JPH0146818B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a particle analyzer that detects particles based on the difference in electrical impedance between the liquid and the particles by passing particles such as blood cells suspended in a liquid through micropores. relates to a particle analyzer that uses three types of threshold circuits to automatically and accurately adjust sensitivity regardless of particle concentration. [Conventional technology] Conventionally, particles such as blood cells are suspended in a liquid such as physiological saline, and passed through micropores formed narrow enough to allow the particles to pass through, thereby reducing the electrical impedance between the liquid and the particles. A device is used that detects particles based on the difference, and then analyzes the size of the particles based on the size of the detection signal.In this particle analyzer, the temperature of the solution and the concentration of electrolytes such as salt can be used to determine the size of the solution itself. The impedance of the particle changes, and therefore the detection sensitivity changes. Therefore, when comparing changes in particles over time in different liquids or testing change characteristics for various chemicals, it is necessary to calculate and correct the sensitivity change in advance. Alternatively, a method is used in which the sensitivity is adjusted separately by attaching an electrode for measuring the impedance of the liquid. [Problem to be solved by the invention] However, by adopting the former method (a method in which sensitivity changes are calculated and corrected in advance), for example, an automatic calculation device is built in to perform correction calculations, and the analysis results after correction are Even if it were possible to output the data, it would be necessary to input the data each time a different liquid was used, and the latter method (method of attaching an electrode for measuring the impedance of the liquid) would complicate the equipment and increase the sample size. There were problems such as contamination between samples due to adhesion of substances. 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. Note that when carrying out a method of adjusting the sensitivity of the device using standard particles, even if particles with fairly uniform particle sizes are used, differences in particle size always occur and normally a normal distribution is shown. 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 applicant filed Japanese Patent Application No. 55-55991 on the same date as the present application for a particle analyzer equipped with a high-level (H-level) threshold circuit and a low-level (L-level) threshold circuit.
A patent application has been filed as Japanese Patent Application No. 55-55992, but since these use the L level as the reference level,
As shown in FIG. 9 of the present application, the L level must be in a flat portion (hereinafter referred to as flat portion) of the cumulative fineness distribution and must be in a stable state. That is, the L level must exist within the long flat area. If the situation is as shown in Fig. 10 of this application, the L level will include noise, and in the situation shown in Fig. 11, the L level will be affected by a slight change in sensitivity.
Since the level deviates from the flat area, counting becomes unstable. However, if there is only one reference level, it is impossible to determine which state in FIGS. 9 to 11 the object is in. Therefore, there is a problem that sensitivity adjustment may not be accurate. The present invention has been made in view of the above points, and aims to provide a particle analyzer that can automatically and accurately adjust sensitivity regardless of the concentration of a particle suspension, and that has a simple circuit configuration. It is something. [Means for Solving the Problems] The particle analyzer of the present invention will be described with reference to the drawings. The particle analyzer of the present invention allows particles suspended in a liquid to pass through micropores and generates an electric connection between the particles and a particle suspension liquid. A particle detection device 1 that detects particles based on the difference and generates an electrical signal proportional to the size of the particles, a variable amplifier 2 connected to this particle detection device, and a high level connected in parallel to this variable amplifier. A first frequency/voltage conversion device 6 connected to the threshold circuit 3, the middle level threshold circuit 4, the low level threshold circuit 5, and the high level threshold circuit.
and a second frequency signal connected to the medium level threshold circuit.
A voltage converter 7 and a counting circuit 17, a third frequency/voltage converter 8 connected to the low level threshold circuit, an amplifier 10 connected to the first frequency/voltage converter, this amplifier and a second frequency/voltage converter 8. A first comparison circuit 11 connected to the voltage converter, and a second comparison circuit 11 connected to the voltage conversion device.
a second comparison circuit 12 connected to the frequency/voltage conversion device and the third frequency/voltage conversion device; a comparison amplifier 13 connected to the first comparison circuit and the second comparison circuit; and this comparison amplifier and the variable amplifier. It is characterized in that it includes a feedback circuit provided between the two. As a feedback circuit, servo motor 1
4, or a mechanism that adjusts the resistance using a feedback signal AD-converted by an AD conversion circuit 16. [Operation] 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 outputs are sent to threshold circuits 3, 4, and 5, and converted into an analog voltage as the number of particles per unit time by frequency/voltage converters 6, 7, and 8, respectively. The signal output from the intermediate level threshold circuit 4 is sent to the subsequent counting circuit 1.
7 or other processing circuits. The analog voltage on the high level side is amplified by the amplifier 10 and the first
The voltage is sent to the comparison circuit 11, where the ratio with the analog voltage on the middle level side is compared. Further, the analog voltage on the middle level side and the analog voltage on the low level side are sent to the second comparison circuit 12 and their ratios are compared. The signals output from the first comparison circuit 11 and the second comparison circuit 12 are compared by a comparison amplifier 13, and fed back to the variable amplifier 2 by a feedback circuit. Here, if the concentration of the suspended liquid, for example, the concentration of the saline solution changes, and the sensitivity changes as shown in Figures 2 and 4, there will be no difference between the L level and the H level, and the set ratio will not be reached. Therefore, a signal is transmitted from the feedback circuit to lower the sensitivity, and the variable amplifier 2 operates to lower the sensitivity. In this way, high level, medium level,
Monitoring is performed using three low-level systems to ensure particle measurements are always performed at the optimum level. [Example] Hereinafter, an example of the present invention will be described 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, a high level threshold circuit 3, a middle level threshold circuit 4 and a low level threshold circuit 5 connected in parallel to the variable amplifier 2, and a high level threshold circuit 3 connected to the high level threshold circuit 3. first frequency/voltage converter 6
, a second frequency/voltage converter 7 and a counting circuit 17 connected to the middle level threshold circuit 4, a third frequency/voltage converter 8 connected to the low level threshold circuit 5, and a first frequency/voltage converter. an amplifier 10 connected to the device 6; this amplifier 10 and a second
A first comparison circuit 11 connected to the frequency/voltage conversion device 7 , a second comparison circuit 12 connected to the second frequency/voltage conversion device 7 and the third frequency/voltage conversion device 8 , and the first comparison circuit 11 and a comparison amplifier 13 connected to the second comparison circuit 12, and a feedback circuit provided between the comparison amplifier 13 and the variable amplifier 2, and the comparison circuit 1
When the outputs of the amplifiers 1 and 12 do not reach a constant value, a signal is transmitted to the variable amplifier 2 by the feedback circuit, and the sensitivity of the variable amplifier 2 is automatically adjusted. The feedback circuit may include a mechanism that adjusts the feedback resistance 15 using a servo motor 14, or an AD conversion circuit 16.
A mechanism is used that adjusts the resistance using a feedback signal that has been AD converted. 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 threshold circuits 3, 4, and 5, and is converted into an analog voltage as the number of particles per unit time by frequency/voltage converters 6, 7, and 8, respectively. The signal leaving the intermediate level threshold circuit 4 is sent to a subsequent counting circuit 17 or other processing circuit. The analog voltage on the high level side is amplified by the amplifier 10 and sent to the first comparison circuit 11, where the ratio with the analog voltage on the middle level side is compared. In addition, the analog voltage on the middle level side and the analog voltage on the low level side are
The signals are sent to the comparison circuit 12 and the ratios are compared. 1st
The signals output from the comparator circuit 11 and the second comparator circuit 12 are compared by a comparator amplifier 13, and fed back to the variable amplifier 2 by a feedback circuit. Here, if the concentration of the suspended liquid, for example, the concentration of the saline solution changes, and the sensitivity changes as shown in Figures 2 and 4, there will be no difference between the L level and the H level, and the set ratio will not be reached. Therefore, a signal is transmitted from the feedback circuit to lower the sensitivity, and the variable amplifier 2 operates to lower the sensitivity. In this way, monitoring can be carried out using the three systems of high level, medium level, and low level, and particle measurement can always be performed at the optimum level. For example, when counting red blood cells, if the detection sensitivity is too high, noise and other unnecessary pulses will be detected as shown in FIG. On the other hand, if the sensitivity is too low, only relatively large red blood cells will be measured. For optimal measurements, it is necessary to set the level of the threshold circuit in the flat part of the cumulative particle size distribution. For example, Figs. 6 and 9 are in a normal and appropriate state (referred to as state A), Figs. 7 and 10 are in a state where the sensitivity is too high (referred to as state B),
If the sensitivity is too low in FIGS. 8 and 11 (referred to as state C), operations such as lowering the sensitivity in state B and increasing the sensitivity in state C are automatically performed. These matters are shown in the table below.

〔Effect of the invention〕

As described above, the particle analyzer of the present invention is provided with a medium-level threshold circuit in addition to the high-level threshold circuit and the low-level threshold circuit, so it is possible to determine which state it is in from FIGS. 9 to 11. If we can reliably discriminate and adjust the sensitivity to the state shown in Figure 9,
Since both the L level and the M level are on the flat part, a sufficiently long flat part is ensured, and stable counting can be performed at the M level. Therefore, the sensitivity can be automatically and precisely adjusted regardless of the particle concentration,
Moreover, since the circuit configuration is simple, it can be easily incorporated into a conventional particle counting device.

[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. Systematic explanatory diagram, Figure 6 is a waveform diagram for normal counting, Figure 7 is a waveform diagram for abnormal noise counting, Figure 8 is a waveform diagram for abnormal counting, and Figure 9 is the waveform diagram for abnormal counting. FIG. 10 is a cumulative particle size distribution curve diagram for the case of FIG. 7, and FIG. 11 is a cumulative particle size distribution curve diagram for the case of FIG. 1... Particle detection device, 2... Variable amplifier, 3...
...High level threshold circuit, 4...Medium level threshold circuit,
5...Low level threshold circuit, 6...First frequency/voltage converter, 7...Second frequency/voltage converter,
8... Third frequency/voltage converter, 10... Amplifier, 11... First comparison circuit, 12... Second comparison circuit, 13... Comparison amplifier, 14... Servo motor, 15... Feedback resistor, 16...A.D.
Conversion circuit, 17... Counting circuit.

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 the particle detection device, a high level threshold circuit, a medium level threshold circuit and a low level threshold circuit connected in parallel to the variable amplifier, and a high level threshold circuit connected to the high level threshold circuit. a first frequency/voltage converter, a second frequency/voltage converter and counting circuit connected to the medium level threshold circuit, a third frequency/voltage converter connected to the low level threshold circuit, and a first frequency/voltage converter and a counting circuit connected to the medium level threshold circuit; an amplifier connected to the voltage converter; a first comparator circuit connected to the amplifier and the second frequency/voltage converter; and a first comparator circuit connected to the second frequency/voltage converter and the third frequency/voltage converter. A particle analysis device comprising two comparison circuits, a comparison amplifier connected to the first comparison circuit and the second comparison circuit, and a feedback circuit provided between the comparison amplifier and the variable amplifier. . 2. The particle analyzer according to claim 1, wherein the feedback circuit comprises a mechanism for adjusting feedback resistance using a servo motor. 3. The particle analyzer according to claim 1, wherein the feedback circuit comprises a mechanism for adjusting resistance using an AD-converted feedback signal.