WO2022228025A1 - 植入式葡萄糖生物传感器及其制备方法 - Google Patents
植入式葡萄糖生物传感器及其制备方法 Download PDFInfo
- Publication number
- WO2022228025A1 WO2022228025A1 PCT/CN2022/084451 CN2022084451W WO2022228025A1 WO 2022228025 A1 WO2022228025 A1 WO 2022228025A1 CN 2022084451 W CN2022084451 W CN 2022084451W WO 2022228025 A1 WO2022228025 A1 WO 2022228025A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- glucose
- glucose oxidase
- implantable
- solution
- oxidase
- Prior art date
Links
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 title claims abstract description 118
- 239000008103 glucose Substances 0.000 title claims abstract description 118
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000004366 Glucose oxidase Substances 0.000 claims abstract description 80
- 108010015776 Glucose oxidase Proteins 0.000 claims abstract description 80
- 229940116332 glucose oxidase Drugs 0.000 claims abstract description 80
- 235000019420 glucose oxidase Nutrition 0.000 claims abstract description 80
- 150000002303 glucose derivatives Chemical class 0.000 claims abstract description 53
- 239000012528 membrane Substances 0.000 claims abstract description 35
- 239000002086 nanomaterial Substances 0.000 claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- 229920001577 copolymer Polymers 0.000 claims description 41
- 239000000243 solution Substances 0.000 claims description 39
- 229910052737 gold Inorganic materials 0.000 claims description 19
- 239000010931 gold Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical class [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 125000003277 amino group Chemical group 0.000 claims description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- 238000000502 dialysis Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 10
- 150000001718 carbodiimides Chemical class 0.000 claims description 8
- 238000005520 cutting process Methods 0.000 claims description 8
- 239000007853 buffer solution Substances 0.000 claims description 7
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 239000000178 monomer Substances 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 6
- 150000004696 coordination complex Chemical class 0.000 claims description 6
- 239000003431 cross linking reagent Substances 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 238000000576 coating method Methods 0.000 claims description 5
- 239000011521 glass Substances 0.000 claims description 5
- 239000002105 nanoparticle Substances 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 4
- XMWRBQBLMFGWIX-UHFFFAOYSA-N C60 fullerene Chemical class C12=C3C(C4=C56)=C7C8=C5C5=C9C%10=C6C6=C4C1=C1C4=C6C6=C%10C%10=C9C9=C%11C5=C8C5=C8C7=C3C3=C7C2=C1C1=C2C4=C6C4=C%10C6=C9C9=C%11C5=C5C8=C3C3=C7C1=C1C2=C4C6=C2C9=C5C3=C12 XMWRBQBLMFGWIX-UHFFFAOYSA-N 0.000 claims description 4
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 229910003472 fullerene Inorganic materials 0.000 claims description 4
- 230000002209 hydrophobic effect Effects 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000007790 solid phase Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 claims description 3
- UTFQLNLIYJOVAD-UHFFFAOYSA-N benzene methyl 2-methylprop-2-enoate Chemical compound C1=CC=CC=C1.COC(=O)C(C)=C UTFQLNLIYJOVAD-UHFFFAOYSA-N 0.000 claims description 3
- 150000001721 carbon Chemical class 0.000 claims description 3
- 239000002041 carbon nanotube Substances 0.000 claims description 3
- 229910021393 carbon nanotube Inorganic materials 0.000 claims description 3
- 229910017052 cobalt Inorganic materials 0.000 claims description 3
- 239000010941 cobalt Substances 0.000 claims description 3
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 3
- 229920001940 conductive polymer Polymers 0.000 claims description 3
- 229910021389 graphene Inorganic materials 0.000 claims description 3
- 229910021392 nanocarbon Inorganic materials 0.000 claims description 3
- -1 poly(dimethylsiloxane) Polymers 0.000 claims description 3
- 238000005507 spraying Methods 0.000 claims description 3
- AOBIOSPNXBMOAT-UHFFFAOYSA-N 2-[2-(oxiran-2-ylmethoxy)ethoxymethyl]oxirane Chemical compound C1OC1COCCOCC1CO1 AOBIOSPNXBMOAT-UHFFFAOYSA-N 0.000 claims description 2
- VUIWJRYTWUGOOF-UHFFFAOYSA-N 2-ethenoxyethanol Chemical compound OCCOC=C VUIWJRYTWUGOOF-UHFFFAOYSA-N 0.000 claims description 2
- XBIPWOJKRZBTQK-UHFFFAOYSA-N 2-methylidenebut-3-enamide Chemical compound NC(=O)C(=C)C=C XBIPWOJKRZBTQK-UHFFFAOYSA-N 0.000 claims description 2
- KGIGUEBEKRSTEW-UHFFFAOYSA-N 2-vinylpyridine Chemical compound C=CC1=CC=CC=N1 KGIGUEBEKRSTEW-UHFFFAOYSA-N 0.000 claims description 2
- QZPSOSOOLFHYRR-UHFFFAOYSA-N 3-hydroxypropyl prop-2-enoate Chemical compound OCCCOC(=O)C=C QZPSOSOOLFHYRR-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 239000011837 N,N-methylenebisacrylamide Substances 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011248 coating agent Substances 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 238000007598 dipping method Methods 0.000 claims description 2
- 238000001548 drop coating Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052762 osmium Inorganic materials 0.000 claims description 2
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 238000004528 spin coating Methods 0.000 claims description 2
- 239000004971 Cross linker Substances 0.000 claims 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims 1
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical compound C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 claims 1
- JAYXSROKFZAHRQ-UHFFFAOYSA-N n,n-bis(oxiran-2-ylmethyl)aniline Chemical compound C1OC1CN(C=1C=CC=CC=1)CC1CO1 JAYXSROKFZAHRQ-UHFFFAOYSA-N 0.000 claims 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims 1
- 239000008280 blood Substances 0.000 abstract description 17
- 210000004369 blood Anatomy 0.000 abstract description 17
- 238000012360 testing method Methods 0.000 abstract description 15
- 239000011159 matrix material Substances 0.000 abstract 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 12
- 238000002484 cyclic voltammetry Methods 0.000 description 10
- 230000004913 activation Effects 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 238000000108 ultra-filtration Methods 0.000 description 9
- 238000005516 engineering process Methods 0.000 description 8
- 230000003197 catalytic effect Effects 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- 238000000835 electrochemical detection Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 229910021607 Silver chloride Inorganic materials 0.000 description 2
- 229920006322 acrylamide copolymer Polymers 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 238000010382 chemical cross-linking Methods 0.000 description 2
- 239000000306 component Substances 0.000 description 2
- 238000006392 deoxygenation reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000005518 electrochemistry Effects 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 2
- 229950004354 phosphorylcholine Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000027756 respiratory electron transport chain Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 1
- 108091052347 Glucose transporter family Proteins 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229910001260 Pt alloy Inorganic materials 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000008358 core component Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000006056 electrooxidation reaction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- LOGFOEGYMPSLHL-UHFFFAOYSA-N osmium;2-pyridin-2-ylpyridine Chemical compound [Os].N1=CC=CC=C1C1=CC=CC=N1 LOGFOEGYMPSLHL-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920002717 polyvinylpyridine Polymers 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/48—Systems using polarography, i.e. measuring changes in current under a slowly-varying voltage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
- A61B5/14865—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/308—Electrodes, e.g. test electrodes; Half-cells at least partially made of carbon
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
- G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
- G01N27/3277—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction being a redox reaction, e.g. detection by cyclic voltammetry
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/28—Electrolytic cell components
- G01N27/30—Electrodes, e.g. test electrodes; Half-cells
- G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
- G01N27/3275—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
- G01N27/3278—Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction involving nanosized elements, e.g. nanogaps or nanoparticles
Definitions
- the invention belongs to the field of blood glucose testing, in particular to an implantable glucose biosensor and a preparation method thereof.
- the performance of the glucose biosensor directly determines the performance and service life of the continuous blood glucose meter.
- the biosensors used in the existing continuous blood glucose meters are all developed based on the first or second generation biosensing technology.
- Dexcom's Dexcom G4, G5 and G6 all use the first-generation biosensing technology to monitor glucose. They monitor glucose indirectly by electrochemically detecting the hydrogen peroxide generated during the oxidation of glucose. Since the electrochemical detection of hydrogen peroxide requires very strict electrodes, only a few materials such as platinum and platinum alloys can be used for the production of the sensor of the continuous blood glucose meter, which greatly increases the cost of the sensor of the continuous blood glucose meter.
- the electrochemical detection of hydrogen peroxide requires a high detection potential, which greatly reduces the anti-interference ability of the continuous blood glucose meter.
- the continuous blood glucose meter developed based on the second-generation biosensing technology is the FreeStyle Libre of Abbott Diabetes Care.
- the second-generation biosensing technology realizes the direct electrochemical detection of glucose by introducing redox mediators-redox polymers into the biosensing membrane. Through the molecular design and optimization of redox mediators, the detection of glucose can be realized at a lower potential, thus greatly improving the anti-interference ability of the continuous blood glucose meter. Since this type of glucose monitoring system performs direct electrochemical detection of glucose through redox mediators, its sensitivity is significantly improved. However, because the redox mediator is a polymer material, it is difficult to precisely control its preparation, which brings uncertainty to the performance of the continuous blood glucose meter.
- the present invention provides a third-generation biosensing technology.
- the glucose biosensor prepared in the present invention can not only be used to manufacture the high-performance glucose biosensor urgently needed for continuous blood glucose meters, but also can be applied in the food industry and other fields.
- other various oxidoreductase-containing biosensors can also be fabricated based on this technology.
- An implantable glucose biosensor the biosensor includes a functionalized substrate electrode; and a glucose sensing membrane composed of electrochemically activated glucose oxidase and conductive nanomaterials; the functionalized substrate electrode includes an aminated
- the aminated carbon electrode is a printed electrode containing aminated graphite, a printed electrode of aminated carbon nanotubes, and an aminated graphene printed electrode. and conductive nanomaterials are combined with chemical crosslinking agents.
- glucose sensing membrane composed of electrochemically activated glucose oxidase and conductive nanomaterials is prepared by the following method:
- S2 The modified glucose oxidase 1 in S1 is mixed with 0.1-1g/mL sodium periodate solution at 20-30°C for 1-5h, and the reaction solution is dialyzed to cut the molecular weight to 1000-30000D, and then separated and purified. And add 0.1-5 mg/mL of gold with free amino groups with a particle size of 10-100 nanometers, mix thoroughly and react at 4 °C for 2-12 h, add 1-10 mg/mL of sodium borohydride to the solution, and at 4 °C mixed reaction for 1-4h, the reaction solution was dialyzed, cut and purified to obtain modified glucose oxidase 2 with a molecular weight of 1000-30000D;
- the metal in the metal complex in S1 is at least one of copper, cobalt, iron, nickel, ruthenium or osmium.
- the metal complex concentration of free amino group in S1 is 1-10 mg/mL; the glucose oxidase concentration is: 1-5 mg/mL; the carbodiimide concentration is 1-10 mmol/; N-hydroxyl The concentration of succinimide is 0.01-0.1 mmol/L.
- cross-linking agent described in S3 is glutaraldehyde, 1,4-butanediol diglycidyl ether, poly(dimethylsiloxane)-diglycidyl ether, tetraglycidyl-4, 4-Diaminodiphenylmethane, polyethylene glycol diglycidyl ether, 4-(2,3-glycidoxy)-N,N-bis(2,3-glycidyl)aniline, epoxy At least one of chloropropane, N,N-methylenebisacrylamide, acetic anhydride, diglycidyl ethyl ether or methyl suberimidate.
- the conductive nanomaterials include metal nanomaterials, conductive glass nanomaterials, conductive polymers, nanocarbons, carbon nanotubes, fullerenes or graphenes.
- the metal nanomaterials are gold nanoparticles; the conductive glass nanomaterials include at least one of ITO, FTO or AZO.
- a preparation method of an implantable glucose biosensor as follows:
- the coating method It is any of a drop coating method, a spray coating method, a spin coating method, or a dipping method.
- the ethanol solution of the acrylate copolymer in step (2) is obtained by the following preparation method: mixing hydrophilic monomers, hydrophobic monomers, absolute ethanol and water, removing oxygen with argon, and then adding Na 2 S 2 O 8 , react at 50-75°C for 12-24h, add acetone to precipitate the copolymer of acrylate and vinyl ether after the reaction, separate the solid-liquid to take the solid phase, and finally dry the solid phase at 60-120°C under vacuum for at least 12h, The ethanol solution of the acrylate copolymer was obtained by dissolving with ethanol.
- the hydrophilic monomer includes at least one of hydroxypropyl acrylate, vinyl ether, vinyl glycol and derivatives thereof or vinyl pyrrolidone;
- the hydrophobic monomer includes methyl methacrylate benzene , at least one of vinyl acrylamide and its derivatives, vinyl pyridine and its derivatives.
- the ethanol solution of the acrylate copolymer described in step (2) can also be directly added with highly biocompatible monomers including phosphorylcholine, functionalized polyethylene oxide or functionalized polypropylene oxide.
- highly biocompatible monomers including phosphorylcholine, functionalized polyethylene oxide or functionalized polypropylene oxide.
- At least one of the acrylate copolymers; hydrophilic and highly biocompatible polymers including polyvinyl alcohol, polylactic acid, hyaluronic acid and its derivatives, chitosan can also be directly added to the solution of acrylate copolymer.
- the hydrophobic polymer and the hydrophilic polymer are in the biological phase.
- the ratio in the capacitive membrane solution can realize the regulation of oxygen and glucose at the same time.
- the glucose oxidase After the glucose biosensor of the present invention undergoes electrochemical activation chemical treatment, the glucose oxidase has been electrochemically activated completely from the inside to the outside, and an efficient electron transfer network is formed between the glucose oxidase molecules.
- the monitorable range of glucose was successfully extended from 10 mmol/L to 40 mmol/L compared with the glucose biosensor without any membrane, and its work
- the curve has a good linearity between 0 and 40mmol/L, and its response time to glucose is 2-3min. It is the continuous glucose monitoring system with the widest linear range at present, which fully meets the glucose monitoring needs of diabetics. While broadening the monitorable range of glucose, its current signal is also well regulated by this biocompatible membrane. Since the detection of glucose is carried out at a very low potential (-50mV to 100mV), the anti-interference ability of drugs such as acetaminophen is very significantly improved.
- Fig. 1 is the cyclic voltammogram of modified glucose oxidase 1 after electrochemical activation in the test example of the present invention; wherein, curve 1 represents the cyclic voltammogram of modified glucose oxidase 1 containing electrochemical activation in PBS buffer solution An diagram, curve 2 represents the cyclic voltammogram containing the electrochemically activated modified glucose oxidase 1 after adding 5 mol/L of glucose.
- FIG. 2 is a schematic diagram of the electron transfer path of the modified glucose oxidase 2 treated with nano-gold in the present invention.
- Fig. 3 is the cyclic voltammogram of the electrochemically activated glucose oxidase 2 containing 10-100nm nano-gold in the test example of the present invention; wherein, curve 1 is the glucose oxidase containing 10-100nm nano-gold processed Cyclic voltammogram of glucose biosensor in PBS buffer solution, curve 2 is the cyclic voltammogram of glucose biosensor containing 10-100nm nano-gold treated with glucose oxidase after adding 10mmol/L glucose.
