WO2022073407A1 - 一种多孔高分子半透膜的制备方法及其产品 - Google Patents

一种多孔高分子半透膜的制备方法及其产品 Download PDF

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WO2022073407A1
WO2022073407A1 PCT/CN2021/117123 CN2021117123W WO2022073407A1 WO 2022073407 A1 WO2022073407 A1 WO 2022073407A1 CN 2021117123 W CN2021117123 W CN 2021117123W WO 2022073407 A1 WO2022073407 A1 WO 2022073407A1
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semipermeable membrane
porous polymer
polymer
hydrophobic
cross
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French (fr)
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邹鹏
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德莱森(北京)医疗科技有限公司
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Priority to US17/996,946 priority Critical patent/US20230311068A1/en
Priority to JP2022559329A priority patent/JP7465583B2/ja
Priority to EP21876927.1A priority patent/EP4108320A4/en
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0002—Organic membrane manufacture
    • B01D67/0006—Organic membrane manufacture by chemical reactions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/76—Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/76—Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74
    • B01D71/82—Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74 characterised by the presence of specified groups, e.g. introduced by chemical after-treatment
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/02—Hydrophilization
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/08—Specific temperatures applied
    • B01D2323/081—Heating
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/12—Specific ratios of components used
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/30—Cross-linking
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/34—Use of radiation
    • B01D2323/345—UV-treatment
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2323/00—Details relating to membrane preparation
    • B01D2323/36—Introduction of specific chemical groups
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2325/00—Details relating to properties of membranes
    • B01D2325/38—Hydrophobic membranes

Definitions

  • the invention relates to the technical field of biosensors, in particular to a method for preparing a porous polymer semipermeable membrane and a product thereof.
  • Polymer semipermeable membranes are crucial components of biosensors, especially implantable biosensors.
  • the most important function of the polymer semipermeable membrane is to control the diffusion rate of biological substances from the external environment to the sensor electrode surface, because the linear response concentration range of the sensor is usually much smaller than the actual biological substance in the environment. concentration.
  • the diffusion rate mainly depends on the hydrophilicity and thickness of the polymer semipermeable membrane: biological substances cannot diffuse in membranes with no or low hydrophilicity. After the water reaches a certain level, the diffusion rate of the biomass increases as the hydrophilicity of the membrane increases.
  • the diffusion rate (the difference between the concentration of biological substances in the external environment and the electrode surface) is inversely proportional to the square of the thickness of the polymer semipermeable membrane, that is, When the structure of the polymer membrane is unchanged, in order to reduce the diffusion rate by half, we need to increase the thickness of the semipermeable membrane to the level of four times.
  • the purpose of the present invention is to provide a method for preparing a porous polymer semipermeable membrane, wherein a mixed solution of a hydrophobic polynorbornene-based polymer material and a hydrophilic small molecule containing a thiol functional group is coated on the surface of a biosensor electrode and subjected to Cross-linking, the polymer hydrophobicity of the obtained product enables the semipermeable membrane to have good adhesion on the surface of the biosensor, and the porous structure can ensure the diffusion of biological substances to the surface of the biosensor, and regulate the biological substance in the case of not significantly changing the thickness of the membrane. Diffusion velocity in semipermeable membranes.
  • a preparation method of a porous polymer semipermeable membrane comprising the following steps: dissolving a hydrophobic polynorbornene-based polymer and a hydrophilic small molecule cross-linking agent containing a thiol functional group in a solvent capable of dissolving both at the same time Mixing to obtain a coating solution; coating the surface of the biosensor electrode, drying, the hydrophobic component and the hydrophilic component are separated during this process, and then the film is formed for cross-linking and then the unreacted hydrophilic small molecular cross-linking is removed. The combined agent is dried again to obtain a porous polymer semipermeable membrane.
  • hydrophilic small molecule cross-linking agent If the proportion of hydrophilic small molecule cross-linking agent is too small, phase separation cannot be formed and a porous structure cannot be formed, or the porous junction is too sparse, and the biological material cannot pass through the semipermeable membrane or the diffusion rate in the semipermeable membrane is too low. If the proportion of hydrophilic small-molecule cross-linking agent is too large, other phase-separated structures will be formed, and the diffusion rate of biological substances in the semipermeable membrane will be too fast.
