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WO2021184843A1 - 植入式生物传感器用三嵌段共聚物及其应用和制备方法 - Google Patents

植入式生物传感器用三嵌段共聚物及其应用和制备方法 Download PDF

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WO2021184843A1
WO2021184843A1 PCT/CN2020/135162 CN2020135162W WO2021184843A1 WO 2021184843 A1 WO2021184843 A1 WO 2021184843A1 CN 2020135162 W CN2020135162 W CN 2020135162W WO 2021184843 A1 WO2021184843 A1 WO 2021184843A1
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block
parts
triblock copolymer
molecular weight
segment material
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PCT/CN2020/135162
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French (fr)
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于非
童晶晶
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微泰医疗器械(杭州)有限公司
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    • C08G18/758—Polyisocyanates or polyisothiocyanates cyclic cycloaliphatic containing two or more cycloaliphatic rings
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G18/00—Polymeric products of isocyanates or isothiocyanates
    • C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
    • C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
    • C08G18/72—Polyisocyanates or polyisothiocyanates
    • C08G18/74—Polyisocyanates or polyisothiocyanates cyclic
    • C08G18/76—Polyisocyanates or polyisothiocyanates cyclic aromatic
    • 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
    • G01N27/40—Semi-permeable membranes or partitions

Definitions

  • the invention relates to the technical field of block copolymers, in particular to a triblock copolymer for implantable biosensors, and also to the application and preparation method of the triblock copolymer.
  • Implantable biosensor refers to a sensor device that can be partially or completely implanted into the human body, which can measure the content of target analyte molecules without the need for additional reagents and pre-separation and treatment of body fluids or blood.
  • the advantage of the implantable biosensor is that it can continuously measure some important physiological and pathological parameters in the body that change over time, such as blood oxygen, blood sugar, virus antibodies, etc., so as to more directly reflect the physical signs of the tested object due to environmental changes, Changes caused by physical activity, diet, and medications.
  • the sensing part of the implanted sensor needs to interact with the analyte in the tissue to detect the presence of the analyte.
  • the biocompatibility permeable membrane has very high technical requirements for its components, such as extremely low cytotoxicity, good hydrophilicity and biocompatibility, appropriate permeability and diffusion performance for the target analyte, and barrier to potential interferences Performance, as well as heat resistance, hydrolysis resistance and resistance to other degradation mechanisms within a given time of use.
  • the material is also required to have a stable chemical molecular structure, so that it can maintain stable properties for a long time before being used. Therefore, the current options for biocompatible permeable membranes are very limited.
  • permeable membranes are mostly made of polyethylene glycol, poly(2-hydroxyethyl methacrylate) and other generally recognized highly biocompatible hydrophilic polymers or their mixtures, and are made by adding polyester Or hydrophobic materials such as polysiloxane are copolymerized with hydrophilic materials or directly mixed to control the overall permeability of the permeable membrane.
  • This type of permeable membrane material has a common problem, that is, the glass transition temperature of the hydrophobic part is lower than room temperature, the mobility is very high, it is easy to migrate to the surface and repel the hydrophilic part, causing the microphase separation of the material.
  • the prior art CN201610792708.4 discloses a high biocompatibility triblock copolymer.
  • the copolymer material in this patent application can also be used in implantable biosensors, it has a permeation and diffusion performance for target analytes.
  • the controllability of the sensor, and the demand for oxygen permeability of the sensor involving the oxidase reaction need to be improved.
  • the material of the present invention has great improvements in these properties.
  • the block copolymer of the present invention is particularly suitable for use as an implantable biosensor biocompatible permeable membrane.
  • the copolymer has extremely low cytotoxicity, good hydrophilicity and biocompatibility, and is suitable for target analytes. Permeation and diffusion properties and barrier properties to potential interferences, as well as heat resistance, hydrolysis resistance and resistance to other degradation mechanisms within a given time of use.
  • a triblock copolymer for implantable biosensors of the present invention is polymerized by adding a block polymerization reagent and a small molecule chain extender to a mixture of the following block materials:
  • Block A a highly hydrophilic soft segment material, selected from dihydroxy, dicarboxyl or diamine-terminated polyethylene glycol, polypropylene glycol and polybutylene glycol, and amine-terminated poly(ethylene glycol)/ One or more of poly(propylene glycol) copolymers with a number average molecular weight of 500-3000;
  • Block B a rigid and highly hydrophobic hard segment material, selected from one or more of dihydroxy or diamine-terminated polycarbonate, bisphenol A polycarbonate and polymethyl methacrylate, the number is average The molecular weight is 1000-3000;
  • Block C flexible polymer, selected from one or more of poly double-end epoxy polysiloxane, dihydroxy polydimethylsiloxane and poly(-2-hydroxyethyl methacrylate) Species with a number average molecular weight of 500-3000;
  • the general formula of the copolymer is (-AbBbC-) n , where A, B, and C are block structures, and b is a block polymerization reagent,
  • a block is 5-40 parts
  • B block is 5-20 parts
  • C block is 20-70 parts
  • block polymerization reactant b is 10-40 parts.
  • the permeable membrane synthesized from the raw materials in the ratio range has a stable and controllable low permeability of water-soluble small molecules, and is suitable for detecting water-soluble small molecules through enzyme reaction (for example: detecting the content of glucose in solution or blood by glucose oxidase) )
  • the biosensor is used to control the rate of penetration of the detected substance to the surface of the sensor.
  • b is an isocyanate-based polymerization reagent.
  • the isocyanate polymerization reactant is selected from one or more of the following substances: 2,4-toluene diisocyanate, 2,6-toluene diisocyanate, cyclohexane dimethylene diisocyanate, 4, 4'-diphenylmethane diisocyanate, xylylene diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate, 4,4'-dicycloethylmethane diisocyanate.
  • the structural formulas of these substances are:
  • the small molecule chain extender is selected from one or more of the following substances: ethylene glycol, water, butanediol, ethylenediamine, hydroquinone dihydroxyethyl ether, benzidine, 3,3'-Dichlorobenzidine, 3,3'-Dichloro-4,4'-Diaminodiphenylmethane.
  • ethylene glycol water, butanediol, ethylenediamine, hydroquinone dihydroxyethyl ether, benzidine, 3,3'-Dichlorobenzidine, 3,3'-Dichloro-4,4'-Diaminodiphenylmethane.
  • the use of the small molecule chain extender as described above allows the block copolymer of the present invention to be further polymerized, and the molecular weight of the final material is increased to make it have the desired performance.
  • a block is 15-30 parts, B block is 5-10 parts, C block is 40-50 parts, and block polymerization reactant b is 20-25 parts. Parts, small molecule chain extender is 0-5 parts.
  • A-b, B-b, and C-b are covalently connected by a urea or carbamate group.
  • the invention also relates to the application of the triblock copolymer in implantable biosensors.
  • the present invention also relates to a method for preparing the triblock copolymer, which includes the following steps:
  • Step 1 Add the highly hydrophilic soft segment material, the rigid and highly hydrophobic hard segment material, and the flexible polymer into an organic solvent and mix them uniformly at 30-45°C; organic solvents include tetrahydrofuran and cyclohexanone Or isobutanol; the total mass ratio of the volume of the organic solvent and the soft segment material with high hydrophilicity, the rigid segment material with high rigidity and hydrophobicity, and the flexible polymer is 2-10ml:1g;
  • Step 2 Add a catalyst to the mixed solution of Step 1, and add a block polymerization reagent dropwise, heat up to 55-70°C, and react for 12-20 hours;
  • the catalyst includes triethylenediamine or tin dibutyl diisooctoate;
  • Step 3 Add a small molecule chain extender to the reaction solution of Step 2, and react for 12h-18h; the quality of the small molecule chain extender and the soft segment material with high hydrophilicity, the hard segment material with rigidity and high hydrophobicity, and the flexibility are more.
  • the total mass ratio of the polymer is 0.1-0.3g:1g;
  • Step 4 After cooling, the reaction product is washed, filtered, and dried to obtain the triblock copolymer.
  • the block copolymer and preparation method of the present invention have the following advantages:
  • the present invention combines the advantages of three types of single polymer molecules so that its block copolymer has the characteristics of adjustable permeability, adjustable physical properties, better hydrolytic stability and heat resistance stability, and Comparing the simple mixing of the three types of polymer molecules, the use of isocyanate chain extenders such as diisocyanates to combine them through the chain extension reaction can prevent the phenomenon of micro-phase separation during the film formation process.
  • the triblock copolymer of the present invention has more stable physical and chemical properties, and has better hydrolysis and heat resistance than simple hydrophilic/hydrophobic copolymers or blends such as polyether and polyester polyurethane.
  • the hydrophilicity, permeability and physical strength of the multi-block copolymer can be continuously adjusted by adjusting the percentage of each block in the material.
  • this material has a significantly improved ratio of oxygen to glucose permeability and the stability of the ratio, which can better avoid oxygen Problems such as decreased sensor measurement accuracy caused by insufficient supply.
  • Fig. 1 is a comparison of the permeability of small molecule analytes (such as glucose) measured when the ratio of hydrophilic material to hydrophobic material is different between the present invention material and the hydrophilic/hydrophobic copolymer or blend material of the prior art.
  • small molecule analytes such as glucose
  • Figure 2 is a comparison between the water and heat resistance of the material of the present invention and the hydrophilic/hydrophobic copolymer or blend material of the prior art.
  • Figure 3 is a comparison of the storage stability of the hydrophilic contact angle on the surface of the film prepared from the material of the present invention and the hydrophilic/hydrophobic copolymer or blend material of the prior art.
  • Figure 4 is a comparison of the ratio of oxygen permeability to glucose permeability of the present invention material and the hydrophilic/hydrophobic copolymer or blended material of the prior art when the glucose permeability is similar.
  • the general formula of the block copolymer of the present invention is AbBbC, where A, B, and C are block structures, b is a block polymerization reagent, and Ab, Bb, and Cb are covalently bonded through urea or urethane groups. connect.
  • A represents a highly hydrophilic soft segment material, which is a block composed of at least one of polyethylene glycol, polypropylene glycol, and polyetheramine.
  • A is preferably selected from dihydroxy, dicarboxyl or diamine-terminated polyethylene
  • B represents a rigid and highly hydrophobic hard segment material, which is a block composed of at least one of polycarbonate and polymethyl methacrylate, and B is preferably selected from dihydroxy or diamine-terminated polycarbonate and bisphenol A
  • C represents a flexible polymer, which is a block composed of at least one of polydimethylsiloxane and poly(2-hydroxyethyl methacrylate), and C is preferably selected from the group consisting of poly-two-terminated epoxy polysiloxane One or more of alkane, dihydroxy polydimethylsiloxane and poly(-2-hydroxyethyl methacrylate), with a number average molecular weight of 500-3000; this type of block plays a certain transitional role Makes the type A block and the type B block less prone to microphase separation during mixing and film formation.
  • b represents a block polymerization reaction agent, specifically an isocyanate block polymerization reaction agent, including one or more of diphenylmethane diisocyanate, hexamethylene diisocyanate, and dicyclohexylmethane diisocyanate.
  • Block and block are connected by isocyanate block polymerization reaction agent through polycondensation mechanism to generate stable polyurethane or polyurea multi-block copolymer.
  • the reaction mechanism is as follows:
  • Q is a small molecule chain extender with bifunctionality, selected from water, ethylene glycol, 1,4-butanediol, benzidine, diethylene glycol, 1,2-propylene glycol, dipropylene glycol, 1 ,6-Hexanediol, neopentyl glycol, diethyltoluenediamine, 3,5-dimethylthiotoluenediamine.
  • the mass parts of the three kinds of blocks and the block polymerization reagent are as follows: A block is 5-40 parts, B block is 5-20 parts, and C block is 20-70 parts.
  • the weight ratio of the block polymerization reactant b is 10-40 parts, and the small molecule chain extender is 0-10 parts.
  • the total number of parts by mass is 100 parts: 15-30 parts for A block, 5-10 parts for B block, 40-50 parts for C block, 20-25 parts for block polymerization reactant b, 0-5 parts of small molecule chain extender.
  • the permeable membrane made of the block copolymer material synthesized according to this raw material ratio has a stable and controllable low permeability of water-soluble small molecules, which is suitable for the detection of water-soluble small molecules by enzyme reaction (for example: detection by glucose oxidase)
  • the biosensor based on the glucose content in the solution or blood is used to control the rate of penetration of the test substance to the surface of the sensor.
  • the triblock copolymer of the present invention is a linear polymer.
  • the preparation method of the above-mentioned high biocompatibility triblock copolymer includes the following steps:
  • Step 1 Add the highly hydrophilic soft segment material, the rigid and highly hydrophobic hard segment material, and the flexible polymer into an organic solvent, and mix them uniformly at 30-45°C; the organic solvent includes tetrahydrofuran or isobutanol , The total mass ratio of the volume of the organic solvent and the soft segment material with high hydrophilicity, the hard segment material with rigidity and high hydrophobicity, and the flexible polymer is 2-10ml:1g.
  • Step 2 Add a catalyst to the mixed solution of Step 1, and add a block polymerization reagent dropwise. The temperature is raised to 55-70° C., and the reaction is carried out for 12-20 hours; the catalyst includes triethylene diamine or dibutyl tin diisooctoate.
  • Step 3 Add a small molecule chain extender to the reaction solution of Step 2, and react for 12h-18h; the volume of deionized water and the soft segment material with high hydrophilicity, the hard segment material with rigidity and high hydrophobicity, and the flexible polymer
  • the total mass ratio is 0.1-0.3g:1g.
  • Step 4 After cooling, the reaction product is washed, filtered, and dried to obtain the triblock copolymer.
  • the triblock copolymer of the present invention in the preparation of biocompatible permeable membranes for implantable biosensors.
  • the prepared permeable membrane has a highly controllable permeability of small molecules, good water resistance and heat resistance, adjustable hydrophilicity and biocompatibility, which is mainly realized by multi-block copolyurea or polyurethane containing amphiphilic molecules of.
  • Raw materials polyetheramine, number average molecular weight 1500; polycarbonate diol, number average molecular weight 3000; diamino-terminated polydimethylsiloxane, number average molecular weight 3000; diphenylmethane diisocyanate; the above raw materials are in accordance with The total mass is 50g, and the ratio of mass parts is 5:10:70:15; 10:9:63:18; 15:9:55:21; 20:8:48:24; 25:8:40:27; 30:7:33:30; 35:7:26:32; 40:6:20:34 to make 8 kinds of polymer materials.
