WO2005059568A1

WO2005059568A1 - Method of detecting tip of disposable pipette tip and a dispensing apparatus using a disposable pipette tip

Info

Publication number: WO2005059568A1
Application number: PCT/JP2004/018963
Authority: WO
Inventors: Toshinobu Niimura
Original assignee: Olympus Corporation
Priority date: 2003-12-16
Filing date: 2004-12-13
Publication date: 2005-06-30
Also published as: JP2005201882A

Abstract

A method of detecting a tip of disposable pipette tip which is applied to a dispensing apparatus where a disposable tip is attached to a nozzle to perform dispensing includes moving, to a tip detecting unit, the nozzle to which the disposable tip is attached, and detecting a tip position of the disposable pipette tip by the tip detection unit.

Description

D E S C R I P T I O N

METHOD OF DETECTING TIP OF DISPOSABLE PIPETTE TIP AND A DISPENSING APPARATUS USING A DISPOSABLE PIPETTE TIP

Technical Field The present invention relates to a method of detecting a tip of a disposable chip, and a dispensing apparatus using the disposable chip. The present invention relates to a method of detecting a tip portion of a disposable chip and a dispensing apparatus using the disposable chip, in which a solution dispensed on a sample tank is sucked as much as possible without collapsing or damaging the sample tank, and a remaining liquid is reduced especially in an automatic dispensing apparatus. Background Art A dispensing apparatus which dispenses a sample solution has been known. The dispensing apparatus has been used as an apparatus which distributes a blood specimen sampled, for example, from a human body to a plurality of containers. In the dispensing apparatus, a sample is sucked by a nozzle having a disposable (formed to be disposable) chip. At this time, the following proposal has been made in order to exactly suck/discharge the sample (Japanese Patent No. 3024890) . According to this proposal, a mark is attached to the disposable chip (referred to simply as the "chip") for a purpose of measuring a correct liquid amount, and is detected. In a case where a tip position of the chip which has sucked the liquid therein is detected (calculated) using this mark as a reference to measure the liquid amount, either or both of an absolute position of the tip of the disposable chip and fitted state of the chip is optically detected. In Jpn. Pat. Appln. KOKAI Publication No. 2002-1092, a liquid discharging apparatus has been described in which tips of a plurality of suction nozzles are brought into contact with a wall surface of a container (micro plate) to such the solution in the container. According to the Jpn. Pat. Appln. KOKAI Publication No. 2002-1092, as shown in FIGS. 5 and 6, in order to separate magnetic particles and solution existing in a micro plate, they are once collected on a wall surface in the container in such a manner as to avoid the tips of the suction nozzles using a magnet, and the tips of the suction nozzles are brought into contact with the wall surface in the container to suck the solution. Disclosure of Invention However, when a tip position of a chip is detected by the above-described dispensing apparatus, a mark attached to the chip is used as a reference. Therefore, the position of the mark differs with position precision of the mark in attaching the mark to the chip or a fitted state of the chip. Therefore, it has been difficult to bring the chip as close as possible with respect to a sample tank and to suck a solution dispensed on the sample tank in such a manner that a remaining liquid is removed as much as possible without collapsing or damaging the sample tank. In the method described in the Jpn. Pat. Appln. KOKAI Publication No. 2002-1092, one method of sucking the solution is described, but the method is not a solution sucking method using a disposable chip. In the Jpn. Pat. Appln. KOKAI Publication No. 2002-1092, the nozzles are brought into contact with the wall surface in a container to suck the solution. Therefore, a method is not described nor suggested in which the nozzles are brought as close as possible with respect to the sample tank instead of bringing the nozzles into contact with sample tank, and the solution dispensed on the sample tank is sucked in such a manner as to leave the remaining liquid as little as position. Conditions concerning a suction operation are not described in the Jpn. Pat. Appln. KOKAI Publication No. 2002-1092. According to the present invention, there are provided a method of detecting a tip of a disposable chip and a dispensing apparatus using the disposable chip. Brief Description of Drawings FIG. 1 is a system diagram of a dispensing apparatus; FIG. 2 is a whole view of the dispensing apparatus; FIG. 3 is a sectional view showing a state in which a chip is fitted in a nozzle; FIG. 4 is a diagram showing a schematic constitution example of a DNA reaction vessel; FIG. 5 is a diagram showing an operation example to position a center of the chip on sensor light in a case where a usual photoelectric sensor is used; FIG. 6 is a photoelectric sensor transmittance change diagram at a time when the chip moves to position E from D in FIG. 5; FIGS. 7A to 7C are diagrams showing a positional relation between the chip and a sensor beam, FIG. 7A is a diagram showing a positional relation in a case where the chip does not interrupt any sensor beam light, FIG. 7B is a diagram showing a positional relation in a case where the tip of the chip contacts the sensor beam light, and FIG. 7C is a diagram showing a positional relation in a case where the chip interrupts the whole sensor beam light; FIG. 8 is a graph showing a quantity of light reaching a photoelectric sensor light receiving section by a transmittance by the positional relation between the chip and the sensor beam light; FIG. 9 is a sectional view showing a state in which the DNA reaction vessel contains a solution, and the chip is inserted in order to suck the solution; FIG. 10 is a diagram showing a state in which the chip lowers in the very vicinity of a sample tank 16 of a DNA reaction vessel 15; FIG. 11 is a graph in a case where a distance between a chip tip and a sample tank surface is changed, and an amount of a liquid remaining on the sample tank surface is measured; FIG. 12 is a graph in a case where a suction speed is changed, and the amount of the liquid remaining on the sample tank surface is measured; FIG. 13 is a diagram of observation of a state in which the chip sucks the solution from the DNA reaction vessel from above the sample tank; FIG. 14 is a diagram showing an example in which a band-like photosensor is used as a chip tip position detection sensor; and FIG. 15 is a diagram showing an example in which the chip tip position detection sensor is attached to a Z-axis. Best Mode for Carrying Out the Invention An embodiment of the present invention will be described hereinafter with reference to the drawings. FIG. 1 is a diagram of a dispensing system including a dispensing apparatus according to the present invention. As shown in FIG. 1, the dispensing system according to the present invention includes a dispensing apparatus 26, an electric unit 59, and a control unit (e.g., main body of a personal computer) 31. Details of the dispensing apparatus 26 are shown in FIG. 2. The electric unit 59 comprises a Z-axis driver controller 27, a Y-axis driver controller 28, a chip tip position sensor amplifier 29, and an X-axis driver controller 30. The control unit 31 is connected, for example, to a keyboard 34 and a pointing device 32 which are input devices, and a display 33, a printer (not shown) and the like which are output devices. FIG. 2 is a whole view of the dispensing apparatus according to the present invention. Each part shown in FIG. 2 will be described in describing an operation, and description thereof is omitted here. In one aspect of the present invention, the apparatus newly comprises a chip tip position detection sensor 11 disposed at a predetermined height from an apparatus base plate 3 via a chip tip position sensor holding plate 10. The operation of the dispensing apparatus according to the present invention will be described hereinafter mainly with reference to FIG. 2. ( Preparation) 1) An operator sets disposable chips 6 (hereinafter referred to simply as the "chips"), a sample container 8 containing a liquid sample (9: solution sample (Hereinafter referred to simply as a "sample")), and a DNA reaction vessel 15 in a dispensing apparatus 26. 2) Power supplies of the control unit 31 (including a monitor 33, etc.), dispensing apparatus 26, and electric unit 59 are turned on to start the system (OS starting of the computer, starting of control program, mechanical initialization of the dispensing apparatus, etc.) . (Apparatus Operation Start) 3) The operator inputs operation conditions for performing a dispensing operation into the control unit 31, and instructs the start of the dispensing operation. At this time, as operation conditions, for example, an amount of the sample 9 to be contained in the DNA reaction vessel 15 and the like are input. All operations are performed hereinafter by the instruction of the control unit 31. A syringe pump 1 operates by the instruction directly from the control unit 31, and other driving units (Z-axis direct-acting robot 21 which moves up/down the nozzles, a Y-axis direct-acting robot 18 which moves the nozzles in parallel in a predetermined direction (Y-direction shown in FIG. 2), and an X-axis direct-acting robot 4 which simultaneously moves a chip stand 5 and a solution container rack 7 in parallel in a direction (direction vertical to a sheet surface in FIG. 2) vertical to a Y-axis) are instructed to operate via driver controllers (27, 28, 30) . For example, RS-232C is used as an interface of communication between the control unit 31 and each driving unit. A signal from the chip tip position detection sensor 11 whose details are described later is amplified by the chip tip position sensor amplifier 29, A-D converted, and notified to the control unit 31. In this case, the communication interface is, for example, a transistor-transistor logic (TTL) or RS-232C. (Chip Attaching) 4) The Y-axis direct-acting robot 18 is operated to move a nozzle 20 which is mounted on the Z-axis direct-acting robot 21 and to which any chip 6 is not attached onto an unused chip 6 disposed on the chip stand 5. The X-axis direct-acting robot 4 also similarly operates, and moves the nozzle 20 onto the unused chip 6 disposed on the chip stand 5. Usually, 96 or 192 chips 6 are set at a predetermined interval in a lattice form on the chip stand 5, and addresses (e.g., #1, #2, #3, ... are assigned) are assigned to positions of the respective chips by software. Management of the addresses and presence of the chip in the address are managed by the control unit 31. Furthermore, the control unit 31 also stores the address of the chip attachable next. When a chip attaching instruction is input from the keyboard 34 or the like, the control unit 31 notifies the address of the next attachable chip to the drivers/controllers 28, 30 for the Y-axis, X-axis direct-acting robots, and the Y-axis, X-axis direct- acting robots 18, 4 move in accordance with the instruction . 5) When the nozzle 20 arrives above the chip 6 to be attached, the Z-axis direct-acting robot 21 moves downwards, the nozzle 20 moves downwards by a predetermined amount, and is pushed into an upper portion of the chip 6 to fit the nozzle 20 into the chip 6 (19), and the chip 6 is attached to the nozzle 20. In this case, a sectional view in a case where a chip 54 is normally attached to a nozzle 46 is shown in FIG. 3. 6) The Z-axis direct-acting robot 21 operates to move up the nozzle 20 to which a chip 19 has been attached to an upper-point position (origin sensor position 55, i.e., position before the nozzle 20 lowers) . In the following description, the nozzle 20 to which the chip 19 has been attached moves by the X-axis, Y-axis, Z-axis direct-acting robots, and it will be described simply as "the chip 19 moves". (Solution Suction) 7) When the Y-axis direct-acting robot 18 operates, the chip 19 moves above the solution container 8 set in the solution container rack 7. At the same time, the X-axis direct-acting robot 4 also operates, and the predetermined solution container 8 on the solution container rack 7 moves under the chip 19. By these operations, the solution container 8 containing the solution 9 scheduled to be sucked into the chip 19 is laid right under the chip 19. 8) A valve 41 of the syringe pump 1 is switched to the side of the chip 19. 9) The Z-axis direct-acting robot 21 operates to move the chip 19 downwards, and the chip 19 is stopped at a position which is as close as possible with respect to the bottom of the solution container 8 and which does not contact the bottom as a stop position of the tip of the chip 19. This stop position is set to a position having a necessary interval in consideration of manufacturing precision of various parts, assembly precision or the like. 10) The syringe pump 1 is driven, and the solution 9 is sucked into the chip 19. A suction amount is, for example, 50 μL. 11) After the suction is completed, the Z-axis direct-acting robot 21 is operated to raise the chip 19 to the upper-point position (origin sensor position 55 ) . (Solution Discharge) 12) The Y-axis direct-acting robot 18 is operated, and the chip 19 which has sucked the solution 9 moves above a hole portion for the sample tank 16 disposed in the DNA reaction vessel 15. 13) The Z-axis direct-acting robot 21 is operated, and the chip 19 which has sucked the solution 9 is lowered to a height of an upper end portion of the sample tank 16 hole portion disposed in the DNA reaction vessel 15. 14) The syringe pump 1 is driven, and a total amount (e.g., 50 μL) of the solution 9 in the chip 19 is discharged to the sample tank 16 of the DNA reaction vessel 15. 15) After completing the discharging, the Z-axis direct-acting robot 21 is operated, and the chip 19 is raised to the upper-point position (origin sensor position 55) . (Solution Reaction) 16) A solution 17 dispensed in the DNA reaction vessel 15 is kept at a temperature of about 50°C by a heater (not shown) , and starts hybridization reaction with a DNA probe (spot on a circle disposed in a DNA micro array 62) disposed in a DNA reaction vessel 60 fixed to the sample tank 16 as shown, for example, in FIG. 4 by solution driving means (not shown) . (Chip Detaching) 17) The Y-axis direct-acting robot 18 is operated, and the chip 19 moves to a position which is in the vicinity of a chip detaching plate 12 disposed on a chip and waste box 13 and in which the chip 19 can be lowered under the chip detaching plate 12 without contacting the chip detaching plate 12. 18) The Z-axis direct-acting robot 21 is operated to lower the chip 19 until the upper surface of the chip 19 is disposed under the chip detaching plate 12. At this time there is an interval of several millimeters between the upper surface of the chip 19 and the lower surface of the chip detaching plate 12. 19) The Y-axis direct-acting robot 18 is operated, and the chip 19 moves to the chip detaching plate 12. 20) The Z-axis direct-acting robot 21 is operated, and the chip 19 is raised to the upper-point position (origin sensor position 55) . In this case, the upper surface of the chip 19 collides with the lower surface of the chip detaching plate 12, and the chip 19 is detached from the nozzle 20 and stored in the waste box 13. (Chip Attaching and Chip Tip Position Detection) 21) Steps 4) to 6) are repeated, and the nozzle

