CN110333286A - Apparatus and method based on ultrasonic standing wave acoustic field cell integral, flexible modulus - Google Patents
Apparatus and method based on ultrasonic standing wave acoustic field cell integral, flexible modulus Download PDFInfo
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Abstract
The invention discloses the apparatus and method based on ultrasonic standing wave acoustic field cell integral, flexible modulus, the measurement method includes the Y-direction initial position according to each cell in ultrasonic standing wave sound field power start time, ideal movements geometric locus is calculated using the Y-direction motion control equation combination standing-wave sound field field strength parameter of cell, cell actual motion geometric locus and its ideal movements geometric locus are mutually fitted by least square method, the integral, flexible modulus of cell is calculated in conjunction with standing-wave sound field field strength parameter；Due to using microchannel chip, the ultrasonic standing wave sound field generated in its microchannel in conjunction with piezoelectric ceramics moves cell by contactless force, and pass through the motion profile of measurement cell, cell integral, flexible modulus is obtained through conversion, it effectively prevents local deformation amount caused by contact measurement method greatly and measures inaccurate problem, also avoid causing contact damage to cell, the vigor of cell has been effectively ensured, and continuous measurement is realized, detection flux is higher.
Description
Technical Field
The invention relates to the field of a device and a method for measuring the overall elastic modulus of cells, in particular to a device and a method for measuring the overall elastic modulus of cells based on an ultrasonic standing wave sound field.
Background
The elastic modulus of the cell (body) is an important physical quantity for characterizing the cell characteristics as the basic mechanical property of the cell; the cell elastic modulus herein refers to the bulk modulus of elasticity (bulk modulus) of the cell, also called the bulk modulus of cell or the cellular body variation modulus.
Specifically, cells are known to be present in P0Volume under pressure V0If the pressure intensity changes todP(i.e. final state pressure minus initial state pressure P0，dPCan be positive or negative), that is, the pressure of the whole body is exerted on the cell, and the variation of the pressure is called volume stressdPVolume change ofdV(i.e. final volume minus initial volume V)0，dVPositive or negative), volume changedVDivided by the initial volume V0Referred to as volume straindV/V0Volume stressdPDivided by the volume straindV/V0Is the overall compressibility of the cell(formula 1) of (A) and (B),Kthe value is positive, in Pa; modulus of elasticity of cells hereinβIntegral compressibility of the cellsKIn inverse proportion, i.e.(equation 2).
At present, the methods for measuring the elastic modulus of cells mainly consist of two methods:
1) atomic Force Microscope (AFM) -based measurement method: measuring a force-distance curve of interaction between the microspheres on the needle tip and the cells by using an atomic force microscope, and fitting and calculating the elastic modulus of the cells by using a model (such as a Hertz model in common use); however, the AFM measurement method is only suitable for measuring adherent cells, and cannot directly measure suspended cells; meanwhile, the microspheres on the needle point can only act with a part of the area of the cell, so that the measured mechanical property is the local mechanical property of the cell, only one cell can be measured at a time, and the detection flux is low; and, because the cells adhere to the substrate, the microspheres on the needle tip can interact with the substrate, and the depth of the pressing in can directly influence the measurement result; in addition, AFM measurements are cumbersome and expensive.
2) The measuring method based on the micropipette comprises the following steps: the method comprises the following steps of (1) enabling cells to be detected to enter a suction tube by adopting negative pressure, and calculating the elastic modulus of the cells by researching the local deformation of the cells (cell membranes) contacted with the tube wall; however, the pipette wall of the micropipette measurement method must be in contact with the cell and needs to be sufficiently deformed, and the amount of deformation of a partial region of the cell may exceed the elastic deformation range thereof; the deformation of the local cell membrane is obtained by the micropipette measuring method, and the integral elastic modulus of the cell cannot be reflected; and, the negative pressure environment used by the micropipette measurement method is also liable to cause damage to cells; in addition, the micropipette measurement method has low detection flux.
Therefore, there is still a need for improvement and development of the prior art.
Disclosure of Invention
In order to solve the technical problems, the invention provides a device for measuring the overall elastic modulus of cells based on an ultrasonic standing wave sound field, which can avoid contact damage to the cells, effectively ensure the vitality of the cells, realize continuous measurement and have higher detection flux.
Meanwhile, the invention also provides a method for measuring the overall elastic modulus of the cell based on the ultrasonic standing wave sound field, which can effectively avoid the problems of large local deformation and inaccurate measurement caused by a contact measurement method, can realize continuous measurement and has higher detection flux.
The technical scheme of the invention is as follows: a device for measuring the overall elastic modulus of cells based on an ultrasonic standing wave sound field comprises a core part, a micro-channel chip and piezoelectric ceramics; the piezoelectric ceramic is positioned below the micro-flow channel and used for generating an ultrasonic standing wave sound field in the micro-flow channel so that the cells are stressed and converged to move near a standing wave node line when flowing along with the solution in which the cells are positioned; the measuring device also comprises a microscope, a camera and a motion trail analysis system; the camera is used for recording an actual cell motion track image in an observation field of view through a microscope and sending the actual cell motion track image to the motion track analysis system for processing; the motion trail analysis system calculates an ideal motion trail curve by utilizing a Y-direction motion control equation of the cell and combining field intensity parameters of a standing wave sound field according to the Y-direction initial position of each cell at the starting moment of the ultrasonic standing wave sound field force, and extracts an actual motion trail curve of the cell recorded by the camera; the motion trail analysis system is also used for fitting an ideal motion trail curve of the cells with an actual motion trail of the cells by a least square method and calculating the overall elastic modulus of the cells by combining field intensity parameters of a standing wave sound field.
The device for measuring the overall elastic modulus of the cell based on the ultrasonic standing wave sound field is characterized in that the Y-direction motion control equation of the cell is as follows:
(formula 3);
wherein,m cell which is representative of the mass of the cell,dtrepresents a variation in the time of day,dyrepresents cells indtThe variation of the displacement of the time segments in the Y direction,R cell represents the radius of the cell and represents the radius of the cell,nrepresenting the wave number of the ultrasonic standing wave,E ac representing the strength of the standing wave sound field,yrepresents the Y-direction position of the cell at time t,μrepresents the dynamic viscosity of the solution (i.e. the medium),φ cell represents the acoustic scale factor, and:
(equation 4);
wherein,ρ cell which is representative of the density of the cells,ρ buffer representing the density of the solution (i.e. the medium),k cell represents the compression factor of the cell and is,k buffer representing the compressibility of the solution (i.e., the medium).
The device for measuring the overall elastic modulus of the cells based on the ultrasonic standing wave sound field comprises: the liquid inlet end of the microflow channel is provided with a liquid inlet and is connected with the injector through an inlet microflow hose, and the liquid outlet end of the microflow channel is provided with a liquid outlet and is connected with the liquid collecting test tube through an outlet microflow hose.
The device for measuring the overall elastic modulus of the cells based on the ultrasonic standing wave sound field comprises: the microfluidic channel is linear, and the cross section of the microfluidic channel is rectangular or trapezoidal.
The device for measuring the overall elastic modulus of the cells based on the ultrasonic standing wave sound field comprises: the micro-channel chip consists of a channel base and a glass cover plate, wherein the channel base is made of silicon substrate, silicon oxide or hard alloy into a sheet shape, and a groove with a rectangular or trapezoidal cross section is made on the upper surface of the channel base by adopting a plasma etching process and serves as a micro-channel; the glass cover plate is made of heat-resistant glass materials into a sheet shape and is tightly bonded with the runner base in a thermal bonding mode.
The device for measuring the overall elastic modulus of the cells based on the ultrasonic standing wave sound field comprises: the piezoelectric ceramic adopts a piezoelectric ceramic piece which applies voltage in the thickness direction Z and generates vibration in the thickness direction Z, two planes on the piezoelectric ceramic piece, which are vertical to the thickness direction, are taken as electrode surfaces, metal silver coatings are plated on the two planes as driving electrodes, and one of the surfaces is adhered to the bottom surface of the micro-channel chip by glue; the piezoelectric ceramics are electrically connected with the function signal generator, the function signal generator generates sine-changed alternating voltage signals as driving signals, and the piezoelectric ceramics are driven to work by the power amplifying device.
A method for measuring the overall elastic modulus of cells based on an ultrasonic standing wave sound field is implemented on the device for measuring the overall elastic modulus of cells based on the ultrasonic standing wave sound field, and the method comprises the following steps:
B. injecting a solution containing a plurality of cells into the microfluidic channel through an injector, and enabling the solution to flow in a laminar flow mode in the microfluidic channel chip at a constant speed along the X direction by adjusting the injection amount or the injection speed of the injector;
C. when a plurality of cells enter a visual field which can be observed by a microscope and a camera, a function signal generator is utilized to apply a working frequency of 1MHz to the piezoelectric ceramic, and an ultrasonic standing wave sound field is generated at an 1/2 standing wave node line of the microfluidic channel; under the action of the ultrasonic standing wave sound field force, each cell moves towards the midline along with the flow of the fluid and finally converges at the position of 1/2 standing wave node line;
D. the camera records an actual motion track image of each cell moving from an initial position to an 1/2 standing wave node line under the action of an ultrasonic standing wave sound field by using a microscope, and sends the actual motion track image to a motion track analysis system for processing;
E. the motion trail analysis system calculates and draws an ideal motion trail curve of a plurality of cells by utilizing a Y-direction motion control equation of the cells and combining field intensity parameters of a standing wave sound field according to the Y-direction initial position of each cell at the start moment of the ultrasonic standing wave sound field force;
F. the motion trail analysis system extracts actual motion trail curves of a plurality of cells recorded by the camera, fits ideal motion trail curves of the plurality of cells with actual motion trails of the plurality of cells through a least square method, and calculates the overall elastic modulus of the cells by combining field intensity parameters of a standing wave sound field.
