JPH0943251A - Dispenser - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a dispenser capable of accurately dispensing with the possibility of the reduction in size. SOLUTION: The dispenser comprises a pipe 14 having a nozzle 4 at its lower end side and a reagent bottle 1 mounted at the upper end side to contain liquid such as reagent or specimen to be dispensed. At the pipe 14 a first microvalve 5, a microregulator 6, a micro-pressure sensor 7, a second microvalve 8 and a micropump 15 sequentially provided from above toward down. The pressure of the reagent flowing in the pipe is measured by the sensor 7, and the regulator 6 maintains the flow rate of the reagent flowing in the pipe constant based on the measured pressure. The reagent is dispensed via the nozzle under the control of the switching time of the second microvalve.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a dispenser for dispensing a liquid such as a reagent or a sample in a predetermined amount.

[0002]

2. Description of the Related Art In recent years, clinical testing equipment has been remarkably developed, and automation and multi-itemization are progressing. These devices are
A reagent or sample corresponding to a measurement item is precisely dispensed into a measurement cell by a dispenser, and a reaction is performed for a predetermined time, and then colorimetric measurement is performed. Moreover, a sensor or the like for detecting the characteristics of the sample can be mounted according to the application. Such an automatic analyzer has a large number of dispensers and a photometric unit, and is large in size, but has many functions such as mass processing, multi-item processing, and emergency processing.

On the other hand, micromachine technology has been developed as an elemental technology, and it has become possible to perform micromachining of silicon by utilizing the lithography technology of semiconductors and, recently, processing using various materials other than silicon. .

As an application example of such a technique, the present inventor has disclosed a "sensor structure and a method of manufacturing the same" in which a sensor is incorporated in a liquid channel formed of silicon.
Proposed in 8. For further complicated processing, Esashi et al. Of Tohoku University disclose a microvalve in Japanese Patent Laid-Open Nos. 1-213523 and 6-95745, and a micropump in Japanese Patent Laid-Open No. 1-266376. In addition, a valve for gas has already been commercialized, and is sold by Redwood Microsystems of the United States under the trade name of Fluistor. The size of this valve is 5.5 x 6.5 x 2
mm, 30 ml / min. Can be obtained.

Attempts have also been made to construct an analysis element by combining a micropump and a microvalve (JP-A-1-178641, JP-A-4-15153).
4, and JP-A-5-240872). These are a combination of a micropump, a microvalve, and a sensor or a photometric unit, and a liquid is moved to the sensor or the photometric unit by the micropump and the microvalve to perform measurement. This allows a very small analysis unit to be constructed.

As shown in FIG. 8, as a dispenser applying the micromachine technology, a microvalve 3 and a micropump 2 are provided in the middle of a pipe, and a nozzle 4 at the tip is provided.
A configuration in which a more dispensed liquid is discharged has been considered. With such a configuration, a required amount of liquid is dispensed through the nozzle 4 by driving the pump 2 for a certain period of time. The valve 3 is for ensuring that the liquid runs out.

[0007]

Since a conventional general dispenser is composed of a syringe, an electromagnetic valve, a motor, etc., when handling a small amount of liquid of tens to hundreds of microliters (microliters). However, there is a problem that the size of the device is several thousand to 10,000 times larger than the amount of liquid handled.
Further, as described above, attempts have also been made to configure an analysis unit by combining a microvalve and a micropump, but it is only enough to move the liquid to the measurement unit, and in order to perform precise measurement. No dispensing mechanism has been considered for accurately diluting and mixing liquids. Further, in the above-mentioned Fluistor dispenser, the precision of dispensing depends largely on the performance of the pump. However, in reality, many micromachines such as pumps and valves have a simple structure, and a large driving force cannot be expected, so the dispensing accuracy is easily affected by the properties of the liquid (pressure, viscosity, temperature, etc.). . Therefore, in view of the above problems, the object of the present invention is to
An object of the present invention is to provide a dispenser which can be miniaturized and can perform accurate dispensing.

[0008]

A dispenser according to a first aspect of the present invention is provided with a discharge port at one end side thereof, and a pipe through which a liquid to be dispensed flows and a pressure of the liquid flowing through the pipe. A pressure sensor that measures and compares it with a reference pressure, a regulator that keeps the flow rate of the liquid constant by feedback control based on the comparison result, and a liquid whose flow rate is kept constant flows to the discharge port for a predetermined time. And a valve that can be opened and closed as described above.

The feature of this embodiment is that by incorporating a liquid pressure control mechanism into the dispensing mechanism, the flow velocity of the liquid flowing through the dispenser can be kept constant while controlling the opening / closing time of the valve for precise dispensing. Is to do.

That is, when the flow rate of the liquid flowing into the dispenser changes, the pressure of the liquid changes at the same time. This fluctuation is detected by the pressure sensor, and the detection result is fed back to the regulator to control the flow rate of the liquid passing through the regulator. By configuring a feedback circuit with these two elements (pressure sensor and regulator), the flow rate of the liquid flowing through the pipe can be kept constant even if the flow rate of the inflowing liquid fluctuates. The valve has a function of controlling passage and interruption of liquid by opening and closing. By combining this feedback circuit and a valve, the flow velocity of the liquid passing through the inside of the dispenser can be kept constant, and by precisely controlling the opening / closing time of the valve downstream thereof, precise dispensing becomes possible.

As the pressure sensor, various structures are conceivable, such as a structure that is easily deformed by pressure and a structure formed of a thin film having a piezoelectric effect. For example, a cantilever structure formed by micromachining silicon may be used to detect the resistance change of silicon due to pressure. One example of the regulator is the one sold under the Fluistor product name mentioned above. The basic structure is the same as the valve, but it is necessary to control the distance between the liquid outlet and the valve appropriately. The pressure is controlled by changing the flow rate of the liquid. This regulator can be set to a predetermined pressure by using it in combination with a pressure sensor. The valve is a valve that shuts or opens the flow of the liquid by opening and closing the valve, and the ones described in JP-A-1-213523 and JP-A-6-95745 and the Fluistor can be used. Further, this valve may be a normally open type or a normally closed type.

