Liquid sample handling system

• US 4,478,094 A
• Filed: 05/05/1983
• Issued: 10/23/1984
• Est. Priority Date: 01/21/1983
• Status: Expired due to Term

• Current Assignee: Cetus Corporation (Novartis Ag)
• Original Assignee: Cetus Corporation (Novartis Ag)
• Inventors: Leath, Richard, Merrill, Roy, Wennberg, Timothy, Widunas, Joseph, Salomaa, Kari
• Primary Examiner(s): Swisher, S. Clement
• Application Number:
  US06/489,866
• Time in Patent Office: 537 Days
• Field of Search: 73/863.32, 73/864.14, 422/65, 422/100
• US Class Current: 73/863.32
• CPC Class Codes: G01N 1/38 Diluting, dispersing or mixing samples
• CPC Class Codes: G01N 2035/103 using disposable tips
• CPC Class Codes: G01N 35/1065 Multiple transfer devices

Abstract

An automatic liquid transfer system includes a horizontally translatable table and a vertically translatable set of pipettes. The table accommodates a titer tray having a multiplicity of receptacles to be filled, or holding liquid samples to be diluted, and a rack housing plural rows of disposable tips. During each cycle in a serial dilution process, a fresh set of tips are picked up by the pipettes and used to transfer liquid in a sterile manner from a sample or diluent source to a row of wells in the titer tray, or from one row to a succeeding row of wells where it is mixed with diluent. Thereafter, the tips are discharged back into the rack to maintain sterile conditions during the process. A sensor is provided on the machine to detect whether all of the tips in each set are disengaged and another set successfully picked up.

Claims

1. A machine for automatically transferring at least a portion of liquid sample from one or more liquid-containing receptacles to one or more other receptacles, comprising:

a head assembly translatable between upper and lower positions along a vertical axis;

means for moving said head assembly along said vertical axis;

a plunger assembly mounted on said head assembly for movement therewith, said plunger assembly including a row of pipettes having depending ends for receiving tips, a row of plungers respectively disposed within said pipettes, and means for moving said plungers within said pipettes to vary their internal volumes;

tip ejector means mounted on said head assembly for removing tips disposed on said depending ends of said pipettes;

a table mounted beneath said head for translation along a horizontal axis, said table having work stations spaced along said axis for respectively accommodating a tray having pipette tip-receiving receptacles and one or more trays providing said liquid-containing receptacles and other receptacles;

means for moving said table along said horizontal axis to place any selected one of the receptacles in registry with said pipettes; and

means for controlling each of said moving means for said head assembly, plungers and table and said tip ejector means to effect transfer of liquid between the liquid-containing receptacles and the other receptacles and to replace tips on the ends of said pipettes with other tips disposed in at least some of the pipette tip-receiving receptacles between predetermined liquid transfer steps.

2. The machine of claim 1 wherein said tip ejector means includes a plate disposed adjacent at least a portion of each of said depending ends and movable downward to push disposable tips from said ends.

3. The machine of claim 2 further including at least one solenoid for moving said plate downwardly.

4. The machine of claim 1 wherein said pipette depending ends are tapered to receive and frictionally hold disposable tips disposed in a tray mounted at a work station when said head assembly is moved toward said lower position.

5. The machine of claim 4 wherein said pipette depending ends are vertically reciprocable relative to said head assembly and said plunger assembly includes compliance spring means for restraining movement of said ends relative to said head assembly to permit pick up of tips with slightly different dimensions by said ends.

6. The machine of claim 4 further including means for detecting failure of a tip to be frictionally retained by at least one of said ends when said head assembly moves toward said upper position.

7. The machine of claim 5 wherein said detecting means includes electro-optical means having a line of sight in registry with said row of pipette tips.

8. The machine of claim 1 wherein said head assembly moving means includes a stepper motor and a rack-and-pinion arrangement interconnecting said stepper motor and said head assembly.

9. The machine of claim 1 wherein said plunger moving means includes a stepper motor and a lead screw drive mechanism interconnecting said stepper motor and said plungers.

10. The machine of claim 1 wherein said table moving means includes a stepper motor and a rack-and-pinion arrangement interconnecting said stepper motor and said table.

11. The machine of claim 1 wherein said control means includes means for monitoring the position of at least one element including said head assembly, plungers and table.

12. The machine of claim 11 wherein said monitoring means includes a sensor producing a reference signal when a monitored element passes a predetermined point in its path of travel.

13. A method for effecting automatic transfer or dilution of liquid samples between a plurality of liquid receptacles positioned for horizontal movement on a support table and being indexable beneath a vertically movable row of pipettes, comprising the steps of:

(a) charging a predetermined volume of a first liquid into one or more receptacles located at a first work station on said table;

(b) arranging at least a row of pipette tips at a second work station on said table;

(c) moving said table to register said row of pipette tips with the row of pipettes;

(d) lowering said pipettes to engage the tips in said registered row and picking up the engaged tips;

(e) moving said table to register the receptacles of said first work station with said row of pipettes;

(f) inserting the engaged tips in the first liquid in said registered receptacles and withdrawing at least least some of the liquid therefrom into said pipettes;

(g) raising said pipettes;

(h) moving said table to register other receptacles with said pipettes;

(i) lowering said pipettes and expelling the liquid in said pipettes into the other receptacles;

(j) raising said pipettes;

(k) moving the table to bring a selected position at said second work station into alignment with said pipettes;

(l) discharging said engaged tips from said pipettes; and

(m) repeating steps b through k until a desired number of transfers or dilutions are completed.

14. The method of claim 13 wherein step i includes at least once after expelling liquid into said other receptacles, withdrawing liquid from said other receptacles into said pipettes to effect mixing of the contents of the other receptacles with the added liquid.

15. The method of claim 13 wherein expelling of liquids in said pipettes in step i includes actuation of a plunger in each pipette while said tips are just above the meniscus of liquid in said receptacles to expel any remaining liquid in said tips through capillary attraction between liquid in said tips and said receptacles.

16. The method of claim 13 further including the step of detecting whether all of the tips in a row are successfully picked up during step d.

17. The method of claim 13 wherein said tips are discharged onto said second work station during step k.

18. The method of claim 13 which includes the further step of detecting whether all tips having been ejected after step l.

19. The method of claim 13 wherein said steps c through j are repeated before steps k through m are performed.

20. An apparatus for handling small liquid samples during filling, transferring or mixing of such liquid samples by repetitive use of the same pipette to transfer liquids between a plurality of sample receptacles having different quantities or types of liquid therein which includes a plurality of syringes, each having a barrel portion and a pipette tip member securable thereto for insertion into said sample receptacles to withdraw liquids. from or inject liquids into said receptacles, and each syringe barrel including a body portion having a cylinder formed therein, a plunger positioned in and fluid sealed for reciprocal motion of said plunger through said cylinder;

an elongated pipette tip member for covering the other end of said cylinder and forming a substantial portion of the fluid volume of said barrel, said tip member having one end frictionally engageable with a portion of the sidewall surface of said body portion to form a fluid seal with said cylinder;

reciprocal means having a member slidably surrounding the exterior of said barrel to contact said tip member to frictionally disengage said tip member from said sidewall surface,

means for supporting a plurality of said pipette tip members in a vertical position for selective frictional engagement with said sidewall surface,

means for reciprocating each of said barrels to frictionally engage said tips with said surface, and

means for actuating said reciprocal means to disengage said tip member from said cylinder, whereby a different pipette tip member may be selectively and automatically changed after any insertion into fluid in a sample receptacle.

21. Apparatus in accordance with claim 20 wherein each of said syringe barrels is resiliently mounted to permit compliance between said barrel portion and said pipette tip member to permit pick up of said tip members of slightly different dimensions.

22. A method for effecting automatic transfer or dilution of liquid samples between a plurality of liquid receptacles comprising the steps of:

(a) positioning said plurality of liquid receptacles for horizontal movement on a support table with said receptacles being indexable beneath a row of pipettes at a first work station, at least one of said liquid receptacles containing a predetermined volume of liquid;

(b) positioning a row of pipettes on a head assembly above said support table and vertically reciprocable relative thereto;

(c) arranging at least a row of pipette tips for horizontal movement on said support table at a second work station thereon;

(d) moving said support table to register said row of pipette tips with the pipettes on said head assembly;

(e) lowering said pipettes to engage the tips in the registered row and picking up the engaged tips;

(f) moving said table to index said liquid-containing receptacles at said first work station under said row of pipettes;

(g) inserting the engaged tips in the liquid in said liquid-containing receptacles and withdrawing at least some of the liquid therefrom into said pipettes;

(h) raising said pipettes;

(i) moving said table to index one or more other receptacles under said pipettes;

(j) lowering said pipettes and expelling the liquid in said pipettes into the other receptacles;

(k) raising said pipettes;

(l) moving the table to bring a selected position at said second work station into alignment with said pipettes; and

(m) discharging said engaged tips from said pipettes.

23. The method of claim 22 which includes repeating steps c through l for successive rows of tips and successive receptacles at said respective work stations until a desired number of transfers or dilutions are completed.

24. The method of claim 22 wherein step j includes at least once after expelling liquid into said receptacle, withdrawing liquid from said receptacle into said pipettes and again expelling liquid from said pipettes to effect mixing of the contents of said receptacles with the added liquid.

25. The method of claim 22 wherein expelling of liquids in said pipettes in step j includes actuation of a plunger in each pipette while said tips are just above the meniscus of liquid in said receptacles to expel any remaining liquid in said tips through capillary attraction between liquid in said tips and said receptacle.