Electronic detection of biological molecules using thin layers

• US 20040248282A1
• Filed: 07/16/2004
• Published: 12/09/2004
• Est. Priority Date: 06/11/2001
• Status: Abandoned Application

• Current Assignee: Genorx Co.
• Original Assignee: Genorx Co.
• Inventors: Sandeep, Kunwar, Sobha M., Pisharody, Mathai, George T.
• Application Number:
  US10/480,409
• Publication Number:
  US 20040248282A1
• Time in Patent Office: Days
• US Class Current: 435/287.2
• CPC Class Codes: B82Y 10/00 Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: C12Q 1/003 Functionalisation
• CPC Class Codes: C12Q 1/68 involving nucleic acids
• CPC Class Codes: C12Q 1/6825 Nucleic acid detection involving sensors
• CPC Class Codes: C12Q 2563/116 electrical properties of nucleic acids, e.g. impedance, conductivity or resistance
• CPC Class Codes: C12Q 2565/607 being a sensor, e.g. electrode
• CPC Class Codes: F41H 11/12 Means for clearing land minefields; Systems specially adapted for detection of landmines
• CPC Class Codes: G01N 27/3278 involving nanosized elements, e.g. nanogaps or nanoparticles nanopores G01N33/48721; magnetic beads G01N27/745
• CPC Class Codes: G01N 33/5438 Electrodes
• CPC Class Codes: G11C 13/0014 comprising cells based on organic memory material
• CPC Class Codes: G11C 13/0019 comprising bio-molecules

Abstract

This invention provides novel sensors that facilitate the detection of essentially any analyte. In general, the biosensors of this invention utilize a binding agent (e.g. biomolecule) to specifically bind to one or more target analytes. In preferred embodiments, the biomolecules spans a gap between two electrodes. Binding of the target analyte changes conductivity of the sensor thereby facilitating ready detection of the binding event and thus detection and/or quantitation of the bound analyte.

Claims

39. A method of making a molecular sensing apparatus comprising one or more electrode pairs, said method comprising:

(a) contacting a first electrode and a second electrode in a first electrode pair in said one or more electrode pairs with a first solution comprising a biological macromolecule;

(b) placing a charge on said first electrode in said first electrode pair to attract said biological macromolecule to said first electrode in said first electrode pair so that said biological macromolecule attaches to said first electrode to form a bound biological macromolecule; and

(c) placing a charge on said second electrode in said first electrode pair to attract a portion of said bound biological macromolecule to said second electrode in said first electrode pair so that said bound biological macromolecule attaches to said second electrode,

wherein said first electrode and said second electrode in said first electrode pair are separated by a spacer and are separated by a distance that would allow said biological macromolecule or biological macromolecule/analyte complex to connect said first electrode to said second electrode.

1. A molecular sensing apparatus comprising:

a substrate;

an insulator overlying said substrate; and

one or more electrode pairs, wherein a first electrode pair in said one or more electrode pairs comprises;

a spacer overlaying a first portion of said insulator;

a first electrode overlaying said spacer; and

a second electrode overlaying a second portion of said insulator, and wherein said second electrode is adjacent to said spacer,

wherein said first electrode and said second electrode are separated by a distance that would allow a biological macromolecule or biological macromolecule/analyte complex to connect said first electrode to said second electrode.

2. The molecular sensing apparatus of claim 1, wherein said biological macromolecule or macromolecule/analyte complex connects said first electrode and said second electrode in said first electrode pair.

3. The molecular sensing apparatus of claim 2, wherein said biological macromolecule is selected from the group consisting of a nucleic acid, a protein, a polysaccharide, a lectin, a lipid, a sugar, and a carbohydrate.

4. The molecular sensing apparatus of claim 2, wherein said biological macromolecule is a nucleic acid.

5. The molecular sensing apparatus of claim 2, wherein said biological macromolecule is functionalized with a chemical group selected from the group consisting of a sulfate, a sulfhydryl, an amine, an aldehyde, a carboxylic acid, a phosphate, a phosphonate, an alkene, an alkyne, a hydroxyl, a bromine, an iodine, a chlorine, a light-activatable group, and a group activatable by an electric potential.

6. The molecular sensing apparatus of claim 1, wherein said spacer comprises an insulator having a resistivity greater than 10⁻

3 ohm-meters.

7. The molecular sensing apparatus of claim 1, wherein said spacer comprises an insulator selected from the group consisting of SiO₂, TiO₂, ZrO₂, quartz, porcelain, ceramic, polystyrene, TEFLON, and an insulating oxide or sulfide of a transition metal in the periodic table of the elements.

