Devices and methods for monitoring an analyte

• US 6,454,710 B1
• Filed: 04/11/2001
• Issued: 09/24/2002
• Est. Priority Date: 04/11/2001
• Status: Expired due to Term

• Current Assignee: Cilag Gmbh International (Johnson & Johnson)
• Original Assignee: Motorola, Inc. (Motorola Solutions, Inc.)
• Inventors: Ballerstadt, Ralph, Polak, Anthony
• Primary Examiner(s): Shaver, Kevin
• Assistant Examiner(s): MALLARI, PATRICIA C
• Application Number:
  US09/832,575
• Time in Patent Office: 531 Days
• Field of Search: 600/316, 600/317, 600/322, 600/365, 204/403, 204/414, 204/415, 356/39
• US Class Current: 600/365
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: B82Y 10/00 Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

A device for monitoring an analyte is described, which includes (a) a support having an interior surface and an exterior surface; (b) a substrate connected to the interior surface of the support; (c) a spacer connected to the interior surface of the support and encompassing the substrate; and (d) a first membrane, permeable to the analyte, having an interior surface and an exterior surface, the interior surface being connected to the spacer. A chamber that encloses the substrate is defined by the interior surface of the support, the spacer, and the interior surface of the first membrane. The spacer exceeds the substrate in elevation such that a void volume exists between the interior surface of the first membrane and the substrate. A method of using the device for the transdermal monitoring of an analyte is also described.

Claims

1. A device for monitoring an analyte, comprising:

a support having an interior surface and an exterior surface;

a substrate connected to the interior surface of the support, wherein the substrate is opaque;

a spacer connected to me interior surface of the support;

a labeled analogue, which binds reversibly to the substrate; and

a first membrane having an interior surface and an exterior surface, the interior surface being connected to the spacer;

wherein

the first membrane is permeable to the analyte and impermeable to the labeled analogue, and the first membrane is substantially transparent to each of an excitation wavelength and an emission wavelength of a fluorescent label;

a dye absorbs a majority of the excitation and emission wavelengths of the fluorescent label;

the interior surface of the support, the spacer, and the interior surface of the first membrane define a chamber which encloses the substrate and the labeled analogue, the chamber further comprises a reference; and

the spacer exceeds the substrate in elevation such that a void volume exists between the interior surface of the first membrane and the substrate.

2. The device of claim 1, wherein the support comprises an adhesive whereby the substrate is immobilized.

3. The device of claim 1, wherein the labeled analogue further comprises a glucose-containing moiety.

4. The device of claim 3, wherein the substrate is intrinsically opaque, or comprises a dye selected from the group consisting of Alkali Blue 6B, Azure A, Evans Blue and Celestine Blue.

5. The device of claim 1, wherein the spacer is comprised of a biocompatible material selected from the group consisting of titanium, stainless steel, acrylate derivatives, silicones, fluorosiloxanes, PTFE, polyimide, polyamide, halogenated hydrocarbon polymers, silica, and urethanes.

6. The device of claim 1, wherein the support comprises an adhesive selected from the group consisting of methyl methacrylate, acrylate derivatives, urethanes, silicones, fluorosiloxane, epoxies, cyanoacrylates and cyanoacrylate esters, whereby the substrate is immobilized.

7. The device of claim 1, wherein the support comprises a hydrogel whereby the substrate is immobilized.

8. The device of claim 1, wherein the substrate is chemically bonded to the interior surface of the support.

9. The device of claim 1, wherein the analyte is glucose.

10. The device of claim 1, wherein the spacer encompasses the substrate.

11. The device of claim 1, wherein the substrate comprises a plurality of pores sufficiently large to permit ingress and egress of the labeled analogue.

12. The device of claim 11, wherein the substrate is comprised of a dextran bead, which bead comprises a plurality of glucose binding sites within the pores.

13. The device of claim 12, wherein the support comprises an adhesive whereby the substrate is immobilized.

14. The device of claim 12, wherein the labeled analogue comprises Concanavalin A.

15. The device of claim 14, wherein the substrate comprises a dye selected from the group consisting of Alkali Blue 6B, Azure A, Evans Blue, and Celestine blue.

16. The device of claim 1, wherein the excitation wavelength of the fluorescent label is substantially the same as an excitation wavelength of the reference, and wherein an emission wavelength of the reference is substantially longer than the emission wavelength of the fluorescent label.

17. The device of claim 16, wherein the reference is selected from the group consisting of quantum dots, tracer dyes, and phycobiliproteins.

18. The method claim 1, further comprising:

detecting the amount of emission from the reference; and

quantitating the amount of analyte based on the amount of emission from the reference.

19. The device of claim 1, wherein the labeled analogue is selected from the group consisting of a labeled antibody, a labeled lectin, a labeled enzyme, a labeled polymer, and combinations thereof.

