Analyte measuring biosensor chip using image scanning system

• US 6,751,491 B2
• Filed: 01/22/2002
• Issued: 06/15/2004
• Est. Priority Date: 09/01/2001
• Status: Expired due to Fees

• Current Assignee: Gensen Technologies, Inc.
• Original Assignee: M-Biotech, Inc.
• Inventors: Han, In Suk, Lew, Seok
• Primary Examiner(s): Nasser, Robert L.
• Application Number:
  US10/054,660
• Publication Number:
  US 20030100822A1
• Time in Patent Office: 875 Days
• Field of Search: 600/345-350, 600/411, 600/427, 600/437, 204/403-1-4, 204/414, 204/415
• US Class Current: 600/345
• CPC Class Codes: A61B 5/0031 Implanted circuitry
• CPC Class Codes: A61B 5/14539 for measuring pH
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors

Abstract

An implantable chip biosensor for detecting an analyte in vivo in body fluids comprises an analyte-sensitive hydrogel slab chemically configured to vary its displacement volume according to changes in concentration of an analyte, such as glucose, in a patient'"'"'s body fluid, the slab being disposed in a groove in a support block. The biosensor chip is ‘read’ by an external scanner configured to quantifiably detect changes in the displacement volume of the hydrogel slab. The support block is made of rigid or semi-rigid support material to restrain expansion of the hydrogel in all but one dimension, and the groove has one or more openings covered with a semipermeable membrane to allow contact between the patient'"'"'s body fluid and the hydrogel. The scanning means may be any type of imaging devices such as an ultrasound scanner, a magnetic resonance imager (MRI), or a computerized tomographic scanner (CT) capable of resolving changes in the slab'"'"'s dimensions.

Claims

1. A biosensor system comprising:

an implantable analyte-sensitive hydrogel slab chemically configured to vary its displacement volume according to changes in concentration of an analyte in a body fluid in a body in which the hydrogel slab is implanted; and

scanning means configured to quantifiably detect changes in the displacement volume of the hydrogel slab when it is implanted within the body by capturing an image of at least a portion of the hydrogel slab.

2. A biosensor system comprising:

an implantable analyte-sensitive hydrogel slab chemically configured to vary its displacement volume according to changes in concentration of an analyte in a body fluid in a body in which the hydrogel slab is implanted;

wherein the hydrogel slab is disposed in a support block formed of a rigid or semi-rigid support material, the support block having one or more openings permitting the body fluid to contact the hydrogel; and

scanning means configured to quantifiably detect changes in the displacement volume of the hydrogel slab when it is implanted within the body.

3. The biosensor system of claim 2, wherein the opening(s) are covered by a semipermeable membrane which is configured to permit passage of the analyte and prevent passage of proteins into the openings.

4. The biosensor system of claim 2, wherein the support block is sized and configured to permit expansion of the hydrogel slab substantially in only one dimension.

5. The biosensor system of claim 2, wherein the support block is characterized by dimensions x, y, and z, and the support block is sized and configured to limit expansion of the hydrogel in dimensions x and z, and to permit expansion of the hydrogel in the y direction.

6. The biosensor system of claim 2, wherein the support block includes a groove in which the hydrogel slab is disposed, and a semi-permeable membrane covers the hydrogel slab and the groove, the membrane being configured to permit passage of the analyte and prevent passage of proteins into the groove.

7. The biosensor system of claim 2, wherein the support block has three dimensions, at least one of said dimensions sized to prevent expansion of the hydrogel slab, and at least one of said dimensions sized to accommodate the hydrogel at its maximal displacement volume.

8. The biosensor system of claim 7, wherein two of said dimensions are sized to prevent expansion of the hydrogel slab.

9. The biosensor system of claim 2, wherein the support block has scale means located adjacent the hydrogel slab for providing known scale dimensional values to compare with the hydrogel slab.

10. The biosensor system of claim 2, wherein the support block includes a groove in which the hydrogel slab is disposed, and further includes a second groove in which a reference hydrogel slab is disposed, the reference hydrogel being chemically configured to lack analyte sensitivity.

