CN113866240B - Leukocyte detection electrode structure and method based on measured electrical impedance correction - Google Patents
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Abstract
The invention provides a white blood cell detection electrode structure and a white blood cell detection electrode method based on measured electrical impedance correction. The ratio of the diagonal transmission time to the vertical transmission time of the cell, which is measured by the electrode structure, is a dimensionless number drawn relation curve, and the measurement result is corrected. The problem of inaccurate data which cannot be avoided by adopting a multi-electrode parallel structure is effectively solved, so that the measurement 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 measured electrical impedance correction.
Background
The leucocyte is used as a characteristic index of some diseases, has great significance for clinical diagnosis, and doctors can assist in judging the disease condition of patients according to the detected results. The appearance of the microfluidic chip brings the traditional biochemical detection into the microscopic world, has the advantages of small required sample injection 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 dimensions of microfluidic chips are typically several micrometers to tens of micrometers, which are similar to the dimensions of cells. In addition, the chip network channel structure is favorable for accurately controlling cells. Therefore, the miniaturization and portability of the flow cytometer are realized by adopting the microfluidic technology, and the flow cytometer has special advantages. The micro-channel section in the micro-fluidic chip has smaller characteristic size, less required sample injection amount of tens to hundreds of micrometers, higher flux of the chip and high detection speed, and can realize rapid detection of samples. In addition, the combination of the microfluidic chip and the intelligent technology brings the portability of the chip into play, facilitates 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 and rapid large-scale micro-nano particle control development in the future.
At present, a microfluidic cell analyzer mainly adopts an electrical impedance principle to count and classify cells, and the specific principle is as follows:
Blood cells are a poor conductor, and a leukocyte suspension is prepared by diluting and hemolyzing a blood sample. 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 inlet of the channel to allow blood cells to flow in from the inlet. As the cell suspension passes through the microfluidic channel, a change in impedance between the two electrodes occurs due to the low conductivity of the cells. Large cells produce a large impedance and smaller cells produce a relatively small impedance, so that the voltage output by the electrodes changes instantaneously to produce a pulse signal, which is referred to as a pass pulse. The extent of the voltage increase depends on the cell volume, the larger the resulting voltage change, and the higher the amplitude of the generated pulse. By measuring these pulse sizes, the cell volume can be determined; recording the number of these pulses can give a result of cell counting; by selecting the pulse size generated by each cell, different cell types can be distinguished and analyzed.
However, the different positions of the cell flowing in the microfluidic channel affect the magnitude of the detection signal, so that if the cells are classified according to the magnitude of the detection signal, an error condition occurs in which the same type of cells are classified into different types. In order to solve the problems of easy aggregation, overlapping and random positions of cell liquid flow and then influence the classification and counting of subsequent cells, scientists design a sheath flow technology to correct the cell. Sheath flow has become an important method for particle focusing and for restricting the flow area of the sample solution as an early particle manipulation method occurs. According to the definition of the Reynolds number, the flow state of the sample solution in the flow channel is basically stable to be laminar by the micron-scale flow channel characteristic dimension, and the sample solution can be reduced to be a trickle under the clamping and forcing action of the sheath flow, so that the focusing of internal sample particles is realized. This fluid encapsulates the flow of another liquid or particle, known as sheath flow, and the encapsulating liquid acts like a scabbard, and is therefore known as sheath fluid. Under certain conditions, when the speed and pressure of the sheath fluid are far greater than those of the fluid wrapped by the sheath fluid, the sheath fluid and the fluid can be driven to be coaxial but kept in a separated and mutually independent state. If the cell suspension is encapsulated, the cells are caused to pass through the sorting counting zone in a single row to effect fluid focusing. However, sheath flow focusing techniques add complexity to the system, especially two-dimensional focusing of flat plate structures, while consuming a significant amount of additional fluid. Meanwhile, the focusing width of the sample solution in the sheath flow particle focusing chip is inversely proportional to the sample injection amount of the sheath flow, but because the focusing width of the sample solution has a limit value, the focusing accuracy of internal particles can be limited, if the sheath flow flowing state is not ideal, such as the sheath flow layer is too thick or the direction deviates, cells or particles to be detected can form aggregation or deviate from a detection plane, the detection accuracy and stability are affected, and misjudgment is easy to cause.
Disclosure of Invention
Aiming at the technical defects existing 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 nonuniform electric field.
In order to achieve the technical purpose of the invention, the invention adopts the following technical scheme:
The utility model provides a white blood cell detection electrode structure based on measurement electrical impedance correction, electrode structure adopts parallel electrode structure to set up many pairs of electrodes, including two pairs of perpendicular measuring electrodes, two pairs of diagonal measuring electrodes and a pair of reference electrode, the reference electrode sets up between two pairs of perpendicular measuring electrodes, two pairs of diagonal measuring electrodes set up respectively in perpendicular measuring electrode's outside, two pairs of diagonal measuring electrodes constitute diagonal measuring differential circuit for measuring cell diagonal transmission current, two pairs of perpendicular measuring electrodes constitute perpendicular measuring differential circuit for measuring cell vertical transmission current.
The reference electrode is used to remove the cross current between the diagonally opposed electrodes of the two pairs of vertical measurement electrodes, thereby making the impedance signal independent of the positional factors.
Preferably, the two pairs of vertical measurement electrodes are a first vertical measurement electrode and a second vertical measurement electrode, and the two pairs of diagonal measurement electrodes are a first diagonal measurement electrode and a second diagonal measurement 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.
If the measurement currents are respectively set to be I 1、i2、i3、i4 in sequence, the vertical measurement differential current I TSV is I 3－i2, and the diagonal measurement differential current I OBQ is I 4－i1.
In another aspect of the present invention, there is also provided a leukocyte detection method based on correction of measured electrical impedance, comprising the steps of:
1) On the basis of three pairs of parallel electrode structures, a pair of measuring electrodes are respectively externally added at the boundaries of two sides to form the cell detection electrode structure, and alternating voltage is applied;
2) Injecting the leukocyte dilution liquid into the fluid channel between the parallel electrodes through the micropump, and measuring cell impedance signals;
3) Obtaining a distribution curve of the white blood cells according to the standard impedance signal-cell number relation;
4) The cell distribution results were corrected using the following formula:
Where y=Δt OBQ/ΔtTSV,ΔtOBQ is the diagonal transport time of the cell, Δt TSV is the vertical transport time of the cell, b is the ratio of the electrode width to the channel height, c is the ratio of the movement of the cell at the center position Δt OBQ/ΔtTSV.
Further, the three-pair parallel electrode structure includes two pairs of vertical measurement electrodes and a pair of reference electrodes disposed between the two pairs of vertical measurement electrodes.
Further, the added measuring electrode is a diagonal measuring electrode, and is used for calculating diagonal transmission time of the cell.
Further, the standard impedance signal-cell number relationship is measured by setting different numbers and particle size of the white blood cell injection electrode structure.
The beneficial effects of the invention are as follows:
The invention measures the parameter of the additional diagonal electrode transmission time by adding the measuring electrodes at the boundaries of two sides, and corrects the measuring result according to the fact that the ratio of the diagonal transmission time Deltat OBQ to the cell vertical transmission time Deltat TSV is a dimensionless number drawing relation curve. The invention is based on the white blood cell detection technology of measuring electrical impedance correction, and can obtain high-quality impedance signals without any cell focusing method. The invention prevents the impedance signal amplitude change of the non-central cells from the influence of the motion position, effectively eliminates the error caused by the factor, solves the problem of limited precision and quality of the data acquisition signal caused by some parallel electrode structures, and promotes the wider application of 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 six-electrode parallel structure and a simulation diagram (b) of a detection signal;
FIG. 3 is a schematic diagram (a) of a ten-electrode parallel structure and a simulation diagram of a detection signal according to the present invention; b-d are corresponding to impedance signal waveform diagrams obtained when the cells respectively move from the top, middle and bottom positions to flow through the channel;
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 the grain sizes of 5um, 6um and 7um; d is a mixed density plot of three types of cells flowing together through the channel;
FIG. 6 is a graph of impedance signal versus quantity; a is the data of the uncorrected independent measurement of the three types of cells, corresponding to a-c in fig. 5; b is data from a mixed assay of three classes of cells, corresponding to FIG. 5d; e is an uncorrected velocity density plot of the velocity of the three types of cells versus the impedance signal; f is a corrected velocity density plot of velocity versus impedance signal for three classes of cells.
Detailed Description
The following description of the present invention will be made more complete and clear in view of the detailed description of the invention, which is to be taken in conjunction with the accompanying drawings that illustrate only some, but not all, of the embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention designs a novel white blood cell detection technology based on measurement electrical impedance correction of non-sheath flow, which can correct impedance signals of cell detection only by simple calibration of a given chip structure, so that the impedance signals are independent of the influence of the vertical position of the cell and the flow velocity of suspension. The invention adopts a differential current measurement mode to measure the vertical transmission time and the oblique transmission time of cells passing through the channel by utilizing a plurality of pairs of electrodes, and corrects the motion trail of the cells in the microfluid by utilizing the measurement result, thereby effectively compensating the result error caused by the nonuniform 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 current generated by the application of voltages of different frequencies reflect the dielectric properties of the cells. Fig. 1a is a schematic diagram of a four-electrode parallel structure, and fig. b is a simulation diagram of a detection signal thereof. When the same cell type moves through the channel at three different locations in the figure, the rate of flow will be different. It can be seen that the change node positions in the horizontal direction of the impedance signal of the same cell are the same, but the corresponding signal magnitude results are different in the vertical position, so that the cell cannot be classified only by the time it takes for the cell to flow through the channel or the impedance signal magnitude.
In order to reduce the cross current and reduce the error of the impedance signal, two reference ground electrodes can be added on the basis of four electrodes, as shown in fig. 2a. Although these reference ground electrodes may remove cross currents between diagonally opposed electrodes, thereby making the impedance signal independent of positional factors. But this approach does not completely eliminate the error as shown in fig. 2 b. The signal detected when flowing 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. Thus, correction of the vertical direction factor of the signal requires a unique correction method.
The invention is based on the above structure, and a pair of measuring electrodes are respectively added at the boundaries of two sides, the specific structure is shown in a figure 3a, the electrode structure adopts a parallel electrode structure to arrange a plurality of pairs of electrodes, and the parallel electrode structure 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 at 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 the vertical transmission current of cells. The reference electrode is used to remove the cross current between the diagonally opposed electrodes of the two pairs of vertical measurement electrodes, thereby making the impedance signal independent of the positional factors.
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 vertical measuring electrode, and a second diagonal measuring electrode. If the measurement currents are respectively set to be I 1、i2、i3、i4 in sequence, the vertical measurement current I TSV is I 3－i2, and the diagonal measurement current I OBQ is I 4－i1.
Compared to the six-electrode structure of fig. 2, the electrode structure of the present application can additionally measure the diagonal transit time Δt OBQ of the cell, and this parameter is independent of the vertical transit time Δt TSV of the cell. In FIG. 3, b-d correspond to waveforms of impedance signals obtained when cells move through the channel from the top, middle and bottom positions, respectively. The distances between two signal peaks of Deltax TSV are the same and 80um, and the distances Deltax OBQ between diagonal current peaks are different and 105, 120 and 135um respectively. Although both Δx TSV and the transit time Δt of the cells are related to the flow rate of the cell suspension, the values of Δx OBQ/ΔxTSV and Δt OBQ/ΔtTSV are dimensionless numbers and are independent of the flow rate and are related only to the particle size of the cells, and thus can be used to provide an independent measure of cell size, correcting the impedance signal of non-central cells.
As shown in FIG. 4, the impedance signal diagrams of the cells at different positions are shown, and the outer sides of the impedance signal diagrams respectively correspond to the impedance signal diagrams of the cells at the positions pointed by the arrows. It can be seen that the impedance measured by the cells at different locations is different, indicating the reason why the impedance signal magnitude cannot be used to classify the cells. The black circles are experimental results, and stars are simulation results, so that the two results are on the same parabolic curve, and have high consistency. The center cell transit time ratio Δt OBQ/ΔtTSV in the graph was about 1.5, which is consistent with the calculation of the value 120 μm/80 μm=1.5 measured when the cell in fig. 3c moves in the center of the channel. Whereas cells moving in a non-center, i.e. top or bottom, have a ratio of Δt OBQ/ΔtTSV that varies from location to location.
The technical scheme of the application is explained below in connection with specific experimental operations.
Three types of cells, namely 5um, 6um and 7um, are respectively injected into the channel through the micropump, impedance signals of the cells flowing through the channel are measured, an impedance signal-transmission time relation graph (figure 5) is drawn, a curved white lump is an actual relation graph obtained by measurement, and a broken line is a curve obtained by fitting. FIGS. 5a-c are graphs of the mixed density of cells of 5um, 6um, and 7um particle sizes, respectively, and FIG. 5d is a graph of the mixed density of three types of cells flowing together through a channel. It can be found that the three relationship curves have similar parabolic trend, and the parabolic relationships presented by different types of cells are different, and the specific relationship can be obtained by parabolic function fitting:
X＝a[1+b(Y-c)2]
Where a is the particle size of the cell, b represents the ratio of the electrode width of the microfluidic channel to the channel height, which varies with the peak height of the impedance signal when the cell moves non-centrally, and c is the ratio of the cell movement at the central position Δt OBQ/ΔtTSV (the median value in the experiment of the present invention is 120 μm/80 μm=1.5 as mentioned above).
Fitting parameters are shown in table 1:
Table 1 fitting parameters
It is known that the constants b and c in the function are not affected by the cell size, and the average value of b and c is taken and substituted into the expression to calculate the parabolic curve equation. The white dashed line is a fitted parabolic plot and it can be seen that experimental data is perfectly fitted. The consistency relation between the fitting curve and experimental data can be used for correcting the error influence of any cell caused by the motion height under the given channel and electrode size, and obtaining the accurate particle size.
As shown in fig. 6, fig. 6a and b show uncorrected histogram datasets for the three cell types of fig. 5, where fig. a is data measured separately for each of the three cell types, corresponding to fig. 5 a-c, and fig. 6b is data for a mixed detection of the three cell types, corresponding to fig. 5d. It can be seen that the histogram data distribution is significantly scattered and inclined due to 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 as follows, and the corrected result is set as Z corrected 1/3:
Where y=Δt OBQ/ΔtTSV,ΔtOBQ is the diagonal transport time of the cell, Δt TSV is the vertical transport time of the cell, b is the ratio of the electrode width to the channel height, c is the ratio of the movement of the cell at the center position Δt OBQ/ΔtTSV of 1.5.
The corrected data are plotted as c and d in fig. 6, which can be seen as a perfect gaussian distribution. In fig. 6, e is an uncorrected velocity density plot of velocities of three types of cells with respect to impedance signals, and it can be seen that the velocity of movement of any type of cell is not constant, which indicates the result of different velocities caused by different positions of cell movement, and at the same time, the density plots of the three types of cells intersect, for example, when the horizontal axis |z corrected|1/3 =6, the corresponding cell types have 6um and 5um, so that the difference in position causes the velocity difference, thereby causing the difference in impedance to affect the determination of the cell types. In fig. 6 f is a velocity density map obtained by correcting the data by the correction method, each cell type after correction has independent density distribution, no intersection, and cell classification counting can be accurately performed. This shows that the correction technique 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 understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to 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 (1)
1. A white blood cell detection method based on measured electrical 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 externally added at the boundaries of two sides to form the cell detection electrode structure, and alternating voltage is applied;
2) Injecting the leukocyte dilution liquid into the fluid channel between the parallel electrodes through the micropump, and measuring cell impedance signals;
3) Obtaining a distribution curve of the white blood cells according to the standard impedance signal-cell number relation;
4) The cell distribution results were corrected using the following formula: wherein/> ，For cell diagonal transit time,/>For the vertical transport time of the cells, b is the ratio of the electrode width to the channel height, c is the movement of the cells in the central position/>Is a ratio of (2);
The electrode structure 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 for measuring 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 the cells;
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 sequentially comprises a first diagonal measuring electrode, a first vertical measuring electrode, a reference electrode, a second vertical measuring electrode and a second diagonal measuring electrode.
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| US4835457A (en) * | 1984-08-24 | 1989-05-30 | Universite Rene Descartes | Apparatus and process for determining the deformability of the red corpuscles in the blood |
| JP2005236922A (en) * | 2004-02-23 | 2005-09-02 | Olympus Corp | Imaging device, driving method for imaging device, and driving program therefor |
| CN109752307A (en) * | 2017-11-03 | 2019-05-14 | 夏普生命科学（欧洲）有限公司 | Coplanar micro- impedance blood count equipment |
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| JP4745056B2 (en) * | 2002-07-20 | 2011-08-10 | アセア バイオサイエンシーズ，インク． | Apparatus and method for measuring cells and fine particles by impedance |
| JP5617532B2 (en) * | 2010-10-29 | 2014-11-05 | ソニー株式会社 | Dielectric cytometry apparatus and cell sorting method using dielectric cytometry |
| DE102011057045A1 (en) * | 2011-12-23 | 2013-06-27 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Monitoring cell and method for analyzing cell and tissue growth |
| GB2501870B (en) * | 2012-04-13 | 2018-07-18 | Smartcare Tech Limited | Improvements in and relating to sample measurement |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4835457A (en) * | 1984-08-24 | 1989-05-30 | Universite Rene Descartes | Apparatus and process for determining the deformability of the red corpuscles in the blood |
| JP2005236922A (en) * | 2004-02-23 | 2005-09-02 | Olympus Corp | Imaging device, driving method for imaging device, and driving program therefor |
| CN109752307A (en) * | 2017-11-03 | 2019-05-14 | 夏普生命科学（欧洲）有限公司 | Coplanar micro- impedance blood count equipment |
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| Title |
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| 微流体流式细胞仪的关键技术;赵精晶;尤政;;清华大学学报(自然科学版)(11);第3-10页 * |
| 稳定微环境微流控细胞培养芯片的设计与制备;马亚会;刘冲;魏娟;刘海侠;李经民;;纳米技术与精密工程(04);第14-18页 * |
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