JPS61181968A - Liquid treating system of large number of sample - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to liquid handling devices, and more particularly to liquid handling devices for use in performing multi-item assays on each of a large number of samples.

It is often necessary in clinical laboratories to perform multiple biochemical assays on each of a large number of separate blood and urine samples. For example, in blood banking,
Blood samples from each of a number of blood donors are blood typed by performing a series of cell agglutination assays. As another example, patients in a clinic or hospital may have sugar in their blood and/or urine;
nitrogen.

Levels of cholesterol, certain blood enzymes, etc. are routinely tested, and therefore each patient's sample may be analyzed by multiple assays.

It is desirable to carry out such assays as quickly and efficiently as possible, and this usually means that
This is best done using automated or semi-automated equipment to perform the sample transfer and assay procedures. In the past, a number of automated or semi-automated liquid handling devices designed for use in laboratory testing procedures have been developed.

Although the apparatus can be operated to perform a variety of liquid handling tasks, it can be used for a wide variety of repetitive liquid handling tasks, such as multiple containers or wells.
11) It is not possible to efficiently dispense a predetermined amount of reagent (one or more reagents) to each container in the tray. This is because the reagents must be distributed individually into the sample container rather than as a group. Also, the individual blood or serum samples themselves, which are typically obtained in sample tubes of relatively large variable sample volume, must be manually dispensed into assay containers.

A related type of liquid handling device is a two-way pipette (x and y) that can be operated to transfer a sample from a sample tube in one tube holder to a sample tube in another tube.
(can be moved in both horizontal directions). The device additionally includes a liquid sensitive probe provided at the end of the pipette for sensing the fluid level in the sample tube from which liquid is to be withdrawn. Although the device allows for the transfer of samples from tubes containing relatively large and variable volume volumes, it is relatively inefficient in multi-assay operations involving large numbers of samples. Part of the inefficiency is due to the need to clean the transfer pipette after each sample transfer operation to avoid sample cross-contamination. The washing step is time consuming and results in undesirable sample dilution. Also, similar to the two-way liquid handling system described above, the device is designed to transfer assay reagent material to assay tubes on an individual basis rather than to several tubes simultaneously.

Other types of known liquid handling devices, and those specifically designed for blood typing, prepare a single sample (e.g. a blood sample) from a sample tube into a predetermined position in a rotating tube holder. The liquid manifold assembly includes a liquid manifold assembly that simultaneously transfers liquid to each of a plurality of test tubes. The manifold assembly includes multiple flexible tubing segments connecting a sample transfer pipette and its pipes to each of multiple sample distribution ports. The manifold is also configured to simultaneously dispense several different assay reagents (eg, those used in blood group assays) to the sample receiving tubes. The reagents are also conveyed from the individual reagent reservoirs to the manifold through flexible tubing segments. Sample and reagent materials are distributed by a percussive pump configured to supply multiple tubing segments.

One drawback with this system is the need to flush the sample material out of the tubing segment after each sample transfer, a relatively time-consuming operation, which also contributes to sample dilution. It can be guided. Another disadvantage is the difficulty in accurately dispensing large sample volumes with butterfly pumps acting on multiple tubing segments.

U.S. Pat. No. 4,478,094 discloses a horizontally movable table for holding multi-container trays;
and an automatic liquid handling device having a vertically movable pipet assembly providing a large number of side-by-side pipettes. The apparatus is operable to draw a predetermined volume of liquid from a row of containers in a tray and simultaneously dispense the samples into other rows in the same tray or in different trays with table movement. The pipette is equipped with a disposable pipette tip that is automatically attached and released before and after each liquid transfer operation.

The device therefore allows several different assay reagents to be dispensed simultaneously into a group of containers in a tray, and the different reagents or samples do not require cleaning the pipette between each step. Allows to be handled continuously without However, that device is limited to small sample volumes and is capable of liquid transfer only in the direction of movement of the table, ie along a path extending in the front-back direction.

As alluded to above, one of the important clinical applications of automated liquid handling equipment is blood typing, which requires multi-item assays on both serum and red blood cell portions. Therefore,
In automated systems used for blood type determination,
It is desirable to provide automated withdrawal of both parts. Typically, a blood sample is prepared for blood typing by centrifugation to separate the blood into an upper serum portion and a lower clot portion. Alternatively, the blood may be treated with an anticoagulant such as EDTA for centrifugation to create an upper plasma portion and a lower packed cell portion. For a centrifuged blood sample placed in a suitable sample holder, the liquid handling device must be able to draw the sample volume from each of its two parts and distribute each into different groups of assay vessels. Must be. The device must therefore have the ability to detect, for each sample, the transfer bit position from which the serum (or plasma) part and the clot (or packed blood cell) part can be drawn. One type of liquid level sensor that has been used includes a globe designed to detect changes in resistivity when the globe is lowered into a sample tube. The probe is sensitive to resistivity changes both at the upper liquid level and at the interface between two parts in the centrifuged blood sample. A disadvantage of this type of probe is the need to clean the probe tip after each sample transfer to prevent sample contamination.

