Diagnostic instruments and methods for detecting analytes

• US 20040132220A1
• Filed: 02/06/2004
• Published: 07/08/2004
• Est. Priority Date: 01/08/2001
• Status: Active Grant

• Current Assignee: Leonard Fish
• Original Assignee: Leonard Fish
• Inventors: Fish, Leonard
• Granted Patent: US 7,435,384 B2
• Time in Patent Office: Days
• US Class Current: 436/525
• CPC Class Codes: B82Y 15/00 Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: G01N 33/54313 the carrier being characterised by its particulate form
• CPC Class Codes: G01N 33/5438 Electrodes
• CPC Class Codes: Y10T 436/143333 Saccharide [e.g., DNA, etc.]

Abstract

An instrument (A) detects in a sample the presence of an analyte. The sample includes electrically readable particles (126) with an agent attached thereto that binds with the analyte or is an analog of the analyte. The instrument includes a port for the sample and a pair of electrodes (25, 30), one of which has a surface portion (30a) with an agent thereat that binds with the analyte or is an analog of the analyte. The electrodes have a first position where they are separated a sufficient distance apart to enable the sample to move between the electrodes and a second position where the electrodes are in close proximity. A detection circuit, including the electrodes, has a first state when the analyte is absent and a second state when the analyte is present. A signaling device provides an indication of the state of the detection circuit.

Claims

1. An instrument for detecting in a sample the presence of a n analyte, said sample, having introduced therein prior to, during, or after the sample is fed into the instrument, electrically readable particles with an agent attached thereto that binds with the analyte, or the agent on the particles is an analog of the analyte and does not bind to the analyte,

said instrument including

a port through which the sample is fed into the instrument,

first and second electrodes, said first electrode including a surface portion having an agent thereat that binds with the analyte, or said agent on the surface portion is an analog of the analyte and does not bind to the analyte,

said electrodes having a first position where they are separated a first distance apart sufficient to enable the sample to move between said electrodes and a second position where the electrodes are in close proximity to each other, said first distance being greater than said second distance,

a detection circuit, including the electrodes, that has a first state when the analyte is absent from the sample and a second state when the analyte is present in the sample, said second position determining the state of the detection circuit,

a signaling device that provides an indication of the state of the detection circuit with the electrodes in the second position.

2. The instrument of claim 1 wherein pressure is applied against any particle or particles bound to the surface portion of said first electrode.

3. The instrument of claim 1 wherein the electrically readable particles have a diameter of from 1 nanometer to 1 millimeter to enable the instrument to detect in the sample a single molecule of analyte.

4. The instrument of claim 1 where the particles are selected from a group consisting of metals and plastics.

5. The instrument of claim 4 where the particles are essentially entirely of gold.

6. The instrument of claim 4 where the particles have an exterior surface of gold and an interior core of an insulator material.

7. The instrument of claim 4 where the particles have an exterior surface made of an insulator material and an interior core of gold.

8. The instrument of claim 4 where the particles include a ferrous metal.

9. The instrument of claim 1 including a system that removes particles that are not bound to the first electrode from between the electrodes prior to operation of the detection circuit.

10. The instrument of claim 1 where the signaling device provides a qualitative read-out identifying the presence of the analyte or a quantitative read-out corresponding to the amount of analyte in the sample.

11. The instrument of claim 1 where the signaling device provides a qualitative read-out identifying the presence of the analyte and a quantitative read-out corresponding to the amount of analyte in the sample.

12. The instrument of claim 1 where the first and second states correspond to differences in conductivity.

13. The instrument of claim 1 where the first and second states correspond to differences in inductance.

14. The instrument of claim 1 where the first and second states correspond to differences in capacitance.

15. The instrument of claim 1 where the first and second states correspond to differences in voltage.

16. The instrument of claim 1 where the first and second states correspond to a phase change.

17. An instrument for detecting in a sample the presence of an analyte having individual molecules with at least two spaced binding sites, said sample, having introduced therein prior to, during, or after the sample is fed into the instrument, electrically readable particles with an agent attached thereto that binds to one of the binding sites,

said instrument including

a port through which the sample is fed into the instrument,

first and second electrodes, said first electrode including a surface portion having an agent thereat that binds with the binding site of the analyte not bound to an electrically readable particle,

said electrodes having a first position where they are separated a first distance apart sufficient to enable the sample to move between said electrodes and a second position where the electrodes are in close proximity to each other, said first distance being greater than said second distance,

a detection circuit, including the electrodes, that has a first state when the analyte is absent from the sample and a second state when the analyte is present in the sample, said second position determining the state of the detection circuit,

a signaling device that provides an indication of the state of the detection circuit with the electrodes in the second position.

18. The instrument of claim 17 wherein pressure is applied against any particle or particles bound to the surface portion of said first electrode.

19. The instrument of claim 17 where the agent on the particle and the agent on the electrode are different.

20. An instrument for detecting in a sample the presence of a n analyte, said sample, having introduced therein prior to, during, or after the sample is fed into the instrument, electrically readable particles with an agent attached thereto that binds to said analyte,

said instrument including

a port through which the sample is fed into the instrument,

first and second electrodes, said first electrode including a surface portion having thereat an analog of the analyte,

said electrodes having a first position where they are separated a first distance apart sufficient to enable the sample to move between said electrodes and a second position where the electrodes are in close proximity to each other, said first distance being greater than said second distance,

a detection circuit, including the first and second electrodes, that has at least one electrical property of the circuit that (a) does not change because the analyte is present in the sample and attaches to the agent on the electrically readable particles and (b) that changes in the absence of the analyte due to the agent on the electrically readable particle binding to the analog of the analyte on the electrode, and

a signaling device that provides an indication when analyte is not present or present.

21. The instrument of claim 20 wherein pressure is applied against any particle or particles bound to the surface portion of said first electrode.

22. The instrument of claim 20 where the agent on the particle and the agent on the electrode are different.

25. The instrument of claim 22 where the agent on the particle and the agent on the electrode are different.

23. An instrument for detecting in a sample the presence of an analyte, said sample, having introduced therein prior to, during, or after the sample is fed into the instrument, electrically readable particles with an agent attached thereto that binds with the analyte,

said instrument including

a port through which the sample is fed into a chamber including a first electrode and a second electrode including a surface portion having thereat an agent that binds with the analyte,

a detection circuit, including the first and second electrodes,

at least one of said electrodes being connected to drive system that moves said electrode between a first position where the detection circuit has a first state and a second position where the detection circuit has a second state when the analyte is present in the sample and attaches to the agent on the electrically readable particles and the agent on the electrode, and

a signaling device that provides an indication of the presence or absence of analyte with the electrodes in the second position.

24. The instrument of claim 23 wherein pressure is applied against any particle or particles bound to the surface portion of said first electrode.

26. An instrument for detecting and identifying multiple analytes in a sample, said sample, having introduced therein prior to, during, or after the sample is fed into the instrument, electrically readable particles, said particles having different classes of binding agents thereon, each class binding with only one of the multiple analytes,

said instrument including

a port through which the sample is fed past a plurality of assay sites formed by pairs of intersecting electrodes that are components of a detection circuit,

each pair of intersecting electrodes including one electrode with a surface portion having thereat a binding agent that binds with only one specific analyte to make each assay site specific to said one analyte,

each said assay site having a first state in the absent of the analyte specific to a site in question and a second state when the analyte specific to the site in question is present and attaches to the binding agent on the electrically readable particles that attach only to the assay site in question,

said detection circuit including a signaling device that provides a n indication for each assay site when analyte is present or absent at an assay site.

27. The instrument of claim 26 when at least one of each pair of electrodes at each assay site is moveable.

28. The instrument of claim 26 including a system that removes particles that are not bound to an electrode at an assay site from between pairs of intersecting electrodes prior to operation of the detection circuit.

29. The instrument of claim 26 where the signaling device provides a qualitative read-out identifying the presence of the analyte or a quantitative read-out corresponding to the amount of analyte in the sample.

30. The instrument of claim 26 wherein pressure is applied against any particle or particles bound to the surface portion of said first electrode.

31. The instrument of claim 26 where the signaling device provides a qualitative read-out identifying the presence of the analyte and a quantitative read-out corresponding to the amount of analyte in the sample.

32. A portable, single use instrument for detecting in a sample the presence of an analyte,

said instrument including

a housing having a size that allows the instrument to be held by a user,

said housing having a passageway therein with a port through which the sample is fed into a testing chamber,

a supply of electrically readable particles with an agent attached thereto that binds with the analyte, said electrically readable particles being introduced into the sample,

a sample collection device including a needle mounted within the housing in advance of the chamber and moveable outward from the housing to make contact with and draw the sample from a host and, after drawing the sample, moveable to within the housing, to feed the sample into the testing chamber,

a pair of electrodes at the chamber, one having a surface portion with an agent thereon that binds with the analyte,

a detection circuit, including the pair of electrodes,

at least one of said electrodes being moveable between a first position where the detection circuit has a first state and a second position where the detection circuit has a second state when the analyte is present in the sample and attaches to the agent on the electrically readable particles and the agent on the electrode.

33. The instrument of claim 32 including a receptacle along the passageway in advance of the testing chamber holding the supply of electrically readable particles.

34. The instrument of claim 32 where the receptacle includes a solid member comprising a matrix material holding the particles, said matrix material dissolving in the sample as said sample flows along the passageway past said solid member to release the particles.

35. The instrument of claim 32 where the sample collection device collects a sample having a volume that does not exceed 5 milliliters.

36. The instrument of 35 where the sample collection device collects a sample having a volume that is from 1 picoliter to 5 milliliters.

37. An instrument for detecting in a sample the presence of multiple classes of analytes,

said instrument including

a grid of assay sites, an electrical property at each site being a function of the absence or present of a specific analyte for a specific class of analytes,

each site including a pair of electrodes at least one being moveable, said electrodes initially spaced apart a distance from 5 nanometers to 10 micrometers, with each pair of electrodes oriented at a right angle with respect to each other,

a detection circuit including each pair of electrodes to produced a change in the electrical property at each individual site whenever the absence or presence of a specific analyte for a specific class of analytes at each site is detected, and

a signaling device providing a signal whenever a response is detected at a specific site by the detection circuit, said signal being specific to identify the site where the response is detected.

38. The instrument of claim 37 where the electrodes formed by a photo-resist etching process.

39. The instrument of claim 37 where the electrodes formed by a plating process.

40. The instrument of claim 37 where the signal provides a qualitative read-out identifying the presence of the analyte detected at each individual site or a quantitative read-out corresponding to the amount of analyte detected at each individual site.

41. The instrument of claim 37 wherein pressure is applied against any particle or particles bound to the surface portion of an electrode, said pressure being not so great as to cause a short circuit between the electrodes.

42. The instrument of claim 37 including a system that removes particles that are not bound to an electrode at an assay site from between pairs of intersecting electrodes prior to operation of the detection circuit movement.

46. The method of claim 41 where the display of results provides a qualitative read-out identifying the presence of the analyte and a quantitative read-out corresponding to the amount of analyte in the sample.

43. An instrument for detecting in a sample the presence an analyte including

a disposable sample collection member removably connected to a receiving module adapted to be connected to a computer to which test data derived from sample collection member is transmitted,

said sample collection member comprising a housing holding a needle mounted to be extended after contact with the subject to withdraw a blood sample from the subject and then be retracted within the housing to introduce the sample into a test chamber including an electrode that is sensitive to an analyte in the sample, the presence of said analyte altering an electrical property of a detection circuit, said detection circuit providing an indication when the analyte is detected or absent.

44. A method of taking, analyzing and reporting results of a blood test after taking a sample from a subject, including the steps of

providing a portable instrument that is held by a user and includes a syringe needle that is contained within a housing so that the user is protected against accidental needle sticks and is extended after firm contact with the subject to pierce the skin and withdraw a blood sample from the subject and then retracted within the housing to introduce the sample into a test chamber including an electrode that is sensitive to an analyte in the sample, the presence of said analyte altering an electrical property of a detection circuit, said detection circuit providing an indication whether the analyte is detected or absent,

while holding the instrument, bringing the instrument into contact with the subject and extending the needle to withdraw blood from the subject, and

retracting the needle within the instrument and depositing the sample in the test chamber where the presence or absence of the analyte is detected by the detection circuit and displayed to report the results.

45. The method of claim 44 wherein said method is conducted within less than 1 hour.

47. A method of detecting in a sample the presence of an analyte, including the steps of

(a) introducing into the sample electrically readable particles with an agent attached thereto that binds with the analyte or is an analog of the analyte,

(b) providing an instrument including

a pair of electrodes, said electrodes having a first position where they are separated a first distance apart sufficient to enable the sample to move between said electrodes and a second position where the electrodes are in close proximity to each other, said first distance being greater than said second distance,

a detection circuit, including the electrodes, that has a first state when the analyte is absent from the sample and a second state when the analyte is present in the sample, said second position determining the state of the detection circuit,

a signaling device that provides an indication of the state of the detection circuit with the electrodes in the second position,

(c) contacting the sample, including the electrically readable particles, with the electrodes while said electrodes are in the first position,

(d) removing any unbound particles from between the electrodes, and

(e) moving the electrodes to the second position.

48. The method of claim 47 where the electrically readable particles have a diameter of from 1 nanometer to 1 millimeter.

49. The method of claim 47 wherein pressure is applied to the electrodes while in the second position.

50. The method of claim 47 where the particles are selected from a group consisting of metals and plastics.

51. The method of claim 50 where the particles are essentially entirely of gold.

52. The method of claim 50 where the particles have an exterior surface of gold and an interior core of an insulator material.

53. The method of claim 50 where the particles have an exterior surface made of an insulator material and an interior core of gold.

54. The method of claim 50 where the particles include a ferrous metal.

55. The method of claim 47 including a system that removes particles that are not bound to the electrode from the vicinity of the electrode prior to operation of the detection circuit.

56. A method of detecting in a sample the presence or absence of a n analyte including the steps of

(a) mixing with the sample electrically readable particles having thereon a binding agent,

(b) passing the sample, including said electrically readable particles, past a pair of moveable electrodes, one of which has a binding agent thereon, said electrodes being connected to a detection circuit with at least one electrical property that is affected or no t affected when the analyte is present and binds or fails to bind with the agent on the electrically readable particles, and

(c) monitoring said electrical property of the detection circuit as the sample passes by the electrode to detect whether said electrical property is affected or is not affected.

57. The method of claim 56 where the particles have a gold core a t least partially coated with an insulator.

58. The method of claim 56 where the sample is blood.

59. A method of detecting the presence of an analyte in a sample comprising binding an electrically readable particle to the analyte to produce a change in an electrical property of an electrical circuit and detecting the change in said electrical property using a pair of moveable electrodes wherein, in the presence of the analyte, the particles bind to at least one electrode.

60. The method of claim 59 where the electrical circuit includes an electrode made of metal.

61. The method of claim 60 where the metal is gold, silver, or platinum.

62. The method of claim 59 where the electrical circuit includes a n electrode made of a semiconductor.

63. The method of claim 62 in which the semiconductor is doped silicon.

64. The method of claim 59 where the electrical circuit includes an electrode made of a photoconductor.

65. The method of claim 64 where the photoconductor is zinc sulfide, zinc selenide, cadmium sulfide, or cadmium selenide.

66. The method of claim 59 where the electrically readable particles comprise a metal.

67. The method of claim 66 where the metal is gold, silver, or platinum.

68. The method of claim 59 where the electrically readable particles are made of graphite.

69. The of claim 59 where the electrically readable particles are made semiconductive material.

70. The method of claim 69 where the semiconductive material is doped silicon.

71. The method of claim 59 where the electrically readable particles are made of a photoconductor.

72. The method of claim 71 where the photoconductor is zinc sulfide, zinc selenide, cadmium sulfide, or cadmium selenide.

73. The method of claim 59 where the electrode is movable.

74. The method of claim 73 in which the said electrode is brought into physical contact with the electrically readable particles.

75. A method of claim 74 in which non-conductive particles are used as spacers between a pair of electrodes.

76. The method of claim 59 where the electrical circuit includes a pair of electrodes, with the particles being bound to one electrode, and a physical element preventing the direct contact between the electrodes.

77. The method of claim 76 where the physical element comprises ridges.

78. The method of claim 76 where the physical element comprises hillocks.

79. The method of claim 59 where the particles have a diameter of from 1 nanometer to 1 millimeter

80. The method of claim 59 where the area of each electrodes exceeds 0.5 square micrometer.

81. The method of claim 80 where the area of the electrodes have a range of from 10 square micrometers to 10 square millimeters.

82. An instrument for detecting in a sample the presence of a specific electrolyte, including

a port through which the sample is fed into the instrument,

first and second electrodes, said first electrode including a surface portion that collects thereat said specific electrolyte, said first electrode being at a first polarity, and said second electrode including a surface portion that collects thereat electrolytes other than said specific electrolyte, said second electrode being at a second polarity opposite said first polarity,

said electrodes having

a first position where they are separated a sufficient distance apart to enable the sample to move there between and to suppress an ion current there between and

a second position where the electrodes are sufficiently close to each other to establish an ion current,

a detection circuit, including the electrodes, that has a first state when the specific electrolyte is absent from the sample and a second state when the specific electrolyte is present in the sample, and

a signaling device that provides an indication when the detection circuit is in the second state.

83. An instrument for detecting in a sample the presence of a specific small molecule, including

a port through which the sample is fed into the instrument,

first and second electrodes, said first electrode including a surface portion that collects thereat said specific small molecule, said first electrode being at a first polarity, and said second electrode including a surface portion that collects thereat small molecules other than said specific small molecule, said second electrode being at a second polarity opposite said first polarity,

said electrodes having

a first position where they are separated a sufficient distance apart to enable the sample to move there between and to suppress an ion current there between, and

a second position where the electrodes are sufficiently close to each other to establish an ion current,

a detection circuit, including the electrodes, that has a first state when the specific small molecule is absent from the sample and a second state when the specific small molecule is present in the sample, and

a signaling device that provides an indication when the detection circuit is in the second state.

84. A method of detecting the presence of an analyte in a whole blood sample including particles having a size of 500 nanometers or more, comprising the steps of

(a) binding an electrically readable particle to the analyte to produce a change in an electrical property of an electrical circuit and detecting the change in said electrical property using a pair of electrodes spaced apart a distance of no greater than 1000 nanometers wherein, in the presence of the analyte, the particles bind to at least one electrode, and

(b) prior to step (a) filtering from the sample the particles.