  • the reaction solvent is 100ml of tetrahydrofuran and 50ml of deionized water.
  • the synthesis method is as follows:
  • Step 1 Add polyetheramine, polycarbonate diol, and diamino-terminated polydimethylsiloxane to tetrahydrofuran, and mix uniformly at 40°C.
  • Step 2 Add triethylene diamine to the mixed solution of step 1, and add diphenylmethane diisocyanate dropwise, heat up to 65° C., and react for 12 hours.
  • Step 3 Add deionized water to the reaction solution of Step 2, and react for 12 hours.
  • Step 4 After cooling, the reaction product is washed, filtered, and dried to obtain the triblock copolymer.
  • Raw materials polyethylene glycol, number average molecular weight 1500; diamino-terminated polydimethylsiloxane, number average molecular weight 3000; diphenylmethane diisocyanate; the above raw materials are 50g in total mass, and the ratio of mass parts is 5 :75:20; 10:68:22; 15:60:25; 20:52:28; 25:45:30; 30:37:33; 35:30:35; 40:22:38 for matching production 8 kinds of polymer materials.
  • the reaction solvent is 100ml of tetrahydrofuran and 50ml of deionized water.
  • the corresponding comparative polymer materials were synthesized according to the above-mentioned synthesis method.
  • Raw materials polyethylene glycol, with a number average molecular weight of 12000; polydimethylsiloxane, with a number average molecular weight of 9000; the above-mentioned raw materials have a total mass of 50g, and the ratio of mass parts is 5:95; 10:90; 15:85; 20:80; 25:75; 30:70; 35:65; 40:60 were mixed in a solvent to make 8 kinds of comparative mixed polymer materials.
  • the reaction solvent is 100 ml of tetrahydrofuran.
  • the corresponding comparative polymer materials were synthesized according to the above-mentioned synthesis method.
  • Raw materials polyetheramine, number average molecular weight 1000, mass 25g; polycarbonate diol, number average molecular weight 5000, mass 10g; diamino-terminated polydimethylsiloxane, number average molecular weight 5000, mass 15g; Tetrahydrofuran, 100ml; Diphenylmethane diisocyanate, mass 12g; Deionized water 50ml.
  • the synthesis method is as follows:
  • Step 1 Add polyetheramine, polycarbonate diol, and diamino-terminated polydimethylsiloxane to tetrahydrofuran, and mix uniformly at 40°C.
  • Step 2 Add triethylene diamine to the mixed solution of step 1, and add diphenylmethane diisocyanate dropwise, heat up to 65° C., and react for 12 hours.
  • Step 3 Add deionized water to the reaction solution of Step 2, and react for 12 hours.
  • Step 4 After cooling, the reaction product is washed, filtered, and dried to obtain the triblock copolymer.
  • Raw materials amino terminated polypropylene glycol, molecular weight 500, mass 15g; polyetheramine, molecular weight 600, mass 10g; poly(bisphenol A carbonate), molecular weight 5000, mass 25g; diamino terminated polydimethylsiloxane Alkane, molecular weight is 20000, mass 10g; poly(2-hydroxyethyl methacrylate), molecular weight is 5000, mass 5g; isobutanol 150ml; hexamethylene diisocyanate, mass 15g; deionized water 150ml.
  • the synthesis method is as follows:
  • Step 1 Add amino-terminated polypropylene glycol, polyetheramine, poly(bisphenol A carbonate), diamino-terminated polydimethylsiloxane, and poly(-2-hydroxyethyl methacrylate) to In isobutanol, mix well at 35°C.
  • Step 2 Add tin dibutyl diisooctoate to the mixed solution of step 1, and add hexamethylene diisocyanate dropwise, increase the temperature to 60° C., and react for 16 hours.
  • Step 3 Add deionized water to the reaction solution of Step 2, and react for 14 hours.
  • Step 4 After cooling, the reaction product is washed, filtered, and dried to obtain the triblock copolymer.
  • Raw materials amino terminated polypropylene glycol, molecular weight 500, mass 8g; polyetheramine, molecular weight 600, mass 10g; poly(bisphenol A carbonate), molecular weight 3000, mass 15g; diamino terminated polydimethylsiloxane Alkane, with a molecular weight of 2400 and a mass of 10 g; poly(2-hydroxyethyl methacrylate) with a molecular weight of 800 and a mass of 10 g; 300 ml of isobutanol; hexamethylene diisocyanate with a mass of 10 g; and 15 ml of ethylene diamine.
  • the synthesis method is as follows:
  • Step 1 Add amino-terminated polypropylene glycol, polyetheramine, poly(bisphenol A carbonate), diamino-terminated polydimethylsiloxane, and poly(-2-hydroxyethyl methacrylate) to In isobutanol, mix well at 35°C.
  • Step 2 Add tin dibutyl diisooctoate to the mixed solution of step 1, and add hexamethylene diisocyanate dropwise, increase the temperature to 60° C., and react for 16 hours.
  • Step 3 Add ethylenediamine to the reaction solution of Step 2, and react for 14 hours.
  • Step 4 After cooling, the reaction product is washed, filtered, and dried to obtain the triblock copolymer.
  • Raw materials amino terminated polyethylene glycol, number average molecular weight 2000, mass 16g; polymethyl methacrylate, number average molecular weight 2000, mass 10g; dicarboxyl terminated polydimethylsiloxane, number average molecular weight 1200, the mass is 20g; tetrahydrofuran, 500ml; 3g isophorone diisocyanate and 6g dicyclohexylmethane diisocyanate; ethylene glycol 10ml.
  • the synthesis method is as follows:
  • Step 1 Add amino-terminated polyethylene glycol, polymethyl methacrylate, and diamino-terminated polydimethylsiloxane to tetrahydrofuran, and mix uniformly at 30°C.
  • Step 2 Add triethylene diamine to the mixed solution of step 1, and add the mixed solution of diphenylmethane diisocyanate and dicyclohexylmethane diisocyanate dropwise, heat up to 55° C., and react for 14 hours.
  • Step 3 Add deethylene glycol to the reaction solution of Step 2, and react for 18 hours.
  • Step 4 After cooling, the reaction product is washed, filtered, and dried to obtain the triblock copolymer.
  • Raw materials amino-terminated polyethylene glycol, number average molecular weight 3000, mass 35g; polycarbonate diol, number average molecular weight 1,200, mass 8g; polymethyl methacrylate, number average molecular weight 1,200, mass 16g; poly( 2-hydroxyethyl methacrylate), number average molecular weight 2500, mass 35g; isobutanol 600ml; trimethylhexamethylene diisocyanate 10g; hydroquinone dihydroxyethyl ether 10ml.
  • the synthesis method is as follows:
  • Step 1 Add amino-terminated polyethylene glycol, polycarbonate diol, polymethyl methacrylate, and poly(-2-hydroxyethyl methacrylate) to isobutanol, at 45°C well mixed.
  • Step 2 Add tin dibutyl diisooctoate to the mixed solution of step 1, and add dicyclohexylmethane diisocyanate dropwise, increase the temperature to 70° C., and react for 20 hours.
  • Step 3 Add hydroquinone dihydroxyethyl ether to the reaction solution of Step 2, and react for 16 hours.
  • Step 4 After cooling, the reaction product is washed, filtered, and dried to obtain the triblock copolymer.
  • the 8 kinds of triblock copolymers prepared in Example 1 and the 8 kinds of polymer materials and 8 kinds of mixed materials prepared in Comparative Examples 1 and 2 were respectively dissolved in an organic solvent such as tetrahydrofuran, and then spin-coated on aluminum Dry the surface of the pan until the solvent has evaporated to prepare a film, and then carefully remove the film from the aluminum pan.
  • an organic solvent such as tetrahydrofuran
  • test method Perform glucose permeability performance test on the prepared film, the test method is as follows:
  • the prepared film is sandwiched between the two solution chambers of the transdermal tester.
  • the solution chamber on one side is filled with high-concentration glucose solution, the other side is added with the same volume of phosphate buffer solution, and then the solutions on both sides are regularly taken out for glucose concentration Test and measure the thickness of the film, and then calculate the glucose permeability of the film through a formula.
  • the higher the proportion of hydrophilic components (such as polypropylene glycol, polyethylene glycol, polyetheramine, etc.) in the material the higher the glucose permeability.
  • the glucose permeability of the material prepared by the present invention has a more ideal linear relationship with its hydrophilic component ratio. This allows the material of the present invention to better control the permeability by changing the ratio of different raw materials to meet the requirements for use in implantable biosensors.
  • the triblock copolymer prepared in Example 2 and the materials prepared in Comparative Example 1 and Comparative Example 2 by using polyethylene glycol of similar mass ratio were respectively prepared into thin films, and the heat resistance and hydrolysis resistance properties were compared.
  • the film preparation process is as follows: the tested material is dissolved in an organic solvent such as tetrahydrofuran, then spin-coated on the surface of the glass sheet and heated to 40°C until the solvent is completely evaporated, so that the tested material forms a thin film on the glass surface.
  • each sample film (about 0.1g per sample) in a constant temperature and humidity oven at 60°C and 100% relative humidity. Take out the sample at 0, 5, 10, 15, 20, and dissolve the sample in an organic solvent such as For tetrahydrofuran, use size exclusion chromatography (SEC) or gel permeation chromatography (GPC) to measure its molecular weight distribution and calculate the number average molecular weight. Compare the calculated number average molecular weight with the unsoaked sample to get the ratio of "average molecular weight/initial molecular weight", expressed as a percentage. As shown in Figure 2, the average molecular weight of the comparative material was significantly reduced after storage at high temperature and high humidity, indicating that its molecules had been partially decomposed, and its resistance to heat and hydrolysis was poor.
  • the triblock copolymer material and polyether polyurethane of the present invention prepared in Example 2 have good hydrolysis resistance and thermal decomposition resistance.
  • the triblock copolymer prepared in Example 3 and the materials prepared in Comparative Example 1 and Comparative Example 2 using similar mass ratios of polyethylene glycol were compared for the hydrophilic contact angle of the film surface.
  • the hydrophilic contact angle test method is to dissolve the tested material in an organic solvent such as tetrahydrofuran, then spin-coat on the surface of the glass sheet and heat it to 40°C until the solvent is completely evaporated, so that the tested material forms a thin film on the glass surface, and then sample the thin film Store at room temperature (about 25°C) and indoor relative humidity (about 20%-40%). Take out the sample regularly (e.g.
  • the surface hydrophilicity of homopolymer blends and diblock copolymers is reduced after being placed for a period of time, while the surface hydrophilicity of the new material prepared in Example 1 is relatively stable. , It will not change much after 6 months of storage at room temperature.
  • the triblock copolymer material prepared in Example 4 and the materials prepared in Comparative Example 3 and Comparative Example 4 were respectively dissolved in an organic solvent such as tetrahydrofuran, and then spin-coated on the surface of an aluminum plate and dried until the solvent was completely evaporated. After forming a film, carefully remove the film from the aluminum pan. Perform oxygen permeability performance test on the prepared film.
  • the test method is as follows:
  • the prepared film is sandwiched between the two solution chambers of the transdermal tester, and the same volume of deoxygenated phosphate buffer solution is added to the solution chambers on both sides and put into the oxygen sensor and then sealed. After that, oxygen is supplied to the solution chamber on one side and the dissolved oxygen test is performed on the solution chambers on both sides regularly. After the dissolved oxygen concentration on both sides is close to equilibrium, the film is taken out for thickness measurement, and then the oxygen permeability of the film is calculated by the formula and the oxygen permeation is calculated The ratio of the rate to the glucose permeability. As shown in FIG. 4, the oxygen/glucose permeability ratio of the material made by the present invention is significantly higher than that of Comparative Example 1 and Comparative Example 2.
  • the synthesized material of the present invention is more suitable for implantable biosensors based on oxidase reaction, especially for the use requirements of implantable glucose sensors based on glucose oxidase.
  • concentration of glucose in the solution or tissue fluid on the outer side of the membrane is higher and the dissolved oxygen concentration is lower, the material membrane made by the present invention can more effectively ensure that the oxygen supply on the inner side of the membrane is higher than the permeated glucose, and ensure that the glucose oxidase reaction is based on The normal operating mechanism of the sensor is not affected by fluctuations in dissolved oxygen concentration.

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Abstract

本发明涉及一种植入式生物传感器用三嵌段共聚物，其通过在以下嵌段物质的混合液中加入嵌段聚合反应剂和小分子扩链剂聚合而成：嵌段A，高亲水性的软段材料，数均分子量在500-3000；嵌段B，刚性高疏水性的硬段材料，数均分子量为1000-3000；嵌段C，柔性多聚物，数均分子量在500-3000；所述嵌段共聚物的通式为A-b-B-b-C，其中，A、B、C为嵌段结构，b为嵌段聚合反应剂，其中，按质量份数总数为100计：A嵌段为5-40份，B嵌段为5-20份，C嵌段为20-70份，嵌段聚合反应剂b为10-40份，小分子扩链剂为0-10份。本发明还涉及所述三嵌段共聚物的应用和制备方法。

Description

植入式生物传感器用三嵌段共聚物及其应用和制备方法 技术领域
本发明涉及嵌段共聚物技术领域，具体涉及一种植入式生物传感器用三嵌段共聚物，还涉及该三嵌段共聚物的应用和制备方法。
背景技术
植入式生物传感器是指一种可以被部分或者全部植入人体的传感器设备，其可以在不需要外加试剂和预先分离处理体液或血液的条件下测定目标分析物分子的含量。植入式生物传感器的优点是可以连续性地测定体内某些随时间变化的重要生理和病理参数，比如血氧、血糖、病毒抗体等，从而更直接地反映被测对象的体征因环境变化、体力活动、饮食和药物而产生的变化。通常来讲，植入式传感器的感应部分需要与组织内的被分析物产生某种互动才可以检测到被分析物的存在，因此，植入式生物传感器与植入组织的互动可控性代表了植入式传感技术的主要特点和技术难度。由于人体内部环境，尤其是微观生物环境异常复杂，目前人类对植入式传感器与植入组织之间的相互作用了解有限。例如植入式传感器的表面物质与人体成分的差异性会引发人体的异体排斥反应机制，从而生成一层主要由纤维蛋白组成的生物隔离层。隔离层会造成传感器与植入组织隔绝，使传感器与组织液的分子渗透和交换受到阻碍，传感器对分析物浓度的检测将失去准确性。因此如何减少异物排斥反应，提高传感器的生物相容性同时保证被分析物能够稳定受控地渗透扩散至传感器感应部分是提高传感器准确性和使用寿命的关键，这通常是由在传感器与组织接触的表面增加一层高生物相容性的薄膜来实现的。
生物相容性渗透膜对其成分有非常高的技术性要求，例如极低的细胞毒性、良好的亲水性和生物相容性、对目标分析物适当的渗透扩散性能和对潜在干扰物的阻隔性能，以及在给定的使用时间内耐热性、耐水解性和对其他降解机制的抗性等等。同时由于生产、运送和贮藏的要求，还需要该材料具 有稳定的化学分子结构，使其在被使用之前的较长时间内保持稳定的性质。因此，目前的生物相容性渗透膜的选择非常有限。目前，此类渗透膜多采用聚乙二醇、聚(2-甲基丙烯酸羟乙酯)等被普遍认可的高生物相容性亲水多聚物或其混合物制成，并通过添加聚酯或聚硅氧烷等疏水性材料与亲水性材料共聚或者直接混合来控制渗透膜的总体渗透率。这种类型的渗透膜材料存在一个共同的问题，就是疏水部分的玻璃化转变温度低于室温，运动性很高，极易迁移至表面并排斥亲水段，造成材料的微相分离。这不仅导致膜材料的渗透率的可控性较差，尤其是当亲水段比例降低时其分析物渗透率会快速非线性下降，还会使限制膜的渗透稳定性随着时间的推移明显下降。同时聚乙二醇，聚酯等材料耐水耐热性较差，在体内环境或高温高湿条件下易发生降解，分子量降低的同时导致渗透膜性质产生变化，因而不利于生产和长期贮藏。
现有技术CN201610792708.4公开了一种高生物相容性的三嵌段共聚物，该专利申请中的共聚物材料虽然也能够用于植入式生物传感器，但对目标分析物的渗透扩散性能的可控性，以及对涉及到氧化酶反应传感器对氧气渗透率的需求有待提高。本发明的材料在这些性能上有较大的改进。
发明内容
本发明的嵌段共聚物特别适合用作植入式生物传感器生物相容性渗透膜，该共聚物具有极低的细胞毒性、良好的亲水性和生物相容性、对目标分析物适当的渗透扩散性能和对潜在干扰物的阻隔性能，以及在给定的使用时间内耐热性、耐水解性和对其他降解机制的抗性。
具体而言，本发明的一种植入式生物传感器用三嵌段共聚物，其通过在以下嵌段物质的混合液中加入嵌段聚合反应剂和小分子扩链剂聚合而成：
嵌段A，高亲水性的软段材料，选自二羟基、二羧基或者二胺基封端的聚乙二醇、聚丙二醇和聚丁二醇以及胺基封端的聚(乙二醇)/聚(丙二醇)共聚物中的一种或多种，数均分子量在500-3000；
嵌段B，刚性高疏水性的硬段材料，选自二羟基或二胺基封端的聚碳酸酯、双酚A聚碳酸酯和聚甲基丙烯酸甲酯中的一种或多种，数均分子量为 1000-3000；
嵌段C，柔性多聚物，选自聚双端环氧基聚硅氧烷、二羟基聚二甲基硅氧烷和聚(甲基丙烯酸-2-羟乙酯)中的一种或多种，数均分子量在500-3000；
所述的共聚物通式为(-A-b-B-b-C-) n，其中，A、B、C为嵌段结构，b为嵌段聚合反应剂，
其中，按质量份数总数为100计：A嵌段为5-40份，B嵌段为5-20份，C嵌段为20-70份，嵌段聚合反应剂b为10-40份，小分子扩链剂为0-10份。
由所述比例范围的原材料合成的渗透膜具有稳定可控的水溶性小分子低渗透率，适用于通过酶反应检测水溶性小分子检测物(例如：通过葡萄糖氧化酶检测溶液或血液中葡萄糖含量)的生物传感器用来控制检测物渗透至传感器表面的速率。
优选地，b为异氰酸酯类聚合反应剂。
优选地，所述异氰酸酯类聚合反应剂选自如下物质中的一种或多种：2,4-甲苯二异氰酸酯、2,6-甲苯二异氰酸酯、环己烷二亚甲基二异氰酸酯、4,4’-二苯基甲烷二异氰酸酯、苯二亚甲基二异氰酸酯、异佛尔酮二异氰酸酯、六亚甲基二异氰酸酯、4,4’-二环乙基甲烷二异氰酸酯。这些物质的结构式分别为：
Figure PCTCN2020135162-appb-000001
Figure PCTCN2020135162-appb-000002
优选地，所述的小分子扩链剂选自如下物质中的一种或多种：乙二醇、水、丁二醇、乙二胺、对苯二酚二羟乙基醚、联苯胺、3,3’-二氯联苯二胺、3,3’-二氯-4,4’-二氨基二苯基甲烷。这些物质的结构式分别为：
HOCH 2CH 2OH          乙二醇、
H 2O                 水、
HOCH 2CH 2CH 2CH 2OH    丁二醇、
H 2NCH 2CH 2NH 2        乙二胺、
Figure PCTCN2020135162-appb-000003
Figure PCTCN2020135162-appb-000004
使用了如上所述的小分子扩链剂使得本发明的嵌段共聚物可以进一步聚合，提高最终材料的分子量，使其具有所期望的性能。
优选地，按质量份数总数为100份计：A嵌段为15-30份，B嵌段为5-10份，C嵌段为40-50份，嵌段聚合反应剂b为20-25份，小分子扩链剂为0-5份。
优选地，A-b、B-b、C-b之间通过脲或氨基甲酸酯基共价键连接。
本发明还涉及所述三嵌段共聚物在植入式生物传感器中的应用。
本发明还涉及制备所述三嵌段共聚物的方法，包括如下步骤：
步骤一、将高亲水性的软段材料、刚性高疏水性的硬段材料、柔性多聚物，加入到有机溶剂中，在30-45℃下混合均匀；有机溶剂包括四氢呋喃、环己酮或异丁醇；有机溶剂的体积和高亲水性的软段材料、刚性高疏水性的硬段材料、柔性多聚物总质量比为2-10ml:1g；
步骤二、向步骤一的混合溶液中加入催化剂，并逐滴加入嵌段聚合反应剂，升温至55-70℃，反应12-20h；催化剂包括三乙烯二胺或者二丁基二异辛酸锡；
步骤三、向步骤二的反应溶液中添加小分子扩链剂，反应12h-18h；小分子扩链剂的质量和高亲水性的软段材料、刚性高疏水性的硬段材料、柔性多聚物总质量比为0.1-0.3g:1g；
步骤四、冷却后，将反应产物冲洗、过滤、干燥，得到所述的三嵌段共聚物。
与现有技术相比，本发明的嵌段共聚物和制备方法具有以下如下优势：
(1)本发明结合了三种类型的单一多聚分子的优点使得其嵌段共聚物具有可调节渗透率、可调节物理性能和较好的水解稳定性和耐热稳定性等特性，与将三类多聚分子简单混合相比，使用二异氰酸酯类等异氰酸酯类扩链剂将它们通过扩链反应结合可防止成膜过程中出现的微相位分离现象。
(2)本发明三嵌段共聚物成膜后其物理化学性质更稳定，比单纯的聚醚类和聚酯类聚氨酯等亲水/疏水共聚或者共混材料耐水解耐热性能更好。
(3)由于嵌段B刚性高疏水性的硬段材料的存在，成膜后的共聚物分子不易发生因分子排列重组而造成的薄膜表面性质变化，尤其是亲水性和小分子分析物渗透率的变化。
(4)该多嵌段共聚物的亲水性、渗透性能和物理强度可以通过调节每种嵌段在材料中的百分比实现连续调节。
(5)在葡萄糖氧化酶型葡萄糖传感器的应用中，与传统渗透膜材料相比，该材料具有与显著提高的氧气与葡萄糖的渗透率比例以及其比例的稳定性，能够更好的避免因氧气供应不足造成的传感器测量精度下降等问题。
附图说明
为了说明而非限制的目的，现在将根据本发明的优选实施例，参考附图来描述本发明的方法和材料，其中：
图1为本发明材料与现有技术的亲水/疏水共聚或者共混材料在亲水材料与疏水材料比例不同时测得的小分子分析物(例如葡萄糖)渗透率比较。
图2为本发明材料与现有技术的亲水/疏水共聚或者共混材料的耐水耐 热性能比较。
图3为本发明材料与现有技术的亲水/疏水共聚或者共混材料制备的薄膜表面亲水性接触角度贮藏稳定性比较。
图4为本发明材料与现有技术的亲水/疏水共聚或者共混材料在葡萄糖渗透率相近时的氧气渗透率与葡萄糖渗透率比例比较。
具体实施方式
以下将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
下面结合实施例和附图对本发明做更进一步地解释。下列实施例仅用于说明本发明，但并不用来限定本发明的实施范围。
本发明的嵌段共聚物通式为A-b-B-b-C，其中，A、B、C为嵌段结构，b为嵌段聚合反应剂，A-b,B-b,C-b之间通过脲或氨基甲酸酯基共价键连接。
A代表高亲水性的软段材料，为聚乙二醇、聚丙二醇、聚醚胺中至少一种构成的嵌段，A优选选自二羟基、二羧基或者二胺基封端的聚乙二醇、聚丙二醇和聚丁二醇以及胺基封端的聚(乙二醇)/聚(丙二醇)共聚物中的一种或多种，数均分子量在500-3000；该类嵌段具有良好的水溶性，可以让目标分析物分子自由渗透。
B代表刚性高疏水性的硬段材料，为聚碳酸酯、聚甲基丙烯酸甲酯中至少一种构成的嵌段，B优选选自二羟基或二胺基封端的聚碳酸酯、双酚A聚碳酸酯和聚甲基丙烯酸甲酯中的一种或多种，数均分子量为1000-3000；该类嵌段提供了必要的物理强度和耐热耐水解的性能，使渗透膜的稳定性更佳。
C代表柔性多聚物，为聚二甲基硅氧烷、聚(甲基丙烯酸-2-羟乙酯)中至少一种构成的嵌段，C优选选自聚双端环氧基聚硅氧烷、二羟基聚二甲基硅氧 烷和聚(甲基丙烯酸-2-羟乙酯)中的一种或多种，数均分子量在500-3000；该类嵌段起到了一定的过渡作用使得A类嵌段和B类嵌段在混合和成膜时不易发生微相分离。
b代表嵌段聚合反应剂，具体为异氰酸酯类嵌段聚合反应剂，包括二苯基甲烷二异氰酸酯、六亚甲基二异氰酸酯、二环己基甲烷二异氰酸酯中的一种或多种。
嵌段与嵌段之间由异氰酸酯类嵌段聚合反应剂通过缩聚机制连接，从而生成稳定的聚氨酯或者聚脲类多嵌段共聚物。反应机理如下：
Figure PCTCN2020135162-appb-000005
Q为具有双官能度的小分子扩链剂，选自水、乙二醇、1,4丁二醇、联苯胺、一缩二乙二醇、1,2-丙二醇、一缩二丙二醇、1,6-己二醇、新戊二醇、二乙基甲苯二胺、3,5-二甲硫基甲苯二胺。
按照总质量份数为100份，三种嵌段和嵌段聚合反应剂的质量份数如下：A嵌段为5-40份，B嵌段为5-20份，C嵌段为20-70份，嵌段聚合反应剂b的重量比例为10-40份，小分子扩链剂为0-10份。优选按质量份数总数为100份计：A嵌段为15-30份，B嵌段为5-10份，C嵌段为40-50份，嵌段聚合反应剂b为20-25份，小分子扩链剂为0-5份。按照这种原材料比例合成的嵌段共聚物材料制成的渗透膜具有稳定可控的水溶性小分子低渗透率，适用于通过酶反应检测水溶性小分子检测物(例如：通过葡萄糖氧化酶检测溶液或血液中葡萄糖含量)的生物传感器用来控制检测物渗透至传感器表面的速率。
本发明的三嵌段共聚物为直链聚合物。
上述高生物相容性的三嵌段共聚物的制备方法，包括如下步骤：
步骤一、将高亲水性的软段材料、刚性高疏水性的硬段材料、柔性多聚物，加入到有机溶剂中，在30-45℃下混合均匀；有机溶剂包括四氢呋喃或异丁醇，有机溶剂的体积和高亲水性的软段材料、刚性高疏水性的硬段材料、柔性多聚物总质量比为2-10ml:1g。
步骤二、向步骤一的混合溶液中加入催化剂，并逐滴加入嵌段聚合反应剂，升温至55-70℃，反应12-20h；催化剂包括三乙烯二胺或者二丁基二异辛酸锡。
步骤三、向步骤二的反应溶液中添加小分子扩链剂，反应12h-18h；去离子水的体积和高亲水性的软段材料、刚性高疏水性的硬段材料、柔性多聚物总质量比为0.1-0.3g:1g。
步骤四、冷却后，将反应产物冲洗、过滤、干燥，得到所述的三嵌段共聚物。
本发明的三嵌段共聚物在制备植入式生物传感器生物相容性渗透膜中的应用。制备的渗透膜拥有高度可控的小分子渗透率，良好的耐水耐热性和可调节的亲水性和生物相容性，这主要是由含有两性分子的多嵌段共聚脲或者聚氨酯来实现的。
实施例1
原料：聚醚胺，数均分子量1500；聚碳酸酯二元醇，数均分子量3000；二氨基封端聚二甲基硅氧烷，数均分子量3000；二苯基甲烷二异氰酸酯；上述原料按照总质量为50g，质量份数比例为5:10:70:15；10:9:63:18；15:9:55:21；20:8:48:24；25:8:40:27；30:7:33:30；35:7:26:32；40:6:20:34进行配比制作8种聚合物材料。反应用溶剂为四氢呋喃100ml，去离子水50ml。合成方法如下：
步骤一、将聚醚胺、聚碳酸酯二元醇、二氨基封端聚二甲基硅氧烷，加入到四氢呋喃中，在40℃下混合均匀。
步骤二、向步骤一的混合溶液中加入三乙烯二胺，并逐滴加入二苯基甲烷二异氰酸酯，升温至65℃，反应12h。
步骤三、向步骤二的反应溶液中添加去离子水，反应12h。
步骤四、冷却后，将反应产物冲洗、过滤、干燥，得到所述的三嵌段共聚物。
对比例1
原料：聚乙二醇，数均分子量1500；二氨基封端聚二甲基硅氧烷，数均分子量3000；二苯基甲烷二异氰酸酯；上述原料按照总质量为50g，质量份数比例为5:75:20；10:68:22；15:60:25；20:52:28；25:45:30；30:37:33；35:30:35；40:22:38进行配比制作8种聚合物材料。反应用溶剂为四氢呋喃100ml，去离子水50ml。按上述合成方法合成相应的对比例聚合材料。
对比例2
原料：聚乙二醇，数均分子量12000；聚二甲基硅氧烷，数均分子量9000；上述原料按照总质量为50g，质量份数比例为5:95；10:90；15:85；20:80；25:75；30:70；35:65；40:60进行配在溶剂中充分混合制作8种对比例混合型聚合材料。反应用溶剂为四氢呋喃100ml。按上述合成方法合成相应的对比例聚合材料。
对比例3
原料：聚醚胺，数均分子量1000，质量为25g；聚碳酸酯二元醇，数均分子量5000，质量为10g；二氨基封端聚二甲基硅氧烷，数均分子量5000，质量为15g；四氢呋喃，100ml；二苯基甲烷二异氰酸酯，质量为12g；去离子水50ml。合成方法如下：
步骤一、将聚醚胺、聚碳酸酯二元醇、二氨基封端聚二甲基硅氧烷，加入到四氢呋喃中，在40℃下混合均匀。
步骤二、向步骤一的混合溶液中加入三乙烯二胺，并逐滴加入二苯基甲烷二异氰酸酯，升温至65℃，反应12h。
步骤三、向步骤二的反应溶液中添加去离子水，反应12h。
步骤四、冷却后，将反应产物冲洗、过滤、干燥，得到所述的三嵌段共聚物。
对比例4
原料：氨基封端聚丙二醇，分子量500，质量15g；聚醚胺，分子量600，质量10g；聚(双酚A碳酸酯)，分子量为5000，质量25g；二氨基封端聚二甲基硅氧烷，分子量为20000，质量10g；聚(甲基丙烯酸-2-羟乙酯)，分子量为5000，质量5g；异丁醇150ml；六亚甲基二异氰酸酯，质量15g；去离子水150ml。合成方法如下：
步骤一、将氨基封端聚丙二醇、聚醚胺、聚(双酚A碳酸酯)、二氨基封端聚二甲基硅氧烷、聚(甲基丙烯酸-2-羟乙酯)，加入到异丁醇中，在35℃下混合均匀。
步骤二、向步骤一的混合溶液中加入二丁基二异辛酸锡，并逐滴加入六亚甲基二异氰酸酯，升温至60℃，反应16h。
步骤三、向步骤二的反应溶液中添加去离子水，反应14h。
步骤四、冷却后，将反应产物冲洗、过滤、干燥，得到所述的三嵌段共聚物。
实施例2
原料：氨基封端聚丙二醇，分子量500，质量8g；聚醚胺，分子量600，质量10g；聚(双酚A碳酸酯)，分子量为3000，质量15g；二氨基封端聚二甲基硅氧烷，分子量为2400，质量10g；聚(甲基丙烯酸-2-羟乙酯)，分子量为800，质量10g；异丁醇300ml；六亚甲基二异氰酸酯，质量10g；乙二胺15ml。合成方法如下：
步骤一、将氨基封端聚丙二醇、聚醚胺、聚(双酚A碳酸酯)、二氨基封端聚二甲基硅氧烷、聚(甲基丙烯酸-2-羟乙酯)，加入到异丁醇中，在35℃下混合均匀。
步骤二、向步骤一的混合溶液中加入二丁基二异辛酸锡，并逐滴加入六亚甲基二异氰酸酯，升温至60℃，反应16h。
步骤三、向步骤二的反应溶液中添加乙二胺，反应14h。
步骤四、冷却后，将反应产物冲洗、过滤、干燥，得到所述的三嵌段共聚物。
实施例3
原料：氨基封端聚乙二醇，数均分子量2000，质量为16g；聚甲基丙烯酸甲酯，数均分子量2000，质量为10g；二羧基封端聚二甲基硅氧烷，数均分子量1200，质量为20g；四氢呋喃，500ml；3g异佛尔酮二异氰酸酯和6g二环己基甲烷二异氰酸酯；乙二醇10ml。合成方法如下：
步骤一、将氨基封端聚乙二醇、聚甲基丙烯酸甲酯、二氨基封端聚二甲基硅氧烷，加入到四氢呋喃中，在30℃下混合均匀。
步骤二、向步骤一的混合溶液中加入三乙烯二胺，并逐滴加入二苯基甲烷二异氰酸酯和二环己基甲烷二异氰酸酯的混合液，升温至55℃，反应14h。
步骤三、向步骤二的反应溶液中添加去乙二醇，反应18h。
步骤四、冷却后，将反应产物冲洗、过滤、干燥，得到所述的三嵌段共聚物。
实施例4
