Non-enzymatic glucose-sensing device with nanoporous structure and conditioning of the nanoporous structure

• US 10,130,290 B1
• Filed: 12/15/2017
• Issued: 11/20/2018
• Est. Priority Date: 11/21/2017
• Status: Active Grant

• Current Assignee: UXN Co., Ltd.
• Original Assignee: UXN Co., Ltd.
• Inventors: Boo, Hankil, Chang, Rae Kyu
• Primary Examiner(s): Cheng, Jacqueline
• Assistant Examiner(s): TRAN, THO Q
• Application Number:
  US15/844,507
• Time in Patent Office: 340 Days
• Field of Search: None
• CPC Class Codes: A61B 2560/0475 Special features of memory means, e.g. removable memory cards
• CPC Class Codes: A61B 2562/0285 Nanoscale sensors
• CPC Class Codes: A61B 2562/125 characterised by the manufacture of electrodes
• CPC Class Codes: A61B 5/0031 Implanted circuitry
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/1473 invasive, e.g. introduced into the body by a catheter A61B5/1482 takes precedence
• CPC Class Codes: A61B 5/1486 using enzyme electrodes, e.g. with immobilised oxidase
• 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 5/72 Signal processing specially adapted for physiological signals or for diagnostic purposes character recognition, recognising digital ink, document-oriented image-based pattern recognition G06V30/00; recognition or understanding of postal images G06V30/424
• CPC Class Codes: A61B 5/742 using visual displays A61B5/339 takes precedence
• CPC Class Codes: B01J 13/0013 from a precipitate
• CPC Class Codes: B05D 5/00 Processes for applying liquids or other fluent materials to surfaces to obtain special surface effects, finishes or structures
• CPC Class Codes: B05D 5/02 to obtain a matt or rough surface
• CPC Class Codes: B82Y 15/00 Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
• CPC Class Codes: B82Y 30/00 Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: B82Y 40/00 Manufacture or treatment of nanostructures
• CPC Class Codes: C09D 5/028 Pigments; Filters
• CPC Class Codes: C09D 5/24 Electrically-conducting paints conductive materials H01B1/00
• CPC Class Codes: C09D 7/67 Particle size smaller than 100 nm
• CPC Class Codes: C12Q 1/006 for glucose
• CPC Class Codes: G01N 2400/00 : Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
• CPC Class Codes: G01N 27/327 : Biochemical electrodes , e.g. electrical or mechanical details for in vitro measurements
• CPC Class Codes: G01N 27/3271 : Amperometric enzyme electrodes for analytes in body fluids, e.g. glucose in blood amperometry per se G01N27/49; aspects concerning the enzyme reagent C12Q1/001
• CPC Class Codes: G01N 27/3335 : the membrane containing at least one organic component G01N27/3271 takes precedence; aspects concerning the enzyme reagent in enzyme electrodes C12Q1/001
• CPC Class Codes: G01N 27/4168 : Oxidation-reduction potential, e.g. for chlorination of water water analysis G01N33/18
• CPC Class Codes: G01N 33/49 : Blood chemical methods for determining blood cell populations G01N33/5094; chemical analysis of blood groups or blood types G01N33/80
• CPC Class Codes: G01N 33/66 : involving blood sugars, e.g. galactose
• CPC Class Codes: Y10S 977/773 : Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/81 : Of specified metal or metal alloy composition
• CPC Class Codes: Y10S 977/896 : Chemical synthesis, e.g. chemical bonding or breaking
• CPC Class Codes: Y10S 977/92 : Detection of biochemical

Abstract

This disclosure relates to a nanoporous composition including a number of clusters of nanoparticles dispersed in a liquid, a nanoporous layer formed of the nanoporous composition, a glucose-oxidation electrode including the nanoporous layer, and a glucose-sensing device and system including the glucose-oxidation electrode. This disclosure also relates to a method of making the nanoporous composition, the nanoporous layer, the glucose-oxidation electrode and the glucose-sensing device and system. Further, this disclosure also relates to devices, systems and methods for continuous glucose monitoring (CGM) and blood glucose monitoring (BGM).

Claims

1. A glucose-sensing electrode, comprising:

an electrically conductive layer;

a nanoporous metal layer formed over the electrically conductive layer;

an electrolyte ion-blocking layer formed over the nanoporous metal layer; and

a biocompatibility layer formed over the electrolyte ion-blocking layer,

wherein the glucose-sensing electrode does not include a glucose-specific enzyme,

wherein, when contacting liquid containing glucose, Na⁺, K⁺, Ca²⁺, Cl⁻

, PO₄³⁻

and CO₃²⁻

, the electrolyte ion-blocking layer is configured to inhibit Na⁺, K⁺, Ca²⁺, Cl⁻

, PO₄³⁻

and CO₃²⁻

contained in the liquid from diffusing toward the nanoporous metal layer such that there is a substantial discontinuity of a combined concentration of Na⁺, K⁺, Ca²⁺, Cl⁻

, PO₄³⁻

and CO₃²⁻

between over and below the electrolyte ion-blocking layer,

wherein the nanoporous metal layer comprises a deposit of irregularly shaped bodies that are formed of numerous nanoparticles having a generally oval or spherical shape with a length ranging between about 2 nm and about 5 nm,

wherein adjacent ones of the irregularly shaped bodies abut one another while forming unoccupied spaces between non-abutting surfaces or portions of the adjacent ones of the irregularly shaped bodies,

wherein abutments between adjacent ones of the irregularly shaped bodies connect the adjacent ones with one another, which continues to other ones of the irregularly shaped bodies to form a three-dimensional interconnected network of irregularly shaped bodies,

wherein the unoccupied spaces between non-abutting surfaces or portions of the adjacent ones of the irregularly shaped bodies are irregularly shaped and connect with other unoccupied spaces formed by other ones of the irregularly shaped bodies,

wherein connections between the unoccupied spaces form a three-dimensional interconnected network of irregularly shaped spaces that is geometrically complementary to and outside the three-dimensional interconnected network of irregularly shaped bodies inside the nanoporous metal layer,

wherein, inside the three-dimensional interconnected network of irregularly shaped bodies, at least part of the nanoparticles are adjacent to each other without an intervening nanoparticle therebetween and apart from each other to define interparticular nanopores therebetween,

whereby the nanoporous metal layer comprises the interparticular nanopores inside the three-dimensional interconnected network of irregularly shaped bodies and further comprises the three-dimensional interconnected network of irregularly shaped spaces outside the three-dimensional interconnected network of irregularly shaped bodies,

wherein at least part of the interparticular nanopores inside the three-dimensional interconnected network of irregularly shaped bodies are in a size ranging between about 0.5 nm and about 3 nm,

wherein at least part of the irregularly shaped spaces of the three-dimensional interconnected network of irregularly shaped spaces are in a size ranging between about 100 nm and about 500 nm.

2. The glucose-sensing electrode of claim 1, wherein when applying a bias voltage of 0.2-0.45 V thereto relative to a reference electrode, the glucose-sensing electrode is configured to cause oxidation of glucose in the nanoporous metal layer and configured to generate an electric current that is a sum of a glucose-oxidation current caused by the glucose oxidation alone and a background current caused by other electrochemical interactions of the liquid and the glucose-sensing electrode,

wherein, when the liquid contains glucose at a concentration of 4-20 mM (72-360 mg/dL), at steady state the glucose-oxidation current is at a level higher than 0.1 μ

A/mMcm² (10 nA/mMcm²).

3. The glucose-sensing electrode of claim 1, wherein the combined concentration below the electrolyte ion-blocking layer is greater than 0% and lower than about 10% of the combined concentration above the electrolyte ion-blocking layer.

4. The glucose-sensing electrode of claim 1, wherein the combined concentration below the electrolyte ion-blocking layer is greater than 0% and lower than about 5% of the combined concentration above the electrolyte ion-blocking layer.

5. The glucose-sensing electrode of claim 1, wherein the electrolyte ion-blocking layer comprises a porous and hydrophobic polymer layer that is configured to limit mobility of Na⁺, K⁺, Ca²⁺, Cl⁻

, PO₄³⁻

and CO₃²⁻

therethrough while not limiting mobility of glucose molecules therethrough.

6. The glucose-sensing electrode of claim 1, wherein the electrolyte ion-blocking layer comprises at least one selected from the group consisting of poly(methyl methacrylate) (PMMA), poly(hydroxyethyl methacrylate) (PHEMA), and poly(methyl methacrylate-co-ethylene glycol dimethacrylate) (PMMA-EG-PMMA).

7. The glucose-sensing electrode of claim 1, wherein the electrolyte ion-blocking layer comprises at least one selected from the group consisting of a copolymer of methylmethacrylate and butylmethacrylate, and polymers obtained from polymerization of one or more monomers including branched or unbranched C1-C8 alkylmethacrylate, branched or unbranched C1-C8 cycloalkylmethacrylate, branched or unbranched C1-C8 alkylacrylate, branched or unbranched C1-C8 cycloalkylcrylate, and branched or unbranched C1-C8 cycloalkylmethacrylate, wherein the one or more monomers are selected from the group consisting of methylmethacrylate, ethylmethacrylate, proplymethacrylate, butylmethacrylate, pentylmethacrylate, hexylmethacrylate, cyclohexylmethacrylate, 2-ethylhexylmethacrylate, methylacrylate, ethylacrylate, proplyacrylate, butylacrylate, pentylacrylate, hexylacrylate, cyclohexylacrylate, and 2-ethylhexylacrylate.

8. The glucose-sensing electrode of claim 1, wherein the glucose-sensing electrode is a continuous glucose monitoring (CGM) electrode, wherein the liquid is bodily fluid of a subject.

9. The glucose-sensing electrode of claim 8, wherein when applying a bias voltage of 0.2-0.45 V thereto relative to a reference electrode, the glucose-sensing electrode is configured to cause oxidation of glucose in the nanoporous metal layer and configured to generate an electric current that is a sum of a glucose-oxidation current caused by the glucose oxidation alone and a background current caused by other electrochemical interactions of the liquid and the glucose-sensing electrode, wherein the electrolyte ion-blocking layer is configured to facilitate conditioning of the glucose-sensing electrode such that conditioning of the glucose-sensing electrode is complete within 30 minutes from contacting the subject'"'"'s bodily fluid with the application of the bias voltage of 0.2-0.45 V.

10. The glucose-sensing electrode of claim 9, wherein conditioning of the glucose-sensing electrode is considered as complete when a rate of decrease of the electric current is smaller than a first predetermined value.

11. The glucose-sensing electrode of claim 9, wherein conditioning of the glucose-sensing electrode is considered as complete when the electric current stays smaller than a second predetermined value.

12. The glucose-sensing electrode of claim 9, wherein conditioning of the glucose-sensing electrode is considered as complete when a rate of decrease of the electric current is smaller than a first predetermined value and when the electric current stays smaller than a second predetermined value.

13. The glucose-sensing electrode of claim 9, wherein the reference electrode is configured to provide a reference level of electric potential for the bias voltage applied to the glucose-sensing electrode, whether reduction of a chemical entity occurs in the reference electrode or not.

14. An apparatus comprising:

a single integrated body comprising a subcutaneous portion and a terminal portion;

the subcutaneous portion comprising the glucose-sensing electrode of claim 1 and a reference electrode, each of which is exposed for contacting interstitial fluid of a first subject when the subcutaneous portion is subcutaneously inserted into the first subject'"'"'s body; and

the terminal portion configured for coupling with a counterpart device and comprising a first terminal electrically connected to the glucose-sensing electrode and a second terminal electrically connected to the reference electrode.

15. A method of continuous glucose monitoring, the method comprising:

providing the apparatus of claim 14;

subcutaneously inserting the subcutaneous portion into a first subject'"'"'s body such that the glucose-sensing electrode and the reference electrode contact interstitial fluid of the first subject'"'"'s body;

causing to apply a bias voltage of 0.2-0.45 V to the glucose-sensing electrode relative to the reference electrode;

measuring electric current generated from the glucose-sensing electrode;

computing a glucose level using an electric current value that is obtained by a measurement of the electric current within less than 1 hour from later of subcutaneous insertion of the subcutaneous portion and application of the bias voltage; and

presenting, on a display, the computed glucose level as that of the first subject within a range between about 4 mM and about 20 mM (between about 72 mg/dL and about 360 mg/dL).

16. The glucose-sensing electrode of claim 1, wherein the nanoporous metal layer is substantially free of a surfactant, wherein if any surfactant is contained in the nanoporous metal layer, the surfactant is in an amount smaller than 0.5 parts by weight with reference to 100 parts by weight of the deposit.

17. The glucose-sensing electrode of claim 1, wherein the three-dimensional interconnected network of irregularly shaped bodies further comprises interparticular nanopores between adjacent nanoparticles in a size ranging between about 0.25 nm and about 4.5 nm.

18. The glucose-sensing electrode of claim 1, wherein the unoccupied spaces forming the three-dimensional interconnected network of irregularly shaped spaces are individually in a size ranging between about 25 nm and about 700 nm.

19. The glucose-sensing electrode of claim 1, wherein the nanoparticles are primarily made of platinum (Pt) or gold (Au), wherein the interparticular nanopores are distributed generally throughout inside the three-dimensional interconnected network of irregularly shaped bodies.

20. The glucose-sensing electrode of claim 1, wherein the nanoparticles are primarily made of platinum (Pt) or gold (Au), wherein the unoccupied spaces of the three-dimensional interconnected network of irregularly shaped spaces are distributed generally throughout in the nanoporous metal layer.