CN113866240A - Leukocyte detection electrode structure and method based on measurement impedance correction - Google Patents
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Abstract
The invention provides a leucocyte detection electrode structure based on measurement electrical impedance correction and a method thereof. The ratio of the diagonal transmission time and the vertical cell transmission time measured by the electrode structure is a dimensionless number-free drawn relation curve, and the measurement result is corrected. The problem of data inaccuracy which cannot be avoided by adopting a multi-electrode parallel structure is effectively solved, so that the measuring result and the real result have high consistency, the reliability of the microfluid detection result is improved, and the method is widely applied.
Description
Technical Field
The invention belongs to the technical field of fluid chips, and particularly relates to a leukocyte detection electrode structure and a leukocyte detection electrode method based on measurement and electrical impedance correction.
Background
The leucocyte is used as the characteristic index of some diseases, which has very important significance for clinical diagnosis, and doctors can assist in judging the illness state of patients according to the detected result. The appearance of the microfluidic chip brings the traditional biochemical detection into the microscopic world, has the advantages of small sample amount, high detection speed, low cost, high portability and the like, realizes early diagnosis and effective prognosis evaluation of diseases, and provides an important means for improving the cure rate of the diseases.
The channel dimension of the microfluidic chip is generally several micrometers to tens of micrometers, which is similar to the dimension of a cell. In addition, the chip network channel structure is beneficial to the accurate control of the cells. Therefore, the flow cytometer is miniaturized and portable by adopting the microfluidic technology, and has special advantages. The characteristic dimension of the section of the micro-channel in the micro-fluidic chip is small, the micro-channel is between dozens of microns and hundreds of microns, the required sample injection amount is small, the flux of the chip is high, the detection speed is high, and the rapid detection of a sample can be realized. In addition, the combination of the microfluidic chip and the intelligent technology enables the portability of the chip to be brought into full play, facilitates the early diagnosis of patients and protects the privacy of the patients to a great extent. The advantages of the microfluidic chip are numerous, and the microfluidic chip is a primary carrier for the accurate, rapid and large-scale micro-nano particle control development in the future.
Currently, the micro-fluidic cell analyzer mainly adopts the electrical impedance principle to count and classify cells, and the specific principle is as follows:
the blood cells are a poor conductor, and are prepared into leukocyte suspension after being diluted and hemolyzed. A constant current is applied to the chip and, since the current is stable, the voltage on the two electrodes is also constant according to ohm's law. Negative pressure is applied at the channel inlet to cause blood cells to flow in from the inlet. When a cell suspension passes through a microfluidic channel, a change in impedance occurs between the two electrodes due to the low conductivity of the cells. Large cells produce large impedance and smaller cells produce relatively small impedance, so that the voltage output by the electrodes changes instantaneously to generate a pulse signal, which is called a pass pulse. The degree of voltage increase depends on the cell volume, with larger volumes causing larger voltage changes and higher pulse amplitudes. Cell volume can be determined by measuring the size of these pulses; the number of the pulses is recorded to obtain a cell counting result; by selecting the pulse size generated by various cells, different types of cells can be distinguished and analyzed.
However, different positions of the cells flowing in the microfluidic channel affect the magnitude of the detection signal, so if the cells are classified according to the difference of the magnitude of the detection signal, the cells of the same type are classified into different types. In order to solve the problems that the cell liquid flow is easy to agglomerate, overlap and have random positions, and then the classification and counting of subsequent cells are influenced, scientists design a sheath flow technology to correct the cell liquid flow. Sheath flow has become an important method for particle focusing and for restricting the sample solution flow area as an early particle manipulation method has emerged. According to the definition of Reynolds number, the characteristic dimension of the flow channel in micron order enables the flow state of the sample solution in the flow channel to be basically stable as laminar flow, and the sample solution can be reduced into a thin flow under the action of sheath flow clamping, so that the focusing of the internal sample particles is realized. This flow of one fluid envelopes the flow of another liquid or particle, known as sheath flow, and the encapsulating liquid resembles a scabbard and is therefore called sheath fluid. Under certain conditions, when the velocity pressure of the sheath fluid is much larger than that of the fluid wrapped by the sheath fluid, the sheath fluid and the fluid can be driven to be coaxial but to be kept separate and independent from each other. If a cell suspension is packed, the cells are caused to pass through the sorting count zone in a single row to achieve fluid focusing. However, the sheath flow focusing technique adds complexity to the system, especially for two-dimensional focusing of flat plate structures, and consumes a large amount of extra fluid to be wasted. Meanwhile, the focusing width of the sample solution in the sheath flow particle focusing chip is inversely proportional to the sampling amount of the sheath flow, but the focusing accuracy of the internal particles is limited due to the limit value of the focusing width of the sample solution, and if the sheath flow flowing state is not ideal, such as the sheath flow layer is too thick or the direction deviates, the cells or particles to be detected form aggregates or deviate from a detection plane, so that the detection accuracy and stability are influenced, and misjudgment is easily caused.
Disclosure of Invention
Aiming at the technical defects in the prior art, the differential current measurement mode utilizes a plurality of pairs of electrodes to measure the vertical transmission time and the oblique transmission time of cells passing through a channel, and utilizes the measurement result to correct the motion track of the cells in the microfluid, thereby effectively compensating the result error caused by the non-uniform electric field.
In order to realize the technical purpose of the invention, the invention specifically adopts the following technical scheme:
the electrode structure adopts a parallel electrode structure to arrange a plurality of pairs of electrodes and comprises two pairs of vertical measuring electrodes, two pairs of diagonal measuring electrodes and a pair of reference electrodes, wherein the reference electrodes are arranged between the two pairs of vertical measuring electrodes, the two pairs of diagonal measuring electrodes are respectively arranged on the outer sides of the vertical measuring electrodes, the two pairs of diagonal measuring electrodes form a diagonal measuring differential circuit and are used for measuring cell diagonal transmission current, and the two pairs of vertical measuring electrodes form a vertical measuring differential circuit and are used for measuring cell vertical transmission current.
The reference electrode is used for removing cross current between two pairs of vertical measuring electrodes and diagonal counter electrodes, so that the impedance signal is independent of a position factor.
Preferably, the two pairs of vertical measuring electrodes are a first vertical measuring electrode and a second vertical measuring electrode, and the two pairs of diagonal measuring electrodes are a first diagonal measuring electrode and a second diagonal measuring electrode.
The parallel electrode structure is sequentially a first diagonal measuring electrode, a first vertical measuring electrode, a reference electrode, a second vertical measuring electrode and a second diagonal measuring electrode.
Respectively setting the measuring current as i1、i2、i3、i4Then the differential current I is measured verticallyTSVIs i3－i2Measuring the differential current I diagonallyOBQIs i4－i1。
In another aspect of the present invention, there is also provided a leukocyte detection method based on measurement impedance correction, including the following steps:
1) on the basis of three pairs of parallel electrode structures, a pair of measuring electrodes are respectively added at the boundaries of two sides to form the cell detection electrode structure, and alternating voltage is applied;
2) injecting a leukocyte diluent into a fluid channel between the parallel electrodes through a micropump, and measuring a cell impedance signal;
3) obtaining a distribution curve of the white blood cells according to the relation of the standard impedance signals and the cell number;
4) the cell distribution results were corrected using the following formula:
wherein, Y is ═ Δ tOBQ/ΔtTSV，ΔtOBQFor the diagonal transit time of the cell,. DELTA.tTSVThe cell vertical transport time, b the ratio of the electrode width to the channel height, c the cell movement at the center position Δ tOBQ/ΔtTSVThe ratio of (a) to (b).
Further, the three pairs of parallel electrode structures include two pairs of vertical measurement electrodes and a pair of reference electrodes disposed between the two pairs of vertical measurement electrodes.
Furthermore, the added measuring electrodes are opposite angle measuring electrodes and are used for calculating opposite angle transmission time of the cells.
Further, the standard impedance signal-cell number relation is obtained by setting different numbers and particle sizes of leukocyte injection electrode structures for measurement.
The invention has the beneficial effects that:
the invention measures the parameter of the transmission time of the additional diagonal electrode by adding the measuring electrode at the boundary of two sides according to the transmission time delta t of the diagonal electrodeOBQAnd cell vertical transport time Δ tTSVThe ratio of (A) is a dimensionless number-free drawn relation curve, and the measurement result is corrected. The invention is based on the white blood cell detection technology of measuring electrical impedance correction, can obtain high-quality impedance signal without any cell focusing method. The invention ensures that the impedance signal amplitude change of the non-central cell is not influenced by the motion position, effectively eliminates the error caused by the factor, solves the problem of limited precision and quality of data acquisition signals caused by some parallel electrode structures, and promotes the wider application of the microfluidic cytometry.
Drawings
FIG. 1 is a schematic diagram (a) of a four-electrode parallel structure and a simulation diagram (b) of a detection signal;
FIG. 2 is a schematic diagram (a) of a parallel structure of six electrodes and a simulation diagram (b) of a detection signal;
FIG. 3 is a diagram of a parallel structure of ten electrodes (a) and a simulation diagram of a detection signal according to the present invention; wherein, the b-d corresponding cells respectively move from the top, the middle and the bottom to flow through the channel to obtain impedance signal oscillograms;
FIG. 4 is a graph of cell impedance signals at different locations;
FIG. 5 is a graph of three different cell densities; wherein a-c are respectively 5um, 6um and 7um in particle size; d is a mixed density map of the three types of cells flowing together through the channel;
FIG. 6 is a graph of impedance signal versus quantity; a is data measured individually for the three types of cells without correction, corresponding to a-c in FIG. 5; b is data from a mixed assay of three types of cells, corresponding to FIG. 5 d; e is an uncorrected velocity density plot of velocity of the three types of cells versus impedance signal; f is a corrected velocity density plot of the velocities of the three types of cells versus the impedance signal.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to specific embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention designs a novel leukocyte detection technology based on measurement impedance correction without sheath flow, and only needs to simply calibrate a given chip structure, so that impedance signals for cell detection can be corrected, and the impedance signals are independent of the influence of the vertical position of cells and the flow rate of suspension. The invention adopts a differential current measurement mode to measure the vertical transmission time and the oblique transmission time of the cells passing through the channel by using a plurality of pairs of electrodes, and corrects the motion track of the cells in the microfluid by using the measurement result, thereby effectively compensating the result error caused by the non-uniform electric field.
Microfluidic cytometry often samples the structure of parallel electrodes, applies alternating voltages to two pairs of electrodes, obtains cell impedance signals by measuring differential currents, and changes in the currents generated by applying voltages of different frequencies reflect the dielectric properties of cells. Fig. 1a is a schematic diagram of a parallel structure of four electrodes, and the corresponding diagram b is a simulation diagram of the detection signal. When the same type of cell moves through the channel at three different positions in the figure, the velocity of the flow through will be different. It can be seen that the positions of the nodes of the impedance signal change in the horizontal direction are the same for the same cell, but the results of the corresponding signal magnitudes are different in the vertical position, so that the cell cannot be classified only by the time when the cell flows through the channel or the magnitude of the impedance signal.
In order to reduce the magnitude of the cross current and reduce the error of the impedance signal, two more reference ground electrodes can be added on the basis of four electrodes, as shown in fig. 2 a. Although these reference ground electrodes may remove cross currents between diagonally opposite electrodes, thereby making the impedance signal independent of the location factor. However, this approach does not completely eliminate the error, as shown in fig. 2 b. The signal detected when the signal flows from a non-central location is still higher than those of the cell flowing in the center, and this phenomenon is more pronounced when the aspect ratio of the channel is larger. Therefore, a unique correction method is required for correcting the vertical direction factor of the signal.
The invention adds a pair of measuring electrodes on the boundary of two sides on the basis of the structure, the concrete structure is shown as a in figure 3, the electrode structure adopts a parallel electrode structure to set a plurality of pairs of electrodes, including two pairs of vertical measuring electrodes, two pairs of diagonal measuring electrodes and a pair of reference electrodes, the reference electrode is set between the two pairs of vertical measuring electrodes, the two pairs of diagonal measuring electrodes are respectively set at the outer side of the vertical measuring electrodes, the two pairs of diagonal measuring electrodes form a diagonal measuring differential circuit for measuring the diagonal transmission current of cells, and the two pairs of vertical measuring electrodes form a vertical measuring differential circuit for measuring the vertical transmission current of cells. The reference electrode is used to remove cross current between two pairs of perpendicular measurement electrodes and the diagonal counter electrode, thereby making the impedance signal independent of the position factor.
Wherein the two pairs of vertical measuring electrodes are a first vertical measuring electrode and a second vertical measuring electrode, and the two pairs of diagonal measuring electrodes are a first diagonal measuring electrode and a second diagonal measuring electrode. The parallel electrode structure is sequentially a first diagonal measuring electrode, a first vertical measuring electrode,A reference electrode, a second perpendicular measurement electrode, and a second diagonal measurement electrode. Respectively setting the measuring current as i1、i2、i3、i4Then the current I is measured verticallyTSVIs i3－i2Measuring the current I diagonallyOBQIs i4－i1。
Compared with the six-electrode structure of FIG. 2, the electrode structure of the present application can additionally measure the diagonal transmission time Δ t of the cellOBQAnd the parameter is independent of the cell vertical transport time deltatTSV. In FIG. 3, b-d correspond to the waveforms of the impedance signals obtained when the cell moves through the channel from the top, middle and bottom positions, respectively. Wherein Δ xTSVThe distance between the two signal peaks is the same, and is 80um, and the distance delta x between the diagonal current peaksOBQDifferent, 105, 120 and 135um, respectively. Although Δ xTSVAnd the cell transit time Δ t are both related to the flow rate of the cell suspension, but Δ xOBQ/ΔxTSVAnd Δ tOBQ/ΔtTSVThe value of (A) is a dimensionless number and is independent of flow rate and is dependent only on the size of the cell size, and therefore can be used to provide an independent measure of cell size, correcting for impedance signals in non-central cells.
As shown in FIG. 4, the impedance signal diagrams of the cells at different positions are shown, and the impedance signal diagrams of the cells at the positions corresponding to the arrows on the outer sides are shown. It can be seen that the measured impedance of the cells at different positions is different, which indicates that the impedance signal can not be used to classify the cells. The black circles are the results of the experiment, and the stars are the results of the simulation, and it can be seen that the results of the two are on the same similar parabolic curve, and have high consistency. The ratio of the central cell transit times Δ t in the figureOBQ/ΔtTSVAbout 1.5, which is consistent with the calculation of figure 3c for the value 120 μm/80 μm-1.5 measured when the cells are moving in the channel center. While cells moving in the non-center, i.e., top or bottom, their Δ tOBQ/ΔtTSVThe ratio varies from location to location.
The technical scheme of the present application is explained below with reference to specific experimental operations.
Three types of cells of 5um, 6um and 7um cells are respectively injected into the channel through the micropump, impedance signals when the cells flow through the channel are measured, and an impedance signal-transmission time relation curve graph (figure 5) is drawn, wherein a curved white ball in the graph is an actual relation graph obtained by measurement, and a dotted line is a curve obtained by fitting. FIGS. 5a-c are graphs of the mixed density of 5um, 6um, and 7um cells, respectively, and FIG. 5d is a graph of the mixed density of three types of cells flowing together through the channel. It can be found that the relationship curves of the three have similar parabolic trends, and the parabolic relationships presented by different types of cells are different, and the specific relationship can be obtained by fitting a parabolic function:
X＝a[1+b(Y-c)2]
wherein a is the particle size of the cell, b represents the ratio of the electrode width of the microfluidic channel to the channel height, and the value varies with the peak height of the impedance signal when the cell moves in a non-central position, and c is the movement of the cell at the central position by delta tOBQ/ΔtTSVThe ratio (value of 120 μm/80 μm in the experiment of the present invention is 1.5 as mentioned above).
The fitting parameters are shown in table 1:
TABLE 1 fitting parameters
It can be seen that constants b and c in the function are not affected by the cell size, and b and c are averaged and substituted into the expression to calculate the parabolic curve equation. The white dotted line is a fitted parabolic graph, and it can be seen that the experimental data are perfectly fitted. The consistency relationship between the fitting curve and experimental data can be used for correcting the error influence of the movement height of any cell under the given channel and electrode sizes, and the accurate particle size is obtained.
As shown in fig. 6, fig. 6a and b show the uncorrected histogram data sets for the three types of cells in fig. 5, where a is the data measured separately for each of the three types of cells, corresponding to a-c in fig. 5, and fig. 6b is the data for the mixed detection of the three types of cells, corresponding to fig. 5 d. It can be seen that the distribution of the histogram data is obviously dispersed and inclined under the influence of the cell movement position factors, and the uncorrected distribution cannot accurately calculate the cell particle size for classification.
The obtained result is corrected by setting the corrected result as Zcorrected 1/3：
Wherein, Y is ═ Δ tOBQ/ΔtTSV，ΔtOBQFor the diagonal transit time of the cell,. DELTA.tTSVThe cell vertical transport time, b the ratio of the electrode width to the channel height, c the cell movement at the center position Δ tOBQ/ΔtTSVThe ratio of (1.5).
The corrected data are plotted as c and d in fig. 6, and it can be seen that the data are perfect gaussian distribution diagrams. FIG. 6 e is an uncorrected velocity density plot of velocity of three cell types versus impedance signal, showing that the velocity of any cell type is not constant, indicating the results of velocity differences due to differences in the location of cell motion, and that the density plots of the three cell types intersect, e.g., the horizontal axis | Zcorrected|1/3When the cell type is 6, since the cell type is 6um and 5um, the determination of the cell type is affected by the difference in impedance due to the difference in speed caused by the difference in position. In fig. 6, f is a velocity density map obtained by correcting the data by the proposed correction method, and each corrected cell type has independent density distribution, and the cells can be classified and counted accurately without crossing. This shows that the correction technology provided by the invention can effectively eliminate the impedance signal change caused by the motion position factor.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (4)
1. The electrode structure is characterized in that a plurality of pairs of electrodes are arranged in a parallel electrode structure and comprise two pairs of vertical measuring electrodes, two pairs of diagonal measuring electrodes and a pair of reference electrodes, the reference electrodes are arranged between the two pairs of vertical measuring electrodes, the two pairs of diagonal measuring electrodes are respectively arranged on the outer sides of the vertical measuring electrodes, the two pairs of diagonal measuring electrodes form a diagonal measuring differential circuit for measuring diagonal transmission current of cells, and the two pairs of vertical measuring electrodes form a vertical measuring differential circuit for measuring vertical transmission current of the cells.
2. The structure of claim 1, wherein the two pairs of vertical measuring electrodes are a first vertical measuring electrode and a second vertical measuring electrode, and the two pairs of diagonal measuring electrodes are a first diagonal measuring electrode and a second diagonal measuring electrode.
3. The leucocyte detection electrode structure based on measured electrical impedance modification of claim 1, wherein the parallel electrode structure is a first diagonal measurement electrode, a first vertical measurement electrode, a reference electrode, a second vertical measurement electrode and a second diagonal measurement electrode in sequence.
4. A leukocyte detection method based on measurement impedance correction is characterized by comprising the following steps:
1) on the basis of three pairs of parallel electrode structures, a pair of measuring electrodes are respectively added at the boundaries of two sides to form the cell detection electrode structure, and alternating voltage is applied;
2) injecting a leukocyte diluent into a fluid channel between the parallel electrodes through a micropump, and measuring a cell impedance signal;
3) obtaining a distribution curve of the white blood cells according to the relation of the standard impedance signals and the cell number;
4) the cell distribution results were corrected using the following formula:
wherein, Y is ═ Δ tOBQ/ΔtTSV，ΔtOBQFor the diagonal transit time of the cell,. DELTA.tTSVThe cell vertical transport time, b the ratio of the electrode width to the channel height, c the cell movement at the center position Δ tOBQ/ΔtTSVThe ratio of (a) to (b).
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