CN117019402A - Screening device for submicron and nanometer-scale particulate matters in solution - Google Patents
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Abstract
The application relates to a screening device for submicron and nanometer-scale particulate matters in solution, which comprises a fluid channel, a fluid flow channel and a fluid flow channel, wherein the fluid channel is provided with an inlet and an outlet; one or more ultra-high frequency bulk acoustic wave resonators disposed on one wall of the fluid channel for emitting bulk acoustic waves that propagate toward the fluid channel, the bulk acoustic waves creating an acoustic fluid channel in a liquid such that particulates in a solution enter the acoustic fluid channel, wherein the solution contains submicron and nanoscale target particulates, the solution entering the fluid channel through the inlet; and the electrode device is arranged on the fluid channel and is used for generating an electric field, screening out target submicron and nanometer-scale particles from the solution entering the acoustic fluid channel under the action of the electric field, and leaving the fluid channel through the outlet. The screening device can capture and screen submicron and nanometer target objects.
Description
Technical Field
The application relates to the field of cell research methodologies and medical instruments, in particular to a screening device for submicron and nanometer-scale particles in a solution.
Background
The particles (Submicron particles) of submicron and nanometer particle level are tiny particles with the size of 0.1-1 micron, and comprise exosomes (exosomes), microorganisms (bacterial viruses and the like), organelles and the like, and have certain influence on human bodies and the environment. Exosomes are extracellular vesicles, typically between 30-150nm in diameter. They are incorporated into the cell membrane by intracellular membrane vesicles and then released outside the cell, with important intercellular communication and signaling functions. A Virus (Virus) is a microorganism, typically between 20-300 nanometers in size, consisting of nucleic acids and proteins, that need to be parasitized for replication in a host cell. They can infect bacteria, animals and plants, and various organisms such as humans. Bacteria (Bacteria) are a kind of prokaryote, and are usually between 0.5 and 5 microns in size, have a single cell structure, have cell walls and cell membranes, can autonomously reproduce and grow, and can also be parasitic in other organisms. Organelles (organelles) exist in the cell in a microstructure with a certain function and shape, and are the main performers of the cells to perform various functions normally.
When the body fluid of the organism contains particles with different physicochemical properties, the active control mode can be adopted to capture, separate and gather the corresponding particles, and the active control mode comprises acoustic forceps, electric forceps, optical forceps and the like. The principle of the active method is mainly to realize uneven Gradient force (Gradient force) through an external force field and push a target to a force field potential well, so as to realize capturing, separating and gathering of particles. Taking 2018 physical Nobel prize optical tweezers as an example, the method is realized by generating a force field matched with a target separation object through a focused laser beam. Based on this principle, scientists have developed electric tweezers of focusing electric field, acoustic tweezers of focusing sound wave, etc
Among these active steering techniques, the focused sound field based acoustic tweezer technique has the main advantages of low dependence on solvents and low requirements on the operating targets. However, conventional acoustic tweezers based on focused acoustic radiation forces tend to produce forces on the order of rawhide (pN) only, and the acoustic radiation forces decay very rapidly as the target size decreases. Although suitable for operation on a cellular scale, capture of target objects on submicron and nanoscale cannot be achieved, and the above biological particulate sizes are all around submicron and nanoscale.
In addition, studies have shown that differences in the charge carried by submicron and nanoscale particulate matter itself can lead to differences in their biological functions. An intensive study of the different sizes, different electrical subtypes in the body fluid of an organism will reveal the differences in biological function of the target particle subtypes in one step. However, there is no mature technical means for accurately screening submicron and nanoscale particles with different sizes and different electrical properties.
Disclosure of Invention
In view of the above problems in the prior art, the application provides a screening device for submicron and nanometer-scale particles in a solution, which can capture and screen submicron and nanometer-scale target objects.
To achieve the above object, a first aspect of the present application provides a screening device for submicron and nanoscale particulate in solution, comprising:
a fluid channel having an inlet and an outlet;
one or more ultra-high frequency bulk acoustic wave resonators disposed on one wall of the fluid channel for emitting bulk acoustic waves that propagate toward the fluid channel, the bulk acoustic waves creating an acoustic fluid channel in a liquid such that particulates in a solution enter the acoustic fluid channel, wherein the solution contains target submicron and nanoscale particulates, the solution entering the fluid channel through the inlet;
And the electrode device is arranged on the fluid channel and is used for generating an electric field, screening out target submicron and nanometer-scale particles from the particles entering the acoustic fluid channel under the action of the electric field, and leaving the fluid channel through the outlet.
By the above, the application adopts the ultra-high frequency bulk acoustic wave resonator which can emit ultra-high frequency bulk acoustic wave, and can effectively control the moving position and direction of submicron and nanometer scale particles in solution through the action of acoustic radiation force and acoustic fluid force.
To achieve the above object, the second aspect of the present application provides a method for sieving submicron and nanoscale particles in solution, comprising:
a solution comprising target submicron and nanoscale particulate enters a fluid channel through an inlet of the fluid channel;
One or more ultra-high frequency bulk acoustic wave resonators arranged on one wall of the fluid channel emit bulk acoustic waves which are transmitted to the opposite side wall of the fluid channel, and an acoustic fluid channel is generated in liquid according to the bulk acoustic waves, so that particles in solution enter the acoustic fluid channel, wherein the solution contains target submicron and nanoscale particles;
the electrode device arranged on the fluid channel generates an electric field, and under the action of the electric field, the target submicron and nanometer-scale particles are screened out from the particles entering the acoustic fluid channel and leave the fluid channel through the outlet of the fluid channel.