Another challenge in automated clinical systems for performing multi-item assays on each of a large number of samples is to provide a "tracking 2 method" that matches each of the multiple samples to a corresponding assay result.

Correctly matching blood typing results to the correct sample donor or recipient is particularly important in blood typing. This is because blood donor discrepancies resulting from errors in blood type identification are often fatal.

A general object of the present invention is to provide an automated liquid handling system capable of performing multi-item assays on each of a large number of individual samples with increased efficiency and accuracy and reduced error over systems known in the art. It is to present the danger of shi.

A related object of the present invention is to provide a system as described above which has the following advantages: (a) rapid transfer of substances from each of a number of samples into several assay vessels or vessels (hereinafter referred to as vessels); and efficient transfer; (a) simultaneous transfer of several different assay reagents into a group of assay vessels; (e) detection of the serum (or plasma) portion and clot (or filling) in the blood sample, preferably by optical detection; (d) electronic tracking of sample numbers and assay results; and (d) electronic tracking of sample numbers and assay results.

In particular, the present invention provides a horizontally movable table for supporting a multi-row array of assay containers, means for moving the table to a selected liquid transfer position, and a preselected volume for the containers in one row of said array. A liquid handling system comprising: a vertically movable head assembly supporting a plurality of fixed position pipettes for transferring a liquid; and means for moving the head assembly to a selected liquid handling position. , a movable sample holder suitable for holding an array of samples, means for moving the sample holder to place successive samples held therein at selected sample transfer positions; a sample transfer pipette attached to said head assembly for movement between a sample transfer position and a position suitable for sequentially dispensing sample into one or more containers in said array; said position; means for moving a sample transfer pipette between and for transferring a selected amount of said respective sample to one or more selected containers in an array of containers supported as above on a table; a control means operatively connected to a table movement means, a head assembly, a sample holder, and a sample transfer pipette for use in performing a multi-item assay on each of a plurality of samples. A liquid handling system comprising:

The drive elements for moving the table, head assembly/sample holder and sample transfer pipette into position during operation of the system are preferably digitally controlled stages, actuated by a per-motor microgrocer. connected to.

A preferred system includes an optical sensor for sensing the approximate water level of each sample in the holder for use in performing assays on a large number of variable volume samples, the sensor being operative during sample transfer operations. , operatively coupled to a microprocessor to control the position of the head assembly for withdrawing samples at one or more predetermined locations within each sample tube.

The preferred embodiment also includes a sample tube and assay tray bar code reader, which operates through a microprocessor to provide electronic tracking of the sample tube number and associated assay results.

The present invention also includes a chip capable of moving the upper and lower blood cell portions from each of a plurality of blood samples contained in the sample tubes at various sample levels to a predetermined water level in each sample tube. A liquid handling system suitable for transfer by a sample transfer pipette, comprising: a sensor for detecting an upper liquid level in each sample tube; / the ratio of the upper and lower parts in the sample; means for calculating the interfacial water level of another; and in response to the information about the interfacial water level, Means for moving the pipette to position it a predetermined distance below the interfacial water level.

FIG. 1 depicts an automated liquid handling system (10) constructed in accordance with the present invention. The system generally includes a liquid handling device (12) and a device (14) for use with the liquid handling device to perform multi-item assays on each of a plurality of samples. The device (12) has two main moving parts: a tray (18), (
a horizontally movable table (16) for supporting one or more trays such as 20) and □(22);
, and a vertically movable head assembly (24) toward and away from the table. The device 14 also has two main moving parts: a movable, capable sample holder (26) for supporting a plurality of sample tubes, such as tubes (28), (30) and (32); and movable between a position on the holder (26) and a position on the table (16) for transferring the sample aliquot from the sample tube to the assay container in the tray on the table (16); Sample transfer piston (34).

The structure of the device (12) is considered with particular reference to FIGS. 1-4. The table (16) is mounted for the purpose of movement on the fixed frame (35) by means of a sliding bearing (36) supported on a guide rod (38) mounted on the frame (Fig. 3). ).

Translational movement of the table is effected by a stepper motor acting on the table via a spool and flexible belt connection, indicated generally at (42) in FIG. 4, on the side of the table (16) as shown. (40). The motor is operable to move the table in a path extending in a fore-and-aft direction (in the direction of arrow (50) in FIG. 1) to place the table in a predetermined liquid transfer position below the head assembly. The motor (40) and the belt connection connecting the motor to the table are also referred to herein as table movement means. Motor (40) and other motors described herein are Stella/4'-
Although a motor, other suitable motors may also be used, such as a DC sustainer motor.

/#--The motor is an electronic control unit (46) installed in the capanie (48) as shown in Figure 3.
It is under the control of the digitized in/4 pulses supplied to the motor from. The microprocessor in its control unit (
47) is constructed according to known microprocessor designs to accomplish the functions of the controller to be described herein. The system consists of input terminals (4
9) (FIG. 1), by means of which detailed program instructions can be provided to the microprocessor of the control unit. The specific sample handling and assay reagent operations available are considered below. Microprocessor (4
7) are also referred to herein as means for controlling the operation of the system.

