Method and apparatus for performing a magnetic separation purification procedure on a sample solution

• US 6,605,213 B1
• Filed: 11/27/2000
• Issued: 08/12/2003
• Est. Priority Date: 05/01/1998
• Status: Expired due to Term

• Current Assignee: Gen-Probe Incorporated (Hologic Incorporated)
• Original Assignee: Gen-Probe Incorporated (Hologic Incorporated)
• Inventors: Burns, Ralph E., Hansberry, Ernest V., Nieglos, Donald J., Kling, John E., Jakub, Cheryl A., Horner, Glenn A., Smith, Robert J., Schneider, Robert E., Ammann, Kelly G.
• Primary Examiner(s): Walker, W. L.
• Assistant Examiner(s): MENON, KRISHNAN S
• Application Number:
  US09/721,921
• Time in Patent Office: 988 Days
• Field of Search: 210/222, 210/695, 210/94, 435/286.7, 436/526, 422/63, 422/64, 422/65, 422/67, 366/110, 366/111, 366/112, 366/208
• US Class Current: 210/222
• CPC Class Codes: B01F 29/10 with receptacles rotated about two different axes, e.g. receptacles having planetary motion
• CPC Class Codes: B01F 29/30 Mixing the contents of individual packages or containers, e.g. by rotating tins or bottles
• CPC Class Codes: B01F 29/322 of two or more containers supported for simultaneous mixing, e.g. for bottles in crates
• CPC Class Codes: B01F 29/40354 arranged for planetary motion
• CPC Class Codes: B01L 2200/147 Employing temperature sensors
• CPC Class Codes: B01L 2300/1822 using Peltier elements
• CPC Class Codes: B01L 2300/1827 using resistive heater
• CPC Class Codes: B01L 7/52 with provision for submitting samples to a predetermined sequence of different temperatures, e.g. for treating nucleic acid samples amplification or hybridisation processes per se C12Q1/68; controlling sequential reactions for synthesis B01J19/0046
• CPC Class Codes: B01L 7/5255 by moving sample containers
• CPC Class Codes: B01L 9/06 Test-tube stands; Test-tube holders
• CPC Class Codes: B03C 1/282 with associated accumulation indicator, e.g. Hall sensor
• CPC Class Codes: B03C 1/288 disposed at the outer circumference of a recipient
• CPC Class Codes: B03C 1/30 Combinations with other devices, not otherwise provided for
• CPC Class Codes: B03C 2201/26 for use in medical or biological applications
• CPC Class Codes: C12Q 1/6813 Hybridisation assays
• CPC Class Codes: C12Q 1/6832 Enhancement of hybridisation reaction
• CPC Class Codes: C12Q 1/6834 Enzymatic or biochemical coupling of nucleic acids to a solid phase
• CPC Class Codes: C12Q 2537/10 the purpose or use of
• CPC Class Codes: G01N 2035/00356 Holding samples at elevated temperature (incubation)
• CPC Class Codes: G01N 2035/00524 Mixing by agitating sample carrier
• CPC Class Codes: G01N 2035/0437 : Cleaning cuvettes or reaction vessels
• CPC Class Codes: G01N 2035/0455 : Coaxial carousels
• CPC Class Codes: G01N 2035/103 : using disposable tips
• CPC Class Codes: G01N 35/0098 : involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation magnetic particles used in immunoassays G01N33/54326; magnetic separation in general B03C
• CPC Class Codes: G01N 35/0099 : comprising robots or similar manipulators robots per se B25J
• CPC Class Codes: G01N 35/025 : having a carousel or turntable for reaction cells or cuvettes
• CPC Class Codes: G01N 35/1065 : Multiple transfer devices
• CPC Class Codes: Y10T 156/1105 : Delaminating process responsive to feed or shape at delamination
• CPC Class Codes: Y10T 156/1906 : Delaminating means responsive to feed or shape at delamination
• CPC Class Codes: Y10T 29/53657 : to apply or remove a resilient article [e.g., tube, sleeve, etc.]
• CPC Class Codes: Y10T 29/53683 : Spreading parts apart or separating them from face to face engagement
• CPC Class Codes: Y10T 29/53843 : Tube, sleeve, or ferrule inserting or removing
• CPC Class Codes: Y10T 436/11 : Automated chemical analysis
• CPC Class Codes: Y10T 436/111666 : Utilizing a centrifuge or compartmented rotor
• CPC Class Codes: Y10T 436/113332 : with conveyance of sample along a test line in a container or rack
• CPC Class Codes: Y10T 436/114998 : with treatment or replacement of aspirator element [e.g., cleaning, etc.]
• CPC Class Codes: Y10T 436/119163 : with aspirator of claimed structure
• CPC Class Codes: Y10T 436/2575 : Volumetric liquid transfer

Abstract

An automated analyzer for performing multiple diagnostic assays simultaneously includes multiple stations, or modules, in which discrete aspects of the assay are performed on fluid samples contained in reaction receptacles. The analyzer includes stations for automatically preparing a specimen sample, incubating the sample at prescribed temperatures for prescribed periods, preforming an analyte isolation procedure, and ascertaining the presence of a target analyte. An automated receptacle transporting system moves the reaction receptacles from one station to the next. The analyzer further includes devices for carrying a plurality of specimen tubes and disposable pipette tips in a machine-accessible manner, a device for agitating containers of target capture reagents comprising suspensions of solid support material and for presenting the containers for machine access thereto, and a device for holding containers of reagents in a temperature controlled environment and presenting the containers for machine access thereto. A method for performing an automated diagnostic assay includes an automated process for isolating and amplifying a target analyte. The process is performed by automatically moving each of a plurality of reaction receptacles containing a solid support material and a fluid sample between stations for incubating the contents of the reaction receptacle and for separating the target analyte bound to the solid support from the fluid sample. An amplification reagent is added to the separated analyte after the analyte separation step and before a final incubation step.

Claims

1. A device for performing a magnetic separation purification procedure on a solution which includes magnetically responsive particles and is contained in a reaction receptacle, said device comprising:

a receptacle carrier unit constructed and arranged to receive a reaction receptacle containing a solution which includes magnetically responsive particles and to carry the reaction receptacle throughout the magnetic separation purification procedure;

a magnet moving structure including at least one magnet generating a magnetic field, said magnet moving structure being constructed and arranged to move said at least one magnet between first and second positions with resect to the reaction receptacle carried in said receptacle carrier unit,

wherein said magnetic field of said at least one magnet draws the magnetically responsive particles to an inner surface of the reaction receptacle adjacent to said at least one magnet when said at least one magnet is in said first position, and wherein the effect of said magnetic field on said magnetically responsive particles is less when said at least one magnet is in said second position than when said at least one magnet is in said first position;

a fluid transfer mechanism constructed and arranged to selectively dispense fluid into the reaction receptacle carried in said receptacle carrier unit and withdraw fluid from the reaction receptacle; and

carrier agitator mechanism operatively coupled to said receptacle carrier unit and constructed and arranged to impart a cyclic motion to said receptacle carrier unit to agitate and mix the solution contained in the reaction receptacle carried in said receptacle carrier unit.

2. A device for performing a magnetic separation purification procedure on a solution which includes magnetically responsive particles and is contained in a reaction receptacle, said device comprising:

a receptacle carrier unit constructed and arranged to receive and releasably hold the reaction receptacle;

a magnet moving structure which includes at least one magnet, said magnet moving structure being constructed and arranged to move said magnet between a first position and a second position with respect to the reaction receptacle, wherein said magnet attracts the magnetically responsive particles to an inner surface of the reaction receptacle adjacent to said magnet when said magnet is in the second position, and wherein the attraction of the magnetically responsive particles to said magnet is greater when said magnet is in the second position than when said magnet is in the first position;

a fluid transfer mechanism constructed and arranged to dispense fluid into and withdraw fluid from the reaction receptacle; and

a carrier agitator mechanism operatively coupled to said receptacle carrier unit and constructed and arranged to impart a cyclic motion to said receptacle carrier unit to agitate and mix the solution contained in the reaction receptacle.

3. The device of claim 2, further comprising a housing defining an interior chamber, wherein said receptacle carrier unit, said magnet moving structure, at least a portion of said fluid transfer mechanism, and said carrier agitator mechanism are disposed within said interior chamber.

4. The device of claim 2, wherein said magnet moving structure is constructed and arranged to pivot about a pivot point and between the first and second positions.

5. The device of claim 2, wherein:

said magnet moving structure has a slot formed therein,

said magnet is mounted to said magnet moving structure on one side of said slot, and

said magnet moving structure is constructed and arranged so that the reaction receptacle held by said receptacle carrier unit is disposed within said slot when said magnet moving structure is in the second position and so that the reaction receptacle is not disposed in said slot when said magnet moving structure is in the first position, thus permitting the reaction receptacle to be moved into or out of said receptacle carrier unit without interference from said magnet moving structure when said magnet moving structure is in the first position.

6. The device of claim 5, wherein said magnet moving structure composes at least one pair of magnets, each magnet of said pair of magnets being disposed on an opposite side of said slot in opposed relation to the other magnet of said pair.

7. The device of claim 4, herein:

said magnet moving structure has a slot formed therein,

said magnet is mounted to said magnet moving structure on one side of said slot, and

said magnet moving structure is constructed and arranged so that the reaction receptacle held by said receptacle carrier unit is disposed within said slot when said magnet moving structure is in the second position and so that the reaction receptacle is not disposed in said slot when said magnet moving structure is in the first position, thus permitting the reaction receptacle to be moved into or out of said receptacle carrier unit without interference from said magnet moving structure when said magnet moving structure is in the first position.

8. The device of claim 7, wherein said magnet moving structure comprises at least one pair of magnets, each magnet of said pair of magnets being disposed on an opposite side of said slot in opposed relation to the other magnet of said pair.

9. The device of claim 4, further comprising an electric actuator operatively coupled to said magnet moving structure for effecting powered pivoting movement of said magnet moving structure about the pivot point and between the first and second positions.

10. The device of claim 9, wherein said electric actuator comprises a drive screw mechanism having one portion thereof fixed to said magnet moving structure at a position spaced from the pivot point and another portion thereof fixed to an adjacent structure that is fixed with respect to said magnet moving structure, wherein powered rotation of one portion of said drive screw mechanism with respect to another portion of said drive screw mechanism effects powered linear movement that causes corresponding powered pivoting movement of said magnet moving structure.

11. The device of claim 2, further comprising one or more sensors constructed and arranged to indicate when said magnet moving structure is in at least one of the first and second positions.

12. The device of claim 11, wherein said sensors comprise optical sensors.

13. The device of claim 12, wherein said fluid transfer mechanism comprises one or more fluid dispense nozzles constructed and arranged to dispense fluid into one or more receptacle, vessels of a reaction receptacle held by said receptacle carrier unit and one or more aspirator tubes constructed and arranged to aspirate fluid from one or more receptacle vessels of a reaction receptacle held by said receptacle carrier unit.

14. The device of claim 13, wherein the number of said aspirator tubes corresponds to the number of said dispense nozzles.

15. The device of claim 13, further comprising a vertically translatable tube holder constructed and arranged to carry said aspirator tubes so as to permit downward movement of said aspirator tubes into the reaction receptacle held by said receptacle carrier unit to aspirate the fluid contents from the reaction receptacle and to permit upward movement of said aspirator tubes out of the reaction receptacle.

16. The device of claim 15, further comprising a tube holder translating mechanism comprising a drive screw threadingly coupled to said tube holder and a motor coupled to said drive screw to effect powered rotation of said drive screw, thereby effecting corresponding linear translation of said tube holder along said drive screw.

17. The device of claim 13, further comprising one or more sensors constructed and arranged to indicate one or more positions of said aspirator tubes.

18. The device of claim 17, wherein said sensors comprise optical sensors.

19. The device of claim 17, wherein said sensors comprise a first sensor constructed and arranged to indicate an up position of said aspirator tubes and a second sensor constructed and arranged to indicate a down position of said aspirator tubes.

20. The device of claim 15, wherein:

said receptacle carrier unit is constructed and arranged to selectively position a reaction receptacle held thereby into a position with respect to said aspirator tubes and said tube holder, so as to permit said tube holder to lower said aspirator tubes into operative engagement with contamination limiting elements carried on the reaction receptacle, and

each of said aspirator tubes is constructed and arranged to releasably hold a contamination limiting element onto an end thereof so as to limit contact between the fluid contents being aspirated by said aspirator tube and an outer portion of said aspirator tube.

21. The device of claim 20, further comprising a contamination limiting element stripping mechanism constructed and arranged to remove the contamination limiting elements held onto the ends of said aspirator tubes upon relative vertical movement of said aspirator tubes by said tube holder with respect to said stripping mechanism.

22. The device of claim 2, wherein said receptacle carrier unit has a slot formed therein which is adapted to receive a reaction receptacle and retaining elements disposed with respect to said slot so as to engage portions of the reaction receptacle and to retain the reaction receptacle within said slot during a magnetic separation purification procedure.

23. The device of claim 22, wherein said retaining elements comprise one or more flanges projecting laterally from portions of the perimeter of said slot, said flanges being constructed and arranged to engage cooperating structure formed on the reaction receptacle when the reaction receptacle is positioned within the receptacle carrier unit.

24. The device of claim 22, wherein said slot is open at one end thereof to permit lateral transfer of a reaction receptacle into and out of said slot.

25. The device of claim 24, wherein said receptacle carrier unit includes a reaction receptacle retaining mechanism constructed and arranged to releasably hold a reaction receptacle within said slot.

26. The device of claim 24, wherein said reaction receptacle retaining mechanism comprises a spring clip mounted at a closed end of said slot, said spring clip being constructed and arranged to retain a reaction receptacle placed into retaining engagement with said spring clip and to release the reaction receptacle upon application of a force sufficient to overcome an elastic retaining force generated by said spring clip.

27. The device of claim 2, wherein said carrier agitator mechanism is constructed and arranged to move said receptacle carrier unit in a cyclic motion comprising a generally horizontal, orbital path.

28. The device of claim 27, wherein said carrier agitator mechanism comprises:

a motor;

a drive pulley drivingly coupled to said motor;

an eccentric drive pin extending from said drive pulley axially with respect to an axis of rotation of said drive pulley and eccentrically located with respect to said axis of rotation of said drive pulley;

an idler pulley;

an eccentric idler pin extending from said idler pulley axially with respect to an axis of rotation of said idler pulley and eccentrically located with respect to said axis of rotation of said idler pulley; and

a belt rotatably coupling said drive pulley and said idler pulley,

wherein said drive pin and said idler pin are coupled to said receptacle carrier unit, whereby driven rotation of said drive pulley by said motor causes corresponding rotation of said idler pulley via said belt and said eccentric drive and idler pins impart the generally horizontal, orbital path of motion to said receptacle carrier unit.

29. The device of claim 28, comprising a sensor to indicate a rotation rate of said idler pulley.

30. The device of claim 29, wherein said sensor comprises an optical sensor.

31. The device of claim 28, further comprising a sensor constructed and arranged to indicate a position of said receptacle carrier unit along said orbital path of motion.

33. A method for performing a magnetic separation purification procedure on a sample solution which includes magnetically responsive particles and is contained in a reaction receptacle, said method comprising:

moving at least one magnet from a first position to a second position with respect to the reaction receptacle, wherein the magnet attracts the magnetically responsive particles to an inner surface of the reaction receptacle adjacent to the magnet when the magnet is in the second position, and wherein the attraction of the magnetically responsive particles to the magnet is greater when the magnet is in the second position than when the magnet is in the first position;

aspirating the sample solution from the reaction receptacle while the magnet is in the second position;

dispensing a wash solution into the reaction receptacle; and

agitating the wash solution by imparting a cyclic motion to the reaction receptacle while the magnet is in the first position, wherein

the reaction receptacle is maintained in a substantially fixed location throughout the magnetic separation purification procedure including said moving, aspirating, dispensing, and agitating steps.

32. The device of claim 34, wherein said sensor comprises an optical sensor.

34. The method of claim 33, wherein said maintaining step comprises releasably holding a reaction receptacle in a receptacle carrier unit that is substantially fixed in space.

35. The method of claim 33, wherein said aspirating step is performed with a fluid transfer mechanism comprising one or more aspirator tubes constructed and arranged to be selectively moved into the reaction receptacle to aspirate the sample solution therefrom.

36. The method of claim 35, wherein said aspirating step further comprises placing a contamination limiting element onto a distal end of each of the aspirator tubes prior to moving the aspirator tubes into the reaction receptacle.

37. The method of claim 33, wherein moving at least one magnet comprises mounting the magnet on a magnet moving structure and moving the magnet between the first and second positions by pivoting the magnet moving structure about a pivot point.

38. The method of claim 33, wherein said agitating step comprises imparting a cyclic generally horizontal, orbital path of motion to the reaction receptacle.

39. The method of claim 33, wherein said aspirating, dispensing, and agitating steps are repeated one or more times during a magnetic separation purification procedure.