11. The biosensor system of claim 2, wherein the hydrogel slab has pendant charged groups selected to confer pH-sensitivity, such that the hydrogel swells or shrinks according to changes in pH.

12. The biosensor system of claim 11, wherein the pendant charged groups confer a net negative charge on the hydrogel slab.

13. The biosensor system of claim 11, wherein the pendant charged groups confer a net positive charge on the hydrogel slab.

14. The biosensor system of claim 2, wherein the hydrogel slab is composed by polymerizing one or more chemical subunits selected from the group consisting of:

acrylamide, dimethyl-acrylamide, sodium acrylate, hydroxypropyl methacrylate, 2-hydroxyethyl methacrylate, diethylaminoethyl methacrylate, isobutyl methacrylate, butyl methacrylate, isopropyl methacrylate, n-alkyl methacrylate, acrylamide, N-isopropylacrylamide, N-tert-butylacrylamide, N,N-dimethylamide, N,N′

-methylene-bis-acrylamide, polyvinyl alcohol, N-[3-(N,N′

-dimethylamino)propyl]-acrylamide, styrene, N,N′

-methylene-bis-acrylamide, polyvinyl alcohol, and 3-methacrylimidophenylboronic acid.

15. The biosensor system of claim 2, wherein the hydrogel slab is chemically configured to vary its displacement volume according to the concentration of glucose in a human body fluid.

16. The biosensor system of claim 15, wherein the hydrogel further includes a quantity of immobilized molecules having glucose oxidase activity.

17. The biosensor system of claim 16, wherein the glucose-binding moieties are selected from the group consisting of:

boronic acids, phenylboronic acid, inactivated glucose-binding enzymes, glucose binding sites derived from glucose-binding enzymes, glucose-specific antibodies, lectins, and glucose binding sites derived from lectins.

18. The biosensor system of claim 16, wherein the complementary molecules are selected from the group consisting of:

diols, poly(vinyl) alcohol, and hexose saccharides.

19. The biosensor system of claim 15, wherein the hydrogel has

a quantity of glucose-binding moieties immobilized therein, and

a quantity of complementary molecules immobilized therein, said complementary molecules configured to selectively bind to said glucose-binding moieties.

20. The biosensor system of claim 2, wherein the support material is selected from the group consisting of:

Teflon, rigid or semi-rigid plastics, stainless steel, ceramics, and composite materials.

30. The biosensor system of claim 7, wherein the scanning unit further includes wireless transmission means operably connected and configured to transmit an output signal reflective of the displacement volume or of the analyte concentration corresponding to the displacement volume to a remote monitoring device.

21. A biosensor system comprising:

an implantable analyte-sensitive hydrogel slab shaped as a filament having a lengthwise dimension Y which is substantially greater than first and second width dimensions X and Z, and chemically configured to vary its displacement volume according to changes in concentration of an analyte in a body fluid in a body in which the hydrogel slab is implanted;

a support block formed of a support material, said hydrogel filament being disposed within the support block; and

scanning means configured to quantifiably detect changes in the displacement volume of the hydrogel slab when it is implanted within the body.

22. The biosensor system of claim 21, wherein the support block is sized and configured to permit expansion of the hydrogel filament in only the Y dimension.

23. The biosensor system of claim 22 wherein the lengthwise dimension Y is between about 0.2 cm and about 2 cm.

24. The biosensor system of claim 22 wherein the lengthwise dimension of the filament is between about 0.2 cm and 1 cm.

25. The biosensor system of claim 21, wherein the lengthwise dimension of the filament is between about 5 and about 50 times each of the first and second widths.

26. The biosensor system of claim 21, wherein X and Z are each between about 0.1 cm and about 1 cm.

27. A biosensor system comprising:

an implantable analyte-sensitive hydrogel slab chemically configured to vary its displacement volume according to changes in concentration of an analyte in a body fluid in a body in which the hydrogel slab is implanted; and

ultrasound detection means configured to quantifiably detect changes in the displacement volume of the hydrogel slab when it is implanted within the body.

28. The biosensor system of claim 27, further including computing means operably associated with the scanning means for translating a measured value of the displacement volume to a corresponding analyte concentration, and producing an output signal reflective thereof.

29. The biosensor system of claim 28, further including a continuous-monitoring alarm unit operably disposed to receive an output signal reflective of the displacement volume or of the analyte concentration corresponding to the displacement volume, said alarm system configured to compare the output signal to a pre-determined safe range and to provide a warning to the patient and/or to caretakers when the output signal falls outside the safe range.

31. The biosensor system of claim 27, wherein the ultrasound detection means forms part of a scanning unit, the scanning unit being portable and sized and shaped to be handheld.

32. The biosensor system of claim 27, wherein the ultrasound detection means forms part of a scanning unit configured for attachment on the surface of a patient'"'"'s body adjacent to the location at which the sensor chip is implanted.

33. A biosensor system comprising:

an implantable analyte-sensitive hydrogel slab chemically configured to vary its displacement volume according to changes in concentration of an analyte in a body fluid in a body in which the hydrogel slab is implanted; and

means for magnetic resonance scanning capable of detecting changes in the displacement volume of the hydrogel slab when it is implanted within the body.

34. A biosensor system comprising:

an implantable analyte-sensitive hydrogel slab chemically configured to vary its displacement volume according to changes in concentration of an analyte in a body fluid in a body in which the hydrogel slab is implanted; and

means for computerized tomography capable of detecting changes in the displacement volume of the hydrogel slab when it is implanted within the body.

35. An implantable biosensor chip for implantation into a patient'"'"'s body comprising:

a support block formed of rigid or semi-rigid, biocompatible material,

a groove in the support block having one or more openings permitting penetration of a patient'"'"'s body fluid,

a semipermeable membrane configured to permit passage of the analyte and prevent passage of proteins into the groove; and

an analyte sensitive hydrogel slab disposed within the groove, said hydrogel slab being chemically configured to vary its displacement volume according to changes in concentration of an analyte in the body fluid, said hydrogel slab being further configured to be detectable by externally-based means for imaging body structures, said hydrogel slab being shaped as a filament having a length dimension Y which is substantially greater than first and second width dimensions X and Z, and wherein the groove is sized to permit expansion of the hydrogel slab in the length dimension and to substantially prevent expansion of the hydrogel slab in one or both of the width dimensions.

36. The biosensor chip of claim 35 wherein the lengthwise dimension Y is between about 0.2 cm and about 2 cm.

37. The biosensor chip of claim 36, wherein the lengthwise dimension of the filament is between about 5 and about 50 times each of the first and second widths.

38. The biosensor chip of claim 35, wherein the support block further has a second groove containing a reference hydrogel slab, the second groove having one or more openings permitting the body fluid to contact the reference hydrogel slab, and the reference hydrogel slab being insensitive to analyte concentration but otherwise substantially identical in dimensions and chemical composition to the analyte-sensitive hydrogel.

39. The biosensor chip of claim 35, wherein the support block is formed of a material selected from the group consisting of:

Teflon, rigid or semi-rigid plastics, stainless steel, ceramics, and composite materials.

40. The biosensor chip of claim 35, wherein the hydrogel slab has pendant charged groups selected to confer pH-sensitivity, such that the hydrogel swells or shrinks according to changes in pH.

41. The biosensor chip of claim 40, wherein the pendant charged groups are selected from the group consisting of:

3-[N,N-dimethylamino)propyl]acrylamide, -(2,2-diethylaminoethyl) methacrylate, N(2,2-dimethylaminoethyl) methacrylate, N-(2,2-dimethylaminoethyl) acrylamide, N,N-dimethyl acrylamide, vinyl pyridine, acrylic acid, methacryl acid, sodium acryl acid, and 2-acrylamino-2-methyl propanesulfonic acid.

42. The biosensor chip of claim 40, wherein the pendant charged groups confer either a net negative charge or a net positive charge on the hydrogel slab.

43. The biosensor chip of claim 35, wherein the hydrogel slab is composed of one or more chemical subunits selected from the group consisting of:

acrylamide, dimethyl-acrylamide, sodium acrylate, hydroxypropyl methacrylate, 2-hydroxyethyl methacrylate, diethylaminoethyl methacrylate, isobutyl methacrylate, butyl methacrylate, isopropyl methacrylate, n-alkyl methacrylate, acrylamide, N-isopropylacrylamide, N-tert-butylacrylamide, N,N-dimethylacrylamide, N,N′

-methylene-bis-acrylamide, polyvinyl alcohol, N-[3-(N,N′

-dimethylamino)propyl]acrylamide, styrene, and 3-methacryl-amidophenylboronic acid.

44. The biosensor chip of claim 35, wherein the hydrogel slab is chemically configured to vary its displacement volume according to the concentration of glucose in a human body fluid.

45. The biosensor chip of claim 44, wherein the hydrogel further includes a quantity of immobilized molecules having glucose oxidase activity.

46. An implantable biosensor chip for implantation into a patient'"'"'s body comprising:

a support block formed of rigid or semi-rigid, biocompatible material;

a groove in the support block having one or more openings permitting penetration of a patient'"'"'s body fluid;

a semipermeable membrane configured to permit passage of the analyte and prevent passage of proteins into the groove;

an analyte sensitive hydrogel slab disposed within the groove, said hydrogel slab being chemically configured to vary its displacement volume according to changes in concentration of an analyte in the body fluid, and said hydrogel slab being further configured to be detectable by externally-based means for imaging body structures; and

scale means disposed on said support block and located adjacent the hydrogel slab for providing known scale dimensional values to compare with the hydrogel slab, said scale means being detectable in simultaneity with the hydrogel slab.

47. An implantable biosensor chip for implantation into a patient'"'"'s body comprising:

a support block formed of rigid or semi-rigid, biocompatible material,

a groove in the support block having one or more openings permitting penetration of a patient'"'"'s body fluid,

a semipermeable membrane configured to permit passage of the analyte and prevent passage of proteins into the groove;

an analyte sensitive hydrogel slab disposed within the groove, said hydrogel slab being chemically configured to vary its displacement volume according to changes in concentration of glucose in a human body fluid, and said hydrogel slab being further configured to be detectable by externally-based means for imaging body structures;

a quantity of glucose-binding moieties immobilized in the hydrogel; and

a quantity of complementary molecules immobilized in the hydrogel, said complementary molecules configured to selectively bind to said glucose-binding moieties.

48. The biosensor chip of claim 47, wherein the glucose-binding moieties are selected from the group consisting of:

boronic acids, phenylboronic acid, 3-methylacrylamido-phenylboronic acid, 3-acrylamidophenylboronic acid, inactivated glucose-binding enzymes, glucose binding sites derived from glucose-binding enzymes, glucose-specific antibodies, lectins, concanavalin A, and glucose binding sites derived from lectins.

49. The biosensor chip of claim 47, wherein the complementary molecules are selected from the group consisting of:

diols, poly(vinyl)alcohol, glucosyloxyethylmethacrylate, acryl glucose, N-(2-D-glucose)acrylamide, and hexose saccharides.

50. The biosensor chip of claim 47, wherein the groove has three dimensions x, y, and z, and wherein the groove is sized to permit expansion of the hydrogel slab in the y-dimension only.

51. An implantable biosensor chip for implantation into a patient'"'"'s body comprising:

a support block formed of rigid or semi-rigid, biocompatible material,

a groove in the support block having one or more openings permitting penetration of a patient'"'"'s body fluid, said groove having three dimensions x, y, and z, and wherein the groove is sized to permit expansion of the hydrogel slab in the y-dimension only;

a semipermeable membrane configured to permit passage of the analyte and prevent passage of proteins into the groove; and

an analyte sensitive hydrogel slab disposed within the groove, said hydrogel slab being chemically configured to vary its displacement volume according to changes in concentration of an analyte in the body fluid, said hydrogel slab being further configured to be detectable by externally-based means for imaging body structures, and wherein under an initial condition the hydrogel slab has a width x₀, thickness z₀, and length y₀, y₀ being between about 5 and about 50 times greater than both x₀ and y₀.

52. The biosensor chip of claim 51, wherein y₀ is between about 0.2 cm and about 2 cm.

53. The biosensor chip of claim 52, wherein the hydrogel slab is made up of a plurality of individual pieces of hydrogel.

54. A method of monitoring an analyte in a patient'"'"'s body fluid in situ, comprising the steps of:

implanting a biosensor chip having a support block formed of rigid or semi-rigid, biocompatible material;

a groove in the support block having one or more openings permitting penetration of a patient'"'"'s body fluid;

a semipermeable membrane configured to permit passage of the analyte and prevent passage of proteins into the groove; and

an analyte sensitive hydrogel slab disposed within the groove, said hydrogel slab being chemically configured to vary its displacement volume according to changes in concentration of an analyte in the body fluid, and said hydrogel slab being further configured to be detectable by externally-based means for imaging body structures in the patient'"'"'s body;

providing means for scanning the hydrogel slab in the biosensor chip implanted within the patient'"'"'s body, and

arranging and operating the hydrogel scanning means to detect changes in the displacement volume of the hydrogel.

55. The method of claim 54, wherein the step of providing hydrogel scanning means is a step of providing ultrasound detection means disposed and configured to detect changes in the displacement volume of the hydrogel.

56. The method of claim 54, wherein the step of providing hydrogel scanning means is a step of providing means for magnetic resonance scanning.

57. The method of claim 54, where including a step of providing computing means operably associated with the scanning means for translating a measured value of the displacement volume to a corresponding analyte concentration, and producing an output signal reflective thereof.

58. The method of claim 57, further including a step of calibrating the displacement volume against the concentration of analyte in a solution, said calibration step including steps of:

contacting the sensor chip with a series of solutions having different known concentrations of analyte,

storing a value of the displacement volume for each of the solutions, and

constructing a calibration curve for translating a measured displacement volume to a corresponding analyte concentration.

59. The method of claim 58, wherein the analyte is glucose.

60. A biosensor system comprising:

an implantable sensor chip including an analyte-sensitive hydrogel slab chemically configured to vary its displacement volume according to changes in concentration of an analyte in a patient'"'"'s body fluid; and

image scanning means configured to image the hydrogel slab and to quantify changes in the displacement volume.

61. The biosensor system of claim 60, wherein the sensor chip further includes a support block made of a rigid or semi-rigid support material, and the hydrogel slab is disposed within a groove formed in the block, the groove having one or more openings permitting the body fluid to contact the hydrogel slab.

62. The biosensor system of claim 61, wherein the groove is sized and configured to permit only one-dimensional elongation or contraction of the hydrogel slab.

63. The biosensor system of claim 61, wherein the sensor chip further includes a reference hydrogel slab disposed within a second groove, there reference hydrogel being chemically configured to be insensitive to analyte concentration but otherwise substantially identical to the analyte-sensitive hydrogel, and the second groove also having an opening permitting contact between the body fluid and the reference hydrogel slab.

64. The biosensor system of claim 61, wherein the sensor chip further includes scale marks disposed adjacent to the hydrogel slab, said scale marks being detectable by the scanning means in simultaneity with the hydrogel slab.

65. The biosensor system of claim 60, wherein the hydrogel slab is chemically configured to vary its displacement volume according to the concentration of glucose in a human body fluid.

66. The biosensor system of claim 65, wherein the hydrogel further includes a quantity of immobilized molecules having glucose oxidase activity.

67. The biosensor system of claim 66, wherein the glucose-binding moieties are selected from the group consisting of:

boronic acids, phenylboronic acid, inactivated glucose-binding enzymes, glucose binding sites derived from glucose-binding enzymes, glucose-specific antibodies, lectins, and glucose binding sites derives from lectins.

68. The biosensor system of claim 65, wherein the hydrogel has

a quantity of glucose-binding moieties immobilized therein, and

a quantity of complementary molecules immobilized therein, said complementary molecules configured to selectively bind to said glucose-binding moieties.