JPH0128334B2 - - Google Patents

Description

Detailed Description of the Invention [Industrial Application Field] The present invention allows particles such as blood cells and platelets suspended in a liquid to pass through micropores, and detects electrical or optical differences between the particles and the particle suspension. A particle analyzer that detects particles based on physical differences; more specifically, a particle analysis device that analyzes particle characteristics based on the dispersion status of particles, that is, the distribution of detection pulses, without depending on particle concentration or particle size as in conventional methods. It is related to the device.

[Conventional technology]

Conventionally, methods for measuring the characteristics of particles such as blood cells and platelets include measuring parameters such as the number of particles per unit volume, average particle volume, particle volume distribution, and particle shape. , methods have been used to classify particles such as platelets, compare various parameters with other specimens, and distinguish between normal and abnormal particles. In particular, analysis and measurement of blood cells, etc.
It is used to test for various blood diseases and to diagnose diseases caused by an increase in white blood cells. On the other hand, analysis of various particles in the industrial field, not just blood cells, is used to monitor processes by detecting the state of dissolution or aggregation of particles when using various particles. These analyzes involve passing particles suspended in a liquid through micropores, as in a conventional blood cell counter, detecting them based on electrical or optical differences between the liquid and the particles, and converting them into pulsed electrical signals. Based on the number of pulses and the size of the pulses, particle size distribution, particle type discrimination, and various statistical processing are performed.

[Problem that the invention seeks to solve]

Normally, even if the particle suspension is uniformly dispersed in the output signal pulse of a particle detection device such as a hemocytometer, a phenomenon called simultaneous passage occurs in which two or more particles enter the detection area at the same time. Therefore, the pulse interval is distributed from several microseconds to several hundred microseconds. Therefore, it is conceivable to use a high-speed arithmetic device that processes at a high speed of several microseconds to measure and store each pulse interval time each time, but on the other hand, there are cases where the pulse interval time is several hundred microseconds. , at this time, there is a waiting time and a standby state, which is extremely uneconomical. Normally, the average pulse interval of detection signals such as red blood cells is about 0.1 to 0.3 milliseconds. In other words, when counting and measuring red blood cells, for example, 100
Micropores on the order of microns are used, and in the case of red blood cells, the blood is diluted to about 50,000, and when 0.25cc of diluted blood is measured, the number of red blood cells in a normal person is about 5 million cells/mm ³ . It will actually detect 25,000 blood cells. In this case, the display of the hemocytometer can be converted to the original concentration by inserting a 1/50 frequency dividing circuit and displaying the number 500 and units of 1,000,000. The counting measurement time is about 5 to 7 seconds, so the average pulse interval is 0.2 to 0.28 milliseconds when the number of pulses is 5 million pieces/mm ³ . Red blood cell concentration doubles to 10 million cells/ ^mm3
Even so, the average pulse time is about 0.1 milliseconds.

Generally, particle detection devices in the industrial field are also designed so that the average pulse interval time is within the above range. In recent years, the processing time of microcomputers that have come to be incorporated into analytical instruments and the like takes several microseconds or more, even for high-speed ones, and for ordinary ones, it takes several tens of microseconds to read data and store the corresponding memory address. It is possible to perform processing such as reading out a stored number, adding 1 to it, and then writing it again.

Pulse intervals range from a few microseconds to hundreds of microseconds, and processing pulse intervals of several microseconds requires a high-speed computing device that can process in a few microseconds, but even then, the processing is not fast enough. In some cases, there is no pulse input, so it is necessary to perform processing such as prohibiting pulse input until one analysis is completed, making it impossible to perform accurate measurements.

On the other hand, since the average pulse interval is on the order of 100 microseconds, it is uneconomical to prepare an arithmetic unit with a processing capacity of several microseconds. That is, it is uneconomical to receive a signal from a particle detector or the like and directly measure and calculate the pulse interval to analyze it, and accurate measurement is also impossible.

