CN105411607B - Subcutaneous tissue insertion type glucose microsensor and preparation method thereof - Google Patents
Subcutaneous tissue insertion type glucose microsensor and preparation method thereof Download PDFInfo
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Abstract
The present invention is a kind of microsensor, particularly to a kind of subcutaneous tissue insertion type glucose microsensor and preparation method thereof.Including base, in described base, it is provided with the lead portion stretching out, the end of described lead portion is connected with Sensor section, described Sensor section is respectively provided in insulated substrate with lead portion.Subcutaneous tissue insertion type glucose microsensor and preparation method thereof compact conformation, improves operating characteristics, lifts service life.
Description
Technical field
The present invention is a kind of microsensor, particularly to a kind of subcutaneous tissue insertion type glucose microsensor and its
Preparation method.
Background technology
Diabetes are a kind of common incretion metabolism diseases of the serious harm human health in global range.Complete in recent years
Ball diabetes prevalence assumes obvious ascendant trend.For diabeticss, blood sugar monitoring most important it is necessary to according to
Blood glucose height formulates corresponding treatment scheme.Factor due to affecting human body level is a lot, and blood glucose has larger fluctuation, and tradition is single
Point blood glucose measurement exists substantially not enough it is impossible to acquisition accurately comprehensively obtains blood glucose information it is impossible to the personalization of the science of formulation is controlled
Treatment scheme, leads to patient blood glucose to be fluctuated, frequently occurs high and low blood glucose, affect patient health, when serious or even threat to life.
For the problems referred to above, recent domestic company researchs and develops the biosensor that can continuously measure blood glucose,
As United States Patent (USP) US 7153265 refers to biosensor, this sensor heeling-in is in subcutaneous tissue, continuous monitoring tissue fluid Fructus Vitis viniferae
Sugar.Domestic patent such as CN200410101080.6 refers to Endermic implantating biological sensors.
It is currently used in the biosensor of continuous glucose monitoring, is substantially and utilizes glucoseoxidase, this enzyme has
Feature to glucose high selectivity.
In view of implantation feasibility and job stability, it is subcutaneously implanted sensor bulk and requires as little as possible, so implantation
When pain less, cause the human body rejection also can be less after implantation, be conducive to normal operation of sensor.It is currently used in human body to plant
Entering glucose microsensor has two classes, and a class is to need guide pin implanted sensor, and base material is generally micro plastic piece, removes and makees
Part for carrier is in addition it is also necessary to consider the arrangement of circuit conductor lead, thus sensor bulk is larger, and implantation process pain is relatively strong,
Effective sensing area of sensor is very limited, can lead to that sensitivity is relatively low, and signal to noise ratio is not good, and implantation rear stability is bad.Pass
Sense device working voltage typically in more than 0.5V (Ag/AgCL reference), in human body on this current potential small molecule chaff interference include anti-bad
Hematic acid, catecholamine etc. can oxidized thus producing interference signal, have a strong impact on accuracy.To this some sensor in design
Increase by a floor height molecular film to stop chaff interference, this often leads to transducer sensitivity and declines, and affects overall performance.In addition sense
Device glucose oxidase enzymatic activity can extend loss with the working time, and enzyme activity is lost to a certain extent, and sensor cannot be just
Often work, usual human body Implantation Time is typically at 72 hours.
Untapped glucose oxidase sensor, the activity of enzyme can decay with the holding time, and loss of activity is to certain journey
Degree, sensor cannot provide stablizes available signal it is impossible to use, therefore glucose oxidase sensor has effect duration,
General only 6 months effect duration, using inconvenience.
Do not need guide pin implanted sensor, base material is generally metal although electrode effective area gets a promotion, but product
Stability is poor, technological process unconventional it is impossible to realize large-scale industrial production.
In addition above two sensor is required for considering circuit turn-on problem, needs the complicated circuit structure of design comparison,
Need to design the tiny circuit lead of non-universal and miniature plug structure, and these structures often reliability not good it may appear that drawing
The breaking problem that line or connector fault cause, thus lead to the sensor cannot normal work.
Content of the invention
The present invention mainly solves the deficiencies in the prior art, and compact conformation degree is high, and sensor bulk is little, significant surface
Long-pending big, corresponding signal is high, good in anti-interference performance, and effect duration is long, reasonable can solve the problems, such as circuit turn-on, reliable and stable,
Easily industrial subcutaneous tissue insertion type glucose microsensor of high-volume and preparation method thereof.
The above-mentioned technical problem of the present invention is mainly addressed by following technical proposals:
A kind of subcutaneous tissue insertion type glucose microsensor, including base, is provided with described base and stretches out
Lead portion, the end of described lead portion is connected with Sensor section, described Sensor section and lead portion
It is respectively provided in insulated substrate;
Described Sensor section include working electrode, reference electrode, to electrode and blank electrode, described working electrode
It is located at the left end in insulated substrate front, described reference electrode is located at the right-hand member in insulated substrate front, described is located to electrode
The left end in insulated substrate front, described blank electrode is located at the right-hand member in insulated substrate front, described working electrode and reference
The interruption-like distribution of electrode, described to electrode and the interruption-like distribution of blank electrode, constitute four electrode systems;
Or,
Described Sensor section includes working electrode, to electrode and reference electrode, described working electrode is located at insulation
The left end of basic unit's end face, the described right-hand member that electrode is located at insulated substrate end face, described working electrode upper end interior
It is provided with reference electrode, described working electrode, to interruption-like point of electrode and reference electrode between wall and the inwall to electrode upper end
Cloth, constitutes three-electrode system;
Or,
Described Sensor section includes working electrode, reference electrode and to electrode, and described working electrode is located at insulation
The left end in basic unit front, described reference electrode is located at the right-hand member in insulated substrate front, and described is located at insulated substrate to electrode
The left end at the back side, described working electrode and the interruption-like distribution of reference electrode, constitute three-electrode system;
Or,
Described Sensor section includes working electrode and reference electrode, and described working electrode is just being located at insulated substrate
Face, described reference electrode is located at the back side of insulated substrate, constitutes two electrode systems;
Described working electrode includes tack coat, and described tack coat overlays on the top of insulated substrate, described tack coat
Top be covered with conductive layer, the top of described conductive layer is covered with inert metal layer, the described top of inert metal layer
Be covered with Catalytic Layer, the described top of Catalytic Layer be covered with enzyme layer, the described top of enzyme layer be covered with macromolecule layer;
Described reference electrode includes reference electrode tack coat, and described tack coat overlays on the top of insulated substrate, described
The top of tack coat be covered with reference electrode conductive layer, the top of described conductive layer is covered with inert metal layer, described inertia
The top of metal level is covered with silver/silver chloride layer, and the top of described reference silver/silver chloride layer is covered with reference macromolecule layer;
Described includes tack coat to electrode, and described tack coat is located at the bottom of insulated substrate, described tack coat
Surface is covered with conductive layer, and the surface of described conductive layer is covered with inert metal layer, and the surface of described inert metal layer is covered with urges
Change layer, the surface of described Catalytic Layer is covered with macromolecule layer;
Described blank electrode includes tack coat, and described electrode adhesion layer is located at the bottom of insulated substrate, and described is viscous
The surface of knot layer is covered with conductive layer, and the surface of described conductive layer is covered with inert metal layer, the surface of described inert metal layer
It is covered with Catalytic Layer, the surface of described Catalytic Layer is covered with macromolecule layer;
Described lead portion is made up of at least one lead assemblies, and described lead assemblies include overlaying on insulated substrate table
Lead first tack coat in face, the surface of described lead first tack coat is covered with lead conductive layer, described lead conductive layer
Surface be covered with lead second tack coat, the surface of described lead second tack coat is covered with lead finish.
Preferably, described lead assemblies are provided with 4, lead assemblies be respectively provided at insulated substrate upper surface left end,
The right-hand member of the right-hand member of insulated substrate upper surface, the left end of insulated substrate lower surface and insulated substrate lower surface, between each lead assemblies
Interruption-like distribution;
Or,
Described lead assemblies are provided with 3, and 3 lead assemblies are divided equally on an end face of insulated substrate;
Or,
Described lead assemblies are provided with 3, and wherein two lead assemblies divide equally the upper surface in insulated substrate, and another draws
Line component is located at the interposition of insulated substrate upper surface;
Or,
Described lead assemblies are provided with 2, and lead assemblies are located at the interposition of insulated substrate upper surface, and another draws
Line component is located at the interposition of insulated substrate lower surface.
The preparation method of subcutaneous tissue insertion type glucose microsensor, is carried out according to the following steps:
(1), the selection of insulated substrate:
Insulated substrate adopts the polyimide insulative thin film of deflection or mylar as carrier, has good physics
And chemical property;
Tool height is write music flexibility, can three-dimensional wiring, limit according to space and change shape;High-low temperature resistant, resistance to combustion;Foldable and not shadow
Ring signal transmission function, static interference can be prevented;Chemical change is stable, and stability, trustworthiness are high;Setting beneficial to Related product
Meter, can reduce assembly work and mistake, and improve the service life of article;Good insulating properties, specific insulation reaches
To 1015 Ω .cm;Excellent to the caking property of conventional matrix, metal and dielectric material;This layer of THICKNESS CONTROL is in 7.5-12.5 micron;
(2), tack coat material selects:
Tack coat includes each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly influences the performance of electrode, due to binding agent
There is chemical reaction in the fabrication process and insulated substrate between, therefore also should select for different insulated substrate corresponding
Binder system, the performance of binding agent must be adapted with insulated substrate;
Tack coat used allows for bearing the erosion of various process conditions and the chemical drugss being used in the mill,
It is not layered or the phenomenon of degraded must have preferable biocompatibility it is contemplated that human body implants binding agent, tack coat adopts
Epoxy resin or crylic acid resin, this layer of THICKNESS CONTROL is in 5-15 micron;
(3), the selection of conductive layer:
Conductive layer includes each conductive layer in Sensor section and lead portion;
The surface of tack coat is conductive layer, and conductive layer adopts rolled copper foil, and THICKNESS CONTROL is in 5-20 micron;
Lead portion needs to prepare lead second tack coat and lead finish on the electrically conductive, and interlayer can pass through rolling process
Increase inter-layer bonding force, electrode part is not required to want the second tack coat and protective layer, prepares corresponding function layer according to different requirements;
(4), the selection of lead second tack coat:
It is lead second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or acrylic resin
Class, this layer of THICKNESS CONTROL is in 5-15 micron;
What front end electrode part needed naked leakage does not apply this layer binder, and interlayer can increase inter-layer bonding force by rolling process;
(5), the selection of protective layer:
It is polyimide insulative thin film outside lead second tack coat of rear end lead portion, protecting film first carries out cutting and adds
Work, exposes the Copper Foil of leading portion electrode area, contact conductor covering protection film;
This layer of THICKNESS CONTROL is in 5-15 micron;Inter-layer bonding force can be increased by rolling process;
(6), electrode part functional layer preparation:
Electrode partly can be divided into working electrode, as needed to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer composition on working electrode Copper Foil is as follows:Inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, by the method preparation of plating, sputtering, can be selected for gold, platinum
Inert metal, this thickness degree be 10-15 micron;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by way of spraying, dipping, coating by enzyme layer, and dip time divides for 5-15
Clock;
Then the glucoseoxidase crosslinking transferring to working electrode with the glutaraldehyde solution that concentration is 5%-20% is admittedly
Fixed, crosslinking temperature is at 25-35 degree Celsius, crosslinked using liquid impregnation crosslinking or gas phase, and crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows:Glucoseoxidase and people's white egg of restructuring is added in phosphate buffer
In vain, glucoseoxidase addition is every milliliter of 50-100 milligram, and people's recombinant albumin addition is every milliliter of 50-100 milligram;
After dissolving fully, the nanometer gold adding 1-5% mixes, and is eventually adding the PVB of 1-5%, PVB refers to polyvinyl butyral resin, mixing
Uniformly;
Nanometer gold utilizes in AOT and the reverse micelle system of hexamethylene System forming to be prepared, and AOT refers to amber glass acid di-isooctyl
Semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, adjusts water, electrolyte, the concentration ratio of surfactant, preparation
The nanogold particle of different-diameter, nanogold particle diameter is in 5-30nm;
After the completion of glucoseoxidase crosslinking, a floor height molecular film can be fixed in electrode by way of dipping, coating,
To strengthen the biosensor organism compatibility, improve vivo performance;
Because nanometer gold has good biocompatibility, can implant in human body the long period, and do not cause bad anti-
Should;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, when shortening enzyme electrode to glucose responding
Between, extend enzyme electrode service life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH2)
GOD(FADH2)+O2→GOD(FAD)+H2O2
glucose-lactone+H2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH2) less stable, it is easier recurring structure and change
Become it is impossible to oxidized become normality glucoseoxidase, this is one of the reason common glucose oxidase electrode enzyme activity is lost;
And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can be rapidly by reduction-state
Glucoseoxidase GOD (FADH2) it is oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state in electrode process
Glucoseoxidase GOD (FADH2) quantity and existence time, reduce loss of enzyme activity, extend electrode life;In addition nanometer
Gold grain addition also increases substantially enzyme electrode and answers speed, shortens the enzyme electrode corresponding time, improves subcutaneous glucose and passes
Signal delay during sensor measurement, improves real-time monitoring accuracy;
Macromolecule layer, in order to provide sensor implantation needed by human body biocompatibility, improves vivo performance;Can be by leaching
Stain, the mode of coating fix a floor height molecular film in electrode, and used macromolecular material is silastic polymer, polyurethane, gathers
One or more mixing therein of sub- peace ester, Polyethylene Glycol;Solvent adopts dehydrated alcohol, oxolane, can be by spraying, leaching
Prepared by stain, the mode of coating;
2., to electrode:
Functional layer on electrode Copper Foil is included to inert metal layer, to Catalytic Layer, to macromolecule layer;Its preparation method with
Working electrode is essentially identical, is not required to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil includes inert metal layer, Catalytic Layer, macromolecule layer;Its preparation method and work
Electrode is identical, is not required to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil includes inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after the completion of the preparation of inert metal layer, is splashed by plating, vacuum
The method penetrated prepares silver/silver chloride layer, prepares silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination;
After the completion of above-mentioned preparation technology, cut finally according to element circuit, obtained sensor, three electrodes and four electrodes
Size sensor is as follows:Implantation human body parts length is not more than 15mm, wide no more than 0.6mm, thick no more than 0.4mm;
Two electrode sizes are as follows:Implantation human body parts length is not more than 15mm, wide no more than 0.3mm, and thickness is not more than
0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrodes composition sensors are it is not necessary in enzyme layer
Add nanometer gold, normal operation of sensor voltage 0.55V, blank electrode is used for detecting background signal and interference signal, improve and pass
Sensor accuracy;
Two electrodes and three electrode sensors, preparation process need to increase nanometer gold in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, is then log out guide pin, sensor is stayed subcutaneous tissue and started working.
