Method and apparatus for controlling magnetic particles by pipetting machine

• US 6,509,193 B1
• Filed: 04/16/1999
• Issued: 01/21/2003
• Est. Priority Date: 05/20/1996
• Status: Expired due to Term

• Current Assignee: Mortarless Technologies LLC
• Original Assignee: Mortarless Technologies LLC
• Inventors: Tajima, Hideji
• Primary Examiner(s): Soderquist, Arlen
• Application Number:
  US09/197,408
• Time in Patent Office: 1,376 Days
• Field of Search: 436/43, 436/47, 436/49, 436/54, 436/174, 436/177, 436/180, 436/807, 436/809, 436/810, 422/63-67, 422/100, 422/101, 210/695, 210/222, 210/223, 702/19
• US Class Current: 436/49
• CPC Class Codes: B03C 1/288 disposed at the outer circumference of a recipient
• CPC Class Codes: B03C 2201/26 for use in medical applications
• 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: Y10S 436/807 Apparatus included in process claim, e.g. physical support structures
• CPC Class Codes: Y10T 436/11 Automated chemical analysis
• 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 436/25 including sample preparation
• CPC Class Codes: Y10T 436/25625 Dilution
• CPC Class Codes: Y10T 436/2575 Volumetric liquid transfer

Abstract

The present invention relates to a method and apparatus for controlling magnetic particles by a sample distributor and is intended to process a sample liquid with high precision, sensitivity and reliability by arresting magnetic particles to separate them from the liquid and by suspending the magnetic particles in a liquid to mix the magnetic particles with the liquid again.

The pipette portion of this invention has a front end portion, a reservoir portion, a liquid passage connecting the front end portion and the reservoir portion, and a separation region in the liquid passage that is subjected to a magnetic field. The pipette portion of this construction draws in or discharges a liquid for processing. This invention includes a process in which when a magnetic particle-suspended liquid is passed through the separation region of the pipette portion, a magnetic field is applied to the separation region from outside the liquid passage to attract the magnetic particles to the inner surface of the liquid passage, thereby separating the magnetic particles from the liquid.

Claims

1. A computer implemented method of controlling a sample distributor, comprising:

entering specification information for controlling the sample distributor, the specification information including at least one operation condition for specifying;

whether a magnetic particle is attracted to an inner sidewall of a liquid passage of the sample distributor by a magnetic field; and

a selection from among;

a specification of whether a suction and discharge operation is performed by the sample distributor, a position of the suction and discharge operation, a time of the suction and discharge operation, an order of the suction and discharge operation, a number of times of the suction and discharge operation, a quantity of the suction and discharge operation, and a speed of the suction and discharge operation;

analyzing the specification information;

generating a processing pattern for the sample distributor based upon the analysis of the specification information; and

generating instructions for executing the processing pattern.

2. The method of claim 1, wherein the specification information includes at least one of:

a material condition and a reaction condition.

3. The method of claim 1, wherein analyzing the specification information comprises determining at least one of:

a number of samples;

a number of divided samples;

a material condition;

a reaction condition;

the operation condition;

whether to perform pre-processing; and

whether to perform mid-processing.

4. The method of claim 1, wherein analyzing the specification information comprises identifying data contained in the specification information, and wherein generating the processing pattern comprises:

setting a processing pattern according to the data contained in the specification information.

5. The method of claim 4, wherein the data is selected from the group consisting of:

a number of divided samples, a total process time for each item, a time taken by each process contained in each item, and a container cartridge position.

6. The method of claim 1, wherein when two or more samples are processed by the system, a minimum incubation time t_min is set to be larger than a total working time T and an incubation time t to be set is an integer times the minimum incubation time t_min.

7. The method of claim 6, wherein when two or more samples are processed by the system and mid-processing is specified, the times required by the mid-processing are shorter than each working time based on each working time, into which the total working time T of the entire processing including one or more reaction processes is partitioned by one or more incubations.

8. The method of claim 1, wherein when divided samples are processed by the system, a minimum incubation time t_min is set to be larger than a total working time T and an incubation time t to be set is an integer times the minimum incubation time t_min.

9. The method of claim 8, wherein when divided samples are processed by the system and mid-processing is specified, the times required by the mid-processing are shorter than each working time based on each working time, into which the total working time T of the entire processing including one or more reaction processes is partitioned by one or more incubations.

10. The method of claim 1, wherein generating instructions for executing the processing pattern comprises:

requesting to draw in a required amount of a sample and discharge it into a container accompanying a necessary agitation;

requesting to attract a plurality of magnetic particles bounded to a target substance suspended in a liquid to the inner sidewall by applying the magnetic field; and

requesting to agitate by drawing into and discharging from a pipette, and requesting to draw and discharge the liquid in the container.

11. The method of claim 1, further comprising:

passing a liquid containing suspended magnetic particles through a separation region of a pipette portion, the separation region being arranged in the liquid passage connecting a front end portion and a reservoir portion of the pipette portion; and

during the passing of the magnetic particle-suspended liquid, applying the magnetic field to the separation region from outside the liquid passage of the pipette portion to attract the magnetic particles to the inner sidewall to separate the magnetic particles from the liquid by translating and rotating the magnetic field into a position proximate the separation region.

52. The control apparatus of claim 10, wherein the specification content analyzing means determines a processing pattern comprising:

a means for requesting to draw in a required amount of a sample and discharge the sample into a container accompanying a necessary agitation;

a means for requesting to attract the magnetic particles bounded to a target substance suspended in a liquid to the inner sidewall by applying the magnetic field;

a means for requesting to agitate by drawing into and discharging from the pipette; and

a means for requesting to draw and discharge the liquid in the container.

12. A system for controlling a sample distributor, comprising:

means for entering specification information for controlling the sample distributor, the specification information including at least one operation condition for specifying;

whether a magnetic particle is attracted to an inner sidewall of a liquid passage of the sample distributor by a magnetic field; and

a selection from among;

a specification of whether a suction and discharge operation is performed by the sample distributor, a position of the suction and discharge operation, a time of the suction and discharge operation, an order of the suction and discharge operation, a number of times of the suction and discharge operation, a quantity of the suction and discharge operation, and a speed of the suction and discharge operation;

means for analyzing the specification information;

means for generating a processing pattern for the sample distributor based upon the analysis of the specification information;

means for generating instructions for executing the processing pattern; and

means for executing the instructions for the processing pattern.

13. The system of claim 12, wherein the means for analyzing comprises:

means for analyzing a sample number;

means for analyzing a sample division;

means for analyzing a reaction content;

means for analyzing a reaction number;

means for analyzing pre-processing; and

means for analyzing mid-processing.

14. The system of claim 12, wherein the means for generating a processing pattern comprises:

means for generating a sample sequence control;

means for generating an arrest sequence control;

means for generating an agitation sequence control; and

means for generating a whole quantity sequence control.

15. A method of controlling magnetic particles by a sample distributor, comprising:

passing a liquid containing suspended magnetic particles through a separation region of a pipette of the sample distributor, wherein the separation region comprises a liquid passage connecting a front end portion and a reservoir portion of the pipette;

applying a magnetic field to the separation region from outside the liquid passage of the pipette to attract the magnetic particles to an inner sidewall surface of the liquid passage to separate the magnetic particles from the liquid;

entering specification information including at least one operation condition for specifying;

whether the magnetic particles are attracted to the inner sidewall surface by the magnetic field; and

a selection from among;

a specification of whether a suction and discharge operation is performed by the sample distributor, a position of the suction and discharge operation, a time of the suction and discharge operation, an order of the suction and discharge operation, a number of times of the suction and discharge operation, a quantity of the suction and discharge operation, and a speed of the suction and discharge operation;

analyzing the specification information entered to determine required processing;

determining a processing pattern which the sample distributor follows based on the specification information; and

giving instructions for execution of processing to the sample distributor, or the sample distributor and a container feeding device, according to the determined processing pattern.

16. The method of claim 15, wherein determining the processing pattern comprises:

based on the specification information, setting the processing pattern so that a suction and discharge speed at which the liquid is drawn into and discharged from the pipette is slow enough to produce a sufficient effect of separation, according to a viscosity of the liquid and a plurality of characteristics of the magnetic particles.

17. The method of claim 15, wherein magnetic particles are arrested in a process comprising:

drawing in and discharging from the pipette, a mixture of a predetermined amount of a sample and a predetermined amount of a magnetic particle-suspended liquid.

18. The method of claim 17, wherein drawing in the mixture to the pipette comprises;

maintaining a bottom level of the liquid drawn in at a position equal to or higher than a lower end area of the separation region.

19. The method of claim 17, wherein drawing in and discharging from the pipette comprises;

keeping a lower end portion of the pipette submerged in a reagent or a cleaning liquid to prevent generation of bubbles due to suction of air.