Drawings
FIG. 1 is a top view of a screening apparatus for submicron and nanoscale particulate in a solution of the present application;
FIG. 2 is a side view of a screening apparatus for submicron and nanoscale particulate in a solution of the present application;
FIG. 3 is a schematic bottom view of a screening apparatus for submicron and nanoscale particulate in a solution of the present application;
FIG. 4 is a schematic effect diagram of a screening device for submicron and nanoscale particulate in a solution of the present application;
FIG. 5 is a schematic illustration of a simulation of the coupling of a super sonic wave to a fluid: (a) acoustic radiation force direction and acoustic pressure distribution; (b) acoustic fluid vortex field flow velocity and size distribution;
FIG. 6 is a schematic diagram of the structure of an ultra-high frequency bulk acoustic wave resonator according to the present application;
FIG. 7 is a schematic diagram of the acoustic action region and vortex channel of an ultra-high frequency bulk acoustic resonator according to the present application;
FIG. 8 is a schematic diagram showing the synthesis of the movement velocity of different surface charge particles in an electric field;
fig. 9 is a schematic view showing a first mounting position and a structure of an electrode chip and an ultra-high frequency bulk acoustic wave resonator according to the present application;
fig. 10 is a schematic view showing a second mounting position and a structure of an electrode chip and an ultra-high frequency bulk acoustic wave resonator according to the present application;
fig. 11 is a schematic view showing a third mounting position and a structure of an electrode chip and an ultra-high frequency bulk acoustic wave resonator according to the present application;
fig. 12 is a schematic view showing a fourth mounting position and a structure of an electrode chip and an ultra-high frequency bulk acoustic wave resonator according to the present application;
fig. 13 is a schematic view showing a fifth mounting position and a structure of an electrode chip and an ultra-high frequency bulk acoustic wave resonator according to the present application;
fig. 14 is a schematic view showing a sixth mounting position and structure of an electrode chip and an ultra-high frequency bulk acoustic wave resonator according to the present application;
fig. 15 is a schematic view showing a seventh mounting position and a structure of an electrode chip and an ultra-high frequency bulk acoustic wave resonator according to the present application;
it should be understood that in the foregoing structural schematic diagrams, the sizes and forms of the respective block diagrams are for reference only and should not constitute an exclusive interpretation of the embodiments of the present application. The relative positions and inclusion relationships between the blocks presented by the structural diagrams are merely illustrative of structural relationships between the blocks, and are not limiting of the physical connection of embodiments of the present application.
Detailed Description
The technical scheme provided by the application is further described below by referring to the accompanying drawings and examples. It should be understood that the system structure and the service scenario provided in the embodiments of the present application are mainly for illustrating possible implementation manners of the technical solutions of the present application, and should not be interpreted as the only limitation to the technical solutions of the present application. As one of ordinary skill in the art can know, with the evolution of the system structure and the appearance of new service scenarios, the technical scheme provided by the application is applicable to similar technical problems.
It should be understood that embodiments of the present application provide a solution screening scheme for submicron and nanoscale particulate, including a solution screening apparatus and method for submicron and nanoscale particulate. Because the principles of solving the problems in these technical solutions are the same or similar, in the following description of the specific embodiments, some repetition is not described in detail, but it should be considered that these specific embodiments have mutual references and can be combined with each other.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. If there is a discrepancy, the meaning described in the present specification or the meaning obtained from the content described in the present specification is used. In addition, the terminology used herein is for the purpose of describing embodiments of the application only and is not intended to be limiting of the application. In order to accurately describe the technical content of the present application and to accurately understand the present application, the following explanation or definition is given for terms used in the present specification before explaining the specific embodiments.
Aiming at capturing and screening submicron and nanometer scale target objects, the application provides a screening device for submicron and nanometer scale particles in a solution, as shown in fig. 1 to 3, the screening device for submicron and nanometer scale particles in the solution comprises:
a fluid channel 1 having an inlet 11 and an outlet 12;
one or more ultra-high frequency bulk acoustic wave resonators 2 disposed on one wall of the fluid channel 1 for emitting bulk acoustic waves that are transmitted to the opposite side wall of the fluid channel 1, generating an acoustic fluid channel in the liquid according to the bulk acoustic waves, such that particles in the solution enter the acoustic fluid channel, wherein the solution contains target submicron and nanoscale particles, and the solution enters the fluid channel 1 through the inlet 11;
the electrode device is arranged on the fluid channel 1 and is used for generating an electric field, and under the action of the electric field, target submicron and nanometer-scale particles are screened out from particles entering the acoustic fluid channel and leave the fluid channel 1 through the outlet 12.
Aiming at the problems that the acoustic tweezers based on the focused acoustic radiation force can only generate the force of the order of magnitude of Bulleyan (pN), the attenuation of the acoustic radiation force along with the decrease of the target size is extremely fast, the acoustic tweezers are suitable for the operation of cell scale, but the capture and screening of submicron and nanoscale target objects cannot be realized, and the accurate screening technical means for different submicron and nanoscale particle subtypes by the existing and mature technical means are not available, the application provides a screening device for submicron and nanoscale particle in solution.
In some embodiments, the fluidic channel may be made of Polydimethylsiloxane (PDMS) prepared by soft lithography, and thus the fluidic channel may be referred to as a PDMS fluidic channel. The fluid passageway is generally closed except for openings for fluid ingress and egress. The cross-section of the fluid channel typically has a size of 0.1-500 μm, which may be of various shapes including oval, rectangular, square, triangular, circular, etc. The fluid channels may be fabricated using a variety of known microfabrication techniques, including but not limited to silica, silicon, quartz, glass, or polymeric materials (e.g., PDMS, plastic, etc.). The fluid channels may be coated with a coating. The coating may change the characteristics of the channels and may be patterned. For example, the coating may be hydrophilic, hydrophobic, magnetic, conductive, or biofunctionalized.
Wherein the height of the PDMS channel is about 20-200. Mu.m, preferably about 10-40. Mu.m, more preferably about 20-40. Mu.m, for example about 25-35. Mu.m.
In some embodiments, the fluid channel may be a single channel, or a plurality of channels arranged in parallel or otherwise in common, having common outputs and inputs, wherein the outflow and inflow of fluid and the flow rate of fluid to each channel may be controlled in common or independently as desired.
The fluid channel can be divided into different areas, and the ultra-high frequency bulk acoustic wave resonator 2 for separating different particles is arranged in the different areas. For example, the uhf resonators separating different particles may have differently shaped acoustic wave generating regions, or apply different powers of bulk acoustic waves, or have different flow rates, or a combination thereof.
In some embodiments, as shown in fig. 1-4, the inlet 11 may include two: the sample inlet and the buffer liquid inlet are communicated with each other in a crossing way. Based on the sheath flow effect, an auxiliary solution (i.e., buffer solution) can be used to control the flow direction and extent of the sample liquid in the fluid channel such that the sample liquid flows sufficiently through the bulk acoustic wave generating region of the ultra-high frequency bulk acoustic wave resonator. The direction and extent of flow of the sample liquid in the fluid channel can be controlled, for example, by controlling the flow rate and inflow area of the auxiliary solution. The inlet may also include a plurality of buffer inlets and a sample inlet. The number of the inlets is set according to actual needs.
In some embodiments, as shown in fig. 1-4, the outlet 12 may include a plurality, and may include a target particle outlet and an impurity particle outlet (which may be a plurality). And a liquid outlet which is used for sieving out target particles and removing residual liquid after impurity particles are removed. The number of the outlets is set according to actual needs.
In some embodiments, the screening device for submicron and nanoscale particulate in solution may further comprise liquid injection and flow rate adjustment means (not shown) for controlling the liquid injection and controlling the flow rate of the liquid. Wherein the liquid may be a liquid containing a sample. For example, the sample is a liquid containing submicron and nanoscale particulate matter (e.g., exosomes, viruses, microorganisms, etc.) to be captured. The flow rate of the injected liquid may be controlled by an external pressure source, an internal pressure source, electro-dynamics or magnetic field dynamics. The external and internal pressure sources may be pumps, such as peristaltic, syringe, or pneumatic pumps, among others. In this embodiment, a syringe pump which is finely tuned by a computer is used to control the flow rate of the liquid injection. Wherein the flow rate range of the liquid is preferably set according to the actual liquid.
In some embodiments, as shown in fig. 1 to 3, one or more uhf bulk acoustic wave resonators 2 are provided on one wall of the fluid channel (typically at the bottom of the fluid channel). The ultra-high frequency bulk acoustic wave resonator 2 is a bulk acoustic wave generating member that generates bulk acoustic waves having a frequency of about 0.5 GHz to 50GHz at the opposite side wall (generally referred to as the top of the fluid channel) of the fluid channel 1, generates a vortex channel (i.e., an acoustic fluid channel) in a solution defined by the boundary of the bulk acoustic wave generating region of the ultra-high frequency bulk acoustic wave resonator 2, as shown in fig. 4, and under conditions of suitable flow rate and bulk acoustic wave power, submicron and nanoscale particulate matters in the solution enter the vortex channel and move along the vortex channel, and at a certain position(s) of the vortex channel, the submicron and nanoscale particulate matters in the solution leave the bulk acoustic wave action region and move downstream, i.e., are released, i.e., leave the vortex channel at a set position (i.e., release point). Since one of the important factors in the separation of submicron and nanoscale particulate matter in solution from the vortex channels is the influence of laminar flow along the direction of the fluid channels, the release point is typically located in the most downstream region of the vortex channels.
The plurality of ultra-high frequency bulk acoustic wave resonators 2 may be identical, set to the same frequency, and generate the same bulk acoustic wave action region. The plurality of ultra-high frequency bulk acoustic wave resonators 2 may be different in frequency, and different bulk acoustic wave action regions may be generated.
The principle of the ultra-high frequency bulk acoustic wave resonator 2 in combination with a fluid channel to generate an acoustic fluid channel is as follows: the ultra-ultrasonic wave propagates in the liquid in the form of pressure waves, i.e. in the form of regular vibration variations of density and pressure, and generates both acoustic pressure effects and acoustic fluid effects in the liquid. The ultra-sonic wave can accomplish energy conversion within a short distance (within 20 μm) from the device surface due to its ultra-super-frequency characteristics as shown in fig. 5 (a), and produce more than 10 10 m/s 2 Is a fluid acceleration of (a). When fluid is ejected upward from the device surface, a stable high-speed rotating micro-scale acoustic streaming vortex is formed due to boundary restriction as shown in fig. 5 (b).
When the biological particles are in the fluid field, they are subjected to multiple forces, including primarily acoustic radiation forces, fluid drag forces, and other forces that cancel each other out to a negligible extent. These two forces are critical for the manipulation of particles by the acoustic fluid channel. From the previous analysis, it is known that sound in a fluid field has a primary effect-sound pressure effect, and that secondary effect-sound fluid effect is induced in the fluid due to sound pressure. The sound wave in the fluid is coupled and propagated with the density and pressure in the fluid in a quasi-equilibrium state. All three can be expressed by the following frequency series form equation:
Wherein the density ρ, the velocity v, the pressure p can be substituted for the variable a therein. The sound wave is formed by three parts in the fluid, A 0 Indicated are directional components in the fluid. A is that 1 Is the first order effect of the sound wave, and is reflected in the periodic distribution of the speed, pressure and density generated along with the sound wave in space. The remainder is a smaller order component and can be ignored. A is that 0 The term corresponds to the acoustic fluid effect and A 1 The term corresponds to the acoustic radiation force effect. The acoustic radiation force is generated due to the pressure generated by the acoustic pressure field on the particles, and the expression is:
wherein the method comprises the steps ofThe acoustic contrast factor is mainly represented by the contrast and difference between the particles and the solution containing the particles, and the larger the difference is, the larger the acoustic radiation force to which the particles are subjected is. ρ p ，ρ f ，β P And beta f The density and compressibility factor, respectively, of the particulate liquid. V (V) p Is the particle volume, p, in the fluid 0 Is the sound pressure, x is the distance between the particle and the sound pressure node, and λ is the sound wave wavelength.
Another part of the acoustic drag force acting on the particles is typically due to the directional effect created by the attenuation of the acoustic wave in the fluid-the acoustic fluid effect. The directional movement of the liquid may create drag forces on the particles therein. The solution formula of the acoustic drag force is as follows:
F drag ＝6πμa(b-v p )
Where v is the velocity of the fluid, v p μ represents the viscosity of the fluid, and a represents the radius of the particle. The acoustic drag force describes the force that when a particle is dragged by a fluid, due to the non-uniform flow rates of the particle and the fluid, will cause the fluid to generate a force on the particle that causes it to follow, such that the particle follows the movement of the fluid.
When two forces are simultaneously applied to the nanoparticles, they are focused through a helical trajectory to the center of the vortex channel. Due to the attenuation of the propagating acoustic wave, the acoustic radiation force will be attenuated as the particles move away from the device. The equilibrium position is where the sound pressure is insufficient to drive the movement of the nanoparticles, at the boundary of the virtual channel.
In some embodiments, as shown in fig. 6, the uhf bulk acoustic wave resonator 2 includes an acoustic wave reflecting layer 206, a bottom electrode layer 205, a piezoelectric layer 204, and a top electrode layer 203, which are sequentially disposed from bottom to top. The overlapping area of the bottom electrode layer, the piezoelectric layer, the top electrode layer and the acoustic wave reflecting layer forms a bulk acoustic wave generating area. The top surface of the ultra-high frequency bulk acoustic wave resonator is arranged on the wall of the fluid channel, and bulk acoustic waves with the propagation direction perpendicular to the wall are generated to the opposite wall; generally, the region formed by the top surface of the ultra-high frequency bulk acoustic wave resonator is a bulk acoustic wave generating region, and is also referred to as a bulk acoustic wave region or a bulk acoustic wave action region in the present application. In one aspect of the application, the area of the acoustic action region is about 500-200000 μm2, preferably about 5000-50000 μm2, most preferably about 10000-25000 μm2. The side length of the bulk acoustic wave generating region is about 30 to 500 μm, preferably about 40 to 300 μm, and most preferably about 50 to 200 μm.
In some embodiments, the shape of the bulk acoustic wave region of action includes at least, but is not limited to, one of: a circle, an ellipse, a semicircle, a parabola, a polygon with an acute or obtuse vertex, a polygon with an arc substituted for the vertex, a polygon with an acute, semicircle or parabola vertex in any combination, or a repeated array or circular array of the same shape. The present application provides an acoustic action region of the shape described above, but any other acoustic action region shape is within the scope of the present application. In the present application, the shape of the bulk acoustic wave generating region of a preferred ultra-high frequency bulk acoustic wave resonator 2 is spindle-shaped (as shown in fig. 1).
In some embodiments, the boundary lines of the bulk acoustic wave generating region of the ultra-high frequency bulk acoustic wave resonator 2 (i.e., the shape of the corresponding vortex channel) are configured to accommodate sub-micron and nano-scale particulate matter in solution moving along the vortex channel to the release point in the vortex channel. Thus, submicron and nanometer particles in the solution can be prevented from being separated from the vortex channel instead of being separated from the vortex channel from the release point according to the setting.
In some embodiments, submicron and nanoscale particulate in solution may enter the vortex channel, remain in the vortex channel and move along the vortex channel to the release point by adjusting the shape of the boundary lines of the bulk acoustic wave generating region of the ultra-high frequency bulk acoustic wave resonator 2, the angle of the boundary lines to the fluid channel, and the shape and location of the bulk acoustic wave action region. The smaller the angle between the boundary line of the bulk acoustic wave generating region and the fluid channel is, the easier the submicron and nanometer-scale particles in the solution are kept moving in the vortex channel, namely the submicron and nanometer-scale particles in the solution separated from the vortex channel are reduced, and the separation efficiency is improved.
In some embodiments, the bulk acoustic wave action region of the ultra-high frequency bulk acoustic wave resonator has a focusing region and a sieving region. The focusing region is located upstream of the bulk acoustic wave action region (i.e., near the sample inflow direction, farther from the release point), and the sieving region is located downstream of the bulk acoustic wave action region (i.e., near the sample outflow direction, nearer to the release point, or including the release point). Wherein the arrangement of the bulk acoustic action region of the focal zone relative to the arrangement of the sieving zone is more suitable for maintaining submicron and nanoscale particulate matter in solution moving in the vortex channel: submicron and nanometer scale particles in the solution in the vortex channel of the focusing area move along the same or similar direction as the laminar flow direction, the vortex drag force is relatively small, and the submicron and nanometer scale particles in the solution are easier to enter and remain in the vortex channel; in the downstream sieving zone, cells focused to the vortex center can be moved in the vortex channel more stably than unfocused submicron and nanoscale particulate. The angle between the boundary line of the bulk acoustic wave action region of the focusing region and the fluid channel is smaller than the angle between the boundary line of the bulk acoustic wave action region of the screening region and the fluid channel. For example, the boundary of the bulk acoustic wave action region of the focusing region is basically consistent with the direction of the fluid channel (for example, the angle is smaller than 10 °), the vortex drag force suffered by the submicron and nanometer scale particles in the vortex channel of the region basically does not change the motion state of the submicron and nanometer scale particles along the laminar flow direction, and only the submicron and nanometer scale particles transversely migrate to the vortex center, so as to realize focusing on the submicron and nanometer scale particles; the boundary of the bulk acoustic wave action area of the screening area is larger in angle with the fluid channel, the moving direction of submicron and nano-scale particles is guided to deviate from the direction of the fluid channel and is transferred to a designated release point, and the submicron and nano-scale particles focused on the center of vortex can be moved in the vortex channel more stably than the non-focused submicron and nano-scale particles in the screening area. The flow velocity of the fluid flowing through the bulk acoustic wave action region of the focusing region is controlled to be less than the flow velocity of the fluid flowing through the bulk acoustic wave action region of the sieving region.
In some embodiments, the ultra-high frequency bulk acoustic wave generated by the ultra-high frequency bulk acoustic wave resonator generates substantially no standing wave in the solution. As shown in fig. 7, the uhf bulk acoustic wave resonator 2 emits bulk acoustic waves that propagate toward the opposite side wall of the fluid channel (e.g., the top of the flow channel), and the acoustic waves attenuate to a volumetric force generated in the fluid such that acoustic jet 500 appears in the solution flowing therethrough, resulting in localized, three-dimensional vortices 501 of the liquid in the fluid channel, with the continuous vortices induced by the uhf bulk acoustic waves forming an acoustic fluid vortex channel. Since the vortex is generated by the volumetric force induced by the attenuation of the acoustic wave, the central axis of the vortex is above the bulk acoustic wave action boundary, and thus the shape of the vortex channel is substantially the same as the shape of the bulk acoustic wave action region, above the bulk acoustic wave action region boundary. The acoustic fluid vortices are caused by the non-linearity of the propagation of sound waves in the liquid medium. The intensity of the amplitude of the sound waves directly determines the intensity of the sound fluid vortex. The amplitude of the ultra-sonic device, namely the amplitude of sound waves, can be regulated and controlled by adjusting the applied power, so that the flow rate of the sound fluid vortex is controlled. The forces experienced by the particles in the vortex (including larger size particles 600, medium size particles 601, smaller size particles 602) include the fluid drag force (Stokes drag force) created by the vortex, the inertial drag force (inertial lift force) created by the laminar flow, and the acoustic radiation force (acoustic radiation force) caused by acoustic wave attenuation. Since the magnitude of the fluid drag force is in a positive relationship with the particle, e.g., particle diameter, and the magnitude of the acoustic radiation force is in a positive relationship with the square of the particle size. As the particles grow, the forces experienced will transition from being dominated by fluid drag to being dominated by acoustic radiation forces that push the particles toward the center of the vortex. Larger particles are subjected to greater acoustic radiation forces to move to the vortex center; while the smaller particles are rotated peripherally by the swirling drag force and further move downstream of the bulk acoustic wave action region by the lateral drag force generated by the laminar flow.
In some embodiments, the ultra-high frequency bulk acoustic wave resonator may be a thin film bulk acoustic wave resonator or a solid state assembly resonator, such as a thickness extensional vibration mode acoustic wave resonator. The frequency of the thin film bulk acoustic resonator is primarily determined by the thickness and material of the piezoelectric layer. The thickness range of the piezoelectric layer of the film bulk acoustic resonator adopted by the application is 1 nm-2 um. The frequency of the ultra-high frequency bulk acoustic wave resonator of the present application is between about 0.5 and 50GHz, preferably between about 1 and 10GHz.
In some embodiments, the plurality of ultra-high frequency bulk acoustic wave resonators may be aligned in a direction that coincides with the direction of fluid motion.
In some embodiments, the ultra-high frequency bulk acoustic resonator is adhesively integrated with the PDMS runner chip. The ultra-high frequency bulk acoustic wave resonator may be disposed at an intermediate position of the fluid channel.
In some embodiments, the screening device for submicron and nanoscale particulate in solution may also include bulk acoustic wave driving and power conditioning devices (not shown). The bulk acoustic wave driving and power adjusting device is connected with the ultra-high frequency bulk acoustic wave resonator 2 and is used for driving the ultra-high frequency bulk acoustic wave resonator 2 to generate bulk acoustic waves and adjusting the power of the bulk acoustic waves generated by the ultra-high frequency bulk acoustic wave resonator 2, and particles entering the vortex channel are adjusted by adjusting the power of the bulk acoustic waves. Particles that do not enter the vortex channel or particles that enter the vortex channel but leave the vortex channel without reaching the designated release point pass through the bulk acoustic wave region and exit in the direction of the sample entering the fluid channel.
The pulsed voltage signal driving the resonator may be driven with pulse width modulation, which may produce any desired waveform, such as a sine wave, square wave, saw tooth wave, or triangular wave. The pulsed voltage signal may also have amplitude or frequency modulation start/stop capability to start or cancel bulk acoustic waves.
In some embodiments, as shown in fig. 1 to 3, the electrode device includes an electrode chip 3 and an electrode driving device (not shown in the drawings); the electrode chip is arranged on the fluid channel 1; electrode driving means (a signal generator capable of applying voltage and frequency to generate uniform and nonuniform electric fields in the chip) is connected to the electrode chip 3 for driving the electrode chip to generate electric fields.
The electrophoresis principle of the application is as follows: laminar flow in the horizontal direction at V F Simultaneously, an electric field is applied in the vertical direction to induce an electrophoretic force (Dielectrophoretic force, DEP) such that target particles and the like in the fluid are moved by the electric field. And velocity V in the vertical direction of the particles due to electrophoresis E Can be derived from the following formula.
Wherein Q is the surface charge of the particles, E is an external electric field, mu is the dynamic viscosity of the fluid, and R is the hydrated particle size of the particles.
Under laminar flow conditions, go upV can be obtained E The size of the particles is inversely proportional to the surface charge of the particles, the same size, but the target particles and impurities having different surface charges are subjected to different electrophoretic forces in the fluid, resulting in different vertical movement speeds of the particles to complete the sieving, as shown in fig. 7.
According to the research, through the difference of the particle sizes, acoustic impedances and potentials of the target particles and the impurity particles, the mutual coordination of the acoustic radiation force and the acoustic fluid force is accurately adjusted by combining the device parameters, so that particles with different characteristics enter different acoustic fluid channels, and the electric field is combined, and the accurate screening of the target particles is realized.
In some embodiments, the mounting positions of the electrode chip and the ultra-high frequency bulk acoustic wave resonator are divided into two cases:
first kind: the electrode chip and the ultra-high frequency bulk acoustic wave resonator are arranged at the same position of the fluid channel. Under the condition, three forces act on the particles simultaneously under the combined action of electric field force, acoustic radiation force and acoustic drag force, so that the multi-property multi-channel screening of the particles is completed.
This case in turn includes the following:
(1) The electrode chip is an electrode with a preset shape, the preset shape can be interdigital, saw tooth and the like, the electrode chip and the ultra-high frequency bulk acoustic wave resonator are arranged on the same wall of the fluid channel, and the arrangement position of the electrode chip is the same as that of the ultra-high frequency bulk acoustic wave resonator.
Fig. 9 (a), 9 (b) and 9 (c) represent three-dimensional views, top views and side views of the structures and layouts of the electrode chip and the ultra-high frequency bulk acoustic wave resonator, respectively, which are all disposed on the bottom surface of the fluid channel, and the electrode chip layout is at the position of the ultra-high frequency bulk acoustic wave resonator. It can be seen that the electrodes arranged in the region of the ultrasonic resonator are such that the particles are subjected to both the effects of the acoustic fluid and the electric field, under which effect the target particles and the impurity particles fall off in different regions of the acoustic fluid channel and are separated by different flow channel outlets, respectively.
(2) The electrode chip is an electrode with a preset shape, the preset shape can be in the shape of an interdigital, a sawtooth and the like, the electrode chip is arranged on the opposite side walls of the fluid channel, and the arrangement position of the electrode chip is opposite to the arrangement position of the ultra-high frequency bulk acoustic wave resonator.
Fig. 10 (a), 10 (b) and 10 (c) represent three-dimensional, top and side views of the structure and layout of an electrode chip and an ultra-high frequency bulk acoustic wave resonator, respectively, the ultra-high frequency bulk acoustic wave resonator being disposed on the bottom surface of the fluid channel, and the electrode chip being disposed on the top surface (opposite side of the bottom surface) of the fluid channel, the position of the electrode chip and the position of the ultra-high frequency bulk acoustic wave resonator being opposite on the fluid channel. The electrodes arranged in opposite regions of the ultrasonic resonator are used for enabling particles to simultaneously receive the effects of acoustic fluid and electric field, and under the effects, target particles and impurity particles fall off in different regions of an acoustic fluid channel and are separated through different flow channel outlets respectively.
In this embodiment, for (1) and (2), since the positive and negative electrodes of the interdigital electrode, the zigzag electrode and the like are on the same plane, the formed electric field intensity is uneven over the whole flow channel height, which is shown by that the electric field intensity is large at the position close to the electrode and small at the position far from the electrode, and the electric field force received by the smaller particles not focused by the acoustic fluid channel 3D may be different due to the difference in the height of the electrodes when passing through the electrophoresis screen.
In this embodiment, since the PDMS runner is fixed, the direction in which the particles are pulled by the liquid is constant, i.e., the liquid flow direction. The direction of DEP force generated by the electrode is respectively towards the positive electrode or the negative electrode according to the dielectric property of the particles, and the angle of the electrode is changed, so that the direction of DEP force is changed, the direction of resultant force formed by the DEP force and the fluid drag force is changed, and the flowing direction of the particles is changed.
For (1) and (2), the electrodes may be oriented, one is that the electrodes are parallel to the flow direction, as shown in fig. 9 and 10, there may be a situation that when particles move above a positive electrode under positive dielectrophoresis force, the particles will no longer move to the sides of the channel, because the particles on both sides of the electrode will move to the electrode under positive dielectrophoresis force, and will flow downstream with the fluid drag force. The other is that the electrodes are angled to the direction of flow, as shown in fig. 11, where fig. 11 (a), 11 (b) and 11 (c) represent three-dimensional, top and side views of the electrode chip and the uhf bulk acoustic resonator structure and layout, respectively, there will be no case where particles flow along the direction of the electrodes, and will move according to the direction of the adjusted resultant force.
(3) The electrode chip comprises a positive electrode patch and a negative electrode patch, the positive electrode patch and the negative electrode patch are respectively arranged on a relative wall of the fluid channel, the relative wall is different from the wall and the opposite side wall of the ultra-high frequency bulk acoustic wave resonator, and the arrangement position of the electrode chip is the same as that of the ultra-high frequency bulk acoustic wave resonator.
As shown in fig. 12, in which fig. 12 (a) and 12 (b) represent three-dimensional views and top views of the structure and layout of an electrode chip and an ultra-high frequency bulk acoustic wave resonator, respectively, the ultra-high frequency bulk acoustic wave resonator is disposed on the bottom surface of a fluid channel, a positive electrode patch and a negative electrode patch are disposed on both side walls of the fluid channel perpendicular to the bottom surface, and the disposition position of the electrode chip is the same as that of the ultra-high frequency bulk acoustic wave resonator. Under this effect, the target particles and the impurity particles fall off in different regions of the acoustic fluid channel and are separated by different flow channel outlets, respectively.
The electrodes manufactured on the two sides of the fluid channel are opposite to each other, so that the formed electric field is more uniform in the height of the fluid channel, and the sorting effect of small particles is improved.
In this embodiment, electrophoresis due to electrodes is generally classified into both electrophoresis and dielectrophoresis. Uniform field electrophoresis generally has the same number of positive and negative electrodes, and can create a uniform electric field in the field as shown in fig. 13, wherein fig. 13 (a) and fig. 13 (b) represent three-dimensional views and top views of the structure and layout of the electrode chip and the uhf bulk acoustic wave resonator, respectively, and the upper and lower electrodes are symmetrically distributed and the number is identical. Dielectrophoresis is generally different in the number of positive and negative electrodes as in fig. 12, and can create an uneven electric field, i.e., dielectrophoresis force, in the field. Therefore, the number of positive electrode patches and the number of negative electrode patches can be the same, or the number of the positive electrode patches and the negative electrode patches can be different, for example, 3 electrodes are set, the middle is the positive electrode, the two sides are the negative electrodes, and the sample is concentrated to the middle electrode under the action of positive dielectrophoresis force. The number of electrodes and the nature of the electric field force are configured according to the desired purpose to be achieved, and electrodes are placed where it is desired to apply an electric field force to the particles to alter the particle flow trajectories.
Second kind: the electrode chip and the ultra-high frequency bulk acoustic wave resonator are arranged at different positions of the fluid channel, the ultra-high frequency bulk acoustic wave resonator is arranged at a position close to the inlet, and the electrode chip is arranged at a position far away from the inlet. The conditions are divided into an upstream one and a downstream one, particles with different sizes and particle diameters can be screened out through electric field screening generated by an upstream ultrahigh frequency bulk acoustic resonator, and particles with different physicochemical properties can be screened out through downstream electrode screening on the basis of sound field screening.
This case in turn includes the following:
(1) The electrode chip is an electrode with a preset shape, the preset shape can be in the shape of an interdigital, a sawtooth and the like, the setting position of the ultra-high frequency bulk acoustic wave resonator is close to the inlet, and the setting position of the electrode chip is far away from the inlet.
As shown in fig. 14, fig. 14 (a) and 14 (b) represent three-dimensional views and top views of the structure and layout of the electrode chip and the uhf bulk acoustic wave resonator, respectively, both of which are disposed on the bottom surface of the fluid channel, and the uhf bulk acoustic wave resonator is disposed at a position close to the inlet and the electrode chip is disposed at a position far from the inlet.
The ultra-high frequency bulk acoustic wave resonator may be disposed on a bottom surface of the fluid channel, and the electrode chip may be disposed on a top surface (opposite side of the bottom surface) of the fluid channel, with the ultra-high frequency bulk acoustic wave resonator disposed at a position close to the inlet and the electrode chip disposed at a position away from the inlet. In this case, particles with different sizes can be screened out by an electric field screening generated by an upstream ultra-high frequency bulk acoustic wave resonator, secondary screening is performed on a downstream electrode in the screened solution, particles with different physicochemical properties are further screened out, and impurity particles and target particles are separated through different outlets.
(2) The electrode chip comprises a positive electrode patch and a negative electrode patch, the positive electrode patch and the negative electrode patch are respectively arranged on a relative wall of the fluid channel, the relative wall is different from a wall and a relative side wall of the ultra-high frequency bulk acoustic wave resonator, the ultra-high frequency bulk acoustic wave resonator is arranged at a position close to the inlet, and the electrode chip is arranged at a position far away from the inlet.
As shown in fig. 15, in which fig. 15 (a) and 15 (b) represent three-dimensional views and top views of the structure and layout of an electrode chip and an ultra-high frequency bulk acoustic wave resonator, respectively, the ultra-high frequency bulk acoustic wave resonator is disposed on the bottom surface of the fluid channel, the positive electrode patch and the negative electrode patch are disposed on both side walls of the fluid channel perpendicular to the bottom surface, and the ultra-high frequency bulk acoustic wave resonator is disposed at a position close to the inlet, and the electrode chip is disposed at a position distant from the inlet. In this case, particles with different sizes can be screened out by an electric field screening generated by an upstream ultra-high frequency bulk acoustic wave resonator, secondary screening is performed on a downstream electrode in the screened solution, particles with different physicochemical properties are further screened out, and impurity particles and target particles are separated through different outlets.
Similarly, the number of positive electrode patches and negative electrode patches may be the same or different, and the number of electrodes may be configured according to the purpose to be achieved, and the electrodes may be placed in a place where an electric field force is required to be applied to the particles to change the flow trajectory of the particles.
The screening device for submicron and nanometer-scale particles in the solution provided by the application can exist alone or can be part of a microfluidic system, for example, can exist in the form of a detachable chip. Microfluidic systems or devices can be used to contain and transport fluid materials such as liquids, with flow channel dimensions on the micrometer, even sub-micrometer and nanometer scale. Typical microfluidic systems and devices generally include structural and functional units of millimeter or smaller dimensions.
In some embodiments, the height of PDMS channels in the screening device for submicron and nanoscale particles in solution according to the present application is preferably 20um for the size and electrical characteristics of the nanoparticles. The ultra-high frequency bulk acoustic wave resonator frequency is preferably 2.01GHz. The control sample input flow rate is preferably 1uL/min and the PBS buffer input flow rate is preferably 2uL/min. The electrodes may be provided with a width of preferably 40 μm, a length of preferably 2.5mm and a thickness of preferably 185nm. The distance between the electrode pairs is preferably set to 4.6 mm.
The present application can be used to obtain or purify desired sub-micrometer and nanometer scale particles in a sample. Can be used for enriching the needed submicron and nanometer scale particles. And also for removing unwanted sub-micron and nano-scale particles from the sample to obtain a purified solution.
Through the cooperation of acoustic fluid and electric field, through the transfer of acoustic fluid, realized the utilization to electric field maximize for the particle is close to the electrode more. The screening can be more rapid than the prior single electric field screening.
The application also provides a screening method of submicron and nanometer-scale particles in the solution, which comprises the following steps:
a solution comprising target submicron and nanoscale particulate enters a fluid channel through an inlet of the fluid channel;
one or more ultra-high frequency bulk acoustic wave resonators arranged on one wall of the fluid channel emit bulk acoustic waves which are transmitted to the opposite side wall of the fluid channel, and an acoustic fluid channel is generated in liquid according to the bulk acoustic waves, so that particles in solution enter the acoustic fluid channel, wherein the solution contains target submicron and nanoscale particles;
the electrode device arranged on the fluid channel generates an electric field, and under the action of the electric field, the target submicron and nanometer-scale particles are screened out from the particles entering the acoustic fluid channel and leave the fluid channel through the outlet of the fluid channel.
