Methods and devices for enhanced biochemical sensing

• US 5,466,348 A
• Filed: 03/12/1993
• Issued: 11/14/1995
• Est. Priority Date: 10/21/1991
• Status: Expired due to Term

• Current Assignee: University of Hawai'i
• Original Assignee: University of Hawai'i
• Inventors: Holm-Kennedy, James W.
• Primary Examiner(s): Gorgos, Kathryn
• Assistant Examiner(s): Bell, Bruce F.
• Application Number:
  US08/030,791
• Time in Patent Office: 977 Days
• Field of Search: 204/403, 204/153.1, 204/153.12, 204/406, 204/420, 204/414
• US Class Current: 205/775
• CPC Class Codes: G01N 27/4145 specially adapted for biomolecules, e.g. gate electrode with immobilised receptors
• CPC Class Codes: G01N 33/54373 involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings

Abstract

A method and application for detecting and measuring the presence of a binding target material employs a semiconductor device having a receptor-covered surface topgate, separated by a dielectric layer from a substrate. Receptors attached to this surface exhibit a chemical selectivity function. Binding occurs in a test solution, with charge associated with the target material modulating at least one device characteristic. According to the present invention, measurement may occur under dry conditions, at a time and location different from when binding occurred, thus substantially eliminating problems associated with ionic shielding and reference electrodes, so prevalent with prior art wet measurement techniques. Preferably the device includes a backgate to which a bias may be applied to restore the device'"'"'s pre-binding characteristics. Measurement of the restorative backgate bias provides a signal indicating binding of the desired target material. The present invention eliminates the reference electrode commonly found in prior art devices and methods. Beads, conjugates and other objects may be used to enhance charge and thus promote sensitivity. Alternatively a distributed channel bipolar device may be used as a sensor. Sensors according to the present invention may be batch produced and combined in arrays with same or differing receptors to provide rapid measurements, including differential and confirmational testing. Such an array may be combined with an electrophoresis gel material to provide enhanced sensitivity, real-time analysis of drifted charged electrophoresis molecules.

Claims

1. A biosensor field effect capacitor device for sensing the presence of a target in a first solution, the device comprising:

a substrate;

an upper region producing a first electrical signal in response to said target'"'"'s presence, said upper region overlying said substrate;

an insulating layer, separating said upper region and said substrate;

a depletion field effect region in said substrate having a depletion width characteristic influenced by said first electrical signal; and

means for detecting changing surface potential at an interface between said insulating layer and said substrate, said means comprising a diode junction, spaced-apart from said upper region and in field effect communication with said depletion field effect region and means for measuring changing diode junction current in response to said target presence;

wherein said target'"'"'s presence modulates said depletion region producing a change in at least one of depletion width capacitance and surface recombination velocity.

2. The device of claim 1, further including resonant means, coupled to said device, for varying a detectable resonant frequency in response to presence of said target.

3. The device of claim 1, wherein said field effect region includes a semiconductor conducting channel.

4. The device of claim 3, wherein said substrate is selected from the group consisting of (a) a semiconductor substrate, (b) an insulating substrate, and (c) a conducting substrate.

5. The device of claim 1, wherein said target is a particle.

6. The device of claim 1, wherein said gate is a gate selected from the group consisting of (i) a buried gate, (ii) a conducting gate, (iii) a gate is disposed beneath said depletion field effect region, and (iv) a gate formed adjacent said depletion field region.

7. The device of claim 1, further including means, coupled to said diode junction, for enhancing an output signal indicating presence of a said target.

8. The device of claim 1, further including means, coupled to said diode junction, for reestablishing a pre-target-presence characteristic of said device.

9. The device of claim 8, wherein said conducting gate couples to a power supply through a blocking capacitor.

10. The device of claim 1, wherein said upper region has a characteristic selected from the group consisting of (i) said upper region is a topgate, (ii) said upper region floats electrically, and (iii) said upper region includes a chemically selective material.

11. The device of claim 1, wherein said upper region floats electrically, and wherein said first electrical signal is produced upon attachment of said target.

