Biocompatible implantable sensor apparatus and methods

• US 10,561,353 B2
• Filed: 06/01/2016
• Issued: 02/18/2020
• Est. Priority Date: 06/01/2016
• Status: Active Grant

• Current Assignee: Mcnair Interests Limited
• Original Assignee: GlySens, Incorporated
• Inventors: Lucisano, Joseph, Javidi, Bahman, Kurbanyan, Lev, Lin, Joe, Routh, Timothy, Walker, Bradley
• Primary Examiner(s): Messersmith, Eric J
• Application Number:
  US15/170,571
• Publication Number:
  US 20170347932A1
• Time in Patent Office: 1,357 Days
• CPC Class Codes: A61B 17/0206 with antagonistic arms as supports for retractor elements
• CPC Class Codes: A61B 17/0218 for minimally invasive surgery A61B17/0281, A61B17/0469, A61B17/12013, A61B17/1285, A61B17/29, A61B17/320016 take precedence
• CPC Class Codes: A61B 17/025 Joint distractors
• CPC Class Codes: A61B 17/1611 the two jaw elements being integral with respective elongate shaft elements
• CPC Class Codes: A61B 17/1757 for the spine
• CPC Class Codes: A61B 17/7032 Screws or hooks with U-shaped head or back through which longitudinal rods pass
• CPC Class Codes: A61B 17/7037 wherein pivoting is blocked when the rod is clamped
• CPC Class Codes: A61B 17/7077 for moving bone anchors attached to vertebrae, thereby displacing the vertebrae
• CPC Class Codes: A61B 17/7079 Tools requiring anchors to be already mounted on an implanted longitudinal or transverse element, e.g. where said element guides the anchor motion
• CPC Class Codes: A61B 17/708 with tubular extensions coaxially mounted on the bone anchors
• CPC Class Codes: A61B 17/7082 for driving, i.e. rotating, screws or screw parts specially adapted for spinal fixation, e.g. for driving polyaxial or tulip-headed screws driving other bone screws A61B17/8875
• CPC Class Codes: A61B 17/7083 Tools for guidance or insertion of tethers, rod-to-anchor connectors, rod-to-rod connectors, or longitudinal elements
• CPC Class Codes: A61B 17/88 Osteosynthesis instruments; Methods or means for implanting or extracting internal or external fixation devices A61B17/7074 takes precedence
• CPC Class Codes: A61B 2017/00473 Distal part, e.g. tip or head A61B2017/00464 takes precedence
• CPC Class Codes: A61B 2017/0256 for the spine
• CPC Class Codes: A61B 2017/564 Methods for bone or joint treatment
• CPC Class Codes: A61B 2017/681 Alignment, compression, or distraction mechanisms
• 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 5/1473 : 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 5/6861 : Capsules, e.g. for swallowing or implanting
• CPC Class Codes: A61F 2/442 : Intervertebral or spinal discs, e.g. resilient non-disc-shaped intervertebral inflatable pockets A61F2/441; non-disc-shaped intervertebral fusion implants A61F2/4455
• CPC Class Codes: A61F 2/4455 : for the fusion of spinal bodies, e.g. intervertebral fusion of adjacent spinal bodies, e.g. fusion cages intervertebral discs A61F2/442
• CPC Class Codes: A61F 2/4611 : of spinal prostheses
• CPC Class Codes: A61F 2002/30131 : horseshoe- or crescent- or C-shaped or U-shaped
• CPC Class Codes: A61F 2002/30772 : Apertures or holes, e.g. of circular cross section
• CPC Class Codes: A61F 2002/4435 : Support means or repair of the natural disc wall, i.e. annulus, e.g. using plates, membranes or meshes
• CPC Class Codes: A61F 2002/4485 : comprising three or more adjacent spinal implants
• CPC Class Codes: A61F 2002/4635 : using minimally invasive surgery
• CPC Class Codes: A61F 2310/00359 : Bone or bony tissue