20. The method of claim 15, further comprising agitating or cleaning the pipette, wherein a percentage of liquid drawn into the pipette from a container can be specified during agitating or cleaning.

21. The method of claim 20, wherein agitating or cleaning comprises:

sucking air into the pipette.

22. The method of claim 15, wherein the pipette comprises a pipette tip removably attached to one or more nozzles of the sample distributor.

23. The method of claim 15, wherein analyzing the specification information entered to determine required processing comprises:

checking a number of samples or a number of divided samples;

checking material conditions, reaction conditions or operation conditions; and

checking if there is any request calling for pre-processing or mid-processing.

24. The method of claims 15, wherein determining a processing pattern which the sample distributor follows based oh the specification information comprises:

setting a processing pattern for a sample specified according to data contained in the sample,

wherein the data includes number of divided samples, a total process time for each sample, a time taken by each process contained in each sample, and a container cartridge position.

25. The method of claim 15, wherein determining a processing pattern which the sample distributor follows based on the specification information,

wherein two or more samples are used, comprises;

setting a minimum incubation time t_min to be larger than a total working time T; and

setting an incubation time t as an integer n times the minimum incubation time t_min;

wherein the total working time T comprises one or more reaction processes excluding the incubation time t; and

wherein the total working time T is entered, measured, or registered.

26. The method of claim 25, wherein the specification information comprises mid-processing,

wherein determining the processing pattern comprises setting one or more mid-processing times shorter than a working time,

wherein the working time is partitioned by one or more incubations into the total working time T of the entire processing, and

wherein the total working time T is entered, measured or registered.

27. The method of claim 15, wherein giving instructions for execution of processing comprises:

requesting to draw in a required amount of sample and discharge the sample into a container accompanying a necessary agitation;

requesting to attract the magnetic particles bounded to a target substance suspended in a liquid to the inner sidewall surface by applying the magnetic field;

requesting to agitate by drawing the liquid into and discharging the liquid from the pipette; and

requesting to draw and discharge the liquid in the container.

28. The method of claim 15, wherein the specification content analyzing means determines a processing pattern comprising:

maintaining a liquid suction speed and discharge speed during reaction, agitation and cleaning faster than a liquid suction speed and discharge speed during the magnetic particle separation process.

29. The method of claim 15, wherein the specification content analyzing means determines a processing pattern comprising:

transferring a plurality of arrested magnetic particles to another position where a target substance bonded to the magnetic particles is subjected to processing,

wherein the arrested magnetic particles are adhering to the inner sidewall surface.

30. The method of claim 15, wherein the specification information is selected from the group consisting of:

material conditions, reaction conditions, and operation conditions.

31. The method of claim 30, wherein the material conditions are selected from the group consisting of materials kinds, quantities, accommodated positions and characteristics of a target substance, a sample, and magnetic particles;

wherein the reaction conditions are selected from the group consisting of number of the reaction, incubation time, and temperature; and

wherein the operation conditions include a specification of whether magnetic particles are attached to the inner sidewall by a magnetic field.

32. The method of controlling magnetic particles by a sample distributor according to claim 15, wherein determining a processing pattern which the sample distributor follows based on the specification information comprises:

setting a processing pattern for one or more items that can be respectively processed successively using the same container cartridge, according to a data set for each item;

wherein the data set includes a number of samples, a number of reactions, number of divided samples, a total process time, a time taken by each process contained in each item, and a container cartridge pattern.

33. A control apparatus for controlling magnetic particles by a sample distributor, comprising:

a pipette having a front end portion, a reservoir portion, a liquid passage connecting the front end portion and the reservoir portion, and a separation region in the liquid passage subjected to an action of a magnetic field;

a sample distribution unit for applying a negative or positive pressure to the interior of the pipette to draw or discharge a magnetic substance-suspended liquid into or from the pipette;

a magnetic field source;

a magnetic field source driving device for driving the magnetic field source to apply or remove a magnetic field to or from the separation region from outside the liquid passage;

a control device for controlling the sample distribution unit and the magnetic field source driving device;

a specification information input means for inputting specification information including at least one operation condition for specifying;

whether the magnetic particles are attracted to an inner sidewall of the liquid passage by the magnetic field; and

a selection from among;

a specification of whether a suction and discharge operation is performed by the sample distributor, a position of the suction and discharge operation, a time of the suction and discharge operation, an order of the suction and discharge operation, a number of times of the suction and discharge operation, a quantity of the suction and discharge operation, and a speed of the suction and discharge operation;

a specification content analyzing means for determining, based on the specification information, a processing pattern that the sample distributor must follow; and

a processing pattern execution instructing means for giving instructions for executing the processing to the sample distributor according to the determined processing pattern.