8. The molecular sensing apparatus of claim 1, wherein said first electrode and said second electrode are separated by a distance in the range of 1 Angstrom to 10⁹ Angstroms.

9. The molecular sensing apparatus of claim 1, wherein said first electrode and said second electrode are separated by a distance less than 500 Angstroms.

10. The molecular sensing apparatus of claim 1, wherein at least one of said first electrode and said second electrode has a resistivity of less than 10⁻

2 ohm-meters.

11. The molecular sensing apparatus of claim 1, wherein at least one of said first electrode and said second electrode has a resistivity of less than 10⁻

3 ohm-meters.

12. The molecular sensing apparatus of claim 1, wherein said first electrode and said second electrode comprise a material selected from the group consisting of ruthenium, osmium, cobalt, rhodium, rubidium, lithium, sodium, potassium, vanadium, cesium, beryllium, magnesium, calcium, chromium, molybdenum, silicon, germanium, aluminum, iridium, nickel, palladium, platinum, iron, copper, titanium, tungsten, silver, gold, zinc, cadmium, indium tin oxide, carbon, and carbon nanotube.

13. The molecular sensing apparatus of claim 1, wherein said first electrode is functionalized with a chemical group that can be derivatized or crosslinked.

14. The molecular sensing apparatus of claim 13, wherein said chemical group is a sulfate, a sulfhydryl, an amine, an aldehyde, a carboxylic acid, a phosphate, a phosphonate, an alkene, an alkyne, a hydroxyl group, a bromine, an iodine, a chlorine, a light-activatable group, or a group activatable by an electric potential.

15. The molecular sensing apparatus of claim 1, wherein at least one of said first electrode and said second electrode is coated with a self-assembled monolayer (SAM).

16. The molecular sensing apparatus of claim 15, wherein said SAM comprises a compound selected from the group consisting of an alkanethiol, a phospholipid, a bola amphiphile, and an oligo(phenylenevinylene).

17. The molecular sensing apparatus of claim 2, wherein the biological macromolecule or macromolecular/analyte complex is attached to the first electrode by a thiol group.

18. The molecular sensing apparatus of claim 2, wherein the biological macromolecule or macromolecular/analyte complex is attached to the first electrode by a phosphorothioate or a phosphonate.

19. The molecular sensing apparatus of claim 2, wherein the biological macromolecule or macromolecular/analyte complex is attached to said first electrode by a linker.

20. The molecular sensing apparatus of claim 19, wherein said linker is selected from the group consisting of DFDNB, DST, ABH, ANB-NOS, EDC, NHS-ASA, and SIA.

21. The molecular sensing apparatus of claim 1, wherein said first electrode comprises a surface with a shape selected from the group consisting of convex, concave, textured, corrugated, patterned uniformly, and randomly patterned.

22. The molecular sensing apparatus of claim 1, wherein the first electrode in said first electrode pair has a first surface and the second electrode in said first electrode pair has a second surface, wherein the first surface is not coplanar to the second surface.

23. The molecular sensing apparatus of claim 1, wherein said one or more electrode pairs are at least 10 electrode pairs.

24. The molecular sensing apparatus of claim 1, wherein said one or more electrode pairs are at least 10,000 electrode pairs.

25. The molecular sensing apparatus of claim 1, wherein said one or more electrode pairs are 10² to 10¹⁰ electrode pairs.

26. The molecular sensing apparatus of claim 1, wherein said one or more electrode pairs are at least 10² electrode pairs per square centimeter of said insulating layer.

27. The molecular sensing apparatus of claim 1, wherein said one or more electrode pairs are at least 1,000,000 electrode pairs per square centimeter of said insulating layer.

28. The molecular sensing apparatus of claim 1, the apparatus further comprising a measurement device electrically coupled to the first electrode and to the second electrode of said first electrode pair.

29. The molecular sensing apparatus of claim 28, wherein said measurement device measures an electromagnetic property selected from the group consisting of direct electric current, alternating electric current, permitivity, resistivity, electron transfer, electron tunneling, electron hopping, electron transport, electron conductance, voltage, electrical impedance, signal loss, dissipation factor, resistance, capacitance, inductance, magnetic field, electrical potential, charge and magnetic potential.

30. The molecular sensing apparatus of claim 1 or 2, further comprising an electrical circuit electrically coupled to the first electrode and the second electrode.

31. The molecular sensing apparatus of claim 30, wherein said electrical circuit comprises an electric signal gating system.

