JP2001091524A - Method and apparatus for dispensing - Google Patents

Abstract

PROBLEM TO BE SOLVED: To detect the level of a discharge destination container when a sample is discharged in a state that the sample is sucked into a resin nozzle. SOLUTION: In a state that a sample 6 is sucked into a nozzle 5, a pressure inside a pipe 10 is adjusted, a part of the sample 6 is made to swell from the opening at the tip of the nozzle, and the nozzle 5 is lowered by keeping this state. When a part of the sample which is made to swell comes into contact with the level of a discharge destination container 7, a pressure is changed suddently. By detecting its change, the level is judged.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an automatic dispensing method and apparatus, and more particularly to a liquid level detecting technique.

[0002]

2. Description of the Related Art At present, in the field of clinical tests such as blood tests, automation is progressing with various devices, and an automatic dispensing device for automatically aspirating and discharging a sample such as serum and a liquid sample such as a reagent is generally used. Have been. In a general automatic dispensing apparatus, for example, the amount of movement of a piston in a dispensing pump composed of a syringe and a piston is controlled, the gas volume of the entire pipe including a nozzle such as a disposable tip is changed, and the nozzle automatically controls the liquid sample. Suction and discharge are performed.
In such an automatic dispensing apparatus, for example, when the nozzle is SU
If it is made of a material that is an electrically good conductor such as S, it is detected that the tip of the nozzle has touched the liquid surface due to a change in electrical resistance or capacitance between the nozzle and the liquid surface. Dispensing is performed based on the liquid level thus performed. However, in this case, it is necessary to form the nozzle with a conductor.

On the other hand, when a nozzle made of an electrically insulating material such as a plastic disposable tip is used, air is continuously discharged from the nozzle tip opening or air is continuously suctioned. The liquid level is determined from the rise in the air pressure in the nozzle due to the nozzle tip being blocked by the liquid level. However, for air discharge or air suction, the inside of the nozzle must be empty, and in the state where the sample is sucked into the nozzle,
Liquid level detection cannot be performed.

Therefore, in order to know the position of the liquid surface at the discharge destination,
A method of estimating a liquid surface position by calculation from a discharge container shape such as a discharge container bottom position, a sectional area, and the like, which can be known in advance, and a liquid amount existing in the container has been adopted.

[0005]

As described above, in the automatic dispensing apparatus which performs the liquid level detection operation by monitoring the air pressure, the liquid level can be detected at the time of suction, but the liquid level at the time of discharge can be detected. Detection is not possible. Therefore, as described above, the liquid level at the time of discharge was estimated by calculation, but it is difficult to accurately estimate the position because there are generally various error factors such as variations in container shape. Yes,
In particular, when the amount of liquid in the discharge destination container is very small, it is extremely difficult to estimate the amount.

Incidentally, it is possible to detect the liquid surface position of the discharge destination using an ultrasonic sensor or an optical sensor, but when a disposable chip or the like is used,
It is also difficult to accurately position the tip of the tip with respect to the liquid level of the discharge destination because of variations in the tip shape.

[0007] In recent years, along with the development of biotechnology, an extremely small amount of dispensing operation such as accurately discharging 1 µl of a liquid sample into a 2 µl container has been demanded.
In order to achieve such a small amount of dispensing, it is required to accurately control the position of the nozzle tip above or below the liquid level in the discharge destination container.

The present invention has been made in view of the above-mentioned conventional problems, and an object of the present invention is to realize a new liquid level detection method for accurately detecting a liquid level or the like by a nozzle.

Another object of the present invention is to provide a dispensing method using a nozzle made of a non-conductive material. The purpose of the present invention is to accurately detect the liquid level.

[0010]

Means for Solving the Problems (1) In order to achieve the above object, according to the present invention, in a state where a sample is sucked into a nozzle, the pressure inside the nozzle is increased and the sample is removed from the nozzle tip opening. A pressure control step of causing a part to swell, a lowering step of lowering the nozzle with respect to a liquid level, and a nozzle inside due to a part of the sample swelling from the nozzle tip opening adhering to the liquid level. And a liquid level detecting step of detecting a pressure change of the liquid.