12. A semiconductor device for sensing the presence of a target in a solution the device comprising:

a substrate;

a topgate region producing a first electrical signal in response to said target'"'"'s presence, said topgate region overlying said substrate;

a second gate region, coupling a second electrical signal to and from said device;

a field effect region disposed in said substrate such that conductance of said device is modulated by an electrical signal from at least one of said topgate region and said second gate region;

wherein said first electrical signal modulates conductance of said device and said device provides an output signal indicating attachment; and

means, coupled to said second gate region, for enhancing said output signal indicating attachment of a said target.

13. The device of claim 12, wherein said field effect region has a characteristic of at least a chosen one of the group consisting of a junction field Field Effect Transistor channel, a Metal Oxide Silicon Field Effect Transistor, and channel, a Metal Insulator Semiconductor Field Effect Transistor channel, an Ion Selective Field Effect Transistor channel, an inversion Field Effect Transistor channel, an accumulation FET channel, a Metal Semiconductor Field Effect Transitior channel, a HETEROJUNCTION Field Effect Transistor channel, a depletion mode Metal Oxide Silicon Field Effect Transistor, a Distributed Channel Bipolar Device, a transistor, and a capacitor.

14. The device of claim 12, wherein said means includes means for monitoring a parameter of said device, and bias means for adjusting a bias at said second gate after attachment to at least partially restore said parameter to a preattachment state, wherein the magnitude of bias adjustment provides a measure of attachment.

15. The device of claim 12, wherein said second gate comprises a semiconductor junction doped to cause a small fraction of an applied second gate bias voltage to modulate said channel conductance.

16. The device of claim 12, further including a conducting gate, said conducting gate is coupled to a power supply through a blocking capacitor.

17. The device of claim 16, further including an insulator, disposed between said topgate region and said field effect region.

18. The device of claim 12, further including attachment means, coupled to said topgate region, for enhancing an output signal indicating attachment of a said target.

19. The device of claim 12, wherein said means includes means for monitoring a parameter of said device, and bias means for adjusting a bias at said topgate region after attachment to at least partially restore said parameter to a preattachment state, wherein the magnitude of bias adjustment provides a measure of attachment.

20. The device of claim 12, further including:

electrical means, on said substrate, for measuring at least one parameter of said solution.

21. The device of claim 20, further including a storage means, on said substrate, coupled to an output of said first electrical means for memorializing at least one parameter of said first environment.

22. The device of claim 20, wherein said first environment includes at least one member selected from the group consisting of a solution, and an electrophoresis separation gel.

23. The device of claim 20, wherein said device is a sensor that includes chemically selective material region.

24. The device of claim 23, wherein said chemically selective material region is produced by patterning.

25. The device of claim 20, further including a layer of material selected from the group consisting of (a) shield material disposed as to selectively shield a region proximate to said field effect region, (b) a layer of inert material disposed to selectively protect a region proximate said field effect region, and (c) a patterned layer of material disposed to selectively influence a region underlying said material in response to said target presence while immersed in said solution and after removal from said solution.

26. The device of claim 12, wherein said first environment is a solution.

27. The device of claim 12, wherein said top region floats electrically.

28. The device of claim 12, wherein said second gate is selected from the group consisting of (i) a buried gate, (ii) a conducting gate, (iii) a gate that is a PN junction, (iv) a gate that is a semiconductor-insulator interface gate, (v) a gate disposed beneath said field effect region, (vi) a gate disposed adjacent said field effect region, and (vii) a P-I-N gate.

29. The device of claim 12, further including a third gate, spaced-apart from said topgate region and in field communication with said field effect region.

30. The device of claim 29, wherein said third gate is selected from the group consisting of (i) a buried gate, (ii) a conducting gate, (iii) a gate that is a PN junction, (iv) a gate that is a semiconductor-insulator interface gate, (v) a gate disposed beneath said field effect region, (vi) a gate disposed adjacent said field effect region, and (vii) a P-I-N gate.

31. The device of claim 12, wherein said means for enhancing includes means for monitoring a parameter of said device, and bias means for adjusting a bias at said second gate to modify measurement sensitivity of said device to attachment by a said target.

32. The device of claim 12, wherein said means for enhancing includes a second semiconductor device having an input lead coupled to said semiconductor device.

33. A method for detecting the presence of a target particle in a solution by use of a field effect device that includes a surface to which a target particle bindingly attaches, the method comprising the following steps:

exposing said device to said solution said attachment leading to an alteration of at least one parameter of said device from a preattachment state;

removing said device from said solution;

measuring, in an environment, said at least one parameter to determine whether attachment of said target particle occurred;

wherein said environment is selected from the group consisting of (a) a gas, (b) a liquid, and (c) a solution.

34. The method of claim 33, wherein said solution is an aqueous solution.

35. The method of claim 33, wherein said solution is an in-vitro solution within a living animal.

36. The method of claim 33, wherein said environment differs from said solution in at least one characteristic selected from the group consisting of (a) a difference in ion concentration, (b) a difference in temperature, and (c) a difference in chemical composition.

37. The method of claim 33, further including the step of providing means for modifying charge associated with said attached target.

38. The method of claim 37, wherein said means are provided in said environment.

39. The method of claim 37, wherein said step of providing means for modifying charge includes the use of at least one mechanism selected from the group consisting of (a) beads, (b) conjugates, (c) conglomerates, and (d) sandwich-like structures.

40. The method of claim 33, wherein said device includes a surface having a chosen region receptive to said attachment, said chosen region resulting from a step selected from the group consisting of (a) embedding a shielding layer in said device during device fabrication, which layer shields said device save for a region underlying said chosen region, (b) forming a pattern mask of inert material on all of said surface save for said chosen region thereof, (c) forming a pattern mask of material on said surface save for said chosen region thereon, said material is selected to influence a region underlying said material in a set manner, and is in response to at least one of said solution and said environment.

41. The method of claim 33, wherein between said step of exposing and said step of measuring, a time interval passes, which time interval has a duration selected from the group consisting of (a) at least an hour, (b) at least a day, and (c) at least a week.

42. The method of claim 33, further including the step of enhancing sensitivity of said step of measuring.

43. The method of claim 42, wherein said step of enhancing including a step selected from the group consisting of (i) varying a bias coupled to said device to restore a pre-attachment value of said at least one parameter, and then measuring bias magnitude required to so restore, (ii) prebiasing said device to a regime associated with high device attachment sensitivity, and (iii) coupling a second device to said device such that said at least one parameter modifies a parameter of said second device, which second device parameter is then measured.

44. The method of claim 33, wherein said device is a field effect device, and wherein said at least one parameter is selected from the group consisting of (a) drain-source current, (b) threshold voltage, (c) gate-source voltage, (d) pinchoff voltage, (e) transconductance, (f) conductance, (g) gate-source capacitance, (h) gate-substrate capacitance, (i) drain-source current, (j) change in drain-source voltage for constant drain-source current, (k) transconductance threshold voltage, and (1) contact potential.

45. A method for detecting the presence of a target particle in a matrix comprising particles separated from a mixture, the method comprising the following steps:

exposing to said matrix a plurality of charge sensing devices disposed on a substrate, wherein each said device includes a surface and at least one device parameter that is altered when said surface comes in charge communication with said target particle; and

measuring said at least one parameter to determine when said surface came in charge communication with said target particle.

46. The method of claim 45, wherein said plurality of charge sensing devices are disposed as an array permitting positional detection of said target particle on said matrix.

47. The method of claim 45, wherein said matrix is selected from the group consisting of (a) an electrophoretic gel, (b) a centrifugal separation matrix, and (c) a chromatographic separation matrix.

48. The method of claim 45, wherein said charge sensing devices include at least one field effect device.

49. The method of claim 48, wherein said at least one parameter is selected from the group consisting of (a) drain-source current, (b) threshold voltage, (c) gate-source voltage, (d) pinchoff voltage, (e) transconductance, (f) conductance, (g) gate-source capacitance, (h) gate-substrate capacitance, (i) drain-source current, (j) change in drain-source voltage for constant drain-source current, (k) transconductance threshold voltage, and (l) contact potential.

50. The method of claim 45, including the further step of enhancing said step of measuring, wherein said step of enhancing includes a step selected from the group consisting of (i) varying a bias coupled to said device to restore a pre-attachment value of said at least one parameter, and then measuring bias magnitude required to so restore, (ii) pre-biasing said device to a regime associated with high device attachment sensitivity, and (iii) coupling a second device to said device such that said at least one parameter modifies a parameter of said second device, which second device parameter is then measured.