32. The molecular sensing apparatus of claim 31, wherein said electric signal gating system comprises a CMOS gating system.

33. The molecular sensing apparatus of claim 1, wherein

a first biological molecule is attached to said first electrode in said first electrode pair, and

a second biological molecule is attached to said second electrode in said first electrode pair;

wherein said first biological molecule and said second biological molecule are the same.

34. The molecular sensing apparatus of claim 1, wherein

a first biological macromolecule or a first biological macromolecule/analyte complex is attached to said first electrode in said first electrode pair, and

a second different biological macromolecule or second different biological macromolecule/analyte complex is attached to said second electrode in said first electrode pair.

35. The molecular sensing apparatus of claim 1 or 2, further comprising a computer electrically coupled to the first electrode and the second electrode in said first electrode pair.

36. The molecular sensing apparatus of claim 1 or 2, wherein one of the first electrode and the second electrode comprises a semiconductor material.

37. The molecular sensing apparatus of claim 36, wherein said semiconductor material has a resistivity ranging from 10⁻

6 Ω

-m to 10⁷ Ω

-m.

38. The molecular sensing apparatus of claim 36, wherein the semiconductor material is selected from the group consisting of silicon, dense silicon carbide, boron carbide, Fe₃O₄, germanium, silicon germanium, silicon carbide, tungsten carbide, titanium carbide, indium phosphide, gallium nitride, gallium phosphide, aluminum phosphide, aluminum arsenide, mercury cadmium telluride, tellurium, selenium, ZnS, ZnO, ZnSe, CdS, ZnTe, GaSe, CdSe, CdTe, GaAs, InP, GaSb, EnAs, Te, PbS, InSb, PbTe, PbSe, and tungsten disulfide.

40. The method of claim 39, wherein said first electrode, said spacer, and said second electrode of an electrode pair in said one or more electrode pairs do not form a sandwich configuration.

41. The method of claim 39 or 40, wherein said biological macromolecule is selected from the group consisting of a nucleic acid, a protein, a polysaccharide, a lectin, and a lipid.

42. The method of claim 39 or 40, wherein said biological macromolecule is functionalized with a chemical group selected from the group consisting of a sulfate, a sulfhydryl, an amine, an aldehyde, a carboxylic acid, a phosphate, a phosphonate, an alkene, an alkyne, a hydroxyl, a bromine, an iodine, a chlorine, a light-activatable group, and a group activatable by an electric potential.

43. The method of claim 39 or 40, wherein said biological macromolecule is a nucleic acid.

44. The method of claim 39 or 40, wherein said spacer is an insulator having a resistivity of greater than 10⁻

3 Ω

-m.

45. The method of claim 39 or 40, wherein said spacer comprises an insulator selected from the group consisting of SiO₂, TiO₂, ZrO₂, porcelain, ceramic, quartz, high resistivity plastic, and an insulating oxide or sulfide of the transition metals in the periodic table of the elements.

46. The method of claim 39 or 40, wherein said first electrode and said second electrode in said first electrode pair are separated by a distance that is in a range from 10 Angstroms to 10⁵ Angstroms.

47. The method of claim 39 or 40, wherein said first electrode and said second electrode in said first electrode pair are separated by a distance that is less than 500 Angstroms.

48. The method of claim 39 or 40, wherein said first electrode and said second electrode in said first electrode pair have a resistivity of less than 10⁻

3 Ω

-m.

49. The method of claim 39 or 40, wherein said first electrode and said second electrode in said first electrode pair comprise a material selected from the group consisting of ruthenium, osmium, cobalt, rhodium, rubidium, lithium, sodium, potassium, vanadium, cesium, beryllium, magnesium, calcium, chromium, molybdenum, silicon, germanium, aluminum, iridium, nickel, palladium, platinum, iron, copper, titanium, tungsten, silver, gold, zinc, cadmium, indium tin oxide, carbon, and a carbon nanotube.

50. The method of claim 39 or 40, wherein said first electrode in said first electrode pair is functionalized to bear a chemical group capable of being further derivatized or crosslinked E prior to said contacting step (a).

51. The method of claim 50, wherein said chemical group capable of being further derivatized or crosslinked is selected from the group consisting of a sulfate, a sulfhydryl, an amine, an aldehyde, a carboxylic acid, a phosphate, a phosphonate, an alkene, an alkyne, a hydroxyl group, a bromine, an iodine, a chlorine, a light-activatable group, and a group activatable by an electric potential.

52. The method of claim 39 or 40, wherein said biological macromolecule is attached to said first electrode in said first electrode pair by an electrically conductive linker.

