JPH01254871A - Method for cleaning dispensing nozzle for analysis apparatus and dispensing nozzle device - Google Patents

Abstract

PURPOSE:To improve the effect and efficiency of cleaning and to operate analyses at a high speed with higher efficiency by oscillating a piezo-electric oscillator which comes into substantial contact with a cleaning liquid, thereby executing cleaning. CONSTITUTION:The cleaning liquid is passed into a dispensing nozzle 1 directed to an aperture 25 for reserving the cleaning liquid and while the tip of the dispensing nozzle 1 is held immersed in the cleaning liquid in the aperture 25, the piezo-electric oscillator 26 which comes into substantial contact with the cleaning liquid is oscillated. Since the piezo-electric oscillator 26 comes into substantial contact with the cleaning liquid in the aperture 25, said oscillator is subjected to an insulation treatment by coating consisting of, for example, an org. high polymer, etc. An AC voltage of an C power supply is impressed thereto with electrodes 28a, 28c on both sides as one terminal and an intermediate electrode 28b as the other terminal. The dispensing nozzle 1 is supported by a dispensing holder 22 and is moved to undergo the prescribed stage by movement of a nozzle moving beam 21.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to a dispensing nozzle used in a biochemical analyzer that measures physiologically active substances using, for example, an immune reaction. The present invention relates to a method for cleaning a liquid dispensing nozzle and a dispensing nozzle device thereof.

(Background of the Invention) Generally speaking, biochemistry analysis devices used in hospitals, laboratories, etc. are not used for analysis, except for preparing the serum or plasma sample and loading the sample into the device. Increasingly, things are being mechanized and automated.

This mechanized and automated operation process usually includes the following:

■ The process of dispensing the sample into the reaction tank ■ The process of dispensing the diluted solution into the reaction tank ■ The process of dispensing the reaction reagent ■ The process of incubating the reaction solution ■ The process of measuring the reaction result by optical means etc. Among the above 1 mulberry production processes, the step (■) in which a certain amount of sample is aspirated and dispensed into the reaction tank according to the test item (or in addition to this, the step (■)) is usually carried out using a sample dispensing nozzle in the equipment. This content is provided by providing a sample container or a dilution water container by moving the container and performing operations such as sucking and discharging liquid. For dilution water, use a pump connected to the dispensing nozzle,
There is also known a system in which the liquid is supplied from the rear end side of the dispensing nozzle using a switching valve or the like.

By the way, since the above-mentioned dispensing nozzle is used for a large number of samples, or is used continuously in the step ① above, it is difficult to measure trace amounts of physiologically active substances, etc. In this type of analyzer, it is generally considered to be important to prevent contamination between liquid phase tiles.

(Prior art) As a specific method for preventing contamination between liquid phase tiles in the above-mentioned analyzer, typical and effective methods include cleaning the nozzle, or cleaning the dispensing nozzle for each sample. There is a method that allows you to replace the chip.

However, although the latter nozzle tip exchange method basically has the purpose of eliminating the need for cleaning operations, when measuring multiple items from one sample, the amount of sample required for each measurement item may differ. However, in such cases, it is not always necessary to clean the nozzle, and replacing the tips requires a complex mechanism for the analyzer, which increases running costs due to the large number of disposable tips. There is a problem in that the overall cost tends to be high.

Various techniques have been developed and proposed, focusing on the advantage that the method of cleaning the nozzle in one layer is suitable for providing a relatively inexpensive device.

For example, cleaning can be carried out by repeatedly suctioning and discharging the cleaning solution using a special nozzle cleaning boat, rinsing with try-on diluted solution (Japanese Patent Application Laid-open No. 55-82054), blowing air onto the nozzle, or applying pressurized air inside the nozzle. A method of blowing out the sample remaining in the nozzle by introducing
No. 61) etc. are known.

(Problem to be solved by the invention) In recent years, there has been a strong demand for this type of biochemical analyzer to accurately measure trace amounts, and for this purpose, liquid samples, diluted liquids, and reagents are required. There is a growing need for accuracy in the amount of liquid dispensed, and there is also an increasing demand for prevention of mixing between liquid phase tiles. In particular, in biochemical analysis such as immunoreaction measurement, the trend towards using small amounts of samples is a major issue, and along with this, the handling of small amounts of liquid by dispensing equipment has become a major issue.

