Monitor for continuous in vivo measurement of glucose concentration

• US 4,436,094 A
• Filed: 01/27/1982
• Issued: 03/13/1984
• Est. Priority Date: 03/09/1981
• Status: Expired due to Fees

• Current Assignee: Eveka Incorporated
• Original Assignee: Evreka, Inc.
• Inventors: Cerami, Anthony
• Primary Examiner(s): Marantz, Sidney
• Application Number:
  US06/343,128
• Time in Patent Office: 776 Days
• Field of Search: 128/635, 204/195 B, 204/1 T, 204/403, 204/415, 23/230 B, 23/901, 436/827
• US Class Current: 600/347
• CPC Class Codes: A61B 5/1486 using enzyme electrodes, e.g. with immobilised oxidase
• CPC Class Codes: A61K 49/0004 Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose
• CPC Class Codes: Y10S 436/827 Lectins
• CPC Class Codes: Y10T 436/144444 Glucose

Abstract

A method for the continuous, in vivo measurement of glucose concentration in animal body fluids such as blood, comprises implanting in the body, in registry with the system for the body fluid, a glucose monitor adapted to measure the concentration of glucose as a function of changes in such electrical charge. The glucose monitor includes an electrode with an electrical charge-transfer medium comprising a reversible complex of a binding macromolecular component and a charge-bearing carbohydrate component. The electrode includes a selectively permeable membrane permitting the ingress and egress of the body fluid. In operation, glucose present in the body fluid displaces the charge-bearing carbohydrate, which then participates in the electrical activity of the electrode so that a measurable change in electrical activity can be observed when the electrode is connected to an appropriate current-responsive meter. Preferably, the macromolecular component comprises one or more lectins, and the charge-bearing carbohydrate component may be one or more of the sugars for which testing is desired.

Claims

1. A method for the continuous in vivo measurement of glucose concentration in animal body fluids comprising:

A. preparing an indwelling glucose monitor adapted to electrically sense variations in the concentration of said glucose in said body fluid, said glucose monitor including a charge-transfer medium comprising a reversible complex of a binding macromolecular component, and a charge-bearing carbohydrate component, said reversible complex reacting with said glucose to change the level of electrical charge sensed by said glucose monitor;

B. placing said glucose monitor in fluid registry with the system of body fluid to be monitored;

C. maintaining said glucose monitor in fluid registry with said system for a period of time sufficient for said body fluid to permeate said glucose monitor, and for any glucose present in said body fluid to react with said reversible complex; and

D. measuring the level of electrical charge sensed by said glucose monitor;

wherein said level of electrical charge varies as a function of the concentration of said glucose, and said monitor is adapted to continually measure variations therein.

2. The method of claim 1 wherein said charge-bearing carbohydrate is retained within said glucose monitor, to enable said glucose monitor to sense reductions in said glucose concentration, and to perform said continual measurement.

3. The method of claim 1 wherein said glucose monitor comprises an electrode having an anode, a cathode spaced apart therefrom, and said electrical charge-transfer medium is disposed therebetween.

4. The method of claim 1 wherein, in accordance with Step B, said glucose monitor is implanted within the body of said animal.

5. The method of claim 4 wherein said glucose monitor is permanently maintained in fluid registry with said system, and said monitor continually measures variations in the concentration of said glucose.

6. The method of claim 1 wherein said charge-bearing carbohydrate component has bound thereto, at least one ionic substituent.

7. The method of claim 6 wherein said ionic substituent is selected from the group consisting of --SO₃^-, ##STR2## arylhydrazines having electrically charged substituents, and mixtures thereof.

8. The method of claims 1, 4 or 5 wherein said glucose concentrations is measured with reference to a current-responsive meter calibrated for such purpose.

9. The method of claims 1, 2, 4 or 3 wherein said charge-bearing carbohydrate component is retained within said monitor by a selectively permeable membrane.

10. The method of claims 1, 2, 4 or 3 wherein said binding macromolecular component comprises a binding protein, said charge-bearing carbohydrate component comprises a sugar having an ionic charge disposed thereon, said sugar selected from the group consisting of monosaccharides, oligosaccharides, and mixtures thereof.

11. The method of claim 10 wherein said binding macromolecular component is fixedly attached to an inert, insoluble substance, and said charge-bearing carbohydrate component is bound thereto in reversible complex.

12. The method of claim 10 wherein said charge-bearing carbohydrate component has bound thereto, at least one ionic substituent.

13. The method of claim 12 wherein said ionic substituent is selected from the group consisting of --SO₃^-, l ##STR3## arylhydrazines having electrically charged substituents, and mixtures thereof.

14. A glucose monitor for the continuous, in vivo measurement of glucose concentration in animal body fluids comprising:

A. an electrode adapted to electrically sense variations in the concentration of said glucose in said body fluid;

B. said electrode including a charge-transfer medium comprising a reversible complex of a binding macromolecular component, and a charge-bearing carbohydrate component;

C. said reversible complex adapted to react with said glucose to change the level of electrical charge sensed by said electrode, to thereby indicate corresponding variations in said glucose concentration.

15. The monitor of claim 14 wherein said binding macromolecular component comprises one or more lectins, and said charge-bearing carbohydrate component, comprises monosaccharides and oligosaccharides containing a material selected from the group consisting of glucose, mannose, and mixtures thereof.

16. The monitor of claim 15 wherein said binding macromolecular component comprises Concanavalin A, and said oligosaccharides contain up to about 6 monosaccharide units.

17. The monitor of claim 14 wherein said charge-bearing carbohydrate component comprises a sugar having one or more reactive sites thereof bound to an ionic substituent, said sugar selected from the group consisting of monosaccharides, oligosaccharides, and mixtures thereof.

18. The monitor of claim 17 wherein said charge-bearing carbohydrate component comprises a sugar having one or more reactive sites thereof bound to an ionic substituent, said sugar selected from the group consisting of monosaccharides, oligosaccharides, and mixtures thereof.

19. The monitor of claim 17 wherein said ionic substituent is selected from the group consisting of --SO₃^-, ##STR4## arylhydrazines having electrically charged substituents, and mixtures thereof.

20. The monitor of claim 14 wherein said electrode comprises:

A. an electrode housing;

B. an anode and a cathode mounted in said housing and spaced apart from each other;

C. said charge-transfer material disposed between said anode and said cathode.

21. The monitor of claim 20 wherein said electrode is enclosed within a membrane selectively permeable to said body fluid, said membrane being permeable to said glucose, but impermeable to said charge-bearing carbohydrate.

22. The monitor of claim 21 wherein said selectively permeable membrane is porous, and defines a pore size limiting passage therethrough to said body fluid, and said glucose.

23. The monitor of claim 22 wherein said selectively permeable membrane defines a surface charge thereon, to prevent the egress from said electrode, of said charge-bearing carbohydrate.

24. The monitor of claims 14, 20 or 21 wherein said binding macromolecular component is selected from the group consisting of natural binding proteins, synthetic binding proteins and mixtures thereof.

25. The monitor of claim 24 wherein said charge-bearing carbohydrate component comprises a sugar having one or more reactive sites thereof bound to an ionic substituent, said sugar selected from the group consisting of monosaccharides, oligosaccharides, and mixtures thereof.

26. The monitor of claim 25 wherein said ionic substituent is selected from the group consisting of --SO₃^-, ##STR5## arylhydrazines having electrically charged substituents, and mixtures thereof.

27. The monitor of claim 21 wherein said charge-bearing carbohydrate component comprises a sugar having one or more reactive sites thereof bound to an ionic substituent, said sugar selected from the group consisting of monosaccharides, oligosaccharides, and mixtures thereof.

28. The monitor of claims 14, 20 or 21 wherein said reversible complex is affixed to an inert, insoluble substrate.

29. The monitor of claim 28 wherein said substrate is prepared from a material selected from the group consisting of natural and synthetic resins, ceramic materials, and mixtures thereof.

30. The monitor of claim 29 wherein said substrate is prepared from a material selected from the group consisting of cellulose, vinyl resins, glass and mixtures thereof.