According to the above configuration, a part of the sample bulges from the opening at the nozzle tip, that is, the pressure in the nozzle rises to a certain extent from the liquid surface opening to the extent that the sample does not become a liquid ball. Is set. When the nozzle in that state is lowered and a part of the raised sample comes into contact with the liquid surface, the pressure in the nozzle rapidly decreases due to the effect of surface tension or the like. The liquid level can be detected indirectly by detecting the pressure change. According to the method according to the present invention, as compared to the liquid level detection method using air discharge or air suction,
Liquid level detection can be performed with good responsiveness. Therefore, the liquid level position can be determined more accurately.

Preferably, the pressure rise value in the pressure control step is determined within a predetermined condition range based on the inner diameter of the nozzle tip opening d and the surface tension σ of the sample, and preferably the pressure rise value is 4σ / D [Pa] is determined. If this condition is satisfied, the formation of liquid droplets can be basically prevented.

Preferably, the pressure control step is performed after the nozzle is positioned above the liquid level, and preferably, the pressure control step is performed while the nozzle is descending with respect to the liquid level. You. According to this configuration, even if a droplet falls, it can be caught by the discharge destination container.

Preferably, the method further includes a descent stopping step of stopping descent of the nozzle based on the detection timing of the pressure change. Desirably, the sample is discharged in a state where a part of the sample swelling from the nozzle tip opening is in contact with the liquid surface and the nozzle tip surface is separated from the liquid surface.
In this way, the liquid level can be accurately detected with good responsiveness,
The discharge level can be freely set, such as discharge immediately before the liquid level or discharge at a position below a predetermined depth from the liquid level.

Preferably, the discharge amount is determined in consideration of a part of the sample swelling from the nozzle tip opening. Desirably, the dispensing required to increase the pressure in the nozzle and bulge a part of the sample from the nozzle tip opening from the estimated operating amount of the dispensing pump required to discharge a predetermined amount of the sample. The actual operation amount of the dispensing pump at the time of discharge is determined by subtracting the preliminary operation amount of the pump. According to this configuration, the discharge amount can be set accurately.

(2) In order to achieve the above object, the present invention provides a nozzle for sucking and discharging a sample, a dispensing pump connected to the nozzle via a pipe, A pressure sensor for detecting the pressure of gas, a transport mechanism for lowering the nozzle, and lowering the nozzle toward the liquid surface in a state where a part of the sample in the nozzle is swelling from the nozzle tip opening, Control means for determining a liquid level based on a detection signal of the pressure sensor.

Preferably, the nozzle comprises a nozzle base and a disposable resin tip mounted on the tip of the nozzle base.

(3) To achieve the above object,
The present invention provides a pressure control step of increasing the pressure in the nozzle while the sample is being sucked into the nozzle to cause a part of the sample to swell from the nozzle tip opening, and lowering the nozzle with respect to the liquid level. A lowering step of detecting the pressure change in the nozzle due to a part of the sample swelling from the nozzle tip opening adhering to the bottom surface of the discharge destination container. .

(4) The increase in the pressure in the nozzle is generally achieved by controlling the operation amount of the piston of the dispensing pump, but other than that, the piezoelectric element or the shape memory alloy provided in the nozzle may be used. Small volume fluctuations may be used. More simply, it can be achieved by raising the temperature in the nozzle by a minute amount using a heater or the like.

[0020]

FIG. 2 is an enlarged sectional view showing a tip of a nozzle of a disposable tip or the like. The liquid sample has already been sucked into the nozzle, and the tip of the nozzle is in the air. (A) shows a state in which the interface between the liquid sample and air is at the same level as the opening at the tip of the nozzle, and (B) shows that the interface swells moderately from the opening at the tip of the nozzle. (C) shows a state in which the interface swells hemispherically from the opening at the nozzle tip.

Here, suppose that the radius of curvature of the interface is R
[M] and the surface tension of the liquid sample is σ [N / m],
As is well known, there is a pressure difference between the inside and outside of the interface,
The pressure on the center side of the radius of curvature is 2σ / R [P
a]. Therefore, after the liquid sample is sucked into the nozzle and the pressure of the gas in the pipe between the pump and the liquid sample is increased, the radius of curvature of the interface gradually increases as shown in FIG. It becomes smaller. Since the minimum value of the radius of curvature at this interface is the radius r [m] of the nozzle opening, the pressure difference at the interface at that time becomes the maximum value, and the maximum value is generally represented by 2σ / r [Pa].

When the pressure rise is applied more than this, the liquid sample in the nozzle jumps out from the tip and forms a liquid ball. However, if the pressure rise is suppressed within the above-mentioned upper limit of pressure, it will not fly out. For example, when the inner diameter of the tip is 0.5 [mm] and the liquid sample is water, the maximum pressure is 500 to 600 [Pa].
About.

As described above, the liquid sample does not jump out of the tip of the dispensing container even if the pressure of the gas in the pipe is increased within a range not exceeding the maximum pressure. Normally, the pressure increase is suppressed to about 1/3 to 1/2 of the maximum pressure. For example, when the maximum pressure is 500 to 600 [Pa], the pressure increase is 200 [P
a].

In such a state, the tip of the nozzle is lowered toward the liquid surface of the discharge destination, and when a part of the liquid sample swelling from the nozzle end touches the liquid surface of the discharge destination, the liquid sample and the air The interface disappears, and the pressure increase due to the above-mentioned surface tension disappears, so that the pressure level sharply decreases.

This state is shown in the example of the pressure waveform in FIG. This graph shows a change when a pressure rise of about 200 [Pa] is generated with respect to the pressure level after the end of the suction and the tip of the nozzle is brought into contact with the liquid surface. The moment you touch the surface,
It can be seen that the increased pressure level has suddenly returned to the original level.

As described above, it is possible to accurately detect that a part of the liquid sample swelling from the nozzle tip touches the liquid surface of the discharge destination container. Therefore, by stopping the lowering of the nozzle at that timing and performing the discharging operation, a very precise dispensing operation can be performed.

When the above operation is performed, as soon as a part of the liquid sample swelling from the nozzle tip touches the liquid surface, the gas volume compressed to generate a pressure rise is directly discharged from the nozzle tip. In the subsequent ejection of the sample, the ejection should be performed after correction such as subtraction of the volume. For example, when a syringe pump or the like is used to increase the pressure, if the syringe pump is pressed by 0.5 μl in the discharge direction to increase the pressure by a predetermined amount, and the prescribed dispensing amount is 2.5 μl Means that the syringe pump is pushed by 2 μl during the discharging operation. Of course, in the above case, when the prescribed dispensing amount is 0.5 μl, the dispensing operation is completed only by slowly pulling up the dispensing tip without performing any discharge operation after detecting the liquid level.

According to the above method, even when a nozzle made of a material that is an electrically insulating material such as a plastic disposable tip is used, the fact that the tip of the nozzle comes into contact with the liquid surface at the time of ejection is responsive. The nozzle tip can be detected well, and the nozzle tip can be accurately positioned at the liquid level in the discharge destination container or at a predetermined level before and after the liquid level. Further, according to the above method, even when the amount of the liquid is very small, it is possible to dispense with high accuracy.

FIG. 1 schematically shows the entire configuration of a dispensing apparatus according to the present invention. Here, FIG. 1 shows a configuration example of a general dispensing apparatus in which the operation amount of a piston of a syringe pump 3 is controlled using, for example, a pulse motor 4 and a ball screw. Pressure sensor 2 to monitor the pressure of the air between 5
Is provided on the pipe 10. Reference numeral 1 denotes a control unit, and reference numeral 9 denotes a transport mechanism.

FIG. 1 shows a state in which a sample 6 to be dispensed is sucked into a nozzle 5 and then a liquid 8 existing in a container 7 as a discharge destination.
3 shows a state in which the position of the liquid level is detected. Hereinafter, this operation will be described.

First, the nozzle 5 is positioned above the discharge destination container 7, and when the nozzle 5 is stationary or when the nozzle 5 is lowered,
A part of the sample 6 bulges downward from the opening at the tip of the nozzle 5. In this case, the control unit 1 causes the syringe pump 3 to increase the pressure of the air in the pipe 10 by a specified pressure while monitoring the output signal of the pressure sensor 2. As described above, assuming that the surface tension of the liquid sample is σ [N / m] and the radius r of the tip of the dispensing tip is r [m], as described above, 1/3 to 1/2 of 2σ / r [Pa]. Pressure. When the pressure setting is completed, while monitoring the pressure,
The nozzle 5 is lowered toward the liquid surface of the discharge destination container 7 by the transport mechanism 9. When the monitored pressure drops rapidly, for example, when the pressure falls below a predetermined threshold value, it is determined that the tip of the nozzle 5 has touched the liquid surface, and the height is estimated as the liquid surface level. Then, based on the liquid level, the height of the nozzle 5 is stopped at a predetermined position, and the sample is discharged in that state. In this case, the prescribed dispensing is achieved by further pushing out the volume obtained by subtracting the volume compressed by the syringe pump 3 to increase the air pressure from the predetermined dispensing amount by the syringe pump 3. Since the liquid level rises with the ejection of the sample, it is desirable to raise the nozzle upward accordingly.

In the above process, if the nozzle is lowered at a relatively low speed and the descent is stopped immediately when a part of the sample comes in contact with the liquid surface, the nozzle tip itself does not come into contact with the liquid surface, Can be discharged.

When no liquid exists in the discharge destination container, the position of the inner bottom surface of the discharge destination container can be detected by applying the above method.

The liquid droplet formation during the nozzle descent may be determined based on the pressure waveform. Further, it is also possible to make the shape of the tip of the nozzle optimal for the above method.

[0035]

As described above, according to the present invention,
The nozzle enables accurate detection of the liquid level and the like. Further, according to the present invention, when the nozzle is made of a non-conductive material and the sample is contained in the nozzle, the liquid level in the discharge destination container at the time of discharging the sample, etc. Can be accurately detected.

[Brief description of the drawings]

FIG. 1 is a conceptual diagram showing an entire configuration of a dispensing apparatus according to the present invention.

FIG. 2 is a diagram showing a state in which a part of a sample swells from a nozzle tip opening.

FIG. 3 is a waveform diagram showing a pressure signal detected by a pressure sensor installed on a pipe.

[Explanation of symbols]

1 control unit, 2 pressure sensor, 3 syringe pump, 4
Motor, 5 nozzles, 10 pipes.

Claims (12)

[Claims] A pressure control step of increasing a pressure in the nozzle and swelling a part of the sample from a nozzle tip opening in a state where the sample is sucked into the nozzle; A lowering step of lowering, and a liquid level detecting step of detecting a pressure change in the nozzle caused by a part of the sample swelling from the nozzle tip opening adhering to the liquid level. Dispensing method. 2. The method according to claim 1, wherein the pressure rise value in the pressure control step is determined within a predetermined condition range based on the inner diameter of the nozzle tip opening d and the surface tension σ of the sample. Dispensing method characterized. 3. The dispensing method according to claim 2, wherein the pressure increase value is determined to a value not exceeding 4σ / d [Pa]. 4. The method according to claim 1, wherein the pressure control step is performed after a nozzle is positioned above the liquid level. 5. The dispensing method according to claim 4, wherein the pressure control step is performed while the nozzle is descending with respect to the liquid level. 6. The dispensing method according to claim 1, further comprising a descent stop step of stopping descent of the nozzle based on the detection timing of the pressure change. 7. The method according to claim 1, wherein a part of the sample swelling from the nozzle tip opening is in contact with a liquid surface and the nozzle tip surface is separated from the liquid surface. A dispensing method characterized by performing discharge. 8. The dispensing method according to claim 1, wherein the discharge amount is determined in consideration of a part of the sample bulging from the nozzle tip opening. 9. The method according to claim 1, wherein the pressure in the nozzle is increased from the estimated operation amount of the dispensing pump required to discharge a predetermined amount of the sample, and a part of the sample is opened from the nozzle tip opening. A dispensing method characterized by subtracting a preliminary operation amount of a dispensing pump required for inflating a liquid to determine an actual operation amount of the dispensing pump at the time of discharge. 10. A nozzle for sucking and discharging a sample, a dispensing pump connected to the nozzle via a pipe, a pressure sensor for detecting a pressure of gas in the pipe, and moving down the nozzle. A transport mechanism for causing the nozzle to descend toward the liquid surface in a state where a part of the sample in the nozzle is swelling from the nozzle tip opening, and based on the detection signal of the pressure sensor, the liquid surface height is adjusted. A control device for determining, and a dispensing device, comprising: 11. The dispensing apparatus according to claim 10, wherein the nozzle comprises a nozzle base and a resin disposable tip mounted on the tip of the nozzle base. 12. A pressure control step of increasing the pressure in the nozzle while the sample is being sucked into the nozzle to cause a part of the sample to bulge from the nozzle tip opening, and A lowering step of lowering, and a bottom face detecting step of detecting a pressure change in the nozzle due to a part of the sample swelling from the nozzle tip opening adhering to the bottom face of the discharge destination container, Dosing method.