53. The method of claim 52, wherein said linker is selected from the group consisting of DFDNB, DST, ABH, ANB-NOS, EDC, NHS-ASA, and SIA.

54. The method of claim 52, wherein said linker is oligo(phenylenevinlyene).

55. The method of claim 39, wherein said one or more electrode pairs are at least ten electrode pairs.

56. The method of claim 39, wherein said one or more electrode pairs are at least 10,000 electrode pairs.

57. The method of claim 39, wherein said one or more electrode pairs are 10² to 10¹⁰ electrode pairs.

58. The method of claim 39, further comprising:

(d) contacting a first electrode and a second electrode in a second electrode pair in said one or more electrode pairs with a second solution comprising a second biological macromolecule;

(e) placing a charge on a first electrode in said second electrode pair to attract said second biological macromolecule to said first electrode in said second electrode pair so that said second biological macromolecule attaches to said first electrode in said second electron pair to form an attached second biological macromolecule; and

(f) placing a charge on said second electrode in said second electrode pair to attract a portion of said attached second biological macromolecule to said second electrode in said second electrode pair so that said second biological macromolecule attaches to said second electrode in said second electrode pair.

59. The method of claim 58, wherein said first solution and said second solution are the same.

60. The method of claim 58, wherein said first solution and said second solution are different.

61. The method of claim 58, wherein said first biological molecule and said second biological molecule are the same.

62. The method of claim 58, wherein said first biological molecule and said second biological molecule are the different.

63. The method of claim 39 or 40, wherein at least one of said first electrode and said second electrode in said first electrode pair comprises a semiconductor material.

64. The method of claim 63, wherein the semiconductor material has a resistivity of less than 10⁻

3 Ω

-m.

65. The method of claim 63, wherein the semiconductor material is selected from the group consisting of silicon, dense silicon carbide, boron carbide, Fe₃O₄, germanium, silicon germanium, silicon carbide, tungsten carbide, titanium carbide, indium phosphide, gallium nitride, gallium phosphide, aluminum phosphide, aluminum arsenide, mercury cadmium telluride, tellurium, selenium, ZnS, ZnO, ZnSe, CdS, ZnTe, GaSe, CdSe, CdTe, GaAs, InP, GaSb, InAs, Te, PbS, InSb, PbTe, PbSe, and tungsten disulfide.

66. The method of claim 39 wherein:

said spacer overlays a first portion of a substrate;

said first electrode of said first electrode pair overlays said spacer; and

said second electrode of said first electrode pair overlays a second portion of said substrate, and wherein said second electrode is adjacent to said spacer.

67. The method of claim 39 wherein there is an insulating layer overlaying a substrate and

said spacer overlays a first portion of said insulator layer;

said first electrode of said first electrode pair overlays said spacer; and

said second electrode of said first electrode pair overlays a second portion of said insulator layer, and wherein said second electrode is adjacent to said spacer.

68. The method of claim 39 wherein said first electrode pair is in a spacer, and wherein said first electrode protrudes from said substrate thereby forming a channel with walls formed, in part, by said first electrode and said second electrode.

69. The method of claim 39 wherein said first electrode pair is in a substrate and wherein a portion of said substrate is removed between said first electrode and said second electrode in said first electrode pair thereby forming a channel with walls formed by said first electrode and said second electrode, and wherein there is a biasing electrode in said channel.

116. The molecular sensing apparatus of claim 1, wherein said first electrode is functionalized with a chemical group that can be derivatized or crosslinked.

117. The molecular sensing apparatus of claim 13, wherein said chemical group is a sulfate, a sulfhydryl, an amine, an aldehyde, a carboxylic acid, a phosphate, a phosphonate, an alkene, an alkyne, a hydroxyl group, a bromine, an iodine, a chlorine, a light-activatable group, or a group activatable by an electric potential.

133. The molecular sensing apparatus of claim 12, wherein said chemical group is selected from the group consisting of a sulfate, a sulfhydryl, an amine, an aldehyde, a carboxylic acid, a phosphate, a phosphonate, an alkene, an alkyne, a hydroxyl, a bromine, an iodine, a chlorine, a light-activatable group, and a group activatable by an electric potential.

154. A method of detecting an analyte using the molecular sensing apparatus of any of claims 1, 70, 106, 124, 152, or 153, the method comprising:

(i) attaching a biological macromolecule to said first electrode;

(ii) contacting the biological macromolecule with a sample potentially comprising said analyte such that any analyte in said sample binds to said biological macromolecule and forms a macromolecule/analyte complex;

(iii) placing a charge on said second electrode to attract a portion of any first macromolecule analyte complex to said second electrode thereby forming a connection between said first electrode and said second electrode; and

(iv) detecting any said connection between said first electrode and said second electrode.

