Optical determination of pH and glucose

• US 8,983,565 B2
• Filed: 07/25/2013
• Issued: 03/17/2015
• Est. Priority Date: 02/06/2007
• Status: Active Grant

• Current Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Inventors: Markle, David R., Suri, Jeff T., Wessling, Ritchie A., Romey, Matthew A.
• Primary Examiner(s): WINAKUR, ERIC FRANK
• Application Number:
  US13/951,125
• Publication Number:
  US 20140058225A1
• Time in Patent Office: 600 Days
• Field of Search: 600/310, 600/316, 600/317, 600/322, 436/164, 436/166, 422/82.08
• US Class Current: 600/317
• CPC Class Codes: A61B 5/1451 for interstitial fluid
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14539 for measuring pH
• CPC Class Codes: A61B 5/1459 invasive, e.g. introduced into the body by a catheter A61B5/1464 takes precedence
• CPC Class Codes: G01N 2400/00 Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose
• CPC Class Codes: G01N 33/84 involving inorganic compounds or pH

Abstract

Embodiments of the present invention are directed to an optical sensor capable of measuring two analytes simultaneously with a single indicator system. In preferred embodiments, the sensor comprises a fluorescent dye having acid and base forms that facilitate ratiometric pH sensing, wherein the dye is further associated with a glucose binding moiety and configured to generate a signal that varies in intensity with the concentration of glucose.

Claims

1. A method for simultaneously determining pH and glucose concentration using a single fluorescent dye, comprising:

providing a system comprising;

an optical sensor, comprising an indicator system, comprising;

a fluorescent dye that exists in first and second different forms depending on pH, wherein the different forms can be distinguished based on their respective first and second emissions; and

a binding moiety that binds glucose, wherein the binding moiety is operably coupled to the fluorescent dye, and wherein binding of glucose by the binding moiety causes an optical change in the apparent concentration of the fluorescent dye related to the concentration of glucose;

wherein a ratio of the first and second emissions is independent of the concentration of glucose;

at least one light source;

at least one detector configured to detect both the first and second emissions; and

a controller configured to monitor signals from the at least one detector and determine the ratio;

inserting the optical sensor into a tissue comprising interstitial fluid;

irradiating the sensor using the at least one light source;

detecting the first emission corresponding to the first form of the fluorescent dye;

detecting the second emission corresponding to the second form of the fluorescent dye;

ratiometrically determining the pH of the interstitial fluid using the controller; and

determining the glucose concentration in the interstitial fluid corrected for pH using the controller.

2. The method of claim 1, further comprising:

using the controller to;

compute a ratio of the intensities of the first and second emissions;

determine the pH of the interstitial fluid by comparing the ratio with a pH standard curve;

select a standard glucose response curve corresponding to the determined pH; and

determine the glucose concentration by comparing the first or second emission to the standard glucose response curve.

3. The method of claim 1, wherein the at least one light source comprises first and second light sources that generate respective first and second different excitation wavelengths.

4. The method of claim 1, wherein the first and second different forms of the fluorescent dye absorb light at a single excitation wavelength and generate the first and second emissions at different wavelengths.

5. The method of claim 4, wherein the first and second different forms of the fluorescent dye absorb light at respective first and second different excitation wavelengths and generate the first and second emissions at different wavelengths.

6. The method of claim 1, wherein the fluorescent dye is a discrete compound.

7. The method of claim 1, wherein the fluorescent dye is selected from HPTS, SNARF-1, SNAFL-1, TSPP and derivatives thereof.

8. The method of claim 1, wherein the fluorescent dye is selected from the group consisting of:

HPTS-CysMA, HPTS-LysMA, and polymers comprised thereof.

9. The method of claim 1, wherein the binding moiety comprises a quencher and one or more binding sites for reversibly binding glucose.

10. The method of claim 9, wherein the quencher is a viologen.

11. The method of claim 9, wherein the one or more binding sites comprises a benzylboronic acid group.

12. The method of claim 1, wherein the binding moiety is a viologen-boronic acid adduct.

13. The method of claim 1, wherein the binding moiety is 3,3′

-oBBV or derivatives thereof.

14. The method of claim 1, wherein the optical sensor comprises physiologically compatible materials and is sized for deployment to an interstitial space comprising interstitial fluid.

15. The method of claim 1, wherein the indicator system further comprises a means for immobilizing the fluorescent dye and the binding moiety.

16. The method of claim 15, wherein the means for immobilizing comprises a hydrogel.

17. The method of claim 1, wherein the fluorescent dye and the binding moiety of the indicator system comprise a single molecule.

18. A method for simultaneously determining the concentration of two or more analytes using a single fluorescent dye, comprising:

providing a system comprising;

an optical sensor, comprising an indicator system, comprising;

a fluorescent dye that exists in first and second different forms depending on the concentration of a first analyte, wherein the different forms can be distinguished based on their respective first and second emissions; and

a binding moiety that binds a second analyte, wherein the binding moiety is operably coupled to the fluorescent dye, and wherein binding of the second analyte by the binding moiety causes an optical change in the apparent concentration of the fluorescent dye related to a concentration of the second analyte;

wherein a ratio of the first and second emissions is independent of the concentration of the second analyte;

at least one light source;

at least one detector configured to detect both the first and second emissions; and

a controller configured to monitor signals from the at least one detector and determine the ratio;

inserting the optical sensor into a tissue comprising interstitial fluid;

irradiating the sensor using the at least one light source;

detecting the first emission corresponding to the first form of the fluorescent dye;

detecting the second emission corresponding to the second form of the fluorescent dye;

ratiometrically determining the concentration of the first analyte of the interstitial fluid using the controller; and

determining the concentration of the second analyte in the interstitial fluid corrected for concentration of the first analyte using the controller.