JP4534013B2 - Library manufacturing apparatus and library manufacturing method - Google Patents

Description

The present invention relates to a library manufacturing apparatus and a library manufacturing method capable of dispensing various types of liquid samples to accurate positions on a library plate using a disposable pipette tip.

Taking inorganic materials as an example, recent advances in fine ceramic technology have made it possible to control the crystal structure, composition, and crystal grain size of ceramic materials on the micron to nanoscale. For this reason, the development of application of ceramic materials to electronic materials and the like is rapidly expanding. Among these, ceramic oxides have a wide range of physical properties in terms of dielectric properties, magnetic properties, electrical conductivity, and the like. The diversity of functions of ceramic materials means that the parameters to be controlled as ceramic materials are extremely diverse including their non-stoichiometry and crystal structure anisotropy.

As a result, ceramic materials obtained by mixing and firing multiple types of inorganic material raw materials that are starting materials at different ratios as in the conventional method are manufactured one by one, and their properties are examined. Not only does it take an enormous amount of time to reach, it is extremely unlikely to lead to accidental discoveries that are beyond intuition and experience. Furthermore, when handling the same type of substance with a plurality of people, the probability of an error due to human error increases. A key point in searching for new ceramic materials is how to systematically control the combination of various raw materials by using an automatic processor.

In addition, even in the case of organic material raw materials, researches on combinations of plural kinds of components have been conducted intensively. For example, in the development of an efficient refrigerant with a small environmental load used for a heat pump device, there is a limit to a single refrigerant, and therefore, a mixed refrigerant of three or more components has been studied (patent) Reference 1). It is well known that in the field of pharmaceuticals, combinatorial techniques are also widely used in the development of effective drugs. In this way, if a large number of samples with different mixing ratios can be generated accurately and in a short time by mixing multiple types of raw materials, the search for new materials in a wide range of science and technology fields is expected to greatly advance. it can.

The inventors have invented and applied for a patent for a chemical reaction processing apparatus that generates and analyzes a large number of samples obtained by mixing a plurality of inorganic material raw materials in combinations of different ratios (Patent Document 2). By using this chemical reaction processing apparatus, a large number of chemical products can be obtained by easy control, and they can be analyzed and evaluated with high efficiency.

When the target is a liquid raw material, the chemical reaction processing apparatus dispenses a liquid sample mixed with the liquid raw material onto a library plate using a pipette tip, and manufactures the library. In addition, in order to analyze and evaluate the obtained chemical product with high efficiency, the necessity of accurately dispensing a large number of liquid samples on a single library plate has increased.

Conventionally, a washing method and a disposable chip method (for example, Patent Document 3) are known as a dispensing method employed in library manufacture. Adopting the disposable tip method can reliably prevent contamination of liquid samples during dispensing, and is widely used in the fields of chemical analysis and clinical testing. Since disposable pipette tips used in the disposable tip method are used in large quantities, those made of general-purpose synthetic resin with low cost are generally used. However, due to the nature of the raw material of general-purpose synthetic resin, the accuracy of the shape of the pipette tip made of general-purpose synthetic resin is not necessarily good, and unless it is special conditions, the shape of what has been stored for a long time will change from the time of manufacture It is inevitable. Therefore, there is a limit to the exact position required for the library. That is, it is difficult to manufacture a precise library of sample formation positions required for automatic measurement of physical properties and the like.

In order to manufacture a library with a precise sample formation position, a dispensing apparatus (Patent Document 4) is known in which a plurality of pipettes are integrated and assembled to dispense a sample liquid into a relatively accurate position. Even with this technique, if the accuracy of the shape of the pipette tip is poor, it is difficult to manufacture a library with a precise sample formation position.

Furthermore, a pipette device (Patent Document 5) is known that detects that a pipette needle (pipette tip) has contacted a reference surface of a reference member and ensures that the pipette needle is accurately transferred to a target position. However, the pipette needle used in this pipetting device is not disposable, and is not suitable for the purpose of dispensing many kinds of samples to the library plate while changing the pipette tip for each sample.

Japanese Patent Laid-Open No. 9-324175 JP 2001-219052 A JP-A-6-289032 JP 2001-153761 A JP-A-5-346433

The present invention broadens the application range of the above-mentioned chemical reaction apparatus developed by the present inventors and makes it more effective. For example, a plurality of types of liquid raw materials are mixed using a combinatorial method and the mixing ratio is different. It is an object of the present invention to provide a library manufacturing apparatus and a library manufacturing method suitable for automatically generating various types of liquid samples and dispensing them at precise positions on a library plate using a disposable pipette tip.

The present invention has been made to solve the above-described problems, and in a library manufacturing apparatus using a disposable pipette tip, the tip position of the pipette tip is detected using a reference member. The present invention relates to a library manufacturing apparatus and a library manufacturing method capable of calculating a difference between a pipette tip mounting head and a reference position of a pipette tip tip defined by the position of a pipette tip mounting head and forming a sample at an accurate position of a library plate. .

That is, the present invention is (1) a library manufacturing apparatus that uses a disposable pipette tip mounted on a pipette tip mounting head fixed to a transfer means, and the tip of the pipette tip approaches the library manufacturing apparatus. Possible mutually orthogonal X and Y directions
A reference member having a horizontal cross section in the upper surface is fixed, and a detection means for detecting that the tip of the pipette tip is close to the cross section in the X direction and the Y direction of the reference member; And a calculating means for calculating a difference between the position of the tip of the pipette tip in the X direction and the Y direction and the reference position of the tip of the pipette tip defined by the position of the pipette tip mounting head at that position. A library manufacturing apparatus.

The material of the disposable pipette tip is not particularly limited, but in consideration of consuming a large amount of the pipette tip, a synthetic resin-made one can be suitably used. The synthetic resin is preferably selected from general-purpose resins such as polyethylene, polypropylene, polyvinyl chloride, and polystyrene, or compounds thereof.

The X direction and the Y direction indicate two axes that substantially form a horizontal plane, and the horizontal plane represents a moving surface of the pipette tip mounting head. The pipette tip mounting head can horizontally transfer the surface indicated by the X direction and the Y direction by the transfer means.

When the entire library manufacturing apparatus is set on the X-axis and Y-axis coordinates, the position of the moving pipette tip mounting head, the tip of the pipette tip having an ideal shape without deformation, which is defined by the position of the pipette tip mounting head (Referred to as “reference position” in this specification) and the position of the tip of the pipette tip detected by the detecting means can be expressed as coordinate points on the coordinates composed of the X-axis and the Y-axis, This is preferable because it can be easily calculated. Also, the pipette tip mounting head moving direction by the transfer means and the X direction of the reference member,
It is preferable to make the Y direction the same as the X axis and the Y axis because the positional relationship can be easily calculated.

In addition, if the position of the sample formed on the library plate fixed to the library manufacturing apparatus is defined as a coordinate point on the coordinates including the X axis and the Y axis, the dispensing position can be accurately calculated. Furthermore, it is preferable that the position of the sample formed on the library plate can be changed because a library having an arbitrary number of samples can be manufactured.

The present invention also provides (2) a disposable pipette tip in which a plurality of types of liquid samples obtained by mixing a plurality of types of liquid raw materials in different mixing ratios in a mixing container are mounted on a pipette tip mounting head fixed to a transfer means. A library manufacturing apparatus that dispenses into a library plate, wherein a reference member having a horizontal top surface having a cross section in the X direction and the Y direction perpendicular to each other, to which the tip of the pipette tip can approach, is fixed to the library manufacturing apparatus. Detecting means for detecting that the tip of the pipette tip is close to the cross section of the reference member in the X direction and the Y direction, the position of the tip of the pipette tip in the X direction and the Y direction detected by the detecting means, Calculation to calculate the difference from the reference position of the pipette tip tip defined by the position of the pipette tip mounting head at the position And the step, is provided with, for each liquid sample of said plurality of kinds,
Before the pipette tip is replaced and dispensed to the library plate mounted on the library manufacturing apparatus, the difference between the detected position of the tip of the pipette tip and the reference position of the tip of the pipette tip is calculated. A library manufacturing apparatus, characterized in that:

The present invention is particularly effective in an apparatus that automatically manufactures a large number of liquid samples, because a large number of libraries can be manufactured in a short time, and a large number of disposable pipette tips are used. is there.

Further, according to the present invention, (3) in the library manufacturing apparatus according to (1) or (2), the detection means injects gas from the tip of the pipette tip and detects a changing back pressure in the pipette tip. It is a library manufacturing apparatus characterized by being a thing.

As a method for injecting gas from the tip of the pipette, it is preferable to use a suction / discharge mechanism for dispensing because the apparatus can be simplified. As the suction / discharge mechanism, it is particularly preferable to use a syringe pump that enables accurate dispensing. As a means for detecting the back pressure, it is preferable to provide a semiconductor type pressure sensor in a portion spatially communicating with the pipette tip. Specifically, a semiconductor-type pressure sensor can be provided in a portion that spatially communicates with the pipette tip in the pipette tip mounting head.

The present invention also provides (4) a library manufacturing method in which a plurality of types of liquid samples are dispensed with a disposable pipette tip attached to a pipette tip mounting head fixed to a transfer means, and (i) the pipette tip is Attaching to the pipette tip attachment head; (i
i) the step of bringing the pipette tip close to the reference member while injecting gas from the X direction by the transfer means, and detecting the change in the back pressure in the pipette tip; and (iii) the pipette tip being moved by the transfer means to the reference member Detecting a change in the back pressure in the pipette tip by injecting gas from the Y direction orthogonal to the X direction to the pipette, and (iv) detecting the change in the back pressure detected in the X direction and the Y direction from the pipette. Detecting the position of the tip of the tip;
(v) calculating a difference between the detected position of the tip of the pipette tip and a reference position of the tip of the pipette tip; (vi) transferring the pipette tip based on the calculation result of the difference; And (vii) discarding the pipette tip, and for each of the liquid samples (i) to (vii) The library manufacturing method is characterized by repeating the step (1).

In addition, the present invention provides (5) a disposable type in which a plurality of types of liquid samples obtained by mixing a plurality of types of liquid raw materials in different mixing ratios in individual mixing containers are mounted on a pipette tip mounting head fixed to a transfer means. A library manufacturing apparatus for dispensing a library plate with a pipette tip, wherein a reference position in the X direction and the Y direction is preset in the pipette tip mounting head, and the pipette tip is mounted in the library manufacturing apparatus. The pipette tip tip position measuring device at the head reference position is provided, and is defined by the measured position of the pipette tip tip at the pipette tip mounting head reference position and the position of the pipette tip mounting head at the reference position. Calculation means for calculating the difference from the reference position of the tip of the pipette tip is provided. The pipette tip is replaced for each of the plurality of types of liquid samples, the pipette tip mounting head having the replaced pipette tip attached is transferred to a reference position, and the library plate attached to the library manufacturing apparatus is attached to the library plate. A library manufacturing apparatus, wherein the difference between the measured position of the tip of the pipette tip and the reference position of the tip of the pipette tip is calculated before dispensing;
It is.

In the present invention, as the pipette tip tip position measuring device, an imaging device such as a CCD camera arranged so as to photograph the tip of the pipette tip from below is suitable. Specifically, the pipette tip tip reference position is adjusted so that it is positioned at the center point of the image taken by the imaging device, and the pipette tip tip is taken from below with the imaging device, and the center point of the image is taken. By calculating the deviation from the image position of the pipette tip tip, the pipette tip tip position can be accurately measured.

According to the library manufacturing apparatus and the library manufacturing method of the present invention, a library in which a sample is formed at an accurate position of a library plate can be manufactured even if the shape accuracy of a disposable pipette tip is poor.

(First embodiment)
Hereinafter, embodiments of the present invention will be described with reference to the drawings. In this embodiment, a case where a plurality of types of liquid samples are automatically manufactured from a plurality of types of liquid raw materials and a library is manufactured from these liquid samples is taken up. At this time, the combination ratio of the plurality of liquid raw materials is automatically calculated by the arithmetic unit by inputting the identification name of the liquid raw material and the number of divisions of the coordinates of the composition diagram.

FIG. 1 is a block diagram showing an embodiment of a library manufacturing apparatus of the present invention, FIG. 2 is a cross-sectional view showing a tip reference position of a pipette tip of the present invention, and FIG. 3 is a pipette used in the present invention. It is sectional drawing which shows the front-end | tip position of a chip | tip. FIG. 4 is a perspective view of a reference member of the library manufacturing apparatus of the present invention, and FIG. 5 is a schematic diagram for explaining a method for detecting the tip position of the pipette tip in the present invention. FIG. 6 is a composition diagram displayed on the display means of the library manufacturing apparatus of the present invention.

First, a method for producing a plurality of types of liquid samples in which a plurality of types of liquid materials are mixed in different mixing ratios in a mixing container will be described with reference to FIG. In FIG. 1, in the input means 2, (1)
Identification name and concentration of plural kinds of liquid materials to be mixed, (2) number of coordinates of composition diagram, (3) operation time of stirring mechanism, (4) number of times of suction / discharge of liquid sample by suction / discharge mechanism, The suction / discharge amount and (5) the type and amount of the additive are input as data. Here, the additive is a substance that essentially does not become a component of the sample, and examples thereof include a catalyst, a solvent, a dispersant, a thickener, and a surfactant. The purpose of adding the additive includes promoting the reaction, maintaining good dispersion of the solute, improving the moldability, and the like.

When the liquid raw material is a liquid inorganic material raw material, it is easy to make the liquid sample have the same molar concentration by setting the concentration to the molar concentration. In other words, if the molar concentration of all the liquid inorganic material raw materials is the same, the molar concentration of the liquid sample can be made constant at all the combination ratios, and the volume of the liquid sample obtained by mixing a plurality of liquid inorganic material raw materials can be increased. It can be made substantially constant and is suitable for subsequent analysis. This is the same when the solute of the liquid raw material is an organic substance.

In the present invention, the molar concentration is defined as follows. The chemical formula is A ₂ O ₃ , B ₂ O ₄ , C
Assuming O ₂ or the like, usually, the molar concentration is 1 mol of A ₂ O ₃ , B ₂ O ₄ , CO ₂ or the like in a 1 liter solution, that is, one chemical formula (for example, A ₂ O ₃ , B ₂ O ₄ , CO ₂ )
In the present invention, the molar concentration of these compounds is _converted into AO _3/2 , BO ₂ , CO in 1 liter of solution.
₂ is defined as including.

Here, the composition diagram is three-dimensional when there are three kinds of raw materials, and is called a ternary composition diagram. Moreover, when there are four types of raw materials, a quaternary composition diagram is obtained. The number of coordinate divisions is the number when the edges connecting the vertices are divided into several parts at equal intervals, and the intersection of lines when lines are drawn at equal intervals parallel to each side. The point on the side or the point on the side is the composition point and indicates the composition ratio. In other words, by increasing the number of coordinate divisions, samples can be generated at finer intervals. The composition point can be easily calculated by adding a sign to the composition point. Moreover, although arbitrary numbers, such as a number and an alphabet, can be selected as a code | symbol, it is preferable to select a number from a viewpoint that a composition point can be distinguished and recognized easily.

Here, when the coordinate division number of the ternary composition diagram is 20, the composition combination is 231. When the coordinate division number is 10, the composition combination is 66. In order to dispense a large number of liquid samples produced from multiple types of raw materials into the library plate without causing any contamination between the liquid samples, a new pipette tip is used for each liquid sample. It is necessary to replace and dispense. In order to economically manufacture the library, it is preferable to use inexpensive pipette tips. As an inexpensive pipette tip, those made of general-purpose synthetic fat are generally used. However, due to the nature of the general-purpose synthetic resin, the shape accuracy varies. That is, in order to manufacture a library free of contamination at low cost, it is important to use a pipette tip made of a general-purpose synthetic resin whose shape accuracy varies.

In addition, the method and apparatus of the present invention can be applied to the case where a library is manufactured by mixing two or more kinds of liquid raw materials. It is not difficult to input a combination ratio of two kinds of liquid raw materials, and the number of liquid samples is limited. However, when mixing three or more ingredients, the calculation of the combination ratio becomes complicated. Therefore, as will be described in the present embodiment, the control unit 1 creates a composition diagram having dimensions corresponding to the number of types of raw materials input from the input unit 2, and sets the number of divisions input from the input unit 2. Accordingly, a composition point that equally divides the ratio of each liquid raw material contained in a liquid sample obtained by mixing a plurality of types of liquid raw materials is determined, and each composition point is given a different symbol,
It is effective to automatically calculate the combination ratio of the plurality of liquid raw materials at the composition points corresponding to those symbols by an arithmetic unit.

The composition diagram is particularly suitable in the case of triangular coordinates for three-component raw materials because it is easily visually recognized. In the present invention, when the identification name of the raw material is input to the input means 2, the raw material name may be input, or the respective raw materials are distinguished and input as raw material 1, raw material 2, raw material 3,. May be. Similarly, when an additive is added, additive 1, additive 2,...
It is also possible to enter them separately.

In addition, sample manufacturing conditions for the liquid raw material to be mixed, that is, stirring time by the stirring mechanism and suction /
The number of times of suction / discharge of the liquid sample by the discharge mechanism and the amount of suction / discharge are input as data.
In addition, conditions such as an atmospheric temperature and an atmospheric gas for sample generation may be input as sample manufacturing conditions.

These data input to the input means 2 are sent to the control means 1 connected by telecommunications. The control means 1 having a storage device and an arithmetic unit automatically executes each element work related to library manufacturing based on the data input to the input means and a preset process.
For example, a keyboard, a touch panel, or the like is selected as the input unit 2, and the data input to the storage device or the arithmetic unit of the control unit 1 is transmitted. The control means 1 creates a composition diagram having dimensions corresponding to the number of types of raw materials input to the input means 2. Next, different signs are given to the composition points determined by the number of divisions input from the input means 2. Here, the composition point is determined by equally dividing the ratio of each raw material contained in a mixture obtained by mixing a plurality of types of raw materials by the number of divisions. The combination ratio of a plurality of raw materials at the composition point corresponding to those signs is automatically calculated, and the control means adds the additive to each of the plurality of samples having different combination ratios in which the liquid raw materials are mixed at the calculated ratio. Samples are generated automatically.

Further, the composition means 31 corresponding to the number of coordinate divisions shown in FIG. 6 is displayed on the display means 3 connected to the control means 1 by electrical communication. Although not shown, the composition points in the composition diagram 31 are all given different symbols. These codes may or may not be displayed.