155. A method of detecting an analyte using the molecular sensing apparatus of any of claims 1, 70, 106, 124, 152, or 153, the method comprising:

(i) attaching a first biological macromolecule to said first electrode;

(ii) attaching a second biological macromolecule to said second electrode;

(iii) contacting said analyte with the first biological macromolecule and the second biological macromolecule thereby forming a macromolecule/analyte complex that connects said first electrode and said second electrode in said first electrode pair; and

(iv) detecting the connection between said first electrode and said second electrode in said first electrode pair.

156. A method of detecting an analyte using the molecular sensing apparatus of any of claims 1, 70, 106, 124, 152, or 153, the method comprising:

(i) detecting an electrical connection between said first electrode and said second electrode when a biological macromolecule forms a connection between said first electrode and said second electrode;

(ii) contacting the biological macromolecule with said analyte whereby said analyte binds to said biological macromolecule thereby forming a macromolecule/analyte complex; and

(iii) detecting a difference in the electrical connection between said first electrode and said second electrode.

157. A method of detecting an analyte using the molecular sensing apparatus of claim 2, the method comprising:

(i) contacting said biological macromolecule with a solution that potentially comprises said analyte; and

(ii) detecting a change in voltage or current that arises between said first electrode and said second electrode as a result of the formation of a macromolecule/analyte complex between said analyte and said biological macromolecule.

48-1. The method of claim 39 or 40, wherein at least one of said first electrode and said second electrode in said first electrode pair has a resistivity of less than 10⁻

3 Ω

-m.

70. A molecular sensing apparatus comprising one or more electrode pairs in a substrate, wherein a first electrode pair in said one or more electrode pairs comprises a first electrode and a second electrode, wherein a portion of the substrate is removed between said first electrode and said second electrode thereby forming a channel within said substrate with walls formed by said first electrode and said second electrode in said first electrode pair.

71. The molecular sensing apparatus of claim 70 wherein said first electrode and said second electrode in said first electrode pair are separated by a distance that would allow a biological macromolecule to connect said first electrode and said second electrode.

72. The molecular sensing apparatus of claim 70 wherein a biological macromolecule connects said first electrode and said second electrode.

73. The molecular sensing apparatus of claim 72 wherein said biological macromolecule is selected from the group consisting of a nucleic acid, a protein, a polysaccharide, a lectin, a lipid, a sugar, and a carbohydrate.

74. The molecular sensing apparatus of claim 72 wherein said biological macromolecule is a nucleic acid.

75. The molecular sensing apparatus of claim 74 wherein said nucleic acid is DNA or mRNA.

76. The molecular sensing apparatus of claim 71 wherein said distance is in the range of 1 Angstrom to 10⁹ Angstroms.

77. The molecular sensing apparatus of claim 71 wherein said distance is less than 500 Angstroms.

78. The molecular sensing apparatus of claim 70 wherein at least one of said first electrode and said second electrode has a resistivity of less than 10⁻

2 ohm-meters.

79. The molecular sensing apparatus of claim 70 wherein at least one of said first electrode and said second electrode has a resistivity of less than 10⁻

3 ohm-meters.

80. The molecular sensing apparatus of claim 79 wherein said first electrode and said second electrode comprise a material selected from the group consisting of ruthenium, osmium, cobalt, rhodium, rubidium, lithium, sodium, potassium, vanadium, cesium, beryllium, magnesium, calcium, chromium, molybdenum, silicon, germanium, aluminum, iridium, nickel, palladium, platinum, iron, copper, titanium, tungsten, silver, gold, zinc, cadmium, indium tin oxide, carbon, and carbon nanotube.

81. The molecular sensing apparatus of claim 80 wherein said first electrode is functionalized with a chemical group that can be derivatized or crosslinked.

82. The molecular sensing apparatus of claim 81 wherein said chemical group is a sulfate, a sulfhydryl, an amine, an aldehyde, a carboxylic acid, a phosphate, a phosphonate, an alkene, an alkyne, a hydroxyl, a bromine, an iodine, a chlorine, a light-activatable group, or a group activatable by an electric potential.

83. The molecular sensing apparatus of claim 70 wherein at least one of said first electrode and said second electrode is coated with a self-assembled monolayer (SAM).

84. The molecular sensing apparatus of claim 83 wherein said SAM comprises a compound selected from the group consisting of an alkanethiol, a phospholipid, a bola amphiphile, and an oligo(phenylenevinylene).

