CN114767105B - Implantable electrochemical biosensor, testing method and implantable medical device - Google Patents
Implantable electrochemical biosensor, testing method and implantable medical device Download PDFInfo
- Publication number
- CN114767105B CN114767105B CN202210711784.3A CN202210711784A CN114767105B CN 114767105 B CN114767105 B CN 114767105B CN 202210711784 A CN202210711784 A CN 202210711784A CN 114767105 B CN114767105 B CN 114767105B
- Authority
- CN
- China
- Prior art keywords
- sensor
- reference electrode
- flexible conductive
- conductive film
- electrode
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000012360 testing method Methods 0.000 title claims abstract description 12
- 238000005452 bending Methods 0.000 claims abstract description 19
- 238000010998 test method Methods 0.000 claims abstract 2
- 239000012528 membrane Substances 0.000 claims description 28
- 239000000758 substrate Substances 0.000 claims description 15
- 229910052709 silver Inorganic materials 0.000 claims description 9
- 239000004332 silver Substances 0.000 claims description 9
- 238000000576 coating method Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 229910021607 Silver chloride Inorganic materials 0.000 claims description 6
- 238000000338 in vitro Methods 0.000 claims description 6
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 claims description 6
- 238000002513 implantation Methods 0.000 claims description 5
- 239000011248 coating agent Substances 0.000 claims description 4
- 229920001940 conductive polymer Polymers 0.000 claims description 4
- 229910052755 nonmetal Inorganic materials 0.000 claims description 3
- 238000004891 communication Methods 0.000 claims 2
- 238000001514 detection method Methods 0.000 description 9
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 239000012491 analyte Substances 0.000 description 7
- 230000007797 corrosion Effects 0.000 description 6
- 238000005260 corrosion Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 238000007598 dipping method Methods 0.000 description 4
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 4
- 229910052737 gold Inorganic materials 0.000 description 4
- 239000010931 gold Substances 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 238000000151 deposition Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 108010015776 Glucose oxidase Proteins 0.000 description 2
- 239000004366 Glucose oxidase Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 229910045601 alloy Inorganic materials 0.000 description 2
- 239000000956 alloy Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000005518 electrochemistry Effects 0.000 description 2
- 238000006056 electrooxidation reaction Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 229940116332 glucose oxidase Drugs 0.000 description 2
- 235000019420 glucose oxidase Nutrition 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 229910052741 iridium Inorganic materials 0.000 description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- HWLDNSXPUQTBOD-UHFFFAOYSA-N platinum-iridium alloy Chemical compound [Ir].[Pt] HWLDNSXPUQTBOD-UHFFFAOYSA-N 0.000 description 2
- 229920006254 polymer film Polymers 0.000 description 2
- 229920000123 polythiophene Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241000270728 Alligator Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 229910001260 Pt alloy Inorganic materials 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 230000000260 hypercholesteremic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012212 insulator Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- -1 nickel metal hydride Chemical class 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229920006289 polycarbonate film Polymers 0.000 description 1
- 229920000139 polyethylene terephthalate Polymers 0.000 description 1
- 239000005020 polyethylene terephthalate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000011527 polyurethane coating Substances 0.000 description 1
- 229920006264 polyurethane film Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
- A61B5/1473—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
- A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
Abstract
The application relates to the field of biosensors, and provides an implantable electrochemical biosensor, a testing method and an implantable medical device, wherein the implantable electrochemical biosensor comprises an electroactive domain, a working electrode and a reference electrode which are separated by an insulating layer, the working electrode and the reference electrode are respectively contacted with the electroactive domain, and the implantable electrochemical biosensor also comprises a flexible conductive film, wherein the flexible conductive film is electrically connected with the reference electrode, and the flexible conductive film is not directly contacted with the working electrode. The application also discloses a test method of the sensor, wherein the reference electrode is electrically connected with the test component through the flexible conductive film. The application also discloses an implantable medical device using the sensor, wherein the sensor can be in a bending state, and the reference electrode is electrically connected with the implantable medical device through the flexible conductive film. The disclosed sensor of this application still can normally work after being bent wantonly, can simplify and detect the flow, improves the security, can not take place to corrode with the pjncture needle inner wall and cohere.
Description
Technical Field
The application relates to the field of biosensors, in particular to an implantable electrochemical biosensor, a testing method and an implantable medical device.
Background
Implantable medical devices for determining the presence and concentration of biological analytes, including sensors partially implanted in the body and in vitro electronics electrically connected to the sensors, can be used to monitor glucose in diabetic patients, cholesterol in hypercholesterolemic patients, and lactate levels during emergency care events. Typically, the sensor has an elongated body including a working electrode, an insulating layer covering the working electrode, and a reference electrode applied to the insulating layer.
The sensor comprises two ends, one end is a sensing end containing an electroactive domain (such as containing enzyme, electron mediator and the like) and is used for being implanted into a body, and a biocompatible membrane is usually coated on the outer layer of the sensing end for the purpose of biological rejection reaction on the sensor; the other end is an electrical connection end for electrically connecting with an external electronic component, and in order to realize and facilitate effective electrical connection between the sensor and the external electronic component, a mode of exposing the working electrode and the reference electrode is generally adopted, and the specific structure is shown in fig. 1.
The working electrode is in the form of a thin wire, and is formed of, for example, platinum, iridium, platinum-iridium, palladium, gold, silver chloride, graphite, a conductive polymer, an alloy, or the like. In addition, the working electrode can be formed by various fabrication techniques, such as depositing a conductive carrier onto a non-conductive substrate.
The reference electrode is typically formed using a silver-containing material, such as a silver/silver chloride coating or the like, by applying a polymer paste containing silver/silver chloride or the like using a pasting, dipping or coating process.
From the viewpoint of weight reduction, the implantable medical device tends to be miniaturized, and thus the overall thickness of the external electronic component is required to be thinner and thinner. The sensor is electrically connected with an in-vitro electronic component as an indispensable sensor, and is realized by arranging a plurality of conductive contacts on the in-vitro electronic component, wherein the conductive contacts are respectively in direct contact connection with a working electrode and a reference electrode of the sensor.
In order to avoid the potential short circuit between the working electrode and the reference electrode, the distance between the conductive contacts is usually increased, and accordingly, the working electrode and the reference electrode are required to have longer parts for electrical connection (as shown in fig. 1), which is in contradiction with the requirement of thinner external electronic components.
One way to better solve the above contradiction is to bend the sensor so that the electrical connection part of the sensor with the external electronic component is arranged in a way of being nearly parallel to the surface of the external electronic component, i.e. the bending is performed between the sensing end and the electrical connection end of the sensor, the sensing end is implanted in the body, and the electrical connection end which is not implanted in the body is electrically connected with the external electronic component.
During use of the implantable medical device, especially when the body is moving, the sensors of the implanted part may be more or less displaced, e.g. twisted, stretched or re-bent, relative to the non-implanted part. In addition, friction between the working and reference electrodes of the sensor and the conductive contacts on the external electronic components is also increased when the sensor implanted in the body is displaced relative to each other. For reference electrodes formed by pasting, dipping or coating processes, the aforementioned twisting, stretching, re-bending or rubbing can result in the detachment of the reference electrode applied to the insulator layer, the breaking of the circuit and thus the overall failure of the sensor, and therefore a sensor is needed that has a reliable electrical connection after being subjected to external forces such as twisting, stretching, re-bending or rubbing.
In addition, in the detection process of the sensor, the sensor after detection can be continuously and normally used, so that the sensor is required to be prevented from being bent during detection, an exposed electrode in the sensor, particularly a reference electrode, is prevented from being worn or damaged, the detection process is complicated, the requirement on detection personnel is harsh, and a special detection auxiliary jig is required.
Furthermore, in order to successfully implant the sensor into the body, it is necessary to use the puncture needle, for example, to place the sensor completely or partially in the cavity of the puncture needle and implant it together with the puncture needle, and then to leave the sensor in the body when the puncture needle is removed.
Generally, the puncture needle is made of hard metal, and although necessary anticorrosion treatment is adopted, the applicant finds that in some extreme cases, contact corrosion similar to that caused by the contact of two different metals can be generated when the reference electrode positioned at the outermost layer of the sensor is contacted with the inner wall of the puncture needle, and when the reference electrode contains chlorine, the corrosion phenomenon is serious, and the adhesion phenomenon is generated, so that the sensor cannot be left in the body when the puncture needle is pulled out.
Even if the sensor can be left in the body, corrosion of the electrodes, particularly the reference electrode, can result in poor electrical connection to the electronics outside the body.
This background is not intended to limit the scope of the claimed subject matter, nor is it intended to limit the claimed subject matter to implementations that solve any or all of the disadvantages or problems noted above.
It should be noted that the above background section merely represents an understanding of the applicant's related art and does not constitute prior art.
Disclosure of Invention
In view of one of the problems with the above-mentioned prior art sensors, the present application provides an implantable electrochemical biosensor.
According to a first aspect of the present disclosure, there is provided an implantable electrochemical biosensor comprising an electroactive domain (containing a substance that participates in or promotes a reaction of an analyte in a living organism, or contributes to rapid migration of electrons, such as a biological enzyme, an electron mediator, etc.), a working electrode and a reference electrode separated by an insulating layer, and a flexible conductive membrane covering the sensor, the flexible conductive membrane being electrically connected to the reference electrode, such as being in parallel abutment with each other, or being disposed to overlap or cover each other, the flexible conductive membrane being disposed insulated from the working electrode in order to avoid unnecessary short circuits between the working electrode and the reference electrode. When the sensor works, the flexible conductive film can be electrically connected with the working electrode through the electronic component. In order to exert the function of keeping the constant potential of the reference electrode, the flexible conductive film is not contacted with the electric active domain.
Preferably, there is at least one predetermined region along the length of the sensor, the predetermined region comprising a flexible conductive membrane in a cross-section perpendicular to the length of the sensor but no reference electrode.
Further, the sensor is provided with a working electrode as a support body, for example, the working electrode is formed by platinum, iridium, platinum-iridium, palladium, gold, silver, alloy, etc., the working electrode is configured to absorb mechanical stress generated by bending the working electrode in a coverage area of the flexible conductive film, and specifically, for example, the working electrode is provided with at least one groove in the coverage area of the flexible conductive film.
More specifically, in one possible implementation, the opening direction of the groove may be set to coincide with the bending direction; in a possible implementation mode, the opening direction of the groove is arranged in a circle which is perpendicular to the length direction of the sensor and surrounds the working electrode serving as the support body, and the bending of the sensor towards any direction in the flexible conductive film covering area is facilitated.
Preferably, the sensor further comprises a biocompatible membrane covering the electroactive domain, and more preferably, the biocompatible membrane further covers a partial region of the reference electrode (depending on the arrangement of the flexible conductive membrane with the reference electrode, the sensor comprises the biocompatible membrane and the reference electrode, or alternatively, the biocompatible membrane, the reference electrode and the flexible conductive membrane, in a cross-section perpendicular to the sensor). The area of the reference electrode not covered by the biocompatible film is at least partially covered by the flexible conductive film, that is, part of the area of the reference electrode may be exposed, or the reference electrode may be covered by the biocompatible film and the flexible conductive film, respectively, without being exposed.
Preferably, the sensor further comprises a substrate, wherein the substrate is a plastically deformable, non-conductive substrate, in which case the working electrode may be formed by, for example, depositing a conductive carrier, such as platinum, gold, copper, silver, or the like, onto the substrate.
Further, the substrate is configured to absorb mechanical stress due to bending of the substrate in the flexible conductive film coverage area, and further, for example, at least one groove is provided.
Further, the sensor can still normally work after being bent, specifically, the sensor can still normally work after being bent in the flexible conductive film covering area, and more specifically, the sensor can still normally work after being bent in the flexible conductive film covering area to the preset direction.
Further, the working electrode is arranged to be plastically deformable so that the working electrode can be bent together with the substrate.
Further, the sensor is a hydrogen peroxide sensitive sensor, and specifically, the working electrode of the sensor measures the current generated by the hydrogen peroxide generated by the bio-enzyme catalyzed reaction of the analyte in the detected organism (for example, the byproduct H generated by the glucose oxidase immobilized in the electroactive domain is used for detecting the glucose content in blood) 2 O 2 ,H 2 O 2 Reacts with the surface of the working electrode to produce two protons (2H) + ) Two electrons (2 e) - ) And one oxygen molecule (O 2 ) The detected current is formed) and can be converted to the content of the detected analyte according to the magnitude of the generated current.
Further, the flexible conductive film is any one of a conductive polymer film, a metal film, a nonmetal film, and a polymer film containing conductive particles, for example, a polythiophene conductive film, a nano-metal wire conductive fiber film, an ITO conductive film, and the like.
Furthermore, the sensor is also connected with a power supply, and the reference electrode is electrically connected with the power supply through the flexible conductive film. The power source may be a battery, such as a battery of different chemistries, such as lithium based chemistry, alkaline batteries, nickel metal hydride, etc.; the power source may also be an electric drive system comprising a battery and electronic components, which may include components such as rectifiers, counters, logic controllers, signal processors, etc.
Further, the reference electrode is formed using a pasting, dipping or coating process, such as a silver/silver chloride coating.
According to a second aspect of the present disclosure, there is provided a method for testing a sensor, including a testing component electrically connected to the sensor, the sensor including a reference electrode and a plurality of electrodes, the testing component including a plurality of conductive interfaces, the plurality of electrodes being electrically connected to the plurality of conductive interfaces, wherein the sensor is the above-mentioned sensor, the reference electrode is electrically connected to the conductive interfaces by a flexible conductive film, and the reference electrode is not directly contacted to the conductive interfaces.
According to a third aspect of the present disclosure, an implantable medical device is provided, which includes a sensor partially implanted in a body and an external electronic component electrically connected to the sensor, wherein the sensor is in a bent state, and the sensor is the above-mentioned sensor.
According to a fourth aspect of the present disclosure, an implantable medical device is provided, which includes a sensor partially implanted in a body and an in vitro electronic component electrically connected to the sensor, wherein the sensor is in a bent state, the sensor is the above sensor, and the bent region is a region covered by the above flexible conductive film.
According to a fifth aspect of the present disclosure, there is provided an implantable medical device, comprising a sensor partially implanted in a body and an external electronic component electrically connected to the sensor, wherein the sensor includes a plurality of electrodes including a reference electrode, the external electronic component includes a plurality of conductive contacts, the plurality of electrodes are electrically connected to the plurality of conductive contacts, the sensor is the above-mentioned sensor, the reference electrode is electrically connected to the conductive contacts by a flexible conductive film, and the reference electrode is not directly connected to the conductive contacts.
According to a sixth aspect of the present disclosure, there is provided an implantable medical device, comprising a sensor partially implanted in a body and a puncture needle for assisting in the implantation of the sensor, the sensor being disposed wholly or partially in a cavity of the puncture needle, the sensor including a plurality of electrodes including a reference electrode, wherein the sensor is the above sensor, and the reference electrode is not in direct contact with an inner wall of the puncture needle.
Compared with the prior art, the scheme disclosed by the application has at least one of the following advantages:
(1) The implantable electrochemical biosensor disclosed by the application can be bent at will, and can still normally work after being bent without causing the disconnection of the electrode, and particularly, the bending of the flexible conductive film covering area can not cause the disconnection of the reference electrode and the overall failure of the sensor.
(2) The disclosed implanted electrochemistry biosensor of this application is after bending, even if appear the reference electrode and peel off from the insulating layer, also can be wrapped up by flexible conducting film, avoids causing secondary risk, improves the security after the implantation.
(3) The implanted electrochemical biosensor disclosed by the application can adopt a detection jig of a common electrochemical sensor to detect, simplifies the detection flow of the existing sensor, and reduces the requirements on detection personnel.
(4) Adopt the implanted medical instrument of the implanted electrochemistry biosensor preparation that this application disclosed, can not appear leading to the sensor electrode to open circuit and the condition that can not normally work because of the motion, the sensor can hardly take place the contact corrosion with the contact of pjncture needle inner wall, avoids appearing the phenomenon of gluing.
Drawings
The following drawings are provided to facilitate a better understanding of the technical solutions of the present application and are provided for purposes of illustration only to depict typical or exemplary embodiments. These drawings are provided to facilitate the reader's understanding of the systems and methods described in this application and should not be taken to limit the breadth, scope, or applicability of the various embodiments.
Fig. 1 is a schematic cross-sectional structure diagram of an implantable electrochemical biosensor in the prior art.
Fig. 2 is a schematic cross-sectional structure diagram of an implantable electrochemical biosensor disclosed in an embodiment of the present application.
Fig. 3 is a schematic cross-sectional structure diagram of an implantable electrochemical biosensor disclosed in another embodiment of the present application.
Fig. 4 is a schematic cross-sectional structure diagram of an implantable electrochemical biosensor disclosed in another embodiment of the present application.
Fig. 5 is a schematic cross-sectional structure diagram of an implantable electrochemical biosensor disclosed in another embodiment of the present application.
Fig. 6 is a schematic cross-sectional structure diagram of an implantable electrochemical biosensor disclosed in another embodiment of the present application.
Fig. 7 is a schematic cross-sectional structure view of an implantable electrochemical biosensor disclosed in another embodiment of the present application.
Fig. 8 is a schematic cross-sectional structure view of an implantable electrochemical biosensor disclosed in another embodiment of the present application.
Fig. 9 is a schematic cross-sectional structure view of an implantable electrochemical biosensor disclosed in another embodiment of the present application.
Fig. 10 is a schematic cross-sectional structure view of an implantable electrochemical biosensor disclosed in another embodiment of the present application.
Fig. 11 is a schematic cross-sectional structure view of an implantable electrochemical biosensor disclosed in another embodiment of the present application.
Fig. 12 is a schematic cross-sectional view of an implantable electrochemical biosensor, which is bent at 90 ° and implanted in a body, according to an embodiment of the present disclosure.
Fig. 13 is an implantable medical device employing an implantable electrochemical biosensor as disclosed herein.
Fig. 14 is a partial enlarged view of a portion a in fig. 13.
Reference numerals are as follows: 100. a sensor; 1. a working electrode; 2. a flexible conductive film; 3. an insulating layer; 4. a reference electrode; 5. an electroactive domain; 6. a biocompatible film; 7. a substrate; 8. recess, 9 conductive contact.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions of the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings.
Referring to fig. 2, the sensor 100 is elongated, e.g., an elongated wire or rod; the cross section in the direction perpendicular to the sensor 100 is a regular shape such as a circle, an ellipse, a rectangle, or the like, or is an arbitrary irregular shape such as a convex polygon, a concave polygon, a quasi-circle, or the like.
The sensor 100 includes a working electrode 1 (e.g., a platinum alloy), a reference electrode 4 (e.g., a silver/silver chloride coating), and an insulating layer 3 (e.g., a polyurethane coating) separating the working electrode 1 and the reference electrode 4, and includes an electroactive domain 5 (e.g., a region where a biological enzyme such as glucose oxidase or catalase is immobilized, or a region where a biological enzyme and an electron mediator are immobilized, or other regions where an analyte concentration in a reaction organism is achieved using non-enzymatic techniques, etc.) at a sensing end, a flexible conductive membrane 2 covering a surface of the sensor 100, e.g., covering at least a portion of the surface of the reference electrode 4 and forming an electrical connection, and the flexible conductive membrane 2 and the working electrode 1 being disposed in an insulating manner, e.g., separated from each other. In the length direction of the sensor 100, the flexible conductive film 2 covers 1% -99% of the length of the reference electrode 4, where 1% is understood to mean that there is at least one area on the reference electrode 4 covered with the flexible conductive film 2; and 99% is understood to mean that there is at least an area of the reference electrode 4 that is not covered by the flexible conductive film 2 in the vicinity of the electroactive zone 5, such that the flexible conductive film 2 is not in contact with the electroactive zone 5, in order to function as a constant potential for the reference electrode 4.
In other examples, the flexible conductive film 2 is covered on the surface of the insulating layer 3 and the reference electrode 4 is in parallel contact with each other (e.g. to help keep the appearance surface of the sensor 100 flat), and in other examples, it is also possible to cover the reference electrode 4 on part of the surface of the flexible conductive film 2. In these examples, there is a predetermined area that includes the flexible conductive film 2 but not the reference electrode 4 in a cross section perpendicular to the lengthwise direction of the sensor 100.
In the portion of the sensor 100 covered by the flexible conductive film 2, at least part of the flexible conductive film may be used for bending or for electrical connection with external electronic components.
The reference electrode 4, the insulating layer 3, the electrically active domains 5, and the flexible conductive film 2 may be formed by applying a coating process such as dipping, dispensing, etc., and depending on the sequence of process steps, the flexible conductive film 2 may be formed to cover all or part of the surface of the reference electrode 4, or the reference electrode 4 may be formed to cover part of the surface of the flexible conductive film 2.
The flexible conductive film 2 may be a conductive polymer film, a metal film, a non-metal film, a polymer film containing conductive particles, for example, a polythiophene conductive film, a nano metal wire conductive fiber film, an ITO conductive film, or the like, as long as the property of being able to have flexibility and conductivity is achieved.
The flexible conductive film 2 is not in direct contact with the working electrode 1, and when the sensor 100 operates, the flexible conductive film 2 can be electrically connected with the working electrode 1 through an electronic component. For example, an analyte (e.g., glucose, cholesterol, lactate, etc.) in an organism undergoes an electrochemical oxidation or reduction reaction by a biological enzyme, or through a series of chemical reactions (at least one of which is an electrochemical oxidation or reduction reaction at the sensor 100), which are converted into an electrical signal that can be correlated to the amount, concentration, or level of the analyte in the organism and collected by the electronic components.
Referring to fig. 3, to overcome the problems of bio-repulsion to the sensor 100, avoiding the substances in the electroactive zone 5 from entering the body, etc., the sensor 100 further comprises a biocompatible film 6 (e.g., polyurethane film, polycarbonate film) covering the length of the portion of the sensor 100 implanted in the body, e.g., the biocompatible film 6 covers the entire area of the electroactive zone 5 and a portion of the area of the flexible conductive membrane 2. The area of the reference electrode 4 not covered by the biocompatible film 6 is at least partially covered by the flexible conductive film 2, i.e. there should be at least one area of the flexible conductive film 2 not covered by the biocompatible film 6, which area is used for electrical connection.
With continued reference to fig. 4, the flexible conductive membrane 2 and the biocompatible membrane 6 each individually cover the reference electrode 4, wherein the portion of the sensor 100 covered by the biocompatible membrane 6 is for implantation in the body.
Referring to fig. 5, reference electrode 4 covers only a partial region of insulating layer 3, the other region of insulating layer 3 is partially covered by flexible conductive film 2 (likewise, flexible conductive film 2 is not in direct contact with working electrode 1), and reference electrode 4 and flexible conductive film 2 are brought into abutment against each other to form an electrical connection, reference electrode 4 is not covered by flexible conductive film 2, and biocompatible film 6 is not covered to flexible conductive film 2. In this example, the sensor 100 has an area covering the flexible conductive film 2 but not the reference electrode 4, i.e. a cross-section (perpendicular to the length direction of the sensor 100) of the sensor 100 in this area contains the flexible conductive film 2 but not the reference electrode 4. In other embodiments, the biocompatible film 6 may cover a portion of the flexible conductive film 2. In other embodiments, reference electrode 4 covers only a portion of insulating layer 3, and other areas of insulating layer 3 are completely covered by flexible conductive film 2. In other embodiments, electrical connection between the reference electrode 4 and the flexible conductive film 2 may be made, for example, by stacking one on top of the other.
Referring to fig. 4 and 5, reference electrode 4 may also be partially exposed in both examples.
Referring to fig. 6 and 7, the biocompatible film 6 and the flexible conductive film 2 cover the entirety of the reference electrode 4 by abutting (fig. 6) or laminating (fig. 7) each other so that no portion of the reference electrode 4 is exposed, and the reference electrode 4 is completely wrapped. In the two embodiments, on one hand, secondary risks caused by the stripping of the reference electrode 4 from the insulating layer 3 can be avoided, and the safety after implantation can be improved; on the other hand, when the sensor 100 is applied to an implantable medical device and is arranged in the inner cavity of the puncture needle, the reference electrode 4 is not in contact with the inner wall of the puncture needle, contact corrosion cannot occur, and the phenomenon of adhesion cannot occur. In other embodiments, the flexible conductive film 2 may be configured to have at least one protrusion, for example, one or more annular protrusions surrounding the sensor 100 are formed, so that when the sensor 100 is disposed in the puncture needle lumen, only the flexible conductive film 2 contacts with the inner wall of the puncture needle, and the reference electrode 4 does not contact with the inner wall of the puncture needle, and contact corrosion and adhesion are not caused.
Referring to fig. 8-10, in order to facilitate the bending of the sensor 100 by using the working electrode 1 as a supporting body of the sensor 100, the area covered by the flexible conductive film 2 of the working electrode 1 (i.e. the length of the working electrode 1 covered by the flexible conductive film 2) is configured to absorb the mechanical stress generated by the bending of the working electrode, for example, at least one groove 8 is provided, and the groove 8 may be disposed in various ways, for example, around the working electrode 1 for one circle (fig. 8 and 9), or disposed on only one side (fig. 10). The biocompatible membrane 6, the flexible conductive membrane 2 and the reference electrode 4 may be arranged separately or in combination with reference to fig. 2-7. In other embodiments, stress reduction and/or absorption may also be achieved by varying the stiffness, elastic modulus, equivalent diameter, etc. of the working electrode 1 in the area covered by the flexible conductive film 2.
Referring to fig. 11, with a substrate 7 (plastically deformable, non-conductive, such as polyurethane, nylon, PET, etc.) as a supporting body of the sensor 100, the working electrode 1 is formed by depositing a conductive carrier (such as platinum, gold, copper, silver, etc.) onto the substrate 7. The biocompatible membrane 6, the flexible conductive membrane 2 and the reference electrode 4 may be arranged as described with reference to fig. 2-7. Similarly, the base 7 may be provided with reference to fig. 8-10 with parameters such as groove 8 (not shown in fig. 11), hardness, modulus of elasticity, or equivalent diameter for absorbing mechanical stresses due to bending of the base 7.
Although the cross-sectional configuration of sensor 100 is shown in a symmetrical manner in fig. 2-11, this should not be understood to preclude embodiments of sensor 100 in which the cross-sectional configuration is asymmetrical.
The sensor 100 shown in fig. 2-11 is further connected to a power source during use, wherein the reference electrode 4 is electrically connected to the power source through the flexible conductive film 2.
In testing the sensor 100 shown in fig. 2-11, for example, whether the sensor 100 is operating properly, the analyte permeability of the biocompatible membrane 6 of the sensor 100, the lifetime of the sensor 100, etc., it is necessary to electrically connect the electrodes of the sensor 100 to the conductive interfaces (e.g., alligator clip, electrode clip, conductive clip, etc.) of the electrochemical workstation, wherein the electrical connection between the reference electrode 4 and the conductive interfaces is achieved by directly contacting the flexible conductive membrane 2 to the conductive interfaces, and there is no concern about damage to the reference electrode 4 by the conductive interfaces.
Fig. 12 shows the sensor 100 shown in fig. 9 after being implanted into a body and bent (e.g., 90 °). The biocompatible film 6 covers the length part of the sensor 100 implanted in the body and extends to the surface of the skin, the reference electrode 4 extends from the sensing end to the bending part, the flexible conductive film 2 covers the insulating layer 3 and is abutted against the reference electrode 4 but not contacted with the surface of the skin and the working electrode 1, and the bending part of the sensor 100 is covered by the flexible conductive film 2. The working electrode 1 and the flexible conductive film 2 exposed on the surface of the skin are used for being electrically connected with an external electronic component.
Fig. 13 shows an implantable medical device using the implantable electrochemical biosensor 100 disclosed in the present application, which includes a sensor 100 that can be partially implanted in vivo and an external electronic component electrically connected to the sensor 100, and referring to fig. 14, the flexible conductive film 2 is in direct contact with the conductive contact 9.
It should be noted that "covering" in the above description includes both direct covering and indirect covering, i.e., the cross section of the covering area (perpendicular to the length direction of the sensor 100) includes at least a covering and a covered object, and may also include other indirectly covered parts. For example, in fig. 3, the biocompatible film 6 covers (directly covers) a portion of the reference electrode 4, i.e., the cross section of the covered area (perpendicular to the longitudinal direction of the sensor 100) includes the biocompatible film 6 and the directly covered reference electrode 4, and also includes the indirectly covered insulating layer 3 and the working electrode 1. As another example, in fig. 3, the biocompatible film 6 covers (directly covers) a portion of the flexible conductive film 2, i.e., the cross section (perpendicular to the length direction of the sensor 100) of the covered area includes the biocompatible film 6 and the directly covered flexible conductive film 2, and further includes the indirectly covered reference electrode 4, the insulating layer 3, and the working electrode 1. As another example, in fig. 5, the region of the insulating layer 3 not covered by the reference electrode 4 is partially covered by the flexible conductive film 2, and the reference electrode 4 is not covered (directly or indirectly) by the flexible conductive film 2, that is, the cross section of the region covered by the flexible conductive film 2 (perpendicular to the longitudinal direction of the sensor 100) includes the flexible conductive film 2, the insulating layer 3 directly covered, and the working electrode 1 indirectly covered, but does not include the reference electrode 4.