The head assembly (24) is similarly mounted for vertical translation on a vertical guide rod by a sliding bearing, such as the rod (51) and bearing (52) shown in dotted lines in FIG. ing. The overall translational movement of the head assembly is (5
6) mechanically coupled to the assembly via a goal screw drive mechanism (5).
4) (Fig. 2). Motor (40)
Similarly, a stepper motor (54) is connected to a device (4) to advance the motor a predetermined distance in a predetermined direction to provide precise control of the vertical position of the head assembly.
6) is driven by the digitization in/4rus. The motor (54) and the mechanical connection between the motor and the head assembly are also collectively referred to herein as the assembly moving means.

Referring to FIGS. 1 to 3, the head assembly (24) is 2-
! ! The four-piece assembly (58) supports the Watt solid (58), and the pipettes 60 are arranged in transverse rows (side-to-side) with respect to the axis of table translation.
Contains a row of 12 pipettes, such as: The pipette is attached to the head assembly by a mounting block (68). Also included in the bit assembly is a plunger mechanism (70) mounted to the head assembly for vertical movement relative to the bit (60). The stick related to (7
2) with a series of plunger rods, one for each pipette (Figure 2).

The rods are mounted on a common actuator (74) such that the actuator (74) itself moves vertically under the control of a stellar motor (78). 76) (Figs. 1 and 2). The motor is mechanically coupled to the actuator via a goal screw drive connection (80) seen in FIG. Translational movement of the plunger rod under the control of the motor (78) changes the internal volume of the pipette and thus pipets fluid in a consistent manner.

aspirate into a pipette or exhale through a pipette.

The key assembly is a solenoid operated par (82) (
2 and 3), this part (82) is a disposable pipe 4 which is supported by a friction fit on the end of the pipette.
operates to release the cut tip. Detailed structural features of the pipette assembly and automatic damming and removal of disposable pipes, conkers, and pipes before and after withdrawing and dispensing a predetermined volume of liquid in all pipettes simultaneously is described in the aforementioned U.S. Pat. No. 4,478,094.

Now, turning to the description of the device (14), the holder (26)
) consists of a pair of open circular plates (84°86), the upper one of which is adapted to receive and support the array of sample tubes as shown. A circular aperture array is provided, such as apertures (88, 89) (FIGS. 1 and 4). 1 with array of openings for sample tubes
Openings formed in the upper plate in a one-to-one correspondence (c+o, 91)
The inner array of smaller openings, such as the one shown in FIG. Referenced and described below.

Referring to FIG. 4, the tube holder is rotatable by a stepper motor (94) to place successive sample tubes into the holder at predetermined sample transfer positions (96). The sample transfer position occupied by tube (32) in FIG.
34), which is indicated by a dashed line (95). Stella/4'-
The motor is mechanically connected to the tube holder via an endless bell (97) which revolves around an axle pulley (98) on the underside of the holder. A motor (94) is operatively coupled to and moves the device (46) to advance the holder by rotational increments corresponding to the distance between adjacent apertures in the holder.
46). Stepper motor (94
) and the mechanical link connecting the motor to the tube holder are also referred to herein as means for moving the holder to a predetermined sample transfer position.

The optical sensor (100) in the device (24) is mounted on the frame (35) adjacent to the tube holder, as best seen in FIG. The sensor has a bracket-like structure, which is a frame (35)
an outer leg (102) attached to and extending above the plate (86) in the holder, and an inner leg (104) terminating near the top surface of the plate. Legs (1
02) carries a column of light emitting elements, such as elements (106), which serve to direct light towards the facing inner sides of the legs (104). Element (106) is a conventional optical electronic element such as a light emitting diode. A corresponding column of light sensing elements, such as elements (108), are located inside the legs (104) and opposite the elements (106). Each of these elements is sensitive to light received from the column of light emitting elements on the leg (102) and generates a voltage voltage proportional to the amount of light received. Each column of light-emitting and light-sensing elements extends from a position adjacent the top of the sample tube located between the two legs to a position approximately corresponding to the mid-section of the tube as seen in FIG. 110, and between them a detector (110) that monitors the level of liquid in the upper part of the tube within the sensing position. As can be seen in FIG. 4, the sensing position occupied by tube (28) in the drawing is two positions before the sample transfer position. That is, the tube in the sensing position is moved to the sample transfer position in two incremental clockwise movements of the tube holder in the drawing.

The photodetector element on the leg (104) is coupled to the control unit's microprocessor, which receives digitized voltage level information from the element and from which it determines at that location. Determine the liquid level in the sample tube. The operation in the ninth microdeposition for determining liquid level involves the step of a series of detectors comparing the voltage level from each photosensitive element with that of an adjacent detector according to known image array processing techniques. . The sensor is also referred to herein as sensor means.

In particular, with reference to FIGS. 1 to 3, the sample transfer bivet in (14) (34) is the block (112) with a weir.
) attached to the head assembly. The block is mounted to the head assembly for side-to-side movement by a worm-screw drive mechanism, and the drive mechanism is also used to move the block between predetermined liquid transfer positions. , Attachment is by a worm screw (116) that is inserted into the large screw in the block.
and a steering motor that can be operated to rotate the screw in a predetermined direction over a predetermined rotation distance (
118). The stepper motor is a control device (
46). The pit drive mechanism is also referred to herein as the pit moving means.

The block (34) is fitted with an internal vertical hole (120) extending through the block and a lower mounting hole (120) projecting from the underside of the block and forming an extension of said hole. made from parts.

As can be seen from Figure 2, the mounting parts are
It is sized and tapered at its lower end so that it can be inserted with a friction fit into a cheek-shaped cap over a disposable sample transfer cap tip such as (92). During sample handling operations, the sample material is exposed to the disposable tip, and the pipette itself remains uncontaminated by successive samples being handled.

Sample liquid is drawn into and then dispensed into the pipette tip on the pipette by a plunger mechanism shown at (124). That Granger mechanism is piitchi! BiK the large volume of the pit to create the internal volume pressure changes necessary to draw liquid into or dispense liquid from the tip.

It operates by moving the doblanger (126) upward or downward. The plunger is attached to a second block (128) which is movable along a rod (130) parallel to the screen (104) so that the plunger moves from side to side in line with the block (112). (Figure 3), as best seen in Figures 1 and 3.
The rod (130) is securely attached to the parr (132) in the plunger mechanism by a pair of ears, such as ears (134), integrally formed with the plunger control parr (132). The par has a steering wheel and a par motor (136° 1
38) can move under the control of These motors are connected to a control device (46) and are responsive to regulated digitized signals from that device in operation. The pipette and plunger construction just described is such that the pipette and associated plunger rod are motorized (118
), and the plunger mechanism has motors (136, 13) for drawing and dispensing the desired volume of sample.
8) can be recognized to allow movement within the pipette under control.

The tip release par (139) in the slide pet is mounted under the pro, ri (112) so as to move between a retracted position and an extended position as seen in FIGS. 2 and 8, respectively. It is installed adjacent to the direction. The par is attached to the lower end of a piston (141) which normally moves between a retracted position and an extended position upon operation of the solenoid (143) (FIG. 2). The solenoid is activated by appropriate signals from the controller (46).

A solenoid-operated par is also referred to herein as a means for releasing the attached PitTig. The system (10) has a pair of tubes for electronically matching the sample tubes to the corresponding group of assay vessels. It has a par code reader. The tray par code reader (seen in Figure 1) is mounted on the frame (35) laterally at the center side of the table (16). The league is supported on a table and placed in position to read the par code, such as the par code (142), of each individual tray, such as tray (22). From FIGS. 1 and 3, one of the three different trays on the table can be read by moving the table to one of three different reading positions so that the par code can be read. - Codes can be recognized to match the record position in that league.

A seven-pull tube par code reader (144) is attached to the lower end area of the sensor leg (104) as seen in FIG.
Code and read alignment. Detection position tube (2
The par code of 8) is shown at (146). The reader (140, 144) is a microprocessor in the control device,
is conventionally configured to provide digitized par code information. The manner in which par code information is stored and used in the controller is described below with reference to FIG.

The operation of a system (10) for performing a group of blood typing assays on each of a number of different volumes of blood samples is described. In the position shown in Figure 1, place the table (16
), each tray such as tray (22) is Rectangular array of assay vessels, typically 1 each
It has 8 rows of 2 assay containers. A row of test containers in the tray (22) is shown sectioned in FIGS. 3.6 and 7 and designated as containers W, to W, 2 as shown. As seen in FIG. 3, the containers are vertically aligned with opposing vias in assembly 58 to receive and remove assay reagents from pipettes in a multi-container liquid handling process. The individual assay vessels are cylindrical shaped in a tray, with a flat or U-shaped bottom or V-shaped bottom depression, and typically have a volume of about 50-250 μl.

The pipette/reagent tray (148) is attached to the pipette assembly (5
4) The tray (148) is also provided with at least one row of disposable tips, such as tips (150), suitable for being friction-fitted and held by individual pipettes in the tray (148). It is provided with assay reagent grooves such as grooves (152) above, each of which is divided into 12 reagent containers, such as those shown as C4 to C1□ in FIG. Containers C1-C12 are aligned with 12 pipettes in the assembly (54) so that the required volume can be drawn from the containers simultaneously by the pipettes. In the particular blood typing operation under consideration, which has a capacity of about 2-5-
Add the following blood group test reagents to the container: Table 1 in the margin below Volume Reagent C1 Type A Blood Cell C2 Type A2 Blood Cell C5 Type fIL Blood Cell C4 Physiological Saline (Plasma/Serum Control) C5... C6 anti-A Serum antibody C7 anti-B Serum antibody C8 anti-A, B Serum antibody C2 anti-D Serum antibody (anti-Rh factor) C1o
Physiological saline (packed red blood cells/clot control) C11
°°°°°.

Cl2 (Packed Red Blood Cell Dilution) First, a blood sample is obtained from each of a number of individual blood donors or blood recipients to be blood typed, and each blood sample is parsed by code (146). - Add to a sample tube, such as a corded tube (28). A blood sample is added to the 6 tubes to a final volume of approximately half or more than the total volume of the tubes to ensure that the upper liquid level in the tubes can be read by the sensor (100).

The sample is conventionally centrifuged in the presence of an anticoagulant to generate a lower packed red blood cell portion and an upper plasma portion, or an upper serum portion and a lower clot portion. The upper plasma portion (156) and the lower packed red blood cell portion (158) are shown in Figures 5-8 for a blood sample in tube (32), and the operation of the system is similar to that of blood treated with anticoagulant. The sample will be described later. Several sample tubes (up to about 50 tubes in this embodiment)
into the sample holder along with the corresponding number of disposable sample transfer bottles and tip tubes. These tips have conventional dimensions and a tapered configuration, partially seen in FIG. 2, and are preferably made of polyethylene or the like. In particular, the tip can be attached to the pipette (34) by a friction fit.
7″ upper chi/
4' - configured to receive the fitting therein and dimensioned to extend into the lower portion of the sample tube, as shown, for withdrawing the lower portion from the sample tube. It has become.

The user now initiates the automatic blood determination operation by instructing the controller via the terminal (49): the number of samples to be assayed; which container receives an aliquot of the lower packed red blood cell portion and how much sample volume should be dispensed into each container; Should I;
the amount of reagent dispensed into each container by the pipette assembly; and the hematocrit value used to calculate the sample interfacial water level in the sample. The user then initiates operation by appropriate signals to the control device.

In the first step of the automated operation, the motor (94) is activated to advance the tube holder in repeating increments until the first sample tube is located in the sensing position (110). Here, the liquid level of the sample is sensed by the system's sensor means and the par code on the tube is read and stored in a read-only memory in the controller's microprocessor. For simplicity purposes, this first tube will be referred to as sample grave 1. However, it is associated with a specific node coater number in the thermal controller.

Next, in order to determine the liquid height of the next sample tube (referred to as sample A2), the controller (94) controls the motor (94) to position this sample tube at the detection position.
46).

The sample level and par code are stored in a read-only memory of the controller at a memory address associated with the second sample.

The third actuation of the motor (94) brings the third sample tube (tube (28) in the drawing) into the t-sensing position and also moves the first sample (tube (32)) into the t-sample transfer bit. Position the sample transfer position along the transfer line.

In this process, the system first (sample grave 3
The controller operates to determine the liquid level of the controller, correlate it with the stored par code, and store that information in a read-only memory in the controller.

Additionally, the system is now operative to perform a sample transfer operation on the sample plate 1.

The sequence of automated steps involved in such a sample transfer operation is illustrated in the partial/side views of FIGS. 5-8. In the first step, the pipette (34) is placed so that the pipette is positioned directly above the disposable tip (92) that is radially adjacent to the sample (32). −
It is moved under the control of a motor (118). The head assembly is then assembled, as shown in solid lines in FIG.
Bii.

The stem, screw motor (52
) is moved in the downward direction. With the pipette tip attached to the pipette, the head assembly is raised slightly and the pipette tip is positioned directly above the sample tube, as shown by the dashed line in FIG. Move the cut slightly to the right in Figure 5.

Referring to FIG. 6, the head assembly is now moved downwardly to insert the lower end of the pipette tip into the upper plasma portion of the tube. The pipette tip is inserted into the plasma sample above a predetermined distance (eg, 1 cIn) below the previously calculated liquid sample level in the tube. The pipette plunger mechanism is now actuated by coordinated movement of the motors (128, 130) to raise the plunger a distance to effect withdrawal of a predetermined volume of upper plasma portion. The head assembly rises again and the sample transfer pipette moves to the right to position 1 pipette 7# directly above the first assay vessel (W,). The head assembly is lowered to position the pipette as shown in phantom in FIG. 6 with the lower end of the tip partially received in the container. At this stage, the pusher mechanism is activated to dispense a predetermined volume aliquot into the first assay vessel. The pipette now moves into the next three assay vessels (W2-W
4) move to a position overlying each of the containers and dispense a predetermined amount of sample into each of these containers under the control of the stepper %-II-(121130).

All operations described are effective for transferring a predetermined amount of the upper plasma portion to each container W, to W4 in the row of containers partially visible in the figure.

The operation of the system for transferring the lower packed red blood cell portion from the sample tube into the next five containers in the same row is illustrated in FIG. In the first step, the head assembly is raised and moved to the left to position the pipette tip directly above the sample tube.The head assembly is now lowered to place the lower end of the pipette between the two sample sections. preferably near the lower end of the sample tube.

The positioning of the lower end of the pipette tip is determined from a calculation based on the previously measured liquid level in the tube and the lowest hematocrit value determined by use, as explained below. By raising the plunger mechanism a predetermined distance, a predetermined amount of the lower packed red blood cell portion is removed.
and transfer a predetermined volume (e.g., 20 μl) of this sample to container W1□, which had been prepared to contain a predetermined dilution volume (e.g., 180 μl of saline). , and mix the diluted red blood cell sample by pipetting and dispensing the mixture several times.

The diluted red blood cells are then pipetted with the same pipette tip into containers W6-W, by successive movements of the pipette to the left in Figure 7 as shown. After dispensing the sample aliquot into the final assay vessel,
Raise the head assembly and move the pipette to the left in the diagram to the position shown in FIG. position it above. To release the pipette tip, lower the head assembly until the pipette tip is partially received in the empty opening, and then close the solenoid (14, 3) as shown in the drawings. , activate it to release Pipe, Tochi, and Gu from the pipette. Another method is to release the chips into a waste basin located to the right of the table.

The sample holder is advanced one step, the sample 2 is placed in the sample transfer position, and the table (16) is moved under the control of the motor (40) to advance the tray (22) one container row and then the next step. A row of containers is placed in position to receive the sample from the second tube. Using a new tray adjacent to the second sample, transfer the sample exactly as described for the first sample, first moving the upper plasma portion and then the packed red blood cell portion of the tray. Repeat this procedure for the first eight sample tubes to transfer the upper and lower portions of the samples into the corresponding assay vessels W1-W4 of each of the eight columns in the tray. and W6~W,. Dispense into assay vessels corresponding to .

The logical steps performed by the controller in the sample transfer operation are shown in FIG.

The theoretical flowchart shown in the figure is designed to transfer light sample aliquots into one tray, performing an operation with eight samples.

Starting from the upper frame in the drawing, the counter is first assigned a value of 1 corresponding to the sample number, and this counter number is determined by the control device from the information received from the sensor (100). Relate to the determined sample water level. Advance the sample holder to place the first sample in the sample transfer position, and move the head assembly to place the tip in the sample transfer position.
As described above, the sample is placed a predetermined distance below the upper sample water level. Distributing the sample liquid in the upper part of the sample tube into the first group of assay containers in the first row of trays.
For single aliquot samples, e.g. urine or cell-free blood fluids, the system can produce a second sample t'' in the same manner.
'process' and this procedure continues until all rows in one tray are filled.

If the controller is programmed to handle blood samples, the microcell in the device will calculate the expected water level at the serum/packed red blood cell interface in the sample tube based on the specified hemadcrit value. do. The calculations can be performed using a single Hemadcrit value entered into the controller at the beginning of system operation, typically a subnormal Hemadcrit value, or an individual Hemadcrit value entered and applied separately to each sample. It may be based on any of the Madcrit values. Normal hematocrit is in the range of about 40-60, i.e. the packed red blood cell portion accounts for 40-6 of the total volume.
It accounts for 0%. Typically, a single input hematocrit 2. When applying hematocrit values to blood cell samples, the predetermined value is a hematocrit value of about 30, which is below normal. For a general or individually specified hematocrit value, the calculation involves multiplying the measured fluid level by the input hematocrit value to yield the upper level of the filled blood cell portion. The calculation function or calculation means in the microprocessor of the control device for determining the upper water level of the filled blood cell portion in each sample tube from the upper liquid level and from the input hematocrit value is shown in FIG. 9 from the bottom. It is shown in the fourth box. The flowchart indicates that the calculations may be based on either a single subnormal input value or individually identified hematocrit values for each sample. After performing the interfacial water level calculations described above.

The system is operated to withdraw and dispense the lower portion into the next group of containers in the first row, and replace the contaminated bi, conker, and zo with fresh ones. The counter then advances by one and the cycle ends with 8 of the trays.
The machine is moved to the "next tray" step so that all the rows are filled and the 8 samples of that draw are distributed into the 8 rows of the next tray. This method
All samples are transferred to separate rows in the tray and/or
or continue until all trays are filled.During the sample transfer operation just described, the system also uses the par-co-P and tables used to match sample tube numbers to the corresponding calibration columns in the trays. Record and memorize information on the location above. Figure 10 shows the tube/verification column tiger;
2 shows a flowchart of the steps performed in the system as part of a king operation. First, set the tray 7-row counter to counting position n = 1, and then turn the motor (40)
by moving the table under the action of the first tray to receive the sample, for example the tray (22
) is placed in a position such that the par code on the tray is read by the league (140). The par code information is input to the controller (46) and stored therein as read-only memory. Next, move the table and place the 2
Place the tray in a position to receive the sample in the containers in the row indicated by 2-1. Information about the table location is placed in the controller's read-only memory to identify the sample receiving column in terms of par-code and column number. The system reads the sample bar code and then stores this code in memory along with the tray bar code and tray row location. The storage facility essentially associated with the sampler code and tracer code and column number information in the read-only memory of the microprocessor is also referred to herein as memory means and is shown in the third column from the bottom in FIG. It is shown as a frame. After the system positions the sample in the sample transfer position and performs the sample transfer operation outlined above with respect to FIG. 9, it increments by one counter tube and repeats the cycle. When all eight rows in the first tray are filled, the system is returned to the start of operation where the second tray (tray 20 in FIG. 4) is read. The above method is repeated until all rows in the second tray are filled and/or all samples are transferred.

At the end of the sample transfer operation, read-only memory in the system has stored information relating to each sample tube number along with one of the eight rows in each of the nine identified trays of the bar coat.

This information, which is stored until all of the blood assays have been performed, is provided to a printer or computer, computer and/or main laboratory computer, allowing the user to view each of the several trays. It may provide a record of the sample tube number associated with the test row. The information may be recalled on a sample-by-sample basis on the screen of the terminal (49') on demand.

At this stage, the serum and packed blood cell portions in each sample (up to 24 samples) have been transferred to individual rows on one or more trays. In particular, each of the individual plasma portions is in a separate column, Nos. 3.4.6 and 7.
have been distributed into containers corresponding to containers W, ~W4 in the figure, and each of the individual diluted packed blood cell portions has been distributed into containers W6 to W, in each row. It has been distributed into a group of containers corresponding to . The system is then operated to transfer a separate assay reagent to each of the nine different sample-containing containers in each column.

This operation involves first moving the table to position a row of disposable bit-covered tips, e.g. tips (150), directly below the pipette row in the pipette assembly (58), and then lowering the head assembly into a friction fit. Biy chips by,
pull it up. The pipette assembly, now equipped with a new disposable BitTip, is inserted into the channel (152) containing the above-described particular group of assay reagents in the first nine containers.
Inside (stop!), move that pipette assembly to the plunger mechanism (
70) to draw a predetermined amount of liquid into each disposable BitChip on the assembly. The pipette may initially be operated in an up-and-down manner to mix the individual reagents.

The head assembly is raised and the table is moved to position the first row of sample-containing assay vessels under the pipettes, f. The head assembly is then lowered to position the tips in their respective containers and the granger mechanism is actuated to release a predetermined amount of reagent into each container. Raise the head assembly, move the table to position the next row of containers below the head assembly, and repeat the reagent dispensing operation in the manner described above until all rows have been filled with the predetermined amount of reagent. return. Thus, in the example of a reagent dispensing operation, each container, corresponding to container W2 in FIG. 3, contains the same predetermined amount of reagent from container C2 in channel (152). Contains substances. The same applies below.

The samples and reagents in each assay may be mixed initially or during incubation by moving the table in a shaking manner with appropriate repeated fluctuating motions on the soaker (40). At the end of the assay period, each container is examined for blood cell agglutination according to commonly used blood typing methods to ascertain the blood type in each of these samples. Preferably, the containers are analyzed by a multi-vessel microspectrometer designed to assay for agglutination in the containers. The spectrometer may be equipped with a microprocessor for determining the blood type of the sample from the agglutination data, and may also be equipped with a par code to correlate each determined blood type with a particular tray and column number. League and row position detectors may also be provided. This information, in turn, can be correlated with sample column position information from the system (10) to provide a direct output relating sample number to blood type.

From the above description, it can be seen how the various objects and features of the invention are combined. This system enables efficient and accurate transfer of small sample aliquots from each of multiple samples to corresponding assay vessels in a multi-vessel tray. As illustrated and described herein, sample transfer may be performed from a large volume of sample. In addition, a sample transfer pipette is used to transfer samples between consecutive samples.

can be handled without the need for flushing or cleaning.

Liquid-transfer operations include liquid-level sensing steps that can be performed by optical sensing rather than resistance-based sensing. The complications associated with cleaning the resistance measurement probe after each sample-transfer operation can thus be avoided. The fluid-level calculation characteristic in this system is based on the general or sample-specific fluid supplied to the system to calculate the interface between the upper and lower filled blood cell fraction portions in a centrifuged blood cell sample. Used with madcrit value. The advantage of this characteristic is that it is possible to remove the lower fraction part without the need to pipette the whole way into the sample tube, and also to be able to remove it even more deeply into the full sample tube. The risk of sample spillage that may occur when inserting a chip can be minimized. Additionally, this calculated characteristic value also necessitates the need for more complex sensor systems designed to distinguish between the upper serum or plasma fraction (which may be completely opaque) and the lower blood cell fraction. It can also be avoided.

Once the various sample fractions have been distributed into the combined vessels in one or more multi-vessel trays, each of the different sample fractions retains each of the plurality of different selected assay reagents. Multiple bit liquid-handling operations that can be dispensed simultaneously into a group of containers can be easily assayed. Additionally, the system allows for the automatic ejection and removal of different groups of disposable pipette tips when it is desired to dispense two or more groups of reagents into one or more reagent containers. becomes possible.

Finally, the system allows automatic tracking between each of a number of different sample tubes and the corresponding tray and tray array on which the multi-item assay was performed. This electrical tracking between the sample tube and the assay results can reduce the amount of time a user would have to spend performing tests and editing test results, and can reduce the amount of time a user would have to spend performing tests and editing test results. When performing multi-item verification for each of the above, it is possible to reduce the risk of process-specific errors.

