Bio-adaptable implantable sensor apparatus and methods

• US 10,638,962 B2
• Filed: 06/29/2016
• Issued: 05/05/2020
• Est. Priority Date: 06/29/2016
• Status: Active Grant

• Current Assignee: Mcnair Interests Limited
• Original Assignee: GlySens, Incorporated
• Inventors: Lucisano, Joseph, Routh, Timothy, Lin, Joe
• Primary Examiner(s): Natnithithadha, Navin
• Application Number:
  US15/197,104
• Publication Number:
  US 20180000395A1
• Time in Patent Office: 1,406 Days
• Field of Search: 600309, 600345-365
• CPC Class Codes: A61B 2562/046 in a matrix array
• CPC Class Codes: A61B 2562/162 Capsule shaped sensor housings, e.g. for swallowing or implantation
• CPC Class Codes: A61B 2562/18 Shielding or protection of sensors from environmental influences, e.g. protection from mechanical damage
• CPC Class Codes: A61B 2562/247 Hygienic covers, i.e. for covering the sensor or apparatus during use
• 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 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
• CPC Class Codes: A61B 5/6861 Capsules, e.g. for swallowing or implanting

Abstract

Biocompatible implantable sensor apparatus and methods of implantation and use. In one embodiment, the sensor apparatus is an oxygen-based glucose sensor having biocompatibility features that mitigate the host tissue response. In one variant, these features include use of a non-enzymatic membrane over each of the individual analyte detectors so as to preclude contact of the surrounding tissue with the underlying enzyme or other matrix, and mitigate vascularization, and insulation of the various electrodes and associated electrolytic processes of the sensor from the surrounding tissue. In one implementation, the sensor region of the implanted apparatus is configured to interlock or imprint the surrounding tissue so as to promote a high degree of glucose molecule diffusion into the individual detectors, and a constant and predictable sensor to blood vessel interface, yet preclude the tissue from bonding to the sensor, especially over extended periods of implant.

Claims

1. An analyte sensor, comprising:

a biocompatible housing having a size and a shape suitable for implantation in a body;

a plurality of glucose-modulated oxygen detectors, at least a working electrode of each of the plurality of glucose-modulated oxygen detectors in communication with at least one glucose oxidase and catalase-embedded material, the at least one glucose oxidase and catalase-embedded material enclosed in a membrane structure, the membrane structure configured to provide a barrier between biological tissues of the body and the at least one glucose oxidase and catalase-embedded material at least when the analyte sensor is implanted in a tissue environment within the body;

circuitry operatively connected to the plurality of glucose-modulated oxygen detectors and configured to process at least a portion of signals generated by at least a portion of said plurality of glucose-modulated oxygen detectors to produce processed signals;

one or more wireless data transmission apparatus configured to transmit at least a portion of said processed signals; and

an electrical power source operatively coupled to at least the circuitry and the data transmission apparatus and configured to provide electrical power thereto;

wherein said circuitry at least in part comprises processing logic which is configured to;

identify one or more of the plurality of glucose-modulated oxygen detectors which each experience signal variations caused by biological processes within the body after the analyte sensor has been implanted in the tissue environment within the body;

based at least in part on the identification, selectively remove glucose-modulated signals respectively generated by the identified one or more of the plurality of glucose-modulated oxygen detectors from processing of a composite glucose-modulated signal; and

generate the composite glucose-modulated signal from other glucose-modulated signals respectively generated by one or more remaining non-identified ones of the plurality of glucose-modulated oxygen detectors which have not experienced the signal variations, the composite glucose-modulated signal useful for calculation of a blood glucose level value.

2. The analyte sensor of claim 1, wherein:

the signal variations caused by biological processes within the body are caused by tissue response of the body due to implantation of the analyte sensor; and

the selective removal of the glucose-modulated signals respectively generated by the identified one or more of the plurality of glucose-modulated oxygen detectors from processing of the composite glucose-modulated signal comprises substitution of first glucose-modulated signals generated by the one or more remaining ones of said plurality of glucose-modulated oxygen detectors of said analyte sensor that have not experienced said signal variations for second glucose-modulated signals generated by the one or more of said plurality of glucose-modulated oxygen detectors that have experienced said signal variations.

3. The analyte sensor of claim 1, wherein the processing logic is further configured to, based at least on the identification of the one or more of the plurality of glucose-modulated oxygen detectors which each experience signal variations, implement an automatic signal scaling process.

4. The analyte sensor of claim 1, wherein the selective removal of the glucose-modulated signals respectively generated by the identified one or more of the plurality of glucose-modulated oxygen detectors from the processing of a composite glucose-modulated signal at least in part comprises:

selective decrease of a weight value associated with the glucose-modulated signals respectively generated by the identified one or more of the plurality of glucose-modulated oxygen detectors during the processing by the circuitry and generation of the composite glucose-modulated signal; and

selective increase of a weight value associated with the other glucose-modulated signals respectively generated by the one or more remaining non-identified ones of the plurality of glucose-modulated oxygen detectors which have not experienced the signal variations during the processing by the circuitry and generation of the composite glucose-modulated signal.

5. The analyte sensor of claim 4, the selective decrease of the weight value-associated with the glucose-modulated signals respectively generated by the identified one or more of the plurality of glucose-modulated oxygen detectors and the selective increase of the weight value associated with the other glucose-modulated signals respectively generated by the one or more remaining non-identified ones of the plurality of glucose-modulated oxygen detectors which have not experienced the signal variations enable the fully subcutaneous implantation and operation of the analyte sensor for at least one year without explant thereof.

6. The analyte sensor of claim 4, wherein the selective decrease of the weight value associated with the glucose-modulated signals respectively generated by the identified one or more of the plurality of glucose-modulated oxygen detectors comprises incremental decrease of the weight value associated with the glucose-modulated signals respectively generated by the identified one or more of the plurality of glucose-modulated oxygen detectors over a period of time of operation of the analyte sensor.

7. The analyte sensor of claim 1, wherein the membrane structure for each of the plurality of glucose-modulated oxygen detectors at least in part comprises a porous crosslinked protein-based material having a plurality of pores of a prescribed pore diameter at least on an outer surface of the membrane structure, the prescribed pore diameter configured to, when the analyte sensor is disposed in the tissue environment within the body, both (i) frustrate vascularization therein, and (ii) permit migration of blood glucose therethrough.

8. The analyte sensor of claim 7, wherein the plurality of pores of the prescribed pore diameter comprises one of:

(i) a plurality of pores of an average pore diameter of approximately 5 microns, or (ii) a plurality of pores of a median pore diameter of approximately 5 microns.

9. The analyte sensor of claim 7, wherein the plurality of pores of the prescribed pore diameter comprises a plurality of pores of an average pore diameter in the range of 5 to 10 microns inclusive.

10. The analyte sensor of claim 7, wherein the plurality of pores of the prescribed pore diameter comprises a plurality of pores having a maximum of 5 microns for each of the plurality of pores.

11. The analyte sensor of claim 7, wherein the porous crosslinked protein-based material is formed from a flowable protein-based material which is subsequently exposed to a cross-linking agent to form a non-flowable protein-based material having the plurality of pores of the prescribed pore diameter.

12. The analyte sensor of claim 1, wherein the membrane structure comprises a plurality of respective membranes each configured to insulate the biological tissues from respective ones of the at least one glucose oxidase and catalase-embedded material of each of the plurality of glucose-modulated oxygen detectors at least when the analyte sensor is disposed in the tissue environment within the body.

13. The analyte sensor of claim 12, wherein each of the plurality of respective membranes comprises a mostly enzyme-free chemically crosslinked albumin-based material.

14. The analyte sensor of claim 1, wherein the at least one glucose oxidase and catalase-embedded material is configured to at least transiently produce hydrogen peroxide in a reaction with blood glucose.