- Fig. 4 is the glucose concentration-current curve of the glucose biosensor covered with the acrylate copolymer film in the test example of the present invention, the detection potential: 0.05V (silver/silver chloride reference electrode).
- Figure 5 is a test example of the present invention (1) a glucose biosensor without an acrylate copolymer permselective membrane and (2) a glucose biosensor covered with an acrylate copolymer permselective membrane Stability of glucose/L in PBS buffer solution. Detection potential: 0.05V (silver/silver chloride reference electrode).
- FIG. 6 is the experimental result of the implantation of the glucose biosensor containing electrochemically activated glucose oxidase in the test example of the present invention; wherein, the circles in the figure represent the blood glucose detection conditions.
- Step 1 Mix 5 mg/mL of osmium-bipyridine complex with free amino groups and 5 mg/mL of glucose oxidase thoroughly, then add 5 mmol/L carbodiimide and 0.1 mmol/L sequentially of N-hydroxysuccinimide, mixed well, and reacted at 4 °C for 12 h. Then, the ultrafiltration bag is used for dialysis, separation and purification to obtain electrochemically activated glucose oxidase 1; the dialysis bag has a cutting molecular weight of 30000D.
- Step 2 After the above-purified modified glucose oxidase 1 was incubated in a sodium periodate solution containing 0.5 g/mL at 20°C for 2.5 hours, the aldehyde group was dialysised by an ultrafiltration bag (cutting molecular weight: 30000D). Glucose oxidase, which decomposes sugar molecules, is separated and purified. Then, 0.1 mg/mL of 10-100 nanometer gold nanoparticles with free amino groups were added to the purified glucose oxidase solution, mixed thoroughly and reacted at 4 °C for 5 h, and then 5 mg/mL of sodium borohydride was added to the solution.
- Step 3 After adding 1% glutaraldehyde to the electrochemically activated glucose oxidase 2 modified by nano-gold, it was coated on the printed electrode of aminated graphite, and reacted at 25°C for 8 hours to obtain a glucose biosensing membrane Then, the ethanol solution of the acrylate copolymer is evenly coated and dropped on the glucose biosensor membrane by the coating method, dried at room temperature, and this step is repeated 3 times to finally obtain the implantable glucose biosensor.
- the method for preparing the ethanol solution of the acrylate copolymer is as follows: a, acrylate copolymer: 150 mL of vinyl ether, 50 mL of methyl methacrylate, 300 mL of absolute ethanol and 15 mL of water, and argon deoxygenation for 40 min. Then, 500 mg of Na 2 S 2 O 8 was added, placed in a closed container, and reacted at 50° C. for 12 h. Then 500 mL of acetone was added to precipitate the acrylate and vinyl ether copolymer and centrifuged. Add ethanol to dissolve, then add 500mL acetone to precipitate, and centrifuge again. This was repeated 3 times, and finally the precipitate was vacuum dried at 60 °C for 12 h.
- Step 1 Mix 1 mg/mL of osmium-biimidazole complex with free amino acid with 1 mg/mL of glucose oxidase, then add 1 mmol/L carbodiimide and 0.01 mmol/L N- Hydroxysuccinimide, mixed well, reacted at 4°C for 12h. Then, the modified glucose oxidase 1 after electrochemical activation was obtained by dialysis with ultrafiltration bag (cut molecular weight: 30000D) and separation and purification.
- Step 2 After culturing the above-purified modified glucose oxidase 1 in a sodium periodate solution containing 0.1 g/mL at 30 °C for 1 h, use ultrafiltration bag dialysis (cutting molecular weight: 1000-30000D) to treat aldehydes with aldehydes. Glucose oxidase, which synthesizes sugar molecules, is isolated and purified.
- Step 3 Mix the nano-gold material modified glucose oxidase 2 with 10% solution of 1,4-butanediol diglycidyl ether and coat it on the printed electrode of the aminated graphite, and react at 20°C for 5h to obtain Glucose biosensing membrane; then the ethanol solution of the acrylate copolymer is evenly coated and dropped on the glucose biosensing membrane by spraying, dried at room temperature, and this step is repeated 3 times to finally obtain the implantable glucose biosensor .
- the preparation method of the ethanol solution of the acrylate copolymer is as follows: acrylate copolymer: 20 mL of hydrophilic vinylpyrrolidone, 50 mL of methyl methacrylate benzene, 100 mL of absolute ethanol and 5 mL of water, deoxygenated by argon for 20 min . Then, 50 mg of Na 2 S 2 O 8 was added, placed in a closed container, and reacted at 50° C. for 16 h. The copolymer was then precipitated by adding 500 mL of acetone and centrifuged. Add ethanol to dissolve, then add 500mL acetone to precipitate, and centrifuge again. This was repeated 4 times, and finally the precipitate was vacuum-dried at 100 °C for 18 h.
- Step 1 Mix 10 mg/mL of cobalt ammine complex with free amino group with 5 mg/mL of glucose oxidase, and then add 10 mmol/L of carbodiimide and 0.1 mmol/L of N-hydroxysuccinic acid in sequence imide, mixed thoroughly, and reacted at 4°C for 48h. Then, the modified glucose oxidase 1 after electrochemical activation was obtained by dialysis with ultrafiltration bag (cut molecular weight: 30000D) and separation and purification.
- Step 2 After the above-purified modified glucose oxidase 1 was incubated in a sodium periodate solution containing 1 g/mL at 30 °C for 5 h, and then dialyzed with an ultrafiltration bag (cutting molecular weight: 30000D) to the aldolized sugars. Molecular glucose oxidase was isolated and purified.
- Step 3 The modified glucose oxidase 2 was coated on the printed electrode of the aminated carbon nanotubes after adding 1% glutaraldehyde, and reacted at 30 °C for 12 h to obtain a glucose biosensing membrane;
- the ethanol solution of the acrylate copolymer is evenly coated and dropped on the glucose biosensor membrane by pulling method, and dried at room temperature, and this step is repeated 6 times to finally obtain the implantable glucose biosensor.
- the method for preparing the ethanol solution of the acrylate copolymer is as follows: acrylate copolymer: 300 mL of vinylpyrrolidone, 100 mL of styrene, 600 mL of absolute ethanol and 30 mL of water, and argon deoxygenation for 60 min. Then 1000 mg of Na 2 S 2 O 8 was added, placed in a closed container, and reacted at 75° C. for 24 h. Then 5000 mL of acetone was added to precipitate the acrylate and vinyl ether copolymer and centrifuged. Add ethanol to dissolve, then add 5000mL acetone to precipitate, and centrifuge again. This was repeated 3 times, and finally the precipitate was vacuum-dried at 120 °C for 20 h.
- Example 2 The experimental operation is the same as in Example 1, except that in Examples 4-10, the nano-gold in step 2 is replaced by fullerene, conductive glass nanomaterial ITO, conductive polymer, nanocarbon, carbon nanotube, fullerene, and graphene. .
- Example 11-18 The experimental operation is the same as that in Example 1, except that in Examples 11-18, phosphorylcholine, functionalized polypropylene oxide, polyvinyl alcohol, hyaluronic acid, chitosan, benzene were added to the ethanol solution of the acrylate copolymer, respectively.
- the modified glucose oxidase 1 after electrochemical activation was characterized by cyclic voltammetry (results are shown in curve 1 of Fig. 1). Curve 1 in Figure 1 clearly shows that after electrochemical modification, small molecules with superior electrochemical properties have been successfully bound to glucose oxidase. In contrast, in the absence of the carbodiimide/N-hydroxysuccinimide chemical cross-linking agent, the glucose oxidase treated as described above did not have any electrochemical activity.