[Brief explanation of the drawing]

1 is a perspective view showing an example of a liquid handling system constructed in accordance with the present invention; FIG. 2 is an enlarged side sectional view taken along line 2-2 in FIG. 1; and FIG. 1 is a front view taken along line 3-3 in FIG. 1; FIG. 4 is a plan view showing the sample-tube holder and horizontally movable table portions of the system of the present invention; FIGS. The figures are respectively schematic diagrams showing the different movement positions of the sample transfer pipe during its operation (Figure 5: disposable pipette, during pick-up of tip; Figure 6: upwards from the sample tube). Withdrawing a fraction sample and distributing sample aliquots into a series of containers in a multi-container tray: FIG. Figure 8: Removal of the disposable pipette tip, f, following sample transfer; and Figures 9 and 10, respectively, when carrying out a series of sample transfer operations and the corresponding sample. FIG. 6 is a schematic diagram showing the operation of the present system when tracking holder and tray row numbers. In the figure, 10 is an automated liquid handling system, 12 is a liquid handling device, 16 is a table, and 24 is to. 26 is a sample holder, and 34 is a sample transfer pipette. Blank space below] = Eroto -2 knee F engineering [To 13-

Claims (1)

Claims: 1. A horizontally movable table for supporting a multi-row array of assay wells; means for moving the table to a selected liquid transfer position; A liquid handling system having a vertically movable head assembly supporting a plurality of fixed position pipettes for transferring volumes of liquid, and means for moving the head assembly to a selected liquid handling position. a movable sample holder suitable for holding an array of samples; means for moving the sample holder to position successive samples held therein at selected sample transfer positions; a sample transfer pipette attached to said head assembly for moving between said sample transfer position and a position suitable for sequentially dispensing sample into one or more wells in said array; means for moving a sample transfer pipette between positions of and transferring a selected amount of said respective sample to one or more selected wells in an array of wells supported as above on a table; a table movement means, a head assembly, a sample holder, and a control means operatively connected to the sample transfer pipette for use in performing a multi-item assay on each of a plurality of samples. A liquid handling system comprising a device. 2. The sample holder in said device is further suitable for supporting an array of disposable pipette tips, in which case each tip is attached to the head assembly when the pipette and corresponding tip assembly are vertically aligned. adapted to be attached to a sample transfer pipette by a friction fit upon downward movement, and characterized in that the sample transfer pipette further comprises means suitable for releasing its attached tip. A liquid handling system according to claim 1, wherein: 3. Liquid handling system according to claim 1 or 2, characterized in that the sample holder is a rotatable holder suitable for holding said samples in a circular arrangement. 4. sensor means for sensing each sample level, wherein said control means controls said head assembly in response to the sample level sensed by said sensor means during a sample transfer operation; For use in performing assays on multiple variable volume samples in sample tubes, further characterized in that the method is operatively connected to sensor means for controlling the position. The liquid handling system according to any one of Item 3. 5. The control means separately extracts samples from the upper portion and the lower blood cell portion of each sample based on the detected water level of the sample and a preselected upper portion/lower portion ratio. Claim for use in carrying out an assay on a blood sample each consisting of an upper part and a lower blood cell part, characterized in that it includes means for calculating the position of the head assembly to be drawn. The liquid handling system according to any one of items 1 to 4. 6. A table mounted for movement along a generally longitudinally extending path, a sample holder mounted for rotation adjacent to one side of the table, and above the table perpendicular to the table. a head assembly mounted on the head assembly for movement in a generally side-to-side direction between a position immediately above the sample holder and a position immediately above the table; a sample transfer pipette, its table, sample holder, head assembly, and associated movement means for moving each of the sample transfer pipettes to a desired position, in a row of wells supported on the table; the moving means for controlling the movement of the table, holder, head assembly and pipette to effect the transfer of a defined volume of each sample supported in the sample holder to at least one of the array of wells; A liquid handling system for performing a multi-item assay on each of a plurality of samples, characterized in that: means operatively connected to a plurality of samples. 7. The method of claim 1 further characterized by a plurality of side-by-side pipettes in said head assembly, each of which is suitable for dispensing a predetermined amount of a selected assay reagent fluid into each of the wells of said row. A liquid handling system according to scope 6. 8. The sample holder is suitable for holding a circular array of disposable pipette tips, in which case each tip is subject to downward movement of the head assembly when the pipette and corresponding tip assembly are vertically aligned. Claim 1, characterized in that the pipette is adapted to be attached to a sample transfer pipette by a friction fit, and that said pipette is further characterized by means suitable for releasing its attached tip. Liquid handling device according to item 6 or 7. 9. A sample having a tip capable of transferring the upper portion and lower blood cell portion from each of a number of blood samples contained in the sample tubes at various sample water levels to a selected water level in each sample tube. A liquid handling system suitable for transfer by a transfer pipette, comprising: a sensor for detecting an upper liquid level in each sample tube; for each sample, a sensor for detecting an upper liquid level in the sample and a preselected upper portion; means for calculating an approximate interfacial water level between the upper part and the lower part in the sample based on the ratio of the upper part and the lower part, and in response to the information about the interfacial water level, the pipette tip is adjusted to A liquid handling system comprising a tip positioning mechanism comprising: means for moving the pipette to position it a selected distance below the pipette. 10. Liquid handling system according to claim 9, characterized in that the sensor is an optical sensor.