  • Y is one of O, S, NH;
  • R 1 is H, direct Chain/branched/cyclic hydrocarbon groups, lipid/ether-containing groups or One of them;
  • R 2 and R 3 are straight chain/branched/cyclic hydrocarbon groups, One of them, R 2 and R 3 can be the same or different;
  • R 4 is one of linear/branched/cyclic hydrocarbon groups;
  • R 5 and R 6 are H or alkyl, and R 5 and R 6 can be same or different;
  • n 1-10,
  • R 7 , R 8 , R 9 are H or alkyl, R 7 and R 8 and R 9 can be the same or different;
  • the molecular weight of the polynorbornene-based polymer is 10000g /mol-2000000g/mol;
  • the hydrophilic small molecule crosslinking agent contains more than 2 thiol functional groups
  • the molecular weight of the polynorbornene-based polymer is 200,000 g/mol-1,000,000 g/mol; and the hydrophilic small molecular crosslinking agent contains 2-4 thiol functional groups.
  • the structural formula of the small molecule crosslinking agent containing 3 thiol functional groups is:
  • the structural formula of the small molecule crosslinking agent containing 4 thiol functional groups is:
  • the solvent is one or a mixture of any two of tetrahydrofuran, ethanol, propanol, isopropanol, butanol, ethylene glycol, and water;
  • the hydrophobic polynorbornene-based polymer in the coating solution The mass concentration is 1%-25%.
  • the coating film is a pull-up coating film, a spin coating film, a blade coating film or a spray coating;
  • the environmental temperature of the film coating process is 15-60°C; the two drying times They are all dried in the environment of 15-80 °C for 1min-2h (the higher the drying temperature, the shorter the time to form the porous structure, but if the temperature is too high, the formation of the porous structure will be affected, because the temperature increases, the activity of the polymer chain At the same time, the properties are also improved, and the small molecule cross-linking agent may also evaporate, thereby affecting the formation of the porous structure).
  • the ambient temperature of the coating process is preferably 25-50°C; after the first drying, the membrane is placed in a gaseous solvent environment to further promote the separation of hydrophobic components and hydrophilic components.
  • the gaseous solvent is the solvent used for dissolving the hydrophobic polynorbornene polymer (such as tetrahydrofuran, ethanol, propanol, butanol, etc.).
  • the crosslinking is to carry out UV crosslinking or heating crosslinking of the polymer semipermeable membrane covering the surface of the biosensor electrode; the UV crosslinking wavelength is 250-400 nm; The thermal cross-linking is a reaction at 50-80° C. for 0.5-4 hours.
  • porous polymer semipermeable membrane prepared by the method described in any one of the preceding items.
  • the aforementioned porous polymer semipermeable membrane has a thickness of 200nm-100 ⁇ m, preferably a thickness of 1-20um.
  • the present invention provides a porous polymer semipermeable membrane, which finally forms a porous structure.
  • the hydrophobicity of the polymer in the porous polymer semipermeable membrane makes the semipermeable membrane have good adhesion on the sensor surface, and the porous structure can ensure that biological substances can diffuse to the sensor surface.
  • the hydrophilicity difference between the hydrophobic polynorbornene-based polymer and the hydrophilic small molecule crosslinking agent, the ratio of the two, and the environmental parameters during the phase separation process the formation of the porous structure can be effectively controlled. Modulate the diffusion rate of biological substances in semipermeable membranes without significantly changing the thickness of the polymer membrane.
  • Figure 1 shows the surface morphology of the porous polymer semipermeable membrane analyzed by atomic force microscopy
  • Figure 2 shows the surface morphology of the non-porous polymer semipermeable membrane analyzed by atomic force microscopy
  • Figure 3 shows the response of the biosensor to glucose concentration when covered with a polymer semipermeable membrane without porous structure
  • Figure 4 shows the response of the biosensor to the glucose concentration when the polymer semipermeable membrane is covered with a porous structure.