The dispenser according to the second aspect of the present invention has a discharge port at one end side, a pipe through which the liquid to be dispensed flows, and the pressure of the liquid flowing through this pipe is measured to obtain a reference pressure. Based on the pressure sensor to compare with and the result of this comparison,
A regulator that keeps the flow rate of the liquid constant by feedback control, and a gas that introduces a gas into the liquid whose flow rate is kept constant to make the liquid flowing through the pipe into a series of liquid parts separated by the gas at regular intervals. Introducing means, a valve that can be opened / closed so that this series of liquid parts can flow to the discharge port, the passage of liquid parts is counted on the upstream side of this valve, and the valves are opened / closed according to the passage of a predetermined number of gas parts. And possible control means.

In the first aspect, precise dispensing is possible by precisely controlling the opening / closing time of the valve, but the precision of the opening / closing time of this valve depends on the response speed of opening / closing of the valve. Generally, the smaller the valve, the faster the response, but to ensure this accuracy,
In this second mode, a gas such as air is introduced into a liquid flowing at a constant flow rate to form a liquid portion separated by a series of gases, and the dispensed amount is determined by counting the number of passages of this liquid portion. By measuring and opening and closing the valve, precise dispensing is possible without depending on the response speed of opening and closing.

In the first and second aspects, a container is provided which is connected to the other end of the pipe and stores the liquid flowing in the pipe, and the fluid is stored in the pipe by the hydraulic pressure of the stored liquid. It is preferable to make it flow.

The pumps and valves formed by micromachines are very small, and a large driving force cannot be expected. Therefore, in order to remove the liquid from the liquid container such as the reagent bottle, an auxiliary transportation means is required. Here, by using the hydraulic pressure of the liquid in the container as the driving force for the liquid, it is possible to drive the dispenser without the need for auxiliary transportation means.

A dispenser according to a third aspect of the present invention comprises a container to which a larger amount of liquid than the amount dispensed at the upper end is supplied, and a horizontal portion located below the upper end and the horizontal portion. A pipe having a liquid reservoir portion bent downward from one end of the horizontal portion and located between the horizontal portion and the upper end, and a branch portion branched downward from the middle of the horizontal portion and having a discharge port at its tip end; A first valve that is provided in a horizontal portion between the other end of the horizontal portion and the branch portion and that can be opened and closed; and a second valve that is provided in the branch portion of the pipe and that can be opened and closed; When the valve is opened and the second valve is closed, a predetermined amount of liquid stored in the horizontal portion up to the first valve and the liquid reservoir is supplied through the container. , First
And a pump that flows to the discharge port by closing the second valve and opening the second valve.

The first and second valves and pumps used in this third aspect may be the same as those described in the first aspect. For the container to which the liquid is supplied, it is sufficient to use a cup with a conical shape, a quadrangular pyramid shape, or the like that becomes narrower toward the bottom, so anisotropic etching of silicon or etching or fine mechanical processing on a glass plate etc. It can be processed relatively easily. A capacity meter is composed of the liquid reservoir of the pipe and a part of the horizontal part, and a predetermined amount of liquid measured by the capacity meter is discharged. As the pump, those disclosed in Japanese Patent Laid-Open No. 1-266376, those in which a plurality of valves are arranged and the valves are sequentially driven, and the like can be used.

In this capacity meter, one end of the liquid reservoir portion on the container side and one end of the horizontal portion on the first valve side communicate with the atmosphere, and when liquid is dripped on the one end on the container side, The liquid level is maintained to be the same as the horizontal level. As a result, a fixed amount of liquid is always stored in this capacity meter. Since this capacitance meter is formed by bending the pipe into a predetermined shape, for example, into a U shape as in the embodiment, a precise one can be easily formed. A precise dispenser can be constructed by taking out the liquid accumulated in the volume meter using a valve and a pump. A plurality of dispensers according to the first to third aspects are prepared, the dispenser and a discharge port of the dispenser are connected to each other, and a common pipe having a common discharge port, the common discharge port and the discharge port are provided. A gas is supplied between different liquids which are provided in the common pipe between the outlet connection parts and flow into the common pipe by different dispensers, and the gas supply means for separating these different liquids by the gas in the common pipe is combined. A dispenser array can thereby be constructed.

In general analysis, various reagents are often used alternately or two or more reagents are mixed and used. In such a case, the analyzer can be downsized by using the dispenser array in which the dispensers are integrated. When using many kinds of reagents, it is impossible to perform accurate analysis by mixing different kinds of reagents at an unnecessary time other than mixing the reagents at the time of analysis. For this reason, in this dispenser array, a gas is supplied between different liquids which are made to flow into a common pipe by different dispensers, and these different liquids are separated by the gas in the common pipe. As a result, mixing of reagents does not occur when unnecessary, and reliable analysis can be performed.

A dispenser array constructed by the dispenser of the present invention, a main pipe through which the liquid to be dispensed flows and having a discharge port at one end, and a discharge pipe in the middle of the main pipe. First and second valves which are sequentially provided and can be opened and closed, and an inflow port and an outflow port are connected between these valves to form a detour, and the main pipe when the second valve is closed. A bypass pipe for bypassing liquid from the bypass pipe, a third valve provided in the bypass pipe and capable of opening and closing, and a pump for flowing the liquid from the bypass pipe to the discharge port when the second and third valves are opened. A measurement unit can be configured by combining a main pipe provided between the second valve and the discharge port, and a photometric unit for photometrically measuring the liquid passing through the second valve.

This measuring unit is used for mixing two or more kinds, for example, a reagent and a sample, and then performing an optical measurement. In this measuring unit,
The first valve is opened, liquids of different kinds are sequentially introduced from the dispenser array into the bypass pipe through the first valve, and then the first valve is closed. Then, the third valve is opened and the pump is operated to circulate the liquid in the bypass. By this circulation, different kinds of liquids introduced independently are gradually mixed. After the completion of mixing and the lapse of a certain reaction time, the liquid is subjected to colorimetric and fluorescence measurements in the photometric section. After the measurement is completed, the second valve is opened while the first valve is closed, and the pump is operated to discharge the test liquid to the outside. With such a configuration, the separated liquids are mixed as needed, and the optical measurement can be efficiently performed. Further, since a mechanism for discharging all the test liquid after measurement is provided, the next measurement can be continuously performed.

In this measuring unit, a temperature control device is provided below the entire bypass, and heating is performed during the reaction time after the completion of mixing, and the temperature is kept constant, thereby shortening the reaction time and improving the reaction time. Reproducibility of various reactions can be obtained.

Since the measuring unit is basically manufactured by using a semiconductor lithography technique or a micro processing technique, it can be integrated similarly to the semiconductor IC technique. For example, as described in the prior art, the size of the valve is set to 5.
If it is 5 × 6.5 × 2 mm and is formed on a 4-inch silicon wafer or a 100 mm square glass plate, about 200 bulbs can be mounted. Even if one pump is configured with three valves, when converted to the dispenser of the first aspect, about 60, about 30 with the dispenser of the second aspect, and the dispenser of the third aspect It is possible to mount about 20 units and about 40 measuring units. Furthermore, it is possible to form on a larger substrate by utilizing giant microtechnology for manufacturing a liquid crystal display.

Therefore, it is possible to efficiently perform a large amount of measurement by constructing an analysis unit array in which a plurality of analysis units in which a dispensing unit and a measurement unit are combined are arranged on one substrate.

The dispenser of the present invention is used as an analysis unit in combination with a microsensor array and an optical measurement unit, and the analysis units are arranged in a matrix to simultaneously measure a plurality of measurement items of a plurality of samples. It is possible to configure an analyzer capable of

If four analysis units are used,
A plurality of analysis units having the same function in the vertical direction and the analysis units having different functions in the horizontal direction are arranged, and the combination of different reagents for one measurement item is arranged in the first and second piping lines in the vertical direction. Connect to
The third and fourth piping lines are connected to the adjacent vertical analysis unit. In addition, the pipe from the first sample injection port is connected to the two upper dispensing units in the horizontal direction, and similarly,
The second sample inlet is connected to the two lower lateral dispensing units below it. Then, the waste liquid discharge pipe lines common to the analysis units arranged in the lateral direction are connected to each other. With such a configuration, two measurement items can be simultaneously measured by two analysis units in the horizontal direction for one sample, and a series of analysis units arranged in the horizontal direction can be arranged in the vertical direction. , It is possible to simultaneously measure a plurality of measurement items of a plurality of samples.

The above-mentioned analysis apparatus can be constructed by further combining a plurality of analysis unit arrays arranged on one substrate. In this case, four card-shaped analysis unit arrays are stored in a file shape, and each analysis unit array is provided with a reagent piping line, a sample injection port, and a waste liquid line. By combining a plurality of analysis unit arrays in this way, a processing capacity similar to that of an automatic analysis device can be obtained, and the number of combined analysis unit arrays can be easily changed, so that the design according to the specifications of the device becomes easy.

[0028]

[Embodiment]

[Embodiment 1] FIG. 1 shows a first embodiment of the micro-dispenser of the present invention. This dispenser has a thin pipe 1 extending downward and having a nozzle 4 at its tip for ejecting the dispensed liquid.
4 is provided. At the upper end of the pipe 14, a storage container composed of a reagent bottle 1 that stores a liquid such as a reagent to be dispensed or a sample is detachably attached. The reagent bottle 1 is connected to the pipe 14 such that the liquid therein gradually flows into the pipe 14 due to the gravity of the liquid by communicating with the pipe 14 with the opening facing downward. The pipe 14 is provided with a first microvalve 5, a microregulator 6, a micropressure sensor 7, a second microvalve 8 and a micropump 15 in this order from above to below. The micro pressure sensor 7 is formed of a thin film having a piezoelectric effect and a structure that is easily deformed by the pressure of the fluid, and various structures can be adopted. For example, a known one having a cantilever beam structure formed by micromachining silicon is used. Further, the micro regulator 6 may be, for example, one sold under the trade name of Fluistor described in the prior art, and the basic structure is the same as that of the valve, but the liquid outlet and the valve are the same. The pressure is controlled by changing the flow rate of the liquid by appropriately controlling the interval. Therefore, by using in combination with the micro pressure sensor 7, the fluid can be set to a predetermined pressure, and as a result, the liquid flowing through the pipe 14 can be maintained at a predetermined flow rate. The microvalves 5 and 8 have, for example, a liquid passage and a valve of a silicon rubber sheet formed on a glass plate or a silicon substrate, and an actuator for opening and closing the valve is provided in JP-A-1-266376.
Those described in can be used. . The micro valve may be a normally open type or a normally closed type. The micro pump 15
For example, the one described in JP-A-1-266376 or the one in which a plurality of three or more valves are arranged and the valves are sequentially driven to form a pump can be used.

Next, the operation of the dispenser having the above structure will be described. The reagent bottle 1 is attached to the upper end of the pipe 14 as shown in the figure, and the first microvalve 5 is opened. As a result, the reagent in the reagent bottle 1 gradually falls into the pipe 14 due to its own weight and flows downward in the pipe 14. This reagent reaches the micro pressure sensor 7 through the micro regulator 6. At this time, the pressure of the reagent flowing through the micro pressure sensor 7 is measured, and the measured pressure is compared with a preset reference pressure. Then, when the measured pressure is higher than the reference pressure, a signal is sent to the microregulator 6 to increase the flow rate and to decrease the flow rate when the measured pressure is lower, and based on this signal, the microregulator 6 detects Controls the flow rate of the reagent flowing through. That is, the micro regulator 6 is feedback-controlled by the signal from the micro pressure sensor 7 so that the flow rate of the reagent flowing therethrough is always constant. By keeping this flow rate constant, the flow velocity of the liquid passing through the micro regulator 6 is kept constant. Then, the reagent whose flow rate is kept constant reaches the second microvalve 8. At this time, the opening / closing time of the microvalve 8 is controlled to dispense a predetermined amount of reagent through the nozzle 4. As a result, a predetermined amount of reagent can be dispensed through the nozzle 4. Dispensing this reagent from the nozzle 4
The micro pump 15 may be driven as needed.

In FIG. 1, reference numeral 13 is a reagent pipe 1.
4 shows a pipe for communicating the inside of the reagent bottle 1 with the atmosphere so as to prevent the inside of the reagent bottle 1 from being negatively pressured by dropping into the inside.

In the dispenser having the above-described structure, the relationship between the pressure and the flow velocity is constant according to Bernoulli's theorem. Therefore, the flow velocity of the fluid can be monitored by monitoring the pressure.

In the dispenser of this embodiment, the reagent is drawn out from the bottom of the reagent bottle 1 and the pressure of the liquid stored in the bottle is used for the transporting power of the reagent. Since the above can be omitted, the structure is simplified and the size can be further reduced. Further, since the micro regulator 6 and the micro pressure sensor 7 form a feedback circuit for keeping the flow rate constant, even if the amount of the reagent flowing into the micro dispenser fluctuates, the dispense amount can be accurately measured. Can be maintained.

As described above, the structure of the microregulator is very similar to that of the valve, and the microregulator can also function as a valve. Therefore, except for the microvalve, only the micropressure sensor 7 and the microregulator 6 constitute the microdispenser. It is also possible to do so. Further, since this micro dispenser does not have the function of transporting the reagent, the function of transporting the reagent may be added by disposing the micro pump 15 at the inlet or the outlet of the micro dispenser.

The position of the micro pressure sensor 7 does not matter as long as it is installed in the vicinity of the micro regulator 6, and good feedback can be provided not only on the downstream side but also on the upstream side of the micro regulator. .

[Embodiment 2] FIG. 2 shows a second embodiment of the microdispenser according to the present invention. This dispenser extends downwards,
A thin pipe 14a having a nozzle 4a for discharging the dispensed liquid is provided at its tip. At the upper end of the pipe 14a, a storage container made up of a reagent bottle 1a that stores a liquid such as a dispensed reagent or sample is detachably attached. The reagent bottle 1a is connected to the pipe 14a such that the liquid therein gradually flows into the pipe 14a due to the gravity of the liquid by communicating with the pipe 14a with the opening facing downward. The pipe 14a is provided with a first micro valve 5a, a micro regulator 6a, a micro pressure sensor 7a, a micro bubble sensor 10a, and a second micro valve 11a in this order from above to below. Further, one end of a branch pipe 14b is connected between the micro pressure sensor 7a of the pipe 14a and the micro bubble sensor 10a. A third micro valve 8a and a micro pump 9a are sequentially provided on the branch pipe 14b. At the other end of the branch pipe 14b, a gas such as air is sent to the pipe 14a via the branch pipe 14b, and the pipe 14a
A gas introduction means (not shown) for connecting the reagent flowing therein to a series of liquid portions separated by gas at regular intervals is connected. As the gas introducing means, a blowing mechanism that continuously blows air at a constant flow rate, a pressure maintaining mechanism that maintains the branch pipe 14b at a constant gas pressure, or the like is used. Microvalve 5 used in this embodiment
The components a, 8a, 11a, the micro regulator 6a, the micro pressure sensor 7a, and the micro pump 9a may be the same as those described in the first embodiment. Further, as the micro bubble sensor 10a, the number of a series of liquid portions separated at regular intervals by gas is used by utilizing the difference in light transmittance between the reagent and air flowing in the pipe 14a using a photo coupler. A means for counting or a means for forming a pair of electrodes on both sides of the flow channel and counting the number of liquid portions depending on the difference in conductivity is used.

The operation of the dispenser of the second embodiment will be described below. By opening the first micro valve 5a, the reagent from the bottom of the reagent bottle 1a passes through the pipe 14a and reaches the micro pressure sensor 7a through the micro valve 5a and the micro regulator 6a. The micro pressure sensor 7a measures the pressure of the flowing reagent, and feeds back to the micro regulator 6a so as to increase the flow rate when the pressure is high and decrease the flow rate when the pressure is low with respect to a predetermined pressure. . Therefore, the flow rate of the reagent passing through the micro regulator 6a is kept constant. A branch pipe 14b for introducing air is connected in the middle of the pipe flowing at a constant flow velocity. A third micro valve 8a and a micro pump 9a are arranged in the branch pipe 14b for introducing air to forcibly supply air at a constant speed into the reagent flowing in the pipe 14a at a constant flow velocity. The air is sent in, and the air and the reagent create a flow segmented at regular intervals. That is,
The reagent flowing in the pipe 14a is a series of reagent portions 2b separated by air 1b at regular intervals. The segmented flow is monitored by the valve sensor 10a, the number of passed reagent portions 2b is counted, and the opening / closing time of the micro valve 11a downstream thereof is controlled to divide a predetermined reagent amount through the nozzle 4a. You can order.

Here, the air pipe 13a is a pipe for supplying air so that the atmospheric pressure applied to the reagent inside the reagent bottle 1a does not decrease due to the dropping of the reagent. Also,
The relationship between the pressure and the flow velocity has a constant relationship from Bernoulli's theorem, and therefore the flow velocity of the fluid can be monitored by monitoring the pressure.

In the dispenser of the second embodiment, the reagent is discharged from the bottom of the reagent bottle 1a, and the pressure of the reagent stored in the bottle is used for the transporting force of the reagent, so that the reagent is transported. Since a pump or the like for that can be omitted, the structure is simplified, and the size can be further reduced. Further, since the micro regulator 6a and the micro pressure sensor 7a form a feedback circuit for keeping the flow rate constant, even if the amount of the reagent flowing into the micro dispenser fluctuates, the dispense amount can be accurately maintained. You can do it.
Further, the accuracy of the opening / closing time of the second valve 11a depends on the response speed of opening / closing of the valve 11a, which may affect the dispensing accuracy. However, air bubbles are intermittently generated in the reagent flowing at a constant flow rate. A series of reagent parts 2b
By counting the number of passages and controlling the opening / closing of the valve 11a, precise dispensing can be performed without depending on the response speed of opening / closing the valve.

As described above, the structure of the microregulator 6a is very similar to that of a valve, and since it can also function as a valve, the microvalve is excluded and only the micropressure sensor 7a and the microregulator 6a serve as a microdispenser. It is also possible to configure the main part. Further, the micro pressure sensor 7a is the micro regulator 6
If it is installed in the vicinity of a, the position does not matter, and good feedback can be performed either before or after the micro regulator 6a.

[Embodiment 3] FIG. 3 shows a third embodiment of the microdispenser of the present invention. The pipe 17 of this dispenser
A branched horizontal portion 17a located below the upper end where the cup-shaped container 8 is provided, and a liquid reservoir 17b that is bent downward from one end of the horizontal portion and is located between the horizontal portion and the upper end. A vertical portion 17 in which a nozzle having a discharge port at the tip is formed by branching downward from the middle of the horizontal portion 17a.
It consists of c and. The horizontal portion 17a of the pipe 17 is provided with a first microvalve 10, a liquid sensor 11, and a first micropump 12a sequentially in the downstream direction. Then, the tip of the horizontal portion 17a is opened and communicates with the atmosphere. In addition, the vertical portion 17c is provided with a second microvalve 16 in order downward.
A second micropump 12b is provided. The liquid reservoir 17b is formed by bending a pipe in a U shape from the base end of the horizontal portion 17a.

The microvalves 10 and 16 and the micropump 12 used in the dispenser of the third embodiment.
As a and 12b, the same as those described in the first embodiment can be used. Further, as the liquid sensor 11,
The bubble sensor described in the second embodiment can be used as it is. Since the cup-shaped container 8 may have a conical shape or a quadrangular pyramid shape as shown in the figure, this can be processed relatively easily by anisotropic etching of silicon or etching or fine mechanical processing on a glass plate or the like. . The liquid reservoir 17b functions as a micro capacity meter by forming a combination with the portion of the horizontal portion 17a up to the valve 10.
As the micropumps 12a and 12b, JP-A 1-2
The one described in 66376 or the one in which a plurality of valves are arranged and the valves are sequentially driven to form a pump is used.

A feature of the dispenser of the third embodiment is that a micro volume meter is used to collect only a limited amount of liquid by the volume of the volume meter. The operation will be described below with reference to FIG.

First, the first valve 10 is opened and the second valve 10 is opened.
With the valve 16 of 1 closed, the liquid is dripped into the cup 8 as shown by the arrow. The dropping amount does not have to be accurate as long as it is a predetermined amount or more. As a result, the dropped liquid accumulates in the liquid reservoir 17b in a certain amount, and the excess liquid passes through the first valve 10 and is discharged from the tip of the horizontal portion 17a to the outside. After that, the first valve 10 is closed, the second valve 16 is opened, the second pump 12b is operated, and the liquid stored in the capacity meter is passed through the nozzle and is indicated by an arrow. Dispense downward as shown.
Similarly, after the first valve 10 is closed, the first pump 12a is also operated to discharge the excess liquid accumulated in the horizontal portion 17a on the downstream side of the valve 10 to the outside.

Next, the function of the microcapacitance meter will be described in more detail. When a liquid is dropped on a pipe having a U-shaped structure with both ends open, the liquid levels on both sides of the pipe are hydrostatically equal. When one of the U-shaped structures is bent horizontally (or folded below) as shown in FIG. 3, the stagnant liquid can stay only below the point where it is bent on both sides of the U-shaped structure. Therefore, even if a certain amount or more of liquid is dropped onto the U-shaped structure, the amount of liquid that stays in the U-shaped structure is always constant and the amount of liquid that exceeds the amount of liquid that can stay flows into the bent flow path, that is, the horizontal portion 17a. . By disposing the first microvalve 10 in the middle of this bent flow path and switching it from the open state to the closed state, the liquid that has flowed in can be interrupted halfway. Further, during this measurement, the second micro valve 16 remains closed and the vertical portion 17c is extremely thin, so that liquid does not flow into the vertical portion 17c. Therefore, as shown by the hatching, the liquid remains in the capacity meter constituted by the liquid reservoir 17b and a part of the horizontal portion 17a, opens the second microvalve 16, and opens the second micropump 12b. By operating, only this measured liquid can be dispensed. Therefore, a precise microcapacitance meter can be formed.

The liquid sensor 11 is for confirming whether or not a predetermined amount or more of liquid has been dripped into the cup-shaped container 8, and when a liquid of a predetermined amount or less is accidentally dripped into the container 8. Since the liquid does not pass through the liquid sensor 11, the presence of the liquid cannot be detected and an error signal is output. Therefore, it is possible to guarantee the accuracy of the operation without dispensing a liquid of a predetermined amount or less.

In this embodiment, the liquid reservoir forming the micro-capacity meter is U-shaped, but may be of any shape such as V-shaped or semi-annular so long as it fulfills the above functions.

In general analysis, various reagents are often used alternately, or two or more reagents are mixed and used. Hereinafter, a case where a dispenser array suitable for such an analysis is constructed by using the dispenser of the above-mentioned embodiment to form a measuring unit in combination with measuring means will be described with reference to FIG. .

