Biomolecular substrate and method and apparatus for examination and diagnosis using the same

• US 20040259083A1
• Filed: 01/09/2003
• Published: 12/23/2004
• Est. Priority Date: 05/11/2001
• Status: Active Grant

• Current Assignee: Panasonic Corporation (Panasonic Holdings Corporation)
• Original Assignee: Panasonic Corporation (Panasonic Holdings Corporation)
• Inventors: Oshima, Mitsuaki
• Granted Patent: US 7,833,701 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00378 Piezoelectric or ink jet dispensers
• CPC Class Codes: B01J 2219/00387 Applications using probes
• CPC Class Codes: B01J 2219/00495 Means for heating or cooling the reaction vessels
• CPC Class Codes: B01J 2219/00518 in the shape of tapes
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/0054 Means for coding or tagging the apparatus or the reagents
• CPC Class Codes: B01J 2219/00547 Bar codes
• CPC Class Codes: B01J 2219/00572 Chemical means
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00617 by chemical means
• CPC Class Codes: B01J 2219/00621 by physical means, e.g. trenches, raised areas
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/00637 by coating it with another layer
• CPC Class Codes: B01J 2219/00648 by the use of solid beads
• CPC Class Codes: B01J 2219/00659 Two-dimensional arrays
• CPC Class Codes: B01J 2219/00673 : Slice arrays
• CPC Class Codes: B01J 2219/00689 : using computers
• CPC Class Codes: B01J 2219/00691 : using robots
• CPC Class Codes: B01J 2219/00693 : Means for quality control
• CPC Class Codes: B01J 2219/00702 : Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/0072 : Organic compounds
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01L 2300/0841 : Drums
• CPC Class Codes: B01L 3/0241 : Drop counters; Drop formers making arrays for combinatorial libraries B01J19/0046; automation of dispensing for analysis G01N35/10
• CPC Class Codes: B01L 3/0244 : using pins
• CPC Class Codes: B01L 3/508 : rigid containers not provided for above
• CPC Class Codes: C40B 40/06 : Libraries containing nucleotides or polynucleotides, or derivatives thereof
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: C40B 70/00 : Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes
• CPC Class Codes: G01N 2035/00158 : Elements containing microarrays, i.e. "biochip"
• CPC Class Codes: G01N 2035/1037 : Using surface tension, e.g. pins or wires
• CPC Class Codes: G01N 2035/1041 : Ink-jet like dispensers
• CPC Class Codes: G01N 33/5436 : with ligand physically entrapped within the solid phase liposomes G01N33/5432; immunological test elements G01N33/54386
• CPC Class Codes: G01N 35/1074 : arranged in a two-dimensional array

Abstract

An object of the present invention is to provide a test apparatus for testing a DNA substrate on which a plurality of DNA fragments for testing are arranged, wherein absolute precision is not required. The above-described problem was solved by providing a substrate on which a plurality of biomolecule spots containing a group of biomolecules (e.g., DNA, etc.) of a specific type are formed, where the pattern or position of the DNA spot is changed depending on specific data so that information of the specific data is recorded on the substrate.

Claims

1. A method for fabricating a biomolecule substrate, comprising the steps of:

1) providing a set of biomolecules and a substrate;

2) enclosing the set of biomolecules into microcapsules on the biomolecule-type-by-biomolecule-type basis; and

3) spraying the biomolecule microcapsules onto the substrate.

2. A method according to claim 1, further comprising the step of washing the biomolecule microcapsules after the enclosing step.

3. A method according to claim 1, wherein the spraying step is performed by an ink jet method.

4. A method according to claim 3, wherein the ink jet method is performed by a Bubble Jets method.

5. A method according to claim 1, further comprising the step of setting the temperature of a solution used in the spraying step to be higher than the melting point of a shell of the biomolecule microcapsulate.

6. A method according to claim 1, wherein the microcapsules of the set of biomolecules of different types are disposed at different positions.

7. A method according to claim 1, wherein the spraying step is performed by a PIN method.

8. A method according to claim 1, wherein the biomolecule contains at least one of DNA, RNA and a peptide.

9. A method according to claim 1, wherein the biomolecule is DNA.

10. A method according to claim 1, wherein the biomolecule is cDNA or genomic DNA.

11. A method according to claim 1, further comprising the step of perform labeling specific to each microcapsule.

73. A test apparatus for information on an organism, comprising:

1) a biomolecule chip according to claim 27 or 30;

2) a sample applying section in fluid communication with the biomolecule chip;

3) a reaction control section for controlling a contact and an interaction between the biomolecule placed on the biomolecule and a biomolecule sample applied from the sample applying section; and

4) a detection section for detecting a signal caused by the interaction, wherein the signal is an indicator for at least one information parameter of the organism, and the signal is related to an address assigned to the non-equal interval or the spot arrangement.

