TISSUE IMPLANTABLE SENSOR WITH HERMETICALLY SEALED HOUSING

• US 20130197332A1
• Filed: 07/26/2012
• Published: 08/01/2013
• Est. Priority Date: 07/26/2011
• Status: Active Grant

• Current Assignee: Mcnair Interests Limited
• Original Assignee: GlySens, Incorporated
• Inventors: Lucisano, Joseph Y., Lin, Joe T., Catlin, Mark B., Choi, William J., Chu, Payton C., Routh, Timothy L., Wallner, Thomas G.
• Granted Patent: US 10,561,351 B2
• Time in Patent Office: Days
• US Class Current: 600/345
• CPC Class Codes: A61B 2562/0209 Special features of electrodes classified in A61B5/24, A61B5/25, A61B5/283, A61B5/291, A61B5/296, A61B5/053
• CPC Class Codes: A61B 2562/04 Arrangements of multiple sensors of the same type
• CPC Class Codes: A61B 5/0031 Implanted circuitry
• CPC Class Codes: A61B 5/076 Permanent implantations telemetry using implanted circuitry A61B5/0031; implanted stimulators for therapy A61N1/3605, A61N1/362, A61N1/372
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14542 for measuring blood gases A61B5/14551 takes precedence
• CPC Class Codes: A61B 5/14546 for measuring analytes not otherwise provided for, e.g. ions, cytochromes
• CPC Class Codes: A61B 5/1473 invasive, e.g. introduced into the body by a catheter A61B5/1482 takes precedence
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: A61B 5/7203 for noise prevention, reduction or removal
• CPC Class Codes: A61B 5/7221 Determining signal validity, reliability or quality A61B5/7207 and A61B5/7217 take precedence
• CPC Class Codes: A61B 5/7278 Artificial waveform generation or derivation, e.g. synthesising signals from measured signals A61B5/327 takes precedence
• CPC Class Codes: Y10T 29/49117 Conductor or circuit manufacturing
• CPC Class Codes: Y10T 29/49826 Assembling or joining

Abstract

A tissue-implantable sensor for measurement of solutes in fluids and gases, such as oxygen and glucose, is provided. The sensor includes: i) a detector array including at least one detector; ii) a telemetry transmission portal; iii) an electrical power source; and iv) circuitry electrically connected to the detector array including signal processing means for determining an analyte level, such as glucose level, in a body fluid contacting the detectors. The sensor components are disposed in a hermetically sealed housing having a size and shape suitable for comfortable, safe, and unobtrusive subcutaneous implantation allowing for in vivo detection and long term monitoring of tissue glucose concentrations by wireless telemetry.

Claims

1. An implantable analyte sensor, comprising:

a) a biocompatible hermetically sealed housing having a size and shape suitable for implantation in the body;

b) a detector array comprising at least one detector and a membrane layer;

c) an electrical power source;

d) circuitry operatively connected to the detector array comprising functionality for accurately processing detector signals; and

e) a telemetry transmission portal for stably transmitting processed detector signals to an external receiver outside of a body when implanted subcutaneously,

wherein c) and d) are disposed within the housing and b) and e) are disposed within or upon the housing.

2. The sensor of claim 1, wherein the detector array comprises at least two detectors.

3. The sensor of claim 2, wherein the detector array comprises between two and eighteen detectors.

4. The sensor of claim 2, wherein the detectors are arranged in a radial pattern.

5. The sensor of claim 2, wherein the detectors comprise electrochemical detectors that utilize at least one counter electrode.

6. The sensor of claim 5, wherein the electrolyte layers of at least two of the detectors have no common aqueous or ionic connection.

7. The sensor of claim 6, wherein the at least two of the detectors utilize separate regions of a common counter electrode, where such separate regions are not in aqueous or ionic contact.

8. The sensor of claim 1, wherein at least one of the detectors utilizes a working electrode, a reference electrode, and a counter electrode.

9. The sensor of claim 8, wherein the working electrode, reference electrode, and counter electrode of at least one of the detectors are arranged such that the ionic path between the reference electrode and the working electrode does not overlap to a significant extent the ionic path between the working and counter electrodes.

