WO2021207994A1 - 一种生物相容性膜、其制备方法及植入式生物传感器 - Google Patents

一种生物相容性膜、其制备方法及植入式生物传感器 Download PDF

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WO2021207994A1
WO2021207994A1 PCT/CN2020/085033 CN2020085033W WO2021207994A1 WO 2021207994 A1 WO2021207994 A1 WO 2021207994A1 CN 2020085033 W CN2020085033 W CN 2020085033W WO 2021207994 A1 WO2021207994 A1 WO 2021207994A1
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biocompatible
glucose
biocompatible membrane
biosensor
copolymer
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PCT/CN2020/085033
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English (en)
French (fr)
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高志强
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三诺生物传感股份有限公司
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Priority to EP20930960.8A priority Critical patent/EP4108696A4/en
Priority to KR1020227032092A priority patent/KR20220143888A/ko
Priority to JP2022554266A priority patent/JP2023516785A/ja
Priority to US17/910,122 priority patent/US20230323079A1/en
Priority to PCT/CN2020/085033 priority patent/WO2021207994A1/zh
Publication of WO2021207994A1 publication Critical patent/WO2021207994A1/zh

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    • C12Q1/006—Enzyme electrodes involving specific analytes or enzymes for glucose
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    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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    • C08L25/00—Compositions of, homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Compositions of derivatives of such polymers
    • C08L25/02—Homopolymers or copolymers of hydrocarbons
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    • C08L39/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions of derivatives of such polymers
    • C08L39/04—Homopolymers or copolymers of monomers containing heterocyclic rings having nitrogen as ring member
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    • C08L83/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
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    • C08L83/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
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    • C09D183/00—Coating compositions based on macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon, with or without sulfur, nitrogen, oxygen, or carbon only; Coating compositions based on derivatives of such polymers
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    • C08L33/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
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    • C08L39/00—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions of derivatives of such polymers
    • C08L39/04—Homopolymers or copolymers of monomers containing heterocyclic rings having nitrogen as ring member

Definitions

  • the invention belongs to the technical field of biosensors, and in particular relates to a biocompatible membrane, a preparation method thereof, and an implantable biosensor.
  • the implantable continuous glucose monitoring system allows diabetics to regulate blood sugar more conveniently and effectively. It can continuously detect blood sugar in real time and has gradually become a powerful tool for blood sugar control.
  • the performance of the biocompatible membrane directly determines the biocompatibility, sensitivity and stability of the implantable continuous glucose monitoring system , Anti-interference ability and working life during live monitoring.
  • Existing implantable continuous monitoring systems such as implantable continuous glucose monitoring systems, are developed based on the first or second generation of biosensing technology.
  • Dexcom s Dexcom G5 and G6 and Medtronic’s Guardian and iPro2, which use the first-generation biosensing technology to continuously monitor glucose, work on the principle of electrochemical detection of glucose during the catalytic oxidation process of glucose oxidase. The hydrogen peroxide generated during reduction indirectly monitors glucose.
  • the continuous glucose monitoring system developed based on the first-generation biosensing technology relies on the natural medium of oxygen in body fluids such as tissue fluid or blood-glucose oxidase to catalyze the oxidation of glucose to monitor glucose, the oxygen in body fluids
  • the content (0.2-0.3 mmol/L) is much lower than glucose (5-10 mmol/L), and its biocompatible membrane must be able to allow oxygen to the maximum extent on the basis of high biocompatibility. Pass, while effectively fetching the passing of glucose.
  • oxygen is hydrophobic, so its biocompatible membrane must also be highly hydrophobic.
  • the requirement of high hydrophobicity has brought huge challenges to the design of biocompatible membranes.
  • Medtronic's Guardian and iPro2 also need to be calibrated twice a day, and their working life is only one week.
  • the second-generation biosensing technology realizes direct electrochemical detection of glucose by introducing a synthetic redox mediator in the biosensor, through the molecular design and optimization of the redox mediator, glucose detection can be It is realized at a very low potential, which greatly improves the anti-interference ability of the implanted continuous glucose monitoring system. Because this type of glucose monitoring system directly electrochemically detects glucose through an artificial redox mediator, its sensitivity has also been significantly improved.
  • oxygen as the natural mediator for glucose oxidase to catalyze the oxidation of glucose, inevitably participates in the catalytic oxidation of glucose, and becomes the key to glucose monitoring. An important interference factor.
  • the purpose of the present invention is to provide a biocompatible membrane, its preparation method and an implantable biosensor.
  • the biocompatible membrane of the present invention can improve the biocompatibility of the biosensor, and can simultaneously treat oxygen and glucose.
  • the regulation of the biocompatibility improves the stability and service life of the biocompatible membrane solution.
  • the present invention provides a biocompatible film, which is mainly made of the following components:
  • Crosslinking agents hydrophilic materials, hydrophobic materials and solvents
  • the crosslinking agent includes poly(dimethylsiloxane)-diglycidyl ether, polyethylene glycol diglycidyl ether and 4-(2,3-glycidyloxy)-N,N-bis( One or more of 2,3-epoxypropyl)aniline;
  • the hydrophilic material includes one or more of polyethylene oxide, polyethylene oxide-containing copolymers, polypropylene oxide, polypropylene oxide-containing copolymers, polyvinylpyrrolidone and polyvinyl alcohol ;
  • the hydrophobic material includes one or more of polyvinylpyridine, vinylpyridine-acrylamide copolymer, polyvinylpyrrole, and vinylpyrrole-acrylamide copolymer.
  • the hydrophilic material is polyethylene oxide or a copolymer containing polyethylene oxide; and the hydrophobic material is polyvinylpyridine.
  • the crosslinking agent is poly(dimethylsiloxane)-diglycidyl ether.
  • the raw material of the biocompatible membrane further includes an enhancer
  • the reinforcing agent includes one or more of styrene-vinylpyridine copolymer, styrene-vinylpyrrole copolymer and styrene-acrylamide copolymer.
  • the reinforcing agent is a styrene-vinylpyridine copolymer.
  • the raw material of the biocompatible membrane also includes a free radical scavenger
  • the free radical scavengers include ethanolamine, propanolamine, isopropanolamine, aniline, polyethylene oxide with terminal amino groups, copolymers of ethylene oxide and polypropylene oxide with terminal amino groups. One or more.
  • the free radical scavenger is ethanolamine.
  • the present invention provides a method for preparing a biocompatible film, which includes the following steps:
  • the crosslinking agent includes poly(dimethylsiloxane)-diglycidyl ether, polyethylene glycol diglycidyl ether and 4-(2,3-glycidyloxy)-N,N-bis( One or more of 2,3-epoxypropyl)aniline;
  • the hydrophilic material includes one or more of polyethylene oxide, polyethylene oxide-containing copolymers, polypropylene oxide, polypropylene oxide-containing copolymers, polyvinylpyrrolidone and polyvinyl alcohol ;
  • the hydrophobic material includes one or more of polyvinylpyridine, vinylpyridine-acrylamide copolymer, polyvinylpyrrole, and vinylpyrrole-acrylamide copolymer;
  • the step A is specifically:
  • the present invention provides an implantable biosensor, which includes a biosensor substrate and a biocompatible film coated on the surface of the biosensor substrate;
  • the biocompatible film is the biocompatible film described above.
  • the present invention provides a biocompatible film, which is mainly made of the following components: a cross-linking agent, a hydrophilic material, a hydrophobic material and a solvent;
  • the cross-linking agent includes poly(dimethylsiloxane)-di-shrinkage One or more of glycerol ether, polyethylene glycol diglycidyl ether and 4-(2,3-glycidoxy)-N,N-bis(2,3-epoxypropyl)aniline;
  • the hydrophilic material includes one or more of polyethylene oxide, polyethylene oxide-containing copolymers, polypropylene oxide, polypropylene oxide-containing copolymers, polyvinylpyrrolidone and polyvinyl alcohol
  • the hydrophobic material includes one or more of polyvinylpyridine, vinylpyridine-acrylamide copolymer, polyvinylpyrrole and vinylpyrrole-acrylamide copolymer.
  • materials with high biocompatibility are selected as raw materials for preparing biocompatible membranes (selectively permeable membranes), and they are optimized and combined, thereby greatly improving the biocompatibility of the glucose biosensor.
  • the components of the selective biocompatible membrane and the ratio between the components such as the types and proportions of the hydrophobic and hydrophilic components, the simultaneous regulation of oxygen and glucose can be achieved.
  • a free radical scavenger after the biocompatible membrane solution is made, the stability and service life of the biocompatible membrane solution are greatly improved, and its stability and service life have not changed significantly within one year , So as to be able to prepare a highly consistent implantable continuous glucose monitoring system.
  • Figure 1 The relationship between the current of the implantable glucose biosensor in the PBS buffer solution of glucose and the number of pulling times in the embodiment 1 of the present invention
  • Figure 2 shows the influence of oxygen on the current signal of the implanted glucose biosensor in Example 1 of the present invention
  • curve a represents the glucose biosensor covered with a biocompatible membrane in Example 1
  • curve b represents the glucose biosensor without a biocompatible membrane Glucose biosensor
  • Figure 3 is the current response curve of the implantable glucose biosensor in Example 1 of the present invention in a PBS buffer solution containing 5mmol/L glucose.
  • Curve a represents the glucose biosensor without a biocompatible membrane, and curve b represents the implementation.
  • Figure 4 is the working curve of the implantable glucose biosensor in Example 1 of the present invention.
  • Curve a represents the glucose biosensor without a biocompatible membrane
  • curve b represents the glucose biosensor covered with a biocompatible membrane in Example 1. sensor;
  • Figure 5 is a human body experiment result of the implantable glucose biosensor in the implantable continuous glucose monitoring system in Example 1 of the present invention
  • Fig. 6 is a two-week experimental result of the implanted glucose biosensor and a foreign brand of dynamic blood glucose meter in the implanted continuous glucose monitoring system of the human body in Example 2 of the present invention.
  • the present invention provides a biocompatible film, which is mainly made of the following components:
  • Crosslinking agents hydrophilic materials, hydrophobic materials and solvents
  • the crosslinking agent includes poly(dimethylsiloxane)-diglycidyl ether, polyethylene glycol diglycidyl ether and 4-(2,3-glycidyloxy)-N,N-bis( One or more of 2,3-epoxypropyl)aniline;
  • the hydrophilic material includes one or more of polyethylene oxide, polyethylene oxide-containing copolymers, polypropylene oxide, polypropylene oxide-containing copolymers, polyvinylpyrrolidone and polyvinyl alcohol ;
  • the hydrophobic material includes one or more of polyvinylpyridine, vinylpyridine-acrylamide copolymer, polyvinylpyrrole, and vinylpyrrole-acrylamide copolymer.
  • the crosslinking agent includes poly(dimethylsiloxane)-diglycidyl ether, polyethylene glycol diglycidyl ether and 4-(2,3-glycidyloxy)-N , One or more of N-bis(2,3-epoxypropyl)aniline, more preferably poly(dimethylsiloxane)-diglycidyl ether; parts by weight of the crosslinking agent It is preferably 500-5000 parts, more preferably 1000-4000 parts, and most preferably 2000-3000 parts. Specifically, in the embodiment of the present invention, it may be 1500 parts or 2000 parts.
  • the hydrophilic material includes one or more of polyethylene oxide, polyethylene oxide-containing copolymers, polypropylene oxide, polypropylene oxide-containing copolymers, polyvinylpyrrolidone and polyvinyl alcohol , More preferably polyethylene oxide or a copolymer containing polyethylene oxide; the weight parts of the hydrophilic material is preferably 5-50 parts, more preferably 10-40 parts, most preferably 20-30 Part, specifically, in the embodiment of the present invention, it may be 20 parts.
  • the hydrophobic material includes one or more of polyvinylpyridine, vinylpyrrole-acrylamide copolymer, polyvinylpyrrole and vinylpyrrole-acrylamide copolymer, more preferably polyvinylpyridine; parts by weight of the hydrophobic material
  • the number is preferably 200-5000 parts, more preferably 500-4000 parts, most preferably 1000-3000 parts, most preferably 2000-2500 parts, specifically, in the embodiment of the present invention, it can be 1000 parts or 2000 parts .
  • the enhancer is a hydrophobic material, which can enhance the mechanical strength of the biocompatible film; preferably includes one or one of styrene-vinylpyridine copolymer, styrene-vinylpyrrole copolymer, and styrene-acrylamide copolymer Several, more preferably styrene-vinylpyridine copolymer; the weight parts of the reinforcing agent is preferably 200-5000 parts, more preferably 500-4000 parts, most preferably 1000-3000 parts, most preferably 2000- 2500 parts, specifically, in the embodiment of the present invention, it may be 1000 parts or 2000 parts.
  • the free radical scavenger can completely consume the free radicals (ie, crosslinking agent) in the solution that have not participated in the reaction, and preferably includes ethanolamine, propanolamine, isopropanolamine, aniline, and polyepoxy with terminal amino groups.
  • the weight parts of the radical scavenger is preferably 200-2000 parts, It is more preferably 500-1000 parts, most preferably 500-800 parts, specifically, in the embodiment of the present invention, it may be 500 parts or 600 parts.
  • the solvent is preferably an alcohol with a volume fraction of 95%, such as one or more of methanol, ethanol, propanol and isopropanol; the weight of the solvent is preferably 20,000 parts.
  • the present invention also provides a method for preparing a biocompatible film, which includes the following steps:
  • the crosslinking agent includes poly(dimethylsiloxane)-diglycidyl ether, polyethylene glycol diglycidyl ether and 4-(2,3-glycidyloxy)-N,N-bis( One or more of 2,3-epoxypropyl)aniline;
  • the hydrophilic material includes one or more of polyethylene oxide, polyethylene oxide-containing copolymers, polypropylene oxide, polypropylene oxide-containing copolymers, polyvinylpyrrolidone and polyvinyl alcohol ;
  • the hydrophobic material includes one or more of polyvinylpyridine, vinylpyridine-acrylamide copolymer, polyvinylpyrrole, and vinylpyrrole-acrylamide copolymer;
  • the types and amounts of the raw materials used to prepare the biocompatible membrane solution of the present invention are consistent with the types and amounts of the raw materials described above, and will not be repeated here.
  • the hydrophilic material, the hydrophobic material and the reinforcing agent are respectively added with an appropriate amount of solvent to prepare the hydrophilic material solution, the hydrophobic material solution and the reinforcing agent solution.
  • the solvents used are all alcohol solvents with a volume fraction of 95%.
  • the mass concentration of the prepared hydrophilic material solution is preferably 5-20 mg/mL, more preferably 10-15 mg/mL; specifically, in an embodiment of the present invention, it may be 10 mg/mL;
  • the mass concentration is preferably 50-300 mg/mL, more preferably 100-200 mg/mL, specifically, in an embodiment of the present invention, it may be 100 mg/mL;
  • the mass concentration of the enhancer solution is preferably 25-300 mg/mL mL, more preferably 50-200 mg/mL, most preferably 100-150 mg/mL, specifically, in an embodiment of the present invention, it may be 100 mg/mL.
  • the crosslinking agent, the hydrophilic material solution, the hydrophobic material solution and the reinforcing agent are mixed, heated and reacted for a certain period of time, then a free radical scavenger is added, and the reaction is continued for a certain period of time to obtain a biocompatible solution.
  • the reaction temperature before adding the radical scavenger is preferably 20 to 70°C, more preferably 30 to 60°C, and most preferably 40 to 50°C. Specifically, in the embodiments of the present invention, it may be 30°C or 60°C; the reaction time before adding the free radical scavenger is preferably 40-120 min, more preferably 50-100 min, most preferably 60-80 min, specifically, in the embodiment of the present invention, it may be 60 min.
  • the reaction temperature after adding the radical scavenger is preferably 20 to 70°C, more preferably 30 to 60°C, most preferably 40 to 50°C, specifically, in the embodiment of the present invention, it may be 30°C or 60°C
  • the thickness of the reaction time for adding a radical scavenger is preferably 40 to 120 minutes, more preferably 50 to 100 minutes, and most preferably 60 to 80 minutes. Specifically, in an embodiment of the present invention, it may be 60 minutes.
  • the purpose of adding ethanolamine is to fully stabilize the viscosity of the solution and ensure the consistency of the product, and at the same time completely consume the free radicals (crosslinking agent) in the solution that have not yet participated in the reaction.
  • the stability and service life of the biocompatible membrane solution have been greatly improved, and its stability and service life have not changed significantly within one year.
  • the viscosity of the obtained biocompatible membrane solution at 25°C is preferably 50 to 1000 mPa, more preferably 100 to 900 mPa ⁇ s, most preferably 200 to 800 mPa ⁇ s, and most preferably 300 to 700 mPa ⁇ s. Specifically, it may be 100 mPa ⁇ s, 200 mPa ⁇ s, 300 mPa ⁇ s, 400 mPa ⁇ s, 500 mPa ⁇ s, 600 mPa ⁇ s, 700 mPa ⁇ s, or 800 mPa ⁇ s.
  • the substrate is immersed in the above-mentioned solution, and a layer of biocompatible membrane solution is coated on the surface of the substrate by using the dipping and pulling method.
  • the substrate is preferably a biosensor, including but not limited to a glucose biosensor, a lactate biosensor and a blood ketone biosensor,
  • the dipping and pulling is preferably performed in a clean environment of class 100,000 and an environment of saturated ethanol vapor.
  • the descent rate of the dipping and pulling is preferably 100-5000 ⁇ m/s, more preferably 500-4000 ⁇ m/s, most preferably 1000-3000 ⁇ m/s, most preferably 1500-2000 ⁇ m/s, specifically, in the present invention In an embodiment, it may be 200 ⁇ m/s, 2000 ⁇ m/s or 5000 ⁇ m/s; the pulling rate of the immersion pulling is preferably 20-300 ⁇ m/s, more preferably 50-250 ⁇ m/s, most preferably 100-200 ⁇ m /s, specifically, in the embodiment of the present invention, it may be 25 ⁇ m/s, 100 ⁇ m/s or 300 ⁇ m/s.
  • the substrate coated with the biocompatible film is dried into a film in a strictly controlled environment.
  • the solvent is completely evaporated, the surface of these glucose biosensors has been completely covered by a thin biocompatible film.
  • the drying temperature is preferably 22 to 25°C, more preferably 23 to 24°C; the present invention has no special restrictions on the drying time, and the solvent is evaporated to dryness.
  • the drying time is 30 to 120 minutes, more preferably 50 to 100 minutes, and most preferably 60 to 80 minutes.
  • the relative humidity of the environment in which the film is dried and formed is preferably 35-45%.
  • the above-mentioned dipping, pulling and drying process can be repeated many times, usually 3 to 4 times to reach the required thickness. Since the biocompatible film in the present invention is formed through multiple film-forming processes, its final regulation of oxygen and glucose can be very convenient and effective through the thickness of the film (the number of times of immersion and pulling) and the biological The formulation of the compatible membrane solution is optimized to achieve the desired effect.
  • the present invention also provides an implantable biosensor, which includes a biosensor substrate and a biocompatible film coated on the surface of the biosensor substrate;
  • the biocompatible film is the biocompatible film described above.
  • the thickness of the biocompatible film is preferably 50 to 500 ⁇ m, more preferably 100 to 400 ⁇ m, and most preferably 200 to 300 ⁇ m.
  • the biosensor is preferably a glucose biosensor, which contains electrochemically activated glucose magnesium oxide.
  • the glucose biosensor in the present invention is based on the third-generation biosensing technology-the electrochemical activation technology of oxidoreductase.
  • the third-generation biosensing technology is a biosensing technology developed by the direct electrochemistry of oxidoreductase.
  • the glucose biosensor containing electrochemically activated glucose oxidase in the present invention developed based on the third-generation biosensing technology not only maintains its catalytic oxidation performance on glucose, but also through direct electrochemical reaction
  • the catalytic oxidation efficiency of glucose is also significantly higher than the catalytic oxidation efficiency of glucose by natural glucose oxidase through oxygen.
  • the direct electrochemistry of glucose oxidase greatly simplifies the design and manufacture of glucose biosensors, and also significantly improves the sensitivity, accuracy, stability, and specificity of glucose biosensors. And anti-interference ability.
  • the present invention coats the highly biocompatible biocompatible membrane of the present invention on the surface of the glucose biosensor containing electrochemically activated glucose oxidase, which can successfully realize the high biocompatibility of the glucose biosensor. Performance, and at the same time realize the precise regulation of oxygen and glucose.
  • implantable biosensor coated with the biocompatible membrane of the present invention can also be applied to other implantable continuous monitoring systems, such as the monitoring of lactic acid and blood ketones.
  • the preparation method of the implantable biosensor of the present invention is the same as the preparation method of the biocompatible membrane described above, except that the matrix in the method is replaced with a glucose biosensor containing electrochemically activated glucose oxidase That's it, the rest of the operations are the same. The present invention will not be repeated here.
  • the present invention provides a biocompatible film, which is made of the following parts by weight: crosslinking agent: 500-5000 parts; hydrophilic material: 5-50 parts; hydrophobic material: 200-5000 parts; reinforcing agent: 200 parts ⁇ 5000 parts; free radical scavenger: 200 ⁇ 2000 parts; solvent: 20000 parts;
  • the hydrophilic material includes polyethylene oxide, copolymers containing polyethylene oxide, polypropylene oxide, and polyethylene oxide One or more of propane copolymer, polyvinylpyrrolidone and polyvinyl alcohol;
  • the hydrophobic material includes polyvinylpyridine, vinylpyridine-acrylamide copolymer, polyvinylpyrrole and vinylpyrrole-acrylamide copolymer One or more;
  • the enhancer includes one or more of styrene-vinylpyridine copolymer, styrene-vinylpyrrole copolymer and styrene-acrylamide copolymer;
  • materials with high biocompatibility are selected as raw materials for preparing biocompatible membranes (selectively permeable membranes), and they are optimized and combined, thereby greatly improving the biocompatibility of the glucose biosensor.
  • the components of the selective biocompatible membrane and the ratio between the components such as the types and proportions of the hydrophobic and hydrophilic components, the simultaneous regulation of oxygen and glucose can be achieved.
  • a free radical scavenger after the biocompatible membrane solution is made, the stability and service life of the biocompatible membrane solution are greatly improved, and its stability and service life have not changed significantly within one year , So as to be able to prepare a highly consistent implantable continuous glucose monitoring system.
  • the glucose biosensor coated with the highly biocompatible biocompatible membrane of the present invention can very effectively and accurately simultaneously regulate oxygen and glucose, and more importantly, the biocompatibility in the present invention
  • the existence of the sexual membrane significantly expands the monitorable range of glucose, and greatly improves the stability and biocompatibility of the glucose biosensor in the human body, which fully meets the need for calibration-free (factory calibration) implantable continuous glucose monitoring system
  • the requirements for the calibration-free implantable continuous glucose monitoring system have laid a solid foundation for mass production.
  • the biocompatible membrane of the present invention can also be applied to other implantable continuous monitoring systems, such as monitoring of lactic acid and blood ketones.
  • biocompatible membrane provided by the present invention, its preparation method and implantable biosensor are described in detail below in conjunction with examples, but it should not be understood as a limitation of the protection scope of the present invention.
  • the solvents in this embodiment are all 95% ethanol.
  • a biocompatible membrane solution is uniformly coated on the glucose biosensor containing electrochemically activated glucose oxidase by dipping and pulling; the descending rate is 2000 ⁇ m /s, the pulling rate is 100 ⁇ m/s; then it is dried for 60 minutes at a temperature of 25°C and a relative humidity of 40%, and then the process of dipping and pulling and drying is repeated 5 times for a total of six cycles of dipping and pulling the film And after the drying cycle, an implantable glucose biosensor is obtained.
  • the glucose biosensor in this embodiment was immersed in a 5mmol/L glucose PBS buffer solution for current detection. The result is shown in Figure 1.
  • Figure 1 shows the glucose biosensor in the embodiment 1 of the present invention. The relationship between the current in the PBS buffer solution and the number of pulls.
  • the glucose biosensor developed based on the third-generation biosensing technology
  • oxygen is the natural medium for glucose oxidase to catalyze the oxidation of glucose
  • body fluids such as tissue fluid Or oxygen in the blood inevitably participates in the catalytic oxidation of glucose.
  • the interference of oxygen will bring great challenges to the accurate monitoring of glucose. Therefore, the present invention has further conducted experiments to prove that this layer of biocompatible membrane can also basically eliminate the interference of oxygen. Signal influence.
  • oxygen is introduced into the PBS buffer solution containing 10mmol/L glucose, the glucose biosensor covered with the biocompatible membrane in Example 1 only has less than 1% attenuation.
  • the present invention successfully realizes the precise regulation of oxygen and glucose by covering the glucose biosensor with a biocompatible membrane, it is necessary to prepare accurate, reproducible and stable, which can be used for implanted glucose continuous
  • the glucose biosensors of the monitoring system it is also necessary to ensure that these sensors have a sufficiently wide linear response range and a high degree of stability, which can be achieved by optimizing the biocompatible membrane on the glucose biosensor.
  • the glucose biosensor undergoes three cycles of immersion, pulling, coating and drying in a biocompatible membrane solution, it is compared with the glucose biosensor without any biocompatible membrane.
  • the response time of glucose has been extended from 2 minutes to 4 minutes, but its current signal is well regulated by this biocompatible membrane, and the stability of the glucose biosensor has also been significantly improved (Figure 3).
  • the monitorable range of glucose has been successfully expanded from 10mmol/L to 35mmol/L, which fully meets the glucose monitoring needs of patients with diabetes ( Figure 4).
  • the biocompatible membrane of the present invention exhibits superior performance in vitro
  • its performance during in vivo monitoring is the most powerful proof of its biocompatibility. Therefore, based on the work in vitro, the present invention applies a glucose biosensor covered with a biocompatible membrane to an implanted continuous glucose monitoring system.
  • the results were good in the first 16 days, and the sensitivity (Baseline) there is no obvious attenuation (Figure 5, a).
  • This is the longest working life glucose biosensor for human monitoring so far. More importantly, its monitored glucose concentration (curve representation) and index
  • the results of blood glucose testing are highly consistent ( Figure 5, panel a). From the 17th day after implantation, the sensitivity of the sensor decreased significantly, and the monitored glucose concentration and the result of the finger blood glucose test began to appear large differences. Therefore, for safety reasons, the working life of the biocompatible membrane in the present invention is set to 15 days.
  • the glucose biosensor of the implantable continuous glucose monitoring system is implanted under the skin, the glucose it monitors is the glucose in the tissue fluid, and there is an inevitable lag between the glucose in the tissue fluid and the finger blood glucose. Therefore, in the morning of the 15th day after the sensor is implanted, the present invention performs a high-frequency finger blood glucose test on blood glucose starting from fasting blood glucose. In the present invention, there is an average 9-minute lag between the concentration change curve of glucose in the tissue fluid detected by the implantable continuous glucose monitoring system and the blood glucose concentration change curve detected by finger blood ( Figure 5, b).
  • the solvents in this embodiment are all 95% n-propanol.
  • a biocompatible membrane solution is uniformly coated on the glucose biosensor containing electrochemically activated glucose oxidase by dipping and pulling; the descending rate is 200 ⁇ m /s, the pulling rate is 25 ⁇ m/s, and then drying for 60 minutes at a temperature of 25°C and a relative humidity of 40%, and then repeating the dipping, pulling and drying process twice for a total of 3 cycles of dipping and pulling the film And after the drying cycle, an implantable glucose biosensor is obtained.
  • the present invention successfully realizes the glucose biosensor which can be used in the implantable continuous glucose monitoring system by covering the biocompatible membrane on the glucose biosensor.
  • the glucose concentration change curve monitored by it is highly consistent with the glucose concentration change curve monitored by a well-known foreign brand (Figure 6).
  • the solvents in this embodiment are all 95% isopropanol.
  • the lactic acid biosensor containing electrochemically activated lactic acid oxidase is uniformly coated with a biocompatible membrane solution by dipping and pulling; the descending rate is 5000 ⁇ m /s, the pulling rate is 300 ⁇ m/s; then, it is dried for 40 minutes at a temperature of 22°C and a relative humidity of 35%, and then the process of dipping, pulling and drying is repeated 3 times. A total of 4 cycles of dipping, pulling and coating are carried out. After the drying cycle, an implantable lactic acid biosensor is obtained. After covering the biocompatible membrane, the linear range of its response to lactic acid was successfully extended from 8mmol/L to 30mmol/L, which fully met the needs of lactic acid in vivo monitoring.

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Abstract

一种生物相容性膜，主要由以下组分制成：交联剂、亲水材料、疏水材料和溶剂。生物相容性膜可以实现同时对氧气和葡萄糖的调控，大大地改善了生物相容性膜溶液的稳定性和使用寿命。还提供了一种生物相容性膜的制备方法及植入式生物传感器。

Description

一种生物相容性膜、其制备方法及植入式生物传感器 技术领域
本发明属于生物传感器技术领域，尤其涉及一种生物相容性膜、其制备方法及植入式生物传感器。
背景技术
近年来迅速发展起来的植入式人体持续监测系统，例如植入式葡萄糖持续监测系统，为千千万万的糖尿病患者带来了福音。糖尿病已成为世界范围内的常见病，根据国际糖尿病联盟的统计，世界上有超过四亿的糖尿病患者，其中中国的糖尿病患者人数就超过一亿。由于现有的医疗技术还没有能够达到根治糖尿病，当前唯一能做的就是最大限度地把血糖控制在正常范围以内，以减少和延缓糖尿病并发症的出现。对于糖尿病患者而言，每天进行自我血糖监测就成了生活的一部分。然而，传统的指血血糖检测局限性很大，只能提供一天中某个时间点的血糖值，要进行较可靠的血糖监控，糖尿病患者就需要每天进行频繁的指血血糖检测，这就给他们的工作和生活带来了极大的不便。另一方面，植入式葡萄糖持续监测系统能让糖尿病患者更方便和更有效地对血糖进行调控。它可以不间断地对血糖进行实时检测，已逐渐地成为血糖调控的有力工具。
作为植入式持续葡萄糖监测系统的生物传感器的主要部件和唯一与活体直接接触的界面，生物相容性膜的性能直接决定了植入式持续葡萄糖监测系统的生物相容性、灵敏度、稳定性、抗干扰能力和进行活体监测时的工作寿命。现有的植入式持续监测系统，例如植入式葡萄糖持续监测系统，都是基于第一或第二代生物传感技术发展起来的。利用第一代生物传感技术对葡萄糖进行持续监测的有德康的Dexcom G5和G6和美敦力的Guardian和iPro2，其工作原理是通过电化学方法检测葡萄糖在葡萄糖氧化酶的催化氧化过程中氧气被还原时生成的过氧化氢来间接地对葡萄糖进行监测。由于基于第一代生物传感技术发展起来的持续葡萄糖监测系统是依赖体液如组织液或血液中的氧气-葡萄糖氧化酶催化氧化葡萄糖的自然媒介体，来实现对葡萄糖的监测，而体液中的氧气含量(0.2-0.3毫摩尔/升)远远低于葡萄糖(5-10毫摩尔/升)，它的生物相容性膜在高度生物相容的基础上，必须能够在最大程度地允许氧气的通过，同时有效地拟制葡萄糖的通过。众所周知，和葡萄糖相比，氧气是疏水的，所以 它的生物相容性膜也必须是高度疏水的。但是，高度疏水的要求给生物相容性膜的设计带来了巨大的挑战，虽然经过20多年的探索，其性能还远远不能满足葡萄糖持续监测的需要。例如，美敦力的Guardian和iPro2还需要每天进行两次校正，它们的工作寿命也只有一个星期。
上世纪末，Heller等人(Accounts of Chemical Research 23(1990)128-134)发现在生物传感膜中引入氧化还原物质-人工氧化还原媒介体(氧化还原小分子如铁氰化物，二茂铁及其衍生物或氧化还原高分子)，葡萄糖氧化酶可以通过这些人工媒介体来实现与电极进行电子交换。基于此原理发展起来的第二代生物传感技术目前被广泛应用于生物传感器，特别是葡萄糖生物传感器，包括植入式持续葡萄糖监测系统的葡萄糖生物传感器，例如雅培糖尿病护理的FreeStyle Libre。由于第二代生物传感技术是通过在生物传感器中引入人工合成的氧化还原媒介体来实现对葡萄糖进行直接的电化学检测，通过对氧化还原媒介体的分子设计和优化，葡萄糖的检测可以在非常低的电位下实现，从而大大地提高了植入式持续葡萄糖监测系统的抗干扰能力。由于这类葡萄糖监测系统是通过人工氧化还原媒介体对葡萄糖进行直接的电化学检测，其灵敏度也得到了显著的改善。另一方面，虽然通过引入人工合成的氧化还原媒介体实现了葡萄糖的直接的电化学检测，氧气作为葡萄糖氧化酶催化氧化葡萄糖的自然媒介体，不可避免地参与葡萄糖的催化氧化，成为葡萄糖监测的一个重要的干扰因素。
为了进一步提高这类植入式持续葡萄糖监测系统的性能，人们引入了各种生物相容性膜，一方面最大限度地消除氧气的干扰，另一方面拓展葡萄糖的可监测范围。鉴于葡萄糖和氧气的亲水性的显著差别，高度的亲水性是这类生物相容性膜的一个基本特性。虽然它们可以非常有效地消除氧气的干扰，但却难以实现有效地和精确地对氧气和葡萄糖进行同时调控。若要有效地调控葡萄糖，就必须显著地增加生物相容性膜的厚度。过厚的生物相容性膜将直接导致植入式持续葡萄糖监测系统对葡萄糖的响应时间过长，出现严重的滞后现象，大大降低其准确性。例如雅培糖尿病护理的FreeStyle Libre在PBS(pH 7.4)缓冲溶液中对葡萄糖的响应时间长达8～10分钟。另外，现有的生物相容性膜的配方中，都存在一个化学交联反应，这就大大地缩短了生物相容性膜溶液的使用寿 命，无形中增加了植入式持续葡萄糖监测系统的生产成本。更为严重的是，随着使用时间的增加，化学交联反应越来越多，生物相容性膜溶液的粘度也越来越大，从而严重地影响到产品的一致性。
发明内容
本发明的目的在于提供一种生物相容性膜、其制备方法及植入式生物传感器，本发明中的生物相容性膜能够提高生物传感器的生物相容性，能够实现同时对氧气和葡萄糖的调控，改善了生物相容性膜溶液的稳定性和使用寿命。
本发明提供一种生物相容性膜，主要由以下组分制成：
交联剂、亲水材料、疏水材料和溶剂；
所述交联剂包括聚(二甲基硅氧烷)-二缩水甘油醚、聚乙二醇二縮水甘油醚和4-(2，3-环氧丙氧基)-N，N-二(2，3-环氧丙基)苯胺中的一种或几种；
所述亲水材料包括聚环氧乙烷、含有聚环氧乙烷的共聚物、聚环氧丙烷、含有聚环氧丙烷的共聚物、聚乙烯吡咯烷酮和聚乙烯醇中的一种或几种；
所述疏水材料包括聚乙烯吡啶、乙烯吡啶-丙烯酰胺共聚物、聚乙烯吡咯以及乙烯吡咯-丙烯酰胺共聚物中的一种或几种。
优选的，所述亲水材料为聚环氧乙烷或含有聚环氧乙烷的共聚物；所述疏水材料为聚乙烯吡啶。
优选的，所述交联剂为聚(二甲基硅氧烷)-二缩水甘油醚。
优选的，生物相容性膜的原料还包括增强剂；
所述增强剂包括苯乙烯-乙烯吡啶共聚物、苯乙烯-乙烯吡咯共聚物和苯乙烯-丙烯酰胺共聚物中的一种或几种。
优选的，所述增强剂为苯乙烯-乙烯吡啶共聚物。
优选的，生物相容性膜的原料还包括自由基清除剂；
所述自由基清除剂包括乙醇胺、丙醇胺、异丙醇胺、苯胺、带有末端氨基的聚环氧乙烷、环氧乙烷的共聚物和带有末端氨基的聚环氧丙烷中的一种或几种。
优选的，所述自由基清除剂为乙醇胺。
本发明提供一种生物相容性膜的制备方法，包括以下步骤：
A)将交联剂、亲水材料和疏水材料在溶剂中混合，在20～70℃下反应 40～120min，在40～70℃下反应40～120min，得到生物相容性膜溶液；
所述交联剂包括聚(二甲基硅氧烷)-二缩水甘油醚、聚乙二醇二縮水甘油醚和4-(2，3-环氧丙氧基)-N，N-二(2，3-环氧丙基)苯胺中的一种或几种；
所述亲水材料包括聚环氧乙烷、含有聚环氧乙烷的共聚物、聚环氧丙烷、含有聚环氧丙烷的共聚物、聚乙烯吡咯烷酮和聚乙烯醇中的一种或几种；
所述疏水材料包括聚乙烯吡啶、乙烯吡啶-丙烯酰胺共聚物、聚乙烯吡咯以及乙烯吡咯-丙烯酰胺共聚物中的一种或几种；
B)将基体浸入所述生物相容性溶液，以浸渍提拉法在基体表面涂布所述生物相容性膜溶液；
C)将涂布有生物相容性膜溶液的基体进行干燥，得到包覆有生物相容性膜的基体。
优选的，所述步骤A具体为：
将交联剂、亲水材料、疏水材料和增强剂在溶剂中混合，在20～70℃下反应40～120min，然后加入自由基清除剂，在40～70℃下反应40～120min，得到生物相容性膜溶液。
本发明提供一种植入式生物传感器，包括生物传感器基体和包覆在所述生物传感器基体表面的生物相容性膜；
所述生物相容性膜为上文所述的生物相容性膜。
本发明提供一种生物相容性膜，主要由以下组分制成：交联剂、亲水材料、疏水材料和溶剂；所述交联剂包括聚(二甲基硅氧烷)-二缩水甘油醚、聚乙二醇二縮水甘油醚和4-(2，3-环氧丙氧基)-N，N-二(2，3-环氧丙基)苯胺中的一种或几种；所述亲水材料包括聚环氧乙烷、含有聚环氧乙烷的共聚物、聚环氧丙烷、含有聚环氧丙烷的共聚物、聚乙烯吡咯烷酮和聚乙烯醇中的一种或几种；所述疏水材料包括聚乙烯吡啶、乙烯吡啶-丙烯酰胺共聚物、聚乙烯吡咯以及乙烯吡咯-丙烯酰胺共聚物中的一种或几种。本发明通过选择具有高度生物相容性的材料来作为制备生物相容性膜(选择性渗透膜)的原料，并对它们进行优化组合，进而大大地提高葡萄糖生物传感器的生物相容性。通过调节选择性生物相容性膜的组分和各组分之间的比例，例如疏水和亲水组分的种类和配比，可以实现同时对氧气和葡萄糖的调控。另外，通过在生物相容性膜溶液制成以后， 加入自由基清除剂，大大地改善了生物相容性膜溶液的稳定性和使用寿命，其稳定性和使用寿命在一年内没有明显地变化，从而能够制备出具有高度一致性的植入式持续葡萄糖监测系统。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图获得其他的附图。
图1本发明实施例1中植入式葡萄糖生物传感器在葡萄糖的PBS缓冲溶液中电流与提拉次数的关系图；
图2为氧气对本发明实施例1中植入式葡萄糖生物传感器的电流信号影响；a曲线代表实施例1中覆盖有生物相容性膜的葡萄糖生物传感器，b曲线代表没有生物相容性膜的葡萄糖生物传感器；
图3为本发明实施例1中植入式葡萄糖生物传感器在含有5mmol/L的葡萄糖的PBS缓冲溶液中的电流响应曲线，a曲线代表没有生物相容性膜的葡萄糖生物传感器，b曲线代表实施例1中覆盖有生物相容性膜的葡萄糖生物传感器；
图4为本发明实施例1中植入式葡萄糖生物传感器的工作曲线，a曲线代表没有生物相容性膜的葡萄糖生物传感器，b曲线代表实施例1中覆盖有生物相容性膜的葡萄糖生物传感器；
图5为本发明实施例1中植入式葡萄糖生物传感器在植入式持续葡萄糖监测系中的人体的实验结果；
图6为本发明实施例2中植入式葡萄糖生物传感器和国外某品牌的动态血糖仪在植入式持续葡萄糖监测系中的人体的两周的实验结果。
具体实施方式
本发明提供了一种生物相容性膜，主要由以下组分制成：
交联剂、亲水材料、疏水材料和溶剂；
所述交联剂包括聚(二甲基硅氧烷)-二缩水甘油醚、聚乙二醇二縮水甘油醚和4-(2，3-环氧丙氧基)-N，N-二(2，3-环氧丙基)苯胺中的一种或几种；
所述亲水材料包括聚环氧乙烷、含有聚环氧乙烷的共聚物、聚环氧丙烷、 含有聚环氧丙烷的共聚物、聚乙烯吡咯烷酮和聚乙烯醇中的一种或几种；
所述疏水材料包括聚乙烯吡啶、乙烯吡啶-丙烯酰胺共聚物、聚乙烯吡咯以及乙烯吡咯-丙烯酰胺共聚物中的一种或几种。
在本发明中，所述交联剂包括聚(二甲基硅氧烷)-二缩水甘油醚、聚乙二醇二縮水甘油醚和4-(2，3-环氧丙氧基)-N，N-二(2，3-环氧丙基)苯胺中的一种或几种，更优选为聚(二甲基硅氧烷)-二缩水甘油醚；所述交联剂的重量份数优选为500～5000份，更优选为1000～4000份，最优选为2000～3000份，具体的，在本发明的实施例中，可以是1500份或2000份。
所述亲水材料包括聚环氧乙烷、含有聚环氧乙烷的共聚物、聚环氧丙烷、含有聚环氧丙烷的共聚物、聚乙烯吡咯烷酮和聚乙烯醇中的一种或几种，更优选为聚环氧乙烷或含有聚环氧乙烷的共聚物；所述亲水材料的重量份数优选为5～50份，更优选为10～40份，最优选为20～30份，具体的，在本发明的实施例中，可以是20份。
所述疏水材料包括聚乙烯吡啶、乙烯吡啶-丙烯酰胺共聚物、聚乙烯吡咯以及乙烯吡咯-丙烯酰胺共聚物中的一种或几种，更优选为聚乙烯吡啶；所述疏水材料的重量份数优选为200～5000份，更优选为500～4000份，最优选为1000～3000份，最优选为2000～2500份，具体的，在本发明的实施例中，可以是1000份或2000份。
所述增强剂为疏水性材料，能够增强生物相容性膜的机械强度；优选包括苯乙烯-乙烯吡啶共聚物、苯乙烯-乙烯吡咯共聚物和苯乙烯-丙烯酰胺共聚物中的一种或几种，更优选为苯乙烯-乙烯吡啶共聚物；所述增强剂的重量份数优选为200～5000份，更优选为500～4000份，最优选为1000～3000份，最优选为2000～2500份，具体的，在本发明的实施例中，可以是1000份或2000份。
所述自由基清除剂能够将溶液中还没有参与反应的自由基(即交联剂)完全消耗掉，优选包括乙醇胺、丙醇胺、异丙醇胺、苯胺、带有末端氨基的聚环氧乙烷、环氧乙烷的共聚物和带有末端氨基的聚环氧丙烷中的一种或几种，更优选为乙醇胺；所述自由基清除剂的重量份数优选为200～2000份，更优选为500～1000份，最优选为500～800份，具体的，在本发明的实施例中，可以是500份或600份。
所述溶剂优选为体积分数为95％的醇类，如甲醇、乙醇、丙醇和异丙醇中的一种或几种；所述溶剂的重量份数优选为20000份。
本发明还提供了一种生物相容性膜的制备方法，包括以下步骤：
A)将交联剂、亲水材料和疏水材料在溶剂中混合，在20～70℃下反应40～120min，在40～70℃下反应40～120min，得到生物相容性膜溶液；
所述交联剂包括聚(二甲基硅氧烷)-二缩水甘油醚、聚乙二醇二縮水甘油醚和4-(2，3-环氧丙氧基)-N，N-二(2，3-环氧丙基)苯胺中的一种或几种；
所述亲水材料包括聚环氧乙烷、含有聚环氧乙烷的共聚物、聚环氧丙烷、含有聚环氧丙烷的共聚物、聚乙烯吡咯烷酮和聚乙烯醇中的一种或几种；
所述疏水材料包括聚乙烯吡啶、乙烯吡啶-丙烯酰胺共聚物、聚乙烯吡咯以及乙烯吡咯-丙烯酰胺共聚物中的一种或几种；
B)将基体浸入所述生物相容性溶液，以浸渍提拉法在基体表面涂布所述生物相容性膜溶液；
C)将涂布有生物相容性膜溶液的基体进行干燥，得到包覆有生物相容性膜的基体。
用于配制本发明中生物相容性膜溶液的原料的种类和用量与上文所述的原料的种类和用量一致，在此不再赘述。
本发明首先将亲水材料、疏水材料和增强剂分别添加适量溶剂配制成亲水材料溶液，疏水材料溶液和增强剂溶液，所使用的溶剂均为体积分数为95％的醇类溶剂。配制得到的亲水材料溶液的质量浓度优选为5～20mg/mL，更优选为10～15mg/mL；具体的，在本发明的实施例中，可以是10mg/mL；所述疏水材料溶液的质量浓度优选为50～300mg/mL，更优选为100～200mg/mL，具体的，在本发明的实施例中，可以是100mg/mL；所述增强剂溶液的质量浓度优选为25～300mg/mL，更优选为50～200mg/mL，最优选为100～150mg/mL，具体的，在本发明的实施例中，可以是100mg/mL。
本发明将交联剂、亲水材料溶液、疏水材料溶液和增强剂混合，加热反应一定时间，然后加入自由基清除剂，继续反应一定时间，得到生物相容性溶液。
在本发明中，加入自由基清除剂之前的反应温度优选为20～70℃，更优选为30～60℃，最优选为40～50℃，具体的，在本发明的实施例中，可以是30℃ 或60℃；加入自由基清除剂之前的反应时间优选为40～120min，更优选为50～100min，最优选为60～80min，具体的，在本发明的实施例中，可以是60min。
加入自由基清除剂之后的反应温度优选为20～70℃，更优选为30～60℃，最优选为40～50℃，具体的，在本发明的实施例中，可以是30℃或60℃；加入自由基清除剂之厚的反应时间优选为40～120min，更优选为50～100min，最优选为60～80min，具体的，在本发明的实施例中，可以是60min。
加入乙醇胺的目的是为了充分稳定溶液的粘度和保证产品的一致性，同时将溶液中的还没有参与反应的自由基(交联剂)完全消耗掉。经过乙醇胺处理以后，生物相容性膜溶液的稳定性和使用寿命得到了极大地改善，其稳定性和使用寿命在一年内没有明显地变化。
反应后，得到的生物相容性膜溶液的在25℃的粘度优选为50～1000mPa反应，更优选为100～900mPa·s，最优选为200～800mPa·s，最优选为300～700mPa·s，具体的，可以是100mPa·s、200mPa·s、300mPa·s、400mPa·s、500mPa·s、600mPa·s、700mPa·s或800mPa·s。
得到生物相容性膜溶液后，本发明将基体浸入上述溶液中，使用浸渍提拉法，在基体表面涂布一层生物相容性膜溶液。
在本发明中，所述基体优选为生物传感器，包括但不限于葡萄糖生物传感器、乳酸生物传感器和血酮生物传感器，
所述浸渍提拉优选在10万级的洁净环境和饱和乙醇蒸汽的环境中进行。所述浸渍提拉的下降速率优选为100～5000μm/s，更优选为500～4000μm/s，最优选为1000～3000μm/s，最优选为1500～2000μm/s，具体的，在本发明的实施例中，可以是200μm/s，2000μm/s或5000μm/s；所述浸渍提拉的提拉速率优选为20～300μm/s，更优选为50～250μm/s，最优选为100～200μm/s，具体的，在本发明的实施例中，可以是25μm/s，100μm/s或300μm/s。
然后将涂布有生物相容性膜的基体在严格控制的环境中干燥成膜，待溶剂完全蒸发，这些葡萄糖生物传感器表面已经被一层薄薄的生物相容性膜完全地覆盖。
在本发明中，所述干燥的温度优选为22～25℃，更优选为23～24℃；所述本发明对所述干燥的时间没有特殊的限制，以蒸干溶剂为止，优选的，所述干 燥的时间为30～120min，更优选为50～100min，最优选为60～80min。所述干燥成膜的环境的相对湿度优选为35～45％。
为增加生物相容性膜的厚度，上述浸渍提拉和干燥的过程可以重复多次，通常3～4次就可以达到所需要的厚度。由于本发明中的生物相容性膜是通过多次成膜过程而形成的，其最终的对氧气和葡萄糖的调控性能可以非常方便和有效地通过对膜的厚度(浸渍提拉次数)和生物相容性膜溶液的配方进行优化，从而达到预期的效果。
本发明还提供了一种植入式生物传感器，包括生物传感器基体和包覆在所述生物传感器基体表面的生物相容性膜；
所述生物相容性膜为上文所述的生物相容性膜。
所述生物相容性膜的厚度优选为50～500μm，更优选为100～400μm，最优选为诶200～300μm。
所述生物传感器优选为葡萄糖生物传感器，所述葡萄糖生物传感器包含电化学活化的葡萄糖氧化镁。
更优选的，本发明中的葡萄糖生物传感器是基于第三代生物传感技术-氧化还原酶的电化学活化技术。第三代生物传感技术是利用氧化还原酶的直接电化学发展起来的生物传感技术。实验表明，基于第三代生物传感技术发展起来的本发明中的含有电化学活化后的葡萄糖氧化酶的葡萄糖生物传感器，不仅保持了其对葡萄糖的催化氧化性能，而且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也有显著地提高。与第二代生物传感技术相比，葡萄糖氧化酶的直接电化学大大地简化了葡萄糖生物传感器的设计和制造，同时还显著地改善了葡萄糖生物传感器的灵敏度、准确性、稳定性、专一性和抗干扰能力。
另一方面，与第二代生物传感技术相似，氧气作为葡萄糖氧化酶催化氧化葡萄糖的自然媒介体，不可避免地参与葡萄糖的催化氧化，成为葡萄糖监测的一个重要的干扰因素。虽然通过直接电化学对葡萄糖的催化氧化效率大大高于葡萄糖氧化酶通过其自然媒介体氧气的催化氧化效率，但依然无法从根本上消除氧气的影响。另外，由于直接电化学对葡萄糖检测的高灵敏度，有效的调控葡萄糖也是第三代生物传感技术所面临的又一难题。这也是为什么虽然植入式 持续葡萄糖监测系已经经过30多年的发展，大多数的植入式持续葡萄糖监测系统的使用寿命还不尽人意。
进一步的，本发明在含有电化学活化后的葡萄糖氧化酶的葡萄糖生物传感器表面包覆本发明中的高度生物相容性的生物相容性膜，可以圆满地实现葡萄糖生物传感器的高度生物相容性，并同时实现对氧气和葡萄糖的精确地调控。
此外，包覆有本发明中的生物相容性膜的植入式生物传感器还可应用于其它植入式持续监测系统，例如乳酸和血酮的监测。
本发明中的植入式生物传感器的制备方法与上文所述的生物相容性膜的制备方法相同，只是将其方法中的基体替换为包含电化学活化后的葡萄糖氧化酶的葡萄糖生物传感器即可，其余操作均相同。本发明在此不再赘述。
本发明提供一种生物相容性膜，由以下重量份数组分制成：交联剂：500～5000份；亲水材料：5～50份；疏水材料：200～5000份；增强剂：200～5000份；自由基清除剂：200～2000份；溶剂：20000份；所述亲水材料包括聚环氧乙烷、含有聚环氧乙烷的共聚物、聚环氧丙烷、含有聚环氧丙烷的共聚物、聚乙烯吡咯烷酮和聚乙烯醇中的一种或几种；所述疏水材料包括聚乙烯吡啶、乙烯吡啶-丙烯酰胺共聚物、聚乙烯吡咯以及乙烯吡咯-丙烯酰胺共聚物中的一种或几种；所述增强剂包括苯乙烯-乙烯吡啶共聚物、苯乙烯-乙烯吡咯共聚物和苯乙烯-丙烯酰胺共聚物中的一种或几种；所述自由基清除剂包括乙醇胺、丙醇胺、异丙醇胺、苯胺、带有末端氨基的聚环氧乙烷、环氧乙烷的共聚物和带有末端氨基的聚环氧丙烷中的一种或几种。本发明通过选择具有高度生物相容性的材料来作为制备生物相容性膜(选择性渗透膜)的原料，并对它们进行优化组合，进而大大地提高葡萄糖生物传感器的生物相容性。通过调节选择性生物相容性膜的组分和各组分之间的比例，例如疏水和亲水组分的种类和配比，可以实现同时对氧气和葡萄糖的调控。另外，通过在生物相容性膜溶液制成以后，加入自由基清除剂，大大地改善了生物相容性膜溶液的稳定性和使用寿命，其稳定性和使用寿命在一年内没有明显地变化，从而能够制备出具有高度一致性的植入式持续葡萄糖监测系统。
本发明中包覆有本发明中的高度生物相容性的生物相容性膜的葡萄糖生物传感器可以非常有效和精确地对氧气和葡萄糖进行同时调控，更重要的是本 发明中的生物相容性膜的存在显著地拓展了葡萄糖的可监测范围，并大大地提高了葡萄糖生物传感器在人体中的稳定性和生物相容性，充分满足了免校正(工厂校正)植入式持续葡萄糖监测系统的要求，为免校正植入式持续葡萄糖监测系统的批量生产打下了坚实的基础。另外，本发明中的生物相容性膜也可以应用到其它植入式持续监测系统，例如乳酸和血酮的监测。
为了进一步说明本发明，以下结合实施例对本发明提供的一种生物相容性膜、其制备方法及植入式生物传感器进行详细描述，但不能将其理解为对本发明保护范围的限定。
实施例1
本实施例中的溶剂均为95％的乙醇。
将2mL的聚(二甲基硅氧烷)-二缩水甘油醚和2mL的10mg/mL聚环氧乙烷，20mL的100mg/mL的聚乙烯吡啶和20mL的100mg/mL的苯乙烯-乙烯吡啶共聚物充分混合，然后在60℃的水浴中加热反应60min。在反应后的生物相容性膜溶液中加入0.5mL的乙醇胺，充分混合后，再次在60℃的水浴中加热反应60min，得到生物相容性膜溶液。
在10万级的洁净室和含有饱和乙醇蒸汽的环境中，以浸渍提拉法在含有电化学活化后的葡萄糖氧化酶的葡萄糖生物传感器上均匀涂布生物相容性膜溶液；下降速率为2000μm/s，提拉速率为100μm/s；然后在温度25℃，相对湿度40％的环境下干燥60min，然后重复浸渍提拉和干燥的过程5次，共进行六个周期的浸渍提拉涂膜和干燥循环以后，得到植入式葡萄糖生物传感器。
将本实施例中的葡萄糖生物传感器浸入5mmol/L的葡萄糖的PBS缓冲溶液中，进行电流检测，结果如图1所示，图1为本发明实施例1中植入式葡萄糖生物传感器在葡萄糖的PBS缓冲溶液中电流与提拉次数的关系图。
如图一所示，当葡萄糖生物传感器完全被生物相容性膜包裹时，随着膜的厚度(浸渍提拉次数)的增加，其通过直接电化学对葡萄糖的催化氧化电流呈指数型地急剧下降，当经过六个周期的浸渍提拉涂膜和干燥循环以后，葡萄糖生物传感器的电流减少到不到原来的1％。这一实验结果表明，本发明中的生物相容性膜可以非常有效地调控葡萄糖(反应在葡萄糖催化氧化电流上)。
如前所述，对于基于第三代生物传感技术发展起来的葡萄糖生物传感器， 在对葡萄糖进行直接的电化学检测时，由于氧气是葡萄糖氧化酶催化氧化葡萄糖的自然媒介体，因而体液如组织液或血液中的氧气就不可避免地参与葡萄糖的催化氧化。如果葡萄糖生物传感器不对氧气进行有效地调控，氧气的干扰就会对葡萄糖的准确监测带来很大的挑战。因此，本发明进一步的进行了实验证实这层生物相容性膜也能够基本上消除氧气的干扰，如图2所示，图2为氧气对本发明实施例1中植入式葡萄糖生物传感器的电流信号影响。当在含有10mmol/L的葡萄糖的PBS缓冲溶液中通入氧气时，实施例1中覆盖有生物相容性膜的葡萄糖生物传感器仅仅有不到1％的衰减，当溶液中的氧气被氩气完全除去后，电流信号也随之恢复到原来的水平(图2，曲线a)。与此相反，氧气通入时，没有生物相容性膜的葡萄糖生物传感器的电流信号出现了明显的衰减，由于没有生物相容性膜的葡萄糖生物传感膜的稳定性原因，当溶液中的氧气被氩气完全除去后，电流信号也没能恢复到原来的水平(图2，曲线b)。
虽然本发明通过在葡萄糖生物传感器上覆盖上生物相容性膜成功地实现了对氧气和葡萄糖的精确调控，要制备出准确性、重现性和稳定性好、可以用于植入式葡萄糖持续监测系统的葡萄糖生物传感器，还要保证这些传感器要有足够宽的线性响应范围和高度的稳定性，这些可以通过优化葡萄糖生物传感器上的生物相容性膜来实现。例如，当葡萄糖生物传感器在经过在生物相容性膜溶液中三个周期的浸渍提拉涂膜和干燥循环处理以后，和没有覆盖任何生物相容性膜的葡萄糖生物传感器相比，虽然其对葡萄糖的响应时间从2分钟被延长到了4分钟，其电流信号却被这层生物相容性膜很好地调控了，而且，葡萄糖生物传感器的稳定性也得到了显著的改善(图3)。与此同时，葡萄糖的可监测范围从10mmol/L被成功地拓展到了35mmol/L，完全满足了糖尿患者的葡萄糖监测需要(图4)。
虽然以上所有实验结果都证实本发明的生物相容性膜在体外展示出优越的性能，其在活体监测时的性能才是对它的生物相容性的最有力的证明。因此，本发明在体外工作的基础上，将覆盖有生物相容性膜的葡萄糖生物传感器应用于植入式持续葡萄糖监测系统，在连续20天的人体试验中，其中前16天结果良好，灵敏度(基线)没有明显的衰减(图5，a图)，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(曲线表示)与指血血糖检测(圆点表示)的结果高度吻合(图5，a图)。从植入后的第17天开始，传感器灵敏度出现明显的衰减，其监测到的葡萄糖浓度与指血血糖检测的结果开始出现较大的差异。因此，为了安全起见，本发明中的生物相容性膜的工作寿命定为15天。
众所周知，由于植入式持续葡萄糖监测系统的葡萄糖生物传感器是植入在皮下，其监测到的葡萄糖是组织液中的葡萄糖，组织液中的葡萄糖与指血血糖有一个不可避免的滞后。因此，本发明在传感器植入后的第15天早上，从空腹血糖开始，对血糖进行高频率的指血血糖检测，结果表明，虽然这两种方法得到的葡萄糖的浓度变化曲线高度吻合，本发明中植入式持续葡萄糖监测系统检测到的组织液中葡萄糖的浓度变化曲线与指血检测到的血糖浓度变化曲线在时间上存在一个平均9分钟的滞后(图5，b图)。
实施例2
本实施例中的溶剂均为95％的正丙醇。
将5mL的聚(二甲基硅氧烷)-二缩水甘油醚和5mL的10mg/mL聚环氧乙烷，50mL的200mg/mL的聚乙烯吡啶和50mL的200mg/mL的苯乙烯-乙烯吡啶共聚物充分混合，然后在40℃的水浴中加热反应120min。在反应后的生物相容性膜溶液中加入2mL的乙醇胺，充分混合后，再次在40℃的水浴中加热反应120min，得到生物相容性膜溶液。
在10万级的洁净室和含有饱和乙醇蒸汽的环境中，以浸渍提拉法在含有电化学活化后的葡萄糖氧化酶的葡萄糖生物传感器上均匀涂布生物相容性膜溶液；下降速率为200μm/s，提拉速率为25μm/s，然后在温度25℃，相对湿度40％的环境下干燥60min，然后重复浸渍提拉和干燥的过程2次，共进行3个周期的浸渍提拉涂膜和干燥循环以后，得到植入式葡萄糖生物传感器。
本发明通过在葡萄糖生物传感器上覆盖上生物相容性膜成功地实现了可以用于植入式葡萄糖持续监测系统的葡萄糖生物传感器。在连续14天的人体试验中，其监测到的葡萄糖浓度变化曲线与国外某知名品牌监测到的葡萄糖浓度变化曲线高度吻合(图6)。
实施例3
本实施例中的溶剂均为95％的异丙醇。
将0.5mL的聚(二甲基硅氧烷)-二缩水甘油醚和0.5mL的10mg/mL聚环氧丙烷，5mL的100mg/mL的聚乙烯吡啶和5mL的100mg/mL的苯乙烯-乙烯吡啶共聚物充分混合，然后在70℃的水浴中加热反应40min。在反应后的生物相容性膜溶液中加入0.2mL的丙醇胺，充分混合后，再次在70℃的水浴中加热反应40min，得到生物相容性膜溶液。
在10万级的洁净室和含有饱和乙醇蒸汽的环境中，以浸渍提拉法在含有电化学活化后的乳酸氧化酶的乳酸生物传感器上均匀涂布生物相容性膜溶液；下降速率为5000μm/s，提拉速率为300μm/s；然后在温度22℃相对湿度35％的环境下干燥40min，然后重复浸渍提拉和干燥的过程3次，共进行4个周期的浸渍提拉涂膜和干燥循环以后，得到植入式乳酸生物传感器。覆盖了生物相容性膜以后，其对乳酸响应的线性范围从8mmol/L被成功地拓展到了30mmol/L，完全满足乳酸活体监测的需要。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 一种生物相容性膜，主要由以下组分制成：
    交联剂、亲水材料、疏水材料和溶剂；
    所述交联剂包括聚(二甲基硅氧烷)-二缩水甘油醚、聚乙二醇二縮水甘油醚和4-(2，3-环氧丙氧基)-N，N-二(2，3-环氧丙基)苯胺中的一种或几种；
    所述亲水材料包括聚环氧乙烷、含有聚环氧乙烷的共聚物、聚环氧丙烷、含有聚环氧丙烷的共聚物、聚乙烯吡咯烷酮和聚乙烯醇中的一种或几种；
    所述疏水材料包括聚乙烯吡啶、乙烯吡啶-丙烯酰胺共聚物、聚乙烯吡咯以及乙烯吡咯-丙烯酰胺共聚物中的一种或几种。
  2. 根据权利要求1所述的生物相容性膜，其特征在于，所述亲水材料为聚环氧乙烷或含有聚环氧乙烷的共聚物；
    所述疏水材料为聚乙烯吡啶。
  3. 根据权利要求1所述的生物相容性膜，其特征在于，所述交联剂为聚(二甲基硅氧烷)-二缩水甘油醚。
  4. 根据权利要求1所述的生物相容性膜，其特征在于，生物相容性膜的原料还包括增强剂；
    所述增强剂包括苯乙烯-乙烯吡啶共聚物、苯乙烯-乙烯吡咯共聚物和苯乙烯-丙烯酰胺共聚物中的一种或几种。
  5. 根据权利要求4所述的生物相容性膜，其特征在于，所述增强剂为苯乙烯-乙烯吡啶共聚物。
  6. 根据权利要求1所述的生物相容性膜，其特征在于，生物相容性膜的原料还包括自由基清除剂；
    所述自由基清除剂包括乙醇胺、丙醇胺、异丙醇胺、苯胺、带有末端氨基的聚环氧乙烷、环氧乙烷的共聚物和带有末端氨基的聚环氧丙烷中的一种或几种。
  7. 根据权利要求6所述的生物相容性膜，其特征在于，所述自由基清除剂为乙醇胺。
  8. 一种生物相容性膜的制备方法，包括以下步骤：
    A)将交联剂、亲水材料和疏水材料在溶剂中混合，在20～70℃下反应40～120min，在40～70℃下反应40～120min，得到生物相容性膜溶液；
    所述交联剂包括聚(二甲基硅氧烷)-二缩水甘油醚、聚乙二醇二縮水甘油醚和4-(2，3-环氧丙氧基)-N，N-二(2，3-环氧丙基)苯胺中的一种或几种；
    所述亲水材料包括聚环氧乙烷、含有聚环氧乙烷的共聚物、聚环氧丙烷、含有聚环氧丙烷的共聚物、聚乙烯吡咯烷酮和聚乙烯醇中的一种或几种；
    所述疏水材料包括聚乙烯吡啶、乙烯吡啶-丙烯酰胺共聚物、聚乙烯吡咯以及乙烯吡咯-丙烯酰胺共聚物中的一种或几种；
    B)将基体浸入所述生物相容性溶液，以浸渍提拉法在基体表面涂布所述生物相容性膜溶液；
    C)将涂布有生物相容性膜溶液的基体进行干燥，得到包覆有生物相容性膜的基体。
  9. 根据权利要求8所述的制备方法，其特征在于，所述步骤A具体为：
    将交联剂、亲水材料、疏水材料和增强剂在溶剂中混合，在20～70℃下反应40～120min，然后加入自由基清除剂，在40～70℃下反应40～120min，得到生物相容性膜溶液。
  10. 一种植入式生物传感器，包括生物传感器基体和包覆在所述生物传感器基体表面的生物相容性膜；
    所述生物相容性膜为权利要求1～7任意一项所述的生物相容性膜或权利要求8～9任意一项所述的制备方法制备得到的生物相容性膜。
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