The demands for accuracy and precision are becoming higher and higher.

Furthermore, apart from the above-mentioned problems, with mechanized and automated devices, there are usually demands to be able to measure a large number of specimens (samples) continuously or for many items at once, and to make these measurement operations more efficient. Therefore, it is extremely important to meet these requirements while also preventing erroneous measurements caused by carryover between samples and carryover between measurement items. Become one.

From this perspective, when considering the conventional nozzle cleaning methods described above, we find that, for example, in the method of cleaning by repeatedly suctioning and discharging the cleaning liquid using a dedicated nozzle cleaning boat, it is possible to increase the cleaning effect by increasing the number of cleanings. On the other hand, there is a problem in that the cleaning operation takes a considerable amount of time, which goes against the demand for speeding up the processing.

Furthermore, the method of rinsing with a sample diluent has the problem that the operation of washing both the outer and inner surfaces of the nozzle is complicated and the amount of liquid required for washing is large. Methods of blowing air into the nozzle or introducing pressurized air inside the nozzle to blow away the sample remaining inside the nozzle have problems in cleaning effectiveness, and
There are problems such as splashing of cleaning fluid.

As described above, it has been difficult with conventional methods to simultaneously satisfy the demands for improved cleaning effectiveness and increased efficiency.

(Means for Solving the Problems) The present invention addresses the increasingly strong demands in the field for higher accuracy and higher performance in analytical measurements, or the simultaneous processing of multiple samples and multiple items in mechanized and automated equipment. In consideration of the demand for rapid processing, we have developed a new method for cleaning a dispensing nozzle for a biochemical analyzer that solves the problem that the application of the conventional technology described above is insufficient, and a dispensing nozzle device used in this method. This is what we intend to provide.

The method for cleaning a dispensing nozzle according to the present invention, which has been made to achieve the above object, is characterized by passing the cleaning liquid through the inside of the dispensing nozzle facing the cleaning liquid reservoir opening, and at the same time passing the cleaning liquid into the cleaning liquid stored in the opening. Cleaning is performed by vibrating a piezoelectric vibrator that is substantially in contact with the cleaning liquid while the nozzle tip is immersed. "Substantially in contact with liquid" means electrically insulated but mechanically coupled for vibration transmission; for example, by insulating the surface of the piezoelectric vibrator. It refers to a structure in which the surface is brought into contact with the liquid, or a stirrer extending from the piezoelectric vibrator is brought into contact with the liquid. The purpose of passing the cleaning liquid inside the dispensing nozzle is to clean the inside of the nozzle.The cleaning liquid may be passed through the nozzle in one direction from the rear end to the tip, or the cleaning liquid may be passed through the nozzle from the tip. It may also be made to be sucked and discharged.

Further, the dispensing nozzle device according to the present invention is characterized by a dispensing nozzle, an opening for a cleaning liquid reservoir into which the dispensing nozzle is inserted from above, a filling means for filling the opening with cleaning liquid, and a dispensing nozzle. The dispensing nozzle includes a means for passing the cleaning liquid into the interior of the dispensing nozzle, and a vibration applying means for vibrating the cleaning liquid in the opening, and the vibration applying means is constituted by a piezoelectric vibrator that comes into contact with the cleaning liquid in the opening. It's where you are.

The piezoelectric vibrator described above is preferably a piezoelectric element constructed by combining a piezoelectric body made of an electrostrictive or piezoelectric material and an electrode because it is easy to control, but there is no particular limitation as long as the amplitude is strong enough to stir the liquid. . For example, ceramic piezoelectric element, P
ZT, crystal, etc. can be used.

In the above-mentioned dispensing nozzle device, the means for passing the cleaning liquid into the nozzle is to provide a liquid feeding mechanism that allows the cleaning liquid to flow through from the rear end side of the nozzle so that it flows out from the nozzle tip as described in the above method, or to flow the cleaning liquid from the nozzle tip. Generally, a pressure applying mechanism such as a cylinder device for transmitting negative pressure and positive pressure is provided in the nozzle so that the nozzle can be sucked and discharged. The piezoelectric vibrator that comes into contact with the cleaning liquid in the opening may be, for example, a monomorph, unimorph, or bimorph type ceramic piezoelectric element.

(Function) In the method and device 3'i of the present invention, the liquid such as the sample attached inside the dispensing nozzle can be reliably removed by passing the cleaning liquid, and the liquid such as the sample adhered to the outer surface of the nozzle can be removed by the cleaning liquid that comes into contact with it. It can be reliably washed and removed by vibration stirring. In particular, the mechanism for removing the liquid adhering to the outer surface of the nozzle is realized as a simple structure in which an alternating voltage is applied to a piezoelectric vibrator that is in contact with the cleaning liquid stored in the opening.

(Example) The present invention will be described below based on embodiments shown in the drawings.

An overall overview of an example of a system incorporating a dispensing nozzle device for carrying out the method of the present invention will be explained with reference to FIG. It is designed to move horizontally and vertically in the direction of the arrow in the figure while being supported by a moving device that does not move.

2 indicates a diluted liquid suction boat, and 3 indicates a cleaning boat (opening for cleaning liquid reservoir) adjacent thereto. The cleaning boat 3 of this example is of the type in which the diluted liquid suction boat 2 is filled with the diluted liquid as a cleaning liquid.

Liquid replenishment to the diluted liquid suction boat is performed by a liquid replenishment system (not shown). The bottom of the cleaning boat 3 is connected via a drain path 9 to an on-off valve 15, a waste liquid tank 10, and a suction pump 11, so that the used cleaning liquid can be appropriately discharged by switching the on-off valve 15 on and off. The specific configuration of the cleaning boat is shown in FIG. 1 and will be described later.

Reference numeral 4 denotes a sample container that holds the sample to be measured. Generally, in mechanized and automated analysis equipment, this sample container is moved by a suitable sample holder, a turntable, or other conveyance means, and the sample container is sucked by a dispensing nozzle. Although it is designed to be moved in and out to a position suitable for mulberry cultivation, the configuration for this is not directly related to the present invention, so illustration and explanation thereof will be omitted.

Reference numeral 9 denotes a reaction container, which provides a reaction chamber in which predetermined immune reactions, etc. are carried out by dispensing samples and reagents.Similar to the sample container described above, in a mechanized/automated analyzer, Samples, reagents, etc. are moved into and out of positions suitable for dispensing operations by the movement of transport means such as sample holders and turntables, but the configuration for this is not directly related to the present invention. Therefore, illustration and explanation thereof will be omitted.

Reference numeral 6 denotes a three-way valve, which is connected to the rear end of the dispensing nozzle 1, and transmits positive pressure and negative pressure from the syringe pump 8 to the dispensing nozzle 1 to act on suction and discharge of a sample, etc. Note that the reason why a three-way valve is used in this example is to take into consideration the case where the liquid from the diluent storage tank indicated by reference numeral 7 in the figure is sent to the dispensing nozzle 1, and from the diluted liquid suction boat mentioned above. In the case of suctioning the diluted liquid, the diluted liquid storage 4g7 is not necessary, and an on-off valve can be used instead of the three-way valve.

An example of the operation of the dispensing operation in the system having the above configuration will be explained.

■Cleaning the nozzle At position 1b, insert the tip (lower end) of the dispensing nozzle into the cleaning boat 3 and clean it.

■ Suction of diluted liquid Insert the lower end of the dispensing nozzle into the diluted liquid suction boat 2 at the position of the IC mark and aspirate the diluted liquid.

■ Aspirating the sample At position 1a, insert the lower end of the dispensing nozzle into the sample in the sample container 4 and aspirate a predetermined amount of sample.

■ Dispensing into the reaction container 5 At the position of the mark 1d, dispense the diluted sample in the nozzle into the reaction container into which the immunoreaction reagent has been filled in advance.

■ Washing the nozzle (same as step (■)) Perform a series of continuous dispensing operations by repeating the above operations (■ to ■) for each sample. Note that the cleaning steps (1) and (2) in this example are performed by suctioning and discharging the cleaning liquid from the tip (lower end) of the nozzle in the cleaning boat 3 by driving a syringe pump.

FIG. 4 shows an overall outline of a system incorporating another dispensing nozzle device.

In this figure, the difference in device configuration from the system in Figure 3 is that the diluted liquid suction boat 2 is omitted, and correspondingly, the path connected to the rear end of the dispensing nozzle 1 is Through the three-way valve 6, the diluted liquid in the diluted liquid storage tank 7 can be sent to the dispensing nozzle 1 with the syringe pump 8, and through the three-way valve 13, the cleaning liquid in the cleaning liquid storage tank 14 can be sent to the dispensing nozzle with the syringe pump 12. The reason is that it is designed to be able to send liquid to 1. The other mechanical structures are the same.

In the dispensing operation of the system in this example, in the steps ① to ② explained in FIG.
There are two differences: (1) the diluent is sucked from the rear end of the nozzle so that the diluted liquid in the diluted liquid storage tank 7 is collected in the nozzle, but the rest is the same. The process involves a series of continuous dispensing operations.

Next, the cleaning operation in the cleaning boat will be explained in more detail.

The cleaning boat 3 shown in FIG. 1 has a structural feature in that one side wall of the casing, which provides a generally rectangular parallelepiped opening (space) 25, is constructed with a bimorph ceramic piezoelectric element 26.

The opening 25 is not particularly limited in its shape, etc., as long as it is large enough to insert the tip (lower end) of the dispensing nozzle.
As a rectangular parallelepiped, the length is 3 to 1 Omm, the width (in the longitudinal direction of the piezoelectric element 26 in FIG. 1) is 3 to 40 mm, and the depth is 10 to 3 mm.
It is sufficient if it is about 0 mm, preferably 3 to 10 mm in length.
In many cases, it is advantageous to set the width to approximately 10 to 30 mm, 10 to 25 mm in width, and 10 to 30 mm in depth in order to suppress the consumption of cleaning liquid.

The piezoelectric element 26 is insulated with, for example, a coating of an organic polymer or the like in order to substantially come into contact with the cleaning liquid in the opening of the cleaning boat. In this example, since this is a bimorph ceramic piezoelectric element, both side electrodes 28a,
28c is used as one terminal, and the intermediate electrode 2Bb is used as the other terminal, so that an alternating voltage from an AC power source 29 is applied.

Note that 30 is a variable resistor for adjusting the applied voltage. When using such a ceramic resonator, a normal commercial AC power source (50 to 6 Hz) can be used for excitation of the resonator, and a voltage adjustment means such as a variable resistor 30 or slideac can be installed to adjust the applied voltage. Appropriate value (0 to 10
0V), but it is of course not limited to this particular power supply configuration.

Note that the dispensing nozzle 1 in this example is connected to the dispensing nozzle holder 2.
2, the nozzle is moved through the predetermined process of σ as explained in FIG. 3 or FIG. 4 by the movement of the nozzle moving beam 21. In addition, the dispensing nozzle holder 22 of this example has a pair of liquid level detection electrodes 23 on the sides of the dispensing nozzle 1.
．． 23 is provided, and this liquid level detection electrode 23.2
3 is also cleaned in view of the fact that it comes into contact with liquid such as a sample for liquid level detection. That is, the dispensing nozzle holder 22 is moved down to a position where the lower ends of the liquid level detection electrodes 23, 23 are immersed in the cleaning liquid.

In the cleaning boat configured as above, for example, the third
In the system shown in the figure, the cleaning process is performed as follows. That is, the dispensing nozzle 1, which has finished dispensing the sample and the diluent into the reaction container 5, is moved to a position facing above the frontage 25 of the cleaning boat shown in FIG. 1 by a screwing means (not shown). Next, the lower end of the nozzle is moved down until it is fully immersed in the cleaning liquid filling the opening, and the syringe pump 8 is driven to suction and discharge the cleaning liquid into the nozzle. Also, at this time, a voltage is applied to the piezoelectric element 26 to impart strength to the cleaning liquid, producing a stirring effect. After this state continues for a predetermined period of time, the cleaning liquid is poured into the drain path 9.
This operation is performed one or more times to complete the cleaning process.

The stirring time due to the vibration of the piezoelectric element is appropriately designed depending on the interval time of the analyzer, the time required for sampling, etc.

When the configuration of the cleaning boat shown in FIG. 1 is applied to the system shown in FIG. Instead, the cleaning liquid will be filled through the nozzle after processing. The inside of the nozzle is cleaned by filling the liquid through the nozzle, and the cleaning liquid is vibrated and stirred by the vibration of the piezoelectric element in the opening 25, so that the outer surface of the nozzle is cleaned.

Note that the cleaning boat may be filled with cleaning liquid by a combination of filling through the inside of the nozzle and filling from the outside as in the system shown in Figure 3. Figure 2 describes a cleaning boat with another configuration. It is for.

The cleaning boat shown in FIG. 2 has an opening 25, a casing made of a rigid body such as plastic, and a piezoelectric element 31 that imparts vibration to the cleaning liquid suspended from the dispensing nozzle holder 22. The case is shown.

Note that the piezoelectric vibrator and the cleaning liquid are in contact with each other by assembling a stirrer into the piezoelectric vibrator that is not immersed, and immersing or contacting the piezoelectric vibrator in the cleaning liquid to ensure a substantial liquid contact state. You can also do that. In short, it is sufficient that the piezoelectric vibrator is substantially (directly or indirectly) in contact with the cleaning liquid so that it can effectively vibrate and stir the cleaning liquid.

Example I A test was carried out to confirm the effectiveness of the method of the present invention by applying the washing boats shown in Fig. 1 (referred to as Example 1) and Fig. 2 (referred to as Example 2) to the system shown in Fig. 4. The measurement method was conducted.

The test consists of dispensing the following test solution, cleaning the nozzle used for dispensing under specified conditions, then dispensing a solution with zero enzyme concentration, and checking how much of the solution in the dispensed reaction container contains the previous sample. This was done by detecting fluorescence to determine whether the enzyme in the solution was carrying over (carryover) from the ratio of enzyme activities. The ordinary light detector was calibrated with 4-methyl umbelliferone (4MU) of known concentration.

To measure the amount of enzyme carryover, an enzyme substrate solution of 200 μC is dispensed into the solution dispensed into the reaction vessels after washing, and a fluorescence detector is used to measure the activity of the enzyme in each reaction vessel. The rate was measured and expressed as a ratio to the enzyme activity contained in the original test solution.

Test solution dispensing procedure ■ Aspirate 50 μm of the diluted solution, then aspirate sample 1 with the following composition at 100 μ°C and dispense into the reaction container.

■ Clean the dispensing nozzle (washed 3 times).

■Next, dispense Enzyme 4 Degree Zero Sample 2 into the reaction container using the same procedure as ■.

■ Clean the dispensing nozzle in the same way as in ■ above (cleaning 3 times: 6 times in total).

■ Dispense the solution with the enzyme concentration as in ■ above.

'[Yes] Same as ■ above (cleaning the dispensing nozzle in 1 (cleaning 3)
times: 9 times in total).

■ Dispense the solution with the enzyme concentration as in ■ above.

■ Clean the dispensing nozzle in the same way as ■ above.

The test solution used, test conditions, etc. are as follows. Note that the same cleaning and dispensing was performed without vibrating the piezoelectric element of the cleaning boat shown in FIG. 1, and the results were used as a comparative example.

Sample: 1. Alkaline phosphatase (ALPase) solution (manufactured by Biozyme) Dispensing amount 100 μm2, A
LPase OM night (8kBSA night)
Dispensing amount: Diluted to 100μ? a: o, 01 yen rHon X-1 [10 portions 50 μ base enzyme substrate.

4-methyl cumbelliferyl phosphate (4MI
IPL Part Master i
200 μm reaction vessel: Polypropylene cup Nozzle Cleaning liquid: Same cleaning conditions as diluted liquid One end is fixed and the other end is free (both ends are fixed in the configuration shown in Figure 1)
In the configuration (length 50 mm), a piezoelectric element whose free end vibrates 2 mm left and right (total 4 mm) when a voltage of 42 V is applied is used.

The apparatus shown in FIG. 2 was constructed (during the test, 42×1 frequency of 50 Hz (commercial power supply) was applied). The test results are shown in Table 1 below. The numbers in the table are relative to the enzyme activity of the 78 solution (containing enzyme) in ■ of the above "Procedure for dispensing the test solution".
Same procedure ■.

Solutions in the reaction vessels ① and ② (sample N, respectively).

1.2.3)), and is the average value of 10 times each.

Table 1 As is clear from the results in Table 1 above, -generally 10-
It is said that an error of about 10-6 is unlikely to affect the judgment of the measurement results, so if an apparatus is designed with an error of about 10-6 or less as a target value, Example 1
．． In method 2, the target value was achieved for the sample Not, which required fewer washings compared to the comparative example, and it was understood that the method of the present invention has excellent effects in terms of speeding up processing, reducing the amount of washing liquid, etc. be done.

(Effects of the Invention) As described above, according to the method and apparatus of the present invention, efficient cleaning can be performed with a small number of cleaning times, and the apparatus configuration is such that a flat piezoelectric vibrator is used in the cleaning liquid filled in the opening for the cleaning liquid reservoir. By bringing it into contact with liquid, it has the effect of being able to form a simple and simple structure, speeding up analysis and measurement operations.
This has the advantage of being effective in streamlining and being able to provide an inexpensive device.

Further, it is effective in improving the reliability of measurement results, and there is little variation in cleaning efficiency, and it is particularly effective in measurements where high concentration and low concentration measurements are performed alternately.

[Brief explanation of the drawing]

Figure 1 is a diagram showing an outline of the configuration of the cleaning boat portion of the dispensing nozzle device according to the present invention, FIG. 2 is a diagram showing the cleaning boat portion of another dispensing nozzle device, and FIG. Overall system configuration of a dispensing nozzle device applying the method of the present invention -
A schematic diagram showing an example. FIG. 4 is a schematic diagram showing an example of the entire system of another configuration of the dispensing nozzle device. 1...Dispensing nozzle 2...Diluted liquid suction boat 3
... Washing boat 4 ... Sample container 5 ... Reaction container 6 ... Three-way valve 7 ... Diluent storage tank
8...Syringe pump 9...Drain path 10
...Waste liquid tank 11...Suction pump 12...
・Syringe pump 13... Three-way valve 14...
-Cleaning liquid storage tank 15...Opening/closing valve 21...Nozzle moving beam 22...Minute 7 Main nozzle holder 23...Liquid level detection sensor 25...Opening for cleaning liquid reservoir 26...Piezoelectric ceramics Vibrator 28a, 28b, 28c... Electrode 29... AC power supply 30... Variable resistor 31
...Piezoelectric ceramic vibrator

Claims (1)

[Scope of Claims] 1. A cleaning liquid is passed through the dispensing nozzle facing the cleaning liquid reservoir opening, and the tip of the dispensing nozzle is immersed in the cleaning liquid in the opening, and the dispensing nozzle is substantially in contact with the cleaning liquid. A method for cleaning a dispensing nozzle for a biochemical analyzer, characterized by vibrating a piezoelectric vibrator. 2. Claim 1, characterized in that the cleaning liquid is passed through the interior of the dispensing nozzle by flowing from the rear end to the tip of the dispensing nozzle.
Cleaning method described in. 3. Claim 1, characterized in that the cleaning liquid is passed through the interior of the dispensing nozzle by suctioning and discharging it from the tip of the dispensing nozzle.
Cleaning method described in. 4. A dispensing nozzle, an opening for a cleaning liquid reservoir into which the dispensing nozzle is inserted from above, a filling means for filling the opening with the cleaning liquid, and a liquid passage means for passing the cleaning liquid into the inside of the dispensing nozzle. , a dispensing nozzle comprising a vibration applying means for vibrating the cleaning liquid in the opening, the vibration applying means being constituted by a piezoelectric vibrator substantially in contact with the cleaning liquid in the opening. Device. 5. The dispensing nozzle device according to claim 4, wherein the piezoelectric vibrator is a monomorph, unimorph, or bimorph type ceramic piezoelectric element. 6. The dispenser according to claim 4 or 5, wherein the liquid passing means is a liquid feeding mechanism that is connected to the rear end of the dispensing nozzle and causes the cleaning liquid to flow from the rear end to the tip of the dispensing nozzle. Note nozzle device. 7. The liquid passing means is a pressure applying mechanism connected to the rear end of the dispensing nozzle that transmits positive and negative pressure effects to the inside of the nozzle to suck and discharge the cleaning liquid from the tip of the dispensing nozzle. The dispensing nozzle device according to claim 4 or 5.