CN105411607A - Subcutaneous tissue involvement type glucose microsensor and preparation method thereof - Google Patents
Subcutaneous tissue involvement type glucose microsensor and preparation method thereof Download PDFInfo
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Abstract
The invention provides a microsensor, and in particular relates to a subcutaneous tissue involvement type glucose microsensor and a preparation method thereof. The subcutaneous tissue involvement type glucose microsensor comprises a base, wherein the base is internally provided with a lead part extending outwards, the tail end of the lead part is connected with a sensor part, and the sensor part and the lead part are arranged on an insulation substrate layer. The subcutaneous tissue involvement type glucose microsensor and the preparation method have the advantages that the structure is compact, the operation performance is improved, and the service life is prolonged.
Description
Technical field
The present invention is a kind of microsensor, particularly a kind of subcutaneous tissue insertion type glucose microsensor and preparation method thereof.
Background technology
Diabetes are common incretion metabolism diseases of the serious harm human health in a kind of global range.Global diabetes prevalence presents obvious ascendant trend in recent years.For diabetics, blood sugar monitoring is most important, must formulate corresponding treatment scheme according to blood glucose height.Because the factor affecting blood sugar for human body level is a lot, blood glucose has larger fluctuation, tradition single point blood glucose is measured exists obviously deficiency, can not obtain and accurately comprehensively obtain blood glucose information, the personalized therapy program of science cannot be formulated, cause patient blood glucose to be fluctuated, the high and low blood glucose of frequent appearance, affect patient health, even threat to life time serious.
For the problems referred to above, recent domestic company researchs and develops can the biosensor of continuous measurement blood glucose, and as US Patent No. 7153265 mentions biosensor, this sensor heeling-in, at subcutaneous tissue, monitors interstitial fluid glucose continuously.Domestic patent such as CN200410101080.6 mentions Endermic implantating biological sensors.
The current biosensor for continuous glucose monitoring, be substantially all utilize glucoseoxidase, this enzyme has the feature to glucose high selectivity.
Consider and implant feasibility and job stability, subcutaneous implanted sensor volume requirement is little as far as possible, keenly feels less when implanting like this, causes human body rejection also can be less after implantation, is conducive to normal operation of sensor.Current have two classes for human body implantation glucose microsensor, one class needs guide pin implanted sensor, base material is generally micro plastic sheet, removes the part as carrier, also needs to consider the arrangement of circuit conductor lead-in wire, thus sensor bulk is larger, implantation process pain is comparatively strong, and effective sensing area of sensor is very limited, and sensitivity can be caused lower, signal to noise ratio is not good, implants rear stability bad.Working sensor voltage generally at more than 0.5V (Ag/AgCL reference), on this current potential in human body micromolecule chaff interference comprise ascorbic acid, catecholamine etc. can oxidized thus produce interfering signal, have a strong impact on accuracy.Increase one deck polymeric membrane in design to stop chaff interference to this some sensor, this often causes transducer sensitivity to decline, and affects overall performance.This outer sensor glucose oxidase enzymatic activity can be lost with prolongs operating time, and enzyme is lived and is lost to a certain degree, and sensor cannot normally work, and usual human body Implantation Time is generally at 72 hours.
Untapped glucose oxidase sensor, the activity of enzyme can decay with the holding time, and loss of activity is to a certain extent, sensor just can not provide stablizes available signal, and cannot use, therefore glucose oxidase sensor has effect duration, general effect duration only has 6 months, uses inconvenience.
Do not need guide pin implanted sensor, base material is generally metal, although electrode effective area gets a promotion, product stability is poor, and technological process is unconventional, cannot realize large-scale industrial production.
In addition above-mentioned two kinds of sensors all need to consider circuit turn-on problem, need the circuit structure of design comparison complexity, need the design tiny circuit lead of non-universal and miniature plug structure, and these structures often reliability is not good, there will be lead-in wire or the open circuit problem that causes of connector fault, thus cause sensor normally to work.
Summary of the invention
The present invention mainly solves the deficiencies in the prior art, compact conformation degree is high, sensor bulk is little, effective area is large, and corresponding signal is high, good in anti-interference performance, effect duration is long, can reasonable solution circuit turn-on problem, reliable and stable, easy industrial subcutaneous tissue insertion type glucose microsensor in enormous quantities and preparation method thereof.
Above-mentioned technical problem of the present invention is mainly solved by following technical proposals:
A kind of subcutaneous tissue insertion type glucose microsensor, comprise base, be provided with outward extending lead portion in described base, the end of described lead portion is connected with Sensor section, and described Sensor section and lead portion are located in insulated substrate respectively;
Described Sensor section comprise working electrode, reference electrode, to electrode and blank electrode, described working electrode 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 left end electrode being located to insulated substrate front, described blank electrode is located at the right-hand member in insulated substrate front, described working electrode and the interruption-like distribution of reference electrode, described to electrode and the interruption-like distribution of blank electrode, form four electrode systems;
Or,
Described Sensor section comprises working electrode, to electrode and reference electrode, described working electrode is located at the left end of insulated substrate one end face, described right-hand member electrode being located to insulated substrate one end face, the inwall of described working electrode upper end and be provided with reference electrode between the inwall of electrode upper end, described working electrode, to electrode and the interruption-like distribution of reference electrode, form three-electrode system;
Or,
Described Sensor section comprises working electrode, reference electrode and to electrode, described working electrode 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 left end electrode being located to the insulated substrate back side, described working electrode and the interruption-like distribution of reference electrode, form three-electrode system;
Or,
Described Sensor section comprises working electrode and reference electrode, and described working electrode is located at the front of insulated substrate, and described reference electrode is located at the back side of insulated substrate, forms two electrode systems;
Described working electrode comprises tack coat, described tack coat overlays on the top of insulated substrate, the top of described tack coat be covered with conductive layer, the top of described conductive layer is covered with inert metal layer, the top of described inert metal layer be covered with Catalytic Layer, the top of described Catalytic Layer be covered with enzyme layer, the top of described enzyme layer be covered with macromolecule layer;
Described reference electrode comprises reference electrode tack coat, described tack coat overlays on the top of insulated substrate, the top of described tack coat is covered with reference electrode conductive layer, the top of described conductive layer is covered with inert metal layer, the top of described inert metal layer is covered with silver/silver chloride layer, and the top of described reference silver/silver chloride layer is covered with reference macromolecule layer;
Described comprises tack coat to electrode, described tack coat is located at the bottom of insulated substrate, the surface of described tack coat is covered with conductive layer, the surface of described conductive layer is covered with inert metal layer, the surface of described inert metal layer is covered with Catalytic Layer, and the surface of described Catalytic Layer is covered with macromolecule layer;
Described blank electrode comprises tack coat, described electrode adhesion layer is located at the bottom of insulated substrate, the surface of described tack coat is covered with conductive layer, the surface of described conductive layer is covered with inert metal layer, the surface of described inert metal layer is covered with Catalytic Layer, and the surface of described Catalytic Layer is covered with macromolecule layer;
Described lead portion is made up of at least one lead assemblies; described lead assemblies comprises lead-in wire first tack coat overlaying on insulated substrate surface; the surface of described lead-in wire first tack coat is covered with lead-in wire conductive layer; the surface of described lead-in wire conductive layer is covered with lead-in wire second tack coat, and the surface of described lead-in wire second tack coat is covered with lead finish.
