CN113493558A - Triblock copolymer for implantable biosensor and application and preparation method thereof - Google Patents
Triblock copolymer for implantable biosensor and application and preparation method thereof Download PDFInfo
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- CN113493558A CN113493558A CN202010192423.3A CN202010192423A CN113493558A CN 113493558 A CN113493558 A CN 113493558A CN 202010192423 A CN202010192423 A CN 202010192423A CN 113493558 A CN113493558 A CN 113493558A
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Abstract
The invention relates to a triblock copolymer for an implantable biosensor, which is prepared by adding a block polymerization reactant and a micromolecule chain extender into a mixed solution of the following block substances: the block A is a high-hydrophilicity soft block material, and the number average molecular weight is 500-3000; the block B is a rigid high-hydrophobicity hard segment material, and the number average molecular weight is 1000-3000; block C, flexible polymer with number average molecular weight of 500-3000; the general formula of the block copolymer is A-B-B-B-C, wherein A, B, C is a block structure, B is a block polymerization reactant, and the total mass parts of the block copolymer are 100: 5-40 parts of A block, 5-20 parts of B block, 20-70 parts of C block, 10-40 parts of block polymerization reactant B and 0-10 parts of small molecular chain extender. The invention also relates to the use and to a method for producing said triblock copolymers.
Description
Technical Field
The invention relates to the technical field of block copolymers, in particular to a triblock copolymer for an implantable biosensor, and also relates to application and a preparation method of the triblock copolymer.
Background
An implantable biosensor refers to a sensor device that can be partially or fully implanted in the human body, which can measure the content of target analyte molecules without the need for an external reagent and a separate treatment of body fluid or blood in advance. The implanted biosensor has the advantage that certain important physiological and pathological parameters, such as blood oxygen, blood sugar, virus antibodies and the like, which change along with time in the body can be continuously measured, so that the change of the physical signs of a measured object caused by environmental change, physical activity, diet and medicines can be more directly reflected. Generally, the sensing portion of an implantable sensor requires some interaction with an analyte in the tissue to detect the presence of the analyte, and thus, the controllability of the interaction between the implantable biosensor and the implanted tissue represents a major feature and technical difficulty of implantable sensing technology. Due to the unusually complex internal human environments, especially microscopic biological environments, human knowledge of the interaction between implantable sensors and implanted tissue is currently limited. For example, the difference between the surface material of the implantable sensor and the composition of the human body can trigger the foreign body rejection reaction mechanism of the human body, thereby generating a biological isolation layer mainly composed of fibrin. The isolation layer can cause the sensor to be isolated from the implanted tissue, so that the molecular permeation and exchange of the sensor and tissue fluid are hindered, and the accuracy of the sensor in detecting the concentration of the analyte is lost. Therefore, how to reduce the foreign body rejection reaction and improve the biocompatibility of the sensor while ensuring the stable and controlled permeation and diffusion of the analyte to the sensing part of the sensor is the key to improve the accuracy and the service life of the sensor, which is usually realized by adding a layer of high-biocompatibility film on the surface of the sensor contacting with the tissue.
Biocompatible permeable membranes have very high technical requirements on their components, such as very low cytotoxicity, good hydrophilicity and biocompatibility, adequate osmotic diffusion properties for the target analyte and barrier properties for potential interferents, and heat resistance, hydrolysis resistance and resistance to other degradation mechanisms over a given period of use, among others. Also, due to manufacturing, shipping and storage requirements, it is desirable that the material have a stable chemical molecular structure such that it retains its stable properties for extended periods of time before it is used. Thus, current biocompatible osmotic membranes are very limited in choice. At present, such osmotic membranes are mostly made of widely accepted hydrophilic polymers with high biocompatibility such as polyethylene glycol, poly (2-hydroxyethyl methacrylate) and the like, or mixtures thereof, and the overall permeability of the osmotic membrane is controlled by adding hydrophobic materials such as polyester or polysiloxane and copolymerizing or directly mixing the hydrophobic materials with hydrophilic materials. A common problem with this type of permeable membrane material is that the hydrophobic portion has a glass transition temperature below room temperature, is very mobile, and readily migrates to the surface and repels the hydrophilic segments, causing microphase separation of the material. This not only results in poor controllability of the permeability of the membrane material, especially the rapid non-linear decrease in the analyte permeability as the proportion of hydrophilic segments decreases, but also results in a significant decrease in the permeation stability of the limiting membrane over time. Meanwhile, materials such as polyethylene glycol and polyester have poor water resistance and heat resistance, are easy to degrade in vivo environment or under high temperature and high humidity conditions, and the property of the permeable membrane is changed while the molecular weight is reduced, so that the production and long-term storage are not facilitated.
The prior art CN201610792708.4 discloses a highly biocompatible triblock copolymer, and the copolymer material in this patent application can also be used in an implantable biosensor, but the controllability of the permeation and diffusion properties of target analytes and the requirement for oxygen permeability of the sensor involving oxidase reaction are to be improved. The materials of the present invention provide a significant improvement in these properties.
Disclosure of Invention
The block copolymers of the present invention are particularly suitable for use as biocompatible permeable membranes for implantable biosensors, having very low cytotoxicity, good hydrophilicity and biocompatibility, suitable pervaporation properties for the target analyte and barrier properties for potential interferents, as well as heat resistance, hydrolysis resistance and resistance to other degradation mechanisms for a given period of use.
Specifically, the triblock copolymer for the implantable biosensor is prepared by adding a block polymerization reactant and a small molecule chain extender into a mixed solution of the following block substances for polymerization:
block A, a highly hydrophilic soft block material selected from one or more of dihydroxy-, dicarboxyl-, or diamino terminated polyethylene glycol, polypropylene glycol, and polybutylene glycol, and amino terminated poly (ethylene glycol)/poly (propylene glycol) copolymers, having a number average molecular weight of 500-3000;
the block B is a rigid high-hydrophobicity hard segment material which is selected from one or more of dihydroxy or diamino terminated polycarbonate, bisphenol A polycarbonate and polymethyl methacrylate, and the number average molecular weight is 1000-3000;
a block C, a flexible polymer, one or more selected from poly (epoxy-terminated polysiloxane), dihydroxy polydimethylsiloxane and poly (2-hydroxyethyl methacrylate), the number average molecular weight is 500-3000;
the general formula of the copolymer is (-A-B-B-B-C-)nWherein A, B, C is a block structure, b is a block polymerization reactant,
wherein the total mass is 100 by mass: 5-40 parts of A block, 5-20 parts of B block, 20-70 parts of C block, 10-40 parts of block polymerization reactant B and 0-10 parts of small molecular chain extender.
The permeable membrane synthesized by the raw materials in the ratio range has stable and controllable low permeability of the water-soluble small molecules, and the biosensor suitable for detecting the water-soluble small molecule detection object through enzyme reaction (for example, detecting the glucose content in solution or blood through glucose oxidase) is used for controlling the speed of the detection object permeating to the sensor surface.
Preferably, b is an isocyanate-based polymerization agent.
Preferably, the isocyanate-based polymerization reactant is selected from one or more of the following: 2, 4-tolylene diisocyanate, 2, 6-tolylene diisocyanate, cyclohexanedimethylene diisocyanate, 4 '-diphenylmethane diisocyanate, xylylene diisocyanate, isophorone diisocyanate, hexamethylene diisocyanate, 4' -dicycloethylmethane diisocyanate. The structural formulae of these substances are respectively:
preferably, 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 ' -dichlorodiphenyldiamine, 3 ' -dichloro-4, 4 ' -diaminodiphenylmethane. The structural formulae of these substances are respectively:
the use of a small chain extender as described above allows the block copolymer of the present invention to be further polymerized, increasing the molecular weight of the final material to give it the desired properties.
Preferably, the total amount of the components is 100 parts by mass: 15-30 parts of A block, 5-10 parts of B block, 40-50 parts of C block, 20-25 parts of block polymerization reactant B and 0-5 parts of small molecular chain extender.
Preferably, A-B, B-B, C-B are linked covalently by urea or urethane groups.
The invention also relates to the use of said triblock copolymer in implantable biosensors.
The invention also relates to a process for preparing said triblock copolymer comprising the steps of:
adding a high-hydrophilicity soft segment material, a rigid high-hydrophobicity hard segment material and a flexible polymer into an organic solvent, and uniformly mixing at 30-45 ℃; the organic solvent comprises tetrahydrofuran, cyclohexanone or isobutanol; the volume of the organic solvent, the total mass ratio of the soft segment material with high hydrophilicity, the hard segment material with rigidity and high hydrophobicity and the flexible polymer is 2-10ml:1 g;
step two, adding a catalyst into the mixed solution obtained in the step one, dropwise adding a block polymerization reactant, heating to 55-70 ℃, and reacting for 12-20 hours; the catalyst comprises triethylene diamine or dibutyl tin diisooctoate;
step three, adding a micromolecular chain extender into the reaction solution obtained in the step two, and reacting for 12-18 h; the total mass ratio of the small molecular chain extender to the soft segment material with high hydrophilicity, the hard segment material with rigidity and high hydrophobicity and the flexible polymer is 0.1-0.3g:1 g;
and step four, after cooling, washing, filtering and drying the reaction product to obtain the triblock copolymer.
Compared with the prior art, the block copolymer and the preparation method have the following advantages:
(1) the invention combines the advantages of three types of single polymeric molecules, so that the segmented copolymer has the characteristics of adjustable permeability, adjustable physical property, better hydrolytic stability, heat-resistant stability and the like, and compared with the simple mixing of the three types of polymeric molecules, the combination of isocyanate chain extenders such as diisocyanate and the like through chain extension reaction can prevent the micro-phase separation phenomenon in the film forming process.
(2) The triblock copolymer of the invention has more stable physical and chemical properties after film formation, and has better hydrolysis resistance and heat resistance than pure hydrophilic/hydrophobic copolymerization or blending materials such as polyether, polyester polyurethane and the like.
(3) Due to the existence of the rigid and highly hydrophobic hard segment material of the block B, the copolymer molecules after film formation are not easy to generate the surface property change of the film caused by molecular arrangement recombination, especially the change of hydrophilicity and the permeability of small molecule analytes.
(4) 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.
(5) In the application of the glucose oxidase type glucose sensor, compared with the traditional permeable membrane material, the material has the advantages that the permeability proportion and the proportion stability of oxygen and glucose are obviously improved, and the problems of reduction of the measurement precision of the sensor and the like caused by insufficient oxygen supply can be better avoided.
Drawings
For purposes of illustration and not limitation, the methods and materials of the present invention will now be described in accordance with the preferred embodiments thereof, with reference to the accompanying drawings, in which:
FIG. 1 is a comparison of the permeability of a small molecule analyte (e.g., glucose) measured for a material of the present invention and a prior art hydrophilic/hydrophobic co-polymeric or blended material at different ratios of hydrophilic to hydrophobic materials.
FIG. 2 is a comparison of the water and heat resistance of the material of the present invention with that of a hydrophilic/hydrophobic copolymer or blend material of the prior art.
FIG. 3 is a comparison of the storage stability of the hydrophilic contact angle of the surface of the film prepared by the material of the present invention and the hydrophilic/hydrophobic copolymerized or blended material of the prior art.
FIG. 4 is a comparison of oxygen permeability and glucose permeability for materials of the present invention and prior art hydrophilic/hydrophobic co-polymeric or blended materials at similar glucose permeability.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention is explained in more detail below with reference to exemplary embodiments and the accompanying drawings. The following examples are provided only for illustrating the present invention and are not intended to limit the scope of the present invention.
The general formula of the block copolymer is A-B-B-B-C, wherein A, B, C is a block structure, B is a block polymerization reactant, and A-B, B-B and C-B are connected through a urea or carbamate group covalent bond.
A represents a high-hydrophilicity soft segment material and is a block formed by at least one of polyethylene glycol, polypropylene glycol and polyether amine, A is preferably one or more selected from dihydroxy, dicarboxyl or diamino terminated polyethylene glycol, polypropylene glycol and polybutylene glycol and amino terminated poly (ethylene glycol)/poly (propylene glycol) copolymer, and the number average molecular weight is 500-3000; the block has good water solubility and can allow target analyte molecules to freely permeate.
B represents rigid and highly hydrophobic hard segment material and is a block formed by at least one of polycarbonate and polymethyl methacrylate, B is preferably selected from one or more of dihydroxy or diamino terminated polycarbonate, bisphenol A polycarbonate and polymethyl methacrylate, and the number average molecular weight is 1000-3000; the block provides necessary physical strength and heat-resistant hydrolysis-resistant performance, so that the permeable membrane has better stability.
C represents a flexible polymer and is a block formed by at least one of polydimethylsiloxane and poly (2-hydroxyethyl methacrylate), C is preferably one or more selected from poly (double-end epoxy polysiloxane), dihydroxy polydimethylsiloxane and poly (2-hydroxyethyl methacrylate), and the number average molecular weight is 500-3000; the block plays a certain transition role, so that the A block and the B block are not easy to generate microphase separation during mixing and film forming.
b represents a block polymerization reactant, in particular an isocyanate block polymerization reactant, comprising one or more of diphenylmethane diisocyanate, hexamethylene diisocyanate and dicyclohexylmethane diisocyanate.
The blocks are connected by isocyanate block polymerization reactants through a polycondensation mechanism, so that stable polyurethane or polyurea multi-block copolymers are generated. The reaction mechanism is as follows:
q is a difunctional small molecule chain extender selected from the group consisting of 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 portions of the three block and block polymerization reactants are as follows according to the total mass portion of 100: 5-40 parts of A block, 5-20 parts of B block, 20-70 parts of C block, 10-40 parts of block polymerization reactant B and 0-10 parts of micromolecule chain extender. Preferably, the total weight of the components is 100 parts by mass: 15-30 parts of A block, 5-10 parts of B block, 40-50 parts of C block, 20-25 parts of block polymerization reactant B and 0-5 parts of small molecular chain extender. The permeable membrane made of the block copolymer material synthesized according to the raw material proportion has stable and controllable low permeability of the water-soluble micromolecule, and a biosensor suitable for detecting the water-soluble micromolecule detection object through enzyme reaction (for example, detecting the content of glucose in solution or blood through glucose oxidase) is used for controlling the speed of the detection object permeating to the sensor surface.
The triblock copolymers of the present invention are linear polymers.
The preparation method of the triblock copolymer with high biocompatibility comprises the following steps:
adding a high-hydrophilicity soft segment material, a rigid high-hydrophobicity hard segment material and a flexible polymer into an organic solvent, and uniformly mixing at 30-45 ℃; the organic solvent comprises tetrahydrofuran or isobutanol, the volume of the organic solvent, the high-hydrophilicity soft segment material, the rigidity high-hydrophobicity hard segment material and the total mass ratio of the flexible polymer is 2-10ml:1 g.
Step two, adding a catalyst into the mixed solution obtained in the step one, dropwise adding a block polymerization reactant, heating to 55-70 ℃, and reacting for 12-20 hours; the catalyst comprises triethylene diamine or dibutyl tin diisooctoate.
Step three, adding a micromolecular chain extender into the reaction solution obtained in the step two, and reacting for 12-18 h; the volume of the deionized water, the total mass ratio of the soft segment material with high hydrophilicity, the hard segment material with rigidity and high hydrophobicity and the flexible polymer are 0.1-0.3g:1 g.
And step four, after cooling, washing, filtering and drying the reaction product to obtain the triblock copolymer.
The triblock copolymer disclosed by the invention is applied to the preparation of an implanted biosensor biocompatible permeable membrane. The prepared permeable membrane has high controllable small molecule permeability, good water resistance and heat resistance and adjustable hydrophilicity and biocompatibility, and is mainly realized by multi-block copolyurea or polyurethane containing amphiphilic molecules.
Example 1
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 raw materials are 50g in total mass, and the mass part ratio 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; 8 polymer materials are prepared according to the proportion of 40:6:20: 34. The solvent for reaction is tetrahydrofuran 100ml and deionized water 50 ml. The synthesis method comprises the following steps:
step one, adding polyether amine, polycarbonate diol and diamino end-capped polydimethylsiloxane into tetrahydrofuran, and uniformly mixing at 40 ℃.
And step two, adding triethylene diamine into the mixed solution obtained in the step one, dropwise adding diphenylmethane diisocyanate, heating to 65 ℃, and reacting for 12 hours.
And step three, adding deionized water into the reaction solution obtained in the step two, and reacting for 12 hours.
And step four, after cooling, washing, filtering and drying the reaction product to obtain the triblock copolymer.
Comparative example 1
Raw materials: polyethylene glycol, number average molecular weight 1500; diamino terminated polydimethylsiloxane, number average molecular weight 3000; diphenylmethane diisocyanate; the raw materials are 50g in total mass, and the mass part ratio is 5:75: 20; 10:68: 22; 15:60: 25; 20:52: 28; 25:45: 30; 30:37: 33; 35:30: 35; the ratio of 40:22:38 was used to prepare 8 polymer materials. The solvent for reaction is tetrahydrofuran 100ml and deionized water 50 ml. The corresponding comparative polymeric material was synthesized as described above.
Comparative example 2
Raw materials: polyethylene glycol, number average molecular weight 12000; polydimethylsiloxane, number average molecular weight 9000; the raw materials are 50g in total mass, and the mass part ratio is 5: 95; 10: 90; 15: 85; 20: 80; 25: 75; 30: 70; 35: 65; 40:60 the 8 comparative example mixed type polymeric materials were prepared by mixing thoroughly in a solvent. The solvent for the reaction was 100ml of tetrahydrofuran. The corresponding comparative polymeric material was synthesized as described above.
Comparative example 3
Raw materials: polyetheramine having a number average molecular weight of 1000 and a mass of 25 g; polycarbonate diol with the number average molecular weight of 5000 and the mass of 10 g; diamino terminated polydimethylsiloxane with a number average molecular weight of 5000 and a mass of 15 g; tetrahydrofuran, 100 ml; diphenylmethane diisocyanate, the mass being 12 g; 50ml of deionized water. The synthesis method comprises the following steps:
step one, adding polyether amine, polycarbonate diol and diamino end-capped polydimethylsiloxane into tetrahydrofuran, and uniformly mixing at 40 ℃.
And step two, adding triethylene diamine into the mixed solution obtained in the step one, dropwise adding diphenylmethane diisocyanate, heating to 65 ℃, and reacting for 12 hours.
And step three, adding deionized water into the reaction solution obtained in the step two, and reacting for 12 hours.
And step four, after cooling, washing, filtering and drying the reaction product to obtain the triblock copolymer.
Comparative example 4
Raw materials: amino-terminated polypropylene glycol with a molecular weight of 500 and a mass of 15 g; polyether amine with molecular weight of 600 and mass of 10 g; poly (bisphenol-a carbonate) having a molecular weight of 5000 and a mass of 25 g; diamino terminated polydimethylsiloxane with molecular weight of 20000 and mass of 10 g; poly (2-hydroxyethyl methacrylate), molecular weight 5000, mass 5 g; 150ml of isobutanol; hexamethylene diisocyanate with the mass of 15 g; 150ml of deionized water. The synthesis method comprises the following steps:
adding amino-terminated polypropylene glycol, polyether amine, poly (bisphenol A carbonate), diamino-terminated polydimethylsiloxane and poly (2-hydroxyethyl methacrylate) into isobutanol, and uniformly mixing at 35 ℃.
And step two, adding dibutyltin diisooctoate into the mixed solution obtained in the step one, dropwise adding hexamethylene diisocyanate, heating to 60 ℃, and reacting for 16 hours.
And step three, adding deionized water into the reaction solution in the step two, and reacting for 14 h.
And step four, after cooling, washing, filtering and drying the reaction product to obtain the triblock copolymer.
Example 2
Raw materials: amino-terminated polypropylene glycol with the molecular weight of 500 and the mass of 8 g; polyether amine with molecular weight of 600 and mass of 10 g; poly (bisphenol-a carbonate) having a molecular weight of 3000 and a mass of 15 g; diamino terminated polydimethylsiloxane having a molecular weight of 2400 and a mass of 10 g; poly (2-hydroxyethyl methacrylate), molecular weight 800, mass 10 g; 300ml of isobutanol; hexamethylene diisocyanate with the mass of 10 g; ethylene diamine (15 ml).
The synthesis method comprises the following steps:
adding amino-terminated polypropylene glycol, polyether amine, poly (bisphenol A carbonate), diamino-terminated polydimethylsiloxane and poly (2-hydroxyethyl methacrylate) into isobutanol, and uniformly mixing at 35 ℃.
And step two, adding dibutyltin diisooctoate into the mixed solution obtained in the step one, dropwise adding hexamethylene diisocyanate, heating to 60 ℃, and reacting for 16 hours.
And step three, adding ethylenediamine into the reaction solution obtained in the step two, and reacting for 14 hours.
And step four, after cooling, washing, filtering and drying the reaction product to obtain the triblock copolymer.
Example 3
Raw materials: amino-terminated polyethylene glycol with a number average molecular weight of 2000 and a mass of 16 g; polymethyl methacrylate with number average molecular weight of 2000 and mass of 10 g; dicarboxy-terminated polydimethylsiloxane having a number average molecular weight of 1200 and a mass of 20 g; tetrahydrofuran, 500 ml; 3g of isophorone diisocyanate and 6g of dicyclohexylmethane diisocyanate; 10ml of ethylene glycol. The synthesis method comprises the following steps:
step one, adding amino-terminated polyethylene glycol, polymethyl methacrylate and diamino-terminated polydimethylsiloxane into tetrahydrofuran, and uniformly mixing at 30 ℃.
And step two, adding triethylene diamine into the mixed solution in the step one, dropwise adding a mixed solution of diphenylmethane diisocyanate and dicyclohexylmethane diisocyanate, heating to 55 ℃, and reacting for 14 hours.
And step three, adding ethylene glycol into the reaction solution obtained in the step two, and reacting for 18 h.
And step four, after cooling, washing, filtering and drying the reaction product to obtain the triblock copolymer.
Example 4
Raw materials: amino-terminated polyethylene glycol with the number-average molecular weight of 3000 and the mass of 35 g; polycarbonate diol, number average molecular weight 1200, mass 8 g; polymethyl methacrylate with number average molecular weight of 1200 and mass of 16 g; poly (2-hydroxyethyl methacrylate), number average molecular weight 2500, mass 35 g; 600ml of isobutanol; 10g of trimethyl hexamethylene diisocyanate; 10ml of hydroquinone dihydroxyethyl ether. The synthesis method comprises the following steps:
adding amino-terminated polyethylene glycol, polycarbonate diol, polymethyl methacrylate and poly (2-hydroxyethyl methacrylate) into isobutanol, and uniformly mixing at 45 ℃.
And step two, adding dibutyltin diisooctoate into the mixed solution obtained in the step one, dropwise adding dicyclohexylmethane diisocyanate, heating to 70 ℃, and reacting for 20 hours.
And step three, adding hydroquinone dihydroxyethyl ether into the reaction solution in the step two, and reacting for 16 h.
And step four, after cooling, washing, filtering and drying the reaction product to obtain the triblock copolymer.
Comparison of Small molecule analyte (glucose) Permeability Performance
The 8 triblock copolymers prepared in example 1 and the 8 polymer materials and 8 mixed materials prepared in comparative example 1 and comparative example 2 were dissolved in an organic solvent such as tetrahydrofuran, respectively, and then spin-coated on the surface of an aluminum pan and air-dried until the solvent was completely evaporated to prepare a thin film, and the thin film was carefully removed from the aluminum pan.