In the library manufacturing apparatus of the present embodiment, the library generation mechanism 4 includes a raw material bottle holding unit 41, a first dispensing pipette holding unit 42, and a mixing container holding unit 43, as shown in FIG.
A stirring mechanism 44, a second pipetting pipette holder 45, and a library plate holder 4
6, a transfer means 47, a suction / discharge mechanism 48, and a reference member 49. Also,
As shown in FIG. 1, the library generation mechanism 4 has an X axis and a Y axis, and each part is stored in the storage means of the control means 1 as X and Y coordinate points. Further, the position of each part can be changed by the input means 2 and stored in the storage device. Further, the positional relationship between the respective parts is calculated by comparing the positions of the X and Y coordinate points by an arithmetic unit. Further, although not shown, the Z axis is set in the vertical direction, and is stored in the storage means in the same manner as the X axis and the Y axis, and is calculated by the arithmetic unit.

In the raw material bottle holding unit 41, three raw material bottles 411 and three additive bottles 411 containing liquid raw materials are held in a rack 412. A pipette tip 421 is held by a rack 422 in the first dispensing pipette holder 42. Also, the mixing container holding part 43
The rack 432 holds 36 mixing containers 431 in which liquid raw materials and additives are dispensed and mixed at a predetermined ratio. In the stirring mechanism 44, six stirring bars 441 are attached to the driving device 442, and each liquid sample in the mixing container 431 can be stirred and mixed by the stirring rod 441 attached to the driving device 442. A pipette tip 451 is held by a rack 452 in the second dispensing pipette holder 45. Library plate holder 4
6, four library plates 461 are mounted and held on the heating device 462.

With the pipette tip mounted on the pipette tip head 481 of the suction / discharge mechanism 48, the position of the tip of the pipette tip is detected by changing the pressure of the gas ejected from the tip of the pipette tip while approaching the reference member 49 from the X and Y directions. Then, by calculating the difference between the detected position and the reference position in the X direction and the Y direction, the deviation of the pipette tip from the reference position can be obtained.

Further, the transfer means 47 includes an X-axis transfer rail 471 and a Y-axis transfer rail 472, and a suction / discharge mechanism 48 is attached to the Y-axis transfer rail so as to be movable on the Y-axis transfer rail. In the suction / discharge mechanism 48, a pipette tip head 481 is attached to a transport head 482, and a pipette tip 421 and a pipette tip 451 are both detachable from the pipette tip head 481. Pipette tip 421 and pipette tip 45
1 is conveyed between predetermined positions by the transfer means 47 as will be described later. Here, the X-axis transfer rail 471 and the Y-axis transfer rail 472 are provided so that the suction / discharge mechanism 48 can be transferred in the X-axis and Y-axis directions shown in FIG.

The reference member 49 is provided with a cross section 492 in the X direction and a cross section 493 in the Y direction orthogonal to each other on a horizontal upper surface 491, and the tip of the pipette tip is accessible to the cross section 492 in the X direction and the cross section 493 in the Y direction. Has been made. The cross section 492 in the X direction and the cross section 493 in the Y direction are
It is made to correspond with the direction of the X-axis and the Y-axis of FIG.

The raw material bottle 411, the additive bottle 411, the pipette tip 421, the mixing container 431, and the pipette tip 451 are detachably held by racks 412, 422, 432, and 452, respectively. In this embodiment, as shown in FIG. 1, six bottles 411 are prepared. Among them, three raw material bottles 411 are prepared and three kinds of liquid raw materials can be dispensed, and three additive bottles 411 are prepared and three kinds of additives are dispensed. Can be done. In addition, 36 mixing containers 431 are prepared, and 36 types of samples having different raw material combination ratios can be manufactured. Here, the number of the mixing containers 431 is not particularly limited, and may be an arbitrary number. For example, when the number of coordinate divisions is 10 in the ternary composition diagram, it is preferable to prepare 66 because liquid samples of all composition points can be manufactured at one time.

The pipette tip 421 is detachably held by the pipette tip head 481 of the suction / discharge mechanism 48, and is used for dispensing into individual mixing containers. That is, the transfer means 47
The pipette tip 421 is mixed with the raw material bottle 411 and the additive bottle 411 and the mixing container 4 by
31, and a predetermined amount of raw materials and additives from the raw material bottle 411 and the additive bottle 411 can be sucked and discharged to the mixing container 431.

The rack 432 of the mixing container 431 can be moved from the vicinity of the dispensing pipette holding part 42 to the lower part of the stirring mechanism 44 as indicated by an arrow. The stirring mechanism 44 is provided with a driving device 442.
6 stirring rods 441 are provided, and the contents of the 6 mixing vessels are stirred and mixed uniformly.
It can be mixed. If the stirring time is set to 1 minute, it takes 6 minutes to stir and homogenize all the liquid samples.

Further, before each liquid sample after stirring is dispensed to the library plate 461 by the pipette tip 451, the liquid sample in the mixing vessel 431 is sucked from the mixing vessel 431 at least once by the pipette tip 451 and mixed by the mixing vessel 431. After discharging into the liquid container, the liquid sample in the mixing container 431 is immediately sucked using the same pipette tip 451, and a predetermined amount of liquid sample is set as a single sample amount at a predetermined position on the library plate 461. It is preferable to dispense into the liquid because it can prevent the components of the liquid sample from being separated or precipitated.

The pipette tip 451 is detachably held by the pipette tip head 481 of the suction / discharge mechanism 48, and the tip of the pipette tip 451 can approach the cross section 492 in the X direction and the cross section 493 in the Y direction of the reference member 49 by the transfer means 47. It has been. Further, when the tip of the pipette tip 451 approaches the cross section 492 in the X direction and the cross section 493 in the Y direction, a syringe pump (not shown) provided in the suction / discharge mechanism 48 from the tip of the pipette tip 451 via the pipette tip head 481. Gas is injected, and the tip of the pipette tip 451 approaches the cross section 492 in the X direction and the cross section 493 in the Y direction, and the pipette tip 4
When the back pressure in 51 changes, it is detected by a pressure sensor (not shown) installed in the transport head 482, which serves as a detection means. The gas injected from the tip of the pipette tip 451 is normally air that is the atmosphere of the library manufacturing apparatus, but a nitrogen atmosphere or the like may be used.

Next, the relationship between the position of the tip of the pipette tip and the position of the tip of the pipette tip having an ideal shape without deformation defined by the position of the pipette tip mounting head 481 will be described with reference to FIGS. As shown in FIG. 2, the coordinate point of the pipette tip mounting head 481 coincides with the coordinate point of the tip of the pipette tip having an ideal shape at X1 and Y1. However, the pipette tips 451 that are actually used vary in shape, and the coordinate point X of the pipette tip mounting head 481
The tip position of the pipette tip is shifted by x1, y1 with respect to 1, Y1.

Next, the reference member will be described with reference to FIG. The reference member has a horizontal upper surface 491 to avoid the risk that the tip of the pipette tip 451 contacts the reference member during transport. Further, it has a cross section 492 in the X direction and a cross section 493 in the Y direction which are orthogonal to each other. If these requirements are provided, any shape can be selected. For example, as shown in FIG. 4 (a), one having a rectangular upper surface, as shown in FIG. 4 (b), having a triangular upper surface, as shown in FIG. 4 (c), a plate shape The upper surface of the body bent into an L shape, FIG.
As shown in (d), the plate-like body 493 and the plate-like body 494 may be separated and fixed so as to form a right angle.

Next, a method for detecting the position of the tip of the pipette tip will be described with reference to FIG. When the tip of the pipette tip 451 approaches the cross-section 493 in the Y direction of the reference member 49 as indicated by an arrow while ejecting gas with a syringe pump (not shown), the pressure (back pressure) in the pipette tip 451
Rises. By detecting the change in pressure with a pressure sensor, the X coordinate of the tip of the pipette tip 451 at the position where the pressure has changed and reached a certain value can be determined. For example,
If the pressure in the atmospheric gas is 100, the position is detected by a change in pressure in the range of 110 to 150. The specific value to be adopted is a tradeoff with the moving speed of the pipette tip,
In order to detect if there is a 15% pressure change while moving 0.1 mm, that is, to set the accuracy to 0.1 mm, this value is set at a constant value of 115 and the pipette tip moving distance is 0.1 mm. What is necessary is just to detect a change.

When the tip of the pipette and the tip 451 is brought close to the cross section 492 of the reference member 49 in the X direction, the Y coordinate of the tip of the pipette tip 451 can be similarly determined. In the case of an ideally shaped pipette tip, a change in pressure is similarly detected. In an actual case, a pipette tip having an almost ideal shape is also mixed. In this case, the position of the tip of the pipette tip 451 is similarly detected. When detecting this position, the tip of the pipette tip 451 is placed on the upper surface 491 of the reference member 49.
If set to be higher, the tip of the pipette tip 451 can be prevented from contacting the reference member 49.

The calculation means is based on the detected coordinate points X1 + x1, Y1 + y1 of the tip of the pipette tip and the coordinate points X1, Y1 of the position of the tip of the pipette tip having an ideal shape without deformation defined by the pipette tip mounting head 481 at that position. Each relative position is calculated. The calculated difference in relative position is converted to obtain a deviation from the reference position, and the pipette tip mounting head 481 is moved by the transfer means 47 so that the tip of the pipette tip is placed at a predetermined position of the library plate stored in the storage means. The tip of the pipette tip 451 can be accurately adjusted to a predetermined position by transferring it so as to match.

That is, the pipette tip 451 can be moved between the mixing container 431 and the library plate 461 by the transfer means 47, and a predetermined amount as one sample amount of the liquid sample is sucked from the mixing container 431, and the library The liquid is discharged at an accurate position of the plate 461. At that time, the liquid sample in the mixing container 431 is removed a predetermined number of times.
After repeating suction and discharge from the pipette, it is possible to dispense a predetermined amount of liquid sample into the library plate 461 by sucking from the mixing container 431 with the pipette tip 451.

When the inner surface of the pipette tip is wetted with the liquid sample once or more during this suction / discharge, the familiarity of the liquid sample with the pipette tip becomes more stable, so the suction / discharge amount becomes stable. In the examples, the same type of pipette is used for dispensing into the mixing container and dispensing into the library plate, but the dispensing volume into the mixing container and the dispensing volume into the library plate are extremely small. If they are different, it is preferable to prepare another pipette holder for the library plate. If the number of samples on the library plate increases, it is preferable to use different types of pipettes.

Next, the operation of the library manufacturing apparatus of the present invention will be described in detail according to the process. First, the liquid raw material is put into the raw material bottle 411, and the liquid additive is put into the additive bottle 411 and held in the raw material bottle rack 412. Next, in the liquid sample dispensing step, a predetermined amount of raw materials and additives are collected from the raw material bottle 411 and additive bottle 411 using the pipette tip 421, transported to the mixing container holding unit 43 by the transfer means 47, and mixed. Dispense into container 431. This operation is repeated for each raw material container 411 and dispensed so as to have different combination ratios for each mixing container 431. Also, a predetermined amount of additive is dispensed into each mixing container 431.

Since liquid raw material is used, the pipette tip 42 using a syringe pump or the like is used as the raw material.
1 can be weighed with a suction capacity of 1, and homogeneous mixing is possible. The pipette tip 421 is automatically replaced with a new one every time the type of raw material or additive changes in order to avoid mixing of the raw material or additive. Here, in order to avoid mixing of raw materials and additives, it is possible to add a cleaning step for the pipette tip 421.

Subsequently, a stirring step is performed. When the dispensing process ends, the rack 432 of the mixing container 431
Moves below the stirring mechanism 44. Then, the stirring bar 441 is placed on the mixing container 431 to be mixed.
Stops where is located. Next, the stirring mechanism 44 is lowered and the stirring bar 441 is moved to the mixing container 431.
The stirring rod 441 starts rotating by the driving device 442, and the raw materials are mixed homogeneously. When the mixing of all the liquid samples is completed, the stirring mechanism 44 rises and the mixing container 43
One rack 432 returns to its original position. In this way, 36 kinds of liquid samples are produced.

Next, a process of manufacturing a library plate by dispensing a plurality of types of liquid samples onto the library plate will be described.
(1) First, the pipette tip 451 is attached to the pipette tip attachment head 481 for one liquid sample. Using this pipette tip, suction and discharge of the liquid sample in one mixing container 431 are repeated.
(2) Next, the pipette tip 451 after discharge is discharged from the tip of the pipette tip 451 by using a syringe pump while the gas is ejected from the tip of the pipette tip 451 by the transfer means 47 from the X direction.
A change in back pressure in the pipette tip 451 is detected by a pressure sensor in proximity to the cross section in the direction.
(3) Next, pipette tip 451 is used to pipette the gas using syringe pump 4
While being ejected from the tip of 51, the transfer means 47 is brought close to the cross section in the X direction of the reference member 49 from the Y direction, and the change in the back pressure in the pipette tip 451 is detected by the pressure sensor.
(4) Next, the position of the tip of the pipette tip 451 is detected from the change in the detected back pressure in the X direction and the Y direction.
(5) Next, the tip position of the pipette tip 451 in the X and Y directions (X1 + x1, Y1 +
The difference between y1) and the reference position (X1, Y1) of the tip of the pipette tip defined by the preset position of the pipette tip mounting head 481 is calculated.
(6) Next, the pipette tip 451 sucks the liquid sample in one mixing container 431 by a predetermined amount, and the tip of the pipette tip matches the predetermined position of the library plate based on the calculation result of the difference. The pipette pipette tip 451 is transferred so that one of the liquid samples is dispensed to a predetermined position on the library plate 461.
(7) Next, the pipette tip 451 is removed from the pipette tip mounting head 481 and discarded.
(8) Next, steps (1) to (7) are repeated for all the liquid samples 2, 3,..., And all the liquid samples are dispensed into the library plate 461.

(Second Embodiment)
Another embodiment will be described with reference to FIG. In this embodiment, an example in which a CCD camera is used as a pipette tip tip position measuring device instead of the reference member 49 and the tip of the pipette tip is taken from below will be described. Here, the configuration other than replacing the reference member 49 with the CCD camera 49 and the method for obtaining the deviation are the same as in the above-described embodiment.

In the pipette tip mounting head 481, the reference position in the X direction and the Y direction is set as the coordinate point, and the ideal pipette tip tip position without deformation is set to the same coordinate point. Reference position. The CCD camera 49 is adjusted so that the coordinate point of the pipette tip tip reference position is positioned at the center point of the image photographed by the CCD camera 49. Further, the library manufacturing apparatus is provided with calculation means for calculating the difference between the position of the pipette tip tip taken at the pipette tip mounting head reference position and the center point of the shot image (reference position of the pipette tip tip). The deviation between the reference position and the photographed tip position of the pipette tip is obtained.

The method for obtaining the deviation from the reference position of the pipette tip is as follows. First, the pipette tip mounting head 481 is moved to the reference position by the transfer means 47 while the pipette tip is mounted on the pipette tip mounting head 481 of the suction / discharge mechanism 48. Next, the tip position of the pipette tip is photographed by the CCD camera 49 from below. By calculating the difference between the pipette tip tip position on the photographed image and the center point of the image photographed by the CCD camera 49 in the X direction and the Y direction, the deviation of the pipette tip tip from the reference position is obtained.

According to the present invention, in a library manufacturing apparatus and a library manufacturing method for dispensing various types of liquid samples to a library plate using a disposable pipette tip, an accurate and high-density library using an inexpensive pipette tip is provided. Can be manufactured. That is, a large number of chemical products can be analyzed and evaluated economically and with high efficiency, and a great contribution can be made to the discovery of new substances.

It is a block diagram which shows embodiment of the library manufacturing apparatus of this invention. It is sectional drawing which shows the reference position of the pipette tip front-end | tip of this invention. It is sectional drawing which shows the front-end | tip position of the pipette tip used for this invention. (A) It is a perspective view of the reference | standard member of the library manufacturing apparatus of this invention. (B) It is a perspective view of the other reference member of the library manufacturing apparatus of this invention. (C) It is a perspective view of the other reference member of the library manufacturing apparatus of this invention. (D) It is a perspective view of the other reference member of the library manufacturing apparatus of this invention. It is a schematic diagram for demonstrating the method to detect the pipette tip front-end | tip position in this invention. It is a composition figure displayed on the display means of the library manufacturing apparatus of this invention.

Explanation of symbols

451 Pipette tip 47 Transfer means 481 Pipette tip mounting head 49 Reference member (CCD camera)

Claims (2)

Disperse multiple types of liquid samples in different mixing ratios in individual mixing containers into library plates with disposable pipette tips mounted on pipette tip mounting heads fixed to the transfer means. A library manufacturing device,
In the library manufacturing apparatus, a reference member having a horizontal upper surface having a cross section in the X direction and the Y direction perpendicular to each other, to which the tip of the pipette tip can approach, is fixed.
The pipette tip mounting head is jetted from the tip of the pipette tip while the pipette tip mounting head is being transferred to the cross section in the X direction and Y direction of the reference member, and the changing back pressure in the pipette tip is detected. Detection means for detecting that the tip of the pipette tip is close;
A calculation means for calculating a difference between a position of the pipette tip tip in the X direction and the Y direction detected by the detection means and a reference position of the pipette tip tip defined by the position of the pipette tip mounting head at the position; Is provided,
  For each of the multiple types of liquid samples, the replaced pipette tip is transferred so as to be close to the reference member by the transfer means,
Before dispensing to the library plate mounted on the library manufacturing apparatus, the difference between the detected position of the tip of the pipette tip and the reference position of the tip of the pipette tip is calculated. Library manufacturing equipment. Disperse multiple types of liquid samples in different mixing ratios in individual mixing containers into library plates with disposable pipette tips mounted on pipette tip mounting heads fixed to the transfer means. A library manufacturing method,
(1) mounting the pipette tip on a pipette tip mounting head;
(2) detecting the change in the back pressure in the pipette tip by causing the pipette tip to approach the reference member from the X direction by the transfer means while jetting gas from the tip of the pipette tip;
(3) detecting the change in the back pressure in the pipette tip by causing the pipette tip to approach the reference member from the Y direction orthogonal to the X direction by injecting gas from the tip of the pipette tip;
(4) detecting the position of the tip of the pipette tip from a change in the detected back pressure in the X direction and the Y direction;
(5) calculating a difference in the X direction and the Y direction between the detected position of the pipette tip tip and a preset reference position of the pipette tip tip;
(6) Based on the calculation result of the difference, the pipette tip is transferred so that the tip of the pipette tip coincides with the predetermined position of the library plate, and one of the liquid samples is determined at the predetermined position of the library plate. Step to dispense into,
(7) discarding the pipette tip;
A library manufacturing method comprising repeating steps (1) to (7) for each liquid sample.

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