74. A test apparatus according to claim 73, further comprising a section for receiving and sending the signal.

75. A test apparatus according to claim 73, further comprising a region for recording the signal.

76. A diagnosis apparatus for a subject, comprising:

1) a biomolecule chip according to claim 27 or 30;

2) a sample applying section in fluid communication with the biomolecule chip;

3) a reaction control section for controlling a contact and an interaction between the biomolecule placed on the biomolecule and a biomolecule sample applied from the sample applying section;

4) a detection section for detecting a signal caused by the biomolecule and a signal caused by the interaction, wherein the signal is an indicator for at least one information parameter of the organism, and the signal is related to an address assigned to the non-equal interval or the spot arrangement; and

5) determining the diagnostic indicator from the signal.

77. A diagnosis apparatus according to claim 76, further comprising a section for receiving and sending the signal.

78. A diagnosis apparatus according to claim 76, further comprising a region for recording the signal.

79. A biological test system, comprising:

A) a main sub system, comprising;

1) a biomolecule chip according to claim 27 or 30;

2) a sample applying section in fluid communication with the biomolecule chip;

3) a reaction control section for controlling a contact and an interaction between the biomolecule placed on the biomolecule and a biomolecule sample applied from the sample applying section;

4) a detection section for detecting a signal caused by the biomolecule and a signal caused by the interaction, wherein the signal is an indicator for at least one information parameter of the organism, and the signal is related to an address assigned to the non-equal interval or the spot arrangement; and

5) a sending and receiving section for sending and receiving a signal, and

B) a sub sub system, comprising;

1) a sending and receiving section for sending and receiving a signal; and

2) a test section for calculating a test value from the signal received from the main sub system,

wherein the main sub system and the sub sub system are connected together via a network.

80. A biological test system according to claim 79, wherein the signal received by the sub sub system contains a signal relating to measurement data measured by the sub sub system.

81. A diagnosis system according to claim 79, wherein the attribute data contains chip ID, personal information data, and biomolecule attribute data,

the main sub system contains the chip ID and the personal information data, but does not contain the biomolecule attribute data, and

the sub sub system contains the chip ID and the biomolecule attribute data, but does not contain the personal information data, and the sub sub system sends the test value, determined in response to a request, to the main sub system.

82. A diagnosis system according to claim 79, wherein the network is the Internet.

83. A diagnosis system according to claim 79, wherein the signal to be sent and received is encrypted.

84. A diagnosis system, comprising:

A) a main sub system, comprising;

1) a biomolecule chip according to claim 27 or 30;

2) a sample applying section in fluid communication with the biomolecule chip;

3) a reaction control section for controlling a contact and an interaction between the biomolecule placed on the biomolecule and a biomolecule sample applied from the sample applying section;

4) a detection section for detecting a signal caused by the biomolecule and a signal caused by the interaction, wherein the signal is an indicator for at least one information parameter of the organism, and the signal is related to an address assigned to the non-equal interval or the spot arrangement; and

5) a sending and receiving section for sending and receiving a signal, and

B) a sub sub system, comprising;

1) a sending and receiving section for sending and receiving a signal; and

2) a determination section for determining the diagnostic indicator from the signal received from the main sub system,

wherein the main sub system and the sub sub system are connected together via a network.

85. A diagnosis system according to claim 84, wherein the signal received by the sub sub system contains a signal relating to measurement data measured by the sub sub system.

86. A diagnosis system according to claim 84, wherein the attribute data contains chip ID, personal information data, and biomolecule attribute data,

the main sub system contains the chip ID and the personal information data, but does not contain the biomolecule attribute data, and

the sub sub system contains the chip ID and the biomolecule attribute data, and data for determining a diagnostic indicator from biomolecule attribute data, but does not contain the personal information data, and the sub sub system sends the diagnostic indicator, determined in response to a request, to the main sub system.

87. A diagnosis system according to claim 84, wherein the network is the Internet.

88. A diagnosis system according to claim 84, wherein the signal to be sent and received is encrypted.

12. A biomolecule chip, comprising:

a substrate; and

biomolecules and chip attribute data arranged on the substrate,

wherein the chip attribute data is arranged in the same region as that of the biomolecules.

13. A biomolecule chip according to claim 12, wherein the chip attribute data contains information relating to chip ID and the substrate.

