CN112326978A - Cell deformability detection chip with multi-stage self-checking function - Google Patents
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Abstract
The invention discloses a cell deformability detection chip with a multistage self-checking function, which comprises a PDMS layer and a glass substrate layer, wherein a flow channel is arranged on the surface of the PDMS layer; the flow channel comprises a sample inlet, a straight flow channel, a sheath fluid inlet and an outlet, wherein the sample inlet and the sheath fluid inlet are respectively communicated with one end of the straight flow channel, and the outlet is communicated with the other end of the straight flow channel; the PDMS layer is also provided with a first-stage impedance detection module and a second-stage impedance detection module; the first-stage impedance detection module and the second-stage impedance detection module are respectively opposite to the direct current channel; the sheath fluid inlet is arranged at the upper side of the flow channel, and the introduced sheath fluid is a magnetic fluid immiscible with water; the electrodes in the first-stage electrical impedance detection module and the second-stage electrical impedance detection module are both planar electrodes and are arranged on the surface of the glass substrate. By adopting the chip provided by the embodiment of the invention, the automatic checking of the detection sensitivity and the accurate regulation and control of the detection sensitivity and the dynamic response range can be realized at the same time.
Description
Technical Field
The invention relates to the technical field of microfluidic chips, in particular to a cell deformability detection chip with a multi-stage self-checking function.
Background
In recent years, technologies for sorting and enriching circulating tumor cells and similar cells in a microfluidic chip based on microfluidic technologies have been developed in stages, and thus have attracted much attention. During the process of pathological change and development, the cell size and cytoskeleton structure of cancer cells can change with time, thereby causing the change of mechanical properties of cells, and the change can provide important information and basis for identifying cell types from opposite side. However, the conventional methods for measuring the mechanical properties of cells (e.g., atomic force microscopy) require not only expensive equipment but also a lot of financial and material resources. Some microfluidic test platforms capable of analyzing the mechanical properties of single cells have been developed, such as using narrow channels to force cell deformation, shear stress to force cell deformation, using dielectrophoresis techniques to induce cell deformation, or by imaging to characterize the deformability of cells.
However, the microfluidic platform still has some defects, such as the defects of unobvious cell deformation, long-time cell capture, inconvenient integration and the like in the experimental process, the detection result is not accurate enough, and the detection flux is difficult to improve. In addition, the sensitivity and the dynamic response range of the chip can be changed by adjusting the size of the detection channel of the electrical impedance detection chip. After the channel size is changed, the precision and sensitivity of the chip need to be checked in a complex calibration process. The existing electrical impedance detection chip does not have a self-checking function. Therefore, there is a need for a chip with self-checking function, which can perform multi-stage detection of cell deformability.
Disclosure of Invention
The present invention provides a cell deformability detection chip having a multistage self-checking function, which can perform multistage monitoring of deformability of cells and has a self-checking function.
In order to solve the technical problem, the embodiment of the invention adopts the following technical scheme:
a cell deformability detection chip with a multistage self-checking function comprises a PDMS layer and a glass substrate layer, wherein a flow channel is arranged on the surface of the PDMS layer; the flow channel comprises a sample inlet, a straight flow channel, a sheath fluid inlet and an outlet, wherein the sample inlet and the sheath fluid inlet are respectively communicated with one end of the straight flow channel, and the outlet is communicated with the other end of the straight flow channel; the PDMS layer is also provided with a first-stage impedance detection module and a second-stage impedance detection module; the first-stage impedance detection module and the second-stage impedance detection module are respectively opposite to the direct current channel; the sheath fluid inlet is arranged at the upper side of the flow channel, and the introduced sheath fluid is a magnetic fluid immiscible with water; the electrodes in the first-stage electrical impedance detection module and the second-stage electrical impedance detection module are both planar electrodes and are arranged on the surface of the glass substrate;
the first-stage electrical impedance detection module is used for calculating the optimal flow ratio of the sheath liquid flow and the sample flow;
the second-stage electrical impedance detection module is used for performing controllable deformation test on cells.
Preferably, the first-stage electrical impedance detection module comprises a first excitation electrode and two first response electrodes positioned on two sides of the first excitation electrode, and the first excitation electrode and the first response electrodes form a differential circuit.