Abstract

Enzymatic and non-enzymatic detectors and associated membrane apparatus, and methods of use, such as within a fully implantable sensor apparatus. In one embodiment, detector performance is controlled through selective use of membrane configurations and enzyme region shapes, which enable accurate detection of blood glucose level within the solid tissue of the living host for extended periods of time. Isolation between the host'"'"'s tissue and the underlying enzymes and reaction byproducts used in the detectors is also advantageously maintained in one embodiment via use of a non-enzyme containing permeable membrane formed of e.g., a biocompatible crosslinked protein-based material. Control of response range and/or rate in some embodiments also permits customization of sensor elements. In one variant, heterogeneous detector elements are used to, e.g., accommodate a wider range of blood glucose concentration within the host. Methods of manufacturing the membranes and detectors, including methods to increase reliability, are also disclosed.

Claims

1. A sensor apparatus, comprising:

a substrate;

signal processing circuitry; and

at least one first detector element and at least one second detector element each in signal communication with the signal processing circuitry, each of the at least one first detector element and the at least one second detector element comprising;

a three-dimensional membrane structure comprising (i) an at least partly enclosed cavity, the at least partly enclosed cavity comprising an enzymatic substance disposed therein, (ii) and at least one spout in communication with the at least partly enclosed cavity;

an electrolyte layer;

one or more electrodes comprising at least a working electrode, a counter electrode, and a reference electrode, an active face of the working electrode, an active face of the counter electrode, and an active face of the reference electrode disposed on an exterior surface of the substrate and at least partly within or contacting said electrolyte layer; and

a non-enzymatic membrane disposed within the at least one spout and at least partly occluding the at least one spout, said non-enzymatic membrane comprising a non-enzymatic material at least partly permeable to an analyte;

wherein the three-dimensional membrane structure is arranged over the exterior surface of the substrate such that (i) the at least partly enclosed cavity is disposed over at least a portion of the active face of the working electrode, and (ii) the at least partly enclosed cavity is offset from the active face of the counter electrode and the active face the reference electrode;

wherein said at least one first detector element is configured to;

(i) have a first response characteristic, and (ii) utilize chemical interaction between at least the analyte and the enzymatic substance to enable generation of a first electrical signal at said at least one electrode of the at least one first detector element, said first electrical signal relating to a blood analyte concentration;

wherein said at least one second detector element is configured to;

(i) have a second response characteristic at least partially different from the first response characteristic, and (ii) utilize chemical interaction between at least the analyte and the enzymatic substance to enable generation of a second electrical signal at the at least one electrode of the at least one second detector element, the second electrical signal relating to the blood analyte concentration; and

wherein the first response characteristic and the second response characteristic are each based at least on a combination of a cross-sectional area of the at least one spout and a fill-level of the non-enzymatic material within the at least one spout being different for the at least one first detector element relative to the at least one second detector element.

2. The sensor apparatus of claim 1, wherein:

the at least one spout of the at least one first detector element is at least mostly enzyme-free and sized to have at least a first cross-sectional area, the first response characteristic based at least on the first cross-sectional area, the first response characteristic configured to enable the first detector element to determine the blood analyte concentration within a first specified range; and

the at least one spout of the at least one second detector element is sized to have at least a second cross-sectional area different from the first cross-sectional area, the second response characteristic based at least on the second cross-sectional area, the second response characteristic configured to enable the second detector element to determine the blood analyte concentration within a second specified range, the second specified range at least partially non-overlapping with the first specified range.

3. The sensor apparatus of claim 2, wherein the sensor apparatus is configured for complete implantation within a living host, and the reference electrode is configured to provide a reference signal, said reference signal useful in determining the blood analyte concentration.

4. The sensor apparatus of claim 3, wherein the at least one reference electrode comprises an oxygen detector, and said chemical interaction between the analyte and the enzymatic substance for each of the at least one first detector element and the at least one second detector element comprises an oxygen-consuming reaction, each of said first electrical signal and the second electrical signal relating at least in part to an unconsumed portion of oxygen which diffuses into said at least partly enclosed cavity via said non-enzymatic membrane in each of the at least one first detector element and the at least one second detector element.

5. The sensor apparatus of claim 1, wherein:

the at least one spout is formed and the non-enzymatic membrane is disposed within the at least one spout so that, between a bottom surface of the cavity and a bottom surface of the non-enzymatic membrane, the at least partly enclosed cavity respectively comprises a first height for the at least one first detector element and a second height for the at least one second detector element;

the first response characteristic is further based on the first height, the first response characteristic configured to enable the first detector element to determine the blood analyte concentration within a first specified period of time of the analyte being introduced into a region external to the at least partly enclosed cavity of the at least one first detector element; and

the second response characteristic is further based on the second height, the second response characteristic configured to enable the second detector element to determine the blood analyte concentration within a second specified period of time of the analyte being introduced into a region external to the at least partly enclosed cavity of the at least one second detector element, the second specified time period at least partially non-overlapping with the first specified time period.

6. The sensor apparatus of claim 1, wherein:

the at least one spout of the at least one first detector element comprises a first shape, the first response characteristic further based on the first shape; and

the at least one spout of the at least one second detector element comprises a second shape different in at least one dimension from the first shape, the second response characteristic further based on the second shape.

7. The sensor apparatus of claim 6, wherein the first shape comprises at least one first curved interior surface in communication with the at least partly enclosed cavity of the at least one first detector element, and the second shape comprises at least one second curved interior surface in communication with the at least partly enclosed cavity of the at least one second detector element, the at least one second curved interior surface having a different degree of curvature relative to the at least one first curved interior surface.

8. The sensor apparatus of claim 1, wherein the non-enzymatic membrane comprises a crosslinked albumin-based compound, and the three-dimensional membrane structure comprises a hydrophobic material having the at least partly enclosed cavity formed therein, the hydrophobic material in communication with at least a portion of the non-enzymatic membrane so as to seal the at least one spout.

9. The sensor apparatus of claim 8, wherein the three-dimensional membrane structure further comprises a permeable layer in communication with at least a portion of the enzymatic substance and at least a portion of the electrolyte layer, the permeable layer permeable to oxygen.

10. The sensor apparatus of claim 9, wherein the enzymatic substance comprises a hydrophilic material having catalase and glucose oxidase co-immobilized therein.

11. The sensor apparatus of claim 10, wherein the chemical interaction at each of the at least one first detector element and the at least one second detector element comprises the following reactions:

glucose+O₂+H₂O→

gluconate+H₂O₂

H₂O₂→

½

O₂+H₂O

glucose+½

O₂→

gluconate.

12. The sensor apparatus of claim 1, wherein:

the first response characteristic and the second response characteristic are each further based at least in part on one or more features of the at least partly enclosed cavity being different for the at least one first detector element relative to the at least one second detector element;

a first base region of the at least partly enclosed cavity of the at least one first detector element is sized in at least a first area thereof so as to enable determination of the blood analyte concentration within a first specified range; and

a second base region of the at least partly enclosed cavity of the at least one second detector element is sized in at least a second area thereof so as to enable determination of the blood analyte concentration within a second specified range at least partially non-overlapping with the first specified range, the second area different from the first area.

13. The sensor apparatus of claim 1, wherein the enzymatic material comprises a material wherein the enzymes thereof are effectively immobilized, and the (i) immobilization of the enzymes, and (ii) the at least partial permeability of the non-enzymatic material of the non-enzymatic membrane to the analyte cooperate to allow the detection of the analyte concentration within a specified blood analyte concentration range for each of the at least one first detector element and the at least one second detector element while at least partly mitigating a foreign body response (FBR) by a tissue of a host living being within which the sensor apparatus is implanted.