15. The analyte sensor of claim 1, wherein the membrane structure comprises, for each of the plurality of glucose-modulated oxygen detectors:

an outer body element having at least one aperture formed therein, the outer body element defining an interior cavity, wherein the at least one glucose oxidase and catalase-embedded material is disposed within the interior cavity; and

a non-enzymatic membrane material disposed at least partly within the at least one aperture.

16. The analyte sensor of claim 15, wherein:

at least the outer body element is configured to electrically insulate the biological tissues from the working electrode during operation when the analyte sensor is disposed in the tissue environment within the body.

17. The analyte sensor of claim 16, wherein:

the outer body element configured to electrically insulate the biological tissues from the working electrode during operation comprises an electrically insulating membrane configured to be disposed between at least the working electrode and the biological tissues when the analyte sensor is disposed in the tissue environment within the body; and

wherein the electrically insulating membrane disposed between at least the working electrode and the biological tissues comprises silicone rubber.

18. The analyte sensor of claim 1, wherein said circuitry at least in part comprises processing logic which is further configured to:

based at least in part on the identification, deactivate the identified one or more of the plurality of glucose-modulated oxygen detectors.

19. The analyte sensor of claim 1, wherein the signal variations caused by biological processes comprises signal variations over time due to one or more foreign body response (FBR) processes.

20. The analyte sensor of claim 1, wherein the signal variations caused by biological processes comprises signal variations over time due to one or more of (i) variations in vascularization, or (ii) long-term variations in blood flow.

21. The analyte sensor of claim 1, wherein the identification of the one or more of the plurality of glucose-modulated oxygen detectors comprises a determination that at least one of an active sensor and a reference sensor of the identified one or more of the plurality of glucose-modulated oxygen detectors fails to meet one or more criteria related to signal stability.

22. The analyte sensor of claim 1, wherein said circuitry at least in part comprises processing logic which is configured to:

based at least in part on the identification, deactivate an active sensor and a reference sensor of the identified one or more of the plurality of glucose-modulated oxygen detectors.

23. An analyte sensor, comprising:

a biocompatible housing having a size and a shape suitable for implantation in a body;

a plurality of glucose-modulated oxygen detectors each comprising an enzymatic material, the enzymatic material enclosed in a membrane structure, the membrane structure configured to provide a barrier between biological tissues of the body and the enzymatic material at least when the analyte sensor is implanted in a tissue environment within the body;

circuitry operatively connected to the plurality of glucose-modulated oxygen detectors and configured to process at least a portion of signals generated by at least a portion of said plurality of glucose-modulated oxygen detectors to produce processed signals;

wireless data transmission apparatus configured to transmit data relating to said processed signals; and

an electrical power source operatively coupled to at least the circuitry and the data transmission apparatus and configured to provide electrical power thereto;

wherein said circuitry at least in part comprises processing logic which is configured to;

identify at least one of the plurality of glucose-modulated oxygen detectors which experiences unacceptable signal performance after the analyte sensor has been implanted in the tissue environment within the body;

based at least in part on the identification, selectively remove glucose-modulated signals generated by the identified at least one of the plurality of glucose-modulated oxygen detectors from generation of a composite glucose-modulated signal, the composite glucose-modulated signal generated using only one or more remaining non-identified ones of the plurality of glucose-modulated oxygen detectors, the composite glucose-modulated signal useful for calculation of a blood glucose level value.

24. The analyte sensor of claim 23, wherein the processing logic is further configured to utilize the composite glucose-modulated signal to calculate at least one blood glucose level value.

25. The analyte sensor of claim 24, wherein the analyte sensor is configured to utilize the wireless data transmission apparatus to wirelessly transmit the at least one blood glucose level value to a data receiver device disposed external to the body.

26. The analyte sensor of claim 24, wherein the analyte sensor is configured to utilize the wireless data transmission apparatus to wirelessly transmit the at least one blood glucose level value to a data receiver device disposed internal to the body, the data receiver device being associated with a medicant delivery system.

27. The analyte sensor of claim 23, wherein the identification of the at least one of the plurality of glucose-modulated oxygen detectors which experiences unacceptable signal performance after the analyte sensor has been implanted in the tissue environment within the body comprises identification of at least one glucose-modulated detector whose performance degrades over a period of time, the period of time being within a time that the analyte sensor is implanted in the body.

28. An analyte sensor, comprising:

a biocompatible housing having a size and a shape suitable for implantation in a body;

a plurality of glucose-modulated oxygen detectors each comprising an enzymatic material, the enzymatic material enclosed in a membrane structure, the membrane structure configured to provide a barrier between biological tissues of the body and the enzymatic material at least when the analyte sensor is implanted in a tissue environment within the body;

circuitry operatively connected to the plurality of glucose-modulated oxygen detectors and configured to process signals generated by said plurality of glucose-modulated oxygen detectors to produce processed signals, the signals generated by each of the plurality of glucose-modulated oxygen detectors having a weight associated therewith;

wireless data transmission apparatus configured to transmit data relating to said processed signals; and

an electrical power source operatively coupled to at least the circuitry and the wireless data transmission apparatus and configured to provide electrical power thereto;

wherein said circuitry at least in part comprises processing logic which is configured to;

identify, after the analyte sensor has been implanted in the tissue environment within the body, at least one of the plurality of glucose-modulated oxygen detectors whose signal performance is experiencing progressive degradation;

based at least in part on the identification, progressively reduce over time a weight of signals generated by the identified at least one of the plurality of glucose-modulated oxygen detectors relative to weights of respective signals from others of the plurality of glucose-modulated oxygen detectors during generation of composite glucose-modulated signals such that the generated composite glucose-modulated signals are, over time, increasingly based on the others of the plurality of glucose-modulated oxygen detectors; and

wherein the composite glucose-modulated signals are useful for calculation of a blood glucose level value.

29. The analyte sensor of claim 28, wherein the processing logic is further configured to:

utilize the composite glucose-modulated signals to calculate at least one blood glucose level value; and

cause utilization of the wireless data transmission apparatus to wirelessly transmit the at least one blood glucose level value to a data receiver device disposed external to the body.

30. The analyte sensor of claim 28, wherein the analyte sensor is configured to utilize the wireless data transmission apparatus to wirelessly transmit at least one blood glucose level value to a data receiver device disposed internal to the body, the data receiver device being associated with a medicant delivery system, the at least one blood glucose level determined based at least on the composite glucose-modulated signals, the at least one blood glucose value useful in determining a medicant dose to be administered by the delivery system.

31. The analyte sensor of claim 28, wherein (i) the identification of the at least one of the plurality of glucose-modulated oxygen detectors whose signal performance is experiencing progressive degradation, and (ii) the progressive reduction over time of the weight of signals, cooperate to enable an increased accuracy of a blood glucose level determined based at least on the composite glucose-modulated signals.

32. A method of operating an implanted analyte sensor having a plurality of glucose-modulated analyte detectors comprising at least one enzymatic material enclosed in a membrane structure, the membrane structure configured to provide a barrier between biological tissues of a body within which the analyte sensor is implanted and the at least one enzymatic material, the method comprising:

identifying, during a period of implantation, one or more of the plurality of glucose-modulated analyte detectors which experience unacceptable signal variations;

based at least in part on the identification, selectively removing first signals generated by the identified one or more of the plurality of glucose-modulated analyte detectors from inclusion in a composite analyte detector signal; and

generating the composite analyte detector signal from second signals generated by one or more remaining non-identified ones of the plurality of glucose-modulated analyte detectors which have not experienced the unacceptable signal variations.

33. The method of claim 32, further comprising using at least the generated composite analyte detector signal to calculate a blood glucose level value.

34. The method of claim 33, wherein the using the at least the generated composite analyte detector signal to calculate a blood glucose level value comprises using computerized logic of the implanted analyte sensor to calculate the blood glucose level.

35. The method of claim 34, wherein the analyte sensor is fully implanted within the body, and the method further comprises wirelessly transmitting the calculated blood glucose level from the fully implanted analyte sensor to a receiver apparatus disposed external to the body.

36. The method of claim 32, wherein the identifying the one or more of the plurality of glucose-modulated analyte detectors comprises determining that analyte migration into the one or more of the plurality of glucose-modulated analyte detectors is at least partially impeded.

37. The method of claim 32, wherein the identifying the one or more of the plurality of glucose-modulated analyte detectors comprises:

identifying an electrical failure of the one or more of the plurality of glucose-modulated analyte detectors; and

deactivating the identified one or more of the plurality of glucose-modulated analyte detectors via circuitry of the implanted analyte sensor so as to at least mitigate stimulation of body response at an implantation site of the analyte sensor.

38. The method of claim 32, wherein:

each of the plurality of glucose-modulated analyte detectors comprises an active sensor and a reference sensor, and wherein the identifying the one or more of the plurality of analyte detectors comprises determining that at least one of the active sensor or the reference sensor of each of the one or more of the plurality of analyte detectors is inoperative; and

the selectively removing comprises deactivating both the active sensor and the reference sensor of each of the one or more of the plurality of analyte detectors.

39. The method of claim 32, wherein:

the selectively removing comprises selectively decreasing a weight value associated with the first signals during the generation of the composite analyte detector signal; and

the method further comprises selectively increasing a weight value associated with the second signals during the generation of the composite analyte detector signal.

40. The method of claim 39, wherein the selectively decreasing the weight value associated with the first signals comprises progressively decreasing the weight value associated with the first signals over a time of operation of the analyte sensor while implanted.

41. A method of operating a fully implanted analyte sensing device so as to extend a useful implanted operating lifetime of the analyte sensing device within a tissue environment of a body, the analyte sensing device comprising a plurality of glucose-modulated detectors, the method comprising:

identifying, when the analyte sensor is implanted in the tissue environment of the body, at least one of the plurality of glucose-modulated detectors which provide degraded glucose-modulated signals;

based at least in part on the identifying, selectively either (i) reducing a weighting associated with, or (ii) removing, glucose-modulated signals generated by the identified at least one of the plurality of glucose-modulated detectors from processing to generate a composite glucose-modulated signal, the reducing weighting or removing increasing an accuracy of the composite glucose-modulated signal relative to a composite glucose-modulated signal generated without the reducing weighting or removing, the increased accuracy enabling said extension of the useful implanted operating lifetime.

42. An implantable analyte sensor, comprising:

a biocompatible housing having a size and a shape each suitable for implantation in a body;

a sensing region comprising at least a plurality of enzymatic analyte detectors;

circuitry operatively connected to the plurality of enzymatic analyte detectors and configured to process at least a portion of signals generated by one or more of the plurality of enzymatic analyte detectors to produce processed signals;

wireless data transmission apparatus configured to transmit data to a receiver at least when the implanted analyte sensor is disposed in a tissue environment within said body;

an electrical power source operatively coupled to at least the circuitry and the wireless data transmission apparatus and configured to provide electrical power thereto; and

at least one membrane apparatus associated with each of the plurality of enzymatic analyte detectors, the at least one membrane apparatus configured to, when the implantable analyte sensor is disposed in the tissue environment within the body, both (i) at least mitigate vascularization therein, and (ii) permit migration of blood analyte therethrough;

wherein the circuitry at least in part comprises processing logic configured to;

identify at least one of the plurality of enzymatic analyte detectors with degraded performance, the degraded performance caused by changing of an interface between the at least one enzymatic analyte detector and surrounding tissue of the body, the changing of the interface due to one or more biological processes within the body;

based at least in part on the identification, selectively either reduce a weighting of or remove signals generated by the identified at least one enzymatic analyte detector from processing of a composite signal; and

generate the composite signal from other signals respectively produced by one or more remaining non-identified ones of the plurality of enzymatic analyte detectors.

43. The implantable analyte sensor of claim 42, wherein each of the enzymatic analyte detectors comprise a porous crosslinked protein-based material having a plurality of pores of a prescribed pore diameter at least on an outer surface of the at least one membrane apparatus, the plurality of pores of the prescribed pore diameter configured to enable said (i) mitigation of vascularization therein, and (ii) migration of blood analyte therethrough.