原料：氨基封端聚乙二醇，数均分子量3000，质量35g；聚碳酸酯二元醇，数均分子量1200，质量8g；聚甲基丙烯酸甲酯，数均分子量1200，质量16g；聚(甲基丙烯酸-2-羟乙酯)，数均分子量2500，质量35g；异丁醇600ml；三甲基六亚甲基二异氰酸酯10g；对苯二酚二羟乙基醚10ml。合成方法如下：
步骤一、将氨基封端聚乙二醇、聚碳酸酯二元醇、聚甲基丙烯酸甲酯、聚(甲基丙烯酸-2-羟乙酯)，加入到异丁醇中，在45℃下混合均匀。
步骤二、向步骤一的混合溶液中加入二丁基二异辛酸锡，并逐滴加入二环己基甲烷二异氰酸酯，升温至70℃，反应20h。
步骤三、向步骤二的反应溶液中添加对苯二酚二羟乙基醚，反应16h。
步骤四、冷却后，将反应产物冲洗、过滤、干燥，得到所述的三嵌段共聚物。
小分子分析物(葡萄糖)渗透率性能比较
将实施例1所制备的8种三嵌段共聚物和对比例1和对比例2中所制备的8种聚合物材料和8种混合材料分别溶解于有机溶剂如四氢呋喃中，然后旋涂于铝盘表面并晾干直至溶剂全部蒸发，制备成薄膜，再从铝盘中小心取下薄膜。
对制备好的薄膜进行葡萄糖渗透率性能测试，测试方法如下：
将制备好的薄膜夹在透皮测试仪两个溶液腔之间，一侧的溶液腔加入高浓度葡萄糖溶液，另一侧加入同等体积的磷酸盐缓冲溶液，之后定时取出两侧溶液进行葡萄糖浓度测试并测量薄膜厚度，之后通过公式计算薄膜的葡萄糖渗透率。如图1所示，材料中的亲水性成分(如聚丙二醇，聚乙二醇，聚醚胺等)所含比例越高，葡萄糖渗透率越高。但与对比例1的双嵌段共聚物材料和对比例2的混合型材料相比，本发明所制成的材料的葡萄糖渗透率与其亲水性成分比例呈更理想的线性关系。这使得本发明的材料可以更好的通过改变不同原料的比例来控制渗透率达到在植入式生物传感器中使用的要求。
耐热耐水解性能比较
将实施例2制备的三嵌段共聚物和对比例1和对比例2中使用相近质量比例的聚乙二醇所制备的材料分别制备成薄膜，进行耐热耐水解性能比较。薄膜制备过程如下：所测材料溶解于有机溶剂如四氢呋喃中，然后旋涂于玻璃片表面并加热至40℃直至溶剂全部蒸发，使所测材料在玻璃表面形成薄膜。
将各样本薄膜(每个样本约0.1g)分别放置于60℃，100％相对湿度的恒温恒湿烘箱中，在0、5、10、15、20时取出样本，将样本溶于有机溶剂如四氢呋喃，使用尺寸排阻色谱法(SEC)或凝胶渗透色谱法(GPC)等方式测量其分子量分布并计算数均分子量。将计算得出的数均分子量与未浸泡过的样本相比即得到“平均分子量/初始分子量”的比值，用百分比的形式表示。如图2所示，对比例材料在高温高湿贮藏后其平均分子量显著降低，表示其分子已部分分解，其耐热耐水解性较差。实施例2所制备的本发明三嵌段共聚物材料和聚醚类聚氨酯拥有较好的水解抗性和热分解抗性。
薄膜表面亲水性接触角度稳定性比较
将实施例3制备的三嵌段共聚物和对比例1和对比例2中使用相近质量比例的聚乙二醇所制备的材料进行薄膜表面亲水性接触角度比较。亲水接触角实验方法为把所测材料溶解于有机溶剂如四氢呋喃中，然后旋涂于玻璃片表面并加热至40℃直至溶剂全部蒸发，使所测材料在玻璃表面形成薄膜，然 后把薄膜样本保存在室温(约25℃)和室内常规相对湿度(约20％-40％)中。定期(例如每个月)将样本取出，在其上滴上一滴约0.05-0.1mL的去离子水，并使用接触角分析仪测定水滴与薄膜表面形成的角度，角度越小说明材料表面亲水性越高。
如图3所示，均聚物共混物和双嵌段共聚物在放置一段时间后，其表面亲水性有所降低，而实施例1中所制备的新材料的表面亲水性比较稳定，在室温下保存6个月依然不会有很大的变化。
薄膜氧气/葡萄糖渗透率比较
将实施例4所制备的三嵌段共聚物材料和对比例3和对比例4所制备的材料分别溶解于有机溶剂如四氢呋喃中，然后旋涂于铝盘表面并晾干直至溶剂全部蒸发，制备成薄膜，再从铝盘中小心取下薄膜。对制备好的薄膜进行氧气渗透率性能测试，测试方法如下：
将制备好的薄膜夹在透皮测试仪两个溶液腔之间，在两侧的溶液腔加入同等体积的除氧磷酸盐缓冲溶液并放入氧气传感器后密封。之后在一侧的溶液腔通氧气并定时对两侧溶液腔进行溶氧度测试，待两侧溶氧浓度接近平衡后取出薄膜进行厚度测量，之后通过公式计算薄膜的氧气渗透率并计算氧气渗透率与葡萄糖渗透率的比例。如图4所示，本发明所制成的材料的氧气/葡萄糖渗透率比例显著高于对比例1及对比例2。因此本发明的所合成的材料更适用于基于氧化酶反应的植入式生物传感器，尤其是基于葡萄糖氧化酶的植入式葡萄糖传感器的使用要求。在薄膜外侧溶液或者组织液葡萄糖浓度较高，溶氧浓度较低的情况下，本发明所制作材料薄膜可以更有效的保证薄膜内侧的氧气供应高于渗透过来的葡萄糖，保证基于葡萄糖氧化酶反应的传感器的正常运作机制不受溶氧浓度波动的影响。

Claims (8)

  1. 一种植入式生物传感器用三嵌段共聚物，其通过在以下嵌段物质的混合液中加入嵌段聚合反应剂和小分子扩链剂聚合而成：
    嵌段A，高亲水性的软段材料，选自二羟基、二羧基或者二胺基封端的聚乙二醇、聚丙二醇和聚丁二醇以及胺基封端的聚(乙二醇)/聚(丙二醇)共聚物中的一种或多种，数均分子量在500-3000；
    嵌段B，刚性高疏水性的硬段材料，选自二羟基或二胺基封端的聚碳酸酯、双酚A聚碳酸酯和聚甲基丙烯酸甲酯中的一种或多种，数均分子量为1000-3000；
    嵌段C，柔性多聚物，选自聚双端环氧基聚硅氧烷、二羟基聚二甲基硅氧烷和聚(甲基丙烯酸-2-羟乙酯)中的一种或多种，数均分子量在500-3000；
    所述嵌段共聚物的通式为(-A-b-B-b-C-) n，其中，A、B、C为嵌段结构，b为嵌段聚合反应剂，
    其中，按质量份数总数为100计：A嵌段为5-40份，B嵌段为5-20份，C嵌段为20-70份，嵌段聚合反应剂b为10-40份，小分子扩链剂为0-10份。
  2. 根据权利要求1所述的植入式生物传感器用三嵌段共聚物，其中b为异氰酸酯类聚合反应剂。
  3. 根据权利要求2所述的植入式生物传感器用三嵌段共聚物，其中所述异氰酸酯类聚合反应剂选自如下物质中的一种或多种：
    Figure PCTCN2020135162-appb-100001
    Figure PCTCN2020135162-appb-100002
  4. 根据权利要求1所述的植入式生物传感器用三嵌段共聚物，其中所述的小分子扩链剂选自如下物质中的一种或多种：
    HO-CH 2-CH 2-OH           乙二醇、
    H 2O                     水、
    HO-CH 2-CH 2-CH 2-CH 2-OH   丁二醇、
    H 2N-CH 2-CH 2-NH 2         乙二胺、
    Figure PCTCN2020135162-appb-100003
    Figure PCTCN2020135162-appb-100004
  5. 根据权利要求1所述的植入式生物传感器用三嵌段共聚物，其特征在于，按质量份数总数为100计：A嵌段为15-30份，B嵌段为5-10份，C嵌段为40-50份，嵌段聚合反应剂b为20-25份，小分子扩链剂为0-5份。
  6. 根据权利要求1所述的植入式生物传感器用三嵌段共聚物，其特征在于，A-b、B-b、C-b之间通过脲或氨基甲酸酯基共价键连接。
  7. 权利要求1-6中任一项所述的三嵌段共聚物在植入式生物传感器中的应用。
  8. 权利要求1-6中任一项所述的三嵌段共聚物的制备方法，包括如下步骤：
    步骤一、将高亲水性的软段材料、刚性高疏水性的硬段材料、柔性多聚物，加入到有机溶剂中，在30-45℃下混合均匀；有机溶剂包括四氢呋喃、环 己酮或异丁醇；有机溶剂的体积和高亲水性的软段材料、刚性高疏水性的硬段材料、柔性多聚物总质量比为2-10ml:1g；
    步骤二、向步骤一的混合溶液中加入催化剂，并逐滴加入嵌段聚合反应剂，升温至55-70℃，反应12-20h；催化剂包括三乙烯二胺或者二丁基二异辛酸锡；
    步骤三、向步骤二的反应溶液中添加小分子扩链剂，反应12h-18h；小分子扩链剂的质量和高亲水性的软段材料、刚性高疏水性的硬段材料、柔性多聚物总质量比为0.1-0.3g:1g；
    步骤四、冷却后，将反应产物冲洗、过滤、干燥，得到所述的三嵌段共聚物。
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