JPH0579944B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to an apparatus for continuously carrying out titration or dilution treatment by transferring a liquid sample between a large number of liquid reservoir hole arrays under automatic control, and a transfer method using the apparatus. More specifically, the first liquid sample is filled into a micro titration tray equipped with a row of liquid reservoir holes, each of which can hold a minute amount of liquid of about 1/10 to 10 milliliters, and then subjected to a continuous dilution process. The present invention relates to a processing device that fills or moves a liquid sample between a number of separate rows of liquid reservoir holes when such a process is required. This continuous dilution processing system basically requires a mixing action of the sample liquid, where the amount of diluent contained in a separate reservoir hole is gradually increased and the mixing processing is performed. A series of diluted sample liquids are obtained in which the concentration of the sample liquid gradually decreases. Therefore, samples with various concentrations can be tested to determine specific properties. For example, the sample liquid may be serum, and tests are performed to determine what concentration of serum will give the best results when acting on a particular substance. [Prior Art] Initially, continuous dilution of liquid samples was performed manually. Liquid samples of different concentrations are mixed with various amounts of diluent contained in each test tube, for example with the aid of a syringe or pipette. This operation requires considerable time when a large number of liquid samples of different concentrations are required. For this purpose, automatic or semi-automatic continuous dilution machines have been developed. An example of this type of machine is disclosed in US Pat. No. 3,188,181. The continuous dilution machine disclosed in this patent is provided with a horizontally movable carrier, and on this carrier is provided a support shelf on which a large number of test tubes are arranged. In this case, a syringe holder for accommodating a shelfless syringe, each connected to a pipette, is provided for vertical movement and is arranged for upward or downward movement by means of a cam mechanism. This allows the pipette to be inserted into a liquid sample stored in a test tube within the support shelf. A pump-operated head, driven by a cam mechanism, reciprocates the syringe to mix the liquid inside the pipette with the diluent liquid inside the test tube. After the mixing operation is completed, the diluent is removed from the test tube, the syringe holder is raised, the carrier is guided towards another row of test tubes, and the operation is repeated.
For example, when a series of dilutions is completed, the first row of test tubes in a test tube rack will contain a liquid sample with undiluted concentration, and the second row will contain a liquid sample with a 50% concentration. , the liquid sample concentration in the third row of test tubes will be 25%, and these concentration percentages will be determined according to the amount of liquid transferred by the pipette. [Problems to be Solved by the Invention] An object of the present invention is to effectively transfer liquid between the liquid reservoir hole arrays without mutual contamination and with no error in the amount of liquid being transferred, and to solve the problem using conventional techniques. A novel liquid sample transfer device and automated transfer of liquid samples utilizing the device capable of serial dilution processing of extremely small volumes of liquid samples with substantially improved performance over that described in the aforementioned U.S. patents. provide a method. More particularly, when dealing with certain types of solutions, it is desirable to prevent intermixing effects between various liquid samples having different concentrations. Basically, this mixing action is performed manually using a disposable tip attached to the underside of the pipette, in which case the pipette draws up the liquid from the reservoir hole and then It has the effect of mixing diluting liquid into other liquid reservoir holes. After each mixing operation described above, the tip is removed from the pipette and replaced with a clean new tip. However, conventionally known continuous dilution machines do not provide an operation to replace the tip between each cycle of the continuous dilution process. Therefore, if it is desired to prevent liquids from mixing with each other, a multi-stage cleaning process is provided to the pipette row built into the machine to clean it, or
Alternatively, a flushing process had to be provided between dilution cycles. However, the insertion of multiple wash steps as described above wastes substantial continuous dilution processing time as multiple steps are added during each cycle. On the other hand, the washing liquid filling process has the drawback of generating a large amount of processing waste liquid. SUMMARY OF THE INVENTION It is therefore a general object of the present invention to quickly and effectively automatically dispose disposable pipette crown tips during sample liquid transfer cycles with the aim of preventing contaminating effects due to intermixing of liquids. It is an object of the present invention to provide a new exchangeable sample liquid transfer device and a transfer method thereof. [Means for Solving the Problems] The above-mentioned object of the present invention is to provide a supporting table that moves horizontally at a position below a row of pipettes that aspirates and dispenses a liquid sample. Both areas are divided into two work areas. The single working area is defined on the front side of the carrier table and carries a sample tray having a grid-like array of reservoir holes capable of accommodating liquid samples and diluents. The second working area is installed at a distance behind the first working area and behind the carrier table. This second work area contains a tip tray with an array of support holes for holding new disposable tips for mounting on the lower end of the pipette. These requirements are necessary in order to automatically replace the pipette tip each time a liquid sample is transferred to prevent contamination caused by mixing of liquids with each other. Further, the upper end of each pipette of the present invention is pressed by a compressible follower spring to flexibly hold and hold the frictional engagement between the two against the spring pressure when the lower end of the pipette is engaged within the tip opening. can do. Furthermore, in a preferred embodiment of the invention, a further liquid sample tray is provided on the carrier table at an intermediate position between the sample tray and the chip tray, which can serve as a reservoir hole for filling liquid of microbiological organisms or for reagents. . Furthermore, as a preferred embodiment of the present invention, an electro-optical detection device is installed on the base frame to detect whether or not all of the tips arranged on the tip tray are attached to the pipette row when exchanging tips for pipettes. It is preferable to do so. Further, the driving sources of all the elements according to the present invention are positionally controlled by a large number of actuation pulses supplied by the microprocessor, or the loading or unloading operation of the chip is appropriately performed. The automatic method for moving a liquid sample is basically to pick up a row of tips held in a tip tray using a pipette row, insert the capped tips toward one of the rows of liquid reservoir holes in the sample tray, and then fill the holes. A portion of the liquid sample is aspirated from the tip, and then the liquid in the tip is discharged into the diluting liquid in the next series of reservoir holes, the plunger is reciprocated to mix the liquid, and finally the tip is poured into the capped tip. After performing a positioning operation, a plunger is operated to discharge all the liquid contained in the pipette, and then the tips are guided to a tip tray and discharged all at once, and a method is provided in which the tips are replaced with new ones each time. EXAMPLES The invention will now be described in detail with reference to the accompanying drawings, which illustrate preferred embodiments of the invention. As shown in FIGS. 1 and 2, an automatic continuous displacement device for liquid sample dilution suitable for carrying out the method of the invention consists of two main movable parts. It includes a horizontally movable liquid sample carrier table 10 and a vertically movable pipette assembly head 12.
As better shown in FIG. 2, for its horizontal movement, the carrier table 10 is mounted on a pair of left and right guide rods 14 fixed on the base frame along the longitudinal direction of the device via a sliding bearing block 16. It is provided so that it can freely slide. The positioning movement of the carrier table 10 is carried out by index drive control of the step motor 18 via a pinion 20 and a rack 22 attached to the underside of the table. Similarly, the vertical movement of the pipette assembly head 12 is carried out by a sliding bearing block 26 attached to the assembly head side which is slidably mounted on a pair of left and right guide rods 24. The positioning control movement of the pipette assembly head 12 is accomplished by indexing control of the step motor 28 via the pinion 30 and rack 32. FIG. 10 shows a plan view of the rack and pinion mechanism for raising and lowering the pipette assembly head 12. The pipette assembly head 12 includes an assembly 34 of a row of pipettes 36 and pump plungers 40 for cooperative pumping motion. The pipette/plunger combination 34 is laterally arranged in a stationary plane perpendicular to the direction of movement of the carrier table 10. The rows of pipettes 36 are removably attached to the assembly head 12 using mounting blocks 37 and coupling pins 33. A plunger mechanism 38 is also mounted on top of the assembly head 12 for vertical movement relative to the in-line pipettes 36.
Plunger mechanism 38 includes a series of plunger rods 40, each plunger rod 40 being insertable within a respective respective pipette 36. All of the plunger rods are attached to a common actuation arm 42 for simultaneous vertical movement. The operating arm 42 is connected to the guide rod 44 through the step motor 46 and the feed screw drive box 48.
be moved along. As best seen in the detailed cross-sectional view of FIG. 3, the relative movement of the plunger rod 40 with respect to the pipette 36 changes the effective volume inside the pipette, thereby causing liquid to be drawn into the pipette or out of the pipette. Liquid may be ejected. An airtight seal using an O-ring 49 is provided between the top surface of the pipette and the plunger rod 40, and the O-ring 49 is held against a ring-shaped packing 47 which is pressed by a follower spring 45. Each pipette 36 has a piston portion 39 inserted for reciprocating displacement into the bore of a cylinder 35 formed in a mounting block 37. pipette 3
6 receives a restraining force in the vertical direction due to the pressing action of the follower spring 45. As a result, in the process of attaching the pipette tip to the lower side of the pipette, each pipette can make a slight vertical movement against the pressing force of the following spring 45. This makes it easier for all pipettes to cap tips 62 of slightly different dimensions and ensures that the bottom open surface of the tips 62 is held on the carrier table at the same level as the corresponding reservoir hole. Ru. A first work area 50 is set on the front side of the upper surface of the carrier table 10, and a second work area 52 is defined on the rear side. A commonly used titration tray is placed in the first working area 50 to constitute a sample tray 54 . This sample tray 54 is a tray for liquid samples in which a lattice-like array of liquid reservoir holes is formed to accommodate liquid. A tip tray 56 is placed in a second working area 52 set on the rear side, in which tips for pipettes that are discarded after each use are held in a row of holes for supporting tips arranged in a grid. A typical titration sample tray 54 has 96 liquid reservoir hole rows arranged in a 12×8 grid. As shown in FIG. 6, the sample tray 54 arranged in the first working area 50 is a horizontally long sample tray 54 with many liquid reservoir holes arranged in the horizontal direction, and 12×7 continuous dilution operations are performed. I can do it. The first row of the grid-shaped reservoirs is then filled with a predetermined amount of the sample liquid to be diluted, and the remaining reservoir holes are filled with a diluent of a predetermined concentration. In this case, the sample tray 56 is arranged so that a row of 12 chip support holes are arranged in a row in the width direction across the tray. Alternatively, as shown in FIG. 7, the sample tray 54 and tips 56 can be arranged along the length of the carrier table 10 to provide 8.times.11 serial dilution operations. As shown in the detailed side view of FIG. 3, the lower outer peripheral surface of each pipette 36 is tapered. The inner lumen of the pipette tip 62, which is disposable after each use in accordance with the present invention, is inserted into a tapered portion of the outer periphery of the pipette so as to frictionally engage it. The chip 62 may be made of a non-wettable polypropylene material, for example. Chip tray 5
After the carrier table 10 guides the row of tips 62 to an indexed position below the row of pipettes, the pipette assembly head 12 is moved by the step motor 28. each pipette 3 when lowered by
A tip is engaged with the lower outer periphery of 6. As previously mentioned, the internal volume of each pipette tip 62 is substantially equal to the total volume of the barrel formed by the outer body of the pipette 36. As best shown in FIGS. 4 and 5, each chip 62 supported in the chip support hole 63 of the chip tray 56 is supported by moving the lower end surface of the chip through the support hole as shown in FIG. Either the tip 62 is brought into contact with the bottom surface, or the lower end of the external fin 65 formed on the outside of the tip 62 is held at the opening periphery of the support hole. The inner circumferential wall of the tip support hole 63 engages with the tapered outer surface 60 of the tip 62 while maintaining its center line correctly. From a single row of pipettes to a single row of tips 62
The simultaneous removal of the chips is performed by a chip removal mechanism. This chip removal mechanism is the first
It has one comb-shaped plate 64 as best illustrated in the figure. The comb-shaped plate 64 has a plurality of recesses surrounding half of the outer circumference of each pipette arranged in a row, and the recessed side portions of the comb teeth surround the outer circumference of the pipette body by 180°. Comb-shaped plate 64
are connected to and supported by a pair of actuating rods 66 that are movable up and down inside the pipette assembly head 12. These actuation rods 66 are connected to a pair of solenoids 68 mounted on top of the pipette assembly head 12.
operated using. When the solenoid 68 is not activated, the tip removal comb plate 64 is
It is held in the upper position shown in the figure. When the solenoid is actuated, it moves the tip removal comb plate 64 downwardly and pushes the plurality of tips 62 downwardly. As a result, the pipette tip attached to the underside of each pipette 36 by frictional engagement can be discharged to the outside. FIG. 9 shows a tip 6 mounted above the step motor 46 for driving the pipette assembly head 12.
FIG. 2 shows a plan view in which an electromagnetic solenoid 68 for emitting 2 is mounted. Each step motor 18, 28 and 4 mentioned above
6 as well as the operation of the solenoid 68 is controlled by a suitable microprocessor 70. Basically, the microprocessor 70 operates as a pulse generator for controlling each of the aforementioned motion elements according to an operating sequence. Thus, the interrelated operating movements of the carrier table 10, the pipette row assembly head 12, the plunger assembly 34 and the tip removal comb plate 64 are carried out one after the other so that the sample tray 54 located on the front side of the carrier table 10 is A dilution operation is performed. Since each of the aforementioned step motors rotates at a number of revolutions responsive to a predetermined number of pulses sent from the microprocessor 70, the precise indexing motion of each movable element is provided by the microprocessor 70. It is controlled appropriately by the number of actuation pulses. In addition to the control means for these various motion element sections, the microprocessor 70 also monitors the movement of each motion element section via a plurality of appropriately positioned sensors. For example, the monitoring device for the carrier table 10 includes a blade-shaped member 72 formed to protrude from the side surface of the carrier table 10 and a blade-shaped member 7
It consists of a Hall effect sensor 74 that senses 2. Therefore, as carrier table 10 moves past a predetermined point, sensor 74 senses the table's advancing position. Each time the carrier table 10 passes the fixed point, the Hall effect sensor 74 sends a signal to the microprocessor 70.
can modify the table's position information and store new position information. Therefore, if the step motor 18 for indexing the table fails to receive the operating pulse signal while the table is moving, or if the number of pulses read into the microprocessor 70 does not match the index position of the table, In this case, the malfunction that occurs at that time will never be carried over during the subsequent cycle operation. In addition to the reference Hall effect sensor 74 described above, a pair of limit sensors 76 can be placed at the front start and rear end of the table travel path. The signals sent by these front and rear sensors indicate that the carrier table 10 is nearing the beginning or end of its movement and cause power to the step motor 18 to be interrupted. or instructs the microprocessor 70 to take other measures regarding shutdown. A similar type of sensor arrangement may be provided to monitor the movement of pipette assembly head 12 and common actuation arm 42. Additionally, a tip sensor may be provided on the device to detect whether all of the tips in a row on the tip tray 56 have been picked up by the pipette row. As shown in FIG. 8, this sensor can be an electro-optic mechanism. This arrangement includes a light emitting diode (LED) 89 or similar light emitting device on one side of the table and a photoelectric element 90 on the opposite side. The two sensor elements are arranged in alignment with the pipette row 36. Thus, when one or more chips 62 are left in the chip support hole 63 aligned with the sensor, the light beam 82 from the light emitting diode 89 is blocked and does not reach the photoelectric element 90. However, if all the tips in a row are picked up simultaneously by the pipette row, the beam will extend across the top of the tip tray 56 and be detected by the photoelectric element 90. By appropriately arranging the light emitting diode 89 and the photoelectric element 90, it is also possible to detect the state in which the chip tray 56 itself is picked up. 12, 13 and 14 show other embodiments of the invention installed on a movable carrier table 10, different from those described above. In this embodiment, another microtitration tray 88 is provided between the sample tray 54 and the tip tray 56. The titration tray 88 may contain a biochemical liquid such as serum or vaccine, or may contain reagents for initial application to the reservoir holes of the sample tray 54. And this second
Although the sample tray 88 of is shown as a specialized sump hole, it may also take the form of a general feed trough or feed pan. For example, the first filling operation of a liquid sample is to fill the first row of reservoir holes in the sample tray 54. After the chip array 62 is removed from the chip tray 56 and replaced with a new chip, the remaining holes remaining in the chip tray 56 are filled with diluted chips transferred from the other reservoir holes of the second sample tray 88. It may be filled with liquid or with another supply of liquid from another tray. As previously mentioned, after use, the pipette tips may be ejected into empty support holes arranged in the tip tray 56. However, it is also conceivable to discharge all the used chips centrally at a suitable location on the carrier table 10. That is, a chip discharging groove may be provided on the carrier table 10, and a collection box for disposable chips may be arranged below the table so that a large number of chips can be dropped into the collection box and disposed of. Alternatively, the collection bottle may be placed elsewhere on the table and used chips may be discharged directly into the collection bottle. The automatic continuous movement device according to the present invention basically operates as follows. That is, initially carrying table 1
After the rows of pipette tips in the tip tray 56 on the tip tray 56 are aligned and aligned with the lower portions of the pipette rows in the pipette assembly head 12, the rows of tips are collectively mounted on the lower end of each pipette. After vertical movement of the pipette assembly head, the carrier table 10 is moved rearward to position and align the tipped pipette row with one of the rows of reservoir holes on the sample liquid tray 54, so that the tipped pipette is placed in the reservoir hole. inserted. The liquid sample is then drawn into the pipette through the holes in the titration tray, and the pipette plunger is then reciprocated to mix the liquid by inserting the tip into the diluent in the next row of holes. Finally, in order to push out all the liquid in the pipette, the tip end position is positioned with respect to the hole, and after discharging the internal liquid, the tip is discharged onto the tip tray 56.
Details of the operation of the present invention will be described by way of example of a program that effectively implements continuous dilution processing operations using a microprocessor.

[Table] Move downward to eject all

TABLE The cycle is repeated a number of times equal to the number of dilutions performed. If chip replacement is not required, step
Steps 001 to 004 and steps 018 to 022 are omitted. Prior to the initiation of a serial dilution operation, the liquid volume is preloaded into the program of the microprocessor 70 without being moved during the process within each cycle. The amount of liquid displacement determines the stroke length that plunger rod 40 is raised during step 007 of the program. Conversely, this operation determines the concentration of the sample liquid in successive arrays of reservoir holes in the sample tray 54. For example, to obtain a dilution concentration band in which the concentration of one hole row liquid is half the concentration of the preceding hole row liquid, the first row of reservoir holes is filled with 100 microliters of liquid sample and , all other reservoir hole rows are each filled with 50 microliters of diluent solution. Microprocessor 70 is configured to transfer 50 microliters from one series of sump holes to the next successive series of sump holes during each cycle. In step 011, the plunger rod 40 is reciprocated up and down approximately five times to achieve a sufficient mixing action. At the beginning of each cycle of successive dilution strokes, plunger rod 40 is placed in the pipette at a defined calibration point. A Hall effect sensor similar to the type described above with respect to carrier table 10 can be used to monitor the position of plunger rod 40. In program step number 014, after the liquid sample and diluent have been mixed in step 011, the plunger and tip are raised so that the lower end of the tip is just clear of the liquid level in the sump hole, and the plunger is brought to the calibration point. Return to push out the liquid inside the pipette (step number 013).
At this time, the lower end of the tip is raised to a point just above the meniscus gas of the liquid accumulated in the liquid reservoir hole. All liquid is then expelled from the pipette by projecting the plunger downwardly past the calibration point. This action effectively blows the liquid out of the pipette by simultaneously expelling some of the air that was forced into the pipette, and which remains inside the tip due to capillary action due to the surface tension acting on the liquid. Moreover, it becomes possible to draw out any liquid that is present between the tip and the container. Such evacuation is particularly effective when the chip is made from a non-wettable plastic material, which is the preferred material as mentioned above. Although the steps described above are mentioned separately, some of them can be performed simultaneously. For example, step 016 and step 017 can be operated at the same time. It will be readily apparent to those skilled in the art that the present invention may be embodied in other forms without departing from the spirit or essential characteristics of the invention. Accordingly, any embodiments disclosed in this specification should be considered illustrative and not restrictive. For example, although a step motor is described as the preferred embodiment of the drive means for the carrier table, pipette assembly head, and plunger mechanism, other precision positioning means may be used, such as a DC servo motor. Therefore, the scope of the present invention is determined by the claims rather than the foregoing description, and all changes within the range equivalent to the claims are to be included within the scope of the present invention. .

[Brief explanation of the drawing]

1 is a perspective view of a serial diluter incorporating features of the present invention; FIG. 2 is a vertical side cross-sectional view of the serial diluter taken along line 2--2 of FIG. 1; and FIG. 3 is a plunger mechanism and pipette. 4 is an enlarged side sectional view of the preferred embodiment of the pipette tips supported in tip support holes on the tip tray; FIG. an enlarged side cross-sectional view showing another embodiment of a pipette tip supported on the opening edge of the hole;
Figure 6 is a plan view of a table relating to the relative arrangement of trays arranged to perform 12 x 7 dilutions, and Fig. 7 is a plan view of a table relating to the relative arrangement of trays arranged to perform 8 x 11 dilutions. 8 is a vertical cross-sectional front view of the automatic serial diluter including line 8--8 of FIG. 1; FIG. 9 is a partial plan view of the apparatus of the invention; FIG. line 10-1
A plan view showing a horizontal section including 0, FIG. 11 is the 8th
Horizontal cross-sectional plan view, including line 11-11 in Figure 12.
The figure is a perspective view of a modified embodiment of the continuous dilution device in which a second sample tray for storing one liquid for liquid transfer or supply is installed at an intermediate position between the tip tray and the sample tray. A plan view of the embodiment shown in the figure, FIG. 14 is line 1 of FIG. 13.
4-14, a vertical side cross-sectional view. 10... Carrying table, 12... Pipette assembly head.

Claims (1)

[Scope of Claims] 1. A device for automatically moving a liquid sample and a diluent between the arrays of liquid reservoir holes, comprising a horizontally movable support table and a vertically movable pipette assembly head; At least one sample tray having a large number of liquid reservoir hole rows is placed on the support table, and the table is mounted on a fixed base frame so as to be indexable and positionable along the front and rear horizontal directions thereof, and The pipette assembly head incorporates a row of pipettes for aspirating and ejecting liquid, and includes a stationary vertical plane perpendicular to the path of motion of the table, and is indexable and adjustable along upright columns fixed on the base frame. Furthermore, the assembly head is equipped with a pipette row, a pump plunger mechanism that cooperates with the pipette row, a tip attached to the lower end of each pipette, and all of the tips attached to the tip at the same time. In the automatic liquid transfer device, the liquid displacing device is provided with a tip removal mechanism for discharging chips to 1st
In the working area 50, a sample tray 54 having a row of liquid reservoir holes for use in titration or dilution processing is placed, and a second working area 52 is provided at a distance behind the first working area 50. pipette 36 for
A tip tray 56 having a row of tip support holes for holding tips 62 to be mounted is placed on the lower end thereof, and the upper end of each pipette 36 incorporated in the pipette assembly head 12 is pressed by a compressed follower spring 45. 1. A device for automatically moving a sample liquid between a series of liquid reservoir holes, the apparatus being characterized in that the sample liquid is supported thereon, thereby facilitating the capping of the tip against the lower end of the pipette. 2. A second sample tray 88 having a liquid reservoir hole array is arranged at an intermediate position between the sample tray 54 placed on the front side of the carrier table 10 and the chip tray 56 placed on the rear side, and a biological drug solution or reagent is placed therein. 2. The device according to claim 1, which is adapted for storage. 3. Electro-optical detection device 8 for detecting whether or not all of the chips arranged in a row held on the tip tray 56 have been picked up to the pipette row side without leaving anything behind during the chip capping process.
9. Apparatus according to claim 1, in which the detection device is arranged with a lateral line of sight aligned with the pipette row. 4. A horizontally movable carrier table 10 is indexed and positioned below a vertically movable pipette row to automatically move liquid samples between the reservoir hole rows held on said carrier table or to The automatic transfer method for diluting a liquid consists of the following steps: (a) initially moving the first working area 50 of the carrier table 10;
(b) supporting at least one row of chips on a chip tray 56 provided in a second working area 52 of said table; (c) moving the carrier table 10 to align the tip row on the tip tray 56 below the pipette row by indexing; and (d) then lowering the pipette row 36 to align it with the pipette row. Each tip placed in the aligned position is attached to the lower end of the pipette under the pressure action of the follower spring 45, (e) then the carrier table 10 is moved and its first
indexing and positioning the row of reservoir holes on the sample tray 54 in the working area 50 below the pipette row; (f) then indexing and positioning the row of reservoir holes on the sample tray 54 of the carrier table 10 positioned below the pipette row; (g) then raising the pipette row; (h) moving the carrier table 10 to move the pipette row to another reservoir hole row; (i) lowering the pipette row and discharging the liquid portion sucked into each pipette into the other liquid reservoir hole to promote mutual mixing of the liquids; ) Then raise the pipette row, and (k) move the carrier table 10 to its second position.
(l) discharging the used tips to the selected location on the second working area 52; Itinerary (b)
A method for automatically moving a liquid sample between arrays of liquid reservoir holes, characterized in that each process from (k) to (k) is repeated multiple times until the titration or dilution process is completed. 5 After discharging the liquid into the other liquid reservoir hole array in the step (i), draw the liquid in the liquid reservoir hole at least once toward the inside of the pipette so that the liquid is contained in the other liquid reservoir hole. 5. A method as claimed in claim 4, characterized in that the mixing action between the liquid and the additional liquid is promoted. 6. In step (i), the liquid in the pipette is discharged by the operation of a plunger in each pipette, and in this case, the tip is held just above the liquid meniscus in the liquid reservoir hole, thereby causing the tip and 5. The method according to claim 4, wherein any remaining liquid can be discharged by adhesion forces based on capillarity that occur in the liquid between the walls of the liquid reservoir hole. 7. The method according to claim 4, wherein the step (d) includes a detection step of checking whether all the chips supported and arranged in a line have been effectively picked up toward the pipette. . 8. A method according to claim 4, characterized in that step (l) is followed by a detection step for determining whether all tips have been removed from the pipette row. 9. The method according to claim 4, wherein each step from (e) to (j) is repeated several times, and then each step (k) and (l) is performed. .