85. The molecular sensing apparatus of claim 72 wherein the biological macromolecule is attached to the first electrode or the second electrode by a thiol group.

86. The molecular sensing apparatus of claim 72 wherein the biological macromolecule is attached to the first electrode or the second electrode by a phosphorothioate or a phosphonate.

87. The molecular sensing apparatus of claim 72 wherein the biological macromolecule is attached to said first electrode or the second electrode by a linker.

88. The molecular sensing apparatus of claim 87 wherein said linker is selected from the group consisting of DFDNB, DST, ABH, ANB-NOS, EDC, NHS-ASA, and SIA.

89. The molecular sensing apparatus of claim 70 wherein the first electrode has a first surface and the second electrode has a second surface, and wherein the first surface is not coplanar to the second surface.

90. The molecular sensing apparatus of claim 70 wherein said one or more electrode pairs are at least 10 electrode pairs.

91. The molecular sensing apparatus of claim 70 wherein said one or more electrode pairs are at least 10,000 electrode pairs.

92. The molecular sensing apparatus of claim 70 wherein said one or more electrode pairs are at least 1,000,000 electrode pairs.

93. The molecular sensing apparatus of claim 70 wherein said one or more electrode pairs are at least 10² electrode pairs per square centimeter of said substrate.

94. The molecular sensing apparatus of claim 70 wherein said one or more electrode pairs are at least 1,000,000 electrode pairs per square centimeter of said substrate.

95. The molecular sensing apparatus of claim 70 the apparatus further comprising a measurement device electrically coupled to the first electrode and to the second electrode of at least one electrode pair in said one or more electrode pairs.

96. The molecular sensing apparatus of claim 95 wherein said measurement device measures an electromagnetic property selected from the group consisting of direct electric current, alternating electric current, permitivity, resistivity, electron transfer, electron tunneling, electron hopping, electron transport, electron conductance, voltage, electrical impedance, signal loss, dissipation factor, resistance, capacitance, inductance, magnetic field, electrical potential, charge and magnetic potential.

97. The molecular sensing apparatus of claim 70 further comprising an electrical circuit electrically coupled to the first electrode and the second electrode.

98. The molecular sensing apparatus of claim 97 wherein said electrical circuit comprises an electric signal gating system.

99. The molecular sensing apparatus of claim 98 wherein said electric signal gating system comprises a CMOS gating system.

100. The molecular sensing apparatus of claim 70 wherein a nucleic acid connects said first electrode and said second electrode.

101. The molecular sensing apparatus of claim 70 wherein

a first biological macromolecule is attached to said first electrode in said first electrode pair, and

a different second biological macromolecule is attached to said second electrode in said first electrode pair.

102. The molecular sensing apparatus of claim 70 further comprising a computer electrically coupled to said first electrode and said second electrode.

103. The molecular sensing apparatus of claim 70 wherein at least one of the first electrode and the second electrode comprises a semiconductor material.

104. The molecular sensing apparatus of claim 103 wherein said semiconductor material has a resistivity of less than 10⁻

3 Ω

-m.

105. The molecular sensing apparatus of claim 104 wherein the semiconductor material is selected from the group consisting of silicon, dense silicon carbide, boron carbide, Fe₃O₄, germanium, silicon germanium, silicon carbide, tungsten carbide, titanium carbide, indium phosphide, gallium nitride, gallium phosphide, aluminum phosphide, aluminum arsenide, mercury cadmium telluride, tellurium, selenium, ZnS, ZnO, ZnSe, CdS, ZnTe, GaSe, CdSe, CdTe, GaAs, InP, GaSb, EnAs, Te, PbS, InSb, PbTe, PbSe, and tungsten disulfide.

106. A molecular sensing apparatus comprising:

a substrate; and

one or more electrode pairs, wherein a first electrode pair in said one or more electrode pairs comprises;

a spacer overlaying a first portion of said substrate;

a first electrode overlaying said spacer; and

a second electrode overlaying a second portion of said substrate, and wherein said second electrode is adjacent to said spacer,

wherein said first electrode and said second electrode are separated by a distance that would allow a biological macromolecule or biological macromolecule/analyte complex to connect said first electrode to said second electrode.

107. The molecular sensing apparatus of claim 106, wherein said biological macromolecule or macromolecule/analyte complex connects said first electrode and said second electrode in said first electrode pair.

108. The molecular sensing apparatus of claim 107, wherein said biological macromolecule is selected from the group consisting of a nucleic acid, a protein, a polysaccharide, a lectin, a lipid, a sugar, and a carbohydrate.

109. The molecular sensing apparatus of claim 107, wherein said biological macromolecule is a nucleic acid.

110. The molecular sensing apparatus of claim 107, wherein said biological macromolecule is functionalized with a chemical group selected from the group consisting of a sulfate, a sulfhydryl, an amine, an aldehyde, a carboxylic acid, a phosphate, a phosphonate, an alkene, an alkyne, a hydroxyl, a bromine, an iodine, a chlorine, a light-activatable group, and a group activatable by an electric potential.

111. The molecular sensing apparatus of claim 106, wherein said first electrode and said second electrode are separated by a distance in the range of 1 Angstrom to 10⁹ Angstroms.

112. The molecular sensing apparatus of claim 106, wherein said first electrode and said second electrode are separated by a distance less than 500 Angstroms.

113. The molecular sensing apparatus of claim 106, wherein at least one of said first electrode and said second electrode has a resistivity of less than 10⁻

2 ohm-meters.

114. The molecular sensing apparatus of claim 106 wherein at least one said first electrode and said second electrode has a resistivity of less than 10⁻

3 ohm-meters.

115. The molecular sensing apparatus of claim 106, wherein said first electrode and said second electrode comprise a material selected from the group consisting of ruthenium, osmium, cobalt, rhodium, rubidium, lithium, sodium, potassium, vanadium, cesium, beryllium, magnesium, calcium, chromium, molybdenum, silicon, germanium, aluminum, iridium, nickel, palladium, platinum, iron, copper, titanium, tungsten, silver, gold, zinc, cadmium, indium tin oxide, carbon, and carbon nanotube.

118. The molecular sensing apparatus of claim 106, wherein at least one of said first electrode and said second electrode is coated with a self-assembled monolayer (SAM).

119. The molecular sensing apparatus of claim 118, wherein said SAM comprises a compound selected from the group consisting of an alkanethiol, a phospholipid, a bola amphiphile, and an oligo(phenylenevinylene).

120. The molecular sensing apparatus of claim 107, wherein the biological macromolecule or macromolecular/analyte complex is attached to the first electrode by a thiol group.

121. The molecular sensing apparatus of claim 107, wherein the biological macromolecule or macromolecular/analyte complex is attached to the first electrode by a phosphorothioate or a phosphonate.

122. The molecular sensing apparatus of claim 107, wherein the biological macromolecule or macromolecular/analyte complex is attached to said first electrode by a linker.

123. The molecular sensing apparatus of claim 122, wherein said linker is selected from the group consisting of DFDNB, DST, ABH, ANB-NOS, EDC, NHS-ASA, and SIA.

124. A molecular sensing apparatus comprising:

one or more electrode pairs, wherein at least one electrode pair in said one or more electrode pairs comprises;

a first electrode;

a second electrode; and

an insulator between said first electrode and said second electrode, wherein a channel is formed between said first electrode and said second electrode; and

wherein said first electrode and said second electrode are separated by a distance that would allow a biological macromolecule or biological macromolecule/analyte complex to connect said first electrode to said second electrode.

125. The molecular sensing apparatus of claim 124, wherein said insulator has a resistivity greater than 10⁻

3 ohm-meters.

126. The molecular sensing apparatus of claim 124, wherein said insulator is selected from the group consisting of SiO₂, TiO₂, ZrO₂, quartz, porcelain, ceramic, polystyrene, TEFLON, and an insulating oxide or sulfide of a transition metal in the periodic table of the elements.

127. The molecular sensing apparatus of claim 124, wherein said first electrode and said second electrode are separated by a distance in the range of 10 Angstroms to 10⁵ Angstroms.

128. The molecular sensing apparatus of claim 124, wherein said first electrode and said second electrode are separated by a distance less than 500 Angstroms.

129. The molecular sensing apparatus of claim 124, wherein at least one of said first electrode and said second electrode has a resistivity of less than 10⁻

2 ohm-meters.

130. The molecular sensing apparatus of claim 124, wherein at least one of said first electrode and said second electrode has a resistivity of less than 10⁻

3 ohm-meters.

131. The molecular sensing apparatus of claim 124, wherein said first electrode and said second electrode each comprises a material selected from the group consisting of ruthenium, osmium, cobalt, rhodium, rubidium, lithium, sodium, potassium, vanadium, cesium, beryllium, magnesium, calcium, chromium, molybdenum, silicon, germanium, aluminum, iridium, nickel, palladium, platinum, iron, copper, titanium, tungsten, silver, gold, zinc, cadmium, indium tin oxide, carbon, and carbon nanotube.

132. The molecular sensing apparatus of claim 124, wherein said first electrode is functionalized with a chemical group that can be derivatized or crosslinked.

134. The molecular sensing apparatus of claim 124, wherein at least one of said first electrode and said second electrode is coated with a self-assembled monolayer (SAM).

135. The molecular sensing apparatus of claim 134, wherein said SAM comprises a compound selected from the group consisting of an alkanethiol, a phospholipid, a bola amphiphile, and an oligophenylenevinylene).

136. The molecular sensing apparatus of claim 124, further comprising a substrate that supports the first electrode and the second electrode, wherein the first electrode and the second electrode are integrated with the substrate.

137. The molecular sensing apparatus of claim 124 wherein said first electrode comprises a surface with a shape selected from the group consisting of convex, concave, textured, corrugated, patterned uniformly, and randomly patterned.

138. The molecular sensing apparatus of claim 124 wherein said first electrode and said second electrode are oriented in a formation selected from the group consisting of annular, planar, and orthogonal.

139. The molecular sensing apparatus of claim 124, wherein the first electrode has a first surface and said second electrode has a second surface, wherein the first surface is not coplanar to the second surface.

140. The molecular sensing apparatus of claim 124, wherein said one or more electrode pairs are at least 10 electrode pairs.

141. The molecular sensing apparatus of claim 124, wherein said one or more electrode pairs are at least 10,000 electrode pairs.

142. The molecular sensing apparatus of claim 124, wherein said one or more electrode pairs are at least 1,000,000 electrode pairs.

143. The molecular sensing apparatus of claim 124, the molecular sensing apparatus further comprising a measurement device electrically coupled to said first electrode and to said second electrode.

144. The molecular sensing apparatus of claim 143, wherein said measurement device measures an electromagnetic property selected from the group consisting of direct electric current, alternating electric current, permitivity, resistivity, electron transfer, electron tunneling, electron hopping, electron transport, electron conductance, voltage, electrical impedance, signal loss, dissipation factor, resistance, capacitance, inductance, magnetic field, electrical potential, charge and magnetic potential.

145. The molecular sensing apparatus of claim 124, further comprising an electrical circuit electrically coupled to the first electrode and the second electrode.

146. The molecular sensing apparatus of claim 145, wherein said electrical circuit comprises an electric signal gating system.

147. The molecular sensing apparatus of claim 146, wherein said electric signal gating system comprises a CMOS gating system.

148. The molecular sensing apparatus of claim 124, further comprising a computer electrically coupled to the first electrode and the second electrode.

149. The molecular sensing apparatus of claim 124, wherein at least one of the first electrode and the second electrode comprises a semiconductor material.

150. The molecular sensing apparatus of claim 149, wherein said semiconductor material has a resistivity ranging from 10⁻

6 Ω

-m to 10⁷ Ω

-m.

151. The molecular sensing apparatus of claim 149, wherein the semiconductor material is selected from the group consisting of silicon, dense silicon carbide, boron carbide, Fe₃O₄, germanium, silicon germanium, silicon carbide, tungsten carbide, titanium carbide, indium phosphide, gallium nitride, gallium phosphide, aluminum phosphide, aluminum arsenide, mercury cadmium telluride, tellurium, selenium, ZnS, ZnO, ZnSe, CdS, ZnTe, GaSe, CdSe, CdTe, GaAs, InP, GaSb, EnAs, Te, PbS, InSb, PbTe;

PbSe, and tungsten disulfide.

152. A molecular sensing apparatus comprising:

a substrate;

one or more electrode pairs, wherein a first electrode pair in said one or more electrode pairs comprises;

a spacer on a first portion of said substrate;

a first electrode on said spacer; and

a second electrode on a second portion of said substrate, and wherein said first electrode and said second electrode are separated by a channel, formed by said spacer and said second electrode, and wherein said first electrode and said second electrode are separated by a distance that would allow a biological macromolecule or biological macromolecule/analyte complex to connect said first electrode to said second electrode.

153. A molecular sensing apparatus comprising:

a substrate;

a spacer on said substrate;

one or more electrode pairs, wherein a first electrode pair in said one or more electrode pairs comprises;

a first electrode on a first portion of said spacer;

a channel formed in a second portion of said spacer; and

a second electrode on the bottom of said channel, and

wherein said first electrode and said second electrode are separated by a distance that would allow a biological macromolecule or biological macromolecule/analyte complex to connect said first electrode to said second electrode.