And (3) testing the glucose permeability of the prepared film by the following steps:
the prepared film is clamped between two solution cavities of a transdermal tester, a high-concentration glucose solution is added into the solution cavity on one side, a phosphate buffer solution with the same volume is added into the solution cavity on the other side, then the solutions on the two sides are taken out at regular time to carry out glucose concentration test and measure the thickness of the film, and then the glucose permeability of the film is calculated through a formula. As shown in FIG. 1, the higher the content of hydrophilic components (such as polypropylene glycol, polyethylene glycol, polyether amine, etc.) in the material, the higher the glucose permeability. However, the glucose permeability of the material made according to the present invention is more ideally linear with respect to the ratio of its hydrophilic components than the diblock copolymer material of comparative example 1 and the hybrid material of comparative example 2. This makes the material of the present invention capable of controlling the permeability by changing the ratio of different materials to meet the requirement of use in implanted biosensor.
Comparison of Heat resistance and hydrolysis resistance
The triblock copolymer prepared in example 2 and the materials prepared in comparative example 1 and comparative example 2 by using polyethylene glycol in similar mass proportion are respectively prepared into films for comparison of heat resistance and hydrolysis resistance. The preparation process of the film is as follows: the material to be tested is dissolved in an organic solvent such as tetrahydrofuran, then spin-coated on the surface of the glass sheet and heated to 40 ℃ until the solvent is completely evaporated, so that the material to be tested forms a thin film on the surface of the glass.
Each sample film (about 0.1g per sample) was placed in a constant temperature and humidity oven at 60 ℃, 100% relative humidity, samples were taken at 0, 5, 10, 15, 20, dissolved in an organic solvent such as tetrahydrofuran, measured for molecular weight distribution and calculated for number average molecular weight using Size Exclusion Chromatography (SEC) or Gel Permeation Chromatography (GPC), etc. The calculated number average molecular weight is compared to the un-soaked sample to obtain the "average molecular weight/initial molecular weight" ratio, expressed as a percentage. As shown in FIG. 2, the average molecular weight of the comparative example material significantly decreased after storage at high temperature and high humidity, indicating that the molecule thereof was partially decomposed and that the heat resistance and hydrolysis resistance thereof were poor. The triblock copolymer material and polyether polyurethane of the present invention prepared in example 2 have good hydrolysis resistance and thermal decomposition resistance.
Comparison of stability of hydrophilic contact angles on the surface of the film
The triblock copolymer prepared in example 3 was compared with the materials prepared in comparative examples 1 and 2 using polyethylene glycol in similar mass ratios for the hydrophilic contact angle of the film surface. The hydrophilic contact angle test method is that the tested material is dissolved in an organic solvent such as tetrahydrofuran, then is coated on the surface of a glass sheet in a spinning mode and is heated to 40 ℃ until the solvent is completely evaporated, so that the tested material forms a thin film on the surface of the glass, and then a thin film sample is stored in room temperature (about 25 ℃) and room normal relative humidity (about 20% -40%). Samples are taken periodically (e.g., every month), a drop of deionized water is applied thereto in an amount of about 0.05-0.1mL, and the angle formed by the drop of water and the surface of the film is measured using a contact angle analyzer, with smaller angles indicating more hydrophilic material surfaces.
As shown in FIG. 3, the surface hydrophilicity of the homopolymer blend and diblock copolymer was reduced after standing for a period of time, while the surface hydrophilicity of the new material prepared in example 1 was stable and remained unchanged for 6 months at room temperature.