34. The control apparatus of claim 33, further comprising a container feeding device for transferring one or more containers to one or more desired positions,

wherein the control device controls the container feeding device,

wherein the specification content analyzing means determines the processing pattern that the container feeding device must follow, and

wherein the processing pattern execution instructing means gives instructions for executing the processing to the container feeding device according to the determined processing pattern.

35. The control apparatus of claim 33, further comprising an analyzing means for analyzing results generated by the execution of the processing pattern execution instructing means.

36. The control apparatus of claim 33, wherein the pipette further comprises a pipette tip having an opening in the reservoir portion,

wherein the opening is removably fitted over a nozzle of the sample distribution unit, and

wherein the control device further controls attaching and detaching of the pipette tip to and from the nozzle.

37. The control apparatus of claim 33, wherein the pipette further comprises a path of motion,

wherein reagents and cleaning liquids required for quantitative and qualitative assay-and extraction of a magnetic particle-suspended liquid and a target substance are supplied in predetermined amounts along the path;

and

wherein the pipette is moved along the path to draw and discharge liquids into and from the pipette.

38. The control apparatus of claim 33, further comprising a container with liquid accomodating portions,

wherein the portions comprise predetermined amounts of reagents and cleaning liquids required for quantitative and qualitative assay and extraction of a magnetic particle-suspended liquid and a target substance, and

wherein the control device moves the container or the liquid accommodating portions to a raised position of the pipette.

39. The control apparatus of claim 33, wherein the container with liquid accomodating portions comprises a plurality of openings, and wherein the openings are covered with a thin film.

40. The control apparatus of claim 33 further comprising pipette tips,

wherein the control device controls the pipette tips, and

wherein the pipette tips are removably fitted to a plurality of nozzles of the sample distribution unit so that the pipette tips can simultaneously perform separation, agitation and cleaning.

41. The control apparatus of claim 40, further comprising a storage unit for storing the pipette tips.

42. The control apparatus of claim 33, wherein the control device operates in a bottom landing mode, comprising:

the front end portion of the pipette contacts the bottom of a container and is recognized by the control device,

the pipette is moved up to a height where the front end portion does not contact the container and,

with the front end portion set close to the bottom of the container, the pipette performs a suction and discharge operation.

43. The control apparatus of claim 33, wherein the sample distribution unit has a plurality of nozzles to which a plurality of pipette tips can be removably fitted, and wherein a liquid level sensor for detecting the level of a liquid is incorporated into one of the nozzles.

44. The control apparatus of claim 33, further comprising a container-installed side and wherein a constant temperature device is arranged on the container-installed side.

45. The control apparatus of claim 33, further comprising a reagent bottle side and wherein a constant temperature device is arranged on the reagent bottle side.

46. The control apparatus of claim 33, further comprising a measuring unit comprising a shielding structure and a measuring device for measuring radiation.

47. The control apparatus of claim 46, wherein the measuring unit further comprises a distribution nozzle for supplying a plurality of reagents.

48. The control apparatus of claim 33, wherein the control device performs according to preset information regarding the amount and kind of reagents to use.

49. The control apparatus of claim 33, wherein the specification content analyzing means analyzes each sample to identify data contained in each sample and determines the processing pattern for a sample according to the data contained in each sample.

50. The control apparatus of claim 33, wherein the specification content analyzing means determines the processing pattern comprising:

a specified content analyzing unit for analyzing contents input by an information input means; and

a processing pattern decision unit for determining a processing pattern that the distributor should follow.

51. The control apparatus of claim 50, wherein the specification content analyzing unit comprises:

a sample number/sample division number decision section that checks a number of samples or a number of divided samples from the information input means;

a processing content and reaction number decision section that checks a sample for material conditions, reaction conditions and operation conditions; and

a pre-processing/mid-processing decision section that checks the processing pattern for a request calling for pre-processing or mid-processing.

53. The control apparatus of claim 33, wherein two or more samples are used,

wherein the specification content analyzing means determines the processing pattern comprising:

setting a minimum incubation time t_min to be larger than a total working time T; and

setting an incubation time t to be an integer n times the minimum incubation time t_min.

54. The control apparatus of claim 53, wherein two or more samples are used;

wherein the specification content analyzing processing pattern determines a processing pattern comprising mid-processing, and

wherein mid-processing comprises;

setting the times required by the mid-processing shorter than the working time which is entered, measured or registered, and into which the total working time T is partitioned by one or more incubations.

55. The control apparatus of claim 33, wherein the specification content analyzing means determines a processing pattern comprising:

setting a suction and discharge speed at which the liquid is drawn into and discharged from the pipette to be slow enough to produce a sufficient effect of separation, when the separation region of the pipette is subjected to a magnetic influence for separation of magnetic particles.

56. The control apparatus of claim 33, wherein the specification content analyzing means determines a processing pattern so that magnetic particles are arrested in a process where a mixture of a predetermined amount of a sample and a predetermined amount of a magnetic particle-suspended liquid is drawn in and discharged in a whole quantity.

57. The control apparatus of claim 56, wherein the specification content analyzing means determines a processing pattern to control a suction drive when the whole quantity of the liquid is drawn in,

wherein a bottom level of the liquid drawn in is raised at a position equal to or higher than a lower end area of the separation region.

58. The control apparatus of claim 33, wherein the specification content analyzing means determines a processing pattern comprising maintaining the lower end portion of the pipette portion submerged in a reagent or a cleaning liquid to prevent generation of bubbles due to suction of air, wherein a liquid is drawn in and discharged at a high speed.

59. The control apparatus of claim 33, wherein the specification content analyzing means determines a processing pattern, wherein a percentage of a liquid drawn in from a container can be specified during agitation or cleaning.

60. The control apparatus of claim 33, wherein the processing pattern execution instruction means comprises sucking air.

61. The control apparatus of claim 33, wherein the processing pattern execution instruction means comprises maintaining a liquid suction speed and a discharge speed during reaction, agitation or cleaning faster than a liquid suction speed and a discharge speed during the magnetic particle separation process.

62. The control apparatus of claim 33, wherein the specification content analyzing means determines a processing pattern comprising:

transferring a plurality of arrested magnetic particles to another position where a target substance bonded to the magnetic particles is subjected to processing,

wherein the arrested magnetic particles adhere to the inner sidewall.

63. The control apparatus of claim 33, wherein the specification information is selected from the group consisting of material conditions, reaction conditions, and operation conditions.

64. The control apparatus of claim 63, wherein the material conditions are selected from the group consisting of materials kinds, quantities, accommodated positions and characteristics of a target substance, a sample, and magnetic particles;

wherein the reaction conditions are selected from the group consisting of number of the reaction, incubation time, and temperature; and

wherein the operation conditions include a specification of whether magnetic particles are attached to the inner sidewall by a magnetic field.

65. The control apparatus of claim 33, wherein the specification content analyzing means determines the processing pattern for one or more items that can be respectively processed successively using the same container cartridge, according to data set for each item;

and wherein the data set includes a number of samples, a total process time, a time taken by each process contained in each item, and a container cartridge positions.

66. A control apparatus for controlling magnetic particles by a sample distributor, comprising:

a pipette tip comprising a front end portion having a diameter that is tapered off toward the front end, a reservoir portion with a greater diameter than the front end portion, a liquid passage narrower than the reservoir portion and larger than the front end portion to connect the front end portion and the reservoir portion, and a separation region in the liquid passage subjected to an action of a magnetic field;

a sample distributor unit comprising a nozzle removably fitted into an opening of the reservoir portion of the pipette tip, to apply a negative or positive pressure into the pipette tip to draw or discharge a liquid into or from the pipette tip;

a magnetic field source arranged so that it can be brought close to or away from an outside surface of the liquid passage;

a magnetic driving device for bringing the magnetic field source close to or away from the liquid passage; and

a control device for controlling an operation and a movement of the sample distributor unit, an attaching and a detaching of the pipette tip to and from the nozzle, and a bringing of the magnetic field source close to or away from the pipette tip, according to a specification information which is entered into the control apparatus, the specification information including at least one operation condition for specifying;

whether the magnetic particles are attracted to an inner surface of the liquid passage by the magnetic field; and

a selection from among;

a specification of whether a suction and discharge operation is performed by the sample distributor, a position of the suction and discharge operation, a time of the suction and discharge operation, an order of the suction and discharge operation, a number of times of the suction and discharge operation, a quantity of the suction and discharge operation, and a speed of the suction and discharge operation.