14. The sensor apparatus of claim 6, wherein:

the at least one spout comprises a first aperture at an exterior surface thereof and a second aperture at an interior surface thereof, the second aperture in communication with the at least partly enclosed cavity;

the first shape comprises at least one first tapered interior surface extended between the first aperture and the second aperture of the at least one spout of the at least one first detector element; and

the second shape comprises at least one second tapered interior surface extended between the first aperture and the second aperture of the at least one spout of the at least one second detector element, the at least one second tapered interior surface having a different degree of tapering relative to the at least one first tapered interior surface.

15. The sensor apparatus of claim 14, wherein the at least one first tapered interior surface of the at least one spout of the at least one first detector element is configured to provide mechanical stability for the non-enzymatic membrane, the first aperture having a greater width than the second aperture.

16. The sensor apparatus of claim 1, wherein:

the at least one first detector element being configured to have the first response characteristic comprises the at least one first detector element being configured for determination of the blood analyte concentration within a first specified analyte concentration range; and

the at least one second detector element being configured to have the second response characteristic comprises the at least one second detector element being configured for determination of the blood analyte within a second specified analyte concentration range at least partially non-overlapping with the first specified analyte concentration range.

17. The analyte detection apparatus of claim 16, wherein:

a first fill-level of non-enzymatic material within the at least one spout of the first detector element is greater than a second fill-level of the non-enzymatic material within the at least one spout of the second detector element; and

the first specified analyte concentration range comprises a higher range relative to the second specified analyte concentration range.

18. The analyte detection apparatus of claim 16, wherein:

at least a first cross-sectional area of the at least one spout of the first detector element is less than a corresponding second cross-sectional area of the at least one spout of the second detector element; and

the first specified analyte concentration range comprises a higher range relative to the second specified analyte concentration range.

19. An analyte detection apparatus for use in a human being, comprising:

a substrate; and

a first detector element configured to detect blood analyte within a first analyte concentration response range, and a second detector element configured to detect blood analyte within a second analyte concentration response range at least partially non-overlapping with the first analyte concentration response range, each of the first detector element and the second detector element comprising;

one or more electrodes disposed on or within the substrate, each of the one or more electrodes comprising at least a terminal configured to enable electrical signals to be communicated from the respective ones of the one more electrodes to a circuit, the one or more electrodes comprising a working electrode, a counter electrode, and a reference electrode;

an electrolyte material in communication with at least a portion of each of the one or more electrodes;

a first membrane element in contact with at least a portion of the electrolyte material;

a second membrane element comprising (i) a cavity formed therein, the cavity having enzymatic material disposed therein, and (ii) at least one spout in communication with the cavity, the second membrane element disposed on an exterior surface of the analyte detection apparatus such that (i) the cavity is associated with the working electrode and is not associated with the counter electrode and the reference electrode, and (ii) the second membrane element forms a three-dimensional structure on the exterior surface of the analyte detection apparatus; and

a non-enzymatic material configured to at least partly occlude at least a portion of the at least one spout and isolate tissue of the human being from the enzymatic material, yet permit analyte and oxygen therethrough, the enzymatic material configured to interact with at least a portion of the analyte and at least a portion of the oxygen entering the cavity via the at least one spout;

wherein the first analyte concentration response range and the second analyte concentration response range are each based at least on a combination of at least one size dimension of the cavity and a thickness of the enzymatic material disposed within the cavity being different for the first detector element relative to the second detector element.

20. The analyte detection apparatus of claim 19, wherein:

the substrate comprises a ceramic material, and the first membrane comprises a polymeric material;

the analyte comprises glucose, and the enzymatic material comprises glucose oxidase and catalase disposed in a crosslinked matrix;

the non-enzymatic material comprises cross-linked albumin; and

the second membrane comprises a silicone-based material.

21. The sensor apparatus of claim 19, wherein:

a first thickness of the enzymatic material for the first detector element is less than that of the second detector element; and

the first analyte concentration response range comprises a lower response range relative to the second analyte concentration response range.

22. A dynamically variable sensor apparatus, comprising:

signal processing circuitry; and

at least one first detector element and at least one second detector element each in signal communication with the signal processing circuitry, the at least one first detector element and the at least one second detector element each comprising;

an at least partly enclosed cavity, the at least partly enclosed cavity comprising at least one enzymatic substance, and at least one aperture in communication with the at least partly enclosed cavity, the aperture at least partly obscured with a non-enzyme, analyte-permeable substance;

an electrolyte layer; and

at least one electrode disposed at least partly within or contacting said electrolyte layer;

wherein said at least one first detector element and said at least one second detector element are each configured to utilize chemical interaction between at least the analyte and their respective enzymatic substance to enable generation of an electrical signal at their respective at least one electrode via their respective electrolyte layer, said electrical signal of the at least one first detector element and said electrical signal of the at least one second detector element each relating to a concentration of said analyte in a region external to their respective cavities;

wherein the at least one first detector element is configured to detect analyte within a first blood analyte concentration range, and the at least one second detector element is configured to detect analyte within a second blood analyte concentration range, the second blood analyte concentration range comprising a lower blood analyte concentration range relative to the first blood analyte concentration range, at least a lower threshold of the second blood analyte concentration range being less than a lower threshold of the first blood analyte concentration range, the first blood analyte concentration range and the second blood analyte concentration range each based on at least one of (i) a shape or dimension of the at least one aperture, (ii) a thickness of the non-enzyme yet permeable substance, or (iii) a shape or dimension of the cavity for the at least one first detector element being different from that for the at least one second detector element; and

wherein the signal processing circuitry is configured for selective utilization of each of the electrical signal generated by the at least one first detector element and the electrical signal generated by the at least one second detector element while the sensor apparatus is operating within a living being, the selective utilization comprising;

identification of a blood analyte concentration;

determination of a trend of the identified blood analyte concentration as a function of at least time;

based at least in part on a determination that the blood analyte concentration is within the first blood analyte concentration range with the blood analyte concentration trending increasing, cause utilization of the electrical signal generated by the at least one first detector element;

based at least in part on a determination that the blood analyte concentration is within the first blood analyte concentration range with the blood analyte concentration trending decreasing, cause utilization of one or more of the electrical signal generated by the at least one first detector element or the electrical signal generated by the at least one second detector element;

based at least in part on a determination that the blood analyte concentration is within the second blood analyte concentration range with the blood analyte concentration trending increasing, cause utilization of one or more of the electrical signal generated by the at least one first detector element or the electrical signal generated by the at least one second detector element; and

based at least in part on a determination that the blood analyte concentration is within the second blood analyte concentration range with the blood analyte concentration trending decreasing, cause utilization of the electrical signal generated by the at least one second detector element.

23. A sensor apparatus, comprising:

signal processing circuitry; and

a first detector element configured to detect blood analyte within a first analyte concentration range, and a second detector element configured to detect blood analyte within a second analyte concentration range, the second analyte concentration range (i) at least partially non-overlapping with the first analyte concentration range and (ii) comprising a lower range relative to the first analyte concentration range, each of the first detector element and the second detector element in signal communication with the signal processing circuitry and comprising;

an electrolyte material;

a membrane element in communication with at least a portion of the electrolyte material, the membrane element comprising a cavity formed therein and at least one spout in communication with the cavity, the cavity having an enzymatic material disposed therein; and

a non-enzymatic material configured to at least partly occlude at least a portion of the at least one spout and isolate tissue of the human being from the enzymatic material, yet permit analyte therethrough, the enzymatic material disposed within the cavity and configured to interact with the analyte entering the cavity via the at least one spout;

at least one working electrode disposed on or within the substrate and in communication with the cavity via at least a portion of the electrolyte material, the at least one working electrode configured to utilize the interaction between the analyte and the enzymatic material to enable generation of an electrical signal;

wherein the signal processing circuitry is configured for selective utilization of each of the electrical signal generated by the at least one first detector element and the electrical signal generated by the at least one second detector element while the sensor apparatus is operating within a living being, the selective utilization comprising;

identification of each of (i) a blood analyte concentration, and (ii) a trend of the identified blood analyte concentration as a function of at least time;

based at least in part on a determination that the blood analyte concentration is within the first blood analyte concentration range with the blood analyte concentration exhibiting a first trend, cause selective utilization of one or both of the electrical signal generated by the at least one first detector element or the electrical signal generated by the at least one second detector element, the selective utilization based at least in part on the first trend; and

based at least in part on a determination that the blood analyte concentration is within the second blood analyte concentration range with the blood analyte concentration exhibiting a second trend, cause selective utilization of one or both of the electrical signal generated by the at least one first detector element or the electrical signal generated by the at least one second detector element, the selective utilization based at least in part on the second trend.

24. The sensor apparatus of claim 23, wherein the first detector element being configured to detect blood analyte within the first analyte concentration range and the second detector element being configured to detect blood analyte within the second analyte concentration range are each based at least on one or more of (i) at least one dimension of the at least one spout or (ii) a fill-level of the at least one spout with the non-enzymatic material being different for the first detector element relative to the second detector element.

25. The sensor apparatus of claim 24, wherein the at least one spout of the second detector element comprises one or more of (i) a greater cross-sectional area or (ii) a lower fill-level with the non-enzymatic material relative to the at least one spout of the first detector element.

26. A sensor apparatus, comprising:

a substrate;

signal processing circuitry;

logic in communication with the signal processing circuitry; and

a first detector element configured to detect blood analyte within a first analyte concentration range, and a second detector element configured to detect blood analyte within a second analyte concentration range, the second analyte concentration range (i) at least partially non-overlapping with the first analyte concentration range and (ii) comprising a lower range relative to the first blood analyte concentration range, each of the first detector element and the second detector element in communication with the signal processing circuitry and comprising;

an electrolyte material;

at least one working electrode disposed on or within the substrate and in communication with at least a portion of the electrolyte material, the at least one working electrode configured to utilize an interaction between blood analyte and an enzymatic material to enable generation of an electrical signal;

wherein the logic is configured to;

identify a trend of a blood analyte concentration as a function of at least time; and

cause selective utilization of one or both of the signal from the first detector element or the signal from the second detector element for use in determination of blood analyte level data based at least on the identified trend of the blood analyte concentration.

27. The sensor apparatus of claim 26, wherein the logic is further configured to identify a blood analyte concentration estimate, the cause of selective utilization of one or both of the signal from the first detector element or the signal from the second detector element further based on the identified blood analyte concentration estimate.

28. The sensor apparatus of claim 26, wherein each of the first detector element and the second detector element further comprises:

one or more non-working electrodes;

a membrane structure in communication with at least a portion of the electrolyte material, the membrane structure comprising (i) a cavity having the enzymatic material disposed therein and (ii) a spout in communication with the cavity, the membrane structure disposed on an exterior surface of the sensor apparatus such that the cavity is associated with the at least one working electrode and is not associated with the one or more non-working electrodes; and

a non-enzymatic membrane disposed within the spout, and configured to (i) at least partly occlude at least a portion of the spout and (ii) isolate tissue of the human being from the enzymatic material, yet permit analyte therethrough.

29. The sensor apparatus of claim 28, wherein the first detector element being configured to detect blood analyte within the first analyte concentration range and the second detector element being configured to detect blood analyte within the second analyte concentration range are each based at least on one or more of at least one dimension of the at least one spout or a fill-level of the at least one spout with the non-enzymatic material being different for the first detector element relative to the second detector element.

30. The sensor apparatus of claim 28, wherein the first detector element being configured to detect blood analyte within the first analyte concentration range and the second detector element being configured to detect blood analyte within the second analyte concentration range are each based at least on one or more of at least one dimension of the cavity or a thickness of the enzymatic material disposed within the cavity being different for the first detector element relative to the second detector element.