Cutaneous methods of measuring body substances

• US 4,401,122 A
• Filed: 08/02/1979
• Issued: 08/30/1983
• Est. Priority Date: 08/02/1979
• Status: Expired due to Term

• Current Assignee: Children's Hospital & Medical Center
• Original Assignee: Children's Hospital & Medical Center
• Inventors: Clark, Leland C. Jr.
• Primary Examiner(s): Apley, Richard J.
• Assistant Examiner(s): Wallen, T. J.
• Application Number:
  US06/063,159
• Time in Patent Office: 1,489 Days
• Field of Search: 128/635, 128/260, 128/633, 356/41, 356/417, 356/427, 422/68, 23/230 LC
• US Class Current: 600/358
• CPC Class Codes: A61B 5/145 Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissuemeasuring of blood pressure or blood flow A61B5/02; non-radiation detecting or locating of foreign bodies in blood A61B5/06
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1477 non-invasive
• CPC Class Codes: A61B 5/1486 using enzyme electrodes, e.g. with immobilised oxidase
• CPC Class Codes: C12Q 1/005 involving specific analytes or enzymes including groups of enzymes, e.g. oxydases; C12Q1/004 takes precedence

Abstract

Cutaneous methods for measurement of substrates in mammalian subjects are disclosed. A condition of the skin is used to measure a number of important substances which diffuse through the skin or are present underneath the skin in the blood or tissue. According to the technique, an enzyme whose activity is specific for a particular substance or substrate is placed on, in or under the skin for reaction. The condition of the skin is then detected by suitable means as a measure of the amount of the substrate in the body. For instance, the enzymatic reaction product or by-product of the reaction is detected directly through the skin as a measure of the amount of substrate. Polarographic electrodes or enzyme electrodes are employed as skin-contact analyzers in the transcutaneous measurement of oxygen or hydrogen peroxide to quantitatively determine blood substances such as glucose and alcohol. In a preferred quantitative technique, the skin is arterialized, i.e., heated or otherwise treated to arterialize the skin capillaries when the measurements are made. Colorimetric detection methods are also employed.

Claims

1. A non-invasive cutaneous method of analyzing body substrates in the body which comprises

contacting in the body of non-gaseous body substrate with an enzyme selected for the substrate being analyzed,

reacting the substrate with the enzyme, and

detecting a condition of the skin without invading the body at the time of the detection as a measure of the amount of substrate in the body.

2. The method of claim 1 comprising placing an oxygen sensitive electrode in contact with the skin, reacting the substrate with an enzyme to produce a decrease in oxygen and detecting said oxygen decrease at the skin as a measure of the amount of substrate.

3. The method of claim 1 comprising locating the enzyme under the skin surface and detecting a condition of the enzymatic reaction at the skin as a measure of the amount of substrate.

4. The method of claim 1 comprising arterializing the skin.

5. The method of claim 4 wherein the skin is arterialized by heating.

6. The method of claim 5 wherein the skin is warmed to a temperature of about 38°

-44°

C.

7. The method of claim 4 wherein the skin is arterialized by chemical treatment.

8. The method of claim 1 comprising injecting the enzyme subcutaneously.

9. The method of claim 8 comprising mixing the enzyme with a material selected from the group consisting of silicone oil and fluorocarbon oil and injecting the mixture subcutaneously.

10. The method of claim 1 comprising subcutaneously implanting the enzyme.

11. The method of claim 10 comprising embedding the enzyme in a thin polymeric sheet and implanting through an incision in the skin.

12. The method of claim 10 comprising implanting a film containing an immobilized enzyme.

13. The method of claim 12 wherein the enzyme is immobilized by entrapment between two layers of a plastic film.

14. The method of claim 12 wherein the film comprises a polymer selected from the group consisting of cellophane, cupraphane, collagen and silicone polymer.

15. The method of claim 12 wherein enzyme is immobilized on the surface of the film by treating with gluteraldehyde solution and then drying.

16. The method of claim 1 comprising immobilizing the enzyme in a container which is selectively permeable for the substrate.

17. A non-invasive cutaneous method of extracorporeally analyzing blood substrates in the body of mammalian subjects which comprises

transcutaneously contacting in the body a non-gaseous substrate with an enzyme selected for the subtrate being analyzed,

reacting the substrate with the enzyme,

arterializing the skin, and

detecting the condition of the skin without invading the body at the time of detection as a measure of the amount of substrate in the blood.

18. The method of claim 17 comprising placing the enzyme in a container under the skin which is selectively permeable for the substrate.

19. The method of claim 17 comprising detecting either oxygen decrease with an extracorporeal electrode as a measure of the amount of substrate.

20. An apparatus for non-invasively measuring body substrates in the body which comprises

means for contacting in the body a non-gaseous body substrate with an enzyme selected for the substrate being analyzed and means for detecting a condition of the skin without invading the body at the time of the detection as a measure of the amount of substrate in the body.

21. The apparatus of claim 20 wherein the detecting means is a oxygen sensitive electrode.

22. The apparatus of claim 20 wherein said detection means is for direct contact with the skin.

23. The apparatus of claim 20 wherein the contacting means is for location under the surface of the skin.

24. The apparatus of claim 20 including means for arterializing the skin.

25. The apparatus of claim 24 comprising a heating element.

26. The apparatus of claim 25 wherein said element is operated at a temperature of about 38°

-44°

C.

27. The apparatus of claim 23 wherein the contacting means comprises an enzyme implant.

28. The apparatus of claim 27 wherein the enzyme implant comprises an enzyme embedded in a thin polymeric sheet.

29. The apparatus of claim 27 wherein the enzyme implant comprises a film containing an immobilized enzyme.

30. The apparatus of claim 29 wherein the enzyme is immobilized between two layers of a plastic film.

31. The apparatus of claim 30 wherein the film comprises a polymer selected from the group consisting of cellophane, cuprophane, collagen and silicone polymer.

32. The apparatus of claim 20 wherein the contacting means is a container having an immobilized enzyme therein and said container is selectively permeable for the substrate.

33. The apparatus of claim 20 comprising further means for vaporizing the substrate and wherein the detecting means is an extracorporeal device.

34. A detection device for analyzing body substrates in the body which comprises an enzyme immobilized in a layer for implantation in the body and for measurement of body substrates in the body without invading the body at the time of measurement while said enzyme layer is implanted.

35. The device of claim 34 wherein said enzyme is immobilized by being embedded in a thin polymeric sheet.

36. The device of claim 34 wherein the enzyme is immobilized between two layers of plastic film.

37. The device of claim 34 wherein the enzyme is immobilized within a container and said container being selectively permeable for the substrate.