20. The device of claim 1, wherein the support is perforated or permeable to the analyte.

21. The device of claim 20, further comprising a second membrane having an interior surface and an exterior surface, wherein the second membrane is permeable to the analyte and impermeable to the labeled analogue, and wherein the interior surface of the second membrane is connected to the exterior surface of the support.

22. The device of claim 21, wherein the first and second membranes are comprised of a biocompatible material selected from the group consisting of cellulose acetate, polysulfones, polycarbonates, poly(vinyl chlorides), polyamides, ethylene vinyl acetate copolymers, poly(vinylidene) fluoride, poly(urethanes), poly(benzimidazoles), cellulose esters, cellulose triacetate, cellulose, cellulose nitrate, regenerated cellulose, cross-linked poly(vinylpyrrolidone);

crosslinked polyacrylamide, crosslinked poly (hydroxy ethyl methacrylate), silicones, fluorosiloxanes, PTFE, and combinations thereof, and wherein the biocompatible material is optionally coated with a biocompatibility-promoting substance selected from the group consisting of polyethylene glycol, basic fibroblast growth factor, and angiogenic substances.

23. The device of claim 21, wherein the exterior surface of the first membrane and the exterior surface of the second membrane are separated by less than about 1000 microns.

24. The device of claim 21, wherein the exterior surface of the first membrane and the exterior surface of the second membrane are separated by less than about 750 microns.

25. The device of claim 21, wherein the exterior surface of the first membrane and the exterior surface of the second membrane are separated by less than about 500 microns.

26. The device of claim 1, being substantially flat and square in shape as viewed along an axis perpendicular to the exterior surface of the first membrane.

27. The device of claim 26, wherein the square has a diameter between about 1 millimeter and about 10 millimeters.

28. The device of claim 1, being substantially flat and rectangular in shape as viewed along an axis perpendicular to the exterior surface of the first membrane.

29. The device of claim 28, wherein the rectangle has a width less than about 10 millimeters, and a length less than about 30 millimeters.

30. The device of claim 1, being substantially flat and elliptical in shape as viewed along an axis perpendicular to the exterior surface of the first membrane.

31. The device of claim 30, wherein the ellipse has a minor axis less than about 10 millimeters, and a major axis less than about 30 millimeters.

32. The device of claim 1, being substantially flat and circular in shape as viewed along an axis perpendicular to the exterior surface of the first membrane.

33. The device of claim 32, wherein the circle has a diameter less than about 10 millimeters.

34. The device of claim 1, wherein a ratio of the void volume to a volume occupied by the substrate is between about 1 and about 5.

35. The device of claim 34, wherein the ratio is less than about 3.

36. The device of claim 34, wherein the ratio is about 1.

37. The device of claim 1, wherein a weight ratio of the labeled analogue to the substrate is between about 0.1 to about 10.

38. The device of claim 1, wherein the dye is attached to the substrate by a divinyl sulfone linker.

39. A method for monitoring an analyte, comprising:

(a) implanting into a subcutaneous region of a patient a device comprising;

a support having an interior surface and an exterior surface;

a substrate connected to the interior surface of the support;

a labeled analogue, which binds reversibly to the substrate;

a spacer connected to the interior surface of the support and encompassing the substrate; and

a first membrane having an interior surface and an exterior surface, the interior surface being connected to the spacer;

wherein

the first membrane is penneable to the analyte and impermeable to the labeled analogue;

the interior surface of the support, the spacer, and the interior surface of the first membrane define a chamber which encloses the substrate and the labeled analogue, the chamber further comprises a reference; and

the spacer exceeds the substrate in elevation such that a void volume exists between the interior surface of the first membrane and the substrate;

(b) illuminating an extracutaneous region of the patient with a light having a wavelength which corresponds to an excitation wavelength of a fluorescent label;

(c) detecting a fluorescence signal corresponding to the emission wavelength of the fluorescent label with an extracutaneous photodetector; and

(d) correlating the fluorescence signal with a concentration of the analyte.

40. The method of claim 39, wherein the analyte is glucose.

41. The method of claim 39, wherein the implanting of the device is such that the exterior surface of the first membrane is positioned parallel to an external dermal layer of the patient.

42. A device for monitoring glucose, comprising:

a perforated support comprising an adhesive surface,

a dextran bead comprising Alkali Blue 6B dye and at least one Concanavalin-A binding site, wherein the bead is connected to the adhesive surface of the support;

a spacer connected to the support;

a labeled analogue comprising dextran labeled with a succinimidyl ester dye;

a first membrane comprising cellulose acetate, the first membrane having an interior surface and an exterior surface, wherein the interior surface is connected to the spacer; and

a second membrane having an interior surface and an exterior surface, wherein the interior surface is connected to the support;

wherein

the First and second membranes are permeable to the glucose and impermeable to the labeled analogue;

the adhesive surface, the spacer, and the interior surface of the first membrane define a chamber which encloses the bead and the labeled analogue; and

the spacer exceeds the bead in elevation such that a void volume exists between the interior surface of the first membrane and the bead.