10. The sensor of claim 3, wherein the detector array comprises between two and eight detectors.

11. The sensor of claim 1, wherein each detector comprises a working electrode, a counter electrode, and a reference electrode.

12. The sensor of claim 11, wherein the working electrode is substantially circular and has a radius between 20 μ

m and 500 μ

m.

13. The sensor of claim 12, wherein the working electrode has a radius of about 300 μ

m.

14. The sensor of claim 11, wherein the working electrode and counter electrode are composed of platinum, and the reference electrode is composed of Ag/AgCl.

15. The sensor of claim 1, wherein the membrane layer comprises a source of glucose oxidase (GO) for catalyzing the reaction of glucose and oxygen, and further wherein the GO of the membrane layer is positioned in operative contact with a working electrode of at least one of the detectors.

16. The sensor of claim 15, where the glucose oxidase has an operating lifetime of greater than six months.

17. The sensor of claim 1, wherein tissue-contacting sites of the membrane layer are substantially biocompatible and non-immunogenic.

18. The sensor of claim 1, wherein the detector array further comprises at least one layer of an electrolyte, at least one layer of a hydrophobic polymer, or combinations thereof.

19. The sensor of claim 18, wherein the hydrophobic polymer comprises polydimethylsiloxane (PDMS).

20. The sensor of claim 18, wherein tissue-contacting aspects of the sensor are substantially biocompatible and non-immunogenic.

21. The sensor of claim 1, wherein the detector array further comprises a coating layer comprising a substantially biocompatible and non-immunogenic material.

22. The sensor of claim 21, wherein the material comprises collagen, albumin, crosslinked collagen, or crosslinked albumin.

23. The sensor of claim 1, wherein the detector array is disposed on a ceramic substrate.

24. The sensor of claim 23, wherein the ceramic substrate comprises alumina.

25. The sensor of claim 23, wherein the ceramic substrate is a planar substrate having a major dimension, a minor dimension, and a thickness.

26. The sensor of claim 25, wherein the major dimension and minor dimension define a generally round, elliptical, square, rectangular, oval, triangular, or polygonal shape.

27. The sensor of claim 1, wherein the circuitry operatively connected to the detector array further comprises functionality for transmitting RF signals at a predetermined carrier frequency.

28. The sensor of claim 27, wherein the telemetry transmission portal conveys the predetermined RF signals.

29. The sensor of claim 27, wherein the RF carrier frequency is between about 30 MHz and 3 GHz.

30. The sensor of claim 27, wherein the RF carrier frequency is within a range selected from the group consisting of:

from about 314 MHz to about 316 MHz;

from about 401 MHz to about 406 MHz;

from about 433 MHz to about 435 MHz;

from about 863 MHz to about 870 MHz;

from about 902 MHz to about 928 MHz; and

from about 2360 MHz to about 2500 MHz.

31. The sensor of claim 1, wherein the electrical power source is a battery with a life of greater than 1 year.

32. The sensor of claim 1, further comprising a tissue anti-slip element on a surface of the detector array.

33. The sensor of claim 32, wherein the tissue anti-slip element promotes interlock of sensor detectors with biological tissue.

34. The sensor of claim 33, wherein the tissue anti-slip element is a three-dimensional membrane layer structure.

35. The sensor of claim 34, wherein the three-dimensional membrane layer structure is produced by variable thickness of the membrane across the detector array.

36. The sensor of claim 1, further comprising an anti-migration element on an outer aspect of the sensor.

37. The sensor of claim 36, wherein the anti-migration element is at least one velour fabric patch.

38. The sensor of claim 36, wherein the anti-migration element is at least one suture attachment means.

39. The sensor of claim 38, wherein the suture attachment means is a through-hole at a site of the sensor or a wire loop coupled to a site of the sensor housing.

40. The sensor of claim 1, wherein the telemetry transmission portal and detector array are opposably positioned within the housing.

41. The sensor of claim 40, wherein the housing is generally planar having a major dimension, a minor dimension and a thickness.

42. The sensor of claim 41, wherein the minor dimension and thickness are each less than about two-thirds of the major dimension.

43. The sensor of claim 40, wherein the housing is generally planar having a major dimension, a minor dimension and a variable thickness across the major or minor dimension.

44. The sensor of claim 43, wherein the housing comprises at least 2 different thicknesses across the major or minor dimension.

45. The sensor of claim 40, wherein the housing has a thickness within 25% of a thickness of the electrical power source.

46. The sensor of claim 1, wherein the telemetry transmission portal and detector array are positioned on non-opposed aspects of the housing.

47. The sensor of claim 46, wherein the housing is generally planar having a major dimension, a minor dimension and a thickness.

48. The sensor of claim 47, wherein the minor dimension and thickness are each less than about two-thirds of the major dimension.

49. The sensor of claim 46, wherein the housing is generally planar having a major dimension, a minor dimension and a variable thickness across the major or minor dimension.

50. The sensor of claim 49, wherein the housing comprises at least 2 different thicknesses across the major or minor dimension.

51. The sensor of claim 46, wherein the housing has a thickness within 25% of a thickness of the electrical power source.

52. The sensor of claim 1, further comprising one or more electronics modules disposed within the housing.

53. The sensor of claim 52, wherein transmission of electrical interference between at least two electronics modules is inhibited or blocked by a partially or entirely interposed electrically conductive shield, thereby reducing noise pickup by sensor measurement circuitry and improving reproducibility of the sensor signal measurements.

54. The sensor of claim 53, wherein the shield is a planar substrate that is entirely interposed between the at least two electronics modules.

55. The sensor of claim 53, wherein each electronics module is disposed on opposing surfaces of the interposed planar substrate.

56. The sensor of claim 53, wherein each electronics module is disposed on a separate planar substrate.

57. The sensor of claim 53, wherein the interposed substrate comprises the electrical power source, and wherein the electrical power source is a battery.

58. The sensor of claim 57, wherein the electronics modules and the battery are disposed between the detector array and telemetry transmission portal.

59. The sensor of claim 58, wherein the detector array, electronics modules, battery and telemetry transmission portal are oriented substantially parallel to a major dimension of the housing.

60. The sensor of claim 58, wherein the detector array, electronics modules, and battery are oriented substantially parallel to a major dimension of the housing, and the telemetry transmission portal is oriented substantially parallel to a minor dimension of the housing.

61. The sensor of claim 53, wherein the electronics modules are disposed between the detector array and telemetry transmission portal and the electrical power source is disposed adjacent to the electronics modules.

62. The sensor of claim 53, wherein the detector array, electronics modules, electrical power source and telemetry transmission portal are oriented substantially parallel to a major dimension of the housing.

63. The sensor of claim 53, wherein the detector array, electronics modules, and electrical power source are oriented substantially parallel to a major dimension of the housing, and the telemetry transmission portal is oriented substantially parallel to a minor dimension of the housing.

64. The sensor of claim 1, wherein the telemetry transmission portal comprises an RF-transparent material for conveying radiated RF signals from the interior of the sensor to the exterior.

65. The sensor of claim 1, wherein the telemetry transmission portal comprises an electrical feedthrough for conducting RF signals from the interior of the sensor to a transmitting antenna located on the exterior of the sensor.

66. The sensor of claim 65, where the transmitting antenna is located on an exterior surface of the telemetry transmission portal.

67. The sensor of claim 1, wherein the telemetry transmission portal comprises a transmitting antenna.

68. The sensor of claim 1, wherein the sensor has a signal delay less than about 40, 30, 20, or 10 minutes.

69. The sensor of claim 1, wherein the detector array is adapted to detect one or more analytes.

70. The sensor of claim 69, wherein the one or more analytes are selected from the group consisting of:

glucose, oxygen, lactate, insulin, cholesterol, nitric acid, glutamate, dopamine, glutamine, ethanol, choline, hydrogen, carbon dioxide, and hydrogen peroxide.

71. The sensor of claim 1, wherein the membrane layer comprises a crosslinked protein.

72. The sensor of claim 1, wherein the membrane layer comprises an immobilized enzyme.

73. The sensor of claim 72, wherein the membrane layer comprises a source of glucose oxides (GO) for catalyzing the reaction between glucose and oxygen.

74. The sensor of claim 73, wherein the membrane layer further comprises catalase.

75. The sensor of claim 1, further comprising an electrical connection means within the housing that provides a path for making electrical contact with the electrodes of the detector array, whereby such contact may be made prior to closure of the housing.

76. The sensor of claim 75, wherein the electrical connection means is utilized during operation of the sensor to maintain connection between the electrodes and one or more electronics modules within the sensor.

77. A method of monitoring glucose level in a subject, comprising:

a) implanting the sensor of claim 1 into a tissue of the subject;

b) detecting sensor signals indicative of a glucose level in the subject; and

c) wirelessly transmitting the sensor signals via the telemetry transmission portal to an external receiver.

78. The method of claim 77, wherein detecting and transmitting is performed near-continuously.

79. The method of claim 77 wherein the transmitting is performed periodically.

80. The method of claim 77, wherein the glucose level is monitored for more than six months without removing the sensor.

81. The method of claim 79, wherein the sensor signals are transmitted at an interval between 30 seconds and 5 minutes.

82. The method of claim 81, wherein the sensor signals are transmitted at an interval between 1 minute and 3 minutes.

83. The method of claim 82, wherein the sensor signals are transmitted at an interval of about 2 minutes.

84. The method of claim 77, wherein the implanting comprises blunt dissection.

85. The method of claim 77, wherein the implanting comprises positioning the sensor so that the telemetry transmission portal is oriented to face toward a skin surface of the subject.

86. The method of claim 77, further comprising calibrating the sensor using the sensor signals related to a glucose excursion.

87. The method of claim 77, further comprising analyzing the glucose level and providing a therapeutic treatment, a therapeutic treatment recommendation, a warning, or combination thereof.

88. A method of monitoring glucose level in a subject, comprising:

a) implanting a plurality of the sensors of claim 1 into at least one tissue of the subject;

b) detecting sensor signals indicative of a glucose level in the subject; and

c) wirelessly transmitting the sensor signals via the telemetry transmission portal to an external receiver.

89. The method of claim 88, further comprising analyzing the glucose level and providing a therapeutic treatment, a therapeutic treatment recommendation, a warning, or combination thereof.

90. A method of treating diabetes in a subject, comprising:

a) implanting the sensor of claim 1 into a tissue of the subject;

b) monitoring the glucose level in the subject;

c) analyzing the glucose level; and

d) providing a therapeutic treatment, a therapeutic treatment recommendation, a warning, or combination thereof.

91. The method of claim 90, wherein the therapeutic treatment comprises administering a therapeutic drug.

92. The method of claim 91, wherein the therapeutic drug is an anti-diabetes drug.

93. A method of manufacturing the medical device of claim 1, comprising:

a) generating a seal between a portion of the housing and a ceramic substrate of the detector array, or between a portion of the housing and the telemetry transmission portal via application of a first joining process; and

b) generating a seal between at least two portions of the housing via application of a second joining process, wherein the resulting housing is hermetically sealed.

94. The method of claim 93, wherein the first joining process is performed by generalized heating of the portion of the housing, and the ceramic substrate or the telemetry transmission portal to produce the seal.

95. The method of claim 94, wherein the first joining process comprises brazing, furnacing, or torching.

96. The method of claim 93, wherein the second joining process is performed by localized heating of the portions of the housing at discrete regions where the seal is generated.

97. The method of claim 96, wherein the second joining process comprises laser or electron beam welding.

98. The method of claim 93, wherein the electrical power source and circuitry are introduced within the at least two portions of the housing before application of the second joining process.

99. A method of manufacturing the medical device of claim 75, comprising:

a) generating a seal between a portion of the housing and a ceramic substrate of the detector array;

b) installing an electrical connector means into a section of the housing that includes the ceramic substrate;

c) establishing electrical connection between the electrodes and the connector means within the housing section;

d) connecting external instrumentation to the connector means to test or electroplate the electrodes.

100. The sensor of claim 2, wherein the at least two detectors are configured to enable an oxygen-sensing differential measurement of an analyte, and membranes of the main analyte detector and the oxygen reference detector are selected to provide matching response times with respect to oxygen changes, thereby minimizing artifactual fluctuations in the sensor-reported analyte level.