Reference numerals 19a, 19b and 19c in the drawing respectively denote first to third dispensers, and as the dispensers, those of the first to third embodiments can be used. The discharge ports (nozzle tips) of these dispensers 19a, 19b, 19c are common pipes 24 having a common discharge port at one end.
Are connected to the base end side of each. In addition, micro valves 21a, 21a are provided near the discharge ports of the pipes of the respective dispensers.
b and 21c, and branch pipes 20a, 20b and 20c for supplying gas such as air are connected. These microvalves may be the same as those described in the above embodiment. In this way, a dispenser array consisting of three dispensers is constructed.

A microsensor array 41 and a micropump 26 are provided downstream of the common pipe 24. As the sensor array 14, for example, an array in which a plurality of microsensors are incorporated in a liquid channel formed on a silicon wafer can be used, as proposed in JP-A-3-122558.

Next, the operation of the measuring unit having such a configuration will be described. First, the first liquid (standard liquid 1)
Is supplied to the dispenser 19a through the liquid inlet 18a, and a predetermined amount of the liquid dispensed by the dispenser is supplied to the micropump 26.
Is operated to lead to the sensor array 41 via the common pipe 24. Then, the first liquid measured by the sensor array 41 is discharged to the outside through the common discharge port. After the first liquid is supplied to the common pipe 24, the first micro valve 21a is opened to supply air to the common pipe 24 as indicated by the arrow. Subsequently, the second liquid (standard liquid 2) is supplied to the second dispenser 19b through the liquid inlet 1
8b, and the liquid dispensed here is guided by the micropump 26 to the sensor array 41 via the common pipe 24, and measurement is performed. Then, similarly to the above, after the second liquid is supplied to the common pipe 24, the second microvalve 21b is opened and air is supplied to the common pipe 24 as indicated by an arrow. Finally, the third liquid (measurement sample)
Is supplied to the third dispenser 19c via the liquid inlet 18c, and the liquid dispensed here is guided to the sensor array 41 via the common pipe 24 by the micropump 26 and the measurement is performed in the same manner as described above. , The third microvalve 2
Air is supplied via 1c.

By configuring the dispenser unit as described above, between the first liquid and the second liquid, and the second liquid.
Air can be allowed to exist between the liquid and the third liquid to prevent the liquids from mixing with each other and dispense a plurality of types of liquids.

As the individual sensors 42 of the sensor array 41 used in the measuring unit having such a structure, electrolyte (Na, K, Cl, Ca, Li measurement), blood gas (P
O ₂ , PCO ₂ , _PH ), an enzyme (glucose, BUN) sensor is used, but the first liquid is the standard liquid 1,
Fully automatic analysis can be performed by measuring the second liquid as the standard liquid 2, calibrating the sensor, and finally measuring the measurement sample such as the blood body.

As described above, by combining the micro-dispenser array and the sensor array, one analysis unit can measure a plurality of items at once, and the analysis device can be configured on-chip. Therefore, miniaturization is possible.

The position of the micro pump may be upstream of the micro sensor array 41. Further, in this embodiment, the array is composed of three pipettes, but if necessary, four arrays are used.
The array may be composed of a number of dispensers other than three.

Next, a plurality of pipettes of the embodiment are combined to form a pipette array, two or more kinds of reagents and samples are mixed, and then a measurement unit for performing optical measurement is shown in FIG. It will be described with reference to FIG.

In FIG. 5, the dispenser array is shown in FIG.
It is omitted because it is substantially the same as that shown in. FIG.
As shown in (a), the common pipe 24, to which a dispenser array (not shown) is connected on the base end side, sequentially has a first micro valve 35, a mixture portion 36, and a second micro valve toward the downstream side. 37, an optical measuring unit 36a, and a first micropump 38 are provided. In addition, the detour pipe 24a is connected to the common pipe 24, the inflow port thereof is connected between the mixture part 36 and the second micro valve 37, and the outflow port is formed between the first micro valve 35 and the mixture part 36. It is connected so that it is connected to. The bypass pipe 24a is provided with a third microvalve 40 and a second micropump 39 toward the downstream side. This bypass pipe 24a and a part of the common pipe 24 including the mixture section 36 constitute a circulating bypass circuit, and a temperature control device 35a and a temperature detecting element 35b are arranged below the bypass circuit to connect the bypass circuit. The flowing liquid can be maintained at a predetermined temperature.

Microvalve 3 used in this device
5, 37, 40 and micropumps 38, 39 are the same as those described in the first embodiment. The mixture portion 36 may be formed by partially increasing the diameter of the common pipe 24.

Next, the operation of the measuring unit having such a configuration will be described with reference to FIG. First, the first valve 35 and the second valve 37 are opened, and the third valve 4 is opened.
With 0 closed, the first pump 38 is operated to sequentially introduce different types of liquid from the dispenser array into a part of the bypass of the optical measurement unit, as indicated by the arrow. Then, the valves 35 and 37 on both sides of the bypass are closed, the third valve 40 is opened, and the pump 39 is operated to circulate the liquid in the bypass. During this circulation, the liquid separated by air is easily mixed in the mixture portion 36 having a diameter larger than that of the flow path. This mixing is continued for a certain period of time, and further incubation is carried out by the temperature control device 35a and the temperature detection element 35b arranged under the entire detour. After the mixing is completed, the driving of the pump 39 is stopped, and this state is maintained for a certain period of time to allow the mixed liquid to react. After this fixed reaction time has elapsed, this mixed liquid is opened by opening the first and second valves 35 and 37,
The valve 40 is closed, and the first pump 38 is driven to lead to the photometric unit 36a for colorimetric measurement. After the completion of this measurement, the third valve 40 is opened and the first and second pumps 39 and 38 are operated to discharge the test liquid from the tip of the common pipe 24 to the outside as shown by the arrow. With such a configuration, the separated liquids are mixed as needed, and the optical measurement can be efficiently performed. Further, since a mechanism for discharging all the test liquid after measurement is provided, the next measurement can be continuously performed. In this measuring unit, the optical measuring unit is incorporated outside the detour, but it can be installed inside the detour.
It is also possible to combine the mixture unit 36 and the photometric unit 36a into one. Further, although the dispenser unit shown in FIG. 4 in which different liquids are separated from each other by air is used, a dispenser array in which different liquids can be sequentially supplied by a valve may be used.

As the photometric section 36a, for example, FIG.
The structure shown in (b) and (c) can be adopted. FIG. 5B shows a silicon substrate in which a channel is formed on the other side surface of the silicon substrate 71 having the silicon oxide film 72 formed on one side surface, and the silicon oxide film 72 is left by anisotropic etching. After the through hole is formed in the central portion of 71, the glass plate 70 is manufactured by anodic bonding to the other side surface of the silicon substrate 71. In such a photometric unit, the liquid 73 is filled in the flow path and the through hole as shown by hatching in the figure, and the light indicated by the arrow 74 is transmitted through the liquid to detect the intensity and spectrum of the transmitted light. Is measured by. In FIG. 5C, the flow paths 76, 76 are formed on both side surfaces of the glass plate 79, and the through holes 81 connecting the flow paths 76, 76 are formed, and the glass plate 79 is further formed. It is configured by laminating glass plates 75 and 78 on both side surfaces of 79 by anodic bonding. In such a photometric unit, the measurement light (indicated by the arrow 77) is transmitted through the through hole 81 to perform the measurement, and the optical path length for the measurement can be secured even if the liquid amount is small. . In this case, it is desirable that the surface of the through hole 81 be covered with a substance having a refractive index lower than that of the liquid so that light can be efficiently transmitted.

A temperature control section 35a is provided under the entire detour.
Also, the temperature detecting element 35b may be provided. Since the optical measurement unit is formed on the glass substrate or the silicon substrate, the back surface is flat. Therefore, the temperature detection device 3 such as the temperature control device 35a or the thermistor can be easily attached to the flat portion.
It is possible to arrange 5ba. By heating, the reaction time can be shortened and good reproducibility of the reaction can be obtained. A Peltier element or the like is used as the temperature control element, but when it is used as a heater only for heating, it is also possible to use an existing panel heater by pasting it together, or by directly pasting a resistor such as a nichrome wire, It is also possible to form the heater by a method such as vapor deposition or sputtering. A thermistor is illustrated as the thermometer, but a thermocouple, a platinum temperature measuring element, etc. can also be used.

Next, a plurality of analysis units composed of the dispenser array and the microsensor array and a plurality of analysis units composed of the dispenser array and the optical measurement unit are combined to simultaneously measure a plurality of measurement items. A possible analyzer will be described with reference to FIG.

This apparatus uses the dispenser unit and the microsensor array described with reference to FIG. 4, and the dispenser array and the optical measurement unit described with reference to FIG. It is possible to form it as an analysis unit array integrated in the. That is, since these measuring units are basically manufactured by using a semiconductor lithography technique or a microfabrication technique, they can be integrated similarly to the semiconductor IC technique. For example, about 200 on a 4-inch silicon wafer or 100 mm square glass plate.
It is possible to mount individual valves. Even if one pump is composed of three valves, when converted to the micro-dispenser of the first embodiment, about 60, about 30 with the micro-dispenser of the second embodiment, and the third embodiment. It is possible to mount about 20 by the Micro Dispenser and about 40 by the micro sensor array shown in FIG. Therefore, as shown in the present embodiment, it is possible to construct an analysis unit array in which four analysis units in which a dispensing unit and a measurement unit are combined are arranged on a 100 mm square glass plate with a sufficient margin.

In FIG. 6, the first analysis unit 51 includes a dispenser array 51a and a microsensor array 51b.
And the second analysis unit 52 comprises the dispenser array 5
2a and an optical measurement unit 52b. Similarly, the third analysis unit 54 includes a dispenser array 54a,
The fourth analysis unit 55 includes a dispenser array 55a and an optical measurement unit 55b. And as shown
An analysis unit that performs the same function (first analysis unit 5
The first and third analysis units 54, and the second analysis unit 52 and the fourth analysis unit 55) are arranged in the vertical direction and perform different functions (first and third analysis units 51). , 54 and the second and fourth analysis units 52, 55) are arranged in the lateral direction, and as a whole, the four analysis units are arranged in a matrix.

The microsensor array 51b. 54b
Is an array of ion sensors for measuring ion concentration, and an array of enzyme sensors for detecting glucose and the like.

The first and second pipe lines 46, 47 for the two reagents for one measurement are provided in the dispenser array 51 of the first and third analysis units 51, 54.
a and 54a are connected so as to supply the reagent 1 and the reagent 2. Similarly, the third and fourth piping lines 49,
50 is connected to supply the reagent 3 and reagent 4 to the dispenser arrays 52a, 55a of the second and fourth analysis units 52, 55. On the other hand, the first sample injection port 48
The pipe 48a from the first and second dispensing units 5
1 and 52, and similarly, the pipe 53a from the second sample injection port 53 is connected to the third and fourth dispensing units 54,
Connected to 55. As a result, the reagents are commonly supplied to the analysis units arranged in the vertical direction, and the sample is commonly supplied to the analysis units arranged in the horizontal direction.
The piping lines 46a and 47a are a collection of waste liquid lines connected to the analysis unit first and second analysis units 51 and 52 and the third and fourth analysis units 54 and 55, respectively.

The operation of the above analyzer will be described below with reference to FIG. The measurement sample 1 is placed in the first sample injection port 48,
Further, the measurement sample 2 is dropped on each of the second sample injection ports 53. As a result, the predetermined amount of measurement sample 1 is
Array 51a, 5 in the analysis unit 51, 52 of
2a, the measurement sample 2 is the third and fourth analysis units 5
Dispensers are dispensed by the dispenser arrays 54a and 55a in 4, 55 and introduced into the microsensor arrays 51b and 54b and the optical measurement units 52b and 55b. Then, the first piping line 46 of the reagent corresponding to the measurement item 1
A predetermined amount of reagent 1 supplied from the analysis unit 51, 5
It dispenses with the dispenser arrays 51a and 54a in 4 and is introduce | transduced into the microsensor arrays 51b and 54b. Similarly, the second piping line 47 of the reagent corresponding to the measurement item 1
A predetermined amount of reagent 2 supplied from the analysis unit 51, 5
It dispenses with the dispenser arrays 51a and 54a in 4 and is introduce | transduced into the microsensor arrays 51b and 54b. With these series of operations, the calibration of the sensor and the measurement of the measurement sample, for example, the electrochemical measurement are performed, and the measurement for the measurement item 1 is completed.

A predetermined amount of the reagent 3 supplied from the third piping line 49 of the reagent corresponding to the measurement item 2 is dispensed by the dispenser arrays 52a and 55a in the analysis units 52 and 55, and the optical measurement unit 52b, 55b. Similarly, the fourth piping line 5 of the reagent corresponding to the measurement item 2
A predetermined amount of the reagent 4 supplied from 0 is used as the analysis unit 52,
It is dispensed by the dispenser arrays 52a, 55a in 55 and introduced into the optical measurement units 52b, 55b. The measurement samples 1 and 2 and the reagents 3 and 4 are mixed in the optical measurement units 52b and 55b, and colorimetric measurement is performed after incubation.

In this pipe connection, a plurality of measurement items can be simultaneously measured for one sample by a horizontal analysis unit, and a series of analysis units arranged in the horizontal direction are arranged in the vertical direction to make a plurality of measurement items. Multiple measurement items of a sample can be measured simultaneously. In this analyzer, an example in which four analysis units each having two columns and two columns are formed is shown, but it is also possible to form an analysis array in which more analysis units are arranged. Further, the combination of the dispenser array and the microsensor array or the optical measurement unit is not limited to this, and various configurations are possible as necessary.

Furthermore, by combining a plurality of analysis arrays arranged on a single substrate, it is possible to realize a processing capacity similar to that of an automatic analyzer. As shown in FIG. 7, 59, 60, 6 card-shaped analysis arrays are used.
1 is stored in a file form, and the first analysis array is provided with reagent piping lines 56, 56a, 56, respectively.
b, 56c, sample injection ports 57, 58, and waste liquid lines 59, 60 are provided. The same reagent piping line, reagent injection port, and waste liquid line are provided for the second and third analysis arrays. By combining a plurality of analysis arrays in this way, it is possible to obtain the processing capacity of an automatic analysis apparatus. Since the combination of analysis arrays can be easily changed, it is easy to design according to the specifications of the device, such as limiting the number of measurement items to increase the number of measurement samples or limiting the number of measurement samples to increase the measurement items. become.

[0070]

INDUSTRIAL APPLICABILITY The dispenser according to the present invention can be miniaturized and can dispense a fixed amount of liquid with high accuracy.

[Brief description of drawings]

FIG. 1 is a diagram schematically showing a micro-dispenser according to a first embodiment of the present invention.

FIG. 2 is a diagram schematically showing a micro dispenser according to a second embodiment of the present invention.

FIG. 3 is a diagram schematically showing a micro dispenser according to a third embodiment of the present invention.

FIG. 4 is a diagram schematically showing a measuring unit configured by combining a micro-dispenser and a measuring means according to an embodiment of the present invention.

FIG. 5 is a diagram schematically showing another example of the measurement unit.

FIG. 6 is a dispenser array configured by combining a plurality of dispensers according to an embodiment of the present invention, and an optical measurement unit,
It is a figure which shows the analyzer which consists of an analysis unit.

FIG. 7 is a perspective view showing an example of the configuration of the analyzer shown in FIG.

FIG. 8 is a diagram schematically showing an example of a conventional dispenser.

[Explanation of symbols]

4 ... Nozzle, 5, 8 ... Micro valve, 6 ... Micro regulator, 7 ... Micro pressure sensor, 14 ... Pipe,
15 ... Micro pump.

Claims (3)

[Claims] 1. A pipe having a discharge port at one end side, through which a liquid to be dispensed flows, a pressure sensor for measuring the pressure of the liquid flowing through the pipe and comparing the pressure with a reference pressure, and based on the comparison result. And a dispenser comprising a regulator that maintains a constant flow rate of the liquid by feedback control, and a valve that can be opened / closed so that the liquid having a constant flow rate flows to a discharge port for a predetermined time. 2. A pipe having a discharge port at one end thereof, through which a liquid to be dispensed flows, a pressure sensor for measuring the pressure of the liquid flowing through the pipe and comparing the pressure with a reference pressure, and based on the comparison result. , A regulator that keeps the flow rate of the liquid constant by feedback control, and a series of liquid parts where the liquid flowing through the pipe is separated at regular intervals by introducing gas into the liquid whose flow rate is kept constant. Gas introduction means, a valve that can be opened and closed so as to cause the series of liquid portions to flow to the discharge port, the passage of the liquid portion is counted on the upstream side of the valve, and the valve is determined according to the passage of a predetermined number of gas portions. And a control means capable of opening and closing. 3. A horizontal part, which is provided with a liquid larger than the amount dispensed to the upper end, is positioned below the upper end, and is bent downward from one end of the horizontal part. Of the liquid reservoir portion located between the upper portion and the upper end, and a branch portion branched downward from the middle of the horizontal portion and having a discharge port at the tip, and the other end of the horizontal portion and the branch portion. A first valve provided in a horizontal portion between the first and second valves, which can be opened / closed, a second valve provided in a branch portion of the pipe, which can be opened / closed, and a first valve are opened, and a second valve is closed. When the first valve is closed, a predetermined amount of liquid supplied through the container and stored in the horizontal portion up to the first valve and the liquid reservoir is closed. A dispenser comprising: a pump that opens the valve to flow to a discharge port.