The present invention has been made in view of the above points, and adds a parameter related to pulse intervals as a degree of dispersion to the conventional parameters related to particles, processes pulse intervals in their raw state, and averages calculation processing. The object of the present invention is to provide a particle analyzer that can be used in a wide range of applications and at a low cost by being configured to perform analysis on various types of particles.

[Means for solving problems]

The particle analyzer of the present invention will be described with reference to the drawings, in which particles suspended in a liquid are passed through micropores, and the particles are analyzed based on electrical or optical differences between the particles and a particle suspension. a particle detection device 1 that detects and generates a signal proportional to the particle size; a signal peak position detection device 2 that receives a signal from this particle detection device and detects the peak position of the signal; A pulse sequential feeder 3 that receives an output signal from a detection device and sequentially feeds the output terminals one after another to generate pulses, and a plurality of RS flip-flops 4 that receive a plurality of outputs from the pulse sequential feeder and generate gate signals. , a plurality of gate circuits 5 that control passage of reference pulses using the gate signals of these RS flip-flops, and a reference pulse generator connected to these gate circuits that generates reference pulses for converting pulse intervals into time. A device 6, a plurality of counting circuits 7 connected to the gate circuit and counting the time corresponding to each pulse interval, and a plurality of counting circuits 7 connected to these counting circuits and reading the counts of the counting circuits and counting the particles according to a predetermined calculation order. It is characterized by including a storage calculation circuit 8 having a function of calculating the distribution curve of the degree of dispersion and various parameters, and a display device 9 and/or a printing device 10 connected to this storage calculation circuit. .

[Effect]

The output signal proportional to the volume of the particle emitted from the particle detection device 1 is sent to the signal peak position detection device 2, which detects the peak position of the signal and generates a pulse that is sharper than the particle signal and has a uniform height. .
The output signal of the signal peak position detection device 2 causes the output ends of the pulse sequential feed device 3 to sequentially feed one after another to generate pulses. On the other hand, the input terminals of the RS flip-flops 4 ₁ , 4 ₂ , 4 ₃ . . . 4 _o are set to S (set).
It has two terminals: and R (reset).
The R (reset) input terminal connected to the adjacent output terminal of the pulse forwarder 3 is shared with the S (set) terminal of the next RS flip-flop.
Therefore, the RS flip-flop that is set to the terminal at the pulse sequential feeder 3 is
When the output from the next terminal of the pulse sequential feeder 3 occurs, it is reset, and the signal between them becomes the output signal (gate signal) of the RS flip-flop and is sent to the next gate circuit 5 ₁ , 5 ₂ , 5 ₃ . . . 5 _o . These gate circuits control the passage of the reference pulse corresponding to the time from the reference pulse generator 6, and count circuits 7 ₁ , 7 ₂ , 7 ₃ . . . It can be measured by counting at _o . That is, the count value of the counting circuit corresponds to each pulse interval. The next memory calculation circuit 8 reads the count value (corresponding to the pulse interval time) of the counting circuit and adds 1 to the number already stored at the corresponding address of the read/write memory 13, that is, the address of the corresponding time. processing is done,
The last read count values of the counting circuits 7 ₁ , 7 ₂ , 7 ₃ . . . 7 _o are reset. The pulses corresponding to the times counted one after another by the counting circuit in this way are classified and stored in a memory at a predetermined location by the storage calculation circuit 8. When it reaches the end of the counting circuit, it returns to the beginning and repeats the sequence. The above calculations are performed in accordance with the calculation order stored in the read-only memory 12. conditions selected by the input device 11;
For example, when a series of measurements is completed under conditions such as 100 pulse interval measurements or a predetermined period of time, the display is displayed on the display device 9 and a graph is printed on the printing device 10. .

〔Example〕

Embodiments of the present invention will be described below based on the drawings. FIG. 1 is a systematic explanatory diagram showing one embodiment of the particle analyzer of the present invention. The particle analyzer of this example allows particles suspended in a liquid to pass through micropores,
A particle detection device 1 that detects particles based on an electrical difference or an optical difference between the particles and a particle suspension and generates a signal proportional to the size of the particles; and a particle detection device 1 that receives a signal from the particle detection device 1. A signal peak position detection device 2 that detects the peak position of the signal by using the particle signal and generates a pulse that is sharper than the particle signal and has a uniform height.
, a pulse sequential feeding device 3 consisting of a shift register, a ring counter, etc., which receives the output signal of the signal peak position detection device 2 and sequentially feeds the output terminals one after another to generate pulses; a plurality of RS flip-flops 4 ₁ which receive a plurality of outputs and generate gate signals;
4 ₂ , 4 ₃ . . . 4 _o , a plurality of gate circuits 5 ₁ , 5 ₂ , ₅ 3 _. A reference pulse generator 6 that generates reference pulses for converting pulse intervals into time, and the gate circuits 5 ₁ , 5 ₂ , 5 ₃
...5 _o and a plurality of counting circuits 7 ₁ , 7 ₂ , 7 that count the time corresponding to each pulse interval
₃ ...7 _o , and a memory calculation circuit 8 which is connected to these counting circuits and has the function of reading the counts of the counting circuits and calculating the distribution curve of the degree of dispersion of particles and various parameters to be described later in accordance with a predetermined calculation order. , a display device 9 and a printing device 10 connected to this storage/arithmetic circuit 8. 11 is an input device for inputting data and conditions, 12 is a read-only memory, and 13 is a read/write memory. Note that instead of providing both the display device 9 and the printing device 10, either the display device or the printing device may be provided.

In the particle analyzer of the present invention configured as described above, the output signal proportional to the volume of particles emitted from the particle detector 1 is transmitted to the signal peak position detector 2.
It detects the peak position of the signal and generates a pulse that is sharper and more uniform in height than the particle signal. The output signal of the signal peak position detection device 2 causes the output ends of the pulse sequential feed device 3 to sequentially feed one after another to generate pulses. On the other hand, the input terminals of the RS flip-flops 4 ₁ , 4 ₂ , _{4 3 .}
It has two terminals, (set) and R (reset), and the R (reset) input terminal connected to the adjacent output terminal of the pulse sequential feeder 3 is connected to the following
It is shared with the S (set) terminal of the RS flip-flop. Therefore, the RS flip-flop which is first set to a certain terminal of the pulse sequential feeder 3 is reset when an output from the next terminal of the pulse sequential feeder 3 occurs, and the signal during that time becomes the RS flip-flop.
It becomes an output signal (gate signal) of the flip-flop and is sent to the next gate circuit 5 ₁ , 5 ₂ , 5 ₃ . . . 5 _o . These gate circuits are connected to the reference pulse generator 6.
_The number of microseconds between pulses can be measured by controlling the passage _of a reference pulse corresponding to _{the time} from . That is, the count value of the counting circuit corresponds to each pulse interval. The next memory calculation circuit 8 reads the count value (corresponding to the pulse interval time) of the counting circuit and adds 1 to the number already stored at the corresponding address of the read/write memory 13, that is, the address of the corresponding time. The counting circuit 7 ₁ , which is processed and finally read out,
7 ₂ , 7 ₃ ...Reset the count value of 7 _o . The pulses corresponding to the times counted one after another by the counting circuit in this way are classified and stored in a memory at a predetermined location by the storage calculation circuit 8. When it reaches the end of the counting circuit, it returns to the beginning and repeats the sequence.
The above calculations are performed in accordance with the calculation order stored in the read-only memory 12. When a series of measurements is completed under the conditions selected by the input device 11, for example, the measurement is to be completed with 100 pulse interval measurements or to be completed in a predetermined time, the display device 9 displays and printing device 10
The graph will be printed.

Next, examples of measurement results will be explained based on FIGS. 2 to 5. FIG. 2 shows a distribution curve obtained at a substantially normal degree of particle dispersion, and is close to a Poisson distribution. On the other hand, a distribution in which particles are considered to be approaching each other and agglomeration is about to occur becomes a bimodal distribution curve as shown in FIG. Figures 4a to 4c show examples in which a reagent is added to a diluted blood solution and measurements are taken in a state where aggregation is likely to occur.Over time, aggregates are formed and the degree of dispersion gradually increases. The number of larger aggregates increases, and peaks appear in widely spaced areas. In this way, red blood cell aggregation reactions, platelet agglutination reactions, etc. can be clearly detected. For these detections, the read/write memory 13 is divided into a plurality of sections, and the first measurement data, the second measurement data, and so on are stored. Therefore, it is also possible to record or display data overlappingly on the same graph. Furthermore, as shown in FIG. 5, it is also possible to set the calculation level using the input device 11 and obtain the following parameters.

(a) Maximum interval 75 microseconds (b) Minimum interval 15 microseconds (c) Maximum interval 350 microseconds Average interval 120 microseconds Interval 182.5 microseconds These conditions are based on the settings from the input device 11 and are read-only. It can be obtained by determining the peak position of the data stored in the read/write memory 13 according to the calculation order of the memory 12, the position where the data crosses the calculation level, or the total average calculation. Of course, the set level, the set measurement end time, the number of measurement intervals, etc. can also be printed and displayed at the same time. The above data can be useful in clinical or industrial fields by measuring particle characteristics, classification, changes over time, etc., along with conventional particle-related information such as the particle size distribution curve of red blood cells.

〔Effect of the invention〕

As explained above, the particle analyzer of the present invention has
Since the pulse sequential feeding device is equipped with multiple rows of pulse interval measuring devices consisting of RS flip-flops, gate circuits, counting circuits, etc., the pulse sequential feeding device allows separate counting circuits to count the number of pulses corresponding to the intervals. This makes it possible to perform averaged calculations and reduce the cost of the device. Further, additional information can be provided to the conventional information regarding particles, and data that can contribute to medical fields such as platelet aggregation reactions or industrial fields can be obtained.

[Brief explanation of drawings]

FIG. 1 is a systematic explanatory diagram showing one embodiment of the particle analyzer of the present invention, and FIGS. 2 to 5 are curve diagrams showing examples of measurement results. DESCRIPTION OF SYMBOLS 1... Particle detection device, 2... Signal peak position detection device, 3... Pulse sequential feed device, 4 ₁ , 4 ₂ , 4
₃ ...4 _o ...RS flip-flop, 5 ₁ , 5 ₂ , 5 ₃
...5 _o ... gate circuit, 6 ... reference pulse generator, 7 ₁ , 7 ₂ , 7 ₃ ...7 _o ... counting circuit, 8 ... memory calculation circuit, 9 ... display device, 10 ... printing device , 11...input device, 12...read-only memory, 13...read/write memory.

Claims (1)

[Claims] 1. Pass particles suspended in a liquid through micropores,
A particle detection device that detects particles based on electrical or optical differences between the particles and a particle suspension and generates a signal proportional to the size of the particles, and a signal that receives the signal from the particle detection device. a signal peak position detection device that detects the peak position of the signal peak position detection device; a pulse sequential feeding device that receives the output signal of this signal peak position detection device and sequentially feeds the output terminals one after another to generate pulses; a plurality of RS flip-flops that generate gate signals in response to the outputs of the RS flip-flops; a plurality of gate circuits that control the passing of reference pulses using the gate signals of these RS flip-flops; a reference pulse generator that generates a reference pulse for conversion into time; a plurality of counting circuits that are connected to the gate circuit and count time corresponding to each pulse interval; and a counting circuit that is connected to these counting circuits. A storage calculation circuit that has a function of reading the counted values of A particle analyzer characterized by comprising: