Photometric glucose measurement system using glucose-sensitive hydrogel

• US 6,835,553 B2
• Filed: 04/11/2002
• Issued: 12/28/2004
• Est. Priority Date: 05/11/1999
• Status: Expired due to Fees

• Current Assignee: M-Biotech, Inc.
• Original Assignee: M-Biotech, Inc.
• Inventors: Han, Man Hee, Han, In Suk, Lew, Seok
• Primary Examiner(s): Redding, David A
• Application Number:
  US10/120,870
• Publication Number:
  US 20020155425A1
• Time in Patent Office: 992 Days
• Field of Search: 435/288.7, 435/14, 435/25, 435/287.1, 359/290, 359/886, 359/296, 436/95, 436/148, 604/891.1, 604/892.1, 356/334, 252/582
• US Class Current: 435/14
• CPC Class Codes: A61B 5/0022 Monitoring a patient using a global network, e.g. telephone networks, internet
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: C12Q 1/001 Enzyme electrodes
• CPC Class Codes: C12Q 1/006 for glucose
• CPC Class Codes: G01N 13/04 Investigating osmotic effects
• CPC Class Codes: G01N 33/66 involving blood sugars, e.g. galactose
• CPC Class Codes: G01N 7/00 Analysing materials by measuring the pressure or volume of a gas or vapour
• CPC Class Codes: Y10T 436/144444 Glucose

Abstract

An implantable biosensor for detecting an analyte in vivo in body fluids comprises an analyte-sensitive hydrogel filament chemically configured to vary its displacement volume according to changes in concentration of an analyte, such as glucose, in a patient'"'"'s body fluid. A photometric displacement transducer placed inside the biosensor is configured to quantifiably detect changes in the displacement volume of the hydrogel filament, such as by detecting the light intensity on a photoreceptor arranged to receive light of varying intensity depending upon the displacement of the hydrogel filament. A battery powered telemeter operably engaged to the photometric displacement transducer sends a radio data signal representing glucose concentration level to a receiver containing an alarm system. The alarm system can automatically notify a person that the analyte level is outside desired predetermined parameters, and/or to automatically inject an agent to counteract the adverse analyte levels.

Claims

1. A biosensor for measuring the concentration of a free analyte in a body fluid, comprising:

a polymeric hydrogel filament that changes its displacement in proportion to the concentration of the free analyte;

a photoreceptor arranged in relation to the polymer hydrogel filament so that the intensity of light received by the photoreceptor varies with the displacement of the polymer hydrogel filament; and

means for reporting a data signal reflective of the measured light intensity on the photoreceptor.

2. The biosensor of claim 1, additionally including a source of light directing light toward the hydrogel filament.

8. The biosensor of claim 2, wherein the photoreceptor is positioned to receive light reflected from the light source by the hydrogel filament, the amount of reflected light received by the photoreceptor depending upon the displacement of the hydrogel filament.

14. The biosensor of claim 1, further including computing means responsive to the data signal for determining the concentration of the free analyte.

15. The biosensor of claim 14, wherein the computing means compares the data signal to a calibration curve to determine the concentration of the free analyte in the body fluid and produce an output signal representing the free analyte concentration.

16. The biosensor of claim 15, wherein the analyte whose concentration is to be measured is glucose and wherein the computing means compares the data signal to a calibration curve to compute a concentration of the free glucose in the body fluid and produce an output signal representing the free glucose concentration.

24. The biosensor of claim 1, wherein the polymeric hydrogel includes analyte binding molecules (ABM) immobilized in the hydrogel, and analyte molecules immobilized in the hydrogel.

25. The biosensor of claim 24, wherein the analyte binding molecule is a glucose binding molecule (GBM) and the immobilized analyte is a hexose saccharide or a polysaccharide.

26. The biosensor of claim 25, wherein the GBM is either boronic acid, GOX, hexokinase, glucosidase, xylose isomerase, glucose phosphorylase, lactate dehydrogenase, or lectins.

27. The biosensor of claim 25, wherein the GBM molecules include genetically modified proteins which have only binding affinity to glucose moieties but having no enzymatic activity.

28. The biosensor of claim 25, wherein the hexose saccharide has a vinyl group conjugated to the Cl hydroxyl group of the hexose saccharide and is selected from the group that consists of a-D-mannopyranoside, p-nitrophenyl-a-D-mannopyranoside, or p-nitrophenyl-a-D-glucopyranoside.

29. The biosensor of claim 25, wherein the hexose saccharide include monomer containing hexose moieties selected from the group consisting of glycidyl acrylate, glycidyl butyl ether, glycidyl cinnamate, or glycidyl methacylate such as glycosyloxyethyl methacrylate.

30. The biosensor of claim 25, wherein the polysaccharide chemically or physically immobilized in the hydrogel filament is any macromolecule that contains polysaccharides.

31. The biosensor of claim 25, wherein the immobilized glucose molecules and immobilized GBM are present at respective cross-linking densities chosen to optimize the amount of hydrogel swelling in response to changes in level of free glucose molecules.

32. The biosensor of claim 24, wherein the analyte binding molecule is selected from the group consisting of:

antibodies, enzymes, membrane receptors, kinases, Protein A, Poly U, Poly A, Poly lysine, triazine dye, nucleoside, thiol, heparin, polysaccharides, Coomassie blue, azure A, and metal-binding peptides, proteins, and chelating agents.

33. The biosensor of claim 24, wherein the immobilized analyte is selected from the group consisting of:

antigens, enzyme cofactors, enzyme substrates, enzyme inhibitors, IGG, sugar, carbohydrate, nucleic acids, nucleotide, nucleoside, cysteine, arginine, lysine, protamine, heparin, dyes, and metal ions.

3. A biosensor for measuring the concentration of a free analyte in a body fluid, comprising:

a polymeric hydrogel filament that changes its displacement in proportion to the concentration of the free analyte;

a photoreceptor arranged in relation to the polymer hydrogel filament so that the intensity of light received by the photoreceptor varies with the displacement of the polymer hydrogel filament;

a source of light directing light toward the photoreceptor with the hydrogel filament positioned between the source of light and the photoreceptor to block a portion of the light from the source of light directed to the photoreceptor, the amount of light blocked depending upon the displacement of the hydrogel filament; and

means for reporting a data signal reflective of the measured light intensity on the photoreceptor.

4. The biosensor of claim 3, wherein the hydrogel filament has one end that moves with the displacement of the hydrogel filament, and wherein the end of the hydrogel filament is positioned between the source of light and the photoreceptor so that movement of the end of the hydrogel filament varies the amount of light blocked.

5. The biosensor of claim 4, further including computing means responsive to the data signal for determining the concentration of the free analyte.

6. The biosensor of claim 5, wherein the computing means compares the data signal to a calibration curve to determine the concentration of the free analyte in the body fluid and produce an output signal representing the free analyte concentration.

7. The biosensor of claim 5, wherein the analyte whose concentration is to be measured is glucose, and wherein the computing means compares the data signal to a calibration curve to compute a concentration of the free glucose in the body fluid and produce an output signal representing the free glucose concentration.

9. A biosensor for measuring the concentration of a free analyte in a body fluid, comprising:

a polymeric hydrogel filament that changes its displacement in proportion to the concentration of the free analyte;

a photoreceptor arranged in relation to the polymer hydrogel filament so that the intensity of light received by the photoreceptor varies with the displacement of the polymer hydrogel filament;

a source of light directing light toward the hydrogel filiment;

reflective material arranged on the hydrogel filament to move with displacement of the hydrogel filament and to reflect light from the source of light toward the photoreceptor, movement of the reflector changing the intensity of light reflected to the photoreceptor; and

means for reporting a data signal reflective of the measured light intensity on the photoreceptor.

10. The biosensor of claim 9, wherein the hydrogel filament has one end that moves with the displacement of the hydrogel filament, and wherein the reflective material is positioned on the end of the hydrogel filament.

11. The biosensor of claim 10, further including computing means responsive to the data signal for determining the concentration of the free analyte.

12. The biosensor of claim 11, wherein the computing means compares the data signal to a calibration curve to determine the concentration of the free analyze in the body fluid and produce an output signal representing the free analyte concentration.

13. The biosensor of claim 11, wherein the analyte whose concentration is to be measured is glucose, and wherein the computing means compares the data signal to a calibration curve to compute a concentration of the free glucose in the body fluid and produce an output signal representing the free glucose concentration.

17. A biosensor for measuring the concentration of glucose, in a body fluid, comprising:

a polymeric hydrogel filament that changes its displacement in proportion to the concentration of glucose;

a photoreceptor arranged in relation to the polymer hydrogel filament so that the intensity of light received by the photoreceptor varies with the displacement of the polymer hydrogel filament;

a battery powered telemeter for reporting a data signal reflective of the measured light intensity on the photoreceptor, receiving means positioned at a location remote to the patient for receiving the data signal; and

computing means responsive to the data signal to compare the data signal to a calibration curve to compute a concentration of the free glucose in the body fluid and produce an output signal representing the free glucose concentration.

18. The biosensor of claim 17, further including computing means operably associated with the receiving means for comparing the data signal to a calibration curve to compute a concentration of the free glucose in the body fluids and produce an output signal representing the glucose concentration.

19. The biosensor of claim 18, wherein the computing means is further configured to compare the detected glucose concentration to a predetermined safe range, and to produce an alarm signal when the detected glucose concentration falls outside the safe range.

20. A biosensor for measuring the concentration of a free analyte in a body fluid, comprising:

a polymeric hydrogel filament that changes its displacement in proportion to the concentration of the free analyte and disposed within a rigid enclosure with at least one area permeable to contact between the hydrogel filament and a fluid being tested and permitting free analyte molecules to diffuse into the filament from the fluid;

a photoreceptor arranged in relation to the polymer hydrogel filament so that the intensity of light received by the photoreceptor varies with the displacement of the polymer hydrogel filament; and

means for reporting a data signal reflective of the measured light intensity on the photoreceptor.

21. The biosensor of claim 20, wherein the permeable area is an open end in the rigid enclosure, and said open end is sealed by a semipermeable membrane that allows the free glucose molecules to diffuse into the hydrogel.

22. The biosensor of claim 20, wherein the enclosure is conjugated with heparin and polyethylene glycol.

23. The biosensor of claim 20, wherein the enclosure is coated with a semipermeable membrane and a biodegradable polymer on the semipermeable membrane.

34. A biosensor for measuring the concentration of a free analyte in a body fluid, comprising:

a polymeric hydrogel filament that chances its displacement in proportion to the concentration of the free analyte;

a photoreceptor arranged in relation to the polymer hydrogel filament so that the intensity of light received by the photoreceptor varies with the displacement of the polymer hydrogel filament;

means for reporting a data signal reflective of the measured light intensity on the photoreceptor;

a reference polymeric hydrogel filament similar to the hydrogel filament but which does not change its displacement in response to the concentration of the free analyte;

a reference photoreceptor arranged in relation to the reference polymer hydrogel filament so that the intensity of light received by the photoreceptor varies with the displacement of the reference polymer hydrogel filament;

means for reporting a reference data signal reflective of the measured light intensity on the reference photoreceptor, and means for compensating the data signal in respones to changes in the reference data signal to compensate for any change in the data signal attributable to factors other than the analyte concentration.

35. A sensor for measuring the concentration of free molecules of an analyte in a fluid, comprising:

a rigid enclosure having an open end and a closed end, the open end being covered by a semipermeable membrane adapted to be placed in the fluid;

a hydrogel positioned within the enclosure between the semipermeable membrane and the closed end, said hydrogel changing its displacement in the enclosure depending upon analyte concentration in the fluid; and

a photoreceptor positioned with respect to the enclosure so that changes in displacement of the hydrogel are accompanied by changes in light intensity detected by the photoreceptor.

36. The sensor of claim 35, including a battery powered telemeter operatively engaged to the photoreceptor.

37. The sensor of claim 35, wherein the hydrogel changes its displacement depending upon the glucose concentration in the fluid, whereby the light intensity detected by the photoreceptor is indicative of the glucose concentration in the fluid.

38. A method of determining the concentration of free analyte in a fluid, comprising the steps of:

providing a hydrogel filament having pendant charged or uncharged moieties, analyte molecules, and analyte-specific binding molecules covalently immobilized therein so that the hydrogel filament will swell to varying degrees upon exposure to varying concentrations of analyte;

enclosing the hydrogel in a rigid structure which has at least one permeable portion for contacting the fluid, the permeable portion permitting free analyte in the fluid to diffuse into the hydrogel, the rigid structure allowing displacement of the hydrogel therein in response to the swelling of the hydrogel in response to analyte concentration in the fluid;

positioning a photoreceptor with respect to the rigid structure so that light intensity on the photoreceptor varies with displacement of the hydrogel;

inserting the permeable portion of the biosensor into the fluid and allowing sufficient time for free analyte molecules to diffuse to equilibrium within the hydrogel;

sensing the light intensity on the photoreceptor and providing a data signal reflective thereof, which is also reflective of the displacement of the hydrogel; and

comparing the sensed hydrogel displacement with a calibration curve to determine analyte concentration of the test fluid.

39. The method of claim 38, wherein the step of comparing the sensed hydrogel displacement with a calibration curve includes the step of providing computing means connected to receive the data signal, compare it to a predetermined calibration curve of displacement change vs. concentration of free analyte molecules, and output a concentration value.

40. The method of claim 38, wherein the step of providing a hydrogel having analyte molecules and analyte-specific binding molecules is the step of providing a hydrogel having glucose molecules and glucose-specific binding molecules whereby the analyte whose concentration is sensed is glucose.