The present invention takes transducer production method, does not have any non-universal circuit lead and miniature plug structure, sensing
Device, inherently on flexible circuitry, fundamentally solves the problems, such as circuit turn-on, it is possible to achieve signals collecting steady in a long-term, will not
Occur causing fault due to circuit breaker.
This transducer production method, because contact conductor is Copper Foil, and has protecting film, and circuit lead is flexible, torsion
Without damaging, lead can be less with volume, and arrangement mode is more flexible, thus can provide bigger space to copper foil electrode.
Sensor bulk can be accomplished, dual sided sensor working electrode effective area can be accomplished, it is less to compare common sensor bulk,
Electrode face amasss more greatly, is conducive to improving sensor vivo performance.
This transducer production method uses for reference more ripening electron industrial circuits preparation technology, technical maturity stable it is easy to real
Existing mass production, improves sensor stability, substantially reduces single sensor cost simultaneously.
Therefore, subcutaneous tissue insertion type glucose microsensor that the present invention provides and preparation method thereof, compact conformation,
Improve operating characteristics, lift service life.
Brief description
Fig. 1 is the structural representation in the present invention;
Fig. 2 is the preparation process schematic diagram of the present invention;
The front schematic view of electrode in Fig. 3 present invention;
The reverse side schematic diagram of electrode in Fig. 4 present invention;
Fig. 5 is A-A cross section structure diagram in Fig. 4;
Fig. 6 is B-B cross section structure diagram in Fig. 4;
Fig. 7 is the schematic diagram of one of which electrode shape in the present invention;
The front schematic view of another kind of electrode shape in Fig. 8 present invention;
Fig. 9 is the reverse structure schematic of Fig. 8;
The front schematic view of another electrode shape in Figure 10 present invention;
Figure 11 is the reverse structure schematic of Figure 10;
Figure 12 is the tabular drawing of sensor of the invention test performance in the solution;
Figure 13 is the performance map of sensor of the invention test performance in the solution;
Figure 14 is sensor performance figure after present invention implantation human body.
Specific embodiment
Below by embodiment, and combine accompanying drawing, technical scheme is described in further detail.
Embodiment 1:As shown in Figure 1, Figure 2, Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9, Figure 10, Figure 11, Figure 12, Figure 13 and Tu
Shown in 14, a kind of subcutaneous tissue insertion type glucose microsensor, including base 1, it is provided with described base 1 and stretches out
Lead portion 2, the described end of lead portion 2 is connected with Sensor section 3, described Sensor section 3 and lead
Part 2 is respectively provided in insulated substrate 4;
Described Sensor section 3 include working electrode 5, reference electrode 6, to electrode 7 and blank electrode 8, described work
Make the left end that electrode 5 is located at insulated substrate 4 front, described reference electrode 6 is located at the right-hand member in insulated substrate 4 front, described
Electrode 7 is located at the left end in insulated substrate 4 front, described blank electrode 8 is located at the right-hand member in insulated substrate 4 front, described
Working electrode 5 and the interruption-like distribution of reference electrode 6, described to electrode 7 and the interruption-like distribution of blank electrode 8, constitute four
Electrode system;
Or,
Described Sensor section 3 includes working electrode 5, to electrode 7 and reference electrode 6, described working electrode 5 is located at
The left end of insulated substrate 4 end face, the described right-hand member that electrode 7 is located at insulated substrate 4 end face, described working electrode 5
It is provided with reference electrode 6, described working electrode 5, to electrode 7 and reference electricity between the inwall of upper end and the inwall to electrode 7 upper end
The interruption-like distribution in pole 6, constitutes three-electrode system;
Or,
Described Sensor section 3 includes working electrode 5, reference electrode 6 and to electrode 7, and described working electrode 5 is located at
The left end in insulated substrate 4 front, described reference electrode 6 is located at the right-hand member in insulated substrate 4 front, and described is located to electrode 7
The left end at insulated substrate 4 back side, described working electrode 5 and the interruption-like distribution of reference electrode 6, constitute three-electrode system;
Or,
Described Sensor section 3 includes working electrode 5 and reference electrode 6, and described working electrode 5 is located at insulated substrate
4 front, described reference electrode 6 is located at the back side of insulated substrate 4, constitutes two electrode systems;
Described working electrode 5 includes tack coat 9, and described tack coat 9 overlays on the top of insulated substrate 4, and described is viscous
The top of knot layer 9 be covered with conductive layer 10, the top of described conductive layer 10 is covered with inert metal layer 11, described inert metal
The top of layer 11 be covered with Catalytic Layer 12, the described top of Catalytic Layer 12 be covered with enzyme layer 13, the top of described enzyme layer 13
Be covered with macromolecule layer 14;
Described reference electrode includes reference electrode tack coat 15, and described tack coat 15 overlays on the top of insulated substrate 4,
The top of described tack coat 15 is covered with reference electrode conductive layer 16, and the top of described conductive layer 16 is covered with inert metal layer
17, the top of described inert metal layer 17 is covered with silver/silver chloride layer 18, and the top of described reference silver/silver chloride layer 18 is covered
There is reference macromolecule layer 19;
Described includes tack coat 20 to electrode, and described tack coat 20 is located at the bottom of insulated substrate 4, described bonding
The surface of layer 20 is covered with conductive layer 21, and the surface of described conductive layer 21 is covered with inert metal layer 22, described inert metal layer
22 surface is covered with Catalytic Layer 23, and the surface of described Catalytic Layer 23 is covered with macromolecule layer 24;
Described blank electrode 8 includes tack coat 25, and described electrode adhesion layer 25 is located at the bottom of insulated substrate 4, institute
The surface of the tack coat 25 stated is covered with conductive layer 26, and the surface of described conductive layer 26 is covered with inert metal layer 27, and described is lazy
The surface of property metal level 27 is covered with Catalytic Layer 28, and the surface of described Catalytic Layer 28 is covered with macromolecule layer 29;
Described lead portion 2 is made up of at least one lead assemblies 30, and described lead assemblies 30 include overlaying on insulation
Lead first tack coat 31 on basic unit 4 surface, the surface of described lead the first tack coat 31 is covered with lead conductive layer 32, described
The surface of lead conductive layer 32 be covered with lead the second tack coat 33, the surface of described lead the second tack coat 33 is covered with lead
Protective layer 34.
Described lead assemblies 30 are provided with 4, and lead assemblies 30 are respectively provided at the left end of insulated substrate 4 upper surface, insulation
The right-hand member of the right-hand member of basic unit 4 upper surface, the left end of insulated substrate 4 lower surface and insulated substrate 4 lower surface, between each lead assemblies 30
Interruption-like distribution;
Or,
Described lead assemblies 30 are provided with 3, and 3 lead assemblies 30 are divided equally on an end face of insulated substrate 4;
Or,
Described lead assemblies 30 are provided with 3, and wherein two lead assemblies 30 divide equally the upper surface in insulated substrate 4, separately
One lead assemblies 30 is located at the interposition of insulated substrate 4 upper surface;
Or,
Described lead assemblies 30 are provided with 2, and lead assemblies 30 are located at the interposition of insulated substrate 4 upper surface, separately
One lead assemblies 30 is located at the interposition of insulated substrate 4 lower surface.
The preparation method of subcutaneous tissue insertion type glucose microsensor, is carried out according to the following steps:
(1), the selection of insulated substrate:
Insulated substrate adopts the polyimide insulative thin film of deflection or mylar as carrier, has good physics
And chemical property;
Tool height is write music flexibility, can three-dimensional wiring, limit according to space and change shape;High-low temperature resistant, resistance to combustion;Foldable and not shadow
Ring signal transmission function, static interference can be prevented;Chemical change is stable, and stability, trustworthiness are high;Setting beneficial to Related product
Meter, can reduce assembly work and mistake, and improve the service life of article;Good insulating properties, specific insulation reaches
To 1015 Ω .cm;Excellent to the caking property of conventional matrix, metal and dielectric material;This layer of THICKNESS CONTROL is at 7.5 microns;
(4), tack coat material selects:
Tack coat includes each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly influences the performance of electrode, due to binding agent
There is chemical reaction in the fabrication process and insulated substrate between, therefore also should select for different insulated substrate corresponding
Binder system, the performance of binding agent must be adapted with insulated substrate;
Tack coat used allows for bearing the erosion of various process conditions and the chemical drugss being used in the mill,
It is not layered or the phenomenon of degraded must have preferable biocompatibility it is contemplated that human body implants binding agent, tack coat adopts
Epoxy resin or crylic acid resin, this layer of THICKNESS CONTROL is at 5 microns;
(5), the selection of conductive layer:
Conductive layer includes each conductive layer in Sensor section and lead portion;
The surface of tack coat is conductive layer, and conductive layer adopts rolled copper foil, and THICKNESS CONTROL is at 5 microns;
Lead portion needs to prepare lead second tack coat and lead finish on the electrically conductive, and interlayer can pass through rolling process
Increase inter-layer bonding force, electrode part is not required to want the second tack coat and protective layer, prepares corresponding function layer according to different requirements;
(4), the selection of lead second tack coat:
It is lead second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or acrylic resin
Class, this layer of THICKNESS CONTROL is at 5 microns;
What front end electrode part needed naked leakage does not apply this layer binder, and interlayer can increase inter-layer bonding force by rolling process;
(5), the selection of protective layer:
It is polyimide insulative thin film outside lead second tack coat of rear end lead portion, protecting film first carries out cutting and adds
Work, exposes the Copper Foil of leading portion electrode area, contact conductor covering protection film;
This layer of THICKNESS CONTROL is at 5 microns;Inter-layer bonding force can be increased by rolling process;
(6), electrode part functional layer preparation:
Electrode partly can be divided into working electrode, as needed to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer composition on working electrode Copper Foil is as follows:Inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, by the method preparation of plating, sputtering, can be selected for gold, platinum
Inert metal, this thickness degree be 10 microns;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by way of spraying, dipping, coating by enzyme layer, and dip time is 5 minutes;
Then fixed with the glucoseoxidase crosslinking that the glutaraldehyde solution that concentration is 5% transfers to working electrode, hand over
Connection temperature is at 25 degrees Celsius, crosslinked using liquid impregnation crosslinking or gas phase, and crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows:Glucoseoxidase and people's white egg of restructuring is added in phosphate buffer
In vain, glucoseoxidase addition is 50 milligrams every milliliter, and people's recombinant albumin addition is 50 milligrams every milliliter;Dissolving is fully
Afterwards, add 1% nanometer gold mixing, be eventually adding 1% PVB, PVB refers to polyvinyl butyral resin, mix homogeneously;
Nanometer gold utilizes in AOT and the reverse micelle system of hexamethylene System forming to be prepared, and AOT refers to amber glass acid di-isooctyl
Semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, adjusts water, electrolyte, the concentration ratio of surfactant, preparation
The nanogold particle of different-diameter, nanogold particle diameter is in 5nm;
After the completion of glucoseoxidase crosslinking, a floor height molecular film can be fixed in electrode by way of dipping, coating,
To strengthen the biosensor organism compatibility, improve vivo performance;
Because nanometer gold has good biocompatibility, can implant in human body the long period, and do not cause bad anti-
Should;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, when shortening enzyme electrode to glucose responding
Between, extend enzyme electrode service life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH2)
GOD(FADH2)+O2→GOD(FAD)+H2O2
glucose-lactone+H2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH2) less stable, it is easier recurring structure and change
Become it is impossible to oxidized become normality glucoseoxidase, this is one of the reason common glucose oxidase electrode enzyme activity is lost;
And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can be rapidly by reduction-state
Glucoseoxidase GOD (FADH2) it is oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state in electrode process
Glucoseoxidase GOD (FADH2) quantity and existence time, reduce loss of enzyme activity, extend electrode life;In addition nanometer
Gold grain addition also increases substantially enzyme electrode and answers speed, shortens the enzyme electrode corresponding time, improves subcutaneous glucose and passes
Signal delay during sensor measurement, improves real-time monitoring accuracy;
Macromolecule layer, in order to provide sensor implantation needed by human body biocompatibility, improves vivo performance;Can be by leaching
Stain, the mode of coating fix a floor height molecular film in electrode, and used macromolecular material is silastic polymer, polyurethane, gathers
One or more mixing therein of sub- peace ester, Polyethylene Glycol;Solvent adopts dehydrated alcohol, oxolane, can be by spraying, leaching
Prepared by stain, the mode of coating;
2., to electrode:
Functional layer on electrode Copper Foil is included to inert metal layer, to Catalytic Layer, to macromolecule layer;Its preparation method with
Working electrode is essentially identical, is not required to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil includes inert metal layer, Catalytic Layer, macromolecule layer;Its preparation method and work
Electrode is identical, is not required to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil includes inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after the completion of the preparation of inert metal layer, is splashed by plating, vacuum
The method penetrated prepares silver/silver chloride layer, prepares silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination;
After the completion of above-mentioned preparation technology, cut finally according to element circuit, obtained sensor, three electrodes and four electrodes
Size sensor is as follows:Implantation human body parts length is not more than 15mm, wide no more than 0.6mm, thick no more than 0.4mm;
Two electrode sizes are as follows:Implantation human body parts length is not more than 15mm, wide no more than 0.3mm, and thickness is not more than
0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrodes composition sensors are it is not necessary in enzyme layer
Add nanometer gold, blank electrode is used for detecting background signal and interference signal, improve sensor accuracy;
Two electrodes and three electrode sensors, preparation process need to increase nanometer gold in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, is then log out guide pin, sensor is stayed subcutaneous tissue and started working.
Embodiment 2:The preparation method of subcutaneous tissue insertion type glucose microsensor, is carried out according to the following steps:
(1), the selection of insulated substrate:
Insulated substrate adopts the polyimide insulative thin film of deflection or mylar as carrier, has good physics
And chemical property;
Tool height is write music flexibility, can three-dimensional wiring, limit according to space and change shape;High-low temperature resistant, resistance to combustion;Foldable and not shadow
Ring signal transmission function, static interference can be prevented;Chemical change is stable, and stability, trustworthiness are high;Setting beneficial to Related product
Meter, can reduce assembly work and mistake, and improve the service life of article;Good insulating properties, specific insulation reaches
To 1015 Ω .cm;Excellent to the caking property of conventional matrix, metal and dielectric material;This layer of THICKNESS CONTROL is at 10 microns;
(6), tack coat material selects:
Tack coat includes each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly influences the performance of electrode, due to binding agent
There is chemical reaction in the fabrication process and insulated substrate between, therefore also should select for different insulated substrate corresponding
Binder system, the performance of binding agent must be adapted with insulated substrate;
Tack coat used allows for bearing the erosion of various process conditions and the chemical drugss being used in the mill,
It is not layered or the phenomenon of degraded must have preferable biocompatibility it is contemplated that human body implants binding agent, tack coat adopts
Epoxy resin or crylic acid resin, this layer of THICKNESS CONTROL is at 10 microns;
(7), the selection of conductive layer:
Conductive layer includes each conductive layer in Sensor section and lead portion;
The surface of tack coat is conductive layer, and conductive layer adopts rolled copper foil, and THICKNESS CONTROL is at 15 microns;
Lead portion needs to prepare lead second tack coat and lead finish on the electrically conductive, and interlayer can pass through rolling process
Increase inter-layer bonding force, electrode part is not required to want the second tack coat and protective layer, prepares corresponding function layer according to different requirements;
(4), the selection of lead second tack coat:
It is lead second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or acrylic resin
Class, this layer of THICKNESS CONTROL is at 10 microns;
What front end electrode part needed naked leakage does not apply this layer binder, and interlayer can increase inter-layer bonding force by rolling process;
(5), the selection of protective layer:
It is polyimide insulative thin film outside lead second tack coat of rear end lead portion, protecting film first carries out cutting and adds
Work, exposes the Copper Foil of leading portion electrode area, contact conductor covering protection film;
This layer of THICKNESS CONTROL is at 10 microns;Inter-layer bonding force can be increased by rolling process;
(6), electrode part functional layer preparation:
Electrode partly can be divided into working electrode, as needed to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer composition on working electrode Copper Foil is as follows:Inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, by the method preparation of plating, sputtering, can be selected for gold, platinum
Inert metal, this thickness degree be 12 microns;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by way of spraying, dipping, coating by enzyme layer, and dip time is 10 points
Clock;
Then fixed with the glucoseoxidase crosslinking that the glutaraldehyde solution that concentration is 15% transfers to working electrode, hand over
Connection temperature is at 30 degrees Celsius, crosslinked using liquid impregnation crosslinking or gas phase, and crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows:Glucoseoxidase and people's white egg of restructuring is added in phosphate buffer
In vain, glucoseoxidase addition is 70 milligrams every milliliter, and people's recombinant albumin addition is 70 milligrams every milliliter;Dissolving is fully
Afterwards, add 2% nanometer gold mixing, be eventually adding 2% PVB, PVB refers to polyvinyl butyral resin, mix homogeneously;
Nanometer gold utilizes in AOT and the reverse micelle system of hexamethylene System forming to be prepared, and AOT refers to amber glass acid di-isooctyl
Semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, adjusts water, electrolyte, the concentration ratio of surfactant, preparation
The nanogold particle of different-diameter, nanogold particle diameter is in 20nm;
After the completion of glucoseoxidase crosslinking, a floor height molecular film can be fixed in electrode by way of dipping, coating,
To strengthen the biosensor organism compatibility, improve vivo performance;
Because nanometer gold has good biocompatibility, can implant in human body the long period, and do not cause bad anti-
Should;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, when shortening enzyme electrode to glucose responding
Between, extend enzyme electrode service life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH2)
GOD(FADH2)+O2→GOD(FAD)+H2O2
glucose-lactone+H2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH2) less stable, it is easier recurring structure and change
Become it is impossible to oxidized become normality glucoseoxidase, this is one of the reason common glucose oxidase electrode enzyme activity is lost;
And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can be rapidly by reduction-state
Glucoseoxidase GOD (FADH2) it is oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state in electrode process
Glucoseoxidase GOD (FADH2) quantity and existence time, reduce loss of enzyme activity, extend electrode life;In addition nanometer
Gold grain addition also increases substantially enzyme electrode and answers speed, shortens the enzyme electrode corresponding time, improves subcutaneous glucose and passes
Signal delay during sensor measurement, improves real-time monitoring accuracy;
Macromolecule layer, in order to provide sensor implantation needed by human body biocompatibility, improves vivo performance;Can be by leaching
Stain, the mode of coating fix a floor height molecular film in electrode, and used macromolecular material is silastic polymer, polyurethane, gathers
One or more mixing therein of sub- peace ester, Polyethylene Glycol;Solvent adopts dehydrated alcohol, oxolane, can be by spraying, leaching
Prepared by stain, the mode of coating;
2., to electrode:
Functional layer on electrode Copper Foil is included to inert metal layer, to Catalytic Layer, to macromolecule layer;Its preparation method with
Working electrode is essentially identical, is not required to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil includes inert metal layer, Catalytic Layer, macromolecule layer;Its preparation method and work
Electrode is identical, is not required to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil includes inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after the completion of the preparation of inert metal layer, is splashed by plating, vacuum
The method penetrated prepares silver/silver chloride layer, prepares silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination;
After the completion of above-mentioned preparation technology, cut finally according to element circuit, obtained sensor, three electrodes and four electrodes
Size sensor is as follows:Implantation human body parts length is not more than 15mm, wide no more than 0.6mm, thick no more than 0.4mm;
Two electrode sizes are as follows:Implantation human body parts length is not more than 15mm, wide no more than 0.3mm, and thickness is not more than
0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrodes composition sensors are it is not necessary in enzyme layer
Add nanometer gold, blank electrode is used for detecting background signal and interference signal, improve sensor accuracy;
Two electrodes and three electrode sensors, preparation process need to increase nanometer in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, is then log out guide pin, sensor is stayed subcutaneous tissue and started working.
Embodiment 3:The preparation method of subcutaneous tissue insertion type glucose microsensor, is carried out according to the following steps:
(1), the selection of insulated substrate:
Insulated substrate adopts the polyimide insulative thin film of deflection or mylar as carrier, has good physics
And chemical property;
Tool height is write music flexibility, can three-dimensional wiring, limit according to space and change shape;High-low temperature resistant, resistance to combustion;Foldable and not shadow
Ring signal transmission function, static interference can be prevented;Chemical change is stable, and stability, trustworthiness are high;Setting beneficial to Related product
Meter, can reduce assembly work and mistake, and improve the service life of article;Good insulating properties, specific insulation reaches
To 1015 Ω .cm;Excellent to the caking property of conventional matrix, metal and dielectric material;This layer of THICKNESS CONTROL is at 12.5 microns;
(8), tack coat material selects:
Tack coat includes each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly influences the performance of electrode, due to binding agent
There is chemical reaction in the fabrication process and insulated substrate between, therefore also should select for different insulated substrate corresponding
Binder system, the performance of binding agent must be adapted with insulated substrate;
Tack coat used allows for bearing the erosion of various process conditions and the chemical drugss being used in the mill,
It is not layered or the phenomenon of degraded must have preferable biocompatibility it is contemplated that human body implants binding agent, tack coat adopts
Epoxy resin or crylic acid resin, this layer of THICKNESS CONTROL is at 10 microns;
(9), the selection of conductive layer:
Conductive layer includes each conductive layer in Sensor section and lead portion;
The surface of tack coat is conductive layer, and conductive layer adopts rolled copper foil, and THICKNESS CONTROL is at 20 microns;
Lead portion needs to prepare lead second tack coat and lead finish on the electrically conductive, and interlayer can pass through rolling process
Increase inter-layer bonding force, electrode part is not required to want the second tack coat and protective layer, prepares corresponding function layer according to different requirements;
(4), the selection of lead second tack coat:
It is lead second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or acrylic resin
Class, this layer of THICKNESS CONTROL is at 15 microns;
What front end electrode part needed naked leakage does not apply this layer binder, and interlayer can increase inter-layer bonding force by rolling process;
(5), the selection of protective layer:
It is polyimide insulative thin film outside lead second tack coat of rear end lead portion, protecting film first carries out cutting and adds
Work, exposes the Copper Foil of leading portion electrode area, contact conductor covering protection film;
This layer of THICKNESS CONTROL is at 15 microns;Inter-layer bonding force can be increased by rolling process;
(6), electrode part functional layer preparation:
Electrode partly can be divided into working electrode, as needed to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer composition on working electrode Copper Foil is as follows:Inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, by the method preparation of plating, sputtering, can be selected for gold, platinum
Inert metal, this thickness degree be 15 microns;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by way of spraying, dipping, coating by enzyme layer, and dip time is 15 points
Clock;
Then fixed with the glucoseoxidase crosslinking that the glutaraldehyde solution that concentration is 20% transfers to working electrode, hand over
Connection temperature is at 35 degrees Celsius, crosslinked using liquid impregnation crosslinking or gas phase, and crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows:Glucoseoxidase and people's white egg of restructuring is added in phosphate buffer
In vain, glucoseoxidase addition is 100 milligrams every milliliter, and people's recombinant albumin addition is 100 milligrams every milliliter;Dissolving is filled
After point, add 5% nanometer gold mixing, be eventually adding 5% PVB, PVB refers to polyvinyl butyral resin, mix homogeneously;
Nanometer gold utilizes in AOT and the reverse micelle system of hexamethylene System forming to be prepared, and AOT refers to amber glass acid di-isooctyl
Semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, adjusts water, electrolyte, the concentration ratio of surfactant, preparation
The nanogold particle of different-diameter, nanogold particle diameter is in 30nm;
After the completion of glucoseoxidase crosslinking, a floor height molecular film can be fixed in electrode by way of dipping, coating,
To strengthen the biosensor organism compatibility, improve vivo performance;
Because nanometer gold has good biocompatibility, can implant in human body the long period, and do not cause bad anti-
Should;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, when shortening enzyme electrode to glucose responding
Between, extend enzyme electrode service life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH2)
GOD(FADH2)+O2→GOD(FAD)+H2O2
glucose-lactone+H2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH2) less stable, it is easier recurring structure and change
Become it is impossible to oxidized become normality glucoseoxidase, this is one of the reason common glucose oxidase electrode enzyme activity is lost;
And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can be rapidly by reduction-state
Glucoseoxidase GOD (FADH2) it is oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state in electrode process
Glucoseoxidase GOD (FADH2) quantity and existence time, reduce loss of enzyme activity, extend electrode life;In addition nanometer
Gold grain addition also increases substantially enzyme electrode and answers speed, shortens the enzyme electrode corresponding time, improves subcutaneous glucose and passes
Signal delay during sensor measurement, improves real-time monitoring accuracy;
Macromolecule layer, in order to provide sensor implantation needed by human body biocompatibility, improves vivo performance;Can be by leaching
Stain, the mode of coating fix a floor height molecular film in electrode, and used macromolecular material is silastic polymer, polyurethane, gathers
One or more mixing therein of sub- peace ester, Polyethylene Glycol;Solvent adopts dehydrated alcohol, oxolane, can be by spraying, leaching
Prepared by stain, the mode of coating;
2., to electrode:
Functional layer on electrode Copper Foil is included to inert metal layer, to Catalytic Layer, to macromolecule layer;Its preparation method with
Working electrode is essentially identical, is not required to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil includes inert metal layer, Catalytic Layer, macromolecule layer;Its preparation method and work
Electrode is identical, is not required to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil includes inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after the completion of the preparation of inert metal layer, is splashed by plating, vacuum
The method penetrated prepares silver/silver chloride layer, prepares silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination;
After the completion of above-mentioned preparation technology, cut finally according to element circuit, obtained sensor, three electrodes and four electrodes
Size sensor is as follows:Implantation human body parts length is not more than 15mm, wide no more than 0.6mm, thick no more than 0.4mm;
Two electrode sizes are as follows:Implantation human body parts length is not more than 15mm, wide no more than 0.3mm, and thickness is not more than
0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrodes composition sensors are it is not necessary in enzyme layer
Add nanometer gold, blank electrode is used for detecting background signal and interference signal, improve sensor accuracy;
Two electrodes and three electrode sensors, preparation process need to increase nanometer gold in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, is then log out guide pin, sensor is stayed subcutaneous tissue and started working.
Embodiment 3:The preparation method of subcutaneous tissue insertion type glucose microsensor, is carried out according to the following steps:
(1), the selection of insulated substrate:
Insulated substrate adopts the polyimide insulative thin film of deflection or mylar as carrier, has good physics
And chemical property;
Tool height is write music flexibility, can three-dimensional wiring, limit according to space and change shape;High-low temperature resistant, resistance to combustion;Foldable and not shadow
Ring signal transmission function, static interference can be prevented;Chemical change is stable, and stability, trustworthiness are high;Setting beneficial to Related product
Meter, can reduce assembly work and mistake, and improve the service life of article;Good insulating properties, specific insulation reaches
To 1015 Ω .cm;Excellent to the caking property of conventional matrix, metal and dielectric material;This layer of THICKNESS CONTROL is at 12.5 microns;
(2), tack coat material selects:
Tack coat includes each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly influences the performance of electrode, due to binding agent
There is chemical reaction in the fabrication process and insulated substrate between, therefore also should select for different insulated substrate corresponding
Binder system, the performance of binding agent must be adapted with insulated substrate;
Tack coat used allows for bearing the erosion of various process conditions and the chemical drugss being used in the mill,
It is not layered or the phenomenon of degraded must have preferable biocompatibility it is contemplated that human body implants binding agent, tack coat adopts
Epoxy resin or crylic acid resin, this layer of THICKNESS CONTROL is at 15 microns;
(3), the selection of conductive layer:
Conductive layer includes each conductive layer in Sensor section and lead portion;
The surface of tack coat is conductive layer, and conductive layer adopts rolled copper foil, and THICKNESS CONTROL is at 20 microns;
Lead portion needs to prepare lead second tack coat and lead finish on the electrically conductive, and interlayer can pass through rolling process
Increase inter-layer bonding force, electrode part is not required to want the second tack coat and protective layer, prepares corresponding function layer according to different requirements;
(4), the selection of lead second tack coat:
It is lead second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or acrylic resin
Class, this layer of THICKNESS CONTROL is at 15 microns;
What front end electrode part needed naked leakage does not apply this layer binder, and interlayer can increase inter-layer bonding force by rolling process;
(5), the selection of protective layer:
It is polyimide insulative thin film outside lead second tack coat of rear end lead portion, protecting film first carries out cutting and adds
Work, exposes the Copper Foil of leading portion electrode area, contact conductor covering protection film;
This layer of THICKNESS CONTROL is at 15 microns;Inter-layer bonding force can be increased by rolling process;
(6), electrode part functional layer preparation:
Electrode partly can be divided into working electrode, as needed to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer composition on working electrode Copper Foil is as follows:Inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, by the method preparation of plating, sputtering, can be selected for gold, platinum
Inert metal, this thickness degree be 15 microns;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by way of spraying, dipping, coating by enzyme layer, and dip time is 15 points
Clock;
Then fixed with the glucoseoxidase crosslinking that the glutaraldehyde solution that concentration is 20% transfers to working electrode, hand over
Connection temperature is at 35 degrees Celsius, crosslinked using liquid impregnation crosslinking or gas phase, and crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows:Glucoseoxidase and people's white egg of restructuring is added in phosphate buffer
In vain, glucoseoxidase addition is 100 milligrams every milliliter, and people's recombinant albumin addition is 100 milligrams every milliliter;Dissolving is filled
After point, add 5% nanometer gold mixing, be eventually adding 5% PVB, PVB refers to polyvinyl butyral resin, mix homogeneously;
Nanometer gold utilizes in AOT and the reverse micelle system of hexamethylene System forming to be prepared, and AOT refers to amber glass acid di-isooctyl
Semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, adjusts water, electrolyte, the concentration ratio of surfactant, preparation
The nanogold particle of different-diameter, nanogold particle diameter is in 30nm;
After the completion of glucoseoxidase crosslinking, a floor height molecular film can be fixed in electrode by way of dipping, coating,
To strengthen the biosensor organism compatibility, improve vivo performance;
Because nanometer gold has good biocompatibility, can implant in human body the long period, and do not cause bad anti-
Should;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, when shortening enzyme electrode to glucose responding
Between, extend enzyme electrode service life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH2)
GOD(FADH2)+O2→GOD(FAD)+H2O2
glucose-lactone+H2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH2) less stable, it is easier recurring structure and change
Become it is impossible to oxidized become normality glucoseoxidase, this is one of the reason common glucose oxidase electrode enzyme activity is lost;
And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can be rapidly by reduction-state
Glucoseoxidase GOD (FADH2) it is oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state in electrode process
Glucoseoxidase GOD (FADH2) quantity and existence time, reduce loss of enzyme activity, extend electrode life;In addition nanometer
Gold grain addition also increases substantially enzyme electrode and answers speed, shortens the enzyme electrode corresponding time, improves subcutaneous glucose and passes
Signal delay during sensor measurement, improves real-time monitoring accuracy;
Macromolecule layer, in order to provide sensor implantation needed by human body biocompatibility, improves vivo performance;Can be by leaching
Stain, the mode of coating fix a floor height molecular film in electrode, and used macromolecular material is silastic polymer, polyurethane, gathers
One or more mixing therein of sub- peace ester, Polyethylene Glycol;Solvent adopts dehydrated alcohol, oxolane, can be by spraying, leaching
Prepared by stain, the mode of coating;
2., to electrode:
Functional layer on electrode Copper Foil is included to inert metal layer, to Catalytic Layer, to macromolecule layer;Its preparation method with
Working electrode is essentially identical, is not required to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil includes inert metal layer, Catalytic Layer, macromolecule layer;Its preparation method and work
Electrode is identical, is not required to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil includes inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after the completion of the preparation of inert metal layer, is splashed by plating, vacuum
The method penetrated prepares silver/silver chloride layer, prepares silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination;
After the completion of above-mentioned preparation technology, cut finally according to element circuit, obtained sensor, three electrodes and four electrodes
Size sensor is as follows:Implantation human body parts length is not more than 15mm, wide no more than 0.6mm, thick no more than 0.4mm;
Two electrode sizes are as follows:Implantation human body parts length is not more than 15mm, wide no more than 0.3mm, and thickness is not more than
0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrodes composition sensors are it is not necessary in enzyme layer
Add nanometer gold, blank electrode is used for detecting background signal and interference signal, improve sensor accuracy;
Two electrodes and three electrode sensors, preparation process need to increase nanometer gold in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, is then log out guide pin, sensor is stayed subcutaneous tissue and started working.
Claims (2)
1. a kind of subcutaneous tissue insertion type glucose microsensor it is characterised in that:Including base (1), described base (1)
In be provided with the lead portion (2) stretching out, the described end of lead portion (2) is connected with Sensor section (3), described
Sensor section (3) and lead portion (2) be respectively provided in insulated substrate (4);
Described Sensor section (3) includes working electrode (5), to electrode (7) and reference electrode (6), described working electrode
(5) it is located at the left end of insulated substrate (4) end face, the described right-hand member that electrode (7) is located at insulated substrate (4) end face, institute
It is provided with reference electrode (6), described work is electric between the inwall of working electrode (5) upper end stated and the inwall to electrode (7) upper end
Pole (5), to electrode (7) and the interruption-like distribution of reference electrode (6), constitute three-electrode system;
Described working electrode (5) includes tack coat (9), and described tack coat (9) overlays on the top of insulated substrate (4), described
The top of tack coat (9) be covered with conductive layer (10), the top of described conductive layer (10) is covered with inert metal layer (11), institute
The top of inert metal layer (11) stated be covered with Catalytic Layer (12), the described top of Catalytic Layer (12) be covered with enzyme layer
(13), the top of described enzyme layer (13) be covered with macromolecule layer (14);
Described reference electrode includes reference electrode tack coat (15), and described tack coat (15) overlays on the upper of insulated substrate (4)
Portion, the top of described tack coat (15) is covered with reference electrode conductive layer (16), and the top of described conductive layer (16) is covered with lazy
Property metal level (17), the top of described inert metal layer (17) is covered with silver/silver chloride layer (18), described reference silver/chlorination
The top of silver layer (18) is covered with reference macromolecule layer (19);
Described includes tack coat (20) to electrode, and described tack coat (20) is located at the bottom of insulated substrate (4), and described is viscous
The surface of knot layer (20) is covered with conductive layer (21), and the surface of described conductive layer (21) is covered with inert metal layer (22), described
The surface of inert metal layer (22) is covered with Catalytic Layer (23), and the surface of described Catalytic Layer (23) is covered with macromolecule layer (24);
Described lead portion (2) is made up of 3 lead assemblies (30), and 3 lead assemblies (30) are divided equally in insulated substrate (4)
On one end face, described lead assemblies (30) include overlaying on the lead first tack coat (31) on insulated substrate (4) surface, described
The surface of lead first tack coat (31) be covered with lead conductive layer (32), the surface of described lead conductive layer (32) is covered with draws
Line second tack coat (33), the surface of described lead second tack coat (33) is covered with lead finish (34);
(1), the selection of insulated substrate:
Insulated substrate adopts the polyimide insulative thin film of deflection or mylar as carrier, and specific insulation reaches 1015
Ω·cm;This layer of THICKNESS CONTROL is in 7.5-12.5 micron;
(2), tack coat material selects:
Tack coat includes each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, tack coat adopts epoxy resin or crylic acid resin, this thickness degree control
System is in 5-15 micron;
(3), the selection of conductive layer:
Conductive layer includes each conductive layer in Sensor section and lead portion;The surface of tack coat is conductive layer, and conductive layer adopts
Rolled copper foil, THICKNESS CONTROL is in 5-20 micron;Lead portion needs to prepare lead second tack coat on the electrically conductive and lead is protected
Sheath, interlayer increases inter-layer bonding force by rolling process, and electrode part is not required to want the second tack coat and protective layer, wants according to different
Ask and prepare corresponding function layer;
(4), the selection of lead second tack coat:
It is lead second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or crylic acid resin,
This layer of THICKNESS CONTROL is in 5-15 micron;What front end electrode part needed naked leakage does not apply this layer binder, and interlayer can pass through rolling process
Increase inter-layer bonding force;
(5), the selection of protective layer:
It is polyimide insulative thin film outside lead second tack coat of rear end lead portion, protecting film first carries out cutting processing, dew
Go out the Copper Foil of leading portion electrode area, contact conductor covering protection film;This layer of THICKNESS CONTROL is in 5-15 micron;Increased by rolling process
Inter-layer bonding force;
(6), electrode part functional layer preparation:
1., working electrode:
Functional layer composition on working electrode Copper Foil is as follows:Inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, by the method preparation of plating, sputtering, with the inertia gold of gold, platinum
Belong to, this thickness degree is 10-15 micron;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by way of spraying, dipping, coating by enzyme layer, and dip time is 5-15 minute;
Then fixed with the glucoseoxidase crosslinking that the glutaraldehyde solution that concentration is 5%-20% transfers to working electrode, crosslinked temperature
Degree is at 25-35 degree Celsius, crosslinked using liquid impregnation crosslinking or gas phase, and crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows:Glucoseoxidase and people's recombinant albumin, Portugal is added in phosphate buffer
Glucoseoxidase addition is every milliliter of 50-100 milligram, and people's recombinant albumin addition is every milliliter of 50-100 milligram;Dissolving
After fully, the nanometer gold adding 1-5% mixes, and is eventually adding the polyvinyl butyral resin of 1-5%, mix homogeneously;
Nanometer gold utilizes in AOT and the reverse micelle system of hexamethylene System forming to be prepared, and AOT refers to the acid di-isooctyl semi-annular jade pendant acid of amber glass
Sodium, by reduction of sodium citrate chloroaurate aqueous solution, adjusts water, electrolyte, the concentration ratio of surfactant, preparation is different
The nanogold particle of diameter, nanogold particle diameter is in 5-30nm;
After the completion of glucoseoxidase crosslinking, fix a floor height molecular film in electrode by way of dipping, coating, to strengthen biography
Sensor biocompatibility, improves vivo performance;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH2)
GOD(FADH2)+O2→GOD(FAD)+H2O2
glucose-lactone+H2O→glucose-acid
Macromolecule layer, fixes a floor height molecular film in electrode, used macromolecular material is silicon rubber by way of dipping, coating
The two or more mixing therein of xanthan polymer, polyurethane, polyimides, Polyethylene Glycol;Solvent adopts dehydrated alcohol, tetrahydrochysene furan
Mutter, prepared by way of spraying, dipping, coating;
2., to electrode:
Functional layer on electrode Copper Foil is included to inert metal layer, to Catalytic Layer, to macromolecule layer;Its preparation method and work
Electrode is essentially identical, is not required to prepare enzyme layer;
3., reference electrode:
Functional layer on reference electrode Copper Foil includes inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after the completion of the preparation of inert metal layer, by plating, vacuum sputtering
Method prepares silver/silver chloride layer, prepares silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination;
After the completion of above-mentioned preparation technology, cut finally according to element circuit, obtained sensor, size sensor is as follows:Plant
Enter human body parts length and be not more than 15mm, wide no more than 0.6mm, thick no more than 0.4mm.
2. the preparation method of a kind of subcutaneous tissue insertion type glucose microsensor according to claim 1, its feature
It is:Carry out according to the following steps:
(1), the selection of insulated substrate:
Insulated substrate adopts the polyimide insulative thin film of deflection or mylar as carrier, and specific insulation reaches 1015
Ω·cm;This layer of THICKNESS CONTROL is in 7.5-12.5 micron;
(2), tack coat material selects:
Tack coat includes each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, tack coat adopts epoxy resin or crylic acid resin, this thickness degree control
System is in 5-15 micron;
(3), the selection of conductive layer:
Conductive layer includes each conductive layer in Sensor section and lead portion;The surface of tack coat is conductive layer, and conductive layer adopts
Rolled copper foil, THICKNESS CONTROL is in 5-20 micron;Lead portion needs to prepare lead second tack coat on the electrically conductive and lead is protected
Sheath, interlayer increases inter-layer bonding force by rolling process, and electrode part is not required to want the second tack coat and protective layer, wants according to different
Ask and prepare corresponding function layer;
(4), the selection of lead second tack coat:
It is lead second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or crylic acid resin,
This layer of THICKNESS CONTROL is in 5-15 micron;What front end electrode part needed naked leakage does not apply this layer binder, and interlayer can pass through rolling process
Increase inter-layer bonding force;
(5), the selection of protective layer:
It is polyimide insulative thin film outside lead second tack coat of rear end lead portion, protecting film first carries out cutting processing, dew
Go out the Copper Foil of leading portion electrode area, contact conductor covering protection film;This layer of THICKNESS CONTROL is in 5-15 micron;Increased by rolling process
Inter-layer bonding force;
(6), electrode part functional layer preparation:
1., working electrode:
Functional layer composition on working electrode Copper Foil is as follows:Inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, by the method preparation of plating, sputtering, with the inertia gold of gold, platinum
Belong to, this thickness degree is 10-15 micron;
Catalytic Layer is platinum black, is prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by way of spraying, dipping, coating by enzyme layer, and dip time is 5-15 minute;
Then fixed with the glucoseoxidase crosslinking that the glutaraldehyde solution that concentration is 5%-20% transfers to working electrode, crosslinked temperature
Degree is at 25-35 degree Celsius, crosslinked using liquid impregnation crosslinking or gas phase, and crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows:Glucoseoxidase and people's recombinant albumin, Portugal is added in phosphate buffer
Glucoseoxidase addition is every milliliter of 50-100 milligram, and people's recombinant albumin addition is every milliliter of 50-100 milligram;Dissolving
After fully, the nanometer gold adding 1-5% mixes, and is eventually adding the polyvinyl butyral resin of 1-5%, mix homogeneously;
Nanometer gold utilizes in AOT and the reverse micelle system of hexamethylene System forming to be prepared, and AOT refers to the acid di-isooctyl semi-annular jade pendant acid of amber glass
Sodium, by reduction of sodium citrate chloroaurate aqueous solution, adjusts water, electrolyte, the concentration ratio of surfactant, preparation is different
The nanogold particle of diameter, nanogold particle diameter is in 5-30nm;
After the completion of glucoseoxidase crosslinking, fix a floor height molecular film in electrode by way of dipping, coating, to strengthen biography
Sensor biocompatibility, improves vivo performance;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH2)
GOD(FADH2)+O2→GOD(FAD)+H2O2
glucose-lactone+H2O→glucose-acid
Macromolecule layer, fixes a floor height molecular film in electrode, used macromolecular material is silicon rubber by way of dipping, coating
The two or more mixing therein of xanthan polymer, polyurethane, polyimides, Polyethylene Glycol;Solvent adopts dehydrated alcohol, tetrahydrochysene furan
Mutter, prepared by way of spraying, dipping, coating;
2., to electrode:
Functional layer on electrode Copper Foil is included to inert metal layer, to Catalytic Layer, to macromolecule layer;Its preparation method and work
Electrode is essentially identical, is not required to prepare enzyme layer;
3., reference electrode:
Functional layer on reference electrode Copper Foil includes inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after the completion of the preparation of inert metal layer, by plating, vacuum sputtering
Method prepares silver/silver chloride layer, prepares silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination;
After the completion of above-mentioned preparation technology, cut finally according to element circuit, obtained sensor, size sensor is as follows:Plant
Enter human body parts length and be not more than 15mm, wide no more than 0.6mm, thick no more than 0.4mm.
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