Methods and materials for controlling the electrochemistry of analyte sensors

Abstract

Embodiments of the invention provide electrochemical analyte sensors having elements designed to modulate their electrochemical reactions as well as methods for making and using such sensors.

Description

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a schematic of the well known reaction between glucose and glucose oxidase. As shown in a stepwise manner, this reaction involves glucose oxidase (GOx), glucose and oxygen in water. In the reductive half of the reaction, two protons and electrons are transferred from β-D-glucose to the enzyme yielding d-gluconolactone. In the oxidative half of the reaction, the enzyme is oxidized by molecular oxygen yielding hydrogen peroxide. The d-gluconolactone then reacts with water to hydrolyze the lactone ring and produce gluconic acid. In certain electrochemical sensors of the invention, the hydrogen peroxide produced by this reaction is oxidized at the working electrode (H₂O₂→ 2H+ + O₂ + 2e⁻).

FIG. 2 provides a diagrammatic view of a typical analyte sensor configuration of the current invention.

Claims

1. A method of performing an electrochemical reaction within an analyte sensor, the method comprising: using an analyte sensor constructed to perform an electrochemical reaction when exposed to an analyte, wherein:the analyte sensor includes at least one electrode disposed upon a base substrate; andthe base substrate includes a geometric feature selected to increase the surface area of an electrochemically reactive surface on the electrode disposed thereon such that surface area to volume ratio of the electrochemically reactive surface area of the electrode disposed on the geometric feature is greater than surface area-to-volume ratio of the reactive surface of the electrode when disposed on a flat surface; andexposing the analyte sensor to an analyte so that a electrochemical reaction is performed within the analyte sensor.

2. The method of claim 1, wherein the geometric feature is a lip, a shoulder, a ridge, a notch, a depression or a channel.

3. The method of claim 1, wherein the analyte sensor comprises a plurality of discrete geometric features having a plurality of electrochemically reactive electrode surfaces.

4. The method of claim 3, wherein the analyte sensor comprises at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 discrete geometric features having a plurality of electrochemically reactive electrode surfaces.

5. The method of claim 1, wherein the electronic signal in response to exposure to the analyte that is generated at the electrochemically reactive surface area of the electrode disposed on the geometric feature is greater than an electronic signal generated an electrochemically reactive surface area of the electrode when the electrode is disposed on a flat surface.

6. The method of claim 1, wherein the analyte sensor is designed to be implantable within a mammal.

7. The method of claim 1, wherein the in vivo lifetime of the analyte sensor having the electrochemically reactive surface area of the electrode disposed on the geometric feature is greater than the in vivo lifetime of an analyte sensor where an electronic signal is generated on an electrochemically reactive surface area of an electrode when the electrode is disposed on a flat surface.

8. The method of claim 1, wherein the geometric feature causes the electrochemically reactive surface area of the electrode to form a nodule.

9. The method of claim 1, wherein the implantable analyte sensor comprises an analyte sensing layer disposed on the electrode, wherein the analyte sensing layer detectably alters the electrical current at the electrode in the presence of an analyte;an optional protein layer disposed on the analyte sensing layer;an adhesion promoting layer disposed on the analyte sensing layer or the optional protein layer, wherein the adhesion promoting layer promotes the adhesion between the analyte sensing layer and an analyte modulating layer disposed on the analyte sensing layer; andan analyte modulating layer disposed on the analyte sensing layer, wherein the analyte modulating layer modulates the diffusion of the analyte therethrough; andan optional cover layer disposed on at least a portion of the analyte modulating layer, wherein the cover layer further includes an aperture over at least a portion of the analyte modulating layer.

10. The method of claim 9, wherein the analyte sensing layer comprises a protein reactive with an analyte present in mammalian blood.

11. The method of claim 10, wherein the protein is glucose oxidase, glucose dehydrogenase, lactate oxidase, hexokinase or lactate dehydrogenase.

12. The method of claim 1, wherein in the electrochemical reaction, hydrogen peroxide is oxidized at the electrochemically reactive surface area of the electrode disposed on the geometric feature.

13. The method of claim 1, wherein the surface area to volume ratio of the electrochemically reactive surface area of the electrode disposed on the geometric feature is at least 10%, 25%, 50%, 75% or 100% greater than surface area-to-volume ratio of the reactive surface of the electrode when disposed on a flat surface.

14. An analyte sensor for detecting an analyte in a fluid, the apparatus comprising: at least one electrode disposed upon a base substrate,

15. The apparatus of claim 14, wherein the geometric feature is a lip, a shoulder, a ridge, a notch, a depression or a channel.

16. The apparatus of claim 14, wherein the analyte sensor comprises a plurality of discrete geometric features having a plurality of electrochemically reactive electrode surfaces.

17. The apparatus of claim 14, wherein the electronic signal in response to exposure to the analyte that is generated at the electrochemically reactive surface area of the electrode disposed on the geometric feature is greater than an electronic signal generated an electrochemically reactive surface area of the electrode when the electrode is disposed on a flat surface.

18. The apparatus of claim 14, wherein the analyte sensor is designed to be implantable within a mammal.

19. The apparatus of claim 18, wherein the in vivo lifetime of the analyte sensor having the electrochemically reactive surface area of the electrode disposed on the geometric feature is greater than the in vivo lifetime of an analyte sensor having an electronic signal generated an electrochemically reactive surface area of an electrode when the electrode is disposed on a flat surface.

20. The apparatus of claim 14, wherein the implantable analyte sensor comprises an analyte sensing layer disposed on the electrode, wherein the analyte sensing layer detectably alters the electrical current at the electrode in the presence of an analyte;an optional protein layer disposed on the analyte sensing layer;an adhesion promoting layer disposed on the analyte sensing layer or the optional protein layer, wherein the adhesion promoting layer promotes the adhesion between the analyte sensing layer and an analyte modulating layer disposed on the analyte sensing layer; andan analyte modulating layer disposed on the analyte sensing layer, wherein the analyte modulating layer modulates the diffusion of the analyte therethrough; andan optional cover layer disposed on at least a portion of the analyte modulating layer, wherein the cover layer further includes an aperture over at least a portion of the analyte modulating layer.

21. A method of modulating electrochemical reactions within an implantable analyte sensor, the method comprising performing electrochemical reactions within an implantable analyte sensor comprising: a working electrode having a reactive surface area, wherein during analyte sensing, the working electrode generates electrons that reduce a plurality of composition species in the electrochemical reaction including oxygen (O2); anda counter electrode having a reactive surface area, wherein the size of the reactive surface area of the counter electrode is selected so as to control the reduction of the plurality of composition species in the electrochemical reaction so that oxygen (O2) is the predominant composition species reduced by the electrons generated at the working electrode;so that electrochemical reactions within the implantable analyte sensor are modulated.

22. The method of claim 21, wherein the surface area of the counter electrode is 1.5, 2, 2.5 or 3 times the size of the working electrode.

23. The method of claim 21, wherein the implantable analyte sensor comprises an analyte sensing layer disposed on the working electrode, wherein the analyte sensing layer detectably alters the electrical current at the working electrode in the presence of an analyte;an optional protein layer disposed on the analyte sensing layer;an adhesion promoting layer disposed on the analyte sensing layer or the optional protein layer, wherein the adhesion promoting layer promotes the adhesion between the analyte sensing layer and an analyte modulating layer disposed on the analyte sensing layer; andan analyte modulating layer disposed on the analyte sensing layer, wherein the analyte modulating layer modulates the diffusion of the analyte therethrough; andan optional cover layer disposed on at least a portion of the analyte modulating layer, wherein the cover layer further includes an aperture over at least a portion of the analyte modulating layer.

24. The method of claim 21, wherein the working electrode and the counter electrode comprise a micro-porous matrix.

25. The method of claim 24, wherein the micro-porous matrix has a surface area that is at least 2, 4, 6, 8, 10, 12, 14, 16 or 18 times the surface area of a non-porous matrix of same dimensions.

26. The method of claim 22, wherein the analyte sensing layer is a protein.

27. The method of claim 26, wherein the protein is glucose oxidase, glucose dehydrogenase, lactate oxidase, hexokinase or lactate dehydrogenase.

28. The method of claim 21, wherein hydrogen peroxide is oxidized at the working electrode.

29. The method of claim 22, wherein the implantable analyte sensor further comprises an interference rejection layer disposed between the surface of the working electrode and the analyte sensing layer.

30. An implantable electrochemical analyte sensor comprising: a working electrode having a reactive surface area, wherein during analyte sensing, the working electrode generates electrons that reduce a plurality of composition species in the electrochemical reaction including oxygen (O2); anda counter electrode having a reactive surface area, wherein the size of the reactive surface area of the counter electrode is selected so as to control the reduction of the plurality of composition species in the electrochemical reaction so that oxygen (O2) is the predominant composition species reduced by the electrons generated at the working electrode;an analyte sensing layer disposed on the working electrode, wherein the analyte sensing layer detectably alters the electrical current at the working electrode in the presence of an analyte;an adhesion promoting layer disposed on the analyte sensing layer or the protein layer, wherein the adhesion promoting layer promotes the adhesion between the analyte sensing layer and an analyte modulating layer disposed on the analyte sensing layer; andan analyte modulating layer disposed on the analyte sensing layer, wherein the analyte modulating layer modulates the diffusion of the analyte therethrough; anda cover layer disposed on at least a portion of the analyte modulating layer, wherein the cover layer further includes an aperture over at least a portion of the analyte modulating layer.

31. A method of making a metallic electrode using cycles of differing electroplating conditions, the method comprising: (a) electroplating a metal composition onto a substrate under a first set of conditions selected to produce a first metal layer having a first surface area and a first adhesion strength between the substrate and the first metal layer; and(b) electroplating a metal composition onto the first metal layer under a second set of conditions selected to produce a second metal layer having a second surface area and a second adhesion strength between the first metal layer and the second metal layer, wherein:(i) the second set of conditions produces a second metal layer having a second surface area that is greater than the first surface area of the first metal layer produced by the first set of conditions; and(ii) the second set of conditions produces a second metal layer having an adhesion with the first metal layer that is greater than the adhesion between the first metal layer and the substrate produced by the first set of conditions;so that the metallic electrode is made using cycles of differing electroplating conditions.

32. The method of claim 31, further comprising: (c) electroplating a metal composition onto the second layer under a third set of conditions selected to produce a third metal layer having a third surface area.

33. The method of claim 32, wherein the third set of conditions produces third metal layer having a greater density than the density of the second metal layer.

34. The method of claim 32, wherein the third set of conditions produces a third metal layer having a third surface area that is less than the second surface area of the second metal layer produced by the second set of conditions.

35. The method of claim 31, wherein the substrate does not comprise platinum.

36. The method of claim 31, wherein the substrate comprises gold.

37. The method of claim 31, wherein the electroplated metal composition comprises platinum black.

38. The method of claim 31, wherein the substrate comprises a geometric feature selected to increase the surface area of the electroplated metal composition.

39. The method of claim 31, wherein a metal composition is electroplated on to a porous substrate.

40. The method of claim 31, wherein the substrate comprises a planar surface and an edge or lip at the boundary of the planar surface and the cycles of differing electroplating conditions further inhibit an uneven deposition of the metal layer electrodeposited onto the planar surface and the edge or lip at the boundary of the planar surface.

41. The method of claim 40, wherein the uneven deposition of the metal layer that is inhibited is a greater deposition of metal on the edge or lip at the boundary of the planar surface relative to the deposition of metal on the planar surface.

42. The method of claim 31, wherein the first metal layer electroplated under a first set of conditions exhibits a resistance to abrasion from the substrate that is greater than the resistance to abrasion exhibited by a metal layer electroplated to the substrate under the second set of conditions.

43. The method of claim 32, wherein surface area of the third layer is at least 160, 170 or 180 times the geometric area of the third layer.

44. The method of claim 32, wherein surface area of the third layer is 230-260 times the geometric area of the third layer.

45. An implantable biosensor comprising: (a) an electrode comprising a plurality of electrodeposited metal layers including: (ii) a first metal layer having a first surface area and a first adhesion strength with a substrate on which the first layer is electrodeposited; and(ii) a second metal layer deposited on the first metal layer, the second metal layer having a second surface area and a second adhesion strength with the first layer on which the second layer is electrodeposited, wherein the second surface area is greater than the first surface area and the second adhesion strength is greater than the first adhesion strength; and(b) an enzyme layer disposed on the electrode, wherein an enzyme in the enzyme layer is capable of reacting with and/or producing a molecule whose change in concentration can be measured by measuring a change in the current at the electrode.

46. The implantable biosensor of claim 45, wherein the electrode comprises a third metal layer deposited on the second metal layer, wherein the third metal layer has a greater density than the density of the second metal layer.

47. The implantable biosensor of claim 45, wherein the enzyme layer comprises glucose oxidase or lactate oxidase.

48. The implantable biosensor of claim 41, wherein the biosensor is a glucose biosensor.

49. An electrode comprising a plurality of electrodeposited metal layers comprising: (a) a first metal layer having a first surface area;(b) a second metal layer deposited on the first metal layer, the second metal layer having a second surface area that is greater than the first surface area of the first metal layer; and(c) a third metal layer deposited on the second metal layer, the third metal layer having a greater density than the density of the second metal layer.

50. The electrode of claim 48, wherein the substrate comprises a geometric feature selected to increase the surface area of the electrodeposited metal composition.