecting the fluorescence flowing through the sample to be detected, converting the fluorescence into an electric signal and sending the electric signal to the data analysis device: the data analysis device is used for obtaining an analysis result according to the electric signal, and the analysis result comprises the concentrations of the fluorescent particles with multiple sizes.
However, the existing manipulation tools have the problems of high cost, low flux, low efficiency and sample damage, and cannot handle the condition of particle agglomeration, so that the sensitivity of sample capture and separation is reduced, and single-particle analysis cannot be realized.
Therefore, there is a need for a fast, accurate, and scalable manipulation apparatus and method that can simultaneously manipulate the position of different sized particles in space to achieve discrete separation in preparation for further analysis.
Disclosure of Invention
The invention provides a method and a device for capturing and separating particles based on an ultrahigh frequency bulk acoustic wave sound flow potential well, which can better separate and capture the particles.
A device for capturing and separating particles based on an ultrahigh frequency bulk acoustic wave sound flow potential well comprises:
the central processing unit is used for sending instruction information to the power source module;
the power adjusting module is used for converting the received instruction information into a power signal and controlling the bulk acoustic wave generated by the ultrahigh frequency bulk acoustic wave resonator through the power signal;
the micro-fluidic chip is positioned above the ultrahigh frequency bulk acoustic resonator, comprises a sample inlet, a sample outlet and a micro-channel and is used for controlling a sample to directionally pass through the micro-channel, and the sample comprises particles with at least one size; and
the ultrahigh frequency bulk acoustic resonator comprises a Bragg reflection layer, a bottom electrode, a piezoelectric layer, an adhesion layer and a top electrode which are sequentially arranged from bottom to top, wherein a microstructure array is arranged on the top electrode, and each microstructure unit in the microstructure array penetrates through the top electrode and the adhesion layer to reach the surface of the piezoelectric layer;
micro liquid is excited by the resonance area around the micro structure unit to generate acoustic fluid vortex, a stagnation area, namely an acoustic flow potential well field, is formed in the middle of the acoustic fluid vortex, and particles are dragged to the acoustic flow potential well field on the micro structure unit by the Stokes dragging force and the acoustic radiation force of the fluid vortex so as to achieve the effect of stably capturing and separating the particles with different sizes.
Also comprises a fluorescence microscope and a CCD camera; the device comprises a fluorescence microscope, a central controller, a CCD camera, a particle distribution information input module, a particle display module and a display module, wherein the fluorescence microscope is provided with the CCD camera, the CCD camera is connected with the central controller, the particle distribution information is obtained through the CCD camera on the fluorescence microscope and is input to the central controller, and the distribution condition of particles is displayed through the central controller.
The power adjusting module comprises a signal generator and a power amplifier, the signal generator receives the instruction information to generate a high-frequency signal, and the high-frequency signal is amplified by the power amplifier to drive the ultrahigh frequency bulk acoustic wave resonator to generate bulk acoustic waves.
The speed of injecting the sample into the micro-channel is 0.5-5 μ l/min, the height of the micro-channel is 200nm-100 μm, and the width of the micro-channel is 100-300 μm.
The power applied to the ultra-high frequency bulk acoustic wave resonator is 100-800mW, the distance between the micro-structural units is 100nm-50 mu m, and the shape of the micro-structural units is circular, oval, rectangular or polygonal.
The particle size is 100nm-30 μm, and the particle is silicon dioxide, magnetic iron oxide, gold, silver, carbon, polystyrene, polylactic acid, polyacrylic acid, polyamide, polyaniline, gelatin, calcium carbonate, barium carbonate, cellulose, pectin, starch, albumin, chitosan, cell, exosome, microvesicle, vesicle, membrane vesicle, virus or bacteria.
The method comprises the steps that a plurality of ultrahigh frequency bulk acoustic wave resonators are arranged on one side of the inner wall of a micro-channel of a micro-fluidic chip, a micro-structure array with one size is arranged on each ultrahigh frequency bulk acoustic wave resonator, and the corresponding ultrahigh frequency bulk acoustic wave resonators are arranged from a sample inlet to a sample outlet according to the size of the micro-structure array from small to large so as to capture particles with different sizes.
The difference between the sizes of the microstructure units in the microstructure array arranged on each ultrahigh frequency bulk acoustic resonator is at least 100nm, and the optimal difference is 1-2 times of the size of the minimum microstructure unit.
The method comprises the steps that a plurality of micro-structure arrays with different sizes are arranged on an ultrahigh frequency bulk acoustic wave resonator, and the micro-structure arrays are arranged along the flowing direction of a sample from small to large according to the sizes so as to capture particles with different sizes.
The difference between the sizes of the microstructure units in the microstructure array on the single ultrahigh frequency bulk acoustic wave resonator is at least 100nm, and the optimal difference is 1-2 times of the minimum microstructure unit size. Preferably, three microstructure arrays are arranged on the single ultrahigh frequency bulk acoustic resonator, and the sizes of the microstructure units in the microstructure arrays are respectively 300nm,500nm and 800nm, or the sizes of the microstructure units in the microstructure arrays are respectively 5 μm,10 μm and 15 μm.
The preparation method of the ultrahigh frequency bulk acoustic wave resonator comprises the following steps:
(1) Obtaining an initial ultrahigh frequency bulk acoustic wave resonator which sequentially comprises a substrate, a Bragg reflection layer, a bottom electrode, a piezoelectric layer, an adhesion layer and a top electrode layer from bottom to top;
(2) Coating a methyl methacrylate film on the top electrode layer, sequentially performing electron beam exposure and development on the methyl methacrylate film based on the microstructure array parameters, removing redundant developing solution, and drying by blowing to obtain a microstructure array based on the methyl methacrylate film;
(3) And (3) etching the top electrode layer on the microstructure array based on the methyl methacrylate film obtained in the step (2) through a first etching solution, drying the first etching solution, etching the adhesion layer through a second etching solution at 40-50 ℃, and removing the methyl methacrylate film through acetone to obtain the final microstructure array ultrahigh frequency bulk acoustic wave resonator. The bottom electrode, the adhesion layer and the top electrode are made of metal, and the metal comprises aluminum, molybdenum, gold, chromium, titanium, copper and alloy thereof. The first etching solution is potassium iodide, and the second etching solution is hydrogen peroxide.
The piezoelectric layer is made of piezoelectric materials, including aluminum nitride, lead zirconate titanate, zinc oxide and doped materials thereof.
The Bragg reflection layer is formed by alternately stacking two materials, including aluminum nitride/molybdenum, aluminum nitride/silicon dioxide or molybdenum/silicon dioxide.
The shape of the ultrahigh frequency bulk acoustic wave resonator is triangular, circular, fusiform, rhombus or pentagonal.
A method for capturing and separating particles based on an ultrahigh frequency bulk acoustic wave sound current potential well uses the ultrahigh frequency bulk acoustic wave sound current potential well to capture and separate particles, which comprises the following steps:
injecting a sample into an inlet of the micro-channel, starting the micro-fluidic chip to control the sample to flow through the micro-channel and then flow out of the sample outlet, wherein the size of the micro-channel is as follows: the width is 100-300 μm, the height is 200nm-100 μm, and the parameters of the sample are as follows: the concentration of the sample was 1X10 7 -1×10 10 The flow rate of the sample is 0.5-5 mul/min, and the particle size of the sample is 100-30 mu m;
starting the power adjusting module through the central processing unit, applying 100-800mW power to the ultrahigh frequency bulk acoustic wave resonator, wherein the size of the microstructure array on the ultrahigh frequency bulk acoustic wave resonator is as follows: the space between the microstructure units is 100-50 μm, the size of the microstructure units is 100-50 μm, the depth is 100-400 nm, and fluorescent sample particles passing through the ultrahigh frequency bulk acoustic wave resonator can be detected to be captured in the microstructure units through a CCD camera to present an array distribution state.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention sets a microstructure array on the ultrahigh frequency bulk acoustic wave resonator, and each microstructure unit penetrates through the top electrode and the adhesion layer, so that the microstructure units do not resonate, further a sound fluid potential well is formed at the microstructure units, a sound flow effect is generated in fluid at the periphery of the microstructure units due to the action of a bulk acoustic pressure field, a fluid vortex is formed, finally, the particles are separated by a fluid vortex Stokes dragging force and a sound radiation force, and the separated particles are dragged to the sound fluid potential well, namely the microstructure units, so that the technical effect of capturing and separating the particles is achieved.
(2) The microstructure can enable the UHF bulk acoustic wave resonator to generate a spatially localized, non-periodic, non-uniform sound field or form a sound field which is not directly related to the size and the position of the resonator, can selectively regulate and control the vibration size and the vibration position, and can adapt to the motion of surrounding fluid without influencing the expected sound fluid potential well effect. Generally, the height of the micro-channel is matched with the distance between the micro-structure units, so that the micro-structure units can be operated better, the distance between the micro-structure units is generally set to be 1-2 times of the optimal unit size, the corresponding height of the micro-channel is 1-2 times of the optimal unit size, the width of the micro-channel is mainly matched with the width of the micro-structure array, in order to ensure that all particles flowing through the micro-channel can pass through the upper part of the micro-structure array, the width of the micro-channel is generally set to be slightly larger than the width of the micro-structure array, and the distance from one side of the inner wall of the micro-channel to one side of the micro-structure array is optimally the width of one micro-structure unit.
Drawings
FIG. 1 is a diagram of an apparatus for trapping and separating particles based on ultra-high frequency bulk acoustic waves according to an embodiment;
fig. 2 is a flowchart of a method for manufacturing an ultra-high frequency bulk acoustic wave resonator according to an embodiment;
fig. 3 is a real object diagram of a circular hole array of the ultra-high frequency bulk acoustic resonator according to the embodiment, where fig. 3a is a real object diagram of a circular hole array plane, and fig. 3b is a depth diagram of a circular hole of the circular hole array;
FIG. 4 is a diagram of a fluorescent particle captured by the UHF bulk acoustic wave resonator prepared in example 1;
FIG. 5 is a diagram of a fluorescent particle captured by the UHF bulk acoustic wave resonator prepared in example 2;
FIG. 6 is a schematic diagram of fluorescent particles captured by an ultra-high frequency bulk acoustic wave resonator prepared in example 3;
FIG. 7 is a schematic view of fluorescent particles captured by the UHF bulk acoustic wave resonator prepared in example 5;
fig. 8 is a schematic view of a principle of fluorescent particles captured by a conventional general ultra-high frequency bulk acoustic wave resonator prepared in comparative example 1, fig. 8a is a sound pressure propagation diagram of the conventional general ultra-high frequency bulk acoustic wave resonator, and fig. 8b is a sound pressure amplitude diagram of the conventional general ultra-high frequency bulk acoustic wave resonator;
fig. 9 is a schematic view of a principle of fluorescent particles captured by the microstructure array ultra-high frequency bulk acoustic wave resonator prepared in embodiment 1, fig. 9a is a sound pressure propagation diagram of the microstructure array ultra-high frequency bulk acoustic wave resonator, and fig. 9b is a sound pressure amplitude diagram of the microstructure array ultra-high frequency bulk acoustic wave resonator;
fig. 10 is a schematic diagram of trapping particles by generating fluid vortex in the uhf bulk acoustic wave resonator prepared in example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the accompanying drawings and examples. It should be understood that the detailed description and specific examples, while indicating the scope of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The invention provides a device for capturing and separating particles based on an ultra-high frequency bulk acoustic wave sound current potential well, as shown in figure 1, which specifically comprises the following components:
the central processing unit is used for sending instruction information to the power source module;
the power adjusting module is used for converting the received instruction information into a power signal and controlling the bulk acoustic wave generated by the ultrahigh frequency bulk acoustic wave resonator through the power signal; the power adjusting module comprises a signal generator and a power amplifier, the signal generator receives the instruction information to generate a high-frequency signal, and the high-frequency signal is amplified by the power amplifier and then drives the ultrahigh frequency bulk acoustic wave resonator to generate bulk acoustic waves;
the micro-fluidic chip is positioned above the ultrahigh frequency bulk acoustic resonator, comprises a sample inlet, a sample outlet and a micro-channel and is used for controlling a sample to directionally pass through the micro-channel, and the sample comprises particles with at least one size; and
the ultrahigh frequency bulk acoustic wave resonator comprises a Bragg reflecting layer, a bottom electrode, a piezoelectric layer, an adhesion layer and a top electrode which are sequentially arranged from bottom to top, wherein a microstructure array is arranged on the top electrode, and each microstructure unit in the microstructure array penetrates through the top electrode and the adhesion layer to reach the surface of the piezoelectric layer;
the particles with different sizes are captured and separated by creating a stagnation region in the middle of the fluid vortex, namely a sound flow potential well field, through exciting the sound fluid vortex generated by the liquid at the periphery of the microstructure unit, the particles can be dragged to the sound fluid potential well on the microstructure unit by the Stokes dragging force and the sound radiation force of the fluid vortex to generate stable capture, after the particles are captured, the potential well is filled, the next particle cannot be captured again, and therefore the separation is completed.
Fluorescence microscopes and CCD cameras; the device comprises a fluorescence microscope, a central controller, a CCD camera, a particle distribution information input module, a particle display module and a display module, wherein the fluorescence microscope is provided with the CCD camera, the CCD camera is connected with the central controller, the particle distribution information is obtained through the CCD camera on the fluorescence microscope and is input into the central controller, and the distribution condition of the particles is displayed through the central controller.
The invention also provides a preparation method of the ultrahigh frequency bulk acoustic wave resonator, which comprises the following steps:
in this case, the electron beam exposure technology and the wet etching technology are used for the first time to prepare the circular gold nanopore array on the surface of the regular pentagonal ultra-high frequency bulk acoustic resonator, and the schematic process flow diagram is shown in fig. 2:
(1) Obtaining an initial ultrahigh frequency bulk acoustic wave resonator which sequentially comprises a silicon substrate, an aluminum nitride/silicon dioxide Bragg reflection layer, a gold bottom electrode, an aluminum nitride piezoelectric layer, a titanium-tungsten adhesion layer and a gold top electrode layer from bottom to top;
(2) Preparing a nanopore array mask layer: firstly, cleaning a gold top electrode by using acetone and isopropanol, then uniformly coating polymethyl methacrylate on the surface of the gold top electrode by using a spin coater, and sequentially setting the spin coater at the rotating speed of 200-500 r/min for 30-60 s and 4000-6000 r/min, the time of 60-90s, optimally 500 r/min, the time of 30 s and 5000 r/min and the time of 60s. Heating at 150-200 deg.C for 60-120s, preferably 180 deg.C for 90s to obtain polymethyl methacrylate film with thickness of 500-1000 nm, preferably 800nm, exposing with electron beam exposure technology, introducing microstructure array parameters, setting current intensity of 0.05-0.15 nA, preferably 0.111nA, and exposure agent intensity of 500-800 μ C/cm 2 Preferably 600. Mu.C/cm 2 Then developing for 3-5min, preferably for 4min, cleaning with clear water and drying to obtain a microstructure array based on the methyl methacrylate film;
(3) Preparing gold nano holes, etching a gold top electrode by using gold etching solution potassium iodide for 5-10s, preferably for 8s, blow-drying by using an air gun after etching is finished, preventing redundant solution from reacting with gold, generating side etching, etching a titanium-tungsten adhesion layer for 4-6min by using hydrogen peroxide at the heating temperature of 40-50 ℃, then soaking for 2-6 min by using acetone, removing the uppermost methyl methacrylate film, and obtaining a micro-structure array of the ultrahigh frequency bulk acoustic wave resonator, wherein a real object diagram is shown in figure 3a, the surface of the ultrahigh frequency bulk acoustic wave resonator is etched with a neat and uniform gold nano hole array, and the diameter of a single gold nano hole is about 550nm by measurement, and the hole interval is 1 mu m. Fig. 3b shows the depth of the circular gold nanopore, measured at 240nm, which is just the sum of the thicknesses of the gold top electrode and the titanium-tungsten adhesion layer of the uhf bulk acoustic resonator. By adjusting the technological parameters, the processing of the aperture size of the round hole of 100nm-50 μm can be realized.
Example 1
In the present case, regular pentagonal ultra-high frequency bulk acoustic wave with microstructure array is utilizedThe effect of the wave resonator on trapping particles was verified. FIG. 4 is a graph of ultra-high frequency bulk acoustic wave resonators with gold nanopore arrays capturing 300nm fluorescent particles, wherein the fluorescent particles are solid polystyrene microspheres with isothiocyanate (FITC) dyes doped inside. The size of the etched nanometer hole is 550nm, the depth is 240nm, the hole spacing is 800nm, the width of the straight micro-flow channel is 100-300 μm, the optimal width is 200 μm, the height is 200nm-100um, the optimal width is 1.1 μm, and the concentration of the prepared 300nm sample is 1x10 7 -1*10 10 One/ml, most preferably 1x10 8 The injection speed of each micro-channel by using a syringe pump or a peristaltic pump is 0.5-5 mul/min, and the optimal speed is 2 mul/min. The resonator is started, the power is set to be 100-800mW, the optimal power is 700mW, fluorescent particles passing through the upper portion of the resonator can be seen under a CCD camera to be rapidly captured in fluid vortex, and finally the fluorescent particles can be pushed to a sound pressure potential well area, namely the inside of the nanopore, and are in an array distribution state.
Example 2
FIG. 5 is a diagram of capture of 15 μm fluorescent particles by a nanopore array-engraved UHF bulk acoustic resonator, wherein the fluorescent particles are solid polystyrene microspheres doped with an isothiocyanic Fluorescein (FITC) dye. The size of the etched nanometer hole is 20 μm, the depth is 240nm, the width of the micro-flow channel of the micro-flow control chip is 100-300 μm, the optimal is 200 μm, the height is 200nm-100 μm, the optimal is 25 μm, and the concentration of the prepared fluorescent particles with the diameter of 15 μm is 1x10 7 -1x10 10 One/ml, most preferably 1x10 7 One per ml. The injection speed of the micro-channel by using a syringe pump or a peristaltic pump is 0.5-5 mul/min, and the optimal speed is 2 mul/min. The resonator is turned on, the power is set to 100-800mW, and the optimal power is 400mW, 15 mu m fluorescent particles can be seen to be captured inside the nano-holes under a CCD camera, and only a single particle is captured in each hole, so that the good dispersion effect is achieved.
Example 3
The present case presents a scheme for simultaneous capture and separation of multiple sized particles. One or more ultrahigh frequency bulk acoustic wave resonators with micro-structure arrays are placed in the micro-channel, the structure of the micro-channel can be designed to be linear, snakelike, spiral, telescopic-expandable and the like, the inlet and the outlet of the micro-channel are respectively one or more, micro-structure arrays with different sizes or different shapes are prepared on the same ultrahigh frequency bulk acoustic wave resonator in different regions, and different combination types and quantities are realized by adjusting the size, the distance and the shape of the units. Fig. 6 is a schematic diagram of a circular nanopore array structure with three sizes on the surface of a single regular pentagonal ultrahigh frequency resonator, the combination of the three sizes of the circular nanopore array structure is 300nm,500nm and 800nm, the array interval of each size is 100nm-50 μm, the optimal size is 1-2 times of the size of a microstructure unit, and the captured nanoparticles are solid microspheres with the density of 1-3 g/ml. The power was set at 600mW (applied to 300nm,500nm, 800nm combination). Because the acoustic fluid potential wells of the array units with different sizes are different, when a mixed sample with particles with multiple sizes enters a sound pressure region, the particles can respectively enter the matched acoustic fluid potential wells, and the capture and separation of the particles with multiple sizes are realized.
Example 4
The difference from example 3 is that the combination of three sizes of the circular nanopore array structure is 5 μm,10 μm,15 μm combination, and the power is set to 300mW.
Example 5
The present embodiment provides that different microstructures are respectively prepared on a plurality of bulk acoustic wave resonators. Fig. 7 is a schematic diagram showing the arrangement and combination of three nanopore array uhf bulk acoustic resonators having different sizes, respectively, placed in the same microchannel. The sizes of the microstructures on the three ultrahigh frequency bulk acoustic wave resonators are 300nm,500nm and 800nm, the array spacing of each size is 100nm-50 mu m, and the optimal size is 1-2 times of the size of the microstructure unit. The entrapped nanoparticles are solid microspheres with a density between 1-3 g/ml. The power of the three resonators is 700mW,600mW and 500mW (applied to the combination of 300nm,500nm and 800 nm), the mixed sample with particles of various sizes is led into the micro-channel and passes through each microstructure in sequence, and the size of the sound fluid potential well is adjusted by setting the power of each ultrahigh frequency bulk acoustic wave resonator, so that the capture and separation of the particles of various sizes are realized.
Example 6
Unlike example 5, the combination of three sizes of the circular nanopore array structure was 5 μm,10 μm,15 μm, and the power was set at 350mW,300mW,200 mW.
Examples 3,4,5,6 all have the advantage of rapid, efficient and accurate separation of multiple paths.
Comparative example 1
Unlike example 1, there is no microstructure array on the uhf bulk acoustic wave resonator.
The principle of capturing particles by the microstructure array on the ultrahigh frequency bulk acoustic resonator provided by the invention is as follows:
first, the change of the sound pressure distribution area of the uhf bulk acoustic wave resonator with or without the microstructure array is compared, and the schematic diagram is shown in fig. 8. The micro-fluidic chip is arranged right above the ultrahigh frequency bulk acoustic wave resonator, the contact positions are tightly attached, and the ultrahigh frequency bulk acoustic wave resonator can generate bulk acoustic waves which are transmitted to the inside of a micro-channel and exponentially attenuated to form a sound pressure gradient area. Fig. 8a is a cross-sectional view of the ultra-high frequency bulk acoustic wave resonator without the microstructure array, wherein sound pressure regions of the ultra-high frequency bulk acoustic wave resonator are continuously and uniformly distributed in the horizontal direction and count and vertically transmit the sound pressure to the inside of the micro-channel, and fig. 8b is a cross-sectional view of the ultra-high frequency bulk acoustic wave resonator without the microstructure array, and the sound pressure amplitude of the ultra-high frequency bulk acoustic wave resonator is large, and the whole region of the resonator can generate resonance, so that the values of a sound high potential energy region and a sound low potential energy region of the resonator are high, the difference is small, and particles cannot be effectively captured.
Fig. 9a is a cross-sectional view of an uhf bulk acoustic resonator with a microstructure array where no resonance occurs due to the lack of a top electrode, thus forming a sound pressure well that couples into a fluid to form an acoustic fluid well. Fig. 9b shows the sound pressure amplitude of the ultra-high frequency bulk acoustic wave resonator with the microstructure array, where the value of the acoustic low potential energy region is almost zero, and the difference between the acoustic high potential energy region and the acoustic low potential energy region is large, so that a stable capture site can be formed in the acoustic low potential energy region, i.e., the microstructure position, and particles can be effectively captured.
The principle of capturing particles by the microstructure array is explained in detail below, as shown in fig. 10, an acoustic pressure region 1 and an acoustic pressure region 2 around the microstructure can generate exponentially attenuated bulk acoustic waves upwards, fluid vortex can be caused by an acoustic flow effect, the vortex 1 is clockwise, the vortex 2 is counterclockwise, and contact regions of the two vortices are acoustic fluid regions, that is, positions of the microstructure and directions of the two vortices are downward. Therefore, when particles pass through, the particles are subjected to acoustic radiation force and fluid vortex stokes drag force and are rapidly captured in the microstructure. The acoustic radiation force is expressed by the following formula:
wherein, the first and the second end of the pipe are connected with each other,Fwhich is indicative of the force of the acoustic radiation,Uthe potential energy of sound is represented by,awhich represents the radius of the particles,pand
representing the first order sound pressure and the sound velocity, respectively, at the location of the microsphere.
And
the compressibility of the microspheres and the liquid respectively,
and
the densities of the microspheres and the liquid respectively,f 1 andf 2 respectively representing the monopole scattering coefficient and the dipole scattering coefficient,
is a hamiltonian.
f 1 Showing that the acoustic radiation force is related to the volume modulus ratio of the particles and the liquid,f 2 indicating that the acoustic radiation force is related to the density of the particles and the liquid. The fluid drag force is formulated as:
wherein the content of the first and second substances,ais the radius of the particles and is,𝜈 d is the relative velocity of the fluid and the particles,𝜇is the liquid viscosity. After the particle is captured, the potential well is filled and the next particle is not captured again, thereby completing the separation. As the particles agglomerate, complex interactions occur in the vortex, eventually dispersing and being driven to the acoustic current well region. The capture capacity of the ultrahigh frequency bulk acoustic wave resonator is related to the depth of a microstructure, the unit interval of the microstructure, the unit size, the unit shape, the height of a micro channel, the application of bulk acoustic waves with different powers, different sample injection flow rates, the size of captured target particles, the material of the captured target particles, or the combination of the units. The magnitude of the drag force and the velocity difference between the fluid and the particles: (𝜈 d ) Proportional to the flow field, the higher the velocity, the smaller the particle size that can be manipulated, and therefore the injection rate into the microchannel is typically set to 0.5-5 μ l/min. The height of the micro-channel and the power applied to the donor acoustic wave resonator both influence the size of vortex, the channel is reduced, the outer layer of the vortex is limited, and only small vortex in the inner layer exists; the power applied to the donor acoustic resonator is increased and the vortex is also increased. Therefore, the flow channel height is usually set to 200nm to 100 μm, the flow channel width is set to 100 to 300 μm, and the applied power is usually set to 100 to 800mW. The distance between the micro-structure units can influence the distance between the vortex 1 and the vortex 2, and when the distance between the two vortices is too large, the acoustic radiation force and the fluid dragging force are too small to capture particles; when two vortices overlap, the acoustic fluid potential trap area is reduced, again reducing the particle trapping capability. Therefore, the microstructure array pitch is usually set to 100nm to 50 μm, and optimally to 1 to 2 times the microstructure unit size. Trapping target particle sizeUsually 100nm to 30 μm, and the material of the capture target particles is usually silicon dioxide, magnetic iron oxide, gold, silver, carbon, polystyrene, polylactic acid, polyacrylic acid, polyamides, polyaniline, gelatin, calcium carbonate, barium carbonate, cellulose, pectin, starch, albumin, chitosan, cells, exosomes, microvesicles, vesicles, membrane vesicles, viruses or bacteria.
Claims (9)
1. A device for capturing and separating particles based on an ultra-high frequency bulk acoustic wave sound current potential well is characterized by comprising:
the central processing unit is used for sending instruction information to the power source module;
the power adjusting module is used for converting the received instruction information into a power signal and controlling the bulk acoustic wave generated by the ultrahigh frequency bulk acoustic wave resonator through the power signal;
the micro-fluidic chip is positioned above the ultrahigh frequency bulk acoustic resonator, comprises a sample inlet, a sample outlet and a micro-channel and is used for controlling a sample to directionally pass through the micro-channel, and the sample comprises particles with at least one size;
the ultrahigh frequency bulk acoustic wave resonator comprises a Bragg reflecting layer, a bottom electrode, a piezoelectric layer, an adhesion layer and a top electrode which are sequentially arranged from bottom to top, a microstructure array is processed on the top electrode, and each microstructure unit in the microstructure array penetrates through the top electrode and the adhesion layer to reach the surface of the piezoelectric layer;
micro liquid is excited by a resonance area at the periphery of the microstructure unit to generate acoustic fluid vortex, a stagnation area, namely an acoustic fluid potential well field, is formed in the middle of the acoustic fluid vortex, and particles are dragged to the acoustic fluid potential well field on the microstructure unit by a fluid vortex Stokes dragging force and an acoustic radiation force so as to achieve the effects of stably capturing and separating particles with different sizes;
the particle size is 100nm-30 μm, and the particle is silicon dioxide, magnetic iron oxide, gold, silver, carbon, polystyrene, polylactic acid, polyacrylic acid, polyamide, polyaniline, gelatin, calcium carbonate, barium carbonate, cellulose, pectin, starch, albumin, chitosan, cell, exosome, microvesicle, vesicle, membrane vesicle, virus or bacteria.
2. The apparatus of claim 1 further comprising a fluorescence microscope and a CCD camera; the device comprises a fluorescence microscope, a central controller, a CCD camera, a particle distribution information input module, a particle display module and a display module, wherein the fluorescence microscope is provided with the CCD camera, the CCD camera is connected with the central controller, the particle distribution information is obtained through the CCD camera on the fluorescence microscope and is input into the central controller, and the distribution condition of the particles is displayed through the central controller.
3. The apparatus as claimed in claim 1, wherein the power adjusting module comprises a signal generator and a power amplifier, the signal generator receives the command information to generate a high frequency signal, and the high frequency signal is amplified by the power amplifier to drive the UHF bulk acoustic wave resonator to generate the UHF bulk acoustic wave.
4. The apparatus of claim 1, wherein the speed of injecting the sample into the microchannel is 0.5-5 μ l/min, the height of the microchannel is 200nm-100 μm, and the width of the microchannel is 100-300 μm.
5. The apparatus as claimed in claim 1, wherein the power applied to the UHF bulk acoustic wave resonator is 100-800mW, the pitch of the microstructure units is 100nm-50 μm, and the microstructure units are circular, elliptical, rectangular or polygonal in shape.
6. The apparatus of claim 1, wherein a plurality of the UHF bulk acoustic wave resonators are disposed on one side of an inner wall of a microchannel of the microfluidic chip, each of the UHF bulk acoustic wave resonators is etched with a micro-structural array having one size, and the corresponding UHF bulk acoustic wave resonators are arranged from a sample inlet to a sample outlet according to the size of the micro-structural array from small to large to capture particles having different sizes.
7. The apparatus of claim 1, wherein a plurality of micro-structural arrays of different sizes are arranged on the UHF bulk acoustic wave resonator, and the micro-structural arrays are arranged from small to large along the flow direction of the sample to capture particles of different sizes.
8. The apparatus of claim 1, wherein the method for preparing the micro-structure array UHF bulk acoustic wave resonator comprises:
(1) Obtaining an initial ultrahigh frequency bulk acoustic wave resonator which sequentially comprises a substrate, a Bragg reflection layer, a bottom electrode, a piezoelectric layer, an adhesion layer and a top electrode layer from bottom to top;
(2) Coating a methyl methacrylate film on the top electrode layer, sequentially performing electron beam exposure and development on the methyl methacrylate film based on the microstructure array parameters, removing redundant developing solution, and drying by blowing to obtain a microstructure array based on the methyl methacrylate film;
(3) And (3) etching the top electrode layer on the microstructure array based on the methyl methacrylate film obtained in the step (2) through a first etching solution, drying the first etching solution, etching the adhesion layer through a second etching solution at 40-50 ℃, and removing the methyl methacrylate film through acetone to obtain the final microstructure array ultrahigh frequency bulk acoustic wave resonator.
9. A method for capturing and separating particles based on a vhf bulk acoustic fluid potential well, wherein the apparatus for capturing and separating particles using the vhf bulk acoustic fluid potential well according to any one of claims 1 to 8 comprises the steps of:
injecting a sample into an inlet of the micro-channel, starting the micro-fluidic chip to control the sample to flow through the micro-channel and then flow out of the sample outlet, wherein the size of the micro-channel is as follows: the width is 100-300 μm, the height is 200nm-100 μm, and the parameters of the sample are as follows: the concentration of the sample was 1X10 7 -1×10 10 The flow rate of the sample is 0.5-5 mul/min, and the particle size of the sample is 100nm-30 mu m;
starting the power adjusting module through the central processing unit, applying 100-800mW power to the UHF bulk acoustic wave resonator, wherein the size of the microstructure array on the UHF bulk acoustic wave resonator is as follows: the space between the micro-structural units is 100nm-50 μm, the size of the micro-structural units is 100nm-50 μm, the depth is 100nm-400nm, and fluorescent sample particles passing through the ultrahigh frequency bulk acoustic wave resonator can be detected to be captured in the micro-structural units through a CCD camera to present an array distribution state.
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