Method of manufacturing an analyte detector element

• US 10,736,553 B2
• Filed: 03/12/2018
• Issued: 08/11/2020
• Est. Priority Date: 07/26/2012
• 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): Kim, Paul D
• Application Number:
  US15/919,052
• Publication Number:
  US 20180353306A1
• Time in Patent Office: 883 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 method of manufacturing an analyte detector, comprising:

disposing an electrolyte material over at least a portion of a detector substrate;

forming a membrane structure over the electrolyte material, the membrane structure comprising a cavity, and an opening to the cavity formed through a shell of the membrane structure;

disposing an enzymatic matrix material within the cavity; and

disposing a porous outer membrane at least partly within the opening, wherein the porous outer membrane comprises a non-enzymatic material; and

wherein the forming the membrane structure comprises selecting a prescribed size for the opening and forming the opening according to the prescribed size, the selecting the prescribed size comprising selecting based at least on a desired permeability ratio between oxygen and glucose molecules into the cavity.

2. The method of claim 1, wherein the selecting based at least on a desired permeability ratio between oxygen and glucose molecules into the cavity comprises selecting so as to achieve at least one of (i) a desired minimum sensitivity, or (ii) a desired maximum sensitivity.

3. The method of claim 1, wherein the forming the membrane structure further comprises selecting a prescribed height for the opening relative to a base portion of the cavity, and forming the opening according to the prescribed height, the selecting the prescribed height comprising selecting based on at least one of (i) a desired response rate, or (ii) a desired detection time.

4. The method of claim 1, wherein the forming the membrane structure further comprises selecting a prescribed diameter of a base portion of the cavity and forming the membrane according to the prescribed diameter of the base portion, the selecting the prescribed diameter comprising selecting based at least on a desired range of blood glucose concentration that can be measured by the analyte detector.

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

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

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

disposing a flowable enzyme matrix material into the cavity via the aperture such that the flowable enzyme matric material contacts at least a portion of an interior wall of the membrane structure;

subsequently cross-linking at least a portion of the flowable enzyme matrix material while disposed within the cavity; and

disposing a non-enzymatic material at least partly within the aperture such that the non-enzymatic material contacts at least a portion of the at least partly cross-linked flowable enzyme matrix material.

6. The method of claim 5, wherein:

the flowable enzyme matrix material at least in part comprises a chemically cross-linkable substance; and

the subsequent cross-linking comprises applying, via the aperture, a flowable cross-linking agent onto the flowable enzyme matrix material disposed in the cavity, thereby forming a crosslinked enzymatic matrix material.

7. The method of claim 6, wherein the disposing of the non-enzymatic material comprises disposing, via the aperture, a flowable non-enzyme matrix material atop the crosslinked enzymatic matrix material.

8. The method of claim 7, wherein the disposing of the non-enzymatic material further comprises chemically cross-linking the non-enzymatic material via applying a cross-linking agent to at least a top surface of the non-enzymatic material disposed at least partly within the aperture.

9. The method of claim 8, wherein the chemical cross-linking of the non-enzymatic material at least partly within the aperture comprises forming a porous outer membrane at least partly within the aperture, the porous outer membrane having a porosity greater than a porosity of the membrane structure.

10. The method of claim 5, wherein the flowable enzyme matrix material comprises a buffer and cross-linking agent, the buffer and cross-linking agent cooperating to at least partly inhibit formation of bubbles or voids within the enzyme matrix material during said disposing the flowable enzyme matrix material into the cavity via the aperture.

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

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

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

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

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

adhering the outer silicone rubber-based membrane to the inner silicone rubber-based membrane such that the inner and outer silicone rubber-based membranes define the cavity;

disposing an enzyme matrix material into the cavity via the aperture such that the enzyme matric material contacts at least a portion of an interior wall of the membrane structure; and

disposing a non-enzymatic material at least partly within the aperture such that the non-enzymatic material contacts at least a portion of the enzyme matrix material.

12. The method of claim 11, further comprising molding the inner silicone rubber-based membrane and the outer silicone rubber-based membrane.

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

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

disposing 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 the enzyme matric material contacts at least a portion of an interior wall of the membrane structure; and

disposing a non-enzymatic material at least partly within the aperture such that the non-enzymatic material contacts at least a portion of the enzyme matrix material;

wherein the disposing the enzyme matrix material into the cavity comprises disposing so as to avoid contamination of at least portions of one or more wall surfaces of the membrane structure defining the aperture by the enzyme matrix material.

14. The method of claim 13, wherein the disposing so as to avoid contamination comprises filling the cavity to a level coincident with a bottom interior edge of the aperture, the filling comprising filling so that none of the flowable enzyme matrix material contacts an interior wall surface of the aperture.

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

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

disposing 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 the enzyme matric material contacts at least a portion of an interior wall of the membrane structure, the enzyme matrix material comprising a buffer and cross-linking agent, the buffer and cross-linking agent cooperating to at least mitigate formation of bubbles or voids within the enzyme matrix material during said disposing of the enzyme matrix material into the cavity; and

disposing a non-enzymatic material at least partly within the aperture such that the non-enzymatic material contacts at least a portion of the enzyme matrix material.

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

providing an electrode over at least a portion of a substrate;

forming an electrolyte layer over the electrode;

forming a hydrophobic membrane structure over the electrolyte layer, the hydrophobic membrane structure comprising (i) a cavity region and (ii) an aperture formed through the hydrophobic membrane structure to the cavity region; and

disposing a non-enzymatic material at least partly within the aperture, wherein the non-enzymatic material comprises a hydrophilic material.

17. The method of claim 16, further comprising:

before disposing the non-enzymatic material at least partly within the aperture, disposing an enzyme matrix within the cavity through the aperture.

18. The method of claim 17, further comprising evacuating or excluding air from within said cavity during said disposing of said enzyme matrix such that formation of voids within said enzyme matrix is avoided.

19. The method of claim 16, further comprising selecting a configuration of the aperture, the selecting based at least on a desired response or performance characteristic of the analyte detector element.

20. The method of claim 19, wherein the desired response or performance characteristic of the analyte detector element comprises a desired range of operation or sensitivity of the analyte detector element.

21. The method of claim 16, wherein the disposing the non-enzymatic material at least partly within the aperture comprises:

disposing a flowable non-enzyme matrix material through the aperture; and

chemically cross-linking the non-enzyme matrix, the chemical cross-linking forming a porous outer membrane within at least a portion of the aperture.

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

providing an electrode over at least part of a substrate;

forming an electrolyte layer over the electrode;

forming a hydrophobic membrane structure over at least part of the electrolyte layer, the hydrophobic membrane structure comprising (i) a cavity region and (ii) an aperture formed through the membrane structure to the cavity region; and

disposing a non-enzymatic material at least partly within the aperture, wherein the disposing the non-enzymatic material at least partly within the aperture comprises forming a porous outer membrane within the aperture, the porous outer membrane having a porosity greater than that of the hydrophobic membrane structure.

23. The method of claim 22, wherein the forming the porous outer membrane comprises controlling a pore size of a plurality of pores within the porous outer membrane.

24. The method of claim 23, wherein the controlling the pore size comprises controlling the pore size so as to:

(i) accommodate diffusion of at least one solute of interest, and (ii) frustrate ingrowth of blood vessels of a host living being into which the analyte detector element has previously been implanted into the pores.

25. The method of claim 23, wherein the pore size ranges from approximately 10 angstroms to approximately 10 microns.

26. The method of claim 22, wherein the forming the porous outer membrane within the aperture comprises:

disposing a flowable non-enzyme matrix material through the aperture; and

chemically cross-linking the non-enzyme material.

27. The method of claim 22, wherein the forming the porous outer membrane within the aperture comprises:

pre-forming the porous outer membrane; and

inserting at least a portion of the pre-formed porous outer membrane into the aperture.

28. The method of claim 22, further comprising selecting a configuration of the aperture, the selecting based at least on a desired response or performance characteristic of the analyte detector element, the selecting a configuration comprising selecting at least one of a shape or a diameter of the aperture.

29. The method of claim 22, further comprising selecting a configuration of the aperture, the selecting based at least on a desired response or performance characteristic of the analyte detector element, the selecting a configuration comprising selecting at least one of a sidewall profile or a depth of the aperture.

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

providing an electrode over at least a portion of a substrate;

forming an electrolyte layer over the electrode;

forming a hydrophobic membrane structure over the electrolyte layer, the hydrophobic membrane structure comprising (i) a cavity region and (ii) an aperture formed through the membrane structure to the cavity region; and

disposing a non-enzymatic material at least partly within the aperture;

wherein the forming the hydrophobic membrane structure comprises molding the hydrophobic membrane structure from a compound comprising silicone rubber.

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

providing an electrode over at least a part of a substrate;

forming an electrolyte layer over the electrode;

forming a hydrophobic membrane structure over the electrolyte layer, the hydrophobic membrane structure comprising (i) a cavity region and (ii) an aperture formed through the membrane structure to the cavity region;

disposing an enzyme matrix within the cavity through the aperture;

evacuating or excluding air from within said cavity during said disposing of said enzyme matrix such that formation of voids within said enzyme matrix is at least mitigated; and

after disposing the enzyme matrix within the cavity, disposing a non-enzymatic material at least partly within the aperture, the non-enzymatic material configured to, when cured, have a prescribed porosity for a prescribed molecular species.