As preferably, described lead assemblies is provided with 4, lead assemblies is located at the right-hand member of the left end of insulated substrate upper surface, the right-hand member of insulated substrate upper surface, the left end of insulated substrate lower surface and insulated substrate lower surface respectively, interruption-like distribution between each lead assemblies;
Or,
Described lead assemblies is provided with 3, and 3 lead assemblies are divided equally on an end face of insulated substrate;
Or,
Described lead assemblies is provided with 3, and wherein two lead assemblies divide equally the upper surface in insulated substrate, and another lead assemblies is located at the interposition of insulated substrate upper surface;
Or,
Described lead assemblies is provided with 2, and a lead assemblies is located at the interposition of insulated substrate upper surface, and another lead assemblies is located at the interposition of insulated substrate lower surface.
The preparation method of subcutaneous tissue insertion type glucose microsensor, carry out according to the following steps:
(1), the selection of insulated substrate:
The polyimide insulative thin film of insulated substrate employing deflection or mylar, as carrier, have good process based prediction model;
The high flexibility of writing music of tool, can three-dimensional wiring, changes shape according to space constraint; High-low temperature resistant, resistance to combustion; Collapsible and do not affect signal propagation function, can static interference be prevented; Chemical change is stablized, and stability, trustworthiness are high; Be beneficial to the design of Related product, assembly work and mistake can be reduced, and improve the service life of related products; Good insulating properties, specific insulation reaches 1015 Ω .cm; Excellent to the caking property of conventional matrix, metal and dielectric material; This layer thickness controls at 7.5-12.5 micron;
(2), tack coat material is selected:
Tack coat comprises each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly has influence on the performance of electrode, owing to there is chemical reaction in the fabrication process between binding agent and insulated substrate, therefore also should select corresponding binder system for different insulated substrate, the performance of binding agent must adapt with insulated substrate;
Tack coat used must can bear the erosion of various process conditions and chemical drugs used in the mill, the not phenomenon of layering or degraded, consider that human body is implanted binding agent and must be had good biocompatibility, tack coat adopts epoxy resin or crylic acid resin, and this layer thickness controls at 5-15 micron;
(3), the selection of conductive layer:
Conductive layer comprises 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 5-20 micron;
Lead portion needs to prepare lead-in wire second tack coat and lead finish on the electrically conductive, and interlayer increases inter-layer bonding force by rolling process, and electrode part does not need the second tack coat and protective layer, requires to prepare corresponding function layer according to difference;
(4), go between the selection of the second tack coat:
Be lead-in wire second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or crylic acid resin, and this layer thickness controls at 5-15 micron;
What front end electrode part needed naked leakage is not coated with this layer binder, and interlayer increases inter-layer bonding force by rolling process;
(5), the selection of protective layer:
Be polyimide insulative thin film outside lead-in wire second tack coat of rear end lead portion, protecting film first carries out cutting processing, exposes the Copper Foil of leading portion electrode area, contact conductor covered with protective film;
This layer thickness controls at 5-15 micron; Inter-layer bonding force is increased by rolling process;
(6), electrode part functional layer preparation:
Electrode part can be divided into working electrode, as required to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer on working electrode Copper Foil is composed as follows: inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, and by the method preparation of plating, sputtering, can select the inert metal of gold, platinum, this layer thickness is 10-15 micron;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by the mode of spraying, dipping, coating by enzyme layer, and dip time is 5-15 minute;
Then by concentration be the glutaraldehyde solution of 5%-20% by crosslinked fixing for the glucoseoxidase transferring to working electrode, crosslinking temperature is at 25-35 degree Celsius, and adopt the crosslinked or gas phase of liquid impregnation to be cross-linked, crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows: in phosphate buffer, add glucoseoxidase and people's recombinant albumin, and glucoseoxidase addition is every milliliter of 50-100 milligram, and people's recombinant albumin addition is every milliliter of 50-100 milligram; Dissolve fully, add the nanometer gold mixing of 1-5%, finally add the PVB of 1-5%, PVB refers to polyvinyl butyral resin, mix homogeneously;
Nanometer gold utilizes in the reverse micelle system of AOT and cyclohexane extraction System forming to be prepared, AOT refers to amber glass acid di-isooctyl semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, regulate the concentration ratio of water, electrolyte, surfactant, prepare the nanogold particle of different-diameter, nanogold particle diameter is at 5-30nm;
After glucoseoxidase has been cross-linked, one deck polymeric membrane can be fixed by the mode of dipping, coating at electrode, to strengthen the biosensor organism compatibility, improve performance in body;
Because nanometer gold has good biocompatibility, in long period implant into body, and can not cause untoward reaction;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, shortens enzyme electrode to the glucose responding time, extending enzyme electrode life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH
2)
GOD(FADH
2)+O
2→GOD(FAD)+H
2O
2
glucose-lactone+H
2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH
2) less stable, changing than being easier to recurring structure, oxidizedly cannot become normality glucoseoxidase, this is one of common glucose oxidase electrode enzyme reason lost alive; And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can rapidly by reduction-state glucoseoxidase GOD (FADH
2) be oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state glucoseoxidase GOD (FADH in electrode process
2) quantity and life period, reduce loss of enzyme activity, extend electrode life; In addition nanogold particle adds and also increases substantially enzyme electrode and answer speed, shortens the enzyme electrode corresponding time, and signal delay when improving subcutaneous glucose sensor measurement, improves Real-Time Monitoring accuracy;
Macromolecule layer, in order to provide biocompatibility needed for sensor implant into body, improves performance in body; Can fix one deck polymeric membrane by the mode of dipping, coating at electrode, used macromolecular material is one or more mixing wherein of silastic polymer, polyurethane, polyurethane, Polyethylene Glycol; Solvent adopts dehydrated alcohol, oxolane, can be prepared by the mode of spraying, dipping, coating;
2., to electrode:
Comprise to inert metal layer, to Catalytic Layer, to macromolecule layer to the functional layer on electrode Copper Foil; Its preparation method and working electrode are substantially identical, do not need to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil comprises inert metal layer, Catalytic Layer, macromolecule layer; Its preparation method is identical with working electrode, does not need to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil comprises inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after prepared by inert metal layer, prepares silver/silver chloride layer, prepare silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination by the method for plating, vacuum sputtering;
After above-mentioned preparation technology completes, finally cut according to element circuit, obtain sensor, three electrodes and four electrode sensor sizes as follows: implant into body partial-length is not more than 15mm, is widely not more than 0.6mm, is thickly not more than 0.4mm;
Two electrode sizes are as follows: implant into body partial-length is not more than 15mm, are widely not more than 0.3mm, are thickly not more than 0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrode composition sensors, do not need to add nanometer gold, normal operation of sensor voltage 0.55V in enzyme layer, blank electrode is used for detection background signal and interfering signal, improves sensor accuracy;
Two electrodes and three electrode sensors, preparation process need increase nanometer gold in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, then exit guide pin, sensor is stayed subcutaneous tissue and started working.
The present invention takes transducer production method, without any non-universal circuit lead and miniature plug structure, sensor, inherently on flexible circuitry, fundamentally solves circuit turn-on problem, signals collecting steady in a long-term can be realized, there will not be because circuit breaker causes fault.
This transducer production method, because contact conductor is Copper Foil, and has protecting film, and circuit lead is flexible, reverse and can not damage, lead-in wire can volume less, arrangement mode is more flexible, thus can provide larger space to copper foil electrode.Sensor bulk can be accomplished, dual sided sensor working electrode effective area can be accomplished, compares common sensor bulk less, and electrode face is long-pending larger, is conducive to improving performance in sensor body.
This transducer production method uses for reference comparatively ripening electron industrial circuits preparation technology, and technical maturity is stablized, and is easy to realize mass production, improves sensor stability, greatly reduces single-sensor cost simultaneously.
Therefore, subcutaneous tissue insertion type glucose microsensor provided by the invention and preparation method thereof, compact conformation, improves operating characteristics, promotes service life.
Accompanying drawing explanation
Fig. 1 is the structural representation in the present invention;
Fig. 2 is preparation process schematic diagram of the present invention;
The front schematic view of electrode in Fig. 3 the present invention;
The reverse side schematic diagram of electrode in Fig. 4 the present invention;
Fig. 5 is A-A sectional structure schematic diagram in Fig. 4;
Fig. 6 is B-B sectional structure schematic diagram in Fig. 4;
Fig. 7 is the schematic diagram of wherein a kind of electrode shape in the present invention;
The front schematic view of another kind of electrode shape in Fig. 8 the present invention;
Fig. 9 is the inverse layer structure schematic diagram of Fig. 8;
The front schematic view of another electrode shape in Figure 10 the present invention;
Figure 11 is the inverse layer structure schematic diagram of Figure 10;
Figure 12 is the tabular drawing of sensor of the present invention test performance in the solution;
Figure 13 is the performance map of sensor of the present invention test performance in the solution;
Figure 14 is sensor performance figure after implant into body of the present invention.
Detailed description of the invention
Below by embodiment, and by reference to the accompanying drawings, technical scheme of the present invention is described in further detail.
Embodiment 1: as shown in Figure 1, Figure 2, shown in Fig. 3, Fig. 4, Fig. 5, Fig. 6, Fig. 7, Fig. 8, Fig. 9, Figure 10, Figure 11, Figure 12, Figure 13 and Figure 14, a kind of subcutaneous tissue insertion type glucose microsensor, comprise base 1, outward extending lead portion 2 is provided with in described base 1, the end of described lead portion 2 is connected with Sensor section 3, and described Sensor section 3 is located in insulated substrate 4 with lead portion 2 respectively;
Described Sensor section 3 comprise working electrode 5, reference electrode 6, to electrode 7 and blank electrode 8, 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, described left end electrode 7 being located to 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, form four electrode systems;
Or,
Described Sensor section 3 comprises working electrode 5, to electrode 7 and reference electrode 6, described working electrode 5 is located at the left end of insulated substrate 4 one end face, described right-hand member electrode 7 being located to insulated substrate 4 one end face, reference electrode 6 is provided with between the inwall of described working electrode 5 upper end and the inwall to electrode 7 upper end, described working electrode 5, to electrode 7 and the interruption-like distribution of reference electrode 6, form three-electrode system;
Or,
Described Sensor section 3 comprises working electrode 5, reference electrode 6 and to electrode 7, 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, described left end electrode 7 being located to insulated substrate 4 back side, described working electrode 5 and the interruption-like distribution of reference electrode 6, form three-electrode system;
Or,
Described Sensor section 3 comprises working electrode 5 and reference electrode 6, and described working electrode 5 is located at the front of insulated substrate 4, and described reference electrode 6 is located at the back side of insulated substrate 4, forms two electrode systems;
Described working electrode 5 comprises tack coat 9, described tack coat 9 overlays on the top of insulated substrate 4, the top of described tack coat 9 be covered with conductive layer 10, the top of described conductive layer 10 is covered with inert metal layer 11, the top of described inert metal layer 11 be covered with Catalytic Layer 12, the top of described 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 comprises reference electrode tack coat 15, 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, 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 with reference macromolecule layer 19;
Described comprises tack coat 20 to electrode, described tack coat 20 is located at the bottom of insulated substrate 4, the surface of described tack coat 20 is covered with conductive layer 21, the surface of described conductive layer 21 is covered with inert metal layer 22, the surface of described 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 blank electrode 8 comprises tack coat 25, described electrode adhesion layer 25 is located at the bottom of insulated substrate 4, the surface of described tack coat 25 is covered with conductive layer 26, the surface of described conductive layer 26 is covered with inert metal layer 27, the surface of described inert metal layer 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; described lead assemblies 30 comprises lead-in wire first tack coat 31 overlaying on insulated substrate 4 surface; the surface of described lead-in wire first tack coat 31 is covered with lead-in wire conductive layer 32; the surface of described lead-in wire conductive layer 32 is covered with lead-in wire second tack coat 33, and the surface of described lead-in wire second tack coat 33 is covered with lead finish 34.
Described lead assemblies 30 is provided with 4, lead assemblies 30 is located at the right-hand member of the left end of insulated substrate 4 upper surface, the right-hand member of insulated substrate 4 upper surface, the left end of insulated substrate 4 lower surface and insulated substrate 4 lower surface respectively, interruption-like distribution between each lead assemblies 30;
Or,
Described lead assemblies 30 is provided with 3, and 3 lead assemblies 30 are divided equally on an end face of insulated substrate 4;
Or,
Described lead assemblies 30 is provided with 3, and wherein two lead assemblies 30 divide equally the upper surface in insulated substrate 4, and another lead assemblies 30 is located at the interposition of insulated substrate 4 upper surface;
Or,
Described lead assemblies 30 is provided with 2, and a lead assemblies 30 is located at the interposition of insulated substrate 4 upper surface, and another lead assemblies 30 is located at the interposition of insulated substrate 4 lower surface.
The preparation method of subcutaneous tissue insertion type glucose microsensor, carry out according to the following steps:
(1), the selection of insulated substrate:
The polyimide insulative thin film of insulated substrate employing deflection or mylar, as carrier, have good process based prediction model;
The high flexibility of writing music of tool, can three-dimensional wiring, changes shape according to space constraint; High-low temperature resistant, resistance to combustion; Collapsible and do not affect signal propagation function, can static interference be prevented; Chemical change is stablized, and stability, trustworthiness are high; Be beneficial to the design of Related product, assembly work and mistake can be reduced, and improve the service life of related products; Good insulating properties, specific insulation reaches 1015 Ω .cm; Excellent to the caking property of conventional matrix, metal and dielectric material; This layer thickness controls at 7.5 microns;
(4), tack coat material is selected:
Tack coat comprises each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly has influence on the performance of electrode, owing to there is chemical reaction in the fabrication process between binding agent and insulated substrate, therefore also should select corresponding binder system for different insulated substrate, the performance of binding agent must adapt with insulated substrate;
Tack coat used must can bear the erosion of various process conditions and chemical drugs used in the mill, the not phenomenon of layering or degraded, consider that human body is implanted binding agent and must be had good biocompatibility, tack coat adopts epoxy resin or crylic acid resin, and this layer thickness controls at 5 microns;
(5), the selection of conductive layer:
Conductive layer comprises 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-in wire second tack coat and lead finish on the electrically conductive, and interlayer increases inter-layer bonding force by rolling process, and electrode part does not need the second tack coat and protective layer, requires to prepare corresponding function layer according to difference;
(4), go between the selection of the second tack coat:
Be lead-in wire second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or crylic acid resin, and this layer thickness controls at 5 microns;
What front end electrode part needed naked leakage is not coated with this layer binder, and interlayer increases inter-layer bonding force by rolling process;
(5), the selection of protective layer:
Be polyimide insulative thin film outside lead-in wire second tack coat of rear end lead portion, protecting film first carries out cutting processing, exposes the Copper Foil of leading portion electrode area, contact conductor covered with protective film;
This layer thickness controls at 5 microns; Inter-layer bonding force is increased by rolling process;
(6), electrode part functional layer preparation:
Electrode part can be divided into working electrode, as required to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer on working electrode Copper Foil is composed as follows: inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, and by the method preparation of plating, sputtering, can select the inert metal of gold, platinum, this layer thickness is 10 microns;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by the mode of spraying, dipping, coating by enzyme layer, and dip time is 5 minutes;
Then by concentration be the glutaraldehyde solution of 5% by crosslinked fixing for the glucoseoxidase transferring to working electrode, crosslinking temperature is at 25 degrees Celsius, and adopt the crosslinked or gas phase of liquid impregnation to be cross-linked, crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows: in phosphate buffer, add glucoseoxidase and people's recombinant albumin, and glucoseoxidase addition is 50 milligrams every milliliter, and people's recombinant albumin addition is 50 milligrams every milliliter; Dissolve fully, add the nanometer gold mixing of 1%, finally add the PVB of 1%, PVB refers to polyvinyl butyral resin, mix homogeneously;
Nanometer gold utilizes in the reverse micelle system of AOT and cyclohexane extraction System forming to be prepared, AOT refers to amber glass acid di-isooctyl semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, regulate the concentration ratio of water, electrolyte, surfactant, prepare the nanogold particle of different-diameter, nanogold particle diameter is at 5nm;
After glucoseoxidase has been cross-linked, one deck polymeric membrane can be fixed by the mode of dipping, coating at electrode, to strengthen the biosensor organism compatibility, improve performance in body;
Because nanometer gold has good biocompatibility, in long period implant into body, and can not cause untoward reaction;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, shortens enzyme electrode to the glucose responding time, extending enzyme electrode life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH
2)
GOD(FADH
2)+O
2→GOD(FAD)+H
2O
2
glucose-lactone+H
2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH
2) less stable, changing than being easier to recurring structure, oxidizedly cannot become normality glucoseoxidase, this is one of common glucose oxidase electrode enzyme reason lost alive; And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can rapidly by reduction-state glucoseoxidase GOD (FADH
2) be oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state glucoseoxidase GOD (FADH in electrode process
2) quantity and life period, reduce loss of enzyme activity, extend electrode life; In addition nanogold particle adds and also increases substantially enzyme electrode and answer speed, shortens the enzyme electrode corresponding time, and signal delay when improving subcutaneous glucose sensor measurement, improves Real-Time Monitoring accuracy;
Macromolecule layer, in order to provide biocompatibility needed for sensor implant into body, improves performance in body; Can fix one deck polymeric membrane by the mode of dipping, coating at electrode, used macromolecular material is one or more mixing wherein of silastic polymer, polyurethane, polyurethane, Polyethylene Glycol; Solvent adopts dehydrated alcohol, oxolane, can be prepared by the mode of spraying, dipping, coating;
2., to electrode:
Comprise to inert metal layer, to Catalytic Layer, to macromolecule layer to the functional layer on electrode Copper Foil; Its preparation method and working electrode are substantially identical, do not need to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil comprises inert metal layer, Catalytic Layer, macromolecule layer; Its preparation method is identical with working electrode, does not need to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil comprises inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after prepared by inert metal layer, prepares silver/silver chloride layer, prepare silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination by the method for plating, vacuum sputtering;
After above-mentioned preparation technology completes, finally cut according to element circuit, obtain sensor, three electrodes and four electrode sensor sizes as follows: implant into body partial-length is not more than 15mm, is widely not more than 0.6mm, is thickly not more than 0.4mm;
Two electrode sizes are as follows: implant into body partial-length is not more than 15mm, are widely not more than 0.3mm, are thickly not more than 0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrode composition sensors, do not need to add nanometer gold in enzyme layer, blank electrode is used for detection background signal and interfering signal, improves sensor accuracy;
Two electrodes and three electrode sensors, preparation process need increase nanometer gold in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, then exit guide pin, sensor is stayed subcutaneous tissue and started working.
Embodiment 2: the preparation method of subcutaneous tissue insertion type glucose microsensor, carry out according to the following steps:
(1), the selection of insulated substrate:
The polyimide insulative thin film of insulated substrate employing deflection or mylar, as carrier, have good process based prediction model;
The high flexibility of writing music of tool, can three-dimensional wiring, changes shape according to space constraint; High-low temperature resistant, resistance to combustion; Collapsible and do not affect signal propagation function, can static interference be prevented; Chemical change is stablized, and stability, trustworthiness are high; Be beneficial to the design of Related product, assembly work and mistake can be reduced, and improve the service life of related products; Good insulating properties, specific insulation reaches 1015 Ω .cm; Excellent to the caking property of conventional matrix, metal and dielectric material; This layer thickness controls at 10 microns;
(6), tack coat material is selected:
Tack coat comprises each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly has influence on the performance of electrode, owing to there is chemical reaction in the fabrication process between binding agent and insulated substrate, therefore also should select corresponding binder system for different insulated substrate, the performance of binding agent must adapt with insulated substrate;
Tack coat used must can bear the erosion of various process conditions and chemical drugs used in the mill, the not phenomenon of layering or degraded, consider that human body is implanted binding agent and must be had good biocompatibility, tack coat adopts epoxy resin or crylic acid resin, and this layer thickness controls at 10 microns;
(7), the selection of conductive layer:
Conductive layer comprises 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-in wire second tack coat and lead finish on the electrically conductive, and interlayer increases inter-layer bonding force by rolling process, and electrode part does not need the second tack coat and protective layer, requires to prepare corresponding function layer according to difference;
(4), go between the selection of the second tack coat:
Be lead-in wire second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or crylic acid resin, and this layer thickness controls at 10 microns;
What front end electrode part needed naked leakage is not coated with this layer binder, and interlayer increases inter-layer bonding force by rolling process;
(5), the selection of protective layer:
Be polyimide insulative thin film outside lead-in wire second tack coat of rear end lead portion, protecting film first carries out cutting processing, exposes the Copper Foil of leading portion electrode area, contact conductor covered with protective film;
This layer thickness controls at 10 microns; Inter-layer bonding force is increased by rolling process;
(6), electrode part functional layer preparation:
Electrode part can be divided into working electrode, as required to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer on working electrode Copper Foil is composed as follows: inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, and by the method preparation of plating, sputtering, can select the inert metal of gold, platinum, this layer thickness is 12 microns;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by the mode of spraying, dipping, coating by enzyme layer, and dip time is 10 minutes;
Then by concentration be the glutaraldehyde solution of 15% by crosslinked fixing for the glucoseoxidase transferring to working electrode, crosslinking temperature is at 30 degrees Celsius, and adopt the crosslinked or gas phase of liquid impregnation to be cross-linked, crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows: in phosphate buffer, add glucoseoxidase and people's recombinant albumin, and glucoseoxidase addition is 70 milligrams every milliliter, and people's recombinant albumin addition is 70 milligrams every milliliter; Dissolve fully, add the nanometer gold mixing of 2%, finally add the PVB of 2%, PVB refers to polyvinyl butyral resin, mix homogeneously;
Nanometer gold utilizes in the reverse micelle system of AOT and cyclohexane extraction System forming to be prepared, AOT refers to amber glass acid di-isooctyl semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, regulate the concentration ratio of water, electrolyte, surfactant, prepare the nanogold particle of different-diameter, nanogold particle diameter is at 20nm;
After glucoseoxidase has been cross-linked, one deck polymeric membrane can be fixed by the mode of dipping, coating at electrode, to strengthen the biosensor organism compatibility, improve performance in body;
Because nanometer gold has good biocompatibility, in long period implant into body, and can not cause untoward reaction;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, shortens enzyme electrode to the glucose responding time, extending enzyme electrode life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH
2)
GOD(FADH
2)+O
2→GOD(FAD)+H
2O
2
glucose-lactone+H
2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH
2) less stable, changing than being easier to recurring structure, oxidizedly cannot become normality glucoseoxidase, this is one of common glucose oxidase electrode enzyme reason lost alive; And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can rapidly by reduction-state glucoseoxidase GOD (FADH
2) be oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state glucoseoxidase GOD (FADH in electrode process
2) quantity and life period, reduce loss of enzyme activity, extend electrode life; In addition nanogold particle adds and also increases substantially enzyme electrode and answer speed, shortens the enzyme electrode corresponding time, and signal delay when improving subcutaneous glucose sensor measurement, improves Real-Time Monitoring accuracy;
Macromolecule layer, in order to provide biocompatibility needed for sensor implant into body, improves performance in body; Can fix one deck polymeric membrane by the mode of dipping, coating at electrode, used macromolecular material is one or more mixing wherein of silastic polymer, polyurethane, polyurethane, Polyethylene Glycol; Solvent adopts dehydrated alcohol, oxolane, can be prepared by the mode of spraying, dipping, coating;
2., to electrode:
Comprise to inert metal layer, to Catalytic Layer, to macromolecule layer to the functional layer on electrode Copper Foil; Its preparation method and working electrode are substantially identical, do not need to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil comprises inert metal layer, Catalytic Layer, macromolecule layer; Its preparation method is identical with working electrode, does not need to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil comprises inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after prepared by inert metal layer, prepares silver/silver chloride layer, prepare silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination by the method for plating, vacuum sputtering;
After above-mentioned preparation technology completes, finally cut according to element circuit, obtain sensor, three electrodes and four electrode sensor sizes as follows: implant into body partial-length is not more than 15mm, is widely not more than 0.6mm, is thickly not more than 0.4mm;
Two electrode sizes are as follows: implant into body partial-length is not more than 15mm, are widely not more than 0.3mm, are thickly not more than 0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrode composition sensors, do not need to add nanometer gold in enzyme layer, blank electrode is used for detection background signal and interfering signal, improves sensor accuracy;
Two electrodes and three electrode sensors, preparation process need increase nanometer in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, then exit guide pin, sensor is stayed subcutaneous tissue and started working.
Embodiment 3: the preparation method of subcutaneous tissue insertion type glucose microsensor, carry out according to the following steps:
(1), the selection of insulated substrate:
The polyimide insulative thin film of insulated substrate employing deflection or mylar, as carrier, have good process based prediction model;
The high flexibility of writing music of tool, can three-dimensional wiring, changes shape according to space constraint; High-low temperature resistant, resistance to combustion; Collapsible and do not affect signal propagation function, can static interference be prevented; Chemical change is stablized, and stability, trustworthiness are high; Be beneficial to the design of Related product, assembly work and mistake can be reduced, and improve the service life of related products; Good insulating properties, specific insulation reaches 1015 Ω .cm; Excellent to the caking property of conventional matrix, metal and dielectric material; This layer thickness controls at 12.5 microns;
(8), tack coat material is selected:
Tack coat comprises each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly has influence on the performance of electrode, owing to there is chemical reaction in the fabrication process between binding agent and insulated substrate, therefore also should select corresponding binder system for different insulated substrate, the performance of binding agent must adapt with insulated substrate;
Tack coat used must can bear the erosion of various process conditions and chemical drugs used in the mill, the not phenomenon of layering or degraded, consider that human body is implanted binding agent and must be had good biocompatibility, tack coat adopts epoxy resin or crylic acid resin, and this layer thickness controls at 10 microns;
(9), the selection of conductive layer:
Conductive layer comprises 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-in wire second tack coat and lead finish on the electrically conductive, and interlayer increases inter-layer bonding force by rolling process, and electrode part does not need the second tack coat and protective layer, requires to prepare corresponding function layer according to difference;
(4), go between the selection of the second tack coat:
Be lead-in wire second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or crylic acid resin, and this layer thickness controls at 15 microns;
What front end electrode part needed naked leakage is not coated with this layer binder, and interlayer increases inter-layer bonding force by rolling process;
(5), the selection of protective layer:
Be polyimide insulative thin film outside lead-in wire second tack coat of rear end lead portion, protecting film first carries out cutting processing, exposes the Copper Foil of leading portion electrode area, contact conductor covered with protective film;
This layer thickness controls at 15 microns; Inter-layer bonding force is increased by rolling process;
(6), electrode part functional layer preparation:
Electrode part can be divided into working electrode, as required to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer on working electrode Copper Foil is composed as follows: inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, and by the method preparation of plating, sputtering, can select the inert metal of gold, platinum, this layer thickness is 15 microns;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by the mode of spraying, dipping, coating by enzyme layer, and dip time is 15 minutes;
Then by concentration be the glutaraldehyde solution of 20% by crosslinked fixing for the glucoseoxidase transferring to working electrode, crosslinking temperature is at 35 degrees Celsius, and adopt the crosslinked or gas phase of liquid impregnation to be cross-linked, crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows: in phosphate buffer, add glucoseoxidase and people's recombinant albumin, and glucoseoxidase addition is 100 milligrams every milliliter, and people's recombinant albumin addition is 100 milligrams every milliliter; Dissolve fully, add the nanometer gold mixing of 5%, finally add the PVB of 5%, PVB refers to polyvinyl butyral resin, mix homogeneously;
Nanometer gold utilizes in the reverse micelle system of AOT and cyclohexane extraction System forming to be prepared, AOT refers to amber glass acid di-isooctyl semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, regulate the concentration ratio of water, electrolyte, surfactant, prepare the nanogold particle of different-diameter, nanogold particle diameter is at 30nm;
After glucoseoxidase has been cross-linked, one deck polymeric membrane can be fixed by the mode of dipping, coating at electrode, to strengthen the biosensor organism compatibility, improve performance in body;
Because nanometer gold has good biocompatibility, in long period implant into body, and can not cause untoward reaction;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, shortens enzyme electrode to the glucose responding time, extending enzyme electrode life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH
2)
GOD(FADH
2)+O
2→GOD(FAD)+H
2O
2
glucose-lactone+H
2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH
2) less stable, changing than being easier to recurring structure, oxidizedly cannot become normality glucoseoxidase, this is one of common glucose oxidase electrode enzyme reason lost alive; And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can rapidly by reduction-state glucoseoxidase GOD (FADH
2) be oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state glucoseoxidase GOD (FADH in electrode process
2) quantity and life period, reduce loss of enzyme activity, extend electrode life; In addition nanogold particle adds and also increases substantially enzyme electrode and answer speed, shortens the enzyme electrode corresponding time, and signal delay when improving subcutaneous glucose sensor measurement, improves Real-Time Monitoring accuracy;
Macromolecule layer, in order to provide biocompatibility needed for sensor implant into body, improves performance in body; Can fix one deck polymeric membrane by the mode of dipping, coating at electrode, used macromolecular material is one or more mixing wherein of silastic polymer, polyurethane, polyurethane, Polyethylene Glycol; Solvent adopts dehydrated alcohol, oxolane, can be prepared by the mode of spraying, dipping, coating;
2., to electrode:
Comprise to inert metal layer, to Catalytic Layer, to macromolecule layer to the functional layer on electrode Copper Foil; Its preparation method and working electrode are substantially identical, do not need to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil comprises inert metal layer, Catalytic Layer, macromolecule layer; Its preparation method is identical with working electrode, does not need to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil comprises inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after prepared by inert metal layer, prepares silver/silver chloride layer, prepare silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination by the method for plating, vacuum sputtering;
After above-mentioned preparation technology completes, finally cut according to element circuit, obtain sensor, three electrodes and four electrode sensor sizes as follows: implant into body partial-length is not more than 15mm, is widely not more than 0.6mm, is thickly not more than 0.4mm;
Two electrode sizes are as follows: implant into body partial-length is not more than 15mm, are widely not more than 0.3mm, are thickly not more than 0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrode composition sensors, do not need to add nanometer gold in enzyme layer, blank electrode is used for detection background signal and interfering signal, improves sensor accuracy;
Two electrodes and three electrode sensors, preparation process need increase nanometer gold in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, then exit guide pin, sensor is stayed subcutaneous tissue and started working.
Embodiment 3: the preparation method of subcutaneous tissue insertion type glucose microsensor, carry out according to the following steps:
(1), the selection of insulated substrate:
The polyimide insulative thin film of insulated substrate employing deflection or mylar, as carrier, have good process based prediction model;
The high flexibility of writing music of tool, can three-dimensional wiring, changes shape according to space constraint; High-low temperature resistant, resistance to combustion; Collapsible and do not affect signal propagation function, can static interference be prevented; Chemical change is stablized, and stability, trustworthiness are high; Be beneficial to the design of Related product, assembly work and mistake can be reduced, and improve the service life of related products; Good insulating properties, specific insulation reaches 1015 Ω .cm; Excellent to the caking property of conventional matrix, metal and dielectric material; This layer thickness controls at 12.5 microns;
(2), tack coat material is selected:
Tack coat comprises each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly has influence on the performance of electrode, owing to there is chemical reaction in the fabrication process between binding agent and insulated substrate, therefore also should select corresponding binder system for different insulated substrate, the performance of binding agent must adapt with insulated substrate;
Tack coat used must can bear the erosion of various process conditions and chemical drugs used in the mill, the not phenomenon of layering or degraded, consider that human body is implanted binding agent and must be had good biocompatibility, tack coat adopts epoxy resin or crylic acid resin, and this layer thickness controls at 15 microns;
(3), the selection of conductive layer:
Conductive layer comprises 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-in wire second tack coat and lead finish on the electrically conductive, and interlayer increases inter-layer bonding force by rolling process, and electrode part does not need the second tack coat and protective layer, requires to prepare corresponding function layer according to difference;
(4), go between the selection of the second tack coat:
Be lead-in wire second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or crylic acid resin, and this layer thickness controls at 15 microns;
What front end electrode part needed naked leakage is not coated with this layer binder, and interlayer increases inter-layer bonding force by rolling process;
(5), the selection of protective layer:
Be polyimide insulative thin film outside lead-in wire second tack coat of rear end lead portion, protecting film first carries out cutting processing, exposes the Copper Foil of leading portion electrode area, contact conductor covered with protective film;
This layer thickness controls at 15 microns; Inter-layer bonding force is increased by rolling process;
(6), electrode part functional layer preparation:
Electrode part can be divided into working electrode, as required to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer on working electrode Copper Foil is composed as follows: inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, and by the method preparation of plating, sputtering, can select the inert metal of gold, platinum, this layer thickness is 15 microns;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by the mode of spraying, dipping, coating by enzyme layer, and dip time is 15 minutes;
