WO2017059604A1 - 基于人工结构声场的微流体系统及操控微粒的方法 - Google Patents

基于人工结构声场的微流体系统及操控微粒的方法 Download PDF

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Publication number
WO2017059604A1
WO2017059604A1 PCT/CN2015/091686 CN2015091686W WO2017059604A1 WO 2017059604 A1 WO2017059604 A1 WO 2017059604A1 CN 2015091686 W CN2015091686 W CN 2015091686W WO 2017059604 A1 WO2017059604 A1 WO 2017059604A1
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Prior art keywords
crystal plate
phononic crystal
ultrasonic
sound field
micro
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PCT/CN2015/091686
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English (en)
French (fr)
Inventor
郑海荣
李飞
蔡飞燕
孟龙
王辰
张成祥
邱维宝
李永川
严飞
牛丽丽
耿刘峰
徐超伟
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中国科学院深圳先进技术研究院
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Priority to US15/742,491 priority Critical patent/US10780437B2/en
Priority to PCT/CN2015/091686 priority patent/WO2017059604A1/zh
Publication of WO2017059604A1 publication Critical patent/WO2017059604A1/zh

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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
    • 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
    • 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
    • B01L3/502715—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 characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • 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
    • B01L3/502769—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 characterised by multiphase flow arrangements
    • B01L3/502784—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 characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics
    • B01L3/502792—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 characterised by multiphase flow arrangements specially adapted for droplet or plug flow, e.g. digital microfluidics for moving individual droplets on a plate, e.g. by locally altering surface tension
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N13/00—Treatment of microorganisms or enzymes with electrical or wave energy, e.g. magnetism, sonic waves
    • 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
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • 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
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0647—Handling flowable solids, e.g. microscopic beads, cells, particles
    • B01L2200/0652—Sorting or classification of particles or molecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0433—Moving fluids with specific forces or mechanical means specific forces vibrational forces
    • B01L2400/0436—Moving fluids with specific forces or mechanical means specific forces vibrational forces acoustic forces, e.g. surface acoustic waves [SAW]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0403—Moving fluids with specific forces or mechanical means specific forces
    • B01L2400/0433—Moving fluids with specific forces or mechanical means specific forces vibrational forces
    • B01L2400/0439—Moving fluids with specific forces or mechanical means specific forces vibrational forces ultrasonic vibrations, vibrating piezo elements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/04—Moving fluids with specific forces or mechanical means
    • B01L2400/0493—Specific techniques used
    • B01L2400/0496—Travelling waves, e.g. in combination with electrical or acoustic forces
    • 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
    • B01L3/50273—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 characterised by the means or forces applied to move the fluids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N2015/0038—Investigating nanoparticles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1006—Investigating individual particles for cytology

Definitions

  • This application relates to microfluidic control techniques, and more particularly to a microfluidic system based on an artificial structure sound field and a method of manipulating particles.
  • Microfluidic chip also known as Lab on a chip, has the advantages of miniaturization, integration, high throughput, low energy consumption, fast analysis, etc., and is now widely used in biology, chemistry, medicine. , environment and other fields.
  • micro-nano particles such as cells, DNA, proteins, polystyrene microspheres, and gold nanoparticles need to be transported by microfluidics to functional units such as sample preparation, reaction, separation, and detection. Therefore, accurate and fast micro-nano particle transport technology provides the necessary power and precise control for microfluidic flow, and is a vital functional module for microfluidic devices.
  • microfluidic devices such as microfluidic pumps, microfluidic channels, and microfluidic valves.
  • microfluidic devices such as microfluidic pumps, microfluidic channels, and microfluidic valves.
  • these micro/nanoparticle transport technologies can be divided into passive and active.
  • Passive technology uses microfluidic properties such as surface tension as the driving force, so it does not require complicated and expensive peripheral equipment and is suitable for various portable microfluidic devices.
  • passive technology is not able to flexibly regulate flow direction and flow as needed. Therefore, passive technology is not suitable for biochemical immunoassays that require complex multi-step operations on microfluidics.
  • active technology based on photodynamic, electroosmotic flow, electrophoresis, magnetophoresis, dielectrophoresis, acoustic microfluidics, etc., mainly uses external force fields such as electric field, magnetic field, light field, and sound field to drive microfluidic flow.
  • external force fields such as electric field, magnetic field, light field, and sound field to drive microfluidic flow.
  • active technology has the disadvantages of complicated processes, the need to introduce moving parts into the microcavity, and unstable performance.
  • the above microfluidic technology needs to be carried out in the microcavity, there is also a problem that the suspended particles block the channel, which limits the flux and the number of uses of the device.
  • Microcavity type microfluidic devices without microfluidic channels are not only simple in process, but also have the advantage of not blocking the channels, and thus become a new direction for the development of microfluidic devices.
  • a microcavity microfluidic device for droplets has been emitted, but this system is not suitable for continuous flow.
  • Interdigital transducer excitation based on MEMS technology The AO mode Lamb wave generated by the vibration of ZnO thin film can induce the acoustic flow effect to transport micro-nano particles, but the flow generated by this method is a linear flow of integrity, and it is difficult to form a complicated path according to the need to change the flow direction.
  • the acoustic micro-flow generated by bubble vibration realizes the transport of micro-nano particles.
  • the bubbles are not uniform, unstable, and difficult to capture, it is difficult to construct a bubble array to form a complicated transport path as needed. Therefore, under continuous flow conditions, transporting micro-nano particles along any path within the microcavity becomes a challenge, restricting the development of microcavity microfluidic devices.
  • the physical delivery method has the advantages of safety and simplicity, and mainly includes methods such as microinjection, electroporation, laser, and ultrasonic (sonic perforation).
  • Microinjection directly injects nucleic acids into the cytoplasm or nucleus through microtubules. This method is not suitable for systemic delivery, requires high operational skills, and usually causes cell death.
  • Electroporation is a simple, fast, high-throughput, and most widely used method of physical delivery.
  • the method utilizes high-intensity electrical pulses to perforate the cell membrane, enhances the permeability of the cell membrane, and allows the drug to pass through the pore into the cytoplasm.
  • the electroporation method has a higher cell death rate.
  • the laser method uses a laser pulse to generate a transient aperture in the cell membrane to transport the exogenous nucleic acid into the cell. This method enables accurate, fixed-point pupils on the cell membrane, but the cost of the laser system is expensive.
  • Ultrasound delivery drug technology has received extensive attention due to its advantages of non-contact, non-invasive, low cost, universal applicability and the like. Similar to electroporation, current ultrasound delivery drug technology is based on the biophysical process of ultrasound combined with ultrasound contrast microbubbles for cell perforation, a process also known as sonoporation: microbubbles in ultrasound Inertial cavitation or steady-state cavitation in the field, and accompanying effects of acoustic radiation, microjet, micro-streaming, shear, etc., in the cell membrane The surface produces repairable pores of several tens of nanometers to several hundred nanometers in size, thereby enhancing the permeability of the cell membrane, so that extracellular DNA, protein and other biological macromolecules can enter the cell through the pores.
  • the microbubbles are unstable and the size is not uniform, and it is difficult to precisely control the cavitation of the microbubble group.
  • the present application provides a microfluidic system based on an artificial structure sound field and a method of manipulating particles.
  • the present application provides a microfluidic system based on an artificial structure sound field, comprising a microcavity for holding a solution containing microparticles, and an ultrasonic emission device, the ultrasonic emission
  • the device is configured to emit ultrasonic waves, and further includes a phononic crystal plate disposed in the microcavity, the phononic crystal plate being an artificial periodic structure for modulating a sound field to manipulate the particles.
  • the present application provides a method for microfluidic manipulation of particles based on an artificial structure sound field, comprising:
  • the ultrasonic transmitting device emits ultrasonic waves, and the sound field is modulated by the phononic crystal plate;
  • the phononic crystal plate manipulates the particles based on the modulation.
  • the ultrasonic emitting device is configured to emit ultrasonic waves
  • the phononic crystal plate is an artificial periodic structure for modulating the sound field to perform the microparticles. Manipulation, providing new means of drug delivery and providing technical support for drug development.
  • FIG. 1 is a schematic structural view of a system of the present application in an embodiment
  • FIG. 2 is a schematic structural view of a phononic crystal plate of the present application in an embodiment
  • FIG. 3 is a flow chart of the method of the present application in an embodiment
  • FIG. 4 is a flow chart of another embodiment of the method of the present application.
  • FIG. 5 is a diagram showing the effect of transporting micro-nano particles along a 90 degree corner phononic crystal plate using the present application
  • FIG. 6 is an effect diagram of transporting micro-nano particles along a 120 degree corner phononic crystal plate using the present application
  • FIG. 7 is a diagram showing the effect of transporting micro-nano particles along a loop phononic crystal plate using the present application.
  • FIG. 8 is an effect diagram of switching between a transport mode and an acquisition mode using the present application.
  • FIG. 9 is a flow chart of a method for constructing a novel microfluid based on an artificial structure sound field in a large-scale cell array lysis or perforation embodiment;
  • FIG. 10 is an effect diagram of microvortex and shear force generated by modulating a sound field using a phononic crystal plate of the present application;
  • FIG. 11 is a view showing an effect of using a cell array formed by the present application and cell lysis;
  • FIG. 12 is a diagram showing the effect of using a cell array formed by the present application and perforating a cell
  • FIG. 13 is a schematic structural view of a phononic crystal plate of the present application in another embodiment.
  • the artificial structure sound field based microfluidic system of the present application has a small size, such as in one embodiment, the piezoelectric ceramic sheet has a size of less than 2 cm, and the phononic crystal plate has a length and width dimension of 15 mm.
  • the height of the PDMS sink is only 4mm.
  • the whole system is integrated on a 50mm *50mm * lmm quartz glass plate, and the phononic crystal plate is located above the piezoelectric ceramic piece, so it can be under the microscope for 30 microns or less. Particles and other particles are manipulated and studied. Therefore, the chip system can be combined with microfluidic technology to manipulate and study particles such as cells below 30 microns under a microscope.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • an artificial structure sound field-based microfluidic system of the present application includes a microcavity, an ultrasonic emitting device, and a phononic crystal plate, and the ultrasonic emitting device is configured to emit ultrasonic waves, and the microcavity It is used to hold a solution containing particles.
  • the phononic crystal plate is placed in a microcavity.
  • the phononic crystal plate is an artificial periodic structure for modulating the sound field to manipulate the particles.
  • the microparticles in the present application include micro-nano particles and/or cells, and the phononic crystal plate is specifically used to modulate the sound field to drive the micro-nano particles to be oriented and transported along the design path; the phononic crystal plate is used to modulate the sound field to capture and arrange the cell-forming cell array.
  • phononic crystal plates can also be used to create microvortex arrays that produce shear forces on cell arrays, induce cell lysis, or can modulate sonication. Since the phononic crystal plates generate acoustic radiation forces to align, capture, and form cell arrays, and generate microvortex arrays to produce quantitatively modulating shear forces on the cell array, which provides repeatable, multi-class, large-scale cells. A statistically significant and accurately quantifiable somatoporous effect that can be quantitatively regulated.
  • the phononic crystal plate may include a substrate 11 and a rib 12, and the rib 12 is disposed on the lower surface of the substrate 11, and a plurality of ribs 12 are disposed, and the plurality of ribs 12 are disposed in parallel and at equal intervals.
  • the ribs 12 are curved or closed in a ring shape.
  • the pattern of the artificial periodic structure can be set as needed, such as The shape of the ridge can be expressed as a line segment, a 90-degree corner-connected line segment, a 120-degree corner-connected line segment, a plurality of 90-degree corner-connected line segments and a line segment combined to form a linear phononic crystal plate, a 90-degree corner sound.
  • the loop phononic crystal plate is shown in Figure 13 (c).
  • the longitudinal section of the ridge may include a rectangle, a triangle, a polygon, or a semicircle.
  • the longitudinal section of the ridge is rectangular, the pitch between the center lines of the rectangle is d, and the thickness of the substrate is h2, 0.15 ⁇ h2 / d ⁇ 0.25.
  • the spacing d between the centerlines of the rectangles is the period of the artificial periodic structure, and the artificial periodic structure is made of a hard material, and is specifically made of a hard material having a transverse wave velocity greater than that of the longitudinal water of the base water.
  • the hard material may be a metal material such as copper, aluminum, steel or other metal material, and the hard material may also be a non-metal material such as glass.
  • the artificial periodic structure is a fence structure having a period of 0.35 mm, a height of 0.05 mm, and a width of 0.05 mm, which is formed on a stainless steel plate having a thickness of 0.1 mm.
  • the size of the artificial cycle structure can also be set as needed.
  • the ultrasonic transmitting device includes a signal generator, a power amplifier, an ultrasonic transducer, the signal generator for generating a transmission signal, the power amplifier for amplifying the transmission signal, and the ultrasonic transducer for The amplified transmitted signal is converted into ultrasonic waves.
  • the ultrasonic transmitting device comprises a signal generator 31, a power amplifier 32 for generating a transmitted signal, and a ultrasonic transducer 33 for amplifying the transmitted signal, ultrasound
  • the transducer is used to convert the amplified transmitted signal into ultrasonic waves.
  • the ultrasonic transmitting device may further comprise an ultrasonic electronic control device, which can be used to set parameters of the signal generator and the power amplifier, and the ultrasonic transducer can be turned on and off, and the ultrasonic transducer can be a single-element ultrasonic transducer One of a linear array ultrasonic transducer, an area array ultrasonic transducer, a phased array ultrasonic transducer, and an interdigital transducer.
  • the resonant frequency of the artificial structure determines the driving frequency of the transmitted ultrasound, which determines the center frequency of the ultrasonic transducer.
  • the ultrasonic transducer uses a single-element ultrasound transducer PZT
  • the 8*8 area array transducer consisting of 4 or 4 single-element transducer PZT4 or 64 single-element transducer PZT4 has a center frequency of 3.8MHz.
  • the signal generator Capturing micro-nano particles and inducing cell lysis or modulating sonic effect ⁇ , the signal generator emits a continuous sinusoidal signal with a frequency of 3.774 MHz; transporting micro-nanoparticles ⁇ , the signal generator emits a Chirp pulse signal with a bandwidth of 3.774 MHz to 3.979 MHz.
  • the signal generator can be a programmable signal generator (AFG3021, Tectronix) and the power amplifier can be a 52dB linear power amplifier (A300, E&I). The signal generated by the signal generator is passed through the power amplifier to excite the ultrasonic transducer to generate ultrasonic waves that excite the phononic crystal plate.
  • the microcavity of the present application comprises an upper bottom 21, a lower bottom 22 and a side wall 23, the side wall enclosing the inner cavity and having a mouth at both ends, the mouth and the inner cavity are penetrated, and the upper bottom and the lower bottom are respectively disposed at At the mouth of the mouth, the upper bottom is set at the upper end of the mouth, and the lower bottom is set at the lower end of the mouth.
  • the upper and lower bases may be made of quartz glass, and the side walls may be made of PDMS (polydimethylsiloxane, polydimethylsiloxane) or glass.
  • the microcavity is in the shape of a rectangular parallelepiped, an upper base made of quartz glass, a lower base made of quartz glass, and four side wall surfaces made of PDMS, the height of which can be set as needed. In this embodiment, the height of the microcavity is 4 mm.
  • the phononic crystal plate is an artificial periodic structure prepared by etching a metal or a non-metal thin plate, and the pattern of the structure determines a moving path of the micro/nano particles; by replacing different patterns of phononic crystals
  • the plate can realize parallel transportation of a large number of micro-nano particles along any design path; by setting different excitation parameters, a large number of micro-nano particles can be flexibly switched between capture and transport modes; by setting different excitation voltages,
  • the microvortex flow field is quantitatively regulated to quantitatively regulate the shear force of the cells to control the degree of pupillary. Therefore, the present application implements a novel microfluidic device that is simple, reliable, disposable, templatable, programmable, parallel processing, high throughput, and versatile.
  • Embodiment 2 is a diagrammatic representation of Embodiment 1
  • the method for artificially constituting a microfluidic manipulation microparticle based on an artificial structure sound field of the present application includes the following steps:
  • Step 102 placing the phononic crystal plate in the microcavity, and the phononic crystal plate is an artificial periodic structure.
  • Step 104 Add a solution containing the microparticles.
  • Step 106 The ultrasonic transmitting device emits ultrasonic waves, and modulates the sound field through the phononic crystal plate.
  • Step 108 The phononic crystal plate manipulates the particles based on the modulation.
  • Step 108 specifically:
  • Step 1082 The phononic crystal plate transports the micro-nano particles based on the modulated sound field
  • the phononic crystal plates are arranged based on the acoustic radiation force generated by the modulated sound field, capture the cell-forming cell array, and generate a microvortex array to generate shear forces on the cell array, induce cell lysis or modulate the sonophoresis effect.
  • step 108 may further include:
  • Step 1084 adjusting a transport path of the micro/nano particles by setting a pattern of ridge arrangement on the phononic crystal plate;
  • the size of the microvortex array is adjusted by setting the thickness of the substrate of the phononic crystal plate and the interval of the ridges.
  • the step 106 may specifically include:
  • Step 1062 The ultrasonic transmitting device is configured to emit a pulse wave, and the center frequency of the signal is the resonant frequency of the phononic crystal plate, and the bandwidth is 15 ⁇ 3 ⁇ 4 ⁇ 100 ⁇ 3 ⁇ 4, and the regulation of the transport speed is realized by changing the voltage. ;
  • the ultrasonic transmitting device is configured to emit a continuous wave, and the micro-nano particles are captured by setting the driving frequency to the resonant frequency of the phononic crystal plate.
  • step 106 may further include:
  • Step 1064 The ultrasonic transmitting device quantitatively regulates the microvortex array by adjusting parameters, thereby quantitatively regulating the shearing force of the cells, thereby controlling the cell pupil degree, realizing cell lysis or modulating sonophoresis. Effects, parameters include excitation voltage, drive frequency, pulse repetition frequency, and pulse duration.
  • step 106 may further include:
  • Step 1066 The ultrasonic transmitting device is configured to emit a sinusoidal pulse signal ⁇ , the center frequency of the signal is the resonant frequency of the phononic crystal plate, and the micro vortex induced by the phononic crystal plate is quantitatively regulated by adjusting the parameter. Thereby quantitatively regulating the shearing force of the cells to control the degree of cell pupillary;
  • the ultrasonic transmitting device is configured to emit a continuous wave, and the driving frequency is set to a resonant frequency of the phononic crystal plate, and the micro-vortex induced by the artificial structure sound field is quantitatively regulated by adjusting the excitation voltage, thereby The amount of shear force is quantitatively regulated to control the degree of cell pupillary.
  • a specific application example of the artificial structure sound field-based microfluidic manipulation particle according to the present application is a micro-nano particle transport implementation, which includes the following steps: [0067] Step 202: Select a suitable phononic crystal plate as needed.
  • Step 204 Injecting the micro-nano particles into the microcavity; in the embodiment, the micro-nano particles may be selected from polystyrene microspheres, specifically polystyrene microspheres 74964-10ML-F having a diameter of 15 ⁇ m.
  • Step 206 The ultrasonic electronic control system sets parameters of the signal generator and the power amplifier.
  • Step 208 Capturing the micro-nano particles in the capture mode.
  • Step 210 The micro-nano particles are transported in the transport mode, and the transport speed can be quantitatively regulated by adjusting the voltage.
  • step 206 specifically includes:
  • the signal generator capturing the micro-nanoparticles, the signal generator emits a continuous sinusoidal signal with a frequency of 3.774 MHz; transporting the micro-nanoparticles, the signal generator emits a Chirp pulse signal with a bandwidth of 3.774 MHz to 3.979 MHz, and adjusts the voltage by regulating the voltage. Speed.
  • Figure 5 is a graph showing the transport of 15 micron polystyrene microspheres along a 90 degree corner path template.
  • the signal generator generates a Chirp pulse signal with a bandwidth of 3.774 MHz - 3.979 MHz, and an ultrasonic transducer is excited by the power amplifier to generate an ultrasonic wave; the ultrasonic excitation artificial periodic structure vibration generates an acoustic flow effect on the surface of the structure.
  • Figure 5 (a) shows the images of different engravings during transport through a CCD camera;
  • Figure 5 (b) shows superimposed images of different engravings showing the trajectories of micro-nano particles. From start to finish, the micro-nano particles move along the design path, and the direction of motion changes by 90 degrees.
  • Figure 6 is a graph showing the transport of 15 micron polystyrene microspheres along a 120 degree corner path template.
  • the signal generator generates a Chirp pulse signal with a bandwidth of 3.774 MHz - 3.979 MHz, and an ultrasonic transducer is excited by the power amplifier to generate an ultrasonic wave; the ultrasonic excitation artificial periodic structure modulates the emission sound field.
  • Figure 6 (a) shows images of different engravings during transport through a CC D camera;
  • Figure 6 (b) shows superimposed images of different engravings showing the trajectories of micro-nano particles. From start to finish, the micro-nano particles move along the design path, and the direction of motion changes by 60 degrees.
  • Figure 7 shows the results of transport of 15 micron polystyrene microspheres along a loop path template.
  • the signal generator produces bandwidth 3.
  • the Chirp pulse signal of 774MHz-3.979MHz is excited by the ultrasonic transducer after the power amplifier to generate ultrasonic waves; the ultrasonic excitation artificial periodic structure vibration modulates the emission sound field.
  • the center image shows that the motion path of the micro-nano particles is a ring-shaped circuit, and the direction of motion is the direction of the reverse pin.
  • Shooting with a CCD camera Images of different engravings and different positions during transport. Initially, the micro-nano particles are located in the upper left and upper right areas. Under the ultrasonic drive, the artificial periodic structure vibrates to modulate the emission sound field, and the micro-nano particles are driven in the direction of the reverse needle through the upper left, lower left, lower right, and upper right of the loop. Position, and eventually return to the initial position. From start to finish, the micro-nano particles move along the design path, and the direction of motion changes 360 degrees.
  • FIG. 8 is a result of switching between the capture mode and the transport mode.
  • the micro-nanoparticles are transported, and the signal generator emits a Chirp pulse signal with a width of 3.774 MHz - 3.979 MHz; the micro-nanoparticles are captured, and the signal generator emits a continuous sinusoidal signal with a frequency of 3.774 MHz. Images of different engravings during transport were captured by a CCD camera.
  • the 15 micron particles are transported along the 120 degree corner path; when the continuous sinusoidal signal is used to excite the enthalpy, the 15 micron particles immediately stop transporting and are captured on the surface of the path template; when the excitation signal changes back to the Chirp pulse After the signal, the captured 15 micron micro-nano particles continue to transport along the design path.
  • FIG. 9 another specific application of the artificial structure-based sound field-based microfluidic manipulation of particles of the present application, that is, a large-scale cell array lysis or perforation method, includes the following steps:
  • Step 302 Injecting the cell solution into the microcavity; in the present embodiment, the cell may be selected from melanoma cells or breast tumor cells.
  • Step 302 setting parameters of the signal generator
  • Step 304 The ultrasonic transmitting device emits ultrasonic waves
  • Step 306 The artificial periodic structure controls the sound field; modulates the acoustic radiation force generated by the sound field, captures the cell forming cell array, and generates a microvortex array to generate shear force on the cell array, induce cell lysis or modulate sound Perforation effect.
  • the method of the present invention is based on the method of the artificially-structured sound field-based microfluidic manipulation of the microparticles.
  • the step 304 specifically includes:
  • the signal generator emits a continuous sinusoidal signal or a pulsed sinusoidal signal with a frequency of 3.774 MHz; quantitatively regulates the microvortex by adjusting parameters such as voltage, driving frequency, pulse repetition frequency, and pulse duration, to quantitatively regulate the shearing force of the cells. , thereby controlling the degree of pupillary.
  • FIG. 10 is a microvortex and shear force generated by a phononic crystal plate modulating a sound field.
  • the signal generator produces a 3.774 MHz continuous sinusoidal signal.
  • the ultrasonic transducer is excited to generate ultrasonic waves; the ultrasonic excitation artificial periodic structure vibration generates a microvortex on the surface of the structure.
  • Figure 10 (a) shows the calculated flow field distribution;
  • Figure 10 (b) shows the shear force distribution calculated further from the flow field distribution;
  • Figure 10 (c) shows the CCD phase. The image of the micro-vortex captured by the machine.
  • Figure 11 is a diagram showing the process of cell array formation and lysis of 15 micron melanoma cells.
  • the signal generator generates a 3.774MHz continuous sinusoidal signal, and the ultrasonic transducer excites the ultrasonic transducer to generate ultrasonic waves; the ultrasonic excitation excites the artificial periodic structure to vibrate the acoustic radiation force generated on the surface of the structure, and captures the cell forming cell matrix
  • the shearing force of the vortex on the cell array causes the cells to lyse.
  • Figure 11 (a) shows the cell array taken by a CCD camera;
  • Figure 11 (b) The process of cell lysis in a cell array.
  • Figure 12 is a graph showing the results of drug entry into cells after perforation of 15 micron melanoma cells.
  • Propidium iodide (PI) fluorescent stain was used in the experiment. Before the pupil, no PI enters the cells and stains them. Therefore, cells cannot be observed in the fluorescence mode. After the pupil, PI enters the cells from outside the cells to stain the cells, so the cells can display red fluorescence.
  • PI Propidium iodide
  • the phononic crystal plate since the phononic crystal plate includes a substrate and a plurality of ridges disposed on the lower surface of the substrate, the ridges are disposed in parallel and spaced apart, and the ribs are curved or closed.
  • the transport path of the micro-nano particles can be flexibly designed.
  • the transport path of the micro-nano particles can be changed, and the artificial periodic structure is used to modulate the sound field, which can be in the microcavity. Achieve parallel transport of a large number of micro-nano particles along any design path.
  • the signal generator achieves fast and flexible switching of the micro-nano particle transport and capture modes by transmitting excitation signals of different parameters.
  • the micro-nano particles flow through the sample preparation, reaction, detection and other unit modules, and the micro-nano particles can be captured in the unit module flowing through the method of changing the signal emission parameters of the signal generator, so as to Perform analytical testing.
  • the emission parameters can be switched from the capture mode parameter to the transport mode parameter, and the micro-nano particles are transported to the next analysis detection unit.
  • the artificial periodic structure is used to modulate the sound field to produce an acoustic radiation force to align, capture, and form a cell array of cells, and to generate a microvortex array to produce a quantizable shear force on the cell array. Since the present application does not require the intervention of microbubbles as compared with the conventional ultrasound combined microbubble delivery technology, the present application can provide reproducible, statistically significant, and accurate quantitative quantitation of various types of large-scale cells. The sonic effect.

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Abstract

一种基于人工结构声场的微流体系统，包括微腔和超声波发射装置，所述微腔用于盛放含有微粒的溶液，所述超声波发射装置用于发射超声波，其特征在于，还包括置于所述微腔内的声子晶体板，所述声子晶体板为人工周期结构，用于调制声场对所述微粒进行操控。一种基于人工结构声场的微流体操控微粒的方法。在具体实施方式中，由于包括微腔、超声波发射装置和声子晶体板，超声波发射装置用于发射超声波，声子晶体板为人工周期结构，用于调制声场对微粒进行操控，为药物递送提供新手段，为药物研发提供技术支持。

Description

基于人工结构声场的微流体系统及操控微粒的方法 技术领域
[0001] 本申请涉及本申请涉及微流体控制技术， 尤其涉及一种基于人工结构声场的微 流体系统及操控微粒的方法。
[0002] 背景技术
[0003] 微流控芯片又被称为芯片实验室 （Lab on a chip) ， 具有微型化、 集成化、 高 通量、 低能耗、 快速分析等优点， 现已广泛应用于生物、 化学、 医学、 环境等 领域。 在微流体分析检测过程中， 细胞、 DNA、 蛋白质、 聚苯乙烯微球、 纳米 金等微纳颗粒需要经微流体输运至样本制备、 反应、 分离、 检测等功能单元。 因此， 精确、 快速的微纳颗粒输运技术为微流体流动提供了必要的动力和精确 控制， 是微流体设备至关重要的功能模块。
[0004] 当前微纳颗粒输运技术主要借助微流体泵、 微流体腔道、 微流体阀门等微流体 器件联合作用实现。 根据微流体泵的类型划分， 这些微纳颗粒输运技术又可分 为被动式和主动式。 被动式技术利用表面张力等微流体自身特性作为驱动力， 因此不需要复杂、 昂贵的外围设备， 适用于各种便携式微流体器件。 但是， 由 于被动式技术无法根据需要对流动方向和流量进行实吋灵活的调控， 因此， 被 动式技术不适用于需对微流体进行复杂多步操作的生化免疫分析等领域。 与被 动式技术相比， 基于光动力、 电渗流、 电泳、 磁泳、 介电泳、 声微流等机制的 主动式技术， 主要利用电场、 磁场、 光场、 声场等外加力场驱动微流体流动， 可提供更加灵活的微流体操作。 但是， 主动式技术存在工艺复杂、 需要在微腔 道内引入活动部件、 性能不稳定等方面的缺点。 另外， 由于上述微流体技术均 需要在微腔道内进行， 因此还存在着悬浮颗粒堵塞腔道的问题， 这限制了器件 的通量和使用次数。
[0005] 没有微流体腔道的微腔型微流体设备不仅工艺简单， 还具有不堵塞腔道的优点 ， 因此成为微流体设备研发的新方向。 利用电场， 已幵发出了针对液滴的微腔 性微流体设备， 但是该系统不适用于连续流。 基于 MEMS工艺， 叉指换能器激励 ZnO薄膜振动产生的 AO模式兰姆波可诱发声流效应输运微纳颗粒， 但是该方法 产生的流动为整体性的直线流动， 难以根据需要改变流动方向形成复杂路径。 近年来， 利用气泡振动产生的声微流实现了微纳颗粒的输运， 但是由于气泡不 均一、 不稳定、 不易捕获， 故难以根据需要构建气泡阵列形成复杂的输运路径 。 因此， 连续流条件下， 在微腔内沿任意路径输运微纳颗粒成为一项挑战， 制 约了微腔性微流体设备的发展。
[0006] 而在药物递送技术领域， 安全高效的药物递送技术是药物研发、 癌症研究、 多 功能干细胞诱导和组织工程等领域的核心技术。 因此， 研究幵发安全可靠、 高 效精确、 易于操作的药物递送技术已成为备受瞩目的前沿方向之一。
[0007] 当前的药物递送技术主要分为三种： 生物学方法、 化学方法和物理方法。 生物 学方法即病毒介导的递送技术， 具有效率高、 易于操作的优点， 但是存在免疫 原性、 细胞毒性和致癌性的问题， 因此安全性难以保障。 化学方法是当前研究 中广泛采用的方法， 包括阳离子脂质体法、 阳离子多聚物法、 阳离子氨基酸法 等方法。 该方法的效率低， 依赖于细胞类型， 且存在药物泄露、 稳定性等问题
[0008] 相比较前两种方法， 物理递送方法具有安全简单的优点， 主要包括微注射法、 电致穿孔法、 激光法和超声法 （声致穿孔） 等方法。 微注射法通过微管将核酸 直接注入细胞质或者细胞核， 该方法不适合系统性递送、 对操作技能要求较高 、 通常会引起细胞死亡。 电致穿孔法是一种简单、 快速、 高通量、 应用最广泛 的物理递送方法。 该方法利用高强度电脉冲对细胞膜造成穿孔， 增强细胞膜的 通透性， 使药物可穿过孔洞进入细胞质。 但电致穿孔法的细胞死亡率较高。 激 光法利用激光脉冲对细胞膜辐射产生瞬吋小孔， 将外源核酸输送至细胞内。 该 方法可实现细胞膜上精确、 定点幵孔， 但是激光系统的造价昂贵。
[0009] 超声递送药物技术因具有非接触、 无创、 低廉、 普遍适用性等优点而受到了广 泛的关注。 与电致穿孔法类似， 当前超声递送药物技术是基于超声联合超声造 影剂微泡对细胞穿孔的生物物理过程实现的， 这一过程也被称为声致穿孔效应 (sonoporation) ： 微泡在超声场中的惯性空化或者稳态空化， 及伴随的声辐射 力、 微射流 （microjet) 、 声微流 （micro- streaming) 、 剪切力等效应， 在细胞膜 表面产生可修复的几十纳米至几百纳米大小的孔隙， 从而增强了细胞膜的通透 性， 使得细胞外的 DNA、 蛋白质等生物大分子可穿过小孔进入细胞内发挥作用 。 但是， 微泡不稳定、 尺寸不均一， 难以对微气泡群的空化进行精确调控。
[0010] 发明内容
[0011] 本申请提供一种基于人工结构声场的微流体系统及操控微粒的方法。
[0012] 根据本申请的第一方面， 本申请提供一种基于人工结构声场的微流体系统， 包 括微腔和超声波发射装置， 所述微腔用于盛放含有微粒的溶液， 所述超声波发 射装置用于发射超声波， 还包括置于所述微腔内的声子晶体板， 所述声子晶体 板为人工周期结构， 用于调制声场对所述微粒进行操控。
[0013] 根据本申请的第二方面， 本申请提供一种基于人工结构声场的微流体操控微粒 的方法， 包括：
[0014] 将声子晶体板置于微腔内， 所述声子晶体板为人工周期结构；
[0015] 加入含有微粒的溶液；
[0016] 超声波发射装置发射超声波， 通过所述声子晶体板对声场进行调制；
[0017] 所述声子晶体板基于所述调制对所述微粒进行操控。
[0018] 由于采用了以上技术方案， 使本申请具备的有益效果在于：
[0019] 在本申请的具体实施方式中， 由于包括微腔、 超声波发射装置和声子晶体板， 超声波发射装置用于发射超声波， 声子晶体板为人工周期结构， 用于调制声场 对微粒进行操控， 为药物递送提供新手段， 为药物研发提供技术支持。
[0020] 附图说明
[0021] 图 1为本申请的系统在一种实施方式中的结构示意图；
[0022] 图 2为本申请的声子晶体板在一种实施方式中的结构示意图；
[0023] 图 3为本申请的方法在一种实施方式中的流程图；
[0024] 图 4为本申请的方法在另一种实施方式中的流程图；
[0025] 图 5为使用本申请沿 90度拐角声子晶体板输运微纳颗粒的效果图；
[0026] 图 6为使用本申请沿 120度拐角声子晶体板输运微纳颗粒的效果图；
[0027] 图 7为使用本申请沿回路声子晶体板输运微纳颗粒的效果图；
[0028] 图 8为使用本申请在输运模式和捕获模式之间切换的效果图。 [0029] 图 9为本申请基于人工结构声场的新型微流体的方法在一种大规模细胞阵列裂 解或者穿孔实施方式中的流程图；
[0030] 图 10为使用本申请的声子晶体板调制声场产生的微涡旋及剪切力的效果图； [0031] 图 11为使用本申请形成的细胞阵列及对细胞裂解的效果图；
[0032] 图 12为使用本申请形成的细胞阵列及对细胞穿孔的效果图；
[0033] 图 13为本申请的声子晶体板在另一种实施方式中的结构示意图。
[0034] 具体实施方式
[0035] 下面通过具体实施方式结合附图对本申请作进一步详细说明。
[0036] 本申请的基于人工结构声场的微流体系统具有较小的尺寸， 比如在一种实施方 式中， 压电陶瓷片的尺寸小于 2cm， 声子晶体板的长宽尺寸 15 mm
*20mm， PDMS水槽的高度仅 4mm， 整个系统在一块 50 mm *50 mm * lmm的石 英玻璃板上加工集成， 且声子晶体板位于压电陶瓷片上方， 所以可在显微镜下 对 30微米以下的细胞等颗粒进行操控和研究。 因此， 本芯片系统可以与微流体 技术结合， 在显微镜下对 30微米以下的细胞等颗粒进行操控和研究。
[0037] 实施例一：
[0038] 如图 1所示， 本申请的基于人工结构声场的微流体系统， 其一种实施方式， 包 括微腔、 超声波发射装置和声子晶体板， 超声波发射装置用于发射超声波， 微 腔用于盛放含有微粒的溶液， 声子晶体板置于微腔内， 声子晶体板为人工周期 结构， 用于调制声场对微粒进行操控。 本申请中的微粒包括微纳颗粒和 /或细胞 ， 声子晶体板具体用于调制声场驱动微纳颗粒沿设计路径定向输运； 声子晶体 板用于调制声场捕获、 排列细胞形成细胞阵列， 以及声子晶体板还可用于产生 微涡旋阵列对细胞阵列产生剪切力， 诱发细胞裂解或者可调控声孔效应。 由于 声子晶体板产生声辐射力以排列、 捕获细胞形成细胞阵列， 以及产生微涡旋阵 列对细胞阵列产生可定量调控的剪切力， 从而可对多种类、 大规模细胞提供可 重复、 有统计学意义、 且能精确定量的可定量调控的声孔效应。
[0039] 如图 2所示， 声子晶体板可以包括基板 11和凸条 12， 凸条 12设置在基板 11下表 面， 凸条 12有多个， 多个凸条 12平行设置且间隔相等。 在一种实施方式中， 凸 条 12为曲线形或封闭的环形。 人工周期结构的图案可以根据需要进行设置， 如 凸条的形态可以表现为线段、 90度拐角连接的线段、 120度拐角连接的线段、 多 个 90度拐角连接的线段与线段组合成的回路， 从而形成直线声子晶体板、 90度 拐角声子晶体板、 120度拐角声子晶体板、 回路声子晶体板， 其中， 90度拐角声 子晶体板如图 13 (a) 所示， 120度拐角声子晶体板如图 13 (b) 所示， 回路声子 晶体板如图 13 (c) 所示。
[0040] 凸条的纵截面可以包括长方形、 三角形、 多边形或半圆形。 在本实施方式中， 凸条的纵截面为长方形， 长方形的中心线之间的间距为 d， 基板的厚度为 h2， 则 0.15≤h2/d≤0.25。 长方形的中心线之间的间距 d为人工周期结构的周期， 人工周 期结构采用硬性材料制成， 具体采用横波速大于基体水的纵波带的硬性材料制 成。 该硬性材料可以为金属材料， 如铜、 铝、 钢或其他金属材料， 该硬性材料 也可以为非金属材料， 如玻璃。 在一种实施方式中， 人工周期结构为在厚度 0.1 mm的不锈钢板上加工制得的周期 0.35mm， 高度 0.05mm， 宽度 0.05mm的栅栏结 构。 人工周期结构的尺寸也可根据需要进行设置。
[0041] 在一种实施方式中， 当凸条的纵截面为长方形吋， 长方形的宽、 高及基板的厚 度相等。 即若长方形的宽为 w,长方形的高为 hi， 则 w=hl=h2。 在本实施方式中 ， 人工周期结构为在厚度 hl+h2=0.1 mm的不锈钢上通过化学刻蚀加工得到的周 期为 d=0.35mm， 高度为 hl=0.05mm， 宽度为 w=0.05mm的栅栏结构。
[0042] 超声波发射装置包括信号发生器、 功率放大器、 超声换能器， 所述信号发生器 用于产生发射信号， 所述功率放大器用于将所述发射信号放大， 所述超声换能 器用于将放大后的发射信号转换为超声波。
[0043] 在一种实施方式中， 超声波发射装置包括信号发生器 31、 功率放大器 32和超声 换能器 33， 信号发生器 31用于产生发射信号， 功率放大器 32用于将发射信号放 大， 超声换能器用于将放大后的发射信号转换为超声波。 超声波发射装置还可 以包括超声电子控制装置， 超声电子控制装置可用于设置信号发生器和功率放 大器的参数， 以及超声换能器的幵启和关闭， 超声换能器可以是单阵元超声换 能器、 线阵超声换能器、 面阵超声换能器、 相控阵超声换能器和叉指换能器中 的一种。 人工结构的共振频率决定了发射超声的驱动频率， 从而决定了超声换 能器的中心频率。 在本具体实施方式中， 超声换能器采用单阵元超声换能器 PZT 4或者 4个单阵元换能器 PZT4构成的 2*2面阵换能器或者 64个单阵元换能器 PZT4 构成的 8*8面阵换能器， 其中心频率为 3.8MHz。 捕获微纳颗粒和诱发细胞裂解或 者可调控声孔效应吋， 信号发生器发射频率 3.774MHz的连续正弦信号； 输运微 纳颗粒吋， 信号发生器发射带宽 3.774MHz-3.979MHz的 Chirp脉冲信号。 在一种 实施方式中， 信号发生器可以是可编程信号发生器 （AFG3021 , Tectronix) ， 功 率放大器可以是 52dB的线性功率放大器 （A300， E&I) 。 信号发生器产生的信 号经功率放大器后激励超声换能器产生超声波， 激励声子晶体板。
[0044] 本申请的微腔包括上底 21、 下底 22和侧壁 23， 侧壁围出内腔且两端设有幵口， 幵口和内腔贯通， 上底和下底分别设置在幵口处， 即上底设置在上端幵口， 下 底设置在下端幵口。 上底和下底可以由石英玻璃制成， 侧壁可以由 PDMS (polydimethylsiloxane , 聚二甲基硅氧烷)或玻璃制成。 在一种实施方式中， 微腔 为长方体形， 由石英玻璃制得的上底、 由石英玻璃制得的下底和 PDMS制得的四 个侧壁面构成， 其高度可根据需要进行设置。 在本具体实施方式中， 微腔的高 度 4mm。
[0045] 在本申请的具体实施方式中， 声子晶体板为刻蚀金属或者非金属薄板制备的人 工周期结构， 结构的图案决定了微纳颗粒的运动路径； 通过替换不同图案的声 子晶体板， 可实现大量微纳颗粒沿任意设计路径进行并行输运； 通过设置不同 激励参数， 可对大量微纳颗粒在捕获和输运两种模式之间进行灵活切换； 通过 设置不同激励电压， 可定量调控微涡旋流场， 从而定量调控细胞所受剪切力大 小， 以控制幵孔程度。 因此， 本申请实现了一种简单可靠、 可丢弃、 模板化、 可编程、 并行处理、 高通量、 多功能的新型微流体器件。
[0046] 实施例二：
[0047] 如图 3所示， 本申请的基于人工结构声场的微流体操控微粒的方法， 其一种实 施方式， 包括以下步骤：
[0048] 步骤 102: 将声子晶体板置于微腔内， 声子晶体板为人工周期结构。
[0049] 步骤 104: 加入含有微粒的溶液。
[0050] 步骤 106: 超声波发射装置发射超声波， 通过声子晶体板对声场进行调制。
[0051] 步骤 108: 声子晶体板基于调制对微粒进行操控。 [0052] 其中步骤 108， 具体包括：
[0053] 步骤 1082: 声子晶体板基于调制声场对微纳颗粒进行输运；
[0054] 声子晶体板基于调制声场产生的声辐射力排列、 捕获细胞形成细胞阵列， 以及 产生微涡旋阵列对细胞阵列产生剪切力， 诱发细胞裂解或者可调控声致穿孔效 应。
[0055] 在一种实施方式中， 步骤 108， 还可以包括：
[0056] 步骤 1084: 通过设置声子晶体板上的凸条排列的图案调整所述微纳颗粒的输运 路径；
[0057] 通过设置声子晶体板的基板的厚度、 凸条的间隔调控所述微涡旋阵列的尺寸。
[0058] 其中， 步骤 106， 具体可以包括：
[0059] 步骤 1062: 超声波发射装置用于发射脉冲波吋， 信号的中心频率为声子晶体板 的共振频率， 带宽 15<¾〜100<¾， 通过改变电压的方式实现对输运速度的调控；
[0060] 超声波发射装置用于发射连续波吋， 通过将驱动频率设为声子晶体板的共振频 率， 从而实现对微纳颗粒进行捕获。
[0061] 在一种实施方式中， 步骤 106还可以包括：
[0062] 步骤 1064: 超声波发射装置通过调节参数对微涡旋阵列进行定量调控， 从而对 细胞所受剪切力大小进行定量调控， 以控制细胞幵孔程度， 实现细胞裂解或者 可调控声致穿孔效应， 参数包括激励电压、 驱动频率、 脉冲重复频率和脉冲持 续吋间。
[0063] 在另一种实施方式中， 步骤 106还可以包括：
[0064] 步骤 1066: 超声波发射装置用于发射正弦脉冲信号吋， 信号的中心频率为声子 晶体板的共振频率， 通过调节所述参数， 对声子晶体板诱发的微涡旋进行定量 调控， 从而对细胞所受剪切力大小进行定量调控， 以控制细胞幵孔程度；
[0065] 超声波发射装置用于发射连续波吋， 驱动频率设为所述声子晶体板的共振频率 ， 通过调节激励电压的方式， 对人工结构声场诱发的微涡旋进行定量调控， 从 而对细胞所受剪切力大小进行定量调控， 以控制细胞幵孔程度。
[0066] 如图 4所示， 为本申请的基于人工结构声场的微流体操控微粒的方法的一种具 体应用例， 即一种微纳颗粒输运实施方式， 包括以下步骤： [0067] 步骤 202: 根据需要选择合适的声子晶体板。
[0068] 步骤 204: 将微纳颗粒注入微腔； 在本实施方式中， 微纳颗粒可选用聚苯乙烯 微球， 具体是直径为 15μηι的聚苯乙烯微球 74964-10ML-F。
[0069] 步骤 206: 超声电子控制系统设定信号发生器和功率放大器的参数。
[0070] 步骤 208: 捕获模式下对微纳颗粒进行捕获。
[0071] 步骤 210: 输运模式下对微纳颗粒进行输运， 通过调节电压可以对输运速度进 行定量调控。
[0072] 本申请的基于人工结构声场的微流体操控微粒的方法， 在一种实施方式中， 其 中步骤 206具体包括：
[0073] 捕获微纳颗粒吋， 信号发生器发射频率 3.774MHz的连续正弦信号； 输运微纳 颗粒吋， 信号发生器发射带宽 3.774MHz-3.979MHz的 Chirp脉冲信号， 并通过调 节电压定量调控输运速度。
[0074] 图 5为 15微米聚苯乙烯微球沿 90度拐角路径模板输运的结果。 信号发生器产生 带宽 3.774MHz-3.979MHz的 Chirp脉冲信号， 经功率放大器后激励超声换能器产 生超声波； 超声波激励人工周期结构振动在结构表面产生声流效应。 图 5 (a) 为 通过 CCD相机拍摄了输运过程中不同吋刻的图像； 图 5 (b) 为不同吋刻的叠加 图像， 显示了微纳颗粒的运动轨迹。 从始至终， 微纳颗粒沿设计路径运动， 运 动方向发生了 90度改变。
[0075] 图 6为 15微米聚苯乙烯微球沿 120度拐角路径模板输运的结果。 信号发生器产生 带宽 3.774MHz-3.979MHz的 Chirp脉冲信号， 经功率放大器后激励超声换能器产 生超声波； 超声波激励人工周期结构对发射声场进行调制。 图 6 (a) 为通过 CC D相机拍摄了输运过程中不同吋刻的图像； 图 6 (b) 为不同吋刻的叠加图像， 显 示了微纳颗粒的运动轨迹。 从始至终， 微纳颗粒沿设计路径运动， 运动方向发 生了 60度改变。
[0076] 图 7为 15微米聚苯乙烯微球沿回路路径模板输运的结果。 信号发生器产生带宽 3.
774MHz-3.979MHz的 Chirp脉冲信号， 经功率放大器后激励超声换能器产生超声 波； 超声波激励人工周期结构振动对发射声场进行调制。 中心图像显示了微纳 颗粒的运动路径为一环型回路， 及运动方向为逆吋针方向。 通过 CCD相机拍摄 了输运过程中不同吋刻、 不同位置的图像。 起初， 微纳颗粒位于左上和右上之 间的区域， 在超声驱动下， 人工周期结构振动调制发射声场， 驱动微纳颗粒沿 逆吋针方向依次经过回路的左上、 左下、 右下、 右上四个位置， 并最终回到初 始位置。 从始至终， 微纳颗粒沿设计路径运动， 运动方向发生了 360度改变。
[0077] 图 8为捕获模式和输运模式切换的结果。 输运微纳颗粒吋， 信号发生器发射带 宽 3.774MHz-3.979MHz的 Chirp脉冲信号； 捕获微纳颗粒吋， 信号发生器发射频 率 3.774MHz的连续正弦信号。 通过 CCD相机拍摄了输运过程中不同吋刻的图像 。 起初在 Chirp脉冲信号激励下， 15微米颗粒沿 120度拐角路径输运； 当改用连续 正弦信号激励吋， 15微米颗粒立刻停止输运， 被捕获在路径模板表面； 当激励 信号变回 Chirp脉冲信号后， 捕获的 15微米微纳颗粒继续沿设计路径输运。
[0078] 如图 9所示， 本申请的基于人工结构声场的微流体操控微粒的方法的另一种具 体应用例， 即一种大规模细胞阵列裂解或者穿孔方法， 包括以下步骤：
[0079] 步骤 302: 将细胞溶液注入微腔； 在本实施方式中， 细胞可选用黑色素瘤细胞 或者乳腺肿瘤细胞。
[0080] 步骤 302: 设定信号发生器的参数；
[0081] 步骤 304: 超声波发射装置发射超声波；
[0082] 步骤 306: 人工周期结构对声场进行调控； 调制声场产生的声辐射力排列、 捕 获细胞形成细胞阵列， 以及产生微涡旋阵列对细胞阵列产生剪切力， 诱发细胞 裂解或者可调控声致穿孔效应。
[0083] 本申请的基于人工结构声场的微流体操控微粒的方法的， 在一种实施方式中， 其中步骤 304具体包括：
[0084] 信号发生器发射频率 3.774MHz的连续正弦信号或者脉冲正弦信号； 通过调节 电压、 驱动频率、 脉冲重复频率、 脉冲持续吋间等参数定量调控微涡旋以定量 调控细胞所受剪切力， 从而控制幵孔程度。
[0085] 图 10为声子晶体板调制声场产生的微涡旋及剪切力。 信号发生器产生 3.774MH z连续正弦信号， 经功率放大器后激励超声换能器产生超声波； 超声波激励人工 周期结构振动在结构表面产生微涡旋。 图 10 (a) 为计算得到的流场分布； 图 10 (b) 为根据流场分布进一步计算得到的剪切力分布； 图 10 (c) 为通过 CCD相 机拍摄到的微涡旋的图像。
[0086] 图 11为对 15微米黑色素瘤细胞形成的细胞阵列及裂解的过程。 信号发生器产生 3.774MHz连续正弦信号， 经功率放大器后激励超声换能器产生超声波； 超声波 激励人工周期结构振动在结构表面产生的声辐射力排列、 捕获细胞形成细胞阵 歹 |J， 产生的微涡旋对细胞阵列的剪切力使细胞发生裂解。 图 11 (a) 为通过 CCD 相机拍摄的细胞阵列； 图 11 (b) 细胞阵列中的细胞裂解的过程。
[0087] 图 12对 15微米黑色素瘤细胞穿孔后， 药物进入细胞后的结果图。 实验中采用碘 化丙啶 (PI)荧光染色剂。 幵孔前， 无 PI进入细胞内对其染色， 故荧光模式下无法 观察到细胞； 幵孔后， PI从细胞外进入细胞内对细胞染色， 故细胞可显示红色荧 光。
[0088] 在本申请的具体实施方式中， 由于声子晶体板包括基板和设置在基板下表面的 多个凸条， 凸条平行设置且间隔相等， 凸条为曲线形或封闭的环形。 通过设计 人工周期结构的图案可灵活设计微纳颗粒的输运路径， 通过替换不同图案的声 子晶体板可更改微纳颗粒的输运路径， 利用人工周期结构调制声场， 可在微腔 内， 实现大量微纳颗粒沿任意设计路径的并行输运。 在本申请的具体实施方式 中， 信号发生器通过发射不同参数的激励信号， 实现了对微纳颗粒输运和捕获 模式的快速灵活切换。 在微流体分析过程中， 微纳颗粒流经样本制备、 反应、 检测等单元模块吋可通过改变信号发生器发射参数的方式， 将微纳颗粒捕获在 流经的单元模块， 以便对微纳颗粒进行分析检测。 当分析检测完成后， 可将发 射参数从捕获模式参数切换至输运模式参数， 将微纳颗粒输运至下一分析检测 单元。 在本申请的具体实施方式中， 人工周期结构用于调制声场产生声辐射力 以排列、 捕获细胞形成细胞阵列， 以及产生微涡旋阵列对细胞阵列产生可定量 调控的剪切力。 由于与传统超声联合微泡的递送技术相比， 本申请不需要微泡 的介入， 因此本申请可对多种类、 大规模细胞提供可重复、 有统计学意义、 且 能精确定量的可定量调控的声孔效应。
[0089] 以上内容是结合具体的实施方式对本发明所作的进一步详细说明， 不能认定本 发明的具体实施只局限于这些说明。 对于本发明所属技术领域的普通技术人员 来说， 在不脱离本发明构思的前提下， 还可以做出若干简单推演或替换。 技术问题 问题的解决方案 发明的有益效果

Claims

权利要求书
一种基于人工结构声场的微流体系统， 包括微腔和超声波发射装置， 所述微腔用于盛放含有微粒的溶液， 所述超声波发射装置用于发射超 声波， 其特征在于， 还包括置于所述微腔内的声子晶体板， 所述声子 晶体板为人工周期结构， 用于调制声场对所述微粒进行操控。
如权利要求 1所述的系统， 其特征在于， 所述声子晶体板包括基板和 设置在所述基板下表面的多个凸条， 所述凸条平行设置且间隔相等。 如权利要求 2所述的系统， 其特征在于， 所述凸条为折线、 曲线形或 封闭的环形。
如权利要求 3所述的系统， 其特征在于， 所述凸条的横截面包括长方 形、 三角形、 多边形或半圆形。
如权利要求 4所述的系统， 其特征在于， 所述凸条的横截面为长方形 ， 所述长方形的中心线之间的间距为 d， 所述基板的厚度为 h2， 贝 1J0.1 5≤h2/d≤0.25。
如权利要求 5所述的系统， 其特征在于， 所述长方形的宽、 所述长方 形的高及所述基板的厚度相等。
如权利要求 1至 6中任一项所述的系统， 其特征在于， 所述超声波发射 装置包括信号发生器、 功率放大器、 超声换能器和超声电子控制装置 ， 所述信号发生器用于产生发射信号， 所述功率放大器用于将所述发 射信号放大， 所述超声换能器用于将放大后的发射信号转换为超声波 ， 所述超声电子控制装置用于设置所述信号发生器和所述功率放大器 的参数， 以及用于设置所述超声换能器的幵关。
如权利要求 1至 6中任一项所述的系统， 其特征在于， 所述微腔包括上 底、 下底和侧壁， 所述侧壁围出内腔且两端设有幵口， 所述上底和所 述下底分别设置在所述幵口处。
如权利要求 8所述的系统， 其特征在于， 所述上底和所述下底由石英 玻璃制成， 所述侧壁由 PDMS或者玻璃制成。
一种基于人工结构声场的微流体操控微粒的方法， 其特征在于， 包 括：
将声子晶体板置于微腔内， 所述声子晶体板为人工周期结构； 加入含有微粒的溶液；
超声波发射装置发射超声波， 通过所述声子晶体板对声场进行调制； 所述声子晶体板基于所述调制对所述微粒进行操控。
[权利要求 11] 如权利要求 10所述的方法， 其特征在于， 所述声子晶体板基于所述 调制对所述微粒进行操控， 包括：
所述声子晶体板基于所述调制声场诱发的声辐射力对微纳颗粒进行输 运；
所述声子晶体板基于所述调制声场产生的声辐射力捕获、 排列细胞形 成细胞阵列， 以及产生微涡旋阵列对细胞阵列产生剪切力， 诱发细胞 裂解或者可调控声致穿孔效应。
[权利要求 12] 如权利要求 11所述的方法， 其特征在于， 所述声子晶体板基于所述 调制对所述微粒进行操控， 还包括：
通过设置所述声子晶体板上的凸条排列的图案调整所述微纳颗粒的输 运路径；
通过设置所述声子晶体板的基板的厚度、 所述凸条的间隔调控所述微 涡旋阵列的尺寸。
[权利要求 13] 如权利要求 10所述的方法， 其特征在于， 所述超声波发射装置发射 超声波， 通过所述声子晶体板对声场进行调制， 具体包括： 所述超声波发射装置用于发射脉冲波吋， 信号的中心频率为所述声子 晶体板的共振频率， 带宽 15<¾〜100<¾， 通过改变电压的方式实现对 输运速度的调控；
所述超声波发射装置用于发射连续波吋， 通过将驱动频率设为所述声 子晶体板的共振频率， 从而实现对微纳颗粒进行捕获。
[权利要求 14] 如权利要求 10所述的方法， 其特征在于， 所述超声波发射装置发射 超声波， 通过所述声子晶体板对声场进行调制， 还包括：
所述超声波发射装置通过调节参数对所述微涡旋阵列进行定量调控， 从而对细胞所受剪切力大小进行定量调控， 以控制细胞幵孔程度， 实 现细胞裂解或者可调控声致穿孔效应， 所述参数包括激励电压、 驱动 频率、 脉冲重复频率和脉冲持续吋间。
[权利要求 15] 如权利要求 14所述的方法， 其特征在于， 所述超声波发射装置发射 超声波， 通过所述声子晶体板对声场进行调制， 还包括：
所述超声波发射装置用于发射正弦脉冲信号吋， 信号的中心频率为所 述声子晶体板的共振频率， 通过调节所述参数， 对所述声子晶体板诱 发的微涡旋进行定量调控， 从而对细胞所受剪切力大小进行定量调控 ， 以控制细胞幵孔程度；
所述超声波发射装置用于发射连续波吋， 驱动频率设为所述声子晶体 板的共振频率， 通过调节激励电压的方式， 对人工结构声场诱发的微 涡旋进行定量调控， 从而对细胞所受剪切力大小进行定量调控， 以控 制细胞幵孔程度。
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