14. A biomolecule chip according to claim 12, further comprising a recording region, wherein the recording region is placed on the same substrate as that of the biomolecule and the chip attribute data, and at least one of subject data and measurement data is recorded in the recording region.

15. A biomolecule chip according to claim 12, wherein the chip attribute data is recorded in such a manner as to be read out by the same means as that for detecting the biomolecule.

16. A biomolecule chip according to claim 12, wherein a specific mark is attached to the substrate.

17. A biomolecule chip according to claim 12, wherein a specific mark is arranged based on the chip attribute data.

18. A biomolecule chip according to claim 12, wherein the chip attribute data contains the biomolecule attribute data.

19. A biomolecule chip according to claim 12, wherein information relating to an address of the biomolecule is further recorded.

20. A biomolecule chip according to claim 19, wherein the address is a tracking address.

21. A biomolecule chip according to claim 12, wherein the chip attribute data is encrypted.

22. A biomolecule chip according to claim 12, wherein data relating to a label used to detect the biomolecule is recorded.

23. A biomolecule chip according to claim 22, wherein the data relating to the label contains at least one of the wavelength of excited light and the wavelength of fluorescence.

24. A biomolecule chip according to claim 12, wherein the biomolecule contains at least one of DNA, RNA and a peptide.

25. A biomolecule chip according to claim 12, wherein the biomolecule is DNA.

26. A biomolecule chip according to claim 12, wherein the biomolecule is cDNA or genomic DNA.

92. Use of a biomolecule chip according to claim 12, 27, 30, 38, or 40 for fabricating an apparatus for testing biological information.

93. Use of a biomolecule chip according to claim 12, 27, 30, 38, or 40 for fabricating an apparatus for diagnosing a subject.

27. A biomolecule chip, comprising:

1) a substrate; and

2) biomolecules arranged on the substrate,

wherein spots of the biomolecules are spaced by at least one non-equal interval, an address of the biomolecule spot can be identified from the non-equal interval.

28. A biomolecule chip according to claim 27, wherein the non-equal interval is modulated.

29. A biomolecule chip according to claim 27, wherein the non-equal interval is present in at least two directions.

31. A biomolecule chip according to claim 27 or 30, wherein a label distinguishable from the biomolecule is placed between the biomolecule spots.

32. A biomolecule chip according to claim 31, wherein the distinguishable label can be detected by detection means.

33. A biomolecule chip according to claim 31, wherein the label is arranged in a horizontal direction and a vertical direction on the substrate.

34. A biomolecule chip according to claim 27 or 30, wherein a synchronization mark is arranged.

35. A biomolecule chip according to claim 27 or 30, wherein the biomolecule contains at least one of DNA, RNA and a peptide.

36. A biomolecule chip according to claim 27 or 30, wherein the biomolecule is DNA.

37. A biomolecule chip according to claim 27 or 30, wherein the biomolecule is cDNA or genomic DNA.

47. A method for detecting information on an organism, comprising the steps of:

1) providing a biomolecule sample from the organism;

2) providing a biomolecule chip according to claim 27 or 30;

3) contacting the biomolecule sample to the biomolecule chip, and placing the biomolecule chip under conditions which causes an interaction between the biomolecule sample and a biomolecule placed on the biomolecule; and

4) detecting a signal caused by the biomolecule and a signal caused by the interaction, wherein the signal is an indicator for at least one information parameter of the organism, and the signal is related to an address assigned to the non-equal interval or the spot arrangement.

48. A method according to claim 47, wherein the biomolecule sample contains nucleic acid, and the biomolecule placed on the biomolecule chip is nucleic acid.

49. A method according to claim 47, wherein the sample contains a protein and the biomolecule placed on the biomolecule chip is an antibody, or the sample contains an antibody and the biomolecule placed on the biomolecule chip is a protein.

50. A method according to claim 47, further comprising labeling the biomolecule sample with a label molecule.

51. A method according to claim 50, wherein the label molecule can be distinguished from the biomolecule placed on the biomolecule chip.

52. A method according to claim 50, wherein the label molecule contains a fluorescent molecule, a photophorescent molecule, a chemoluminescent molecule, or a radioactive isotope.

53. A method according to claim 47, wherein the signal detecting step is performed at a site different from where the interaction occurs.

54. A method according to claim 47, wherein the signal detecting step is performed at the same site as where the interaction occurs.

55. A method according to claim 47, further comprising encrypting the signal.

56. A method according to claim 47, further comprising subjecting the signal to filtering so as to extract only signal relating to required information.

57. A method for diagnosing a subject, comprising the steps of:

1) providing a sample from the subject;

2) providing a biomolecule chip according to claim 27 or 30;

3) contacting the biomolecule sample to the biomolecule chip, and placing the biomolecule chip under conditions which cause an interaction between the biomolecule sample and a biomolecule placed on the biomolecule;

4) detecting a signal caused by the biomolecule and a signal caused by the interaction, wherein the signal is at least one diagnostic indicator for the subject, and the signal is related to an address assigned to the non-equal interval or the spot arrangement; and

5) determining the diagnostic indicator from the signal.

58. A method according to claim 57, wherein the sample is nucleic acid, and the biomolecule placed on the biomolecule chip is nucleic acid.

59. A method according to claim 57, wherein the sample contains a protein and the biomolecule placed on the biomolecule chip is an antibody, or the sample contains an antibody and the biomolecule placed on the biomolecule chip is a protein.

60. A method according to claim 57, further comprising labeling the sample with a label molecule.

61. A method according to claim 60, wherein the label molecule can be distinguished from the biomolecule placed on the biomolecule chip.

62. A method according to claim 60, wherein the label molecule is a fluorescence molecule, a photophorescent molecule, a chemoluminescent molecule, or a radioactive isotope.

63. A method according to claim 57, wherein the diagnostic indicator is an indicator for a disease or a disorder.

64. A method according to claim 57, wherein the diagnostic indicator is based on single nucleotide polymorphism (SNP).

65. A method according to claim 57, wherein the diagnostic indicator is based on a genetic disease.

66. A method according to claim 57, wherein the diagnostic indicator is based on the expression level of a protein.

67. A method according to claim 57, wherein the diagnostic indicator is based on a test result of a biochemical test.

68. A method according to claim 57, wherein the determining step is performed at a site different from where the interaction occurs.

69. A method according to claim 57, wherein the signal detecting step is performed at the same site as where the interaction occurs.

70. A method according to claim 57, further comprising encrypting the signal.

71. A method according to claim 57, further comprising subjecting the signal to filtering so as to extract only signal relating to required information.

72. A method according to claim 57, wherein in the detecting step biomolecule attribute data is hidden, and in the determining step personal information data is hidden.

30. A biomolecule chip, comprising:

1) a substrate; and

2) biomolecules arranged on the substrate,

wherein the biomolecules include a distinguishable first biomolecule and a distinguishable second biomolecule, an address of the biomolecule can be identified based on an arrangement of spots of the first biomolecules and spots of the second biomolecule.

38. A biomolecule chip, comprising:

1) a substrate; and

2) biomolecules arranged on the substrate,

wherein spots storing attribute data are arranged on a side of the substrate opposite to a side on which spots of the biomolecules are arranged.

39. A biomolecule chip according to claim 38, wherein the attribute data is address information.

40. A biomolecule chip, comprising:

1) a substrate;

2) biomolecules arranged on the substrate; and

3) a data recording region.

41. A biomolecule chip according to claim 40, wherein the data recording region is placed on the side opposite to the side on which the biomolecules are arranged.

42. A method for detecting a label of a biomolecule chip, comprising the steps of:

1) providing a biomolecule chip on which at least one labeled biomolecule is arranged;

2) switching detection elements sequentially for detecting the biomolecules on the biomolecule chip; and

3) identifying a signal detected by the detection element.

43. A method according to claim 42, further comprising:

4) adding up each detected signal.

44. A method according to claim 42, wherein the signal is separated by a wavelength separation mirror.

45. A method according to claim 42, wherein the biomolecule substrate further contains a synchronization mark, and the label is identified based on the synchronization mark.

46. A method according to claim 42, wherein the biomolecule substrate contains address information on a rear side of the biomolecule, and the label is identified based on the address information.

89. A test apparatus for biological information, comprising:

a support for a substrate;

a plurality of groups of biomolecules arranged on the substrate, each group containining the biomolecules of the same type;

shifting means for shifting the substrate;

a light source for exciting a fluorescence substance labeling a sample to be tested; and

optical means for converging light from the light source,

wherein the light source is caused to emit light intermittently in response to an intermittent emission signal so as to excite the fluorescence substance,

fluorescence from the fluorescence substance is detected by a photodetector during a period of time when the intermittent emission signal is paused,

identification information is reproduced from an arrangement of the DNAs, and

the biomolecules emitting fluorescence is identified.

90. A test apparatus according to claim 89, further comprising means for adding up detected detection signals.

91. A test apparatus according to claim 89, further comprising a wavelength separation mirror.