Preferably, the second-stage electrical impedance detection module comprises a front detection submodule and a rear detection submodule; the front detection submodule applies sheath fluid flow extrusion to the cells, the rear detection submodule is internally provided with a strong magnetic field, and the strong magnetic field applies magnetic fluid extrusion to the cells.
Preferably, the diameter of the flow channel of the front detection submodule is smaller than the diameter of the direct current channel and larger than the diameter of the cell to be detected; the second-stage electrical impedance detection module comprises a second excitation electrode and a second response electrode positioned on one side of the second excitation electrode, and the fluid in the front detection submodule is subjected to electrical signal acquisition through the second excitation electrode and the second response electrode to obtain the deformation degree of the cell under the extrusion of the flow channel and the time of the cell passing through the front detection submodule.
Preferably, a strong magnetic field is arranged in the rear detection submodule; the second-stage electrical impedance detection module further comprises a second excitation electrode and a third response electrode positioned on the other side of the third excitation electrode, and fluid in the post-detection submodule is subjected to electrical signal acquisition through the second excitation electrode and the third response electrode, so that the deformation degree of the cells under the extrusion of the magnetic field and the time for the cells to pass through the post-detection submodule are obtained.
Preferably, the cross section of the direct current channel is a rectangle with a long side parallel to the glass substrate layer.
Preferably, the cross section of the straight flow channel is a rectangle with a long side parallel to the glass substrate, the ratio of the long side to the short side is about 2, the length of the straight flow channel satisfies the shortest migration length calculated according to the particle diameter, the height of the flow channel and the lateral migration rate, and the calculation formula of the shortest migration length is as follows:
wherein L isminDenotes the shortest migration length, H denotes the channel height, ULThe lateral migration rate is shown, and U represents the particle diameter.
Compared with the prior art, the cell deformability detection chip with the multi-stage self-checking function can be used for carrying out multi-stage monitoring on deformability of cells and has the self-checking function. The cell deformability detection chip with the multistage self-checking function comprises a PDMS layer and a glass substrate layer, wherein a flow channel is arranged on the surface of the PDMS layer; the flow channel comprises a sample inlet, a straight flow channel, a sheath fluid inlet and an outlet, wherein the sample inlet and the sheath fluid inlet are respectively communicated with one end of the straight flow channel, and the outlet is communicated with the other end of the straight flow channel; the PDMS layer is also provided with a first-stage impedance detection module and a second-stage impedance detection module; the first-stage impedance detection module and the second-stage impedance detection module are respectively opposite to the direct current channel; the sheath fluid inlet is arranged at the upper side of the flow channel, and the introduced sheath fluid is a magnetic fluid immiscible with water; the electrodes in the first-stage electrical impedance detection module and the second-stage electrical impedance detection module are both planar electrodes and are arranged on the surface of the glass substrate. By arranging a first-stage electrical impedance detection module, calculating the optimal flow ratio of sheath liquid flow and sample flow, and checking the sensitivity of a detection channel; and a second-stage electrical impedance detection module is arranged to perform controllable deformation test on the cells. The method realizes the multi-stage detection of the cell deformability, applies larger stress to the cells, and simultaneously can accurately adjust the stress borne by the cells, greatly improves the identification precision, and provides more convincing identification basis.
Drawings
FIG. 1 is a schematic view of the overall structure of the present invention;
FIG. 2 is a schematic diagram of the stress condition of the particles in the DC channel;
FIG. 3 is a schematic view of a cross-sectional focus position of a particle within a straight flow channel;
FIG. 4 is a schematic view of the focusing process of particles in a straight flow channel;
FIG. 5 is a schematic process diagram of a first stage electrical impedance detection module;
FIG. 6 is a schematic diagram of the deformation process of the cell in the second-stage electrical impedance detection module;
fig. 7 is a schematic diagram of the electrical detection principle of the electrical detection module.
The figure shows that: the device comprises a sample inlet 1, a sheath fluid inlet 2, a first response electrode 3, a first excitation electrode 4, a second response electrode 5, a second excitation electrode 6, a second-stage electrical impedance detection module 7, an outlet 8, a front detection submodule 9, a rear detection submodule 10, a first-stage electrical impedance detection module 11 and a third response electrode 12.
Detailed Description
The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features.
As shown in fig. 1, the cell deformability detection chip with the multistage self-checking function according to the embodiment of the present invention includes a PDMS layer and a glass substrate layer, where a flow channel is disposed on the surface of the PDMS layer; the flow channel comprises a sample inlet 1, a straight flow channel, a sheath fluid inlet 2 and an outlet 8, wherein the sample inlet 1 and the sheath fluid inlet 2 are respectively communicated with one end of the straight flow channel, and the outlet 8 is communicated with the other end of the straight flow channel; the PDMS layer is also provided with a first-stage impedance detection module 11 and a second-stage impedance detection module 7; the first-stage impedance detection module 11 and the second-stage impedance detection module 7 are respectively opposite to a direct current channel; the sheath fluid inlet 2 is arranged at the upper side of the flow channel, and the introduced sheath fluid is magnetic fluid which is immiscible with water; the electrodes in the first-stage impedance detection module 11 and the second-stage impedance detection module 7 are both planar electrodes and are arranged on the surface of a glass substrate;
the first-stage electrical impedance detection module 11 is used for calculating the optimal flow ratio of the sheath liquid flow and the sample flow;
the second-stage electrical impedance detection module 7 is used for performing controllable deformation test on the cells.
The cell deformability detection module is used for detecting the cell deformation, and the cell deformation detection module is used for detecting the cell deformation; realized measuring the proportion of two kinds of fluids in the runner to the component analysis of the fluid that the cell was located, combined experimental result to adjust solution composition, possessed from check function, made this set of device can be used to measure the multiple particle diameter difference, the tumour cell of the nature difference, can constantly adjust the experimental scheme at the in-process of experiment simultaneously, made the experimental design rationalize more. After the characteristic detection is carried out on the cells, the integrity and the activity of the cells can be ensured, and the cells can be conveniently analyzed and researched in the next step. The device provided by the invention can be widely applied to the fields of clinical diagnosis, biological research, biochemical analysis and the like.
In the cell deformability detection chip with the multi-stage self-checking function of the above embodiment, preferably, the first-stage electrical impedance detection module 11 includes a first excitation electrode 4 and two first response electrodes 3 located at two sides of the first excitation electrode, and the first excitation electrode 4 and the first response electrodes 3 form a differential circuit. Calibrating the chip before the experiment to obtain the broadband amplitude-frequency response of the flow channel when the sheath liquid flow and the sample flow occupy the flow channel at a fixed ratio, and comparing and calculating the actually measured response signal with the calibration signal in the experiment process to obtain the ratio of the sheath liquid flow to the sample flow occupying the flow channel in the experiment; and (3) adjusting the proportion of the sheath fluid flow and the sample fluid occupying the flow channel according to the pressure condition of the cells in the experimental process, and recording each adjustment until the optimal proportion is found out. As shown in fig. 7, the first excitation electrode 4 and the first response electrodes 3 on both sides of the first excitation electrode 4 in the first-stage electrical impedance detection module 11 form a differential circuit, an electrical signal generated by the electrical impedance spectrometer is applied to the flow channel through the first excitation electrode 4 above the flow channel, and then a signal on the first response electrode 3 measured below the flow channel is collected to realize measurement of the broadband impedance information of the cell. Specifically, before the experiment, calibrating the chip to obtain the broadband amplitude-frequency response of the flow channel when the sheath liquid flow and the sample flow occupy the flow channel at a fixed ratio, and in the experiment process, comparing and calculating the actually measured response signal with the calibration signal to obtain the ratio of the sheath liquid flow and the sample flow occupying the flow channel in the experiment; and (3) adjusting the proportion of the sheath fluid flow and the sample fluid occupying the flow channel according to the pressure condition of the cells in the experimental process, and recording each adjustment until the optimal proportion is found out.
Preferably, the second-stage electrical impedance detection module 7 comprises a front detection submodule 9 and a rear detection submodule 10; the front detection submodule 9 applies sheath fluid flow extrusion to cells, and the rear detection submodule 10 is internally provided with a strong magnetic field which applies magnetic fluid extrusion to the cells. Through setting up front and back detection submodule 10, realize multistage to the cell extrusion test.
Preferably, the diameter of the flow channel of the front detection submodule 9 is smaller than the diameter of the straight flow channel and larger than the diameter of the cell to be detected; the second-stage electrical impedance detection module 7 comprises a second excitation electrode 6 and a second response electrode 5 positioned on one side of the second excitation electrode 6, and the fluid in the front detection submodule 9 is subjected to electrical signal acquisition through the second excitation electrode and the second response electrode 5, so that the deformation degree of the cell under the extrusion of the flow channel and the time of the cell passing through the front detection submodule 9 are obtained. As shown in fig. 5, the diameter of the flow channel in the second-stage electrical impedance detection module 7 is smaller than that of the previous flow channel, and in the flow channel of the previous detection submodule 9, due to the narrowing of the flow channel, the sheath fluid flow and the wall surface will jointly apply stress to the cell, forcing it to deform, and when the cell passes through the second response electrode 5, the response signal is sent by the second response electrode 5 and is collected by the current signal amplification device to enter the computer. And when no cell passes through the detection channel, the amplitude-frequency response of the detection channel is detected, the flow ratio of the nuclear sheath fluid flow to the sample flow is analyzed and calculated, and the sensitivity of the detection channel is checked by combining an experimental result, so that the self-checking function is realized.
Preferably, a strong magnetic field is arranged in the rear detection submodule 10; the second-stage electrical impedance detection module 7 further comprises a second excitation electrode 6 and a third response electrode 12 positioned on the other side of the third excitation electrode, and the second excitation electrode and the third response electrode 12 are used for collecting electrical signals of fluid in the post-detection submodule 10 to obtain the deformation degree of the cells under the extrusion of the magnetic field and the time for the cells to pass through the post-detection submodule 10. As shown in fig. 6, in the post-detection submodule 10 of the second-stage electrical impedance detection module 7, a strong magnetic field is arranged at the lower side of the flow channel, the magnetic fluid is attracted downwards by the strong magnetic field, on the basis of stress applied by sheath fluid flow, the magnetic fluid and the wall surface jointly extrude the cells in the sample fluid again to force the cells to deform, the third response electrode 12 collects the electrical signals of the cells when passing through the deformation region to obtain the deformation size and the time when the cells pass through the deformation region, the passing time of the cells when the cells pass through the deformation region can be obtained by measuring the peak width in the signal diagram, the peak value in the obtained signal diagram under the same frequency can be compared with the peak value generated when the cells pass through the component analysis module to obtain the deformation degree of the cells, and thus the deformation capability of the cells can be.
Preferably, the cross section of the direct current channel is a rectangle with a long side parallel to the glass substrate layer. In this embodiment, the preparation material of each flow channel is Polydimethylsiloxane (PDMS), and may also be made of materials that do not interfere with the electrical impedance signal, such as glass, epoxy resin, polymethyl methacrylate (PMMA), Polycarbonate (PC), and the like. The prototype device is prepared by a soft lithography process, and the specific preparation process comprises the steps of performing lithography on an SU-8 male mold, performing PDMS pouring, performing close packaging on a PDMS-glass bond by using a vacuum oxygen plasma bond and technology, and the like. In addition, the preparation of the male die can also be realized by the aid of the technologies of silicon wet method/deep reactive ion etching, ultra-precision machining, metal electroplating, photosensitive circuit board etching and the like.
Preferably, the cross section of the straight flow channel is a rectangle with a long side parallel to the glass substrate, the ratio of the long side to the short side is about 2, the length of the straight flow channel satisfies the shortest migration length calculated according to the particle diameter, the height of the flow channel and the lateral migration rate, and the calculation formula of the shortest migration length is as follows:
wherein L isminDenotes the shortest migration length, H denotes the channel height, ULThe lateral migration rate is shown, and U represents the particle diameter.
As shown in fig. 2 and fig. 3, the circulating tumor cells in the sample and their neighboring cells enter the straight flow channel together, in the newtonian fluid with limited reynolds number (Re), the cells are subjected to the effect of inertial migration in the straight flow channel, so that the cells randomly dispersed in the sample at the inlet are subjected to a dragging Force (FD) of the fluid along the streamline direction and an inertial lift Force (FL) perpendicular to the streamline direction when moving in the straight flow channel along the main direction, and the inertial lift force is composed of two component forces, one is a wall-induced lift force (Fs) pointing from the wall to the center of the flow channel, and the other is a shear-induced lift force (Fw) pointing from the center of the flow channel to the wall. Under the combined action of the two, the particles finally migrate to a certain equilibrium position between the center of the flow channel and the wall surface. In the Poiseuille flow, the motion of neutral particles always lags behind the fluid, so that the rotation-induced lift force is opposite to the velocity gradient direction of the fluid, so that the particles close to the wall surface migrate to the center of the wall surface of the flow channel and the lateral migration velocity (U)L) Is the main parameter for measuring the migration phenomenon. The length of the straight flow channel is satisfied according to the particle diameter, the height of the flow channel and the fluidThe shortest migration length calculated by the characteristic speed and the transverse migration rate is calculated by the following formula:
as shown in FIG. 4, the shortest flow channel length required for the whole process of particle inertial migration can be calculated by the lateral migration rate, and the cells finally gather at the central position of the two long sides of the straight flow channel after passing through the straight flow channel.
The working process of the cell deformability detection chip with the multistage self-checking function in the embodiment is as follows: firstly, a sample flow and a sheath fluid flow enter a flow channel from a sample inlet 1 and a sheath fluid inlet 2, and cells are subjected to an inertial migration effect in a direct-current channel and are gathered at the central positions of two long sides of the direct-current channel after passing through the direct-current channel; before the experiment, the chip is calibrated, the broadband amplitude-frequency response of the flow channel when the sheath liquid flow and the sample flow occupy the fixed proportion of the wide flow channel is obtained by detection of the first-stage impedance detection module 11, and the broadband amplitude-frequency response of the flow channel when the sheath liquid flow and the sample flow occupy the fixed proportion of the narrow flow channel is obtained by detection of the submodule 9 in the second-stage impedance detection module 7. In the experimental process, after a sample flow and a sheath liquid flow enter a first-stage electrical impedance detection module 11, differential detection of response signals is carried out through a differential circuit formed by a first exciting electrode 4 and a first response electrode 3, the influence of environmental noise and flow fluctuation on the detection is eliminated, power supplies in different modes are accessed by the exciting electrodes, electrical impedance measurement of different modes and different parameters is carried out on cells, the actually measured response signals and calibration signals are compared and calculated, and the proportion of the sheath liquid flow and the sample flow occupying a flow channel in the experiment is obtained; then the cell enters a second-stage impedance detection module 7, when the cell passes through a flow channel of a front detection submodule 9, sheath liquid flow extrusion is carried out on the cell by utilizing the change of the width of the flow channel, and a response signal is fed back through a second response electrode 5; then the magnetic fluid without cells is attracted downwards through the strong magnetic field of the rear detection sub-module 10, the magnetic fluid extrusion of the cells is realized, and a response signal is fed back through the third response electrode 12; and finally, obtaining the deformation degree of the cell under the two-time extrusion and the time of the cell passing through two deformation areas, adjusting the proportion of the sheath liquid flow and the sample flow occupying the flow channel according to the quality of the cell under the pressure condition in the experimental process, recording each adjustment until the optimal sheath liquid flow-sample flow proportion is found out, measuring the peak width in the signal diagram to obtain the passing time of the cell passing through the deformation area, and comparing the peak value in the obtained signal diagram under the same frequency with the peak value generated when the cell passes through the component analysis module to obtain the deformation degree of the cell, thereby identifying the deformation capability of the cell.
Compared with the prior art, the cell deformability detection chip with the multi-stage self-checking function is adopted, and the optimal flow ratio of sheath liquid flow and sample flow is calculated by arranging the first-stage electrical impedance detection module, so that the sensitivity of a detection channel is checked; and a second-stage electrical impedance detection module is arranged to perform controllable deformation test on the cells. The method can accurately adjust the stress on the cell while applying larger stress on the cell, greatly improve the identification precision and provide more convincing identification basis.
The embodiments of the present invention are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention. That is, all equivalent changes and modifications made according to the content of the claims of the present invention should be regarded as the technical scope of the present invention.
Claims (7)
1. A cell deformability detection chip with a multistage self-checking function is characterized by comprising a PDMS layer and a glass substrate layer, wherein a flow channel is arranged on the surface of the PDMS layer; the flow channel comprises a sample inlet (1), a straight flow channel, a sheath fluid inlet (2) and an outlet (8), wherein the sample inlet (1) and the sheath fluid inlet (2) are respectively communicated with one end of the straight flow channel, and the outlet (8) is communicated with the other end of the straight flow channel; the PDMS layer is also provided with a first-stage impedance detection module (11) and a second-stage impedance detection module (7); the first-stage electrical impedance detection module (11) and the second-stage electrical impedance detection module (7) are respectively opposite to the direct current channel; the sheath fluid inflow port (2) is arranged at the upper side of the flow channel, and introduced sheath fluid is magnetic fluid which is immiscible with water; the electrodes in the first-stage electrical impedance detection module (11) and the second-stage electrical impedance detection module (7) are both planar electrodes and are arranged on the surface of the glass substrate;
the first-stage electrical impedance detection module (11) is used for calculating the optimal flow ratio of the sheath liquid flow and the sample flow;
the second-stage electrical impedance detection module (7) is used for performing controllable deformation test on cells.
2. The cell deformability detection chip with multi-stage self-checking function according to claim 1, wherein the first-stage electrical impedance detection module (11) includes a first excitation electrode (4) and two first response electrodes (3) located at both sides of the first excitation electrode, and the first excitation electrode (4) and the first response electrodes (3) form a differential circuit.
3. The cell deformability detection chip with multi-stage self-checking function according to claim 1, wherein the second-stage electrical impedance detection module (7) includes a front detection submodule (9) and a rear detection submodule (10); the front detection submodule (9) applies sheath liquid flow extrusion to cells, the rear detection submodule (10) is internally provided with a strong magnetic field, and the strong magnetic field applies magnetic fluid extrusion to the cells.
4. The cell deformability detection chip with the multi-stage self-checking function as claimed in claim 3, wherein the flow channel diameter of the front detection submodule (9) is smaller than the diameter of the straight flow channel and larger than the diameter of the cell to be detected; the second-stage electrical impedance detection module (7) comprises a second excitation electrode (6) and a second response electrode (5) positioned on one side of the second excitation electrode (6), and the fluid in the front detection submodule is subjected to electrical signal acquisition through the second excitation electrode (6) and the second response electrode (5) to obtain the deformation degree of the cell under the extrusion of the flow channel and the time of the cell passing through the front detection submodule.
5. The cell deformability detection chip with the multi-stage self-checking function as claimed in claim 3, characterized in that the post-detection submodule (9) is provided with a strong magnetic field; the second-stage electrical impedance detection module (7) further comprises a second excitation electrode (6) and a third response electrode (12) positioned on the other side of the third excitation electrode (6), and the second excitation electrode (6) and the third response electrode (12) are used for collecting electric signals of fluid in the post-detection submodule to obtain the deformation degree of the cells under the extrusion of the magnetic field and the time of the cells passing through the post-detection submodule.
6. The chip for detecting cell deformability having a multistage self-checking function as claimed in claim 1, wherein the cross section of the straight flow channel is a rectangle whose long side is parallel to the glass substrate layer.
7. The chip for detecting cell deformability with multi-stage self-checking function according to claim 1, wherein the cross section of the straight flow channel is a rectangle having a long side parallel to the glass substrate, the ratio of the long side to the short side is about 2, the length of the straight flow channel satisfies the shortest migration length calculated from the particle diameter, the height of the flow channel and the lateral migration rate, and the calculation formula of the shortest migration length is:
wherein L isminDenotes the shortest migration length, H denotes the channel height, ULThe lateral migration rate is shown, and U represents the particle diameter.
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| CN113866074A (en) * | 2021-09-27 | 2021-12-31 | 四川成电医联科技咨询有限公司 | Impedance method's leucocyte classification count micro-fluidic chip based on position compensation |
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