20 is fitted into the chip 6. 22) The Y-axis direct-acting robot 18 is operated, and the chip 19 moves to a chip tip position detection sensor 11 position. A height (G) at which the sensor light of the chip tip position sensor is disposed is positioned with high precision, and known. 23) The Z-axis direct-acting robot 21 is operated to lower the chip 19 to a position (e.g., a position shown in FIG. 7C as described later in detail) capable of securely detecting the chip 19 by the chip tip position detection sensor 11. In this case, when the chip 19 is lowered, the chip tip position detection sensor 11 does not have to detect the chip 19. A positional relation between the chip tip position at a lowering time and the chip tip detection sensor has such an extent that the tip position of the chip 19 comes to about a maximum diameter of the chip 19 from a center of the sensor light. 24) The Y-axis direct-acting robot 18 is operated in this state, and the chip 19 moves as described with reference to FIG. 5 to obtain a state capable of detecting the chip 19. FIG. 5 is a diagram showing an operation example to position a center of the chip on sensor light in a case where a usual photoelectric sensor is used. FIG. 5 shows movement of the chip from an upper-portion direction. In FIG. 5, for example, assuming that the chip 19 lowers to a position 38 of FIG. 5, the Y-axis robot is operated, and the chip 19 moves to a position 38-1 and next to a position 38-2. Here, when the chip 19 moves to the position 38-2 (E) from the position 38 (D), the chip 19 is assumed to move across sensor light 47.

Then, a light quantity of the sensor light 47 changes as shown in FIG. 6. When the chip 19 moves to position E from position D as shown in FIG. 6, transmittance of the sensor light 47 gradually decreases (i.e., shielding is detected) before position d, and reaches a minimum value. The transmittance rises once in the vicinity of the center of the chip 19. The transmittance decreases again, reaches the minimum value again, thereafter gradually increases, and is 100% past position e, and a state in which any chip 19 is not detected is brought. A small mountain is formed in middle. When light scattered or reflected by the chip decreases substantially in a middle portion of the chip, and light passing through the chip increases, the mountain is formed.