Then by concentration be the glutaraldehyde solution of 20% by crosslinked fixing for the glucoseoxidase transferring to working electrode, crosslinking temperature is at 35 degrees Celsius, and adopt the crosslinked or gas phase of liquid impregnation to be cross-linked, crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows: in phosphate buffer, add glucoseoxidase and people's recombinant albumin, and glucoseoxidase addition is 100 milligrams every milliliter, and people's recombinant albumin addition is 100 milligrams every milliliter; Dissolve fully, add the nanometer gold mixing of 5%, finally add the PVB of 5%, PVB refers to polyvinyl butyral resin, mix homogeneously;
Nanometer gold utilizes in the reverse micelle system of AOT and cyclohexane extraction System forming to be prepared, AOT refers to amber glass acid di-isooctyl semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, regulate the concentration ratio of water, electrolyte, surfactant, prepare the nanogold particle of different-diameter, nanogold particle diameter is at 30nm;
After glucoseoxidase has been cross-linked, one deck polymeric membrane can be fixed by the mode of dipping, coating at electrode, to strengthen the biosensor organism compatibility, improve performance in body;
Because nanometer gold has good biocompatibility, in long period implant into body, and can not cause untoward reaction;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, shortens enzyme electrode to the glucose responding time, extending enzyme electrode life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH
2)
GOD(FADH
2)+O
2→GOD(FAD)+H
2O
2
glucose-lactone+H
2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH
2) less stable, changing than being easier to recurring structure, oxidizedly cannot become normality glucoseoxidase, this is one of common glucose oxidase electrode enzyme reason lost alive; And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can rapidly by reduction-state glucoseoxidase GOD (FADH
2) be oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state glucoseoxidase GOD (FADH in electrode process
2) quantity and life period, reduce loss of enzyme activity, extend electrode life; In addition nanogold particle adds and also increases substantially enzyme electrode and answer speed, shortens the enzyme electrode corresponding time, and signal delay when improving subcutaneous glucose sensor measurement, improves Real-Time Monitoring accuracy;
Macromolecule layer, in order to provide biocompatibility needed for sensor implant into body, improves performance in body; Can fix one deck polymeric membrane by the mode of dipping, coating at electrode, used macromolecular material is one or more mixing wherein of silastic polymer, polyurethane, polyurethane, Polyethylene Glycol; Solvent adopts dehydrated alcohol, oxolane, can be prepared by the mode of spraying, dipping, coating;
2., to electrode:
Comprise to inert metal layer, to Catalytic Layer, to macromolecule layer to the functional layer on electrode Copper Foil; Its preparation method and working electrode are substantially identical, do not need to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil comprises inert metal layer, Catalytic Layer, macromolecule layer; Its preparation method is identical with working electrode, does not need to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil comprises inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after prepared by inert metal layer, prepares silver/silver chloride layer, prepare silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination by the method for plating, vacuum sputtering;
After above-mentioned preparation technology completes, finally cut according to element circuit, obtain sensor, three electrodes and four electrode sensor sizes as follows: implant into body partial-length is not more than 15mm, is widely not more than 0.6mm, is thickly not more than 0.4mm;
Two electrode sizes are as follows: implant into body partial-length is not more than 15mm, are widely not more than 0.3mm, are thickly not more than 0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrode composition sensors, do not need to add nanometer gold in enzyme layer, blank electrode is used for detection background signal and interfering signal, improves sensor accuracy;
Two electrodes and three electrode sensors, preparation process need increase nanometer gold in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, then exit guide pin, sensor is stayed subcutaneous tissue and started working.
Claims (3)
1. a subcutaneous tissue insertion type glucose microsensor, it is characterized in that: comprise base (1), outward extending lead portion (2) is provided with in described base (1), the end of described lead portion (2) is connected with Sensor section (3), and described Sensor section (3) and lead portion (2) are located in insulated substrate (4) respectively;
Described Sensor section (3) comprises working electrode (5), reference electrode (6), to electrode (7) and blank electrode (8), 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, described left end electrode (7) being located to 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 reference electrode (6) interruption-like distribution, described to electrode (7) and blank electrode (8) interruption-like distribution, form four electrode systems,
Or,
Described Sensor section (3) comprises 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, described right-hand member electrode (7) being located to insulated substrate (4) end face, reference electrode (6) is provided with between the inwall of described working electrode (5) upper end and the inwall to electrode (7) upper end, described working electrode (5), to electrode (7) and reference electrode (6) interruption-like distribution, form three-electrode system;
Or,
Described Sensor section (3) comprises working electrode (5), reference electrode (6) and to electrode (7), 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, described left end electrode (7) being located to insulated substrate (4) back side, described working electrode (5) and reference electrode (6) interruption-like distribution, form three-electrode system;
Or,
Described Sensor section (3) comprises working electrode (5) and reference electrode (6), described working electrode (5) is located at the front of insulated substrate (4), described reference electrode (6) is located at the back side of insulated substrate (4), forms two electrode systems;
Described working electrode (5) comprises tack coat (9), described tack coat (9) overlays on the top of insulated substrate (4), the top of described tack coat (9) be covered with conductive layer (10), the top of described conductive layer (10) is covered with inert metal layer (11), the top of described inert metal layer (11) be covered with Catalytic Layer (12), the top of described 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 comprises reference electrode tack coat (15), 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), 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 with reference macromolecule layer (19);
Described comprises tack coat (20) to electrode, described tack coat (20) is located at the bottom of insulated substrate (4), the surface of described tack coat (20) is covered with conductive layer (21), the surface of described conductive layer (21) is covered with inert metal layer (22), the surface of described 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 blank electrode (8) comprises tack coat (25), described electrode adhesion layer (25) is located at the bottom of insulated substrate (4), the surface of described tack coat (25) is covered with conductive layer (26), the surface of described conductive layer (26) is covered with inert metal layer (27), the surface of described inert metal layer (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); described lead assemblies (30) comprises lead-in wire first tack coat (31) overlaying on insulated substrate (4) surface; the surface of described lead-in wire first tack coat (31) is covered with lead-in wire conductive layer (32); the surface of described lead-in wire conductive layer (32) is covered with lead-in wire second tack coat (33), and the surface of described lead-in wire second tack coat (33) is covered with lead finish (34).
2. subcutaneous tissue insertion type glucose microsensor according to claim 1, it is characterized in that: described lead assemblies (30) is provided with 4, lead assemblies (30) is located at the right-hand member of the left end of insulated substrate (4) upper surface, the right-hand member of insulated substrate (4) upper surface, the left end of insulated substrate (4) lower surface and insulated substrate (4) lower surface respectively, interruption-like distribution between each lead assemblies (30);
Or,
Described lead assemblies (30) is provided with 3, and 3 lead assemblies (30) are divided equally on an end face of insulated substrate (4);
Or,
Described lead assemblies (30) is provided with 3, wherein two lead assemblies (30) divide equally the upper surface in insulated substrate (4), and another lead assemblies (30) is located at the interposition of insulated substrate (4) upper surface;
Or,
Described lead assemblies (30) is provided with 2, a lead assemblies (30) is located at the interposition of insulated substrate (4) upper surface, and another lead assemblies (30) is located at the interposition of insulated substrate (4) lower surface.
3. the preparation method of subcutaneous tissue insertion type glucose microsensor according to claim 1 and 2, is characterized in that carrying out according to the following steps:
(1), the selection of insulated substrate:
The polyimide insulative thin film of insulated substrate employing deflection or mylar, as carrier, have good process based prediction model;
The high flexibility of writing music of tool, can three-dimensional wiring, changes shape according to space constraint; High-low temperature resistant, resistance to combustion; Collapsible and do not affect signal propagation function, can static interference be prevented; Chemical change is stablized, and stability, trustworthiness are high; Be beneficial to the design of Related product, assembly work and mistake can be reduced, and improve the service life of related products; Good insulating properties, specific insulation reaches 1015 Ω .cm; Excellent to the caking property of conventional matrix, metal and dielectric material; This layer thickness controls at 7.5-12.5 micron;
(2), tack coat material is selected:
Tack coat comprises each tack coat in Sensor section and lead portion;
The tow sides coating tack coat of insulated substrate, this layer of performance directly has influence on the performance of electrode, owing to there is chemical reaction in the fabrication process between binding agent and insulated substrate, therefore also should select corresponding binder system for different insulated substrate, the performance of binding agent must adapt with insulated substrate;
Tack coat used must can bear the erosion of various process conditions and chemical drugs used in the mill, the not phenomenon of layering or degraded, consider that human body is implanted binding agent and must be had good biocompatibility, tack coat adopts epoxy resin or crylic acid resin, and this layer thickness controls at 5-15 micron;
(3), the selection of conductive layer:
Conductive layer comprises 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 5-20 micron;
Lead portion needs to prepare lead-in wire second tack coat and lead finish on the electrically conductive, and interlayer increases inter-layer bonding force by rolling process, and electrode part does not need the second tack coat and protective layer, requires to prepare corresponding function layer according to difference;
(4), go between the selection of the second tack coat:
Be lead-in wire second tack coat outside the conductive layer of rear end lead portion, binding agent adopts epoxy resin or crylic acid resin, and this layer thickness controls at 5-15 micron;
What front end electrode part needed naked leakage is not coated with this layer binder, and interlayer increases inter-layer bonding force by rolling process;
(5), the selection of protective layer:
Be polyimide insulative thin film outside lead-in wire second tack coat of rear end lead portion, protecting film first carries out cutting processing, exposes the Copper Foil of leading portion electrode area, contact conductor covered with protective film;
This layer thickness controls at 5-15 micron; Inter-layer bonding force is increased by rolling process;
(6), electrode part functional layer preparation:
Electrode part can be divided into working electrode, as required to electrode, reference electrode, blank electrode;
1., working electrode:
Functional layer on working electrode Copper Foil is composed as follows: inert metal layer, Catalytic Layer, enzyme layer, macromolecule layer;
Inert metal layer is prepared on the Copper Foil of electrode area, and by the method preparation of plating, sputtering, can select the inert metal of gold, platinum, this layer thickness is 10-15 micron;
Catalytic Layer is platinum black, can be prepared by electro-plating method;
Enzymatic solution is transferred on working electrode by the mode of spraying, dipping, coating by enzyme layer, and dip time is 5-15 minute;
Then by concentration be the glutaraldehyde solution of 5%-20% by crosslinked fixing for the glucoseoxidase transferring to working electrode, crosslinking temperature is at 25-35 degree Celsius, and adopt the crosslinked or gas phase of liquid impregnation to be cross-linked, crosslinking time is 30-60min;
Enzymatic solution preparation process used is as follows: in phosphate buffer, add glucoseoxidase and people's recombinant albumin, and glucoseoxidase addition is every milliliter of 50-100 milligram, and people's recombinant albumin addition is every milliliter of 50-100 milligram; Dissolve fully, add the nanometer gold mixing of 1-5%, finally add the PVB of 1-5%, PVB refers to polyvinyl butyral resin, mix homogeneously;
Nanometer gold utilizes in the reverse micelle system of AOT and cyclohexane extraction System forming to be prepared, AOT refers to amber glass acid di-isooctyl semi-annular jade pendant acid sodium, by reduction of sodium citrate chloroaurate aqueous solution, regulate the concentration ratio of water, electrolyte, surfactant, prepare the nanogold particle of different-diameter, nanogold particle diameter is at 5-30nm;
After glucoseoxidase has been cross-linked, one deck polymeric membrane can be fixed by the mode of dipping, coating at electrode, to strengthen the biosensor organism compatibility, improve performance in body;
Because nanometer gold has good biocompatibility, in long period implant into body, and can not cause untoward reaction;
Nanometer gold has good electric conductivity, can improve the sensitivity of enzyme electrode, shortens enzyme electrode to the glucose responding time, extending enzyme electrode life;
The reaction of glucose oxidase electrode oxidizing glucose is made up of two step enzyme reactions:
D-glucose+GOD(FAD)→glucose-lactone+GOD(FADH
2)
GOD(FADH
2)+O
2→GOD(FAD)+H
2O
2
glucose-lactone+H
2O→glucose-acid
In said process, reduction-state glucoseoxidase GOD (FADH
2) less stable, changing than being easier to recurring structure, oxidizedly cannot become normality glucoseoxidase, this is one of common glucose oxidase electrode enzyme reason lost alive; And after enzyme layer adds nanogold particle, nanogold particle has the characteristic absorbing electronics from environment, can rapidly by reduction-state glucoseoxidase GOD (FADH
2) be oxidized to Steady state glucose oxidase GOD (FAD), reduce reduction-state glucoseoxidase GOD (FADH in electrode process
2) quantity and life period, reduce loss of enzyme activity, extend electrode life; In addition nanogold particle adds and also increases substantially enzyme electrode and answer speed, shortens the enzyme electrode corresponding time, and signal delay when improving subcutaneous glucose sensor measurement, improves Real-Time Monitoring accuracy;
Macromolecule layer, in order to provide biocompatibility needed for sensor implant into body, improves performance in body; Can fix one deck polymeric membrane by the mode of dipping, coating at electrode, used macromolecular material is one or more mixing wherein of silastic polymer, polyurethane, polyurethane, Polyethylene Glycol; Solvent adopts dehydrated alcohol, oxolane, can be prepared by the mode of spraying, dipping, coating;
2., to electrode:
Comprise to inert metal layer, to Catalytic Layer, to macromolecule layer to the functional layer on electrode Copper Foil; Its preparation method and working electrode are substantially identical, do not need to prepare enzyme layer;
3., blank electrode:
Functional layer on blank electrode Copper Foil comprises inert metal layer, Catalytic Layer, macromolecule layer; Its preparation method is identical with working electrode, does not need to prepare enzyme layer;
4., reference electrode:
Functional layer on reference electrode Copper Foil comprises inert metal layer, reference silver/silver chloride layer, macromolecule layer;
Inert metal layer preparation method is identical with working electrode, after prepared by inert metal layer, prepares silver/silver chloride layer, prepare silver/silver chloride layer, finally prepare macromolecule adventitia after electrochemistry chlorination by the method for plating, vacuum sputtering;
After above-mentioned preparation technology completes, finally cut according to element circuit, obtain sensor, three electrodes and four electrode sensor sizes as follows: implant into body partial-length is not more than 15mm, is widely not more than 0.6mm, is thickly not more than 0.4mm;
Two electrode sizes are as follows: implant into body partial-length is not more than 15mm, are widely not more than 0.3mm, are thickly not more than 0.4mm;
By above-mentioned working electrode, to electrode, reference electrode, blank electrode, four electrode composition sensors, do not need to add nanometer gold in enzyme layer, blank electrode is used for detection background signal and interfering signal, improves sensor accuracy;
Two electrodes and three electrode sensors, preparation process need increase nanometer gold in enzyme layer;
Sensor can be implanted subcutaneous by guide pin, then exit guide pin, sensor is stayed subcutaneous tissue and started working.
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