The method for measuring the overall elastic modulus of the cell based on the ultrasonic standing wave sound field is characterized in that in the step E, the motion control equation of the cell in the Y direction is as follows:
(formula 3);
wherein,m cell which is representative of the mass of the cell,dtrepresents a variation in the time of day,dyrepresents cells indtThe variation of the displacement of the time segments in the Y direction,R cell represents the radius of the cell and represents the radius of the cell,nrepresenting the wave number of the ultrasonic standing wave,E ac representing the strength of the standing wave sound field,yrepresents the Y-direction position of the cell at time t,μrepresents the dynamic viscosity of the solution and is,φ cell represents the acoustic scale factor, and:
(equation 4);
wherein,ρ cell representsThe density of the cells is such that,ρ buffer which represents the density of the solution and is,k cell represents the compression factor of the cell and is,k buffer representing the compressibility of the solution.
The method for measuring the overall elastic modulus of the cells based on the ultrasonic standing wave sound field comprises a step A of calibrating the field intensity parameters of the standing wave sound field of the micro-channel chip by using standard particles before the step B, wherein the step A specifically comprises the following steps:
a1, using polystyrene microspheres as standard particles, injecting a solution containing a plurality of standard particles into a microfluidic channel through an injector, and enabling the solution to flow at a constant speed in the X direction in a laminar flow mode in the microfluidic channel chip by adjusting the injection amount or the injection speed of the injector;
a2, when a plurality of standard particles enter a visual field observable by a microscope and a camera, applying a working frequency of 1MHz to piezoelectric ceramics by using a function signal generator, and generating an ultrasonic standing wave sound field at a 1/2 standing wave node line of a microfluidic channel; the standard particles move towards the middle line along with the flow of the fluid and finally converge at 1/2 standing wave node line positions;
a3, recording motion track images of each standard particle moving from the initial position to 1/2 standing wave node line under the action of an ultrasonic standing wave sound field by a camera through a microscope, and sending the motion track images to a motion track analysis system for processing;
a4, the motion trail analysis system extracts the actual motion trail curves of a plurality of standard particles recorded by the camera, and calculates the field intensity parameters of the standing wave sound field of the micro-channel chip by using the Y-direction motion control equation of the standard particles and the compression coefficient of the standard particles according to the Y-direction initial position of each standard particle at the start moment of the ultrasonic standing wave sound field force.
The method for measuring the overall elastic modulus of the cells based on the ultrasonic standing wave sound field is characterized in that in the step A4, the motion control equation of the standard particles in the Y direction is as follows:
(equation 5);
wherein,m sp represents the mass of the standard particles and is,dtrepresents a variation in the time of day,dyrepresents a standard particle indtThe variation of the displacement of the time segments in the Y direction,R sp represents the radius of the standard particle and represents the radius of the standard particle,nrepresenting the wave number of the ultrasonic standing wave,E ac representing the strength of the standing wave sound field,yrepresenting the Y-directional position of the standard particle at time t,μrepresents the dynamic viscosity of the solution and is,φ sp represents the acoustic scale factor, and:
(equation 6);
wherein,ρ sp represents the density of the standard particles and represents the density of the standard particles,ρ buffer which represents the density of the solution and is,k sp representing the compressibility of the standard particle,k buffer representing the compressibility of the solution.
According to the device and the method for measuring the overall elastic modulus of the cell based on the ultrasonic standing wave sound field, the microfluidic channel is adopted, the ultrasonic standing wave sound field generated by the piezoelectric ceramic is combined to enable the cell to move under stress, the overall elastic modulus of the cell is obtained through conversion by measuring the movement track of the cell, the problems of large local deformation and inaccurate measurement caused by a contact measurement method are effectively avoided, the contact damage to the cell is also avoided, and the activity of the cell is effectively ensured; the movement tracks of a plurality of cells can be recorded simultaneously in a single observation visual field range, so that continuous measurement is realized, and the detection flux is high; the cell type can be measured is many, the range is wide, the method is particularly suitable for some cells which cannot adhere to the wall or are not easy to adhere to the wall, such as circulating tumor cells, and the circulating tumor cells after measurement can be completely used for subsequent cell culture, phenotype identification, metabolic activity detection, toxicological analysis and the like; the method is simple and quick to operate, strong in repeatability and integration and has certain application value.
Drawings
FIG. 1 is a schematic structural diagram of a core part of an embodiment of the device for measuring the overall elastic modulus of cells based on an ultrasonic standing wave sound field;
FIG. 2 is a working schematic diagram of an embodiment of the invention based on ultrasonic standing wave acoustic field to measure the overall elastic modulus of cells;
FIG. 3 is an actual motion trajectory image of an embodiment of the invention based on an ultrasonic standing wave sound field to measure the overall elastic modulus of cells;
FIG. 4 is an ideal motion trajectory curve of an embodiment of the invention based on an ultrasonic standing wave sound field to measure the overall elastic modulus of cells;
fig. 5 is a motion trajectory curve of fig. 3 after image processing and trajectory extraction by the motion trajectory analysis system.
Detailed Description
The embodiments and examples of the present invention will be described in detail below with reference to the accompanying drawings, and the described embodiments are only for the purpose of illustrating the present invention and are not intended to limit the embodiments of the present invention.
As shown in FIG. 1, FIG. 1 is a schematic structural diagram of the core part of an embodiment of the apparatus for measuring the overall elastic modulus of cells based on an ultrasonic standing wave acoustic field, the core part of the measuring apparatus is composed of a micro flow channel chip 100 and a piezoelectric ceramic 200; the micro-flow channel chip 100 is provided with a micro-flow channel 111, the piezoelectric ceramic 200 is in contact with the bottom surface of the micro-flow channel chip 100, and the piezoelectric ceramic 200 is positioned below the micro-flow channel 111 and is used for generating an ultrasonic standing wave sound field in the micro-flow channel 111 so as to enable cells suspended in the micro-flow channel 111 to move under the action of the non-contact field force; when the cells flow through an ultrasonic standing wave sound field along with a solution (such as a single cell suspension) where the cells are located, the cells are subjected to the action force of the sound field pointing to a standing wave node and gather to move near a standing wave node line;
the measuring device further comprises a microscope, a camera and a motion trail analysis system (all not shown); the camera records the actual movement track image of the cell in the observation field of view through a microscope and sends the actual movement track image to a movement track analysis system for processing; the motion trail analysis system is used for analyzing the motion trailThe Y-direction initial position of each cell at the starting moment of the ultrasonic standing wave sound field force is combined with the field intensity parameter of the standing wave sound field by utilizing the Y-direction motion control equation of the cellE ac Calculating an ideal motion track curve, and extracting a cell actual motion track curve recorded by the camera; the motion trail analysis system is also used for fitting an ideal motion trail curve of the cells with an actual motion trail of the cells by a least square method and calculating the overall elastic modulus of the cells by combining field intensity parameters of a standing wave sound fieldβ。
Preferably, the Y-direction motion control equation of the cell is as follows:
(formula 3);
wherein,m cell which is representative of the mass of the cell,dtrepresents a variation in the time of day,dyrepresents cells indtThe variation of the displacement of the time segments in the Y direction,d 2 y/dt 2 is an algebraic notation of the second derivative,R cell represents the radius of the cell and represents the radius of the cell,nrepresenting the wave number of the ultrasonic standing wave,E ac representing the strength of the standing wave sound field,yrepresents the Y-direction position of the cell at time t,μrepresents the dynamic viscosity of the solution (medium),φ cell represents the acoustic scale factor, and:
(equation 4);
wherein,ρ cell which is representative of the density of the cells,ρ buffer represents the density of the solution (medium),k cell representing the compressibility (bulk modulus of elasticity with respect to the cell) of the cellβIn inverse proportion),k buffer representing the compressibility of the solution (medium), and the field strength parameter of the standing wave sound fieldE ac Of cellsρ cell And solutions (media)ρ buffer 、k buffer Are all known.
Specifically, the liquid inlet end of the microfluidic channel 111 is provided with a liquid inlet 111a and is connected to an injector (not shown) via an inlet microfluidic hose 121, and the liquid outlet end of the microfluidic channel 111 is provided with a liquid outlet 111b and is connected to a liquid collection test tube (not shown) via an outlet microfluidic hose 122; the cells with their solutions flow into the microfluidic channel 111 from the inlet 111a through the inlet microfluidic tube 121, flow in the microfluidic channel 111 in a laminar flow, and flow out of the microfluidic channel 111 from the outlet 111b through the outlet microfluidic tube 122.
The laminar flow form refers to a flow mode of liquid (i.e., fluid) flowing in the microfluidic channel 111 under a low Reynolds number, and the Reynolds number (Reynolds number) is a dimensionless number that can be used for representing a fluid flow condition, is a similar criterion number that characterizes viscous influence in fluid mechanics, and is a basis for judging flow characteristics, when the Reynolds number is small, the influence of viscous force on a flow field is greater than inertia, disturbance of flow velocity in the flow field is attenuated due to the viscous force, and the fluid flow is stable to form a laminar flow; on the contrary, if the reynolds number is larger, the influence of inertia on the flow field is larger than the viscous force, the fluid flow is unstable, the small change of the flow velocity is easy to develop and strengthen, and a turbulent flow or turbulent flow field is formed; in the pipe flow, the flow with the Reynolds number smaller than 2300 is laminar flow, the flow with the Reynolds number equal to 2300-4000 is in a transition state, and the flow with the Reynolds number larger than 4000 is turbulent flow.
Preferably, the microfluidic channel 111 is linear and has a rectangular or trapezoidal cross section.
In the preferred embodiment of the device for measuring the overall elastic modulus of cells based on the ultrasonic standing wave sound field, in order to facilitate a camera to clearly record the flow state of the cells in the microfluidic channel 111 through a microscope, specifically, the microfluidic channel chip 100 is composed of a channel base 110 and a glass cover plate 120, the channel base 110 can be made into a sheet with a thickness of 500 micrometers by using silicon substrates, silicon oxide or hard alloy, and a plasma etching process is adopted to make a groove with a rectangular or trapezoidal cross section on the upper surface of the channel base 110 as the microfluidic channel 111, for example, a rectangular groove with a width of 750 micrometers and a depth of 100 micrometers is etched; the glass cover plate 120 can be made of heat-resistant glass material into a sheet with a thickness of 1 mm, and is tightly bonded with the runner base 110 in a thermal bonding manner; through holes with a diameter of 700 micrometers are respectively formed in the glass cover plate 120 as a liquid inlet 111a and a liquid outlet 111b for fluid, and are connected with a liquid collection tube (not shown) or a syringe (not shown) through a micro-fluid hose (not shown) with an inner diameter of 500 micrometers, for example; in order to ensure that the flow of the single cell suspension in the microfluidic channel 111 is in the form of low reynolds number laminar flow and take into account the realizability and accuracy requirements of the subsequent measurement, the flow speed of the single cell suspension in the microfluidic channel 111 is controlled within 200 μm/s by adjusting the injection amount of the injector, for example, 10-20 μ l/h.
The piezoelectric ceramic 200 can be a PNT-5 type piezoelectric ceramic piece which applies voltage in the thickness direction Z and generates vibration in the thickness direction Z (namely Z polarization in the thickness direction), two planes on the piezoelectric ceramic 200, which are vertical to the epsilon-33 direction (namely the thickness direction), are used as electrode surfaces, metal silver coatings are plated as driving electrodes, and one surface of the piezoelectric ceramic piece is adhered to the bottom surface of the flow channel base 110 of the micro-flow channel chip 100 by alpha-cyanoacrylate glue; the piezoelectric ceramic 200 is electrically connected to a function signal generator (not shown), the function signal generator generates a sinusoidally varying alternating voltage signal as a driving signal, and the piezoelectric ceramic 200 is driven to work by a power amplifier (not shown); the piezoelectric ceramic 200 is used as a vibration source of an ultrasonic sound field, ultrasonic vibration generated by the piezoelectric ceramic passes through the wall surface of the flow channel of the microfluidic channel 111, a sound field is generated in fluid between the two side walls of the flow channel, and when the vibration frequency of the sound field is the fundamental frequency resonance frequency of the ultrasonic vibration of the fluid in the flow channel, a standing wave node line is generated at the position of the middle line of the flow channel of the microfluidic channel 111 to form an ultrasonic standing wave sound field.
With reference to fig. 2, fig. 2 is a working schematic diagram of an embodiment of the present invention for measuring the overall elastic modulus of a cell based on an ultrasonic standing wave sound field, and according to the apparatus for measuring the overall elastic modulus of a cell based on the ultrasonic standing wave sound field, the present invention further provides a method for measuring the overall elastic modulus of a cell based on the ultrasonic standing wave sound field, which specifically includes the following steps:
step S320, injecting a solution with a specified concentration (i.e. a single-cell suspension with a certain concentration, for example, a phosphate buffer solution with a solution (medium) of 0.01 mol/L) into the microfluidic channel 111 from the liquid inlet 111a through the inlet microfluidic tube 121 by a syringe, and adjusting the injection amount or the injection speed of the syringe, for example, 10-20 μ L/h or 200 μm/S, so that the single-cell suspension flows in the microfluidic chip 100 at a uniform speed in the X direction in a laminar flow manner;
step S330, when a plurality of cells C enter the visual field observable by the microscope and the camera, applying a working frequency of 1MHz to the piezoelectric ceramic 200 by using a function signal generator, and generating an ultrasonic standing wave sound field at 1/2 standing wave node line 111C (namely a central line) of the microfluidic channel 111 in FIG. 2; when the piezoelectric ceramic 200 starts to work, the initial positions of the cells C in the Y direction are different, the distances from the central line are different, and the movement tracks when the cells C are stressed are also different, and under the action of the ultrasonic standing wave sound field force, the cells C move to the central line along with the flow of the fluid (i.e., the solution (medium)), and finally converge to the position of the 1/2 standing wave node line 111C to move;
step S340, recording an actual motion track image of each cell C moving from the initial position to the 1/2 standing wave node line 111C under the action of the ultrasonic standing wave sound field by the camera through a microscope, and sending the actual motion track image to a motion track analysis system for processing; FIG. 3 is an actual motion trace image of an embodiment of the present invention based on an ultrasonic standing wave acoustic field to measure the overall elastic modulus of a cell, wherein the X direction represents a time axis, the Y direction represents a moving distance of the cell C in the Y direction, and the curve representsS 1 Represents the actual movement track curve of the cell C when flowing along with the solution (medium);
step S350, the motion trail analysis system utilizes a Y-direction motion control equation of the cells to combine with the field intensity parameters of the standing wave sound field according to the Y-direction initial position of each cell C at the starting moment of the ultrasonic standing wave sound field forceE ac Calculating and drawing an ideal motion trajectory curve of a plurality of cells C; FIG. 4 is a schematic diagram of the ultrasonic standing wave acoustic field-based cell measurement method of the present invention, as shown in FIG. 4Ideal motion trace curve of the bulk modulus embodiment, the abscissa represents the time axis, the ordinate represents the moving distance in the Y direction, the curveS 0 Represents an ideal movement trajectory curve of the cell C;
step S360, the motion trail analysis system extracts actual motion trail curves of a plurality of cells C recorded by the camera, fits ideal motion trail curves of the plurality of cells C with actual motion trails of the plurality of cells C through a least square method, and combines field intensity parameters of a standing wave sound fieldE ac Calculating the bulk modulus of elasticity of cell Cβ(ii) a FIG. 5 is a graph of the motion trajectory of FIG. 3 after image processing and trajectory extraction by the motion trajectory analysis system, with the abscissa representing the time axis, the ordinate representing the moving distance in the Y direction, and the graphS 2 Representing the actual motion trajectory curve of the cell C after image processing and trajectory extraction by the motion trajectory analysis system.
Specifically, in step S350, the Y-direction motion control equation for the cell C moving in the Y-direction in fig. 2 is as follows:
(formula 3);
wherein,m cell represents the mass of the cells C,dtrepresents a variation in the time of day,dyrepresents cell C indtThe variation of the displacement of the time segments in the Y direction,d 2 y/dt 2 is an algebraic notation of the second derivative,R cell represents the radius of the cell C and represents the radius of the cell C,nrepresenting the wave number of the ultrasonic standing wave,E ac representing the strength of the standing wave sound field,yrepresents the Y-directional position of the cell C at time t,μrepresents the dynamic viscosity of the solution (medium),φ cell represents the acoustic scale factor, and:
(equation 4);
wherein,ρ cell represents the density of the cells C and represents the density of the cells C,ρ buffer represents the density of the solution (medium),k cell representing the compressibility (bulk modulus of elasticity with cells) of cell CβIn inverse proportion),k buffer representing the compressibility of the solution (medium), and the field strength parameter of the standing wave sound fieldE ac Of cell Cρ cell And solutions (media)ρ buffer 、k buffer Are all known.
In the specific embodiment of the method for measuring the overall elastic modulus of the cell based on the ultrasonic standing wave sound field, the ultrasonic sound field strength of different micro-channel chips 100 may be different due to the differences between the fabrication of the micro-channel chip 100 and the working environment, and in order to avoid the influence of the differences on the measurement, the method further includes step S310 before step S320, wherein the standard particles B are used to measure the standing wave sound field strength parameters of the micro-channel chip 100E ac A step of performing calibration, where step S310 specifically includes:
step S311, using polystyrene microspheres with a diameter of 10 μm as standard particles B, injecting a solution (e.g., a phosphate buffer solution whose solution (medium) may be 0.01 mol/L) containing a plurality of standard particles B at a specified concentration from a liquid inlet 111a into the microfluidic channel 111 through the inlet microfluidic tube 121 by an injector, and adjusting the injection amount or the injection speed of the injector, for example, 10-20 μ L/h or 200 μm/S, so that the solution containing the standard particles B flows in the microfluidic channel chip 100 at a uniform speed in the X direction in a laminar flow;
step S312, when the plurality of standard particles B enter the observable field of view of the microscope and the camera, applying a working frequency of 1MHz to the piezoelectric ceramic 200 by using the function signal generator, and generating an ultrasonic standing wave sound field at 1/2 standing wave node line 111c (i.e., the central line) of the microfluidic channel 111 in fig. 2; when the piezoelectric ceramic 200 starts to work, the initial positions of the standard particles B are different, the distances from the central line are different, and the motion trajectories when the piezoelectric ceramic is stressed are also different, and under the action of the ultrasonic standing wave sound field force, the standard particles B move to the central line along with the flow of the fluid (i.e., the solution (medium)), and finally converge to the position of the 1/2 standing wave node line 111c to move;
step S313, the camera records the motion track image of each standard particle B moving from the initial position to the 1/2 standing wave node line 111c under the action of the ultrasonic standing wave sound field by using a microscope, and sends the motion track image to the motion track analysis system for processing;
step S314, the motion trail analysis system extracts actual motion trail curves of a plurality of standard particles B recorded by the camera, and according to the Y-direction initial position of each standard particle B at the starting moment of the ultrasonic standing wave acoustic field force, the Y-direction motion control equation of the standard particle B is combined with the compression coefficient of the standard particle Bk SP Calculating the field strength parameter of the standing wave sound field of the micro-channel chip 100E ac And its tolerance range (i.e., confidence).
Specifically, the standard particles B move with a fluid (i.e., a solution (medium)) at a constant speed along the X direction in fig. 2, and the flow speed of the fluid is determined by a flow input device (e.g., a syringe) and can be adjusted as required; meanwhile, the Y-direction control equation for the movement of the standard particles B in the Y-direction in FIG. 2 is as follows (note: the same as the aforementioned Y-direction control equation for the cells C except that the parameters relating to the cells C are all replaced with the parameters relating to the standard particles B):
(equation 5);
wherein,m sp represents the mass of the standard particle B,dtrepresents a variation in the time of day,dyrepresents a standard particle B indtThe variation of the displacement of the time segments in the Y direction,d 2 y/dt 2 is an algebraic notation of the second derivative,R sp represents the radius of the standard particle B,n·representing the wave number of the ultrasonic standing wave,E ac representing the strength of the standing wave sound field,yrepresents the Y-directional position of the standard particle B at time t,μrepresents the dynamic viscosity of the solution (medium),φ sp represents the acoustic scale factor, and:
(equation 6);
wherein,ρ sp represents the density of the standard particle B,ρ buffer represents the density of the solution (medium),k sp represents the compressibility of the standard particle B,k buffer representing the compressibility of the solution (medium), of the standard particles Bρ sp 、k sp And solutions (media)ρ buffer 、k buffer Are all known.
It should be understood that the above-mentioned embodiments are merely preferred examples of the present invention, and not restrictive, but rather, all the changes, substitutions, alterations and modifications that come within the spirit and scope of the invention as described above may be made by those skilled in the art, and all the changes, substitutions, alterations and modifications that fall within the scope of the appended claims should be construed as being included in the present invention.
Claims (10)
1. The utility model provides a device based on whole elastic modulus of ultrasonic standing wave sound field measurement cell which characterized in that: the core part of the micro-channel piezoelectric ceramic chip consists of a micro-channel chip and piezoelectric ceramics; the piezoelectric ceramic is positioned below the micro-flow channel and used for generating an ultrasonic standing wave sound field in the micro-flow channel so that the cells are stressed and converged to move near a standing wave node line when flowing along with the solution in which the cells are positioned; the measuring device also comprises a microscope, a camera and a motion trail analysis system; the camera is used for recording an actual cell motion track image in an observation field of view through a microscope and sending the actual cell motion track image to the motion track analysis system for processing; the motion trail analysis system calculates an ideal motion trail curve by utilizing a Y-direction motion control equation of the cell and combining field intensity parameters of a standing wave sound field according to the Y-direction initial position of each cell at the starting moment of the ultrasonic standing wave sound field force, and extracts an actual motion trail curve of the cell recorded by the camera; the motion trail analysis system is also used for fitting an ideal motion trail curve of the cells with an actual motion trail of the cells by a least square method and calculating the overall elastic modulus of the cells by combining field intensity parameters of a standing wave sound field.
2. The device for measuring the overall elastic modulus of the cell based on the ultrasonic standing wave acoustic field is characterized in that the Y-direction motion control equation of the cell is as follows:
(formula 3);
wherein,m cell which is representative of the mass of the cell,dtrepresents a variation in the time of day,dyrepresents cells indtThe variation of the displacement of the time segments in the Y direction,R cell represents the radius of the cell and represents the radius of the cell,nrepresenting the wave number of the ultrasonic standing wave,E ac representing the strength of the standing wave sound field,yrepresents the Y-direction position of the cell at time t,μrepresents the dynamic viscosity of the solution (i.e. the medium),φ cell represents the acoustic scale factor, and:
(equation 4);
wherein,ρ cell which is representative of the density of the cells,ρ buffer representing the density of the solution (i.e. the medium),k cell represents the compression factor of the cell and is,k buffer representing the compressibility of the solution (i.e., the medium).
3. The device for measuring the overall elastic modulus of the cell based on the ultrasonic standing wave acoustic field according to claim 1, wherein: the liquid inlet end of the microflow channel is provided with a liquid inlet and is connected with the injector through an inlet microflow hose, and the liquid outlet end of the microflow channel is provided with a liquid outlet and is connected with the liquid collecting test tube through an outlet microflow hose.
4. The device for measuring the overall elastic modulus of the cell based on the ultrasonic standing wave acoustic field according to claim 1, wherein: the microfluidic channel is linear, and the cross section of the microfluidic channel is rectangular or trapezoidal.
5. The device for measuring the overall elastic modulus of the cell based on the ultrasonic standing wave acoustic field according to claim 1, wherein: the micro-channel chip consists of a channel base and a glass cover plate, wherein the channel base is made of silicon substrate, silicon oxide or hard alloy into a sheet shape, and a groove with a rectangular or trapezoidal cross section is made on the upper surface of the channel base by adopting a plasma etching process and serves as a micro-channel; the glass cover plate is made of heat-resistant glass materials into a sheet shape and is tightly bonded with the runner base in a thermal bonding mode.
6. The device for measuring the overall elastic modulus of the cell based on the ultrasonic standing wave acoustic field according to claim 1, wherein: the piezoelectric ceramic adopts a piezoelectric ceramic piece which applies voltage in the thickness direction Z and generates vibration in the thickness direction Z, two planes on the piezoelectric ceramic piece, which are vertical to the thickness direction, are taken as electrode surfaces, metal silver coatings are plated on the two planes as driving electrodes, and one of the surfaces is adhered to the bottom surface of the micro-channel chip by glue; the piezoelectric ceramics are electrically connected with the function signal generator, the function signal generator generates sine-changed alternating voltage signals as driving signals, and the piezoelectric ceramics are driven to work by the power amplifying device.
7. A method for measuring the overall elastic modulus of cells based on an ultrasonic standing wave sound field is implemented on the device for measuring the overall elastic modulus of cells based on the ultrasonic standing wave sound field, which is disclosed by any one of claims 1 to 6, and is characterized by comprising the following steps of:
B. injecting a solution containing a plurality of cells into the microfluidic channel through an injector, and enabling the solution to flow in a laminar flow mode in the microfluidic channel chip at a constant speed along the X direction by adjusting the injection amount or the injection speed of the injector;
C. when a plurality of cells enter a visual field which can be observed by a microscope and a camera, a function signal generator is utilized to apply a working frequency of 1MHz to the piezoelectric ceramic, and an ultrasonic standing wave sound field is generated at an 1/2 standing wave node line of the microfluidic channel; under the action of the ultrasonic standing wave sound field force, each cell moves towards the midline along with the flow of the fluid and finally converges at the position of 1/2 standing wave node line;
D. the camera records an actual motion track image of each cell moving from an initial position to an 1/2 standing wave node line under the action of an ultrasonic standing wave sound field by using a microscope, and sends the actual motion track image to a motion track analysis system for processing;
E. the motion trail analysis system calculates and draws an ideal motion trail curve of a plurality of cells by utilizing a Y-direction motion control equation of the cells and combining field intensity parameters of a standing wave sound field according to the Y-direction initial position of each cell at the start moment of the ultrasonic standing wave sound field force;
F. the motion trail analysis system extracts actual motion trail curves of a plurality of cells recorded by the camera, fits ideal motion trail curves of the plurality of cells with actual motion trails of the plurality of cells through a least square method, and calculates the overall elastic modulus of the cells by combining field intensity parameters of a standing wave sound field.
8. The method for measuring the bulk elastic modulus of the cells based on the ultrasonic standing wave acoustic field according to claim 7, wherein in the step E, the Y-direction motion control equation of the cells is as follows:
(formula 3);
wherein,m cell which is representative of the mass of the cell,dtrepresents a variation in the time of day,dyrepresents cells indtThe variation of the displacement of the time segments in the Y direction,R cell representing cell halvesThe diameter of the steel wire is measured,nrepresenting the wave number of the ultrasonic standing wave,E ac representing the strength of the standing wave sound field,yrepresents the Y-direction position of the cell at time t,μrepresents the dynamic viscosity of the solution and is,φ cell represents the acoustic scale factor, and:
(equation 4);
wherein,ρ cell which is representative of the density of the cells,ρ buffer which represents the density of the solution and is,k cell represents the compression factor of the cell and is,k buffer representing the compressibility of the solution.
9. The method for measuring the overall elastic modulus of the cells based on the ultrasonic standing wave acoustic field according to claim 7, further comprising a step A of calibrating the field strength parameters of the standing wave acoustic field of the micro flow channel chip by using the standard particles before the step B, wherein the step A specifically comprises:
a1, using polystyrene microspheres as standard particles, injecting a solution containing a plurality of standard particles into a microfluidic channel through an injector, and enabling the solution to flow at a constant speed in the X direction in a laminar flow mode in the microfluidic channel chip by adjusting the injection amount or the injection speed of the injector;
a2, when a plurality of standard particles enter a visual field observable by a microscope and a camera, applying a working frequency of 1MHz to piezoelectric ceramics by using a function signal generator, and generating an ultrasonic standing wave sound field at a 1/2 standing wave node line of a microfluidic channel; the standard particles move towards the middle line along with the flow of the fluid and finally converge at 1/2 standing wave node line positions;
a3, recording motion track images of each standard particle moving from the initial position to 1/2 standing wave node line under the action of an ultrasonic standing wave sound field by a camera through a microscope, and sending the motion track images to a motion track analysis system for processing;
a4, the motion trail analysis system extracts the actual motion trail curves of a plurality of standard particles recorded by the camera, and calculates the field intensity parameters of the standing wave sound field of the micro-channel chip by using the Y-direction motion control equation of the standard particles and the compression coefficient of the standard particles according to the Y-direction initial position of each standard particle at the start moment of the ultrasonic standing wave sound field force.
10. The method for measuring the bulk modulus of elasticity of the cells based on the ultrasonic standing wave acoustic field according to claim 9, wherein in the step A4, the Y-direction motion control equation of the standard particles is as follows:
(equation 5);
wherein,m sp represents the mass of the standard particles and is,dtrepresents a variation in the time of day,dyrepresents a standard particle indtThe variation of the displacement of the time segments in the Y direction,R sp represents the radius of the standard particle and represents the radius of the standard particle,nrepresenting the wave number of the ultrasonic standing wave,E ac representing the strength of the standing wave sound field,yrepresenting the Y-directional position of the standard particle at time t,μrepresents the dynamic viscosity of the solution and is,φ sp represents the acoustic scale factor, and:
(equation 6);
wherein,ρ sp represents the density of the standard particles and represents the density of the standard particles,ρ buffer which represents the density of the solution and is,k sp representing the compressibility of the standard particle,k buffer representing the compressibility of the solution.
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