In addition, the terms "first, second, third, etc." or module a, module B, module C, etc. in the description and the claims are used merely to distinguish similar objects from a specific ordering of the objects, it being understood that the specific order or sequence may be interchanged if allowed to enable embodiments of the application described herein to be practiced otherwise than as illustrated or described.
In the above description, reference numerals indicating steps such as S110, S120, … …, etc. do not necessarily indicate that the steps are performed in this order, and the order of the steps may be interchanged or performed simultaneously as the case may be.
The term "comprising" as used in the description and claims should not be interpreted as being limited to what is listed thereafter; it does not exclude other elements or steps. Thus, it should be interpreted as specifying the presence of the stated features, integers, steps or components as referred to, but does not preclude the presence or addition of one or more other features, integers, steps or components, or groups thereof. Thus, the expression "a device comprising means a and B" should not be limited to a device consisting of only components a and B.
Reference in the specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the application. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments as would be apparent to one of ordinary skill in the art from this disclosure.
Note that the above is only a preferred embodiment of the present application and the technical principle applied. It will be understood by those skilled in the art that the present application is not limited to the particular embodiments described herein, but is capable of various obvious changes, rearrangements and substitutions as will now become apparent to those skilled in the art without departing from the scope of the application. Therefore, while the application has been described in connection with the above embodiments, the application is not limited to the above embodiments, but may include many other equivalent embodiments without departing from the spirit of the application, which fall within the scope of the application.
Claims (10)
1. A screening device for submicron and nanoscale particulate in a solution, comprising:
a fluid channel having an inlet and an outlet;
one or more ultra-high frequency bulk acoustic wave resonators disposed on one wall of the fluid channel for emitting bulk acoustic waves that propagate toward the fluid channel, the bulk acoustic waves creating an acoustic fluid channel in a liquid such that particulates in a solution enter the acoustic fluid channel, wherein the solution contains target submicron and nanoscale particulates, the solution entering the fluid channel through the inlet;
And the electrode device is arranged on the fluid channel and is used for generating an electric field, screening out target submicron and nanometer-scale particles from the particles entering the acoustic fluid channel under the action of the electric field, and leaving the fluid channel through the outlet.
2. The screening device of claim 1, wherein the electrode device comprises an electrode chip and an electrode drive device;
the electrode chip is arranged in the fluid channel; the electrode driving device is connected with the electrode chip and used for driving the electrode chip to generate an electric field.
3. A screening device according to claim 2, wherein said electrode chip and said ultra-high frequency bulk acoustic resonator are arranged at the same location in said fluid channel.
4. A screening device according to claim 3, wherein said electrode chip is disposed at the same location of said fluid channel as said ultra-high frequency bulk acoustic wave resonator, comprising:
the electrode chip is an electrode with a preset shape, the electrode chip and the ultra-high frequency bulk acoustic wave resonator are arranged on the same wall of the fluid channel, and the arrangement position of the electrode chip is the same as that of the ultra-high frequency bulk acoustic wave resonator.
5. A screening device according to claim 3, wherein said electrode chip is disposed at the same location of said fluid channel as said ultra-high frequency bulk acoustic wave resonator, comprising:
the electrode chip is an electrode with a preset shape, the electrode chip is arranged on the opposite side walls of the fluid channel, and the arrangement position of the electrode chip is opposite to the arrangement position of the ultra-high frequency bulk acoustic wave resonator.
6. A screening device according to claim 3, wherein said electrode chip is disposed at the same location of said fluid channel as said ultra-high frequency bulk acoustic wave resonator, comprising:
the electrode chip comprises a positive electrode patch and a negative electrode patch, the positive electrode patch and the negative electrode patch are respectively arranged on a corresponding wall of the fluid channel, the corresponding wall is different from the wall arranged by the ultra-high frequency bulk acoustic wave resonator and the opposite side wall of the wall, and the arrangement position of the electrode chip is the same as that of the ultra-high frequency bulk acoustic wave resonator.
7. A screening device according to claim 2, wherein said electrode chip is located at a different position in said fluid path than said ultra-high frequency bulk acoustic wave resonator, said ultra-high frequency bulk acoustic wave resonator being located proximate said inlet, said electrode chip being located remotely from said inlet.
8. The screening apparatus of claim 7, wherein said electrode chip is disposed at a different location on said fluid path than said ultra-high frequency bulk acoustic wave resonator, said ultra-high frequency bulk acoustic wave resonator being disposed proximate said inlet, said electrode chip being disposed remotely from said inlet, comprising:
the electrode chip is an electrode with a preset shape, the setting position of the ultra-high frequency bulk acoustic wave resonator is close to the inlet, and the setting position of the electrode chip is far away from the inlet.
9. The screening apparatus of claim 7, wherein said electrode chip is disposed at a different location on said fluid path than said ultra-high frequency bulk acoustic wave resonator, said ultra-high frequency bulk acoustic wave resonator being disposed proximate said inlet, said electrode chip being disposed remotely from said inlet, comprising:
the electrode chip comprises a positive electrode patch and a negative electrode patch, the positive electrode patch and the negative electrode patch are respectively arranged on a relative wall of the fluid channel, the relative wall is different from a wall arranged by the ultra-high frequency bulk acoustic wave resonator and a side wall opposite to the wall, the arrangement position of the ultra-high frequency bulk acoustic wave resonator is close to the inlet, and the arrangement position of the electrode chip is far away from the inlet.
10. A screening device according to claim 4, 5, 6, 8 or 9, wherein the electrode chips are arranged at the same position as the flow direction of the solution in the fluid channel or at an angle to the flow direction of the solution in the fluid channel.
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