BIOCOMPATIBLE IMPLANTABLE SENSOR APPARATUS AND METHODS

• US 20170347932A1
• Filed: 06/01/2016
• Published: 12/07/2017
• 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
• Granted Patent: US 10,561,353 B2
• Time in Patent Office: 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. Sensor apparatus, comprising:

signal processing circuitry; and

at least one detector element in signal communication with the signal processing circuitry, the at least one detector element comprising;

a substantially enclosed cavity, the substantially enclosed cavity comprising at least one enzymatic substance, and at least one aperture in communication with the cavity;

an electrolyte layer;

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

a non-enzymatic membrane configured to mitigate blood vessel ingrowth and at least partly occluding said aperture, said membrane comprising a material at least partly permeable to an analyte;

wherein said at least one detector element is configured to utilize chemical interaction between at least the analyte and the enzymatic substance to enable generation of an electrical signal at said electrode via said electrolyte layer, said electrical signal relating to a concentration of said analyte in a region external to the cavity and the non-enzymatic membrane.

2. The sensor apparatus of claim 1, wherein the aperture is substantially enzyme-free and sized in at least a diameter thereof so as to enable determination of the concentration of said analyte in the region external to the cavity within a desired range.

3. The sensor apparatus of claim 2, wherein the sensor apparatus is configured for complete implantation within a living host, and further comprises at least one reference detector in signal communication with the signal processing circuitry and configured to provide a reference signal, said reference signal useful in determining said concentration of said analyte.

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

5. The sensor apparatus of claim 1, wherein the aperture is formed and the non-enzymatic membrane disposed within the aperture so that the cavity comprises a height between a bottom surface thereof and a bottom surface of the membrane, the height selected so as to enable determination of the concentration of said analyte in the region external to the cavity within a desired period of time of the analyte being introduced into the region external to the cavity.

6. The sensor apparatus of claim 1, wherein the substantially enclosed cavity comprises a shape, the shape selected so as to enable determination of the concentration of said analyte in the region external to the cavity within at least one of:

(i) a desired range; and

/or (ii) a desired period of time of the analyte being introduced into the region.

7. The sensor apparatus of claim 6, wherein the shape comprises a spout, the aperture formed within a top surface of the spout.

8. The sensor apparatus of claim 7, wherein the spout comprises at least one curved interior surface in communication with the cavity.

9. The sensor apparatus of claim 1, wherein the protein-based non-enzymatic membrane comprises a crosslinked albumin-based compound, and the cavity is formed substantially within a hydrophobic material in communication with at least a portion of the non-enzymatic membrane so as to substantially seal the aperture.

10. The sensor apparatus of claim 9, further comprising a permeable layer in communication with at least a portion of the enzymatic substance, the permeable layer permeable to oxygen.

11. The sensor apparatus of claim 10, wherein the enzymatic substance comprises a hydrophilic material comprised of catalase and glucose oxidase.

12. The sensor apparatus of claim 9, wherein the chemical interaction comprises the following reactions:

glucose+O₂+H₂O→

gluconate+H₂O₂

H₂O₂→

½

O₂→

H₂O

glucose+½

O₂→

gluconate

13. The sensor apparatus of claim 9, wherein the a base region of the cavity is sized in at least a diameter thereof so as to enable determination of the concentration of said analyte in the region external to the cavity within a desired range.

14. The sensor apparatus of claim 9, wherein the enzymatic material comprises a material wherein the enzymes thereof are substantially immobilized, and the (i) immobilization, and (ii) at least partial permeability of the non-enzymatic membrane to the analyte, cooperate to allow the detection of the analyte concentration while substantially mitigating a foreign body response (FBR) by a tissue of a host living being within which the sensor apparatus is implanted.

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

a substrate;

at least one electrode disposed on or within the substrate, the at least one electrode comprising at least a terminal configured to enable electrical signals to be communicated from the electrode to a circuit;

an electrolyte material in communication with at least a portion of the at least one electrode;

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

a second membrane element comprising a cavity formed therein, and at least one aperture;

a non-enzymatic material configured to substantially occlude the aperture and isolate tissue of the human being from underlying enzymatic materials, yet permit analyte and oxygen therethrough; and

an enzymatic material disposed within the cavity and configured to interact with the analyte and at least a portion of the oxygen entering the cavity via the aperture;

wherein a response characteristic of the analyte detection apparatus is controlled at least in part by a shape of the second membrane element.

16. The analyte detection apparatus of claim 15, wherein:

the substrate comprises a ceramic material, the first membrane comprises a polymeric material, and the second membrane element comprises a silicone rubber-based material;

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

the non-enzymatic material comprises albumin.

17. 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 and second detector elements each comprising;

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

an electrolyte layer; and

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

wherein said at least one first and second detector elements 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 electrodes via their respective electrolyte layer, said electrical signal relating to a concentration of said analyte in a region external to their respective cavities; and

wherein at least one of (i) a shape or dimension of the aperture, (ii) a thickness of the non-enzyme yet permeable substance, and/or (iii) a shape or dimension of the cavity, for the at least one first detector element is different from that for the second at least one detector element, thereby enabling said at least one first detector element and said at least one second detector element to have a different operational characteristic from the other.

18. The sensor apparatus of claim 17, wherein the signal processing circuitry is configured to enable selective use of the electrical signal generated by the at least one first detector element or the at least one second detector element while the sensor apparatus is operating within a living being.

19. The sensor apparatus of claim 17, wherein the selective use of the electrical signal generated by the at least one first detector element or the at least one second detector element comprises:

determining a trend in the glucose concentration;

determining a glucose concentration; and

if the determined glucose concentration exceeds or falls below a prescribed threshold, switching between the at least one first detector element and the at least one second detector element.

20. A method of mitigating a foreign body response (FBR) within a living being while monitoring blood glucose level using an implanted sensor apparatus, the method comprising:

allowing at least oxygen molecules and glucose molecules from the living being'"'"'s blood to permeate through a non-enzymatic layer or membrane to an enzyme-containing material with which the oxygen molecules and glucose molecules can chemically interact, said chemical interaction enabling said monitoring; and

at least mitigating egress of enzymes within the enzyme-containing material outward through the layer or membrane or a periphery thereof.

21. The method of claim 20, wherein the at least mitigating egress comprises mechanically immobilizing the enzymes within a crosslinked matrix.

22. The method of claim 20, further comprising mitigating blood vessel ingrowth into at least a portion of the non-enzymatic layer or membrane.

23. The method of claim 22, wherein the mitigating blood vessel ingrowth into at least a portion of the non-enzymatic layer or membrane comprises utilizing a crosslinked matrix of an albumin-based material for the non-enzymatic layer or membrane.

24. A method of manufacturing an analyte detector element, comprising:

embedding at least one electrode within a substrate;

disposing an electrolyte over at least a portion of the substrate, including at least a portion of the electrode;

forming a membrane structure over the electrolyte, the membrane structure comprising a cavity and an aperture communicating with the cavity;

disposing an enzyme matrix material into the cavity via the aperture such that it at least contacts the inner membrane; and

forming a layer of non-enzymatic material at least partly within the aperture such that it at least partly contacts the enzyme matrix material.

25. The method of claim 24, wherein the disposing an enzyme matrix material into the cavity comprises:

disposing a substantially liquefied enzyme matrix material into the cavity; and

subsequently cross-linking the substantially liquefied matrix material while in the cavity.

26. The method of claim 25, wherein the substantially liquefied enzyme matrix material comprises at least a portion of a chemical cross-linking agent, and the subsequent cross-linking comprises application of a substantially liquefied cross-linking agent to the substantially liquefied matrix material in the cavity via the aperture.

27. The method of claim 26, wherein the forming a layer of non-enzymatic material at least partly within the aperture such that it at least partly contacts the enzyme matrix material comprises disposing a substantially liquefied non-enzyme matrix material atop the crosslinked enzymatic matrix material via the aperture.

28. The method of claim 27, wherein the forming a layer of non-enzymatic material further comprises chemically cross-linking the non-enzymatic material within the aperture via a cross-linking agent applied to at least a top surface of the non-enzymatic material within the aperture.

29. The method of claim 25, wherein the forming a membrane structure over the electrolyte comprises:

forming an inner silicone rubber-based membrane over at least a portion of the electrolyte;

forming an outer silicone rubber-based membrane having the aperture formed therein; and

adhering the outer membrane to the inner membrane such that the inner and outer membranes form the cavity.

30. The method of claim 25, wherein the disposing the substantially liquefied enzyme matrix material into the cavity comprises avoiding contamination of one or more wall surfaces of the formed membrane defining the aperture by the substantially liquefied enzyme matrix material.

31. An implanted blood glucose sensor optimized for extended implantation within a host, the sensor configured to both (i) mitigate a foreign body response (FBR) during said implantation, and (ii) discourage blood vessel ingrowth into a sensing region of the sensor, the sensor comprising:

a non-enzymatic membrane configured for contact with tissue of the host when the sensor is implanted therein, the membrane configured to allow at least oxygen molecules and glucose molecules from the host'"'"'s blood to permeate therethrough to an underlying enzyme-containing material with which the oxygen molecules and glucose molecules can chemically interact, said chemical interaction enabling monitoring of said blood glucose; and

wherein the non-enzymatic membrane comprises a prescribed maximal pore size so as to cause said discouragement of said blood vessel ingrowth.