Direct mapping of DNA chips to detector arrays

• US 6,784,982 B1
• Filed: 11/04/1999
• Issued: 08/31/2004
• Est. Priority Date: 11/04/1999
• Status: Expired due to Term

• Current Assignee: University of Minnesota
• Original Assignee: Regents of The University of Minnesota (University of Minnesota)
• Inventors: Talghader, Joseph J., Sanders, Mark A., Blumenfeld, Martin
• Primary Examiner(s): Nguyen, Tu T.
• Application Number:
  US09/434,027
• Time in Patent Office: 1,762 Days
• Field of Search: 356/71-73, 356/36-50, 356/244, 356/246, 422/50, 422/68.1
• US Class Current: 356/71
• CPC Class Codes: B01J 2219/00529 DNA chips
• CPC Class Codes: B01J 2219/00702 Processes involving means for analysing and characterising the products
• CPC Class Codes: G06T 1/0007 Image acquisition

Abstract

A device for detecting the pattern of polynucleic acid hybridization to a surface, the device includes (a) a positioning device for receiving a nucleic acid chip and keeping the chip in a sampling position, the nucleic acid chip being an object with a flat sample surface and an opposed surface that is joined to the sample surface by a thickness, with the sample surface having sequences of nucleic acids immobilized thereto, with each sequence being immobilized to a particular chip address. And, (b) an electronic light detector array, the detector array comprising detector pixels, the detector pixels being sensors located at particular detector pixel addresses, wherein the sampling position places the sample surface of the chip at a well-defined position relative to the electronic light detector array so that light leaving a chip address is substantially directed onto at least one detector pixel with an address that is correlated to the chip address.

Claims

1. A device for detecting the pattern of polynucleic acid hybridization to a surface, the device comprising:

(a) a nucleic acid chip holder configured to receive a nucleic acid chip and keep the chip in a sampling position;

the nucleic acid chip being an object with a flat sample surface and an opposed surface that is joined to the sample surface by a thickness, with the sample surface having sequences of nucleic acids immobilized thereto, with each sequence being immobilized to a particular chip address;

(b) an optical filter that selectively transmits light;

(c) an electronic light detector array, the detector array comprising detector pixels, the detector pixels being sensors located at particular detector pixel addresses; and

(d) a light source that generates source light wherein the sampling position is a position that places the sample surface of the chip in a well-defined spatial relationship relative to the electronic light detector array so that the source light that touches a chip address on the sample surface is substantially directed onto at least one detector pixel with an address that is correlated to the chip address.

2. The device of claim 1 wherein the chip address to the detector pixel correlation is one-to-one, whereby the light to aching a single chip address is directed to substantially one detector pixel.

3. The device of claim 1 wherein more than one detector pixel is correlated to one chip address.

4. The device of claim 1 wherein light leaving the sample surface of the chip passes through the chip thickness before reaching the detector pixels.

5. The device of claim 4 wherein the light leaving the sample surface of the chip passes through an optical filter.

6. The device of claim 5 comprising a mapping lens that changes the direction of light rays leaving the sample surface of the chip, wherein the mapping lens is located between the sample surface and the detector pixels.

7. The device of claim 6 wherein the mapping lens is a reducing lens.

8. The device of claim 6 wherein the mapping lens is a magnifying lens.

9. The device of claim 6 wherein the mapping lens comprises a light collimator.

10. The device of claim 6 wherein the mapping lens and the optical filter are combined into one apparatus.

11. The device of claim 6 wherein the chip further comprises the mapping lens.

12. The device of claim 11 wherein the bottom surface of the chip comprises a curved surface that functions as the mapping lens.

13. The device of claim 5 wherein the chip is in direct physical contact with the filter.

14. The device of claim 13 wherein the bottom surface of the chip is in contact with the filter.

15. The device of claim 14 wherein the filter and the detector array are in direct physical contact.

16. The device of claim 5 wherein the bottom surface of the chip is in direct physical contact with the filter.

17. The device of claim 4 wherein the nucleic acids are DNA.

18. The device of claim 4 wherein the chip is made of quartz.

19. The device of claim 4 wherein the chip is made of glass.

20. The device of claim 4 wherein the chip is made of light-transmissive plastic.

21. The device of claim 20 wherein the plastic is polystyrene.

22. The device of claim 4 comprising the chip, wherein the chip comprises an optical filter.

23. The device of claim 22 wherein the chip bottom surface is coated with an optical coating.

24. The device of claim 23 wherein the chip is in direct physical contact with the electronic light detector array.

25. The device of claim 4 wherein the detector array detector pixels are in direct physical contact with the optical filter.

26. The device of claim 25 wherein all of the detector array detector pixels are in direct physical contact with the optical filter.

27. A device for detecting the pattern of polynucleic acid hybridization to a surface, the device comprising:

(a) a nucleic acid chip holder configured to receive a nucleic acid chip and keep the chip in a sampling position;

the nucleic acid chip being an object with a flat sample surface and an opposed surface that is joined to the sample surface by a thickness, with the sample surface having sequences of nucleic acids immobilized thereto, with each sequence being immobilized to a particular chip address; and

(b) an electronic light detector array, the detector array comprising detector pixels, the detector pixels being sensors located at particular detector pixel addresses;

wherein the sampling position places the sample surface of the chip at a well-defined position relative to the electronic light detector array so that source light from a light source that touches a chip address on the sample surface is substantially directed onto at least one detector pixel with an address that is correlated to the chip address.

28. The device of claim 27 wherein the chip address to the detector pixel correlation is one-to-one.

29. The device of claim 27 wherein more than one detector pixel is correlated to one chip address.

30. The device of claim 27 wherein light leaving the sample surface of the chip passes through the chip thickness before reaching the detector pixels.

31. The device of claim 27 wherein the light leaving the sample surface of the chip passes through an optical filter.

32. The device of claim 31 wherein the optical filter allows substantially only light generated at the sample surface to pass to the detector.

33. The device of claim 32 wherein the optical filter substantially blocks the source light.

34. The device of claim 27 wherein the chip and the detector array are in direct physical contact.

35. The device of claim 34 wherein all wavelengths of light that touch the sample surface of the DNA chip are allowed to pass to the detector array.

36. The device of claim 35 wherein no optical filter is used in the light path between the sample surface and the detector array.

37. The device of claim 35 wherein all wavelengths of the source light are allowed to reach the detector pixels.

38. The device of claim 34 wherein the chip comprises an optical filter.

39. The device of claim 34 wherein the chip further comprises a mapping lens.

40. The device of claim 27 wherein the position of a dark spot on the sample surface, the dark spot being a spot that substantially blocks the passage of light, is mapped directly onto the detector array.

41. The device of claim 27 wherein the light source is used to illuminate the sample surface so that light leaving the sample surface is projected onto the detector array so that a dark spot on the sample surface, the dark spot being a spot on the sample surface that blocks more light than the surrounding surface, causes less light to be received by at least one detector pixel, whereby the address of the dark spot on the sample surface is detected.

42. A device for detecting the pattern of polynucleic acid hybridization to a surface, the device comprising:

(a) a nucleic acid chip holder configured to receive a nucleic acid chip and keep the chip in a sampling position;

the nucleic acid chip being an object with a flat sample surface and an opposed surface that is joined to the sample surface by a thickness, with the sample surface having sequences of nucleic acids immobilized thereto, with each sequence being immobilized to a particular chip address; and

(b) an electronic light detector array, the detector array comprising detector pixels, the detector pixels being sensors located at particular detector pixel addresses;

wherein the sampling position places the sample surface of the chip at a well-defined position relative to the electronic light detector array so that light leaving a chip address is substantially directed onto at least one detector pixel with an address that is correlated to the chip address.

43. The device of claim 42 wherein the chip address to the detector pixel correlation is one-to-one.

44. The device of claim 42 wherein more than one detector pixel is correlated to one chip address.

45. The device of claim 42 further including at least one optical lens, the optical lens being used to map an image of the sample surface onto the electronic light detector array.

46. The device of claim 45 wherein the number of all optical lenses used to map an image of the sample surface onto the electronic light detector array is one.

47. The device of claim 45 wherein the number of all optical lenses used to map an image of the sample surface onto the electronic light detector array is two.

48. The device of claim 42 wherein light leaving the sample surface of the chip is generated by chemiluminescence.

49. The device of claim 42 wherein light leaving the sample surface of the chip is generated by fluorescence.

50. The device of claim 42 wherein light leaving the sample surface of the chip is generated by two-photon excitation.

51. The device of claim 42 wherein light leaving the sample surface of the chip is generated by multi-photon excitation.

52. The device of claim 42 wherein the light leaving the sample surface is generated by fluorescence and polynucleic acids that attach to the sample surface cause a quenching of fluorescence.

53. The device of claim 52 wherein the light leaving the sample surface is generated by fluorescence and polynucleic acids that attach to the sample surface have attached molecules that cause a quenching of fluorescence.

54. The device of claim 42 wherein light leaving the sample surface of the chip is generated by a light source that generates source light.

55. The device of claim 54 wherein the source light is light that is detectable by the human eye.

56. The device of claim 42 wherein the light leaving the sample surface is generated by a light source that generates source light and polynucleic acides that attach to the sample surface have attached molecules that cause a decrease of the intensity of the light that leaves the sample surface.

57. The device of claim 42 wherein the light leaving the sample surface of the chip passes through an optical filter.

58. The device of claim 57 wherein the optical filter allows substantially only light generated at the sample surface to pass to the detector.

59. The device of claim 58 wherein the optical filter substantially blocks the light that is not generated at the sample surface.

60. The device of claim 42 wherein the chip and the detector array are in direct physical contact.

61. The device of claim 42 wherein light leaving the sample surface of the chip passes through the chip thickness before reaching the detector pixels.

62. The device of claim 42 wherein all wavelengths of light that touch the sample surface of the DNA chip are allowed to pass to the detector array.

63. The device of claim 62 wherein no optical filter is used in the light path between the sample surface and the detector array.

64. The device of claim 62 wherein all wavelengths of the source light are allowed to reach the detector pixels.

65. The device of claim 64 wherein the length of the light path is between 15 microns and 1 centimeter.

66. A system for imaging spots of polynucleic acid on a polynucleic acid chip, the system comprising:

(a) light source means that emits source light;

(b) light detector means, the light detector means including detector pixels;

(c) holding means for holding the chip, the chip comprising a top sample surface and a bottom, the sample surface having addresses, the holding means being positioned relative to the light detector means so that light leaving a sample surface address is mapped onto at least one detector pixel;

(d) electronic data processing means that processes electronic data from the chip;

(e) data transmitting means that transmits data from the electronic light detector array

(f) the system having a sample light path, which is the light path that must be to the electronic data processing means; and

traveled by all of the light that leaves the sample surface and is detectable by the light detector means.

67. The system of claim 66 wherein the sample light path is less than 15 microns.

68. The system of claim 66 wherein every point of the sample light path has an index of refraction that is greater than 1.0.

69. The system of claim 68 wherein the sample light path is comprised of solid materials.

70. The system of claim 66 wherein the sample light path does not include an optical lens that magnifies the image of the sample surface.

71. The system of claim 66 wherein the sample light path does not include an optical lens that reduces the image of the sample surface.

72. The system of claim 66 wherein the sample light path is less than 1 centimeter.

73. The system of claim 66 wherein the sample light path is less than one millimeter.

74. The system of claim 66 wherein the sample light path is less than 200 microns.

75. The system of claim 66 wherein the sample light path is less than 75 microns.

76. The system of claim 66 wherein the sample light path is less than 35 microns.

77. A method for detecting spots of polynucleic acid on a polynucleic acid chip, the method comprising the following steps:

(a) loading a polynucleic acid chip in a holder,

(b) positioning the holder at a sampling position, the sampling position being a position relative to a light detector that establishes a sampling distance between the top sample surface of the chip and the light detector that allows light that emanates from a point approximately at the surface of the chip to travel along a short light path to the light detector, and

(c) using a detection means to detect the signal generated by the light detector.

78. The method of claim 77 wherein the short light path is less than four millimeters.

79. The method of claim 77 wherein the short light path is less than 200 microns.

80. The method of claim 77 wherein the light path is substantially linear.

81. The method of claim 78 comprising the steps of using a positioning means to bring the holder from a loading position to the sampling position.

82. The method of claim 81 wherein the positioning means comprises a sliding mechanism.

83. The method of claim 82 wherein the positioning means comprises a motor.

84. The method of claim 83 wherein a chip is loaded into the holder while the holder is in a loading position and a switch is activated to turn the motor on to slide the holder to the sampling position.

85. The method of claim 77 further comprising focusing steps, the focusing steps comprising:

(i) moving the holder to a new position,

(ii) using the light detector, the detection means, and a graphic display means to visualize the surface of the sample; and

(iii) repeating steps (i) and (ii) until a sampling distance desired by a user is achieved.

86. The method of claim 85 wherein the focusing steps are automatically performed by a programmable computer.