CN101530327A - Needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring and manufacturing method thereof - Google Patents
Needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring and manufacturing method thereof Download PDFInfo
- Publication number
- CN101530327A CN101530327A CN200910097842A CN200910097842A CN101530327A CN 101530327 A CN101530327 A CN 101530327A CN 200910097842 A CN200910097842 A CN 200910097842A CN 200910097842 A CN200910097842 A CN 200910097842A CN 101530327 A CN101530327 A CN 101530327A
- Authority
- CN
- China
- Prior art keywords
- layer
- needle
- macromolecular material
- silver
- glucose sensor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
Abstract
The invention discloses a needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring and manufacturing method thereof. The sensor comprises a needle reference electrode (2) and at least one needle working electrode (1) including a conducting layer (8) and an enzyme membrane layer (6), and is characterized in that the working electrode (1) further comprises a polymer material inner membrane layer (7) and a polymer material control diffusion layer (5), and the conducting layer (8), the polymer material inner membrane layer (7), the enzyme membrane layer (6) and the polymer material control diffusion layer (5) are coated in turn from inner to outside. According to the manufacturing method in the invention, the glucose sensor has good stability, high flexibility, wide linear range of output current and glucose concentration, short response time, continuous real-time monitoring, good fastness and stability of enzyme bonding, high flexibility, selectivity and repeatability.
Description
Technical field
The present invention relates to a kind of needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring and preparation method thereof, relate in particular to a kind of to be fixed with needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring of glucoseoxidase and preparation method thereof in needle-like formula reference electrode, the working electrode.
Background technology
First kind tradition blood sugar monitoring instrument is that the wound gauge is arranged, and its method is that finger tip is got blood measurement check.Second class is a non-invasive blood-sugar detecting instrument, comprises subcutaneous tissue interstitial fluid glucose detection instrument and spectrum analysis blood glucose meter.The 3rd class is the continous way blood sugar monitoring instrument, and the approval that the portable CGMS that is made by MiniMed company has obtained FDA is used for successive blood glucose measurement.This instrument adds a glucose sensor at the front end of fine needle head, implants subcutaneous tissue, utilizes the every 10s of contained glucoseoxidase to measure subcutaneous tissue and asks the consumption of oxygen in the liquid or the generation of hydroxyl ion, converts dextrose equivalent whereby to.Meansigma methods of the every 5min record of this instrument has 288 data every day altogether, and every recorder can store the data in 2 weeks continuously.Needed to hospital data to be downloaded in the common computer by infrared interface or RS232 serial ports every 3 days, just can make complete blood glucose figure and statistical value, its scope that can measure is 40～400mg/dl.The benefit of CGMS is can not influence daily life, 3 days blood glucose value can be made a continually varying curve, and button keeps a record when insulin injection, diet, motion or other accident, can't detected high/low blood glucose to remedy 1 day 4 times blood sugar monitorings institute, especially the hypoglycemia of asking midnight or moving period reaches hyperglycemia after the meal, and can open-and-shutly observe sunrise effect or hypoglycemia bounce-back, the doctor just can formulate the corresponding treatment scheme according to this.The shortcoming of CGMS is to provide real-time blood sugar measured to patient, and the doctor can only be provided data downloaded data afterwards.
Applied for that if any the people name is called the PCT application of " blood touch sensor ", international filing date is on 09 08th, 2005, and international open day is on 03 16th, 2006, and international application no is PCT/US2005/032102, and international publication number is WO/2006/029293.This device is specially adapted to pick off and directly touches in vivo blood.This device comprise a pick off can detect sample existence and assembly tool.Assembler has a sensor terminal, be fixed on the pick off, and assembly tool is to be fit to unite use with the Venous flow device.By uniting use with the Venous flow device, assembly tool blood direct pick off and in the Venous flow contacts.The Venous flow device makes the direct contact of pick off comprise the blood of some materials, but is not limited only to be used for venous duct and outside blood circulation, as is used for extra oxide-film or hemodialysis.
In the continuous blood sugar measuring system, glucose sensor is vital, also is a still unsolved now difficult problem, and many researchs all show: it is feasible being undertaken in the continuous monitoring of body glucose by implantable glucose sensor.Consider operating facility, safety and need the more practical situation of emat sensor, but the implantation of pick off should be chosen in the subcutaneous pick off that is used for implantable bioartificial body continuous measurement chemical constituent, and must satisfy its corresponding organism characteristic.These characteristics all bio-compatibility with pick off are relevant.Under the situation that has implant to implant, biological tissue or organ all can react and receptor response in a organized way, this has special selectivity with regard to meaning the chemical compound that pick off not only will have pair need to detect, and behind implanting tissue long relatively during in good stable arranged and be good response time properties the fast-changing power of test of measured object concentration.
Summary of the invention
The present invention is directed to the deficiency that glucose sensor bio-compatibility in the prior art is poor, its blood glucose value at that time can not be provided to user in real time, good needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring of a kind of bio-compatibility and preparation method thereof is provided.In order to solve the problems of the technologies described above, the present invention is solved by following technical proposals:
Needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring, comprise a needle-like formula reference electrode and at least one needle-like formula working electrode, working electrode comprises conductive layer and enzyme membrane layer, described working electrode also comprises macromolecular material theca interna and macromolecular material control diffusion layer, and conductive layer, macromolecular material theca interna, enzyme membrane layer and macromolecular material control diffusion layer cover successively from the inside to the outside and form.
The enzyme membrane layer contains glucoseoxidase and catalase, is one deck enzyme glue-line.The enzyme membrane layer can oxidizing glucose and hydrogen peroxide.
When needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring of the present invention adopts a plurality of working electrode, a plurality of working electrode parallel connections.One of them is as main working electrode, and main working electrode adopts optimal way to choose, and all the other working electrodes are the back work electrode.Working electrode and reference electrode constitute the loop and form electrochemical sensor.
Working electrode and reference electrode can be fixed by plastic feet, and plastic feet designs for circular arc, and the vertical base circular arc of electrode, wireless launcher embed in the base and with electrode and link to each other.The material of plastic feet can be any one material in polypropylene, poly-imines, polrvinyl chloride, polyethers, polyester, Merlon, polyethylene, polyamide, polyurethane, polrvinyl chloride, poly terephthalic acid butenylidene ester, polyethylene terephthalate, polyoxygenated benzene or the acrylonitrile-butadiene resin, preferably polyethylene.
As preferably, the conductive layer of working electrode is made of from inside to outside successively metallic matrix, intermediate metal, layer of precious metal.
As preferably, the material of the metallic matrix of the conductive layer of described working electrode can be any one of rustless steel, copper or titanium, preferred rustless steel;
The material of intermediate metal can be in titanium, nickel, gold, platinum, palladium, rhodium, iridium or the chromium any one, preferred palladium;
The material of layer of precious metal can be any one in palladium, rhodium, iridium, chromium or the platinum, preferred palladium and platinum.
Conductive layer need have enough rigidity, can thrust skin at an easy rate.
As preferably, the material of macromolecular material theca interna can be any one in poly terephthalic acid butenylidene ester, polyethylene terephthalate, polyoxygenated benzene, acrylonitrile-butadiene resin, silane resin, epoxy resin or the acetate fiber, according to the film forming characteristics of material on conductive layer, preferred epoxy and acetate fiber, consider that glucoseoxidase adopts cross-linking method to be linked on the macromolecular material theca interna, preferred especially acetate fiber;
The material of macromolecular material control diffusion layer can be any one in cellulose acetate, Merlon, polyvinyl alcohol, polyurethane, polyurethane, politef or the polrvinyl chloride, the polyurethane good biocompatibility, good filming performance is arranged, so optimization polyurethane;
The hydrophilic hydration layer of the many space lattices of macromolecular material control diffusion layer surface parcel one deck, material can be the chitosan of porous polyvinyl alcohol, Polyethylene Glycol, carboxylation, in carboxymethyl cellulose, hydroxyethyl-cellulose, low oligosaccharide or the dioxygen starch any one, preferred material is a porous polyethylene alcohol, the porous polyethylene alcohol of elite 60 μ m.
The effect of macromolecular material theca interna is to insulate and exclude the micromolecule chaff interference to comprise ascorbic acid and a spot of amino uric acid, bilirubin, catecholamine, medicine and other various metabolite, only allow hydrogen peroxide to enter aciculiform metal microelectrode surface, can reduce the electrochemistry of working electrode and disturb.
Glucoseoxidase is learned the response power of glucose, and only in lower concentration of glucose scope, glucoseoxidase is only linear response to the response of concentration of glucose.Thereby the present invention covers one deck macromolecular material control diffusion barrier at the enzyme membrane laminar surface.The macromolecular material control diffusion layer of working electrode has the selection permeability, make the glucose molecule diffusion in the blood see through this floor height molecular film arrival glucose oxidase film surface, reduce the diffusion velocity of glucose molecule, make the control procedure of the diffusion process of glucose molecule as entire reaction, concentration of glucose in the enzyme membrane remains in the lower concentration range, reaches the purpose that enlarges the range of linearity.
Macromolecular material control diffusion layer can stop the loss of enzyme, the selection impregnability can be slowed down the diffusion than macromole such as albumen etc., electrode interference can be reduced, the detection range of linearity of pick off can also be increased by the amount that the restriction glucose is diffused into working electrode.If the impregnability of this tunic oxygen greater than the impregnability of glucose, can also be improved the dependence of electrode pair oxygen.Macromolecular material control diffusion layer can filter macromole and cell, and entire reaction is played the DIFFUSION CONTROLLED effect.
If have the fibrous tissue of enriching vascularity on the glucose sensor surface, blood just can be easier to be diffused into the surface of glucose sensor, and then glucose sensor just can be measured the variation of blood-glucose preferably.This has just shortened the response time of glucose sensor, thereby reaches real-time monitoring.And if had abundant vascular tissue on glucose sensor surface, could make glucose sensor work can be under not gauged situation steady in a long-term.The fixing hydrophilic high molecular material layer of the many space lattices of one deck on the surface of glucose sensor, can promote the formation of neovascularity around pick off, thereby shortened the response time of glucose sensor, can also effectively increase the glucose and the oxygen concentration of glucose sensor surrounding tissue simultaneously.
As preferably, reference electrode is silver/silver chloride electrode, comprises three layers of conductive layer, silver/silver chloride layer and macromolecular material theca externas from inside to outside successively.
As preferably, the conductive layer of described reference electrode is made of from inside to outside successively metallic matrix and silver layer, and the material of metallic matrix can be any one in rustless steel, copper or the titanium, preferred rustless steel; The material of the macromolecular material theca externa of reference electrode can be any one in cellulose acetate, Merlon, polyvinyl alcohol, polyurethane, polyurethane, politef or the polrvinyl chloride, preferably polyethylene alcohol.
As preferably, the metallic matrix diameter R7 of the conductive layer of described working electrode is 0.15～0.25mm, preferred 0.2mm, and the metal base surface granular size is 30nm;
Metal transfer layer thickness R6 is 0.05 μ m～1 μ m, and granular size is 100nm;
Layer of precious metal thickness R5 is 1 μ m～3 μ m, and granular size is 30nm;
Enzyme membrane layer thickness R3 is 0.05 μ m～1 μ m;
Macromolecular material control thickness of diffusion layer R2 is 5 μ m～10 μ m.
The hydrophilic hydration layer of one deck space lattice of macromolecular material control diffusion layer surface parcel, its thickness R1 is 3 μ m～6 μ m.
The silver thickness R10 of reference electrode is 0.05 μ m～1 μ m, and silver-colored granular size is about 100nm.
The invention also discloses a kind of manufacture method of needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring:
The macromolecular material theca interna is combined in the surface of conductive layer by a kind of mode of coating or dipping, preferred coating process;
The enzyme membrane layer is with glutaraldehyde as cross linker, is carrier with bovine serum albumin or cyclodextrin or gelatin, by cross-linking method with covalent bond is legal is fixed on the macromolecular material theca interna surface;
Macromolecular material control diffusion layer adopts the mode of coating or dipping to be fixed on the enzyme membrane laminar surface, preferred coating process;
The conductive layer surface of working electrode carries out the surface active pretreatment with the oxonium ion etching method.Metal base surface at conductive layer deposits one deck gold layer as intermediate metal, the platinum black granule of the loose shape of gold electrode surfaces electro-deposition one deck, amboceptor and enzyme directly are adsorbed on the platinum black electrode surface, to satisfy the electrode requirement of electrochemical oxidation hydrogen peroxide under the physiological environment of pH=7.4.Platinum black porous microparticle has that specific surface area is big, electro-catalysis ability, good characteristic such as strong, the gold electrode of modifying through platinum black is in the enzyme immobilization process, utilize the particulate porosity characteristic of platinum black, the enzyme molecular energy is adsorbed on the platinum black electrode surface securely, by changing electro-deposition voltage, can control the size and the sedimentation of platinum black electrode specific surface area.Thereby platinum black provides enough big area to make electrode process be the control of glucose diffusion process, and Zhi Bei glucose sensor has the characteristics of little, the highly sensitive and high conformity of volume like this.The platinum black electrode surface energy of high loose shape effectively increases the signal to noise ratio of sensor current signal output, improves the hydrophilic of electrode surface, thereby reduces the enzyme loss.
Before the deposition platinum black, carry out pretreatment, can effectively improve the resistance to corrosion of electrode, reduce electrode impedance, strengthen the degree of cross linking of platinum black granule and gold electrode with the method counter electrode surface of physics or chemistry.The present invention adopts the method for oxygen rie that gold electrode surfaces is carried out pretreatment, can remove the pollutant of electrode surface, can also play the effect on activated electrode surface simultaneously.The condition of etching can be done suitable adjustment according to the situation of electrode surface, and electroplating voltage, sedimentation time and different electrolytes proportioning all will influence the thickness and the density of film.
The advantage of enzyme membrane layer combined techniques of the present invention is the bonded fastness of enzyme, good stability, sensitivity, selectivity and repeatability height.
The hydrophilic hydration layer of the many space lattices of macromolecular material control diffusion layer surface parcel one deck.
As preferably, the conductive layer of working electrode is made of from inside to outside successively metallic matrix, intermediate metal, layer of precious metal;
The intermediate metal of conductive layer can pass through any one method in chemical deposition, magnetron sputtering or the electro-plating method attached to metal base surface, preferred magnetically controlled sputter method;
The layer of precious metal of conductive layer can pass through any one method in chemical deposition, magnetron sputtering or the electro-plating method attached to the metal transfer laminar surface.
As preferably, reference electrode is silver/silver chloride electrode, comprises three layers of conductive layer, silver/silver chloride layer and macromolecular material theca externas from inside to outside successively; The conductive layer of reference electrode is made of from inside to outside successively metallic matrix and silver layer, and the material of metallic matrix can be any one in rustless steel, copper or the titanium;
The metal base surface of reference electrode crosses one deck silver by any one method in electro-plating method, chemical deposition or the magnetron sputtering method, and preferred electro-plating method carries out chlorination and forms silver/silver chloride layer, and granular size is 100nm;
The material of the macromolecular material theca externa of reference electrode can be any one in cellulose acetate, Merlon, polyvinyl alcohol, polyurethane, polyurethane, politef or the polrvinyl chloride;
The macromolecular material theca externa of reference electrode is fixed on silver/silver chloride layer surface by any one method in coating or the dipping.
According to glucoseoxidase the response power of glucose is learned, only in lower concentration of glucose scope, glucoseoxidase is only linear response to the response of concentration of glucose.Thereby the present invention covers one deck macromolecular material control diffusion layer in glucose oxidase layer.Macromolecular material control diffusion layer makes the glucose molecule diffusion in the blood see through the macromolecule membrane arrival glucose oxidase layer surface that this layer has the selection permeability, thereby reduce the diffusion velocity of glucose molecule, make the control procedure of the diffusion process of glucose molecule as entire reaction, concentration of glucose in the glucose oxidase layer remains in the lower concentration range, reaches the purpose that enlarges the range of linearity.
According to clinical requirement, the glucose sensor range of linearity upper limit must reach 30mmol.Under this upper limit, the analytical characteristics of pick off such as sensitivity, linear zone etc., stability is by the thickness and the preparation method decision of macromolecular material control diffusion barrier.The glucose sensor of the present invention range of linearity upper limit reaches more than the 30mmol.
The present invention can be used for the detection of human body or animal skins undertissue liquid glucose, and implant site is that subcutaneous tissue can be arm or abdominal part position, and preferred implant site is a subcutaneous tissue of abdomen.Glucose sensor continuous operation of the present invention is no less than 72 hours.
Implanted tester is subcutaneous for detecting head of the present invention, glucose in the subcutaneous intercellular fluid of tester carries out dialysis the working sensor electrode surface by semipermeable membrane, carry out dialysis working sensor electrode surface glucose and enzyme and react, the signal of telecommunication reflection tissue liquid glucose level of generation.
The decay of implanting the back transducer sensitivity is relevant with the structure of pick off, and subject matter is that the catalytic reaction of enzyme when hypoxgia is suppressed the electrochemistry interference with some little endogenous molecules.The problem of hypoxgia can reduce the area of enzyme reaction by the infiltration area that relatively increases oxygen, uses the film of high-solubility oxygen or use the hydrophobicity outer membrane optionally to reduce glucose to be diffused in the enzyme membrane layer and to solve.Electrochemistry is disturbed can have optionally that film and non-conductive polymeric membrane solve by use.
According to manufacture method of the present invention, but the range of linearity of glucose sensor good stability, susceptiveness height, output current and concentration of glucose is extensive, the short continuous real-time monitoring of response time, the bonded fastness of enzyme, good stability, sensitivity, selectivity and repeatability height.
Description of drawings
Fig. 1 is the glucose sensor structural representation.
Fig. 2 is the vertical view of Fig. 1.
Fig. 3 is the amplification view of work electricity level.
Fig. 4 is the amplification view with reference to the electricity level.
Fig. 5 is the glucose solution test result figure of glucose sensor at external phosphate-buffered reagent.
The current value of Fig. 6 for using glucose sensor of the present invention to measure in real time continuously.
The specific embodiment
Below in conjunction with the accompanying drawing and the specific embodiment the present invention is described in further detail:
Working electrode 1 and reference electrode 2 can pass through plastic feet 3, and the fixed wireless discharger embeds in the plastic feet 3 and with working electrode 1 and links to each other with reference electrode 2.
In the present embodiment:
The metallic matrix 83 material selection rustless steels of conductive layer 8;
The intermediate metal 82 material selection palladiums of conductive layer 8;
The layer of precious metal 81 material selection palladiums of conductive layer 8;
The material selection acetate fiber of macromolecular material theca interna 7;
The material selection polyurethane of macromolecular material control diffusion layer 5;
The hydrophilic hydration layer 4 of one deck space lattice of macromolecular material control diffusion layer 5 surface parcels, the porous polyethylene alcohol of hydrophilic hydration layer 4 material selection 60 μ m;
The material of plastic feet 3 is a polyethylene;
Wherein 9 is the centrage of pick off.
According to 8 identical glucose sensors of following thickness R parameter preparation.
| Parameter | |
|
Layer of precious metal 81 | Macromolecular |
|
| Thickness (R) | R7＝200μm | R6＝0.05μm | R5＝1μm | R4＝3μm | R3＝0.05μm |
| Parameter | Macromolecular material |
Hydrophilic hydration layer 4 | |
|
Macromolecular material theca externa 10 |
| Thickness (R) | R2＝5μm | R1＝3μm | R11＝200μm | R10＝0.05μm | R8＝5μm |
Show 1:8 glucose sensor dimensional parameters table
These 8 glucose sensors are in the glucose solution test of external phosphate-buffered reagent, and test voltage both positive and negative polarity voltage difference is 0.55V, and test result is as follows:
| Concentration of glucose (mmol/L) | Pick off 1 | Pick off 2 | Pick off 3 | Pick off 4 | Pick off 5 | Pick off 6 | Pick off 7 | Pick off 8 |
| 0 | 37 | 30 | 30 | 33 | 30 | 35 | 31 | 31 |
| 5 | 150 | 145 | 147 | 143 | 143 | 149 | 141 | 141 |
| 10 | 263 | 260 | 267 | 255 | 255 | 276 | 256 | 257 |
| 15 | 373 | 378 | 388 | 364 | 373 | 404 | 373 | 378 |
| 20 | 490 | 497 | 508 | 475 | 488 | 529 | 493 | 498 |
| 25 | 603 | 611 | 626 | 585 | 602 | 653 | 605 | 610 |
| 30 | 708 | 715 | 744 | 697 | 709 | 771 | 710 | 713 |
| Linear (%) | 99.996 | 99.997 | 99.998 | 99.999 | 99.996 | 99.979 | 99.987 | 99.982 |
Show the glucose solution table with test results (unit: nA) of 2:8 pick off at external phosphate-buffered reagent
Guaranteeing under the clinical service condition that the linear test of glucose sensor glucose of the present invention is greater than 30mmol/L, linearity reaches 99.9%, and sensitivity is greater than 25nA/ (mmol/L), and sensitivity is better; The performance unanimity of each pick off, stable.
The layer of precious metal 81 material selection platinum of conductive layer 8;
The material selection epoxy resin of macromolecular material theca interna 7;
Also prepare 8 identical glucose sensors (being that pick off 9 is to pick off 16) according to following thickness R.
| Parameter | |
|
Layer of precious metal 81 | Macromolecular |
|
| Thickness (R) | R7＝250μμm | R6＝1μm | R5＝3μm | R4＝3μm | R3＝1μm |
| Parameter | Macromolecular material |
Hydrophilic hydration layer 4 | |
|
Macromolecular material theca externa 10 |
| Thickness (R) | R2＝10μm | R1＝6μm | R11＝250μm | R10＝1μm | R8＝10μm |
Table 3: pick off 9 is to the dimensional parameters table of pick off 16
These 7 glucose sensors are in the glucose solution test of external phosphate-buffered reagent, and test voltage both positive and negative polarity voltage difference is 0.55V, and test result is as follows:
| Concentration of glucose (mmol/L) | Pick off 9 | Pick off 10 | Pick off 11 | Pick off 12 | Pick off 13 | Pick off 14 | Pick off 15 | Pick off 16 |
| 0 | 36 | 30 | 31 | 32 | 31 | 33 | 31 | 30 |
| 5 | 149 | 143 | 148 | 144 | 144 | 147 | 140 | 142 |
| 10 | 263 | 260 | 268 | 254 | 256 | 275 | 255 | 258 |
| 15 | 372 | 377 | 389 | 364 | 374 | 402 | 372 | 377 |
| 20 | 489 | 496 | 509 | 474 | 489 | 528 | 492 | 497 |
| 25 | 602 | 610 | 627 | 584 | 603 | 652 | 604 | 610 |
| 30 | 707 | 713 | 745 | 696 | 711 | 770 | 710 | 713 |
| Linear (%) | 99.994 | 99.987 | 99.998 | 99.994 | 99.991 | 99.979 | 99.987 | 99.980 |
Show the glucose solution table with test results (unit: nA) of 4:8 pick off at external phosphate-buffered reagent
Guaranteeing under the clinical service condition that the linear test of glucose sensor glucose of the present invention is greater than 27mmol/L, the linearity test height of reaching the standard grade, linearity reaches 99.9%; Sensitivity is 28nA/ (mmol/L), and sensitivity is better; The performance unanimity of each pick off, stable.
The conductive layer 8 of working electrode 1 is made of from inside to outside successively metallic matrix 83, intermediate metal 82, layer of precious metal 81.
Layer of precious metal 81 by electro-plating method attached to intermediate metal 82 surfaces;
Macromolecular material theca interna 7 is combined in the surface of conductive layer 8 by the mode of coating;
Macromolecular material control diffusion layer 5 adopts the mode of coating to be fixed on enzyme membrane layer 6 surface;
One deck silver is crossed by the electro-plating method method in metallic matrix 122 surfaces of reference electrode 2, carries out chlorination and forms silver/silver chloride layer 11, and granular size is 100nm;
Macromolecular material theca externa 10 is fixed on silver/silver chloride layer 11 surfaces by coating process.
Pick off with this method preparation can reach embodiment 1 described effect.
Embodiment 4, make the method for the needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring of embodiment 2: as different from Example 3: enzyme membrane layer 6 is with glutaraldehyde as cross linker, with the gelatin is carrier, by cross-linking method with covalent bond is legal is fixed on macromolecular material theca interna 7 surfaces;
Macromolecular material control diffusion layer 5 adopts the mode of dipping to be fixed on enzyme membrane layer 6 surface;
Other step is identical with embodiment 3, and the pick off for preparing with this method can reach embodiment 2 described effects.
In a word, the above only is preferred embodiment of the present invention, and all equalizations of being done according to the present patent application claim change and modify, and all should belong to the covering scope of patent of the present invention.
Claims (10)
1. needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring, comprise a needle-like formula reference electrode (2) and at least one needle-like formula working electrode (1), working electrode (1) comprises conductive layer (8) and enzyme membrane layer (6), it is characterized in that: described working electrode (1) also comprises macromolecular material theca interna (7) and macromolecular material control diffusion layer (5), and conductive layer (8), macromolecular material theca interna (7), enzyme membrane layer (6) and macromolecular material control diffusion layer (5) cover successively from the inside to the outside and form.
2. needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring according to claim 1 is characterized in that: the conductive layer (8) of working electrode (1) is made of from inside to outside successively metallic matrix (83), intermediate metal (82), layer of precious metal (81).
3. needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring according to claim 2 is characterized in that:
The material of the metallic matrix (83) of (1) conductive layer (8) of described working electrode can be any one of rustless steel, copper or titanium;
The material of intermediate metal (82) can be in titanium, nickel, gold, platinum, palladium, rhodium, iridium or the chromium any one;
The material of layer of precious metal (81) can be any one in palladium, rhodium, iridium, chromium or the platinum.
4. needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring according to claim 1 is characterized in that:
The material of macromolecular material theca interna (7) can be any one in poly terephthalic acid butenylidene ester, polyethylene terephthalate, polyoxygenated benzene, acrylonitrile-butadiene resin, silane resin, epoxy resin or the acetate fiber;
The material of macromolecular material control diffusion layer (5) can be any one in cellulose acetate, Merlon, polyvinyl alcohol, polyurethane, polyurethane, politef or the polrvinyl chloride;
The hydrophilic hydration layer (4) of the many space lattices of macromolecular material control diffusion layer (5) surface parcel one deck, material can be the chitosan of porous polyvinyl alcohol, Polyethylene Glycol, carboxylation, any one in carboxymethyl cellulose, hydroxyethyl-cellulose, low oligosaccharide or the dioxygen starch.
5. needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring according to claim 1, it is characterized in that: reference electrode (2) is for silver/silver chloride electrode, comprises (10) three layers of conductive layer (12), silver/silver chloride layer (11) and macromolecular material theca externas from inside to outside successively.
6. needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring according to claim 5 is characterized in that:
The conductive layer (12) of described reference electrode (2) is made of from inside to outside successively metallic matrix (122) and silver layer (121), and the material of metallic matrix (122) can be any one in rustless steel, copper or the titanium;
The material of the macromolecular material theca externa (10) of reference electrode (2) can be any one in cellulose acetate, Merlon, polyvinyl alcohol, polyurethane, polyurethane, politef or the polrvinyl chloride.
7. needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring according to claim 1 is characterized in that:
Metallic matrix (83) the diameter R7 of the conductive layer (8) of described working electrode (1) is 0.15～0.25mm;
Intermediate metal (82) thickness R6 is 0.05 μ m～1 μ m, and granular size is 100nm;
Layer of precious metal (81) thickness R5 is 1 μ m～3 μ m, and granular size is 30nm;
Enzyme membrane layer (6) thickness R3 is 0.05 μ m～1 μ m;
Macromolecular material control diffusion layer (5) thickness R2 is 5 μ m～10 μ m;
Silver layer (121) the thickness R10 of reference electrode (2) is 0.05 μ m～1 μ m, and silver-colored granular size is about 100nm.
8. make the method for the described needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring of claim 1, it is characterized in that:
Macromolecular material theca interna (7) is combined in the surface of conductive layer (8) by a kind of mode of coating or dipping;
Enzyme membrane layer (6) is with glutaraldehyde as cross linker, is carrier with bovine serum albumin or cyclodextrin or gelatin, by cross-linking method with covalent bond is legal is fixed on macromolecular material theca interna (7) surface;
Macromolecular material control diffusion layer (5) adopts the mode of coating or dipping to be fixed on enzyme membrane layer (6) surface.
9. the manufacture method of needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring according to claim 8 is characterized in that:
The conductive layer (8) of working electrode (1) is made of from inside to outside successively metallic matrix (83), intermediate metal (82), layer of precious metal (81);
The layer of precious metal (81) of conductive layer (8) can pass through any one method in chemical deposition, magnetron sputtering or the electro-plating method attached to intermediate metal (82) surface;
The intermediate metal (82) of conductive layer (8) can pass through any one method in chemical deposition, magnetron sputtering or the electro-plating method attached to metallic matrix (83) surface.