Membrane oxygen/glucose permeability comparison
The triblock copolymer material prepared in example 4 and the materials prepared in comparative examples 3 and 4 were dissolved in an organic solvent such as tetrahydrofuran, respectively, and then spin-coated on the surface of an aluminum pan and air-dried until the solvent was completely evaporated to prepare a thin film, and the thin film was carefully removed from the aluminum pan. And (3) testing the oxygen permeability of the prepared film by the following steps:
the prepared film is clamped between two solution cavities of a transdermal tester, and the solution cavities on the two sides are added with the deoxygenation phosphate buffer solution with the same volume and are sealed after being placed into an oxygen sensor. And then introducing oxygen into the solution cavity on one side, testing the dissolved oxygen of the solution cavities on the two sides at regular time, taking out the film for thickness measurement after the dissolved oxygen concentration on the two sides is close to balance, and then calculating the oxygen permeability of the film by a formula and calculating the proportion of the oxygen permeability to the glucose permeability. As shown in fig. 4, the oxygen/glucose permeability ratio of the material made according to the present invention was significantly higher than that of comparative examples 1 and 2. Therefore, the synthesized material is more suitable for the use requirement of an implantable biosensor based on oxidase reaction, in particular an implantable glucose sensor based on glucose oxidase. Under the conditions that the concentration of glucose in solution or interstitial fluid outside the film is higher and the concentration of dissolved oxygen is lower, the material film prepared by the invention can more effectively ensure that the oxygen supply at the inner side of the film is higher than that of permeated glucose, and ensure that the normal operation mechanism of the sensor based on the glucose oxidase reaction is not influenced by the fluctuation of the concentration of the dissolved oxygen.
Claims (8)
1. A triblock copolymer for an implantable biosensor is prepared by adding a block polymerization reactant and a small molecule chain extender into a mixed solution of the following block substances for polymerization:
block A, a highly hydrophilic soft block material selected from one or more of dihydroxy-, dicarboxyl-, or diamino terminated polyethylene glycol, polypropylene glycol, and polybutylene glycol, and amino terminated poly (ethylene glycol)/poly (propylene glycol) copolymers, having a number average molecular weight of 500-3000;
the block B is a rigid high-hydrophobicity hard segment material which is selected from one or more of dihydroxy or diamino terminated polycarbonate, bisphenol A polycarbonate and polymethyl methacrylate, and the number average molecular weight is 1000-3000;
a block C, a flexible polymer, one or more selected from poly (epoxy-terminated polysiloxane), dihydroxy polydimethylsiloxane and poly (2-hydroxyethyl methacrylate), the number average molecular weight is 500-3000;
the general formula of the block copolymer is (-A-B-B-B-C-)nWherein A, B, C is a block structure, b is a block polymerization reactant,
wherein the total mass is 100 by mass: 5-40 parts of A block, 5-20 parts of B block, 20-70 parts of C block, 10-40 parts of block polymerization reactant B and 0-10 parts of small molecular chain extender.
2. The triblock copolymer for an implantable biosensor according to claim 1, wherein b is an isocyanate based polymerization reagent.
5. the triblock copolymer for an implantable biosensor according to claim 1, wherein the triblock copolymer comprises, based on 100 parts by weight in total: 15-30 parts of A block, 5-10 parts of B block, 40-50 parts of C block, 20-25 parts of block polymerization reactant B and 0-5 parts of small molecular chain extender.
6. The triblock copolymer of claim 1, wherein a-B, B-B, and C-B are covalently linked by urea or urethane groups.
7. Use of the triblock copolymer of any of claims 1-6 in an implantable biosensor.
8. A process for the preparation of the triblock copolymer of any of claims 1-6 comprising the steps of:
adding a high-hydrophilicity soft segment material, a rigid high-hydrophobicity hard segment material and a flexible polymer into an organic solvent, and uniformly mixing at 30-45 ℃; the organic solvent comprises tetrahydrofuran, cyclohexanone or isobutanol; the volume of the organic solvent, the total mass ratio of the soft segment material with high hydrophilicity, the hard segment material with rigidity and high hydrophobicity and the flexible polymer is 2-10ml:1 g;
step two, adding a catalyst into the mixed solution obtained in the step one, dropwise adding a block polymerization reactant, heating to 55-70 ℃, and reacting for 12-20 hours; the catalyst comprises triethylene diamine or dibutyl tin diisooctoate;
step three, adding a micromolecular chain extender into the reaction solution obtained in the step two, and reacting for 12-18 h; the total mass ratio of the small molecular chain extender to the soft segment material with high hydrophilicity, the hard segment material with rigidity and high hydrophobicity and the flexible polymer is 0.1-0.3g:1 g;
and step four, after cooling, washing, filtering and drying the reaction product to obtain the triblock copolymer.
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