Sensor with increased biocompatibility

• US 20070007133A1
• Filed: 03/29/2006
• Published: 01/11/2007
• Est. Priority Date: 09/30/2003
• Status: Active Grant

• Current Assignee: Roche Diabetes Care Inc. (Roche Holding AG)
• Original Assignee: Roche Diagnostics Operations Incorporated (Roche Holding AG)
• Inventors: Buck, Harvey, Jernigan, Walter, Mang, Andre, Garrison, Michael
• Granted Patent: US 8,180,423 B2
• Time in Patent Office: Days
• US Class Current: 204/403.140
• CPC Class Codes: A61B 2562/02 Details of sensors specially adapted for in-vivo measurements
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: C12Q 1/006 for glucose

Abstract

Sensors and methods for producing them are disclosed. A cavity is created and filled with a reagent that includes a conductive matrix, enzyme, catalyst, and binding agent, in a preferred embodiment. The cavity is substantially enclosed, leaving enough of an opening to allow the sample to enter. A portion of the material surrounding the cavity is preferably permeable to a substance useful for measuring reaction, but not to the reagent or the sample. Cavities that have the shape of a cone, conical frustum, pyramidal frustum, and right circular cylinder are given as examples. Other systems include a membrane that contains the sensor'"'"'s active area and defines an internal volume of fluid, where the membrane or internal volume has a particular geometric relationship to the active area.

Claims

1. An electrochemical biosensor for in vivo use, comprising:

a first layer having at least a top surface, a bottom surface, and a first end;

a second layer having a top surface substantially adjacent the bottom surface of the first layer;

a first contact, adapted for electrical connection to a meter, adjacent to the first end of the first layer;

the first layer and the second layer defining a cavity with an opening through the top surface of the first layer, the opening being spaced apart from the first end of the first layer; and

a reagent filling at least 20% of the cavity, the reagent comprising an electrically conductive matrix and an enzyme;

wherein the matrix is electrically connected to the first contact.

2. The electrochemical biosensor of claim 1, wherein the first layer is made of a non-conductive material.

3. The electrochemical biosensor of claim 1, wherein the second layer is made of a non-conductive material.

4. The electrochemical biosensor of claim 1, wherein the first layer is made of polyimide.

5. The electrochemical biosensor of claim 1, wherein the first layer has an average thickness between about 10 μ

m and about 130 μ

m.

6. The electrochemical biosensor of claim 5, wherein the first layer has an average thickness between about 20 μ

m and about 50 μ

m.

7. The electrochemical biosensor of claim 1, wherein:

the opening has an area A; and

each cross-section of the cavity taken parallel to the opening that does not intersect the reagent has an area of at least A.

8. The electrochemical biosensor of claim 1, wherein each cross-section of the cavity taken parallel to the opening has an area of at least A.

9. The electrochemical biosensor of claim 8, wherein cross-sections of the cavity taken parallel to the opening have monotonically increasing area as they are taken farther from the opening.

10. The electrochemical biosensor of claim 1, wherein the ratio of the volume of the cavity to the area of the opening is at least about the distance between the top surface and the bottom surface.

11. An electrochemical biosensor system, comprising:

an electrochemical sensor strip according to claim 1;

and

a meter adapted to apply an electrical signal to the sensor electrodes and measure an electrical response.

12. The system of claim 11, wherein:

the reagent is selected to react with an analyte in a bodily fluid; and

the meter is further adapted to generate a measurement signal corresponding to the concentration of the analyte in the bodily fluid.

13. A strip for testing the concentration or presence of an analyte, comprising:

a first layer having

a top surface and a bottom surface,

a contact end and a sensing end,

a first contact and a second contact at or near the contact end,

a first electrode location at or near the sensing end;

a second electrode location near the first electrode location, and

a cavity within and defined by the first layer at the first electrode location, the cavity having an opening through the top surface;

at least two conductors on the first layer, including

a first conductor electrically connecting the cavity and the first contact, and

a second conductor electrically connecting the second electrode location and the second contact;

a conductive matrix filling at least about 20% of the cavity'"'"'s volume, the matrix comprising a reagent; and

a reference electrode at the second electrode location.

14. The strip of claim 13, wherein the cavity is substantially surrounded, except at the opening, by one or more materials that are non-permeable by the analyte.

15. The strip of claim 14, wherein at least one of the one or more materials is oxygen-permeable.

16. The strip of claim 15, wherein one or more of the at least one oxygen-permeable material has a side disposed adjacent to the bottom surface of the first layer.

17. The strip of claim 14, wherein at least one of the one or more materials is permeable to a co-reactant to the reagent.

18. The strip of claim 13, wherein at least a portion of the cavity is defined by a material that is oxygen-permeable.

19. The strip of claim 18, wherein the material that is oxygen-permeable is adjacent to the bottom surface of the first layer.

20. The strip of claim 13, wherein the depositing fills at least about 80% of the cavity'"'"'s volume.

21. The strip of claim 13, wherein the first conductor extends into the cavity to at least partially define the cavity.

22. The strip of claim 13, wherein the first conductor is disposed along the top surface of the first layer.

23. The strip of claim 13, wherein the first conductor is disposed along the bottom surface of the first layer.

24. The strip of claim 13, wherein the conductive matrix fills at least about 80% of the cavity'"'"'s volume.

25. The strip of claim 13, wherein the conductive matrix substantially fills the cavity.

26. An electrochemical sensor, comprising:

a substrate;

a reference electrode; and

a working electrode substantially filling a cavity that is at least partially defined by the substrate, the working electrode comprising a porous conducting matrix and an enzyme;

wherein the reference electrode is electrically connectable to the working electrode through a liquid sample.

27. The electrochemical sensor of claim 26, wherein the conducting matrix comprises carbon particles.

28. The electrochemical sensor of claim 26, wherein the enzyme is glucose oxidase.

29. The electrochemical sensor of claim 26, wherein the working electrode further comprises a catalyst.

30. The electrochemical sensor of claim 29, wherein the catalyst comprises manganese dioxide.

31. The electrochemical sensor of claim 26, wherein the working electrode further comprises a binding agent.

32. The electrochemical sensor of claim 31, wherein the binding agent is a polymer.

33. The electrochemical sensor of claim 31, wherein the working electrode further comprises a catalyst.

34. The electrochemical sensor of claim 33, wherein the catalyst is manganese dioxide.

35. The electrochemical sensor of claim 33, wherein the binding agent is a polymer.

36. The electrochemical sensor of claim 26, wherein the cavity has a substantially cylindrical shape.

37. The electrochemical sensor of claim 26, wherein the cavity has substantially the shape of a pyramidal frustum.

38. The electrochemical sensor of claim 26, wherein the cavity has substantially the shape of a conical frustum.

39. The electrochemical sensor of claim 26, wherein:

the cavity has

a smaller surface and

a larger surface that has a surface area at least as large as that of the smaller surface; and

the smaller surface is open sufficiently to allow analyte to pass into the cavity.

40. The electrochemical sensor of claim 39, wherein the larger surface is adjacent an oxygen-permeable material.

41. The electrochemical sensor of claim 39, wherein the smaller surface is circular.

42. The electrochemical sensor of claim 39, wherein the larger surface is circular.

43. The electrochemical sensor of claim 42, wherein the smaller surface is circular.

44. The electrochemical sensor of claim 26, wherein a first surface of the working electrode is open such that a sample can enter into the electrode without the sample passing through a diffusion-limiting layer.

45. A biosensor system for in vivo use, comprising:

a biosensor having an active area responsive to an analyte in a biological fluid; and

an interfacial membrane positioned over the active area, so that the analyte passes through at least a portion of the membrane to reach the biosensor for measurement;

wherein the membrane is spaced apart from the active area, and

the portion of the membrane has a surface area at least twice that of the active area.

46. The biosensor system of claim 45, wherein the portion of the membrane has a surface area at least four times that of the active area.

47. The biosensor system of claim 45, wherein the portion of the membrane has a surface area at least ten times that of the active area.

48. The biosensor system of claim 45, wherein the portion of the membrane has a surface area at least 100 times that of the active area.

49. The biosensor system of claim 45, wherein the membrane does not contact the active area.

50. A biosensor system for in vivo use, comprising:

a biosensor having an active area responsive to an analyte in a biological fluid; and

an interfacial membrane positioned over the active area, so that the analyte passes from an external volume of fluid, through at least a portion of the membrane, into an internal volume defined by the biosensor and the membrane;

wherein the size of the internal volume is at least about s^3/2/10, where s is the area of the sensor'"'"'s active area; and

the internal volume is in contact with the active area of the biosensor.

51. The biosensor system of claim 50 that is in place, wherein the diffusion coefficient of the analyte in the fluid within the membrane is at least about as high as the diffusion coefficient of the analyte in the membrane.

52. The biosensor system of claim 50, wherein the size of the internal volume is at least about s^3/2.

53. The biosensor system of claim 50, wherein the size of the internal volume is at least about 10 s^3/2.

54. A biosensor system for in vivo use, comprising:

a biosensor having an active area responsive to an analyte in a biological fluid; and

an interfacial membrane positioned over the active area, so that the analyte passes from an external volume of fluid, through at least a portion of the membrane, into an internal volume defined at least in part by the biosensor and the membrane;

wherein the interfacial membrane is between about 10 μ

m and about 100 μ

m away from the active area at its nearest point.

55. A subcutaneous sensor for in vivo testing of the concentration or presence of an analyte, comprising a sensor head that can be implanted into the subcutaneous space, the sensor head having:

a sensor active surface that is sensitive for the analyte, and

a membrane that encapsulates at least a part of the active surface, wherein the membrane is spaced from the active surface to provide an internal volume between the active surface and the membrane when the sensor is implanted into the subcutaneous tissue.

56. The subcutaneous sensor of claim 55, comprising a chemical reagent.

57. The subcutaneous sensor of claim 55, wherein the membrane is connected to the sensor head by a biocompatible glue.

58. The subcutaneous sensor of claim 55, wherein the membrane is heat-sealed to the sensor head.

59. The subcutaneous sensor of claim 55, wherein the sensor uses an electrochemical system for measurement.

60. The subcutaneous sensor of claim 55, wherein the sensor is coated with a biocompatible polymer that is permeable to the analyte.

61. The subcutaneous sensor of claim 60, wherein the sensor head is coated with MPC.

62. The subcutaneous sensor of claim 55, wherein the membrane is a semipermeable dialysis hollow fiber.

63. The subcutaneous sensor of claim 55, wherein the membrane is made of a material selected from the group consisting of polyamide and polysulphone.

64. The subcutaneous sensor of claim 55, wherein:

the sensor is a glucose sensor; and

the membrane is made of a material having a cutoff between about 10 kD and about 100 kD.

65. The subcutaneous sensor of claim 55, wherein the internal volume is filled with ringer solution.