It is to be understood that the described embodiments are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the described embodiments of the present application, belong to the protection scope of the present application. In addition, the embodiments and features of the embodiments in the present application may be combined with each other without conflict. Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this application belongs.
Claims (14)
1. An implantable electrochemical biosensor comprising an electroactive zone, a working electrode and a reference electrode separated by an insulating layer, the working electrode and the reference electrode being in contact with the electroactive zone, respectively, characterized in that:
the flexible conductive film is electrically connected with the reference electrode, is not in contact with the electroactive domain, and is arranged in an insulated mode with the working electrode;
the working electrode is plastically deformable;
the sensor is in a bending state, the sensor is bent in the flexible conductive film covering area, and the sensor cannot cause the disconnection of the electrode after being bent.
2. The sensor of claim 1, wherein: there is at least one predetermined area along the length of the sensor, the predetermined area including the flexible conductive membrane but not the reference electrode in a cross-section perpendicular to the length of the sensor.
3. The sensor of claim 1, wherein: the sensor takes the working electrode as a supporting body, and the working electrode is configured to absorb mechanical stress generated by bending of the working electrode in an area covered by the flexible conductive film.
4. The sensor of claim 1, wherein: the sensor also includes a biocompatible membrane covering the electroactive domain.
5. The sensor of claim 4, wherein: the biocompatible membrane also covers a partial area of the reference electrode.
6. The sensor of claim 1, wherein: the sensor also includes a substrate that is a plastically deformable, non-conductive substrate.
7. The sensor of claim 6, wherein: the substrate is configured to absorb mechanical stress resulting from bending of the substrate within an area covered by the flexible conductive film.
8. The sensor of any one of claims 1-7, wherein: the sensor is a hydrogen peroxide sensitive sensor.
9. The sensor of any one of claims 1-7, wherein: the flexible conductive film is any one of a conductive polymer film, a metal film and a nonmetal film.
10. The sensor of any one of claims 1-7, wherein: the reference electrode is a silver/silver chloride coating.
11. The sensor of any one of claims 1-7, wherein: the sensor is also connected with a power supply, and the reference electrode is electrically connected with the power supply through the flexible conductive film.
12. A method of testing a sensor comprising performing a test using a test assembly in electrical communication with the sensor, the sensor comprising a plurality of electrodes including a reference electrode, the test assembly comprising a plurality of conductive interfaces, the plurality of electrodes being in electrical communication with the plurality of conductive interfaces, the method comprising: the sensor is according to any one of claims 1-11, and the reference electrode is electrically connected to the conductive interface by direct contact with the conductive interface through the flexible conductive membrane.
13. An implantable medical device comprising a sensor partially implanted in a body and an in vitro electronics electrically coupled to the sensor, the sensor comprising a plurality of electrodes including a reference electrode, the in vitro electronics comprising a plurality of conductive contacts, the plurality of electrodes being electrically coupled to the plurality of conductive contacts, wherein: the sensor is according to any one of claims 1 to 11, and the reference electrode is electrically connected to the conductive contact by direct contact with the conductive contact through the flexible conductive membrane.
14. An implantable medical device, comprising a sensor partially implanted in a body and a puncture needle for assisting the implantation of the sensor, wherein the sensor is arranged in a cavity of the puncture needle, the sensor comprises a plurality of electrodes including a reference electrode, and the implantable medical device is characterized in that: the sensor of any of claims 1-11, wherein the reference electrode is not in direct contact with the inner wall of the needle.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210711784.3A CN114767105B (en) | 2022-06-22 | 2022-06-22 | Implantable electrochemical biosensor, testing method and implantable medical device |
PCT/CN2023/099147 WO2023246519A1 (en) | 2022-06-22 | 2023-06-08 | Implantable electrochemical biosensor, test method, and implantable medical instrument |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210711784.3A CN114767105B (en) | 2022-06-22 | 2022-06-22 | Implantable electrochemical biosensor, testing method and implantable medical device |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114767105A CN114767105A (en) | 2022-07-22 |
CN114767105B true CN114767105B (en) | 2022-10-14 |
Family
ID=82422297
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210711784.3A Active CN114767105B (en) | 2022-06-22 | 2022-06-22 | Implantable electrochemical biosensor, testing method and implantable medical device |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN114767105B (en) |
WO (1) | WO2023246519A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114767105B (en) * | 2022-06-22 | 2022-10-14 | 苏州百孝医疗科技有限公司 | Implantable electrochemical biosensor, testing method and implantable medical device |
CN115474929A (en) * | 2022-09-05 | 2022-12-16 | 苏州百孝医疗科技有限公司 | Implanted biosensor and preparation method thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105411607A (en) * | 2015-11-16 | 2016-03-23 | 杭州亿信网络科技有限公司 | Subcutaneous tissue involvement type glucose microsensor and preparation method thereof |
CN209751051U (en) * | 2018-11-14 | 2019-12-10 | 贝生(广州)传感科技有限公司 | implant device of continuous glucose monitoring system |
CN211796750U (en) * | 2019-07-18 | 2020-10-30 | 浙江荷清柔性电子技术有限公司 | Implant applicator |
CN112860093A (en) * | 2019-11-28 | 2021-05-28 | 深圳市华科创智技术有限公司 | Flexible folding touch sensor and manufacturing method thereof |
CN114027834A (en) * | 2021-09-27 | 2022-02-11 | 杭州脉理生物科技有限公司 | Double-sided flexible sensor and preparation method and application thereof |
CN216846637U (en) * | 2022-03-14 | 2022-06-28 | 轻昂化学(深圳)有限公司 | Flexible sensor array arranged along linear path |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1349096A (en) * | 2000-10-13 | 2002-05-15 | 聿新科技股份有限公司 | Electrochemical electrode test piece and its making process |
AU2003267970A1 (en) * | 2003-06-17 | 2005-01-28 | Huang, Alice, Y. | Structure and manufacturing method of disposable electrochemical sensor strip |
EP2254458A1 (en) * | 2008-02-04 | 2010-12-01 | Bayer HealthCare, LLC | Semiconductor based analyte sensors and methods |
US9131885B2 (en) * | 2009-07-02 | 2015-09-15 | Dexcom, Inc. | Analyte sensors and methods of manufacturing same |
FR3024982B1 (en) * | 2014-08-21 | 2018-03-09 | Universite Grenoble Alpes | METHOD FOR MANUFACTURING A CONDUCTIVE FILM OF AN ELECTROCHEMICAL BIOREACTOR |
CN112932477A (en) * | 2015-10-19 | 2021-06-11 | 中国农业大学 | Blood glucose sensor implanted in interocular scleral interstitial fluid of live fish eyeball and preparation method thereof |
TWI694530B (en) * | 2019-03-08 | 2020-05-21 | 致茂電子股份有限公司 | Electrical component testing mothed and testing probe |
CN114485976A (en) * | 2022-01-18 | 2022-05-13 | 福建师范大学 | Multifunctional sensor and preparation method thereof |
CN114767105B (en) * | 2022-06-22 | 2022-10-14 | 苏州百孝医疗科技有限公司 | Implantable electrochemical biosensor, testing method and implantable medical device |
-
2022
- 2022-06-22 CN CN202210711784.3A patent/CN114767105B/en active Active
-
2023
- 2023-06-08 WO PCT/CN2023/099147 patent/WO2023246519A1/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105411607A (en) * | 2015-11-16 | 2016-03-23 | 杭州亿信网络科技有限公司 | Subcutaneous tissue involvement type glucose microsensor and preparation method thereof |
CN209751051U (en) * | 2018-11-14 | 2019-12-10 | 贝生(广州)传感科技有限公司 | implant device of continuous glucose monitoring system |
CN211796750U (en) * | 2019-07-18 | 2020-10-30 | 浙江荷清柔性电子技术有限公司 | Implant applicator |
CN112860093A (en) * | 2019-11-28 | 2021-05-28 | 深圳市华科创智技术有限公司 | Flexible folding touch sensor and manufacturing method thereof |
CN114027834A (en) * | 2021-09-27 | 2022-02-11 | 杭州脉理生物科技有限公司 | Double-sided flexible sensor and preparation method and application thereof |
CN216846637U (en) * | 2022-03-14 | 2022-06-28 | 轻昂化学(深圳)有限公司 | Flexible sensor array arranged along linear path |
Also Published As
Publication number | Publication date |
---|---|
CN114767105A (en) | 2022-07-22 |
WO2023246519A1 (en) | 2023-12-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN114767105B (en) | Implantable electrochemical biosensor, testing method and implantable medical device | |
US8187433B2 (en) | Compound material analyte sensor | |
US20230135297A1 (en) | Electrode systems for electrochemical sensors | |
EP2501285B1 (en) | Multi-conductor lead configurations useful with medical device systems | |
US6965791B1 (en) | Implantable biosensor system, apparatus and method | |
US9394563B2 (en) | Electrode system for measuring an analyte concentration under in-vivo conditions | |
US10060877B2 (en) | Electrochemical sensor for determining an analyte concentration | |
US20170325745A1 (en) | Biosensor and method for providing a biosensor | |
US11399753B2 (en) | Electrochemical sensor and method for producing thereof | |
US20200029869A1 (en) | Nonenzymatic determination of glucose at near neutral ph values based on the use of nafion and platinum black coated microneedle electrode array | |
WO2022016639A1 (en) | Subcutaneously implanted glucose sensor with three electrodes and manufacturing method therefor | |
JPS62133937A (en) | Percataneous sensor | |
JP4681606B2 (en) | Composite metal analyte sensor | |
WO2023279311A1 (en) | Micro analyte sensor | |
FI129463B (en) | Device for sampling one or more analytes |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |