Equilibrium non-consuming fluorescence sensor for real time intravascular glucose measurement

• US 9,693,720 B2
• Filed: 04/17/2014
• Issued: 07/04/2017
• Est. Priority Date: 05/10/2007
• Status: Active Grant

• Current Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Minimed Incorporated (Medtronic Plc)
• Inventors: Markle, David R., Markle, William
• Primary Examiner(s): Winakur, Eric
• Assistant Examiner(s): Liu, Chu Chuan (JJ)
• Application Number:
  US14/255,482
• Publication Number:
  US 20150080685A1
• Time in Patent Office: 1,174 Days
• Field of Search: 600310, 600316, 600317, 600322, 600341, 600342, 422 8205- 8211, 436166
• 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: A61B 5/14735 comprising an immobilised reagent

Abstract

Embodiments of the present invention relates to analyte sensors. In particular, the preferred embodiments of the present invention relate to non-consuming intravascular glucose sensors based on fluorescence chemistry.

Claims

1. A sensor for determining pH and glucose concentration comprising:

an optical fiber comprising a fluorescence chemical indicator, the chemical indicator system comprising a single type of fluorophore that generates a fluorescence emission signal when excited by light and a glucose binding moiety to modulate the florescence emission signal, wherein the fluorophore is sensitive to both pH and glucose concentration when the fluorophore is operably coupled to the glucose binding moiety and the extent of modulation of the fluorescence emission signal by the glucose binding moiety is related to the amount of glucose bound to the glucose binding moiety, and wherein the fluorophore comprises an acid form that absorbs light at a first excitation wavelength and a base form that absorbs light at a second excitation wavelength;

a light source configured, to deliver the first excitation wavelength and the second excitation wavelength;

a detector configured to detect a first fluorescence emission signal generated by the fluorophore in response to the first excitation wavelength and a second fluorescence emission signal generated by the fluorophore in response to the second excitation wavelength, wherein the first and second fluorescence emission signal are each dependent on pH; and

a controller configured to monitor emission signals from the detector, to ratiometrically determine the pH using the first and second fluorescence emission signals and to determine the glucose concentration using one of the first fluorescence emission signal and the second fluorescence emission signal, wherein the determining of the pH and the determining of the glucose concentration are performed simultaneously, and to correct the determined glucose concentration based on the determined pH, wherein the fluorophore is HPTS-triCysMA.

2. The sensor of claim 1, wherein the fluorescence emission signal comprises a fluorescence intensity.

3. The sensor of claim 1, wherein the fluorescence emission signal comprises a fluorescence lifetime.

4. The sensor of claim 1, wherein the light source is a laser.

5. The sensor of claim 1, wherein the light source is a light emitting diode.

6. The sensor of claim 1, wherein the sensor further comprises a hydrogel that immobilizes the glucose binding moiety and the fluorophore and is permeable to glucose.

7. The sensor of claim 1, wherein the sensor further comprises a membrane wherein the glucose binding moiety and the fluorophore are retained within a volume at least partially enclosed by the membrane.

8. A method for determining glucose concentration and pH comprising:

inserting the sensor of claim 1 into a patient;

exciting the fluorophore with light;

detecting the first fluorescence emission signal and the second fluorescence emission signal; and

simultaneously and ratiometrically determining the pH and the concentration of glucose.

9. The method of claim 8, wherein the light is a pulse of light.

10. The method of claim 9, further comprising measuring the decay of the fluorescence emission signal over time;

and calculating a fluorescence lifetime.

11. The method of claim 8, wherein the light is frequency modulated.

12. The method of claim 11, further comprising measuring the phase shift between the first fluorescence emission signal and the light.

13. The method of claim 12, further comprising calculating a fluorescence lifetime.

14. The sensor of claim 1, wherein, the glucose binding moiety comprises an aromatic boronic acid.

15. The sensor of claim 14, wherein the aromatic boronic acid is coupled to a viologen.

16. The sensor of claim 1, wherein the fluorophore and the glucose binding moiety are not covalently bound to one another.

17. The sensor of claim 1, wherein the sensor further comprises a hydrogel that covalently bonds the glucose binding moiety and the fluorophore and is permeable to glucose.

18. The sensor of claim 2, wherein a ratio of the first fluorescence emission signal to the second fluorescence emission signal is independent of the concentration of glucose.