10. the manufacture method of needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring according to claim 8 is characterized in that:
Reference electrode (2) is silver/silver chloride electrode, comprises (10) three layers of conductive layer (12), silver/silver chloride layer (11) and macromolecular material theca externas from inside to outside successively;
The conductive layer (12) of described reference electrode (2) is made of from inside to outside successively metallic matrix (122) and silver layer (121), and the material of metallic matrix (122) can be any one in rustless steel, copper or the titanium;
One deck silver is crossed by any one method in electro-plating method, chemical deposition or the magnetron sputtering method in metallic matrix (122) surface of reference electrode (2), carries out chlorination and forms silver/silver chloride layer (11), and granular size is 100nm;
The material of the macromolecular material theca externa (10) of reference electrode (2) can be any one in cellulose acetate, Merlon, polyvinyl alcohol, polyurethane, polyurethane, politef or the polrvinyl chloride;
The macromolecular material theca externa (10) of reference electrode (2) is fixed on silver/silver chloride layer (11) surface by any one method in coating or the dipping.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910097842A CN101530327B (en) | 2009-04-20 | 2009-04-20 | Needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring and manufacturing method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910097842A CN101530327B (en) | 2009-04-20 | 2009-04-20 | Needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring and manufacturing method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101530327A true CN101530327A (en) | 2009-09-16 |
| CN101530327B CN101530327B (en) | 2012-09-05 |
Family
ID=41101337
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910097842A Active CN101530327B (en) | 2009-04-20 | 2009-04-20 | Needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring and manufacturing method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101530327B (en) |
Cited By (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102178513A (en) * | 2011-05-05 | 2011-09-14 | 长沙三诺生物传感技术股份有限公司 | Sandwich type biological sensor |
| CN102920465A (en) * | 2012-10-26 | 2013-02-13 | 浙江大学 | Glucose sensor |
| CN102939539A (en) * | 2010-02-19 | 2013-02-20 | 灯船医药有限公司 | Subcutaneous glucose sensor |
| CN103519828A (en) * | 2013-11-04 | 2014-01-22 | 李秀 | Analyte detection system and sensing label thereof |
| CN105073001A (en) * | 2012-12-06 | 2015-11-18 | 美敦力迷你迈德公司 | Microarray electrodes useful with analyte sensors and methods for making and using them |
| CN105943058A (en) * | 2016-05-19 | 2016-09-21 | 杭州宇壳科技有限公司 | Flexible electrochemical electrode, continuous glucose monitoring sensor and preparation method thereof |
| CN105997061A (en) * | 2016-05-17 | 2016-10-12 | 段晏文 | Bio-electricity signal collecting device |
| CN106983951A (en) * | 2017-05-04 | 2017-07-28 | 梁曦 | A kind of analyte monitoring and automatic chemical feeding system |
| WO2017198116A1 (en) * | 2016-05-19 | 2017-11-23 | 杭州志宗生物科技有限公司 | Electrochemical electrode, continuous glucose monitoring sensor and preparation method therefor |
| CN107620098A (en) * | 2017-08-23 | 2018-01-23 | 河南航天精工制造有限公司 | A kind of steel alloy plating silverware and preparation method thereof |
| CN108169466A (en) * | 2012-06-08 | 2018-06-15 | 美敦力迷你迈德公司 | Application of the electrochemical impedance spectroscopy in sensing system, equipment and associated method |
| CN109406589A (en) * | 2018-11-23 | 2019-03-01 | 浙江大学 | A kind of implanted blood sugar test probe and its production method based on silk-screen printing |
| CN109689881A (en) * | 2016-09-16 | 2019-04-26 | 伊士曼化工公司 | The biological sensor electrode prepared by physical vapour deposition (PVD) |
| CN109781989A (en) * | 2017-11-10 | 2019-05-21 | 上海瀚联医疗技术股份有限公司 | The method and biosensor of blood sugar test |
| CN111248924A (en) * | 2019-06-24 | 2020-06-09 | 深圳硅基传感科技有限公司 | Working electrode of glucose monitoring probe and manufacturing method thereof |
| CN111307901A (en) * | 2019-08-20 | 2020-06-19 | 深圳硅基传感科技有限公司 | Preparation method of working electrode of glucose sensor |
| CN111307906A (en) * | 2017-12-29 | 2020-06-19 | 深圳硅基传感科技有限公司 | Analyte monitoring probe |
| CN111803086A (en) * | 2020-07-24 | 2020-10-23 | 湖州美奇医疗器械有限公司 | Three-electrode subcutaneous implanted glucose sensor and manufacturing method thereof |
| CN111896587A (en) * | 2020-08-12 | 2020-11-06 | 湖州美奇医疗器械有限公司 | Blood glucose monitoring sensor test fixture |
| CN113030219A (en) * | 2021-05-24 | 2021-06-25 | 广州新诚生物科技有限公司 | Continuous glucose monitoring sensor and application thereof |
| CN113083647A (en) * | 2019-12-23 | 2021-07-09 | 浙江荷清柔性电子技术有限公司 | Polymer diffusion-limiting membrane layer, preparation method thereof and glucose sensor |
| CN114280126A (en) * | 2021-12-28 | 2022-04-05 | 杭州电子科技大学 | Enzyme-free sensor for measuring tear glucose concentration and detection method |
| WO2022081034A1 (en) * | 2020-10-13 | 2022-04-21 | Qatar University | Sensors for detection of under deposit corrosion and methods of preparing same |
| CN114778628A (en) * | 2022-04-25 | 2022-07-22 | 北京怡成生物电子技术股份有限公司 | Flexible working electrode and enzyme sensor |
| US11630075B2 (en) | 2016-09-16 | 2023-04-18 | Eastman Chemical Company | Biosensor electrodes prepared by physical vapor deposition |
| CN116269363A (en) * | 2023-05-09 | 2023-06-23 | 北京中器华康科技发展有限公司 | Glucose sensor with reaction cavity structure and capable of being used for subcutaneous detection |
| US11835481B2 (en) | 2016-06-15 | 2023-12-05 | Eastman Chemical Company | Physical vapor deposited biosensor components |
| US11881549B2 (en) | 2017-06-22 | 2024-01-23 | Eastman Chemical Company | Physical vapor deposited electrode for electrochemical sensors |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU94044169A (en) * | 1994-12-16 | 1996-10-20 | И.А. Кочетов | Multiple analytical member |
| CN1277116C (en) * | 2004-03-22 | 2006-09-27 | 南开大学 | Biological enzyme electrode for biosensor, and its prepn. method |
| CN100367906C (en) * | 2004-12-08 | 2008-02-13 | 圣美迪诺医疗科技(湖州)有限公司 | Endermic implantating biological sensors |
-
2009
- 2009-04-20 CN CN200910097842A patent/CN101530327B/en active Active
Cited By (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102939539A (en) * | 2010-02-19 | 2013-02-20 | 灯船医药有限公司 | Subcutaneous glucose sensor |
| CN102178513B (en) * | 2011-05-05 | 2013-02-27 | 长沙三诺生物传感技术股份有限公司 | Sandwich type biological sensor |
| CN102178513A (en) * | 2011-05-05 | 2011-09-14 | 长沙三诺生物传感技术股份有限公司 | Sandwich type biological sensor |
| US10905365B2 (en) | 2012-06-08 | 2021-02-02 | Medtronic Minimed, Inc. | Application of electrochemical impedance spectroscopy in sensor systems, devices, and related methods |
| US11234624B2 (en) | 2012-06-08 | 2022-02-01 | Medtronic Minimed, Inc. | Application of electrochemical impedance spectroscopy in sensor systems, devices, and related methods |
| US11160477B2 (en) | 2012-06-08 | 2021-11-02 | Medtronic Minimed, Inc. | Application of electrochemical impedance spectroscopy in sensor systems, devices, and related methods |
| CN108169466A (en) * | 2012-06-08 | 2018-06-15 | 美敦力迷你迈德公司 | Application of the electrochemical impedance spectroscopy in sensing system, equipment and associated method |
| US10660555B2 (en) | 2012-06-08 | 2020-05-26 | Medtronic Minimed, Inc. | Application of electrochemical impedance spectroscopy in sensor systems, devices, and related methods |
| CN108169466B (en) * | 2012-06-08 | 2020-05-05 | 美敦力迷你迈德公司 | Use of electrochemical impedance spectroscopy in sensor systems, devices, and related methods |
| CN102920465A (en) * | 2012-10-26 | 2013-02-13 | 浙江大学 | Glucose sensor |
| CN105073001A (en) * | 2012-12-06 | 2015-11-18 | 美敦力迷你迈德公司 | Microarray electrodes useful with analyte sensors and methods for making and using them |
| CN103519828A (en) * | 2013-11-04 | 2014-01-22 | 李秀 | Analyte detection system and sensing label thereof |
| CN103519828B (en) * | 2013-11-04 | 2015-04-29 | 理康互联科技(北京)有限公司 | Analyte detection system and sensing label thereof |
| CN105997061B (en) * | 2016-05-17 | 2020-11-24 | 段晏文 | Bioelectric signal acquisition device |
| CN105997061A (en) * | 2016-05-17 | 2016-10-12 | 段晏文 | Bio-electricity signal collecting device |
| WO2017198116A1 (en) * | 2016-05-19 | 2017-11-23 | 杭州志宗生物科技有限公司 | Electrochemical electrode, continuous glucose monitoring sensor and preparation method therefor |
| CN105943058B (en) * | 2016-05-19 | 2019-02-05 | 浙江大学 | Flexible electrochemical electrode, continuous glucose monitoring sensor and preparation method thereof |
| CN105943058A (en) * | 2016-05-19 | 2016-09-21 | 杭州宇壳科技有限公司 | Flexible electrochemical electrode, continuous glucose monitoring sensor and preparation method thereof |
| US11835481B2 (en) | 2016-06-15 | 2023-12-05 | Eastman Chemical Company | Physical vapor deposited biosensor components |
| CN109689881A (en) * | 2016-09-16 | 2019-04-26 | 伊士曼化工公司 | The biological sensor electrode prepared by physical vapour deposition (PVD) |
| US11624723B2 (en) | 2016-09-16 | 2023-04-11 | Eastman Chemical Company | Biosensor electrodes prepared by physical vapor deposition |
| US11630075B2 (en) | 2016-09-16 | 2023-04-18 | Eastman Chemical Company | Biosensor electrodes prepared by physical vapor deposition |
| CN106983951A (en) * | 2017-05-04 | 2017-07-28 | 梁曦 | A kind of analyte monitoring and automatic chemical feeding system |
| US11881549B2 (en) | 2017-06-22 | 2024-01-23 | Eastman Chemical Company | Physical vapor deposited electrode for electrochemical sensors |
| CN107620098A (en) * | 2017-08-23 | 2018-01-23 | 河南航天精工制造有限公司 | A kind of steel alloy plating silverware and preparation method thereof |
| CN109781989A (en) * | 2017-11-10 | 2019-05-21 | 上海瀚联医疗技术股份有限公司 | The method and biosensor of blood sugar test |
| CN111307906B (en) * | 2017-12-29 | 2022-01-11 | 深圳硅基传感科技有限公司 | Analyte monitoring probe |
| CN111307906A (en) * | 2017-12-29 | 2020-06-19 | 深圳硅基传感科技有限公司 | Analyte monitoring probe |
| CN112964770A (en) * | 2017-12-29 | 2021-06-15 | 深圳硅基传感科技有限公司 | Glucose monitoring probe and glucose monitor |
| CN109406589A (en) * | 2018-11-23 | 2019-03-01 | 浙江大学 | A kind of implanted blood sugar test probe and its production method based on silk-screen printing |
| CN109406589B (en) * | 2018-11-23 | 2023-07-21 | 浙江大学 | Implantable blood glucose test probe and manufacturing method thereof based on screen printing |