- the experimental results show that, after the above electrochemical activation treatment, the present invention establishes an electron channel in the glucose oxidase from the inside to the outside - from the catalytic active center of the glucose oxidase to its surface, and the catalytic active center of the glucose oxidase is now A very fast electron exchange can be performed directly with the electrode, and the direct electrochemistry of glucose oxidase has been successfully realized.
- the glucose biosensor in the embodiment of the present invention 1 is applied to the dynamic blood glucose meter:
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Physics & Mathematics (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Pathology (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Electrochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Surgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Medical Informatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Biophysics (AREA)
- Optics & Photonics (AREA)
- Nanotechnology (AREA)
- Emergency Medicine (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
一种植入式葡萄糖生物传感器及其制备方法,属于血糖测试技术领域。植入式葡萄糖生物传感器包括功能化的基体电极,以及由电化学活化的葡萄糖氧化酶和导电纳米材料组成的葡萄糖传感膜。
Description
本发明属于血糖测试术领域,尤其是涉及植入式葡萄糖生物传感器及其制备方法。
作为动态血糖仪的核心部件,葡萄糖生物传感器的性能直接决定了动态血糖仪的性能和使用寿命。现有的动态血糖仪所使用的生物传感器都是基于第一或第二代生物传感技术发展起来的。例如德康的Dexcom G4、G5和G6都是利用第一代生物传感技术对葡萄糖进行监测,它们是通过电化学方法检测葡萄糖氧化过程中生成的过氧化氢间接地对葡萄糖进行监测。由于电化学方法检测过氧化氢对电极要求非常苛刻,只有铂和铂合金等极少数几种材料能用于动态血糖仪的传感器的制作,这就大大增加了动态血糖仪的传感器的成本。另外,过氧化氢的电化学检测要求较高的检测电位,因而大大降低了动态血糖仪的抗干扰能力。基于第二代生物传感技术发展起来的动态血糖仪有雅培糖尿病护理的FreeStyle Libre。第二代生物传感技术是通过在生物传感膜中引入氧化还原介体-氧化还原高分子来实现对葡萄糖进行直接的电化学检测。通过对氧化还原介体的分子设计和优化,葡萄糖的检测可以在较低的电位下实现,从而大大提高了动态血糖仪的抗干扰能力。由于这类葡萄糖监测系统是通过氧化还原介体对葡萄糖进行直接的电化学检测,其灵敏度得到了显著的改善。但由于氧化还原介体为高分子材料,使其制备难于得到精确的控制,给动态血糖仪的性能带来不确定性。
为了g服第一和第二代生物传感技术的缺点,提高葡萄糖动态检测的灵敏度、准确性、稳定性、专一性和抗干扰能力,并延长动态血糖仪的使用寿命,同时大大地降低葡萄糖生物传感器的成本。第三代生物传感技术的超长 寿命的葡萄糖生物传感器因应而生。
发明内容
为解决上述技术问题,本发明提供了一种第三代生物传感技术,本发明中制备得到的葡萄糖生物传感器不仅可以用于制造动态血糖仪所急需的高性能葡萄糖生物传感器,而且还可以应用于食品工业等其它领域。另外,基于此技术也可以制造其它各种含有氧化还原酶的生物传感器。
一种植入式葡萄糖生物传感器,所述生物传感器包括功能化的基体电极;以及,由电化学活化的葡萄糖氧化酶和导电纳米材料组成的葡萄糖传感膜;所述功能化的基体电极包括氨基化的碳电极,氨基化的碳电极为含有氨基化石墨的印刷电极、氨基化纳米碳管的印刷电极、氨基化石墨烯印刷电极,所述功能化的基体电极与由电化学活化的葡萄糖氧化酶和导电纳米材料通过化学交联剂进行结合。
进一步的,所述由电化学活化的葡萄糖氧化酶和导电纳米材料组成的葡萄糖传感膜通过以下方法制备得到:
S1:将带有游离氨基的金属络合物与葡萄糖氧化酶充分混合,然后依次加入碳化二亚胺和N-羟基琥珀酰亚胺,充分混合后,在4℃反应12-48h,将反应液进行透析切割并提纯得到分子量为1000-30000D的改性葡萄糖氧化酶1;
S2:将S1中改性葡萄糖氧化酶1与0.1-1g/mL的高碘酸钠溶液在20-30℃混合反应1-5h,将反应液透析切割分子量为1000-30000D,之后分离和提纯,并加入0.1-5mg/mL的带有游离氨基的粒径为10-100纳米金,充分混合后在4℃反应2-12h,向溶液中加入1-10mg/mL的硼氢化钠,并在4℃混合反应1-4h,将反应液进行透析切割并提纯得到分子量为1000-30000D的改性葡萄糖氧化酶2;
S3:将S2中制备得到的改性葡萄糖氧化酶2在PBS缓冲溶液与0.1-5%的交联剂溶液混合反应,得到所述由含有电化学活化的葡萄糖氧化酶和导电纳米材料的葡萄糖传感膜。
进一步的,S1中所述金属络合物中金属为铜、钴、铁、镍、钌或锇中的至少一种。
进一步的,S1中游离氨基的金属络合物浓度为1-10mg/mL;所述葡萄糖氧化酶浓度为:1-5mg/mL;所述碳化二亚胺浓度为1-10mmol/;N-羟基琥珀酰亚胺浓度为0.01-0.1mmol/L。
进一步的,S3中所述交联剂为戊二醛、1,4-丁二醇二缩水甘油醚、聚(二甲基硅氧烷)-二缩水甘油醚、四环氧丙基-4,4-二氨基二苯甲烷、聚乙二醇二縮水甘油醚、4-(2,3-环氧丙氧基)-N,N-二(2,3-环氧丙基)苯胺、环氧氯丙烷、N,N-亚甲基双丙烯酰胺、乙酸酐、二缩水甘油基乙醚或辛二亚氨酸甲酯中的至少一种。
进一步的,所述导电纳米材料包括金属纳米材料、导电玻璃纳米材料、导电高分子、纳米碳、纳米碳管、富勒烯或石墨烯中任一种。
进一步的,所述金属纳米材料为纳米金;所述导电玻璃纳米材料包括ITO、FTO或AZO中的至少一种。
一种植入式葡萄糖生物传感器的制备方法,如下所述:
(1)、将电化学活化的葡萄糖氧化酶和导电纳米材料组成的葡萄糖传感膜涂布在功能化的基体电极上,在20-30℃条件下反应5-12h,即得葡萄糖生物传感膜;
(2)、将丙烯酸酯共聚物的乙醇溶液均匀涂布在葡萄糖生物传感膜上,室温干燥,重复本步骤2-6次,最后得到所述植入式葡萄糖生物传感器;所述涂布方法为滴落涂布法、喷涂法、旋转镀膜法或浸渍提拉法中的任一种。
进一步的,步骤(2)中所述丙烯酸酯共聚物的乙醇溶液通过以下制备方法得到:将亲水单体、疏水性单体、无水乙醇与水混合,氩气除氧,然后加入Na
2S
2O
8,在50-75℃反应12-24h,反应结束加入丙酮沉淀丙烯酸酯与乙烯基醚共聚物,固液分离取固相,最后将固相在60-120℃真空干燥至少12h,用乙醇溶解最后得到丙烯酸酯共聚物的乙醇溶液。
进一步的,所述亲水单体包括丙烯酸羟丙酯、乙烯基醚、乙烯基乙二醇及其衍生物或乙烯吡咯烷酮中的至少一种;所述疏水性单体包括甲基丙烯酸甲酯苯、乙烯丙烯酰胺及其衍生物、乙烯吡啶及其衍生物中的至少一种。
进一步的,步骤(2)中所述丙烯酸酯共聚物的乙醇溶液还可以直接加入具有高度生物相容性单体包括磷酸胆碱、功能化的聚环氧乙烷或功能化的聚环氧丙烷中的至少一种;也可以在丙烯酸酯共聚物的溶液中直接加入亲水性并具有高度生物相容性的聚合物包括聚乙烯醇、聚乳酸、透明质酸及其衍生物、壳聚糖及其衍生物、纤维素及其衍生物、海藻酸及其衍生物、聚乙烯吡啶、苯乙烯和乙烯吡啶共聚物、苯乙烯和乙烯吡咯共聚物、苯乙烯和丙烯酰胺共聚物中的至少一种。
本发明的上述技术方案相比现有技术具有以下优点:
(1)本发明通过调节选择性滲透膜的组成和各组分之间的比例,例如聚合物分子中疏水和亲水组分的种类和配比,疏水聚合物和亲水聚合物在生物相容性膜溶液中的配比,可以实现同时对氧气和葡萄糖的调控。我们经过详细的研究和实验发现在电化学活化的葡萄糖氧化酶的生物传感膜上覆盖一层丙烯酸酯共聚物的薄膜可以实现以上目的。
(2)本发明葡萄糖生物传感经过电化学活化化学处理以后,葡萄糖氧化酶从内到外已经被彻底地电化学活化,而且在葡萄糖氧化酶分子之间形成一个高效的电子传递网络。
(3)本发明中发现,在这个葡萄糖生物传感膜上覆盖了丙烯酸酯共聚物选择性滲透膜可以显著改善其稳定性,同时也大大地提高了葡萄糖生物传感器的生物相容性,进而大大地延长了其工作寿命。经过7天的连续测试实验,其电流信号只有不到2%的衰减,相比之下,没有丙烯酸酯共聚物选择性滲透膜覆盖的葡萄糖生物传感器的电流信号在7天内的连续测试中其电流衰减了60%以上。
(4)当葡萄糖生物传感器的表面覆盖了丙烯酸酯共聚物薄膜时,和没有覆盖任何膜的葡萄糖生物传感器相比,葡萄糖的可监测范围从10mmol/L 被成功地拓展到40mmol/L,其工作曲线在0到40mmol/L之间呈良好的线性,其对葡萄糖的响应时间为2-3min,是目前线性范围最宽的持续葡萄糖监测系统,完全满足了糖尿病人的葡萄糖监测需要。在拓宽葡萄糖的可监测范围的同时,其电流信号也被这层生物相容性膜很好地调控了。由于葡萄糖的检测是在非常低的电位下(-50mV至100mV)进行的,其对乙酰氨基酚类等的药物的抗干扰能力得到非常显著地改善。
为了使本发明的内容更容易被清楚的理解,下面根据本发明的具体实施例并结合附图,对本发明作进一步详细的说明,其中
图1是本发明测试例中电化学活化后的改性葡萄糖氧化酶1的循环伏安图;其中,曲线1表示含有电化学活化后的改性葡萄糖氧化酶1在PBS缓冲溶液中的循环伏安图,曲线2表示含有电化学活化后的改性葡萄糖氧化酶1加入5mol/L的葡萄糖后的循环伏安图。
图2是本发明中含有纳米金处理过的改性葡萄糖氧化酶2的电子传递路径示意图。
图3是本发明测试例中含有10-100nm的纳米金处理过的电化学活化的葡萄糖氧化酶2的循环伏安图;其中,曲线1为含有10-100nm的纳米金处理过的葡萄糖氧化酶葡萄糖生物传感器在PBS缓冲溶液中的循环伏安图,曲线2为含有10-100nm的纳米金处理过的葡萄糖氧化酶葡萄糖生物传感器加入10mmol/L葡萄糖后的循环伏安图。
图4是本发明测试例中覆盖有丙烯酸酯共聚物薄膜的葡萄糖生物传感器的葡萄糖浓度-电流曲线,检测电位:0.05V(银/氯化银参比电极)。
图5是本发明测试例中(1)没有丙烯酸酯共聚物选择性滲透膜的葡萄糖生物传感器和(2)覆盖有丙烯酸酯共聚物选择性滲透膜选择性滲透膜的葡萄糖生物传感器和含有在20mmol/L的葡萄糖的PBS缓冲溶液中的稳定性。检测电位:0.05V(银/氯化银参比电极)。
图6是本发明测试例中含有电化学活化的葡萄糖氧化酶的葡萄糖生物传感器植入实验结果;其中,图中圆点表示指血血糖检测情况。
下面结合附图和具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实施例1
步骤1:将5mg/mL的带有游离氨基的锇-联吡啶络合物与5mg/mL的葡萄糖氧化酶充分混合,然后依次加入5毫摩尔/升的碳化二亚胺和0.1毫摩尔/升的N-羟基琥珀酰亚胺,充分混合后,在4℃反应12h。然后利用超滤袋透析并进行分离和提纯得到电化学活化后葡萄糖氧化酶1;所述透析袋切割分子量为30000D。
步骤2:将上述提纯后的改性葡萄糖氧化酶1在含有0.5g/mL的高碘酸钠溶液在20℃培养2.5h后,利用超滤袋透析(切割分子量:30000D)对带有醛基化糖分子的葡萄糖氧化酶进行分离和提纯。然后在提纯葡萄糖氧化酶溶液中加入0.1mg/mL的带有游离氨基的10-100纳米的纳米金,充分混合后在4℃反应5h,然后在溶液中加入5mg/mL的硼氢化钠,充分混合后在4℃反应2.5h,反应结束后,再次利用超滤袋透析(切割分子量:30000D)对修饰过葡萄糖氧化酶进行分离和提纯得到纳米金改性的电化学活化的葡萄糖氧化酶2;
步骤3:将纳米金改性的电化学活化的葡萄糖氧化酶2加入1%戊二醛后,涂布在氨基化石墨的印刷电极,在25℃条件下反应8h,即得葡萄糖生物传感膜;之后采用涂布法将丙烯酸酯共聚物的乙醇溶液均匀涂布滴落在葡萄糖生物传感膜上,室温干燥,重复本步骤3次,最终得到所述植入式葡萄糖生物传感器。
其中,丙烯酸酯共聚物的乙醇溶液制备方法为:a,丙烯酸酯共聚物:150mL的乙烯基醚、50mL甲基丙烯酸甲酯与300mL的无水乙醇和15mL的水,氩气除氧40min。然后加入500mg的Na
2S
2O
8,置于密闭容器中,在50℃ 反应12h。然后加入500mL丙酮沉淀丙烯酸酯和乙烯基醚共聚物,并离心分离。加乙醇溶解,再加入500mL丙酮沉淀,再次离心分离。反复3次,最后将沉淀物在60℃真空干燥12h。
实施例2
步骤1:将1mg/mL的带有游离氨基锇-联咪唑络合物与1mg/mL的葡萄糖氧化酶充分混合,然后依次加入1mmol/L的碳化二亚胺和0.01毫摩尔/升的N-羟基琥珀酰亚胺,充分混合后,在4℃反应12h。然后利用超滤袋透析(切割分子量:30000D)并进行分离和提纯得到电化学活化后的改性葡萄糖氧化酶1。
步骤2:将上述提纯后的改性葡萄糖氧化酶1在含有0.1g/mL的高碘酸钠溶液在30℃培养1h后,利用超滤袋透析(切割分子量:1000-30000D)对带有醛基化糖分子的葡萄糖氧化酶进行分离和提纯。然后在提纯葡萄糖氧化酶溶液中加入0.1mg/mL的带有游离氨基的10nm的纳米金,充分混合后在4℃反应2h,然后在溶液中加入1mg/mL的硼氢化钠,充分混合后在4℃反应1h,反应结束后,再次利用超滤袋透析(切割分子量:30000D)对修饰过葡萄糖氧化酶进行分离和提纯得到纳米金材料改性葡萄糖氧化酶2。
步骤3:将纳米金材料改性葡萄糖氧化酶2与10%的1,4-丁二醇二缩水甘油醚溶液混合涂布在氨基化石墨的印刷电极,在20℃条件下反应5h,即得葡萄糖生物传感膜;之后采用喷涂法将丙烯酸酯共聚物的乙醇溶液均匀涂布滴落在葡萄糖生物传感膜上,室温干燥,重复本步骤3次,最终得到所述植入式葡萄糖生物传感器。
其中,丙烯酸酯共聚物的乙醇溶液制备方法为:丙烯酸酯共聚物:20mL的亲水性乙烯吡咯烷酮、50mL的甲基丙烯酸甲酯苯、100mL的无水乙醇和5mL的水,氩气除氧20min。然后加入50mg的Na
2S
2O
8,置于密闭容器中,在50℃反应16h。然后加入500mL丙酮沉淀共聚物,并离心分离。加乙醇溶解,再加入500mL丙酮沉淀,再次离心分离。反复4次,最后将沉淀物在100℃真空干燥18h。
实施例3
步骤1:将10mg/mL的带有游离氨基的钴氨络合物与5mg/mL的葡萄糖氧化酶充分混合,然后依次加入10mmol/L的碳化二亚胺和0.1mmol/L的N-羟基琥珀酰亚胺,充分混合后,在4℃反应48h。然后利用超滤袋透析(切割分子量:30000D)并进行分离和提纯得到电化学活化后的改性葡萄糖氧化酶1。
步骤2:将上述提纯后的改性葡萄糖氧化酶1在含有1g/mL的高碘酸钠溶液在30℃培养5h后,利用超滤袋透析(切割分子量:30000D)对带有醛基化糖分子的葡萄糖氧化酶进行分离和提纯。然后在提纯葡萄糖氧化酶溶液中加入5mg/mL的带有游离氨基的100nm的纳米金,充分混合后在4℃反应12h,然后在溶液中加入10mg/mL的硼氢化钠,充分混合后在4℃反应1h,反应结束后再次利用超滤袋透析(切割分子量:30000D)对修饰过葡萄糖氧化酶进行分离和提纯得到改性葡萄糖氧化酶2。
步骤3:将改性葡萄糖氧化酶2在加入1%戊二醛后涂布在氨基化纳米碳管的印刷电极,在30℃条件下反应12h,即得葡萄糖生物传感膜;之后采用浸渍提拉法将丙烯酸酯共聚物的乙醇溶液均匀涂布滴落在葡萄糖生物传感膜上,室温干燥,重复本步骤6次,最终得到所述植入式葡萄糖生物传感器。
其中,丙烯酸酯共聚物的乙醇溶液制备方法为:丙烯酸酯共聚物:300mL的乙烯吡咯烷酮、100mL苯乙烯、与600mL的无水乙醇和30mL的水,氩气除氧60min。然后加入1000mg的Na
2S
2O
8,置于密闭容器中,在75℃反应24h。然后加入5000mL丙酮沉淀丙烯酸酯和乙烯基醚共聚物,并离心分离。加乙醇溶解,再加入5000mL丙酮沉淀,再次离心分离。反复3次,最后将沉淀物在120℃真空干燥20h。
实施例4-10
实验操作同实施例1,区别实施例4-10中分别将步骤2中纳米金替换为富勒烯、导电玻璃纳米材料ITO、导电高分子、纳米碳、纳米碳管、富勒烯、 石墨烯。
实施例11-18
实验操作同实施例1,区别在于实施例11-18分别在丙烯酸酯共聚物的乙醇溶液中加入磷酸胆碱、功能化的聚环氧丙烷、聚乙烯醇、透明质酸、壳聚糖、苯乙烯和乙烯吡啶共聚物、苯乙烯和乙烯吡咯共聚物、苯乙烯和丙烯酰胺共聚物。
测试例
为了验证本发明实施例1中方案的可行性,先进行如下测试:
(1)验证步骤1中得到电化学活化后的改性葡萄糖氧化酶1中电化学性能小分子是否成功键合到葡萄糖氧化酶上,进行如下测试:
首先利用循环伏安法对修饰过的电化学活化后的改性葡萄糖氧化酶1进行表征(结果见图1曲线1)。由图1中曲线1清楚地表明经过电化学修饰处理后,电化学性能优越的小分子已经被成功地键合到葡萄糖氧化酶上。与之相反,在没有碳化二亚胺/N-羟基琥珀酰亚胺化学交联剂存在时,经过上述处理的葡萄糖氧化酶没有任何的电化学活性。
(2)验证步骤1中得到电化学活化后的改性葡萄糖氧化酶1中电化学处理不会对改性葡萄糖氧化酶1的催化活性中心产生明显的影响。
因此对电化学活化后的改性葡萄糖氧化酶1的催化活性进行评估。因此在含有电化学活化过的改性葡萄糖氧化酶1的PBS缓冲溶液中加入葡萄糖,再次用循环伏安法对电化学活化后的改性葡萄糖氧化酶1进行表征结果见图1曲线2所示,在加入葡萄糖后,电化学活化后的改性葡萄糖氧化酶1的循环伏安图清晰地展示了一个典型的电化学催化过程。进一步的实验表明电化学活化后的改性葡萄糖氧化酶1不仅保持了其对葡萄糖的催化氧化性能,其通过直接电化学对葡萄糖的催化氧化效率比天然葡萄糖氧化酶通过氧气对葡萄糖的催化氧化效率提高了两个数量级。
综上实验结果表明,经过以上电化学活化处理,本发明在葡萄糖氧化酶 中从内到外-从葡萄糖氧化酶催化活性中心到其表面,建立起了一条电子通道,葡萄糖氧化酶催化活性中心现在可以直接与电极进行非常快速的电子交换,成功地实现了葡萄糖氧化酶的直接电化学。
(2)验证步骤3中所得纳米金材料改性葡萄糖氧化酶性能。
我们发现经过化学交联的纳米金材料改性葡萄糖氧化酶仍然保持着它们的直接电化学,纳米金材料改性葡萄糖氧化酶在电极上呈现出良好的电化学性能,而且是一个典型的表面电化学现象(峰电位差远远小于59mV)(结果见图3,曲线1)。当在PBS缓冲溶液中加入10mmol/L的葡萄糖后,与电化学活化后的葡萄糖氧化酶在溶液中的行为相似,葡萄糖生物传感膜的循环伏安图清晰地展示了一个典型的电化学催化过程(图3,曲线2)。以上实验结果证明化学活化并交联没有对电化学活化后的葡萄糖氧化酶产生显著的影响,这就为电化学活化后的葡萄糖氧化酶在动态血糖仪中的应用铺平了道路。
(3)验证实施例1中葡萄糖生物传感膜表面涂布丙烯酸酯共聚物薄膜时对葡萄糖生物传感性能影响:
实验结果见图4,由图4可知:图4中曲线1代表表面覆盖了丙烯酸酯共聚物薄膜葡萄糖生物传感器,曲线2代表未覆盖丙烯酸酯共聚物薄膜葡萄糖生物传感器;当葡萄糖生物传感器的表面覆盖了丙烯酸酯共聚物薄膜时,和没有覆盖任何膜的葡萄糖生物传感器相比,葡萄糖的可监测范围从10mmol/L被成功地拓展到40mmol/L,其工作曲线在1.0到40mmol/L之间呈良好的线性,其对葡萄糖的响应时间为2-3分钟,是目前线性范围最宽的持续葡萄糖监测系统,完全满足了糖尿病人的葡萄糖监测需要。在拓宽葡萄糖的可监测范围的同时,其电流信号也被这层生物相容性膜很好地调控了。由于葡萄糖的检测是在非常低的电位下(-50-100mV)进行的,其对乙酰氨基酚类等的药物的抗干扰能力得到非常显著地改善。
本发明葡萄糖生物传感器稳定性实验结果见图5,由图中可知,经过7天的连续测试实验,其电流信号只有不到2%的衰减(图5,曲线2);相比之 下,没有丙烯酸酯共聚物选择性滲透膜覆盖的葡萄糖生物传感器的电流信号在7天内的连续测试中其电流衰减了60%以上(图5,曲线1)。由此可见,本发明葡萄糖生物传感器膜上覆盖了丙烯酸酯共聚物选择性滲透膜可以显著改善其稳定性,同时也大大地提高了葡萄糖生物传感器的生物相容性,进而大大地延长了其工作寿命。
(4)将本发明实施例1中的葡萄糖生物传感器应用于动态血糖仪:
结果见图6,由图6可知:葡萄糖生物传感器生物相容性和稳定性都得到了显著的改善,在连续20天的人体试验中,灵敏度没有明显的变化。这是迄今为止工作寿命最长的用于人体监测的葡萄糖生物传感器,更重要的是,其监测到的葡萄糖浓度与指血血糖检测(图中圆点)的结果高度吻合。
显然,上述实施例仅是为清楚地说明所作的举例,并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
- 一种植入式葡萄糖生物传感器,其特征在于:所述生物传感器包括功能化的基体电极;以及,由电化学活化的葡萄糖氧化酶和导电纳米材料组成的葡萄糖传感膜;其中,所述功能化的基体电极包括氨基化的碳电极,所述氨基化的碳电极为含有氨基化石墨的印刷电极、氨基化纳米碳管的印刷电极、氨基化石墨烯印刷电极;所述功能化的基体电极与电化学活化的葡萄糖氧化酶和导电纳米材料通过化学交联剂进行结合。
- 根据权利要求1所述的植入式葡萄糖生物传感器,其特征在于:所述由电化学活化的葡萄糖氧化酶和导电纳米材料组成的葡萄糖传感膜通过以下方法制备得到:S1:将带有游离氨基的金属络合物与葡萄糖氧化酶充分混合,然后依次加入碳化二亚胺和N-羟基琥珀酰亚胺,充分混合后,在4℃反应12-48h,将反应液进行透析切割并提纯得到分子量为1000-30000D的改性葡萄糖氧化酶1;S2:将S1中改性葡萄糖氧化酶1与0.1-1g/mL的高碘酸钠溶液在20-30℃混合反应1-5h,将反应液透析切割分子量为1000-30000D,之后分离和提纯,并加入0.1-5mg/mL的带有游离氨基的粒径为10-100nm纳米金,充分混合后在4℃反应2-12h,向溶液中加入1-10mg/mL的硼氢化钠,并在4℃混合反应1-4h,将反应液进行透析切割并提纯得到分子量为1000-30000D的改性葡萄糖氧化酶2;S3:将S2中制备得到的改性葡萄糖氧化酶2在PBS缓冲溶液与0.1-5%的交联剂溶液混合反应,得到所述由电化学活化的葡萄糖氧化酶和导电纳米材料的葡萄糖传感膜。
- 根据权利要求2所述的植入式葡萄糖生物传感器,其特征在于:S1中所述金属络合物中金属为铜、钴、铁、镍、钌或锇中的至少一种。
- 根据权利要求2所述的植入式葡萄糖生物传感器,其特征在于:S1中游离氨基的金属络合物浓度为1-10mg/mL;所述葡萄糖氧化酶浓度为:1-5 mg/mL;所述碳化二亚胺浓度为1-10mmol/;N-羟基琥珀酰亚胺浓度为0.01-0.1mmol/L。
- 根据权利要求2所述的植入式葡萄糖生物传感器,其特征在于:S3中所述交联剂为戊二醛、1,4-丁二醇二缩水甘油醚、聚(二甲基硅氧烷)-二缩水甘油醚、四环氧丙基-4,4-二氨基二苯甲烷、聚乙二醇二縮水甘油醚、4-(2,3-环氧丙氧基)-N,N-二(2,3-环氧丙基)苯胺、环氧氯丙烷、N,N-亚甲基双丙烯酰胺、乙酸酐、二缩水甘油基乙醚或辛二亚氨酸甲酯中的至少一种。
- 根据权利要求1所述的植入式葡萄糖生物传感器,其特征在于:所述导电纳米材料包括金属纳米材料、导电玻璃纳米材料、导电高分子、纳米碳、纳米碳管、富勒烯或石墨烯中任一种。
- 根据权利要求1所述的植入式葡萄糖生物传感器,其特征在于:所述金属纳米材料为纳米金;所述导电玻璃纳米材料包括ITO、FTO或AZO中的至少一种。
- 一种如权利要求1-7中任一项所述的植入式葡萄糖生物传感器的制备方法,其特征在于:方法如下:(1)、将由电化学活化的葡萄糖氧化酶和导电纳米材料组成的葡萄糖传感膜涂布在功能化的基体电极上,在20-30℃条件下反应5-12h,即得葡萄糖生物传感膜;(2)、将丙烯酸酯共聚物的乙醇溶液均匀涂布在葡萄糖生物传感膜上,室温干燥,重复本步骤2-6次,最后得到所述植入式葡萄糖生物传感器;所述涂布方法为滴落涂布法、喷涂法、旋转镀膜法或浸渍提拉法中的任一种。
- 根据权利要求8所述的植入式葡萄糖生物传感器的制备方法,其特征在于:步骤(2)中所述丙烯酸酯共聚物的乙醇溶液通过以下制备方法得到:将亲水单体、疏水性单体、无水乙醇与水混合,氩气除氧,然后加入Na 2S 2O 8,在50-75℃反应12-24h,反应结束加入丙酮沉淀丙烯酸酯与乙烯基醚共聚物,固液分离取固相,最后将固相在60-120℃真空干燥至少12h,用乙醇溶解最后 得到丙烯酸酯共聚物的乙醇溶液。
- 根据权利要求9所述的植入式葡萄糖生物传感器的制备方法,其特征在于:所述亲水单体包括丙烯酸羟丙酯、乙烯基醚、乙烯基乙二醇及其衍生物或乙烯吡咯烷酮中的至少一种;所述疏水性单体包括甲基丙烯酸甲酯苯、乙烯丙烯酰胺及其衍生物、乙烯吡啶及其衍生物中的至少一种。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110475330.6A CN113325058A (zh) | 2021-04-29 | 2021-04-29 | 植入式葡萄糖生物传感器及其制备方法 |
CN202110475330.6 | 2021-04-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022228025A1 true WO2022228025A1 (zh) | 2022-11-03 |
Family
ID=77413942
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/084451 WO2022228025A1 (zh) | 2021-04-29 | 2022-03-31 | 植入式葡萄糖生物传感器及其制备方法 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN113325058A (zh) |
WO (1) | WO2022228025A1 (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113325058A (zh) * | 2021-04-29 | 2021-08-31 | 苏州中星医疗技术有限公司 | 植入式葡萄糖生物传感器及其制备方法 |
CN113717955A (zh) * | 2021-09-02 | 2021-11-30 | 苏州中星医疗技术有限公司 | 葡萄糖生物传感器及其葡萄糖传感膜、葡萄糖脱氢酶 |
CN113720889A (zh) * | 2021-09-02 | 2021-11-30 | 苏州中星医疗技术有限公司 | 葡萄糖生物传感器及其葡萄糖生物传感膜 |
CN113916957B (zh) * | 2021-10-29 | 2023-06-16 | 重庆医科大学 | GPBCs/CC及其葡萄糖传感器和应用 |
CN114384135B (zh) * | 2022-01-25 | 2023-05-02 | 江苏跃凯生物技术有限公司 | 一种导电纳米材料葡萄糖传感材料及其制备方法和应用 |
CN114609213A (zh) * | 2022-03-17 | 2022-06-10 | 苏州中星医疗技术有限公司 | 葡萄糖传感器及其制备方法、应用 |
CN114778645A (zh) * | 2022-05-24 | 2022-07-22 | 四川大学 | 一种双金属中心导电纳米材料葡萄糖传感及其制备方法和应用 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080034972A1 (en) * | 2006-08-10 | 2008-02-14 | The Regents Of The University Of California | Membranes with controlled permeability to polar and apolar molecules in solution and methods of making same |
CN108273069A (zh) * | 2018-01-15 | 2018-07-13 | 湖北省中医院 | 一种β-葡萄糖苷酶偶联磁性纳米粒子的制备方法 |
CN108918625A (zh) * | 2018-07-27 | 2018-11-30 | 三诺生物传感股份有限公司 | 一种生物传感膜的制备方法、生物传感膜及监测装置 |
CN111248924A (zh) * | 2019-06-24 | 2020-06-09 | 深圳硅基传感科技有限公司 | 葡萄糖监测探头的工作电极及其制作方法 |
CN111929352A (zh) * | 2019-06-24 | 2020-11-13 | 深圳硅基传感科技有限公司 | 葡萄糖监测探头 |
CN113325058A (zh) * | 2021-04-29 | 2021-08-31 | 苏州中星医疗技术有限公司 | 植入式葡萄糖生物传感器及其制备方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8808515B2 (en) * | 2007-01-31 | 2014-08-19 | Abbott Diabetes Care Inc. | Heterocyclic nitrogen containing polymers coated analyte monitoring device and methods of use |
CN104134805A (zh) * | 2014-07-29 | 2014-11-05 | 武汉理工大学 | 一种柔性三维纳米生物电极及其制备方法 |
CN105266826B (zh) * | 2015-11-16 | 2016-08-31 | 杭州亿信网络科技有限公司 | 皮下组织介入式针状葡萄糖传感器及其制备方法 |
CN209878659U (zh) * | 2017-12-29 | 2019-12-31 | 深圳硅基传感科技有限公司 | 葡萄糖监测探头的工作电极 |
CN110057889B (zh) * | 2018-12-29 | 2021-03-16 | 深圳硅基传感科技有限公司 | 葡萄糖监测探头的工作电极及其制作方法 |
CN109264709B (zh) * | 2018-09-03 | 2021-08-31 | 浙江理工大学 | 一种氧化石墨烯修饰的可植入生物传感器的制备方法 |
CN109655513B (zh) * | 2019-01-25 | 2023-10-17 | 天津大学 | 一种自校准葡萄糖连续监测系统及其制备方法 |
-
2021
- 2021-04-29 CN CN202110475330.6A patent/CN113325058A/zh active Pending
-
2022
- 2022-03-31 WO PCT/CN2022/084451 patent/WO2022228025A1/zh active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080034972A1 (en) * | 2006-08-10 | 2008-02-14 | The Regents Of The University Of California | Membranes with controlled permeability to polar and apolar molecules in solution and methods of making same |
CN108273069A (zh) * | 2018-01-15 | 2018-07-13 | 湖北省中医院 | 一种β-葡萄糖苷酶偶联磁性纳米粒子的制备方法 |
CN108918625A (zh) * | 2018-07-27 | 2018-11-30 | 三诺生物传感股份有限公司 | 一种生物传感膜的制备方法、生物传感膜及监测装置 |
CN111248924A (zh) * | 2019-06-24 | 2020-06-09 | 深圳硅基传感科技有限公司 | 葡萄糖监测探头的工作电极及其制作方法 |
CN111929352A (zh) * | 2019-06-24 | 2020-11-13 | 深圳硅基传感科技有限公司 | 葡萄糖监测探头 |
CN113325058A (zh) * | 2021-04-29 | 2021-08-31 | 苏州中星医疗技术有限公司 | 植入式葡萄糖生物传感器及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CN113325058A (zh) | 2021-08-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2022228025A1 (zh) | 植入式葡萄糖生物传感器及其制备方法 | |
Eivazzadeh-Keihan et al. | Applications of carbon-based conductive nanomaterials in biosensors | |
Shrestha et al. | High-performance glucose biosensor based on chitosan-glucose oxidase immobilized polypyrrole/Nafion/functionalized multi-walled carbon nanotubes bio-nanohybrid film | |
Li et al. | Rational design and applications of conducting polymer hydrogels as electrochemical biosensors | |
Aghamiri et al. | Immobilization of cytochrome c and its application as electrochemical biosensors | |
CN105943058B (zh) | 柔性电化学电极、连续葡萄糖监测传感器及其制备方法 | |
Burrs et al. | A comparative study of graphene–hydrogel hybrid bionanocomposites for biosensing | |
Lu et al. | Carbon nanofiber-based composites for the construction of mediator-free biosensors | |
Baghayeri et al. | Direct electrochemistry and electrocatalysis of hemoglobin immobilized on biocompatible poly (styrene-alternative-maleic acid)/functionalized multi-wall carbon nanotubes blends | |
Wang et al. | Carbon nanotube/chitosan/gold nanoparticles-based glucose biosensor prepared by a layer-by-layer technique | |
Fang et al. | Biocompatibility of CS–PPy nanocomposites and their application to glucose biosensor | |
Xu et al. | Biopolymer and carbon nanotubes interface prepared by self-assembly for studying the electrochemistry of microperoxidase-11 | |
CN111624244B (zh) | 一种葡萄糖氧化酶纳米胶囊传感器及其制备和应用 | |
CN110618179A (zh) | 一种基于纳米多孔金属膜的葡萄糖电化学微电极传感器 | |
Baghayeri et al. | Facile synthesis of PSMA-g-3ABA/MWCNTs nanocomposite as a substrate for hemoglobin immobilization: application to catalysis of H2O2 | |
Zhang et al. | Molecularly imprinted photo-sensitive polyglutamic acid nanoparticles for electrochemical sensing of hemoglobin | |
Dalkiran et al. | Polyphenazine and polytriphenylmethane redox polymer/nanomaterial–based electrochemical sensors and biosensors: a review | |
Szewczyk et al. | Polydopamine films: Electrochemical growth and sensing applications | |
Li et al. | The impact of recent developments in electrochemical POC sensor for blood sugar care | |
Kwon et al. | High-performance biosensors based on enzyme precipitate coating in gold nanoparticle-conjugated single-walled carbon nanotube network films | |
Derkus et al. | Evaluation of protein immobilization capacity on various carbon nanotube embedded hydrogel biomaterials | |
CN113311033A (zh) | 乳酸生物传感器 | |
Gupta et al. | Functionalized multi-walled carbon nanotubes/polyvinyl alcohol membrane coated glassy carbon electrode for efficient enzyme immobilization and glucose sensing | |
Ghanbari et al. | Ionic liquid-based sensors | |
CN113717955A (zh) | 葡萄糖生物传感器及其葡萄糖传感膜、葡萄糖脱氢酶 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22794497 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 22794497 Country of ref document: EP Kind code of ref document: A1 |