Here, since the chip is detected from position d to e, a substantially middle point between the positions d and e can be speculated as a central axis position of the chip 19. As shown in FIG. 6, a middle point of a position where the transmittance indicates a minimum value may be regarded as a central axis position of the chip 19, and the central axis position of the chip 19 may be determined by this operation. It is to be noted that also in a case where the chip 19 is lowered, and the position is position 39 or 40, the chip in the position 39 moves between positions 39-1 and 39-2, or the chip in the position 40 moves between positions 40-1 and 40-2, so that the center position of the chip 19 can be determined. For example, a moving distance on one side, for example, a maximum value between 38 and 38-1 is set to a value equal to that of the diameter of the chip 19. The reason is that when the chip 19 moves and stopped above the chip tip position detection sensor 11, the position of the chip 19 is set in such a manner as to comes substantially above the sensor light 47. Even when the Y-axis is adjusted to the sensor position as indicated by a designed value and the chip 19 is lowered, the chip 19 cannot be detected in some case. The following three respects are considered as factors. 1) There is a possibility that a central axis of the chip 6 does not agree with that of the nozzle 20 at a chip attaching time, and the chip 6 is inclined and fitted into the nozzle 20. 2) There is a possibility that the chip 6 itself is bent because of a manufacturing (injection forming) problem or the chip 6, and storage problem. 3) Because of a compound factor of 1) and 2) . Therefore, unless steps are performed like the present steps, the correct chip tip position cannot be measured. If the chip cannot be detected by the sensor even by the moving of the chip by the diameter of the hole of the DNA reaction vessel 15 for the above-described causes, this is regarded as an error. In this case, the chip is not correctly fitted in some case, and therefore a discarding operation with respect to the waste box 13 may be performed. In this case, it is considered that disadvantages such as shift of the chip stand or the chip itself, shift along the Z-axis, defect of the chip and the like occur. Furthermore, a message asking an operator of the apparatus for a countermeasure, or a warning is preferably output. Especially, when the chip cannot be detected repeatedly a plurality of times by the sensor, it is considered that a degree of the disadvantage is high. It is important to output the message asking the operator of the apparatus for the countermeasure, or output the warning. The height of the chip tip position detection sensor 11 is set to a height which can be detected unless lowering the chip 19, then a step of lowering the chip 19 is not required, but there is a possibility that the chip is judged to be normally attached in the case of the above 1) to 3) . In this case, the nozzle 20 needs to be movable above the origin sensor position 55. When the chip tip position detection sensor 11 is a photoelectric sensor in this manner, the sensor light is a fine parallel light beam, and the chip 19 cannot be detected unless positioned in the beam. Therefore, the nozzle 20 is lowered to a height at which the sensor light can be shielded securely by the chip 19 in a position (designed dimension) substantially intersecting with the sensor light. Next, when the chip 19 moves in a Y-direction (in both plus/minus directions) by a predetermined amount, the position of the chip 19 can be securely detected. The moving amount is determined by a shift of an actual position of the chip 19 from the designed dimension, but the maximum value is not more than the diameter of the hole (in which the sample tank 16 is laid) disposed in the DNA reaction vessel 15. 25) The Y-axis direct-acting robot 18 is operated, and the chip 19 moves to the central axis position of the chip 19 obtained by calculation of the control unit 31 based on a control signal (obtainable by the driver and controller 28 for the Y-axis direct-acting robot) of the Y-axis direct-acting robot 18, and an output of the chip tip position detection sensor 11. By this movement, the central axis of the chip 19 substantially crosses that of the chip tip detection sensor at right angles. When the chip 19 moves, the chip tip position detection sensor 11 has a state of having detected the chip 19. This state is shown in FIG. 7C. As shown in FIG. 7C, sensor light 48 emitted from a light emitting portion 36 is interrupted by the chip 19, and a part (light 49) only is received by a light receiving portion 37. 26) The Z-axis direct-acting robot 21 is operated from this state, and raised by one step together with the chip 19. In this case, a step width is, for example, about 0.05 mm in accordance with a minimum unit of a Z-axis direct-acting robot control signal. After raising the chip, an output of the chip tip position detection sensor 11 is confirmed. When the chip 19 continues to be detected (state shown in FIG. 7C or 7B) , the chip is further raised by one step. This operation is continued until the chip 19 is not detected (state shown in FIG. 7A) . Transmittance of the sensor light corresponding to FIGS. 7A to 7C is shown in A to C of FIG. 8. A Z-axis position in which the chip 19 is not detected is regarded as a first tentative chip tip position. The Z-axis position can be obtained from the control signal (the driver and controller 27 for the Z-axis direct-acting robot) of the Z-axis direct-acting robot 21. 27) Steps 23) to 26) are repeated once more, and a second tentative chip tip position is measured. When values of the first and second tentative chip tip positions agree with each other in a predetermined range (e.g., 0.05 mm or less), the first tentative chip tip position is regarded as a measured chip tip position . When the values of the first and second tentative chip tip positions do not fall in a predetermined range, there is a possibility that fitting of the chip 19 is oblique, or the chip 19 is bent. Therefore, the Z-axis direct-acting robot 21 is once operated, and raised to the upper-point position (origin sensor position 55) together with 19. Next, steps 17) to 20) are performed to remove the chip 19, and further the step 21) and steps thereafter are performed. A true tip position of the chip cannot be detected by the chip tip position detection sensor 11, and an offset amount I is necessarily generated. The offset amount I is an offset distance from a chip tip vicinity position stably detectable by the chip tip position detection sensor 11 to an actual tip position, and is determined by conditions such as detection sensitivity of the chip tip position detection sensor 11, setting, beam light diameter, transmittance of the chip 19, shape and the like. When these conditions are constant, the value of the offset amount I is constant in an allowable range in the design. 28) The Z-axis direct-acting robot 21 is operated, and the chip 19 is raised to the upper-point position (origin sensor position 55). (Waste Liquid Suction) 29) The hybridization reaction started from the step 16) is ended. A reaction time is a necessary/sufficient time for the hybridization reaction . 30) The Y-axis direct-acting robot 18 moves, and the chip 19 whose tip position is measured moves above the hole portion for the sample tank 16 disposed in the DNA reaction vessel 15. Strictly, as shown in FIG. 9, the solution is preferably sucked, when the chip 19 is in the vicinity of (distance between the sample tank wall surface and a chip tip portion outer periphery is not more than chip tip diameter) a hole portion edge for the sample tank. The reasons are as follows . When the edge of the hole (sample tank wall surface and corner constituted by the sample tank wall surface) has higher wettability by adhering forces (wetting) of various types of solutions with respect to the DNA reaction vessel 15, the solution 17 rises along the wall surface of the sample tank 16, and the solution 17 surface becomes concave. When the chip 19 is lowered in the solution 17, and when the wettability is high, the solution 17 rises outside the chip 19 by the adhering force of the solution 17 with respect to the chip surface. Furthermore, when the chip 19 is lowered in the vicinity of the edge of the hole in the sample tank 16, capillary phenomenon occurs between the sample tank 16 wall surface and the chip 19 wall surface, and more solution 17 gathers. Therefore, more solution 17 can be sucked. Since the adhering force of the solution 17 is utilized in order to suck more solution 17 in this case, the surface of the DNA reaction vessel 15 or the chip 19 preferably wets easily to a certain degree. Needless to say, when the adhering force of the solution 17 is excessively strong, the solution 17 to be sucked does not easily peel from the surface of the DNA reaction vessel 15 or the chip 19, and more solution 17 cannot be sucked. A balance between the surface tension of the solution 17 and the adhering force of the solution 17 is required. The DNA reaction vessel 15 used in this embodiment is an injection molded member using a polycarbonate resin. The sample tank 16 has a porous film formed of aluminum oxide. The solution 17 is a nucleic acid solution. As the materials of the DNA reaction vessel

15 and the chip 19, besides the above-described materials, thermoplastic resins may be used such as polystyrene, polyethylene, vinyl chloride, polyacetal, polymethyl pentene, and polyethylene terephthalate . In FIG. 9, reference numeral 64 denotes a sample tank reinforcing plate. 31) As shown in FIG. 10, the Z-axis direct- acting robot 21 is operated, and the chip 19 whose tip position has been detected is lowered to a height at an interval of F (distance between the chip tip and the sample tank) from the surface of the sample tank

16 disposed in the DNA reaction vessel 15. In this case, in increasing the solution amount which can be sucked, it is important to lower the chip position to almost F = 0 without bringing the chip into contact with the sample tank. FIG. 11 is a graph in a case where a distance between a chip tip and a sample tank surface is changed, and an amount of a liquid remaining on the sample tank surface is measured. It is seen that the remaining liquid amount increases as the distance between the chip tip and the sample tank surface increases. When the distance between the chip tip and the sample tank surface is 0.2 mm or less, the remaining liquid amount in the reaction vessel is approximately equal. Therefore, considering various component tolerances or assembly tolerances, when the distance between the chip tip and the sample tank surface is about 0.2 mm or less, the apparatus is usable without any practical problem. However, when the chip contacts the sample tank, the sample tank is scratched, or the sample tank itself is broken. Therefore, F needs to be surely larger than 0 mm. Therefore, a height at which the sample tank 16 is laid is set to H±J (J is a plus-side total value of dimension tolerances of the sample base 14, the DNA reaction vessel 15, and the sample tank 16) . In this case, the lowering amount at this time is obtained by G-H in a case where there is not any error, and is obtained by G-H-I-J considering the error. In an actual case, the total plus-side tolerance J of the sample tank height is set as a safety value for preventing the sample tank from being broken or contacted by the chip 19, because all the components cannot be uniform at the plus-side limit value of the dimension tolerance. Therefore, the value of F is approximately securely larger than 0 mm (e.g., the value of F is designed in such a manner as to be about 0.1 mm) . 32) The syringe pump 1 is operated, and the solution 17 on the sample tank 16 is sucked. The suction amount is not less than at least 1.2 times (preferably 1.4 times) the solution amount discharged in the step 14), and the volume of the chip is set to an upper limit. The suction speed is set to a remarkably low speed, for example, of 8 μL/second or less, and the solution is sucked as much as possible utilizing viscosity or surface tension of the solution. The chip 19 used this time is a general chip having a volume of 200 μL and formed of a polypropylene material. FIG. 12 is a graph in a case where the suction speed is changed, and the amount of the liquid remaining on the sample tank surface is measured. It is seen that the remaining liquid amount increases, when the suction speed is higher than 8 μL/second. FIG. 13 is a diagram of observation of a state in which the chip 19 sucks the solution from the DNA reaction vessel 15 from above the sample tank 16. The state changes from the left as follows. First, the chip 19 is lowered to a predetermined position ((a) of FIG. 13) in a state in which the DNA reaction vessel 15 contains the solution 17. When the suction starts in this state, liquid surface lowers, but the whole sample tank surface is coated with the solution ((b) of FIG. 13). When the suction is further continued, a sample tank surface 65 appears around a middle of the sample tank 16 ((c) of FIG. 13). When the suction is further continued, the solution amount decreases, and the sample tank surface considerably appears ( (d) of FIG. 13) . At this time, the solution adhering to the chip tip continues to be sucked. When the suction is continued, the solution is eliminated around the chip tip, and the solution exists only on the tip. Even when the suction is further continued by the syringe pump at this time, the solution has a force for adhering to the sample tank surface 65. Therefore, unless the force is overcome, the movement of the solution in the chip stops and the solution cannot be sucked into the chip. Therefore, when the movement of the solution in the chip stops, the suction of the syringe pump is stopped, then the chip is raised, and the solution on the chip tip portion remains on the sample tank surface 65. Then, the suction amount of the solution 17 is set to preferably at least

1.2 times or more, more preferably 1.4 times or more the solution amount dispensed on the sample tank 16 in such a manner that the adhering force of the solution onto the sample tank surface 65 is overcome, and the solution on the chip tip portion can be sucked as much as possible. When the suction amount is set in this manner, and the suction is completed, the solution on the sample tank surface is substantially sucked, and an annular solution 66 slightly remains on the sample tank wall surface and the corner constituted by the sample tank surface ((e) of FIG. 13). 33) After the operation of the syringe pump 1 is completed, the operation is stopped for a predetermined time, and the apparatus is left to stand. This is a time elapsed until pressures in the syringe pump 1, valve 41, Teflon tube 25, nozzle 20, and chip 19 are stabilized. 34) The Z-axis direct-acting robot 21 is operated, and the chip 19 which has sucked the solution is raised to the upper-point position (origin sensor position 55) . (Waste Liquid, Chip Detaching) 35) The Y-axis direct-acting robot 18 is operated to move the chip 19 to a position in which the chip 19 is capable of lowering under the chip detaching plate 12 without contacting the chip detaching plate 12 in the vicinity of the chip detaching plate 12 disposed on the chip and waste box 13. 36) The Z-axis direct-acting robot 21 is operated to lower the chip 19 until the upper surface of the chip 19 comes under the chip detaching plate 12. At this time an interval of several millimeters is disposed between the upper surface of the chip 19 and the lower surface of the chip detaching plate 12. 37) The syringe pump 1 is operated, and the solution in the chip 19 is discharged into the waste box 13. The discharge amount at this time is a total amount sucked in the step 32) . A reason why the chip 19 is emptied before detaching the chip 19 is as follows. To remove the chip 19, when the chip 19 contains the solution, there is a possibility that air flows into the chip 19 from the tip thereof by an increase of a content in the chip 19 at the removing time, and the liquid in the chip 19 flows in reverse in the nozzle. To prevent this possibility, the chip 19 needs to be emptied before removing the chip 19. Even when the syringe pump is operated, the inside of the chip is kept at a positive pressure, and the chip 19 is removed while discharging the solution in the step 39) of removing the chip 19, the liquid in the chip 19 can be prevented from being passed in reverse in the nozzle 20. 38) The Y-axis direct-acting robot 18 is operated, and the chip 19 moves to the chip detaching plate 12. 39) The Z-axis direct-acting robot 21 is operated, and the chip 19 is raised to the upper-point position (origin sensor position 55). In this case, the upper surface of the chip 19 collides with the lower surface of the chip detaching plate 12, and the chip 19 is detached from the nozzle 20, and stored in the waste box 13. (Cleaning) 40) After the above (chip attaching), (the solution is sucked) from a cleaning buffer (not shown) set in the solution container rack 7, and the respective steps of (solution discharging), cleaning by solution driving by solution driving means (not shown) , (chip detaching) , (chip attaching, and chip tip position detection) , (waste liquid suction) , and (waste liquid, chip detaching) are performed. Accordingly, the cleaning after the hybridization reaction is performed. The cleaning operation may be performed several times while changing several types of cleaning buffers. The operation may be repeated several times using the same cleaning buffer. (Photometry) 41) The DNA reaction vessel 15 is carried to a photometry unit (not shown) (or is sometimes laid in the dispensing apparatus) , and a hybridization result is optically measured. The following invention can be extracted from the above-described embodiments. The following respective inventions may be used singly or in an appropriate combination thereof. A method of detecting a tip of a disposable chip which is applied to a dispensing apparatus where a disposable chip is attached to a nozzle to perform dispensing according to an aspect of the present invention, comprises: moving, to a chip tip detection unit, the nozzle to which the disposable chip is attached; and detecting a tip position of the disposable chip by the chip tip detection unit. With this aspect, following manners are preferable. (1) The chip tip detection unit is a photoelectric sensor. (2) In (1), the detecting the tip position of the disposable chip has: lowering the tip of the chip below sensor beam light of the photoelectric sensor; reciprocating the chip in a horizontal direction at least once to detect the chip; and moving the chip in a vertical direction in a detection position of the chip to determine a position in which the chip cannot be detected as the chip tip position. (3) In (l)or (2), sucking a liquid on a sample tank using the chip is further provided, and in the sucking the liquid on the sample tank, assuming that a beam light center position from a sensor to detect the known tip position of the chip is G, a height of the upper surface of the sample tank on which a known liquid to be sucked is laid is H, an offset value between a detected chip tip position and an actual chip tip position is I, and a total value of dimension tolerances of the sample tank upper surface height in manufacturing is J, a lowering amount to lower the chip to the vicinity of the upper surface of the sample tank is obtained by a formula G-H-I-J using the chip tip position detected by a chip tip position detection sensor as a reference. A dispensing apparatus using a disposable chip according to another aspect of the present invention comprises: tip position detection means for detecting a tip position of the disposable chip in a state in which the disposable chip is attached to a nozzle. With this aspect, following manners are preferable. (1) The tip position detection means detects the tip position of the disposable chip in contact with the tip position of the disposable chip, or in non-contact with the tip position of the disposable chip . (2) In (1), the tip position detection means is any of a photoelectric sensor, a magnetic sensor, a balance, and a TV camera. (3) In a case where the tip position detection means is the photoelectric sensor, the chip is lowered until the tip position of the chip comes below beam light from the photoelectric sensor, the chip moves in at least one reciprocating direction in a horizontal direction to detect a chip position, the chip moves in a vertical direction in a detection position of the chip, and a position in which the chip cannot be detected is determined as a chip tip position. (4) In a case where the tip position detection means is a photoelectric sensor, when liquid on the sample tank is sucked using the chip, assuming that a beam light center position from a sensor to detect the known tip position of the chip is G, a height of the upper surface of the sample tank on which a known liquid to be sucked is laid is H, an offset value between a detected chip tip position and an actual chip tip position is I, and a total value of dimension tolerances of the sample tank upper surface height in manufacturing is J, a lowering amount to lower the chip to the vicinity of the upper surface of the sample tank is obtained by a formula G-H-I-J using the chip tip position detected by a chip tip position detection sensor as a reference. (5) It is judged that fitting between the chip and the nozzle, the chip itself, or the chip tip position detection sensor is not correct, and an error is output in a case where the tip position detection means is incapable of detecting the chip. (6) It is judged that fitting between the chip and the nozzle is not correct, and an error is output in a case where the tip position detection means detects that a distance between a known origin position of a Z-axis direct-acting robot and the chip tip position detected by the chip tip position detection sensor is smaller than a predetermined value. (7) The position of the chip tip is set and the solution is sucked in such a manner that a distance between the chip tip and a sample tank wall surface is substantially not more than a diameter of the chip tip, and a distance between the chip tip and the sample tank surface is a predetermined value. (8) In, (7), a flow rate to suck the solution is a speed of 8 μL/second or less. (9) In (7), a suction amount of the solution is at least 1.2 times or more the amount of the solution dispensed on the sample tank, and is not more than a volume of the chip. (10) In (7), a distance between the chip tip and the sample tank surface is substantially 0.2 mm or less . (11) In (7), the chip has a tapered shape that the chip is thinned toward a tip portion and the sample tank wall surface is formed at an angle that the chip is not interfered with the sample tank surface . The present invention is not limited to the above-described respective embodiments. For example, as shown in FIG. 14, a band-like photo sensor may be used as the chip tip position detection sensor 11. In this case, light 45 between a light emitting portion 44 and a light receiving portion 35 has a band shape. Therefore, for example, when the chip 19 is in any of positions 51 to 53, detection is possible. When the chip 19 is raised by the Z-axis direct-acting robot 21, an area of the tip of the chip 19 gradually decreases, finally the chip 19 is not detected, and therefore the position may be regarded as the tip position of the chip 19. By the use of the band-like photosensor in this manner, the chip can be detected unless the chip 19 moves in the Y-direction. In the above-described embodiment, the chip tip position detection sensor 11 is attached to the apparatus base plate 3, but the chip tip position detection sensor 11 (57) may be attached to the

Z-axis. FIG. 15 shows an example in which the chip tip position detection sensor 57 is attached via a holding plate 58. By this arrangement, even when the Z-axis position is in any position of a Y-direction, the nozzle moves up/down when necessary, and the tip position of the chip and fitting of the chip into the nozzle can be confirmed. In this case, it is necessary to dispose the Y-axis 18 in parallel with the apparatus base plate 3. In the above-described embodiment, the photoelectric sensor has been described as the example of the chip tip position detection sensor, but the present invention is not limited to this embodiment. For example, when the chip is formed of a metal, a magnetic sensor may be disposed, and further a contact type sensor may be used. A TV camera is disposed in the position of the chip tip position detection sensor 11, an image of the chip tip is picked up, and the tip position of the chip may be detected by processing the image. When the chip is formed of a material capable of passing a current, a conductive state may be detected. Furthermore, the position of the tip of the chip can be detected by presence of contact using the sensor capable of detecting weight as in a balance. Furthermore, in the above-described embodiment, the tip position of the chip is detected (measured) twice, but the operation may be performed even once, or three times or more. The tip position of the chip is preferably detected twice or more. In the above-described embodiment, the DNA reaction vessel has been described as an example, and the present invention is applicable to a protein analysis container, antigen-antibody reaction vessel, biochemical reaction vessel or the like. Additionally, various modifications can be performed within the scope in an implementation stage. Furthermore, the above-described respective embodiments include various stages of inventions, and various inventions can be extracted by an appropriate combination of a plurality of described constituting factors. For example, even when several constituting requirements are removed from all the constituting factors described in the respective embodiments, the problem described in paragraphs of the problem to be solved by the invention can be solved. When the effect described in the effect of the present invention is obtained, a constitution from which the constituting requirement has been removed can be extracted as the invention. According to the present invention, since the tip of the chip can be precisely detected, the solution in the sample tank can be sufficiently sucked, and the remaining liquid can be reduced. In the suction step, the sample tank or a solid phase carrier in the sample tank is not broken or damaged. Furthermore, unlike Japanese Patent No. 3024890, the disposable chip does not have to be marked. When the position of the chip in sucking the solution, a speed (flow rate) for sucking the solution, and a suction amount are concretely determined with respect to the sample tank, the solution on the sample tank can be sucked, and the remaining liquid can be reduced. According to the aspect of the present invention, since the chip is not brought into contact with the sample tank surface, the wall surface or the like, looseness or shift of fitting between the nozzle and the chip by the contact does not occur. Therefore, dispensing defects are not caused such as liquid leakage from the chip tip by generation of leakage between the nozzle and the chip, and shortage of suction amount. Parts can be prevented from being interfered because the chip tip position is bent with respect to a nozzle axis by the contact. Furthermore, disadvantages (suction defect, discharge defect, dirt of the apparatus or sample contamination by flying/scattering, etc.) by deformation of the chip tip caused when the chip tip is brought into contact with the sample tank surface can also be prevented.

Claims

C L A I M S 1. A method of detecting a tip of a disposable chip which is applied to a dispensing apparatus where a disposable chip is attached to a nozzle to perform dispensing, the method comprising: moving, to a chip tip detection unit, the nozzle to which the disposable chip is attached; and detecting a tip position of the disposable chip by the chip tip detection unit. 2. The method of detecting the tip of the disposable chip according to claim 1, wherein the chip tip detection unit is a photoelectric sensor. 3. The method of detecting the tip of the disposable chip according to claim 2, wherein the detecting the tip position of the disposable chip has: lowering the tip of the chip below sensor beam light of the photoelectric sensor; reciprocating the chip in a horizontal direction at least once to detect the chip; and moving the chip in a vertical direction in a detection position of the chip to determine a position in which the chip cannot be detected as the chip tip position. 4. The method of detecting the tip of the disposable chip according to claim 2 or 3, further comprising sucking a liquid on a sample tank using the chip, wherein in the sucking the liquid on the sample tank, assuming that a beam light center position from a sensor to detect the known tip position of the chip is G, a height of the upper surface of the sample tank on which a known liquid to be sucked is laid is H, an offset value between a detected chip tip position and an actual chip tip position is I, and a total value of dimension tolerances of the sample tank upper surface height in manufacturing is J, a lowering amount to lower the chip to the vicinity of the upper surface of the sample tank is obtained by a formula G-H-I-J using the chip tip position detected by a chip tip position detection sensor as a reference. 5. A dispensing apparatus using a disposable chip, comprising: tip position detection means for detecting a tip position of the disposable chip in a state in which the disposable chip is attached to a nozzle. 6. The dispensing apparatus according to claim 5, wherein the tip position detection means detects the tip position of the disposable chip in contact with the tip position of the disposable chip, or in non-contact with the tip position of the disposable chip. 7. The dispensing apparatus according to claim 6, wherein the tip position detection means is any of a photoelectric sensor, a magnetic sensor, and a TV camera . 8. The dispensing apparatus according to any one of claims 5 to 7, wherein in a case where the tip position detection means is the photoelectric sensor, the chip is lowered until the tip position of the chip comes below beam light from the photoelectric sensor, the chip moves in at least one reciprocating direction in a horizontal direction to detect a chip position, the chip moves in a vertical direction in a detection position of the chip, and a position in which the chip cannot be detected is determined as a chip tip position . 9. The dispensing apparatus according to any one of claims 5 to 8, wherein in a case where the tip position detection means is a photoelectric sensor, when liquid on the sample tank is sucked using the chip, assuming that a beam light center position from a sensor to detect the known tip position of the chip is G, a height of the upper surface of the sample tank on which a known liquid to be sucked is laid is H, an offset value between a detected chip tip position and an actual chip tip position is I, and a total value of dimension tolerances of the sample tank upper surface height in manufacturing is J, a lowering amount to lower the chip to the vicinity of the upper surface of the sample tank is obtained by a formula G-H-I-J using the chip tip position detected by a chip tip position detection sensor as a reference. 10. The dispensing apparatus according to any one of claims 5 to 9, wherein it is judged that fitting between the chip and the nozzle, the chip itself, or the chip tip position detection sensor is not correct, and an error is output in a case where the tip position detection means is incapable of detecting the chip. 11. The dispensing apparatus according to any one of claims 5 to 9, wherein it is judged that fitting between the chip and the nozzle is not correct, and an error is output in a case where the tip position detection means detects that a distance between a known origin position of a Z-axis direct- acting robot and the chip tip position detected by the chip tip position detection sensor is smaller than a predetermined value. 12. The dispensing apparatus according to any one of claims 5 to 11, wherein the position of the chip tip is set and the solution is sucked in such a manner that a distance between the chip tip and a sample tank wall surface is substantially not more than a diameter of the chip tip, and a distance between the chip tip and the sample tank surface is a predetermined value. 13. The dispensing apparatus according to claim 12, wherein a flow rate to suck the solution is a speed of 8 μL/second or less. 14. The dispensing apparatus according to claim 12, wherein a suction amount of the solution is at least 1.2 times or more the amount of the solution dispensed on the sample tank, and is not more than a volume of the chip. 15. The dispensing apparatus according to claim 12, wherein a distance between the chip tip and the sample tank surface is substantially 0.2 mm or less. 16. The dispensing apparatus according to claim 12, wherein the chip has a tapered shape that the chip is thinned toward a tip portion and the sample tank wall surface is formed at an angle that the chip is not interfered with the sample tank surface .