| CN111248924A (en) * | 2019-06-24 | 2020-06-09 | 深圳硅基传感科技有限公司 | Working electrode of glucose monitoring probe and manufacturing method thereof |
| CN111307901B (en) * | 2019-08-20 | 2024-02-20 | 深圳硅基传感科技有限公司 | Method for preparing working electrode of glucose sensor |
| CN111307901A (en) * | 2019-08-20 | 2020-06-19 | 深圳硅基传感科技有限公司 | Preparation method of working electrode of glucose sensor |
| CN113083647A (en) * | 2019-12-23 | 2021-07-09 | 浙江荷清柔性电子技术有限公司 | Polymer diffusion-limiting membrane layer, preparation method thereof and glucose sensor |
| CN113083647B (en) * | 2019-12-23 | 2023-06-27 | 浙江荷清柔性电子技术有限公司 | Polymer diffusion limiting membrane layer, preparation method thereof and glucose sensor |
| CN111803086A (en) * | 2020-07-24 | 2020-10-23 | 湖州美奇医疗器械有限公司 | Three-electrode subcutaneous implanted glucose sensor and manufacturing method thereof |
| CN111896587A (en) * | 2020-08-12 | 2020-11-06 | 湖州美奇医疗器械有限公司 | Blood glucose monitoring sensor test fixture |
| WO2022081034A1 (en) * | 2020-10-13 | 2022-04-21 | Qatar University | Sensors for detection of under deposit corrosion and methods of preparing same |
| CN113030219A (en) * | 2021-05-24 | 2021-06-25 | 广州新诚生物科技有限公司 | Continuous glucose monitoring sensor and application thereof |
| CN114280126B (en) * | 2021-12-28 | 2023-09-26 | 杭州电子科技大学 | Enzyme-free sensor for measuring tear glucose concentration and detection method |
| CN114280126A (en) * | 2021-12-28 | 2022-04-05 | 杭州电子科技大学 | Enzyme-free sensor for measuring tear glucose concentration and detection method |
| CN114778628A (en) * | 2022-04-25 | 2022-07-22 | 北京怡成生物电子技术股份有限公司 | Flexible working electrode and enzyme sensor |
| CN116269363A (en) * | 2023-05-09 | 2023-06-23 | 北京中器华康科技发展有限公司 | Glucose sensor with reaction cavity structure and capable of being used for subcutaneous detection |
| CN116269363B (en) * | 2023-05-09 | 2024-03-08 | 北京中器华康科技发展有限公司 | Glucose sensor with reaction cavity structure and capable of being used for subcutaneous detection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101530327B (en) | 2012-09-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101530327B (en) | Needle amperometric determination type glucose sensor for subcutaneous tissue real-time monitoring and manufacturing method thereof | |
| EP1841363B1 (en) | Catheter-free implantable needle biosensor | |
| US10772540B2 (en) | Microarray electrodes useful with analyte sensors and methods for making and using them | |
| CN111248924B (en) | Working electrode of glucose monitoring probe and manufacturing method thereof | |
| Alcock et al. | Continuous analyte monitoring to aid clinical practice | |
| EP2190502B1 (en) | Combined sensor and infusion set using separated sites | |
| KR101433550B1 (en) | Transdermal analyte monitoring system and method for analyte detection | |
| CN102686159B (en) | Multi-conductor lead configurations useful with medical device systems and methods for making and using them | |
| CN105307567B (en) | It is electroplated to reduce glucose sensor oxygen and respond and reduce electrode edge using pulse current and grow | |
| TW201010670A (en) | Electrode system for measuring an analyte concentration under in-vivo conditions | |
| KR20140082642A (en) | Tissue implantable sensor with hermetically sealed housing | |
| CA3088417A1 (en) | Multilayer electrochemical analyte sensors and methods for making and using them | |
| Zou et al. | Minimally invasive electrochemical continuous glucose monitoring sensors: Recent progress and perspective | |
| Cha et al. | Compatibility of nitric oxide release with implantable enzymatic glucose sensors based on osmium (III/II) mediated electrochemistry | |
| CN101530328A (en) | Hypodermic glucose sensor and making method thereof | |
| CN111307906B (en) | Analyte monitoring probe | |
| Voskerician et al. | Electrochemical characterization and in vivo biocompatibility of a thick-film printed sensor for continuous in vivo monitoring | |
| CN107296614A (en) | Blood sugar monitor based on biocompatibility electrode | |
| CN117647571A (en) | Electrochemical biosensor electrode suitable for analyte detection and preparation method thereof | |
| Frost et al. | In vivo sensors for continuous monitoring of blood gases, glucose, and lactate: biocompatibility challenges and potential solutions | |
| Majdinasab | Wearable Electrochemical Biosensors for Glucose Monitoring | |
| CN116649970A (en) | Sensor for monitoring lactic acid and preparation method thereof | |
| CN115644866A (en) | Application of SEBS (styrene-ethylene-butylene-styrene) as implantable bioelectrode substrate and implantable bioelectrode |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: HUZHOU MEIQI MEDICAL EQUIPMENT CO., LTD. Free format text: FORMER OWNER: HUZHOU AIMIQI BIOTECHNOLOGY CONSULTING SERVICES LTD. Effective date: 20111212 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20111212 Address after: 313000 Zhejiang city of Huzhou Province Hangzhou North Bridge Road No. 399 Nuclear Industrial Park No. 3 Building 4 floor Applicant after: HUZHOU MEIQI MEDICAL EQUIPMENT CO., LTD. Address before: Nuclear Industrial Park No. 399 313000 Zhejiang city of Huzhou Province Hangzhou Road No. 3 Building 4 layer Applicant before: Huzhou Aimiqi Biotechnology Consulting Services Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |