JPH0146816B2 - - Google Patents

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention allows particles such as blood cells suspended in a liquid to pass through micropores, and detects the particles based on the difference in electrical impedance between the liquid and the particles. For particle analyzers of this type, even if the environment changes and the magnitude of the output signal from the particle detector changes, the gain (sensitivity) of the analyzer is automatically adjusted, and the output signal from the adjusted signal output line is adjusted automatically. This invention relates to a particle analyzer that outputs a signal of a constant size.

[Conventional technology]

Conventionally, particles such as blood cells are suspended in a liquid such as physiological saline, passed through micropores formed narrow enough for the particles to pass through, and the particles are separated based on the difference in electrical impedance between the liquid and the particles. A particle analyzer is used that detects particles and then analyzes the size of the particles based on the magnitude of the detection signal. However, in this particle analyzer, the impedance of the liquid itself changes depending on the temperature of the liquid and the concentration of electrolytes such as salt. Therefore, the detection sensitivity changes, and therefore, when comparing the changes over time of particles in different liquids or testing the change characteristics for various chemicals, it is necessary to calculate and correct the sensitivity changes in advance, or to One method is to attach an electrode for impedance measurement and adjust the sensitivity separately.

[Problem that the invention seeks to solve]

However, even if the former method (method of calculating and correcting sensitivity changes in advance) is adopted, for example by incorporating an automatic calculation device to perform correction calculations and outputting the corrected analysis results, different results may occur. It is necessary to input data each time the liquid is diluted, and the latter method (method of attaching an electrode for measuring the impedance of the liquid) not only complicates the equipment but also causes contamination between samples due to adhesion of the sample. There were some problems, such as: Regardless of which of the above methods is adopted, it is necessary to thoroughly clean the detection device with the liquid to be used next before changing to a liquid with a different electrical impedance.

Next, the results of experiments conducted by the present inventor will be explained. FIGS. 1 and 2 show the output signal waveforms of the particle detection device when the saline solution concentration is changed using the same particles. This measurement example is a result obtained by detecting a voltage change from a constant current source based on a difference in specific resistance. In other words, Figure 1 is an example of measurement using the concentration of normal saline (0.9% saline).
Figure 2 shows an example of the same particles suspended in 0.4% saline. Since the current is constant, the pulse is larger in 0.4% saline, where the absolute value of the impedance change is higher, and the detection sensitivity increases as shown in Figure 2. FIGS. 3 and 4 show the above differences using particle size distribution curves. FIG. 3 shows the case of 0.9% saline solution, and FIG. 4 shows the case of 0.4% saline solution. The solid line shows the cumulative particle size distribution curve, and the broken line shows the normal particle size distribution curve.

When implementing the method of adjusting the sensitivity of the device using standard particles as described above, even if particles with fairly uniform particle sizes are used, differences in particle size always occur and normally a normal distribution is exhibited. One possible method for this purpose is to obtain the average particle volume using an integration circuit and a division circuit, and adjust the sensitivity so that the average particle volume is always constant. However, this requires a complex circuit configuration, such as a circuit that performs high-speed AD conversion of detected pulses, a circuit that integrates these pulses, and a circuit that divides the integrated value by the number of detected pulses. The cost would be too high.

The present invention has been made in view of the above points, and aims to provide a particle analyzer that can automatically adjust sensitivity regardless of the concentration of a particle suspension and has a simple circuit configuration. be.

[Means for solving problems]

The particle analyzer of the present invention will be described with reference to the drawings. Particles suspended in a liquid are passed through micropores, and the particles are detected based on the electrical difference between the particles and the particle suspension liquid. A particle detection device 1 that generates an electric signal proportional to the particle size, a variable amplifier 2 connected to this particle detection device, and a high-level pulse signal monitoring circuit 4 connected in parallel to this variable amplifier via a switch 3. and a low level pulse signal monitoring circuit 5, a comparison circuit 6 connected to these monitoring circuits, a feedback circuit 7 provided between this comparison circuit and the variable amplifier, and an adjustment signal connected to the switch. output line 8;
When the particle detection device 1 is cleaned in advance with different particle suspension liquids and the outputs of the monitoring circuits 4 and 5 do not reach a constant ratio, a signal is transmitted to the variable amplifier 2 by the feedback circuit 7, and the output of the variable amplifier 2 is It is characterized in that the sensitivity is lowered and an adjusted signal is output from the adjustment signal output line 8.

As mentioned above, when changing to a different particle suspension liquid, it is necessary to clean the area around the detector with that liquid beforehand, and the present invention does not adjust the detection sensitivity of the device at the same time as this cleaning. That is. As the sensitivity adjusting means in the present invention, particles such as plastic particles, which do not change even if the electrolyte concentration such as common salt is changed, are used. These plastic particles have their average volume or particle size distribution measured in advance and are used as standard particles.

[Effect]

A signal detected by the particle detection device 1 based on the impedance difference between the particles and the liquid and converted into a pulse is input to the variable amplifier 2. variable amplifier 2
The output is sent to a switch 3 for starting gain adjustment and to a subsequent counting circuit or other processing circuit. Now, when the switch 3 is closed to adjust the sensitivity, a signal is sent to the two monitoring circuits 4 and 5. As shown in FIGS. 6 and 7, the high level pulse monitoring circuit 4 monitors high level pulse signals, while the low level pulse signal monitoring circuit 5 monitors lower level pulse signals. The L level is set to a level at which pulses due to all standard particles slightly above the noise level can be confirmed. Moreover, the H level is, for example, in FIG.
It is set at a position where the number of particles is halved. The outputs of these two monitoring circuits 4 and 5 are converted into an analog voltage as the number of particles per unit time using a frequency/voltage converter, for example, and compared in a comparator circuit 6 so that the ratio is constant, and a feedback circuit 7 The signal is fed back to the variable amplifier 2. If the suspended liquid concentration, for example the saline concentration, changes and the
When the sensitivity changes as shown in the figure and FIG. 4, there is no difference between the L level and the H level and the set ratio is not reached, so a signal is transmitted from the feedback circuit 7 to lower the sensitivity. It operates to lower the sensitivity of the variable amplifier 2. Once the sensitivity is set, the sensitivity is maintained even if the switch 3 is opened, and the adjusted signal is output from the adjustment signal output line 8.

〔Example〕

Embodiments of the present invention will be described below based on the drawings. As shown in Figure 5, the particle analyzer of this example has the following features:
A particle detection device 1 that detects particles by passing particles suspended in a liquid through micropores based on the electrical difference between the particles and the particle suspension liquid, and generates an electric signal proportional to the size of the particles; A variable amplifier 2 connected to the particle detection device 1, and a high level pulse signal monitoring circuit 4 and a low level pulse signal monitoring circuit 5 connected in parallel to the variable amplifier 2 via a switch 3.
, a comparison circuit 6 connected to these monitoring circuits 4 and 5, a feedback circuit 7 provided between this comparison circuit 6 and the variable amplifier 2, and an adjustment signal output line connected to the switch 3. 8, the particle detection device 1 is cleaned in advance with different particle suspension liquids, and when the outputs of the monitoring circuits 4 and 5 do not reach a constant ratio, a signal is transmitted to the variable amplifier 2 by the feedback circuit 7. Then, variable amplifier 2
It is configured to automatically lower the sensitivity of the signal and output the adjusted signal from the adjustment signal output line 8.

In the apparatus configured as described above, a signal detected by the particle detection device 1 based on the impedance difference between the particles and the liquid and converted into a pulse is input to the variable amplifier 2. The output of the variable amplifier 2 is sent to a switch 3 for starting gain adjustment and to a subsequent counting circuit or other processing circuit.
Now, when the switch 3 is closed to adjust the sensitivity, a signal is sent to the two monitoring circuits 4 and 5. As shown in FIGS. 6 and 7, the high level pulse monitoring circuit 4 monitors high level pulse signals, while the low level pulse signal monitoring circuit 5 monitors lower level pulse signals. The L level is set to a level at which pulses due to all standard particles slightly above the noise level can be confirmed.
Further, the H level is set at a position where the number of particles is halved, as shown in FIG. 7, for example. The outputs of these two monitoring circuits 4 and 5 are converted into an analog voltage as the number of particles per unit time using a frequency/voltage converter, for example, and compared in a comparator circuit 6 so that the ratio is constant, and a feedback circuit 7 The signal is fed back to the variable amplifier 2. If the suspension concentration, for example the saline concentration, changes and the sensitivity changes as shown in Figures 2 and 4,
Since there is no difference between the L level and the H level and the set ratio is not reached, the feedback circuit 7
A signal is transmitted to lower the sensitivity of the variable amplifier 2, and the variable amplifier 2 operates to lower the sensitivity. Once the sensitivity is set, the sensitivity is maintained even if the switch 3 is opened, and the adjusted signal is output from the adjustment signal output line 8.

Next, an actual circuit example will be explained based on FIGS. 8 and 9. The device shown in FIG. 8 uses a high-level threshold circuit 10 and a frequency/voltage converter 11 instead of the high-level pulse signal monitoring circuit, and a low-level threshold circuit instead of the low-level pulse signal monitoring circuit. 12 and a frequency/voltage converter 13, the frequency/voltage converter 11 on the high level side
A double amplifier 14 is connected to the double amplifier 14.
A comparison amplifier 15 (voltage comparator) is connected to the frequency/voltage converter 13 on the low level side, and the comparison amplifier 15 is connected to the servo motor 1.
6 to the variable amplifier 2, and the feedback resistor 17 of the variable amplifier 2 is adjusted using the servo motor 16. Further, the device shown in FIG. 9 uses an AD conversion circuit 18 as the feedback circuit, and uses the AD-converted feedback signal to stepwise switch a plurality of resistors 20 instead of the feedback resistor 17. It is something. The other configurations are the same as in the case of FIG. The above L level system corresponds to the denominator of division, and for example, the particle concentration in the particle suspension liquid is always constant for standard particles, or the particle detector's micropores are clogged. As long as there is no contamination, the output of this system is always constant, so it is possible to form a feedback loop with an H level system. However, it is usually desirable to add one drop of concentrated standard particles when cleaning the detection section of the device and adjust the sensitivity using that liquid. Furthermore, since the number of particles passing through the micropores per unit time is easily affected by the viscosity of the liquid, it is necessary to provide a system based on the L level in consideration of fluctuations. Therefore, the sensitivity can be adjusted independently of the number or concentration of standard particles. In FIGS. 8 and 9, in order to detect the difference between the H level and the L level using the comparator amplifier 15, for convenience, the H level is doubled using the double amplifier 14. Although the voltage is made to match the voltage depending on the number of particles, the same effect can be obtained by providing a voltage dividing circuit using a resistor in the L level system.

The sensitivity is adjusted as described above, and the output signal is, for example, comparing the MCV (mean corpuscular volume) and particle size distribution curve of red blood cells with normal saline concentration (physiological saline) by changing the saline concentration. This is particularly effective when analyzing how changes occur over time. For such measurements, usually
It is customary to keep the temperature constant, and changes in liquid impedance due to temperature changes need not be taken into account. In normal MCV measurements of red blood cells, correction is performed by measuring temperature with a thermistor or the like and adding a parameter for impedance changes due to temperature changes to a variable amplifier.

[Effects of the Invention] Since the particle analyzer of the present invention is configured as described above, the sensitivity can be automatically adjusted regardless of the concentration of particles, and the circuit configuration is simple, so it is easier to use than conventional particle analyzers. This has the advantage that it can be easily incorporated into a counting device or the like.

[Brief explanation of drawings]

Figures 1 and 2 show the output signal waveforms of the particle detection device when the saline concentration is changed using the same particles, and Figure 1 is a waveform diagram for 0.9% saline;
Figure 2 is a waveform diagram for 0.4% saline, Figure 3 is a curve diagram showing the cumulative particle size distribution curve (solid line) and particle size distribution curve (dashed line) for 0.9% saline shown in Figure 1; Figure 4 is a curve diagram showing the cumulative particle size distribution curve (solid line) and particle size distribution curve (broken line) in the case of 0.4% saline shown in Figure 2, and Figure 5 shows an embodiment of the particle analyzer of the present invention. The configuration diagram, FIGS. 6 and 7 are explanatory diagrams showing the monitoring status of the pulse signal monitoring circuit, FIG. 8 is a systematic explanatory diagram showing another embodiment of the device of the present invention, and FIG. 9 is an explanatory diagram showing the monitoring state of the pulse signal monitoring circuit. FIG. 7 is a systematic explanatory diagram showing still another embodiment of the device. 1... Particle detection device, 2... Variable amplifier, 3...
...Switch, 4...High level pulse signal monitoring circuit, 5...Low level pulse signal monitoring circuit, 6...
Comparison circuit, 7... Feedback circuit, 8... Adjustment signal output line, 10... High level threshold circuit,
11... Frequency/voltage converter, 12... Low level threshold circuit, 13... Frequency/voltage converter, 1
4...2x amplifier, 15...comparison amplifier, 16...
...Servo motor, 17...Feedback resistance,
18...AD conversion circuit, 20...resistor.

Claims (1)

[Claims] 1. Particles suspended in a liquid are passed through micropores, and the particles are detected based on the electrical difference between the particles and the liquid in which the particles are suspended, and an electrical signal proportional to the size of the particles is generated. A particle detection device, a variable amplifier connected to this particle detection device, a high level pulse signal monitoring circuit and a low level pulse signal monitoring circuit connected in parallel to this variable amplifier via a switch, and these monitoring circuits. A particle detection device using different particle suspending liquids, comprising: a connected comparison circuit; a feedback circuit provided between the comparison circuit and the variable amplifier; and an adjustment signal output line connected to the switch. When the output of the monitoring circuit is not at a constant rate, the feedback circuit transmits a signal to the variable amplifier to reduce the sensitivity of the variable amplifier and output the adjusted signal from the adjustment signal output line. A particle analysis device characterized by: 2. The particle analyzer according to claim 1, wherein the pulse signal monitoring circuit comprises a threshold circuit and a frequency/voltage converter. 3. The particle analyzer according to claim 2, wherein the feedback circuit comprises a mechanism for adjusting feedback resistance using a servo motor. 4. The particle analyzer according to claim 2, wherein the feedback circuit comprises a mechanism for switching the resistance stepwise using an AD-converted feedback signal.