  • Embodiment 1 of the present invention a preparation method of a porous polymer semipermeable membrane:
  • Embodiment 2 A kind of preparation method of porous polymer semipermeable membrane:
  • Embodiment 3 A kind of preparation method of porous polymer semipermeable membrane:
  • Embodiment 4 A kind of preparation method of porous polymer semipermeable membrane:
  • Embodiment 5 A kind of preparation method of porous polymer semipermeable membrane:
  • Embodiment 6 A kind of preparation method of porous polymer semipermeable membrane:
  • Embodiment 7 A kind of preparation method of porous polymer semipermeable membrane:
  • Embodiment 8 A kind of preparation method of porous polymer semipermeable membrane:
  • the biosensors were phase-separated; the polymer film was then cross-linked by heating and cross-linked at 80 °C for 2 hours; after cross-linking, the biosensor was immersed in ethanol for 1 minute to remove unreacted
  • the porous polymer semipermeable membrane was obtained by drying again at 25°C for 2 hours with a thickness of 8 ⁇ m.
  • the inventor also conducted a comparative experiment to prepare a comparative biosensor (by reducing the dosage ratio of the hydrophilic cross-linking agent, the same biosensor was coated on the surface to form no
  • the performance of the porous polymer semipermeable membrane biosensor obtained in Example 1 was compared with that of the polyN-n-butyloxanorborneneimide film with a porous structure.
  • the thickness of the porous polymer semipermeable membrane obtained in Example 1 was measured to be about 12 ⁇ m using the Filmetrics F40 spectral measurement system.
  • Figure 1 shows the results obtained by using AFM to characterize the surface of the polymer membrane. As shown in the figure, the enriched hydrophilic small molecules form droplets and are distributed in the hydrophobic polymer membrane structure. A hole-like structure revealed by dark circular spots was left in the membrane;
  • the thickness of the polymer film without porous structure was measured to be 6 ⁇ m by the Filmetrics F40 spectroscopic measurement system.
  • Figure 2 shows the results obtained by using AFM to characterize the surface of the polymer membrane without porous structure.
  • the swelling degree in phosphate buffer after cross-linking of poly-N-propyl oxanorborneimide without porous structure is 109%, and it is difficult for glucose to diffuse through this highly hydrophobic semipermeable membrane to reach the electrode surface, A current response was generated; the poly-N-butyloxanorborneneimide membrane with porous structure had a swelling degree of 111% in phosphate solution, which was only slightly higher than that of the membrane without porous structure.
  • Example 2 The same raw materials as in Example 1, the obtained non-porous structure polymer membrane biosensor (comparative example);
  • the biosensor is based on PET, and a three-electrode structure is formed by inkjet printing gold conductive ink: the working electrode and the reference electrode are located on the front of the sensor, the surface of the working electrode is attached with glucose oxidase, and Ag/AgCl constitutes the reference electrode; The gold conductive layer forms the counter electrode.
  • the sensor was placed in a phosphate buffer of glucose to measure the response to changes in glucose concentration.
  • the non-porous structure polymer membrane biosensor with a thickness of 6 ⁇ m cannot respond to the concentration change of glucose in solution, as shown in Figure 3; while the porous polymer semipermeable membrane biosensor responds rapidly to the concentration change of glucose in solution, as shown in Figure 4 .
  • the swelling degree of the porous polymer membrane was slightly increased, and the degree of increase could not significantly improve the diffusion rate of glucose in the semipermeable membrane.
  • the comparison experiment of the response of biosensors made of polymer semipermeable membranes with porous and non-porous structures to changes in glucose concentration in different thicknesses even if the thickness of the polymer semi-permeable membrane with porous structure is twice that of the polymer membrane without porous structure, it has The porous structure of the polymer semipermeable membrane can still significantly improve the glucose diffusion ability and ensure the response ability of the biosensor.

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Abstract

本发明提供一种多孔高分子半透膜的制备方法，将疏水性聚降冰片烯类高分子与含硫醇官能团的亲水性小分子交联剂在可同时溶解二者的溶剂中溶解混合，得涂膜溶液；在生物传感器电极表面进行涂膜，干燥、疏水性与亲水性成分相分离，之后成膜交联后移除未反应亲水性小分子交联剂，再次干燥得多孔高分子半透膜；还公开了产品。本发明制备方法所得产品，高分子的疏水性使多孔高分子半透膜在生物传感器表面有良好的附着力，多孔结构保证生物物质扩散到生物传感器表面，且在不明显改变高分子膜厚度的情况下调节生物物质在半透膜中的扩散速度。

Description

一种多孔高分子半透膜的制备方法及其产品 技术领域
本发明涉及生物传感器技术领域，尤其涉及一种多孔高分子半透膜制备方法及其产品。
背景技术
高分子半透膜是生物传感器，尤其是可植入生物传感器至关重要的组成部分。以电化学生物传感器为例，高分子半透膜最重要的功能是控制生物物质从外部环境到传感器电极表面的扩散速度，这是因为传感器的线性响应浓度范围通常远小于环境中生物物质的实际浓度。对于小分子生物物质，其扩散速度主要取决于高分子半透膜的亲水性与厚度：生物物质无法在没有亲水性及低亲水性的的膜中进行扩散，当高分子膜的亲水性达到一定水平后，生物物质的扩散速度随着膜亲水性的增加而提高。为了降低生物物质在亲水性半透膜中的扩散速度，人们往往采用增加半透膜厚度的方法，但是，此方法对于植入型生物传感器很多时候并不可取：如果把生物物质从外部环境到传感器电极表面看成一个一维扩散体系，根据费克第二定律，扩散速度(生物物质在外部环境与电极表面的浓度差)与高分子半透膜厚度的平方成反比，也就是说，当高分子膜的结构不变时，为了将扩散速度降低一半，我们需要把半透膜的厚度增加到四倍的水平。这往往需要我们经过多次涂膜才能得到所需要的厚度，同时，多次涂膜也给生产中膜厚度的控制带来不便，使同批次一致性难以得到保证。另外，可植入生物传感器在使用中经常会与周围的肌肉、脂肪等软组织产生摩擦，而亲水性的高分子膜在疏水性的生物传感器表面往往附着力较差，这会降低传感器的稳定性，严重的时候还会出现半透膜从传感器表面脱落的情况。
发明内容
本发明的目的在于提供一种多孔高分子半透膜的制备方法，将疏水聚降冰片烯类高分子材料与含硫醇官能团的亲水小分子的混合溶液涂覆于生物传感器电极表面并进行交联，所得产物的高分子疏水性使半透膜在生物传感器表面有良好的附着力，多孔结构能够保证生物物质扩散到生物传感器表面，且在不明显改变膜厚度的情况下调节生物物质在半透膜中的扩散速度。
为达到以上目的，本发明技术方案如下：
一种多孔高分子半透膜的制备方法，包括如下步骤：将疏水性聚降冰片烯类高分子与含硫醇官能团的亲水性小分子交联剂在可同时溶解二者的溶剂中溶解混合，得涂膜溶液；在生物传感器电极表面进行涂膜，干燥、此过程中疏水性成分与亲水性成分产生相分离，之后成膜进行交联后移除未反应亲水性小分子交联剂，再次干燥制得多孔高分子半透膜。亲水性小分子交联剂比例太小则无法形成相分离不能产生多孔结构，或多孔结过疏，生物物质无法穿过半透膜或 在半透膜中的扩散速度过低。亲水性小分子交联剂比例太多则会形成其他相分离结构，使生物物质在半透膜中的扩散速度过快。
前述多孔高分子半透膜的制备方法，所述疏水性聚降冰片烯类高分子的结构式如下：
Figure PCTCN2021117123-appb-000001
其中Z为CH 2、CH 2CH 2、O、S、N-R 4或C＝C(R 5R 6)中的一种；Y为O、S、NH中的一种；R 1为H、直链/含支链/环状烃基、含脂类/醚类的基团或
Figure PCTCN2021117123-appb-000002
中的一种；R 2、R 3为直链/含支链/环状烃基、
Figure PCTCN2021117123-appb-000003
中的一种，R 2与R 3可相同或不同；R 4为直链/含支链/环状烃基中的一种；R 5、R 6为H或烷基，R 5与R 6可相同或不同；n＝1-10，R 7、R 8、R 9为H或烷基，R 7与R 8与R 9可相同或不同；所述聚降冰片烯类高分子的分子量为10000g/mol–2000000g/mol；所述亲水性小分子交联剂含2个以上硫醇官能团。
前述多孔高分子半透膜的制备方法，所述聚降冰片烯类高分子的分子量为200000g/mol–1000000g/mol；所述亲水性小分子交联剂含2-4个硫醇官能团。
前述多孔高分子半透膜的制备方法，所述含2个硫醇官能团的小分子交联剂结构式为：
Figure PCTCN2021117123-appb-000004
中的一种，其中n＝1-10；
所述含3个硫醇官能团的小分子交联剂结构式为：
Figure PCTCN2021117123-appb-000005
其中n＝1-10,m＝0-5，各个硫醇支链的长度可相同，也可不同；
所述含4个硫醇官能团的小分子交联剂结构式为：
Figure PCTCN2021117123-appb-000006
其中n＝1-10，各个硫醇支链的长度可相同，也可不同。
前述多孔高分子半透膜的制备方法，所述疏水性聚降冰片烯类高分子与亲水性小分子交联剂的用量比例按照C＝C:-SH摩尔比为10∶1至1∶20；所述溶剂为四氢呋喃、乙醇、丙醇、异丙醇、丁醇、乙二醇、水中的一种或者任意两种的混合物；所述涂膜溶液中疏水性聚降冰片烯 类高分子的质量浓度为1％-25％。
前述多孔高分子半透膜的制备方法，所述涂膜为提拉涂膜、旋转涂膜、刮刀涂膜或喷涂；所述涂膜过程的环境温度为15-60℃；所述两次干燥均为在15-80℃环境中干燥1min-2h(干燥温度越高，形成多孔结构的时间越短，但如果温度过高则会影响多孔结构的形成，因为温度升高，高分子链的活动性也同时提高，且小分子交联剂也有可能蒸发，从而影响多孔结构的形成)。
前述多孔高分子半透膜的制备方法，所述涂膜过程的环境温度优选为25-50℃；第一次干燥后将膜放置于气态溶剂环境中进一步促进疏水性成分与亲水性成分的相分离，所述气态溶剂为溶解疏水性聚降冰片烯类高分子所用的溶剂(如四氢呋喃、乙醇、丙醇、丁醇等)。
前述多孔高分子半透膜的制备方法，所述交联为将覆于生物传感器电极表面的高分子半透膜进行UV交联或加热交联；所述UV交联波长为250-400nm；所述加热交联为50-80℃下反应0.5-4小时。
如前任一项所述方法制得的多孔高分子半透膜。
前述的多孔高分子半透膜，膜厚度为200nm-100μm，优选厚度1-20um。
与现有技术相比，本发明的有益效果是：
本发明提供了一种多孔高分子半透膜，其最终形成多孔结构。多孔高分子半透膜中高分子的疏水性使半透膜在传感器表面有着良好的附着力，多孔结构能够保证生物物质可以扩散到传感器表面。通过控制疏水聚降冰片烯类高分子与亲水小分子交联剂成分间的亲水性差异、两者的比例以及相分离过程中的环境参数，可以有效的控制多孔结构的形成，从而在不明显改变高分子膜厚度的情况下调节生物物质在半透膜中的扩散速度。
附图说明
图1为原子力显微镜分析多孔高分子半透膜的表面形态；
图2为原子力显微镜分析无多孔高分子半透膜的表面形态；
图3为覆有无多孔结构的高分子半透膜时，生物传感器对葡萄糖浓度的响应；
图4为覆有多孔结构的高分子半透膜时，生物传感器对葡萄糖浓度的响应。
具体实施方式
本发明实施例1：一种多孔高分子半透膜的制备方法：
聚N-正丁基氧杂降冰片烯酰亚胺(分子量为100000g/mol)与季戊四醇四巯基乙酸酯(摩尔比C＝C:-SH＝1:4)在四氢呋喃/正丁醇(V THF:V n-Butanol＝1:4)混合溶剂中溶解形成涂膜溶液(高分子聚N-正丁基氧杂降冰片烯酰亚胺的质量百分比浓度为10％)；将生物传感器浸入涂膜溶液中，30℃下用提拉法在生物传感器的电极表面涂覆一层高分子膜；在30℃环境下干燥60分钟，此过程中疏水性成分与亲水性成分产生相分离；对高分子膜进行UV交联，UV波长365nm，能 量密度25mW·cm -2下，交联时间4分钟；交联后，将生物传感器浸入正丁醇中1分钟，移除未反应的季戊四醇四巯基乙酸酯，30℃环境下干燥60分钟后得多孔高分子半透膜，厚度为12μm。
实施例2：一种多孔高分子半透膜的制备方法：
Figure PCTCN2021117123-appb-000007
(分子量为50000g/mol)与
Figure PCTCN2021117123-appb-000008
(摩尔比C＝C:-SH＝1:20)在四氢呋喃/异丙醇(V THF:V iso-propanol＝1:1)混合溶剂中溶解形成涂膜溶液(高分子
Figure PCTCN2021117123-appb-000009
的质量百分比浓度为10％)；25℃下在生物传感器电极表面进行刮刀涂膜；在30℃环境下干燥30分钟，此过程中疏水性成分与亲水性成分产生相分离；之后对高分子膜进行UV交联，UV交联波长254nm，能量密度25mW·cm -2下，交联时间6分钟；交联后，将传感器浸入乙醇中1分钟，移除未反应的
Figure PCTCN2021117123-appb-000010
再次在30℃环境下干燥120分钟后得多孔高分子半透膜，厚度为13μm。
实施例3：一种多孔高分子半透膜的制备方法：
Figure PCTCN2021117123-appb-000011
(分子量为20000g/mol)与
Figure PCTCN2021117123-appb-000012
(摩尔比C＝C:-SH＝1:2)在异丙醇溶剂中溶解形成涂膜溶液(高分子
Figure PCTCN2021117123-appb-000013
的质量百分比浓度为2％)；20℃下在生物传感器电极表面进行旋转涂膜；在40℃环境下干燥30分钟，此过程中疏水性成分与亲水性成分产生相分离；之后对高分子膜进行加热交联，80℃下交联1小时；交联后，将传感器浸入乙醇中10秒，移除未反应的
Figure PCTCN2021117123-appb-000014
40℃环境下干燥60分钟后得多孔高分子半透膜，厚度为350nm。
实施例4：一种多孔高分子半透膜的制备方法：
Figure PCTCN2021117123-appb-000015
(分子量为2000000g/mol)与
Figure PCTCN2021117123-appb-000016
(摩尔比C＝C:-SH＝1:6)在乙醇溶剂中溶解形成涂膜溶液(高分子
Figure PCTCN2021117123-appb-000017
的质量百分比浓度为20％)；35℃下在生物传感器电极表面进行喷涂涂膜；在50℃环境下干燥120分钟，此过程中疏水性成分与亲水性成分产生相分离；之后对高分子膜加热交联，80℃下交联120分钟；交联后，将传感器浸入乙醇中1分钟，移除未反应的
Figure PCTCN2021117123-appb-000018
50℃环境下干燥120分钟后得多孔高分子半透膜，厚度为70μm。
实施例5：一种多孔高分子半透膜的制备方法：
Figure PCTCN2021117123-appb-000019
(分子量为100000g/mol)与聚硫醇(摩尔比C＝C:-SH＝1:5)在丙醇溶剂中溶解形成涂膜溶液(高分子
Figure PCTCN2021117123-appb-000020
的质量百分比浓度为15％)；将生物传感器浸入涂膜溶液中，35℃下在生物传感器电极表面进行提拉涂膜；在20℃环境下干燥1小时，此过程中疏水性成分与亲水性成分产生相分离；之后对高分子膜进行UV交联，UV波长365nm，能量密度25mW·cm -2下，交联时间8分钟；交联后，将传感器浸入乙醇中1分钟，移除未反应的聚硫醇，再次在20℃环境下干燥1小时后得多孔高分子半透膜，厚度为12μm。
实施例6：一种多孔高分子半透膜的制备方法：
Figure PCTCN2021117123-appb-000021
(分子量为300000g/mol)与
Figure PCTCN2021117123-appb-000022
(摩尔比C＝C:-SH＝9:1)在四氢呋喃溶剂中溶解形成涂膜溶液(高分子
Figure PCTCN2021117123-appb-000023
的质量百分比浓度为15％)；将生物传感器浸入涂膜溶液中，20℃下在生物传感器电极表面进行提拉涂膜；20℃环境下干燥40分钟，此过程中疏水性成分与亲水性成分产生相分离，随后放置于25℃乙醇的饱和蒸汽中进一步促进疏水性成分与亲水性成分的相分离；之后对高分子膜进行UV交联，UV交联波长300nm能量密度20mW·cm -2下，交联时间5分钟；交联后，将传感器浸入乙醇中1分钟，移除未反应的
Figure PCTCN2021117123-appb-000024
再次30℃环境下干燥40分钟后得多孔高分子半透膜，厚度为13μm。
实施例7：一种多孔高分子半透膜的制备方法：
Figure PCTCN2021117123-appb-000025
(分子量为150000g/mol)与
Figure PCTCN2021117123-appb-000026
(摩尔比C＝C:-SH＝10:7)在异丙醇溶剂中溶解形成涂膜溶液(高分子
Figure PCTCN2021117123-appb-000027
的质量百分比浓度为15％)；20℃下在生物传感器电极表面进行刮刀涂膜；在35℃环境下干燥60分钟，此过程中疏水性成分与亲水 性成分产生相分离；之后对高分子膜进行UV交联，UV交联波长365nm，能量密度100mW·cm -2下，交联时间5分钟；交联后将生物传感器浸入乙醇中1分钟，移除未反应
Figure PCTCN2021117123-appb-000028
再次35℃环境下干燥60分钟得多孔高分子半透膜，厚度为40μm。
实施例8：一种多孔高分子半透膜的制备方法：
Figure PCTCN2021117123-appb-000029
(分子量为600000g/mol)与
Figure PCTCN2021117123-appb-000030
(摩尔比C＝C:-SH＝10:7)在乙醇中溶解形成涂膜溶液(高分子
Figure PCTCN2021117123-appb-000031
的质量百分比浓度为10％)；将生物传感器浸入涂膜溶液中，25℃下在生物传感器电极表面进行提拉涂膜；在25℃环境下干燥2小时，此过程中疏水性成分与亲水性成分产生相分离；之后对高分子膜进行加热交联，80℃下交联2小时；交联后将生物传感器浸入乙醇中1分钟，移除未反应
Figure PCTCN2021117123-appb-000032
再次在25℃环境下干燥2小时得多孔高分子半透膜，厚度为8μm。
为了验证本发明多孔高分子半透膜的使用效果，发明人还进行了对比试验，制备了比较用生物传感器(通过降低亲水性交联剂的用量比例，在同样的生物传感器表面涂覆形成没有多孔结构的聚N-正丁基氧杂降冰片烯酰亚胺薄膜)，与上述实施例1所得多孔高分子半透膜生物传感器进行性能对比。
实验例：
一、高分子半透膜的多孔结构
利用Filmetrics F40光谱测量系统测得实施例1所得多孔高分子半透膜厚度约12μm。图1展示了对高分子膜表面利用AFM进行表征所得到的结果，如图所示，富集的亲水性小分子形成微液滴分布在疏水性的高分子膜结构中，被移除后在膜中留下了深色圆斑显示的孔状结构；
利用Filmetrics F40光谱测量系统测得无多孔结构高分子膜的厚度为6μm。图2展示了对无多孔结构高分子膜表面利用AFM进行表征所得到的结果。
二、高分子半透膜溶胀度对比实验结果
1.实验内容
利用表面等离子共振实验测量高分子膜在水中的溶胀度。
2.实验结果
没有多孔结构的聚N-正丙基氧杂降冰片烯酰亚胺交联后在磷酸盐缓冲液中的溶胀度为109％，葡萄糖难以扩散穿过此高疏水性半透膜到达电极表面，产生电流响应；具有多孔结构的聚N-正丁基氧杂降冰片烯酰亚胺膜在磷酸盐溶液中的溶胀度为111％，仅略高于没有多孔结构的膜。
3.结论
由实验结果可知，有多孔结构的聚N-正丁基氧杂降冰片烯酰亚胺薄膜与没有多孔结构薄膜在水中溶胀度的差异不大，多孔薄膜的高分子网络构架保持了聚N-正丁基氧杂降冰片烯酰亚胺的疏水性特点。
三、生物传感器对溶液中葡萄糖浓度变化的响应对比实验
1.实验材料
实施例1所得多孔高分子半透膜生物传感器；
与实施例1反应原料相同，所得无多孔结构高分子膜生物传感器(对比例)；
生物传感器以PET为基底，通过喷墨打印金导电墨水形成三电极结构：其中，工作电极及参比电极位于传感器正面，工作电极表面附着葡萄糖氧化酶，Ag/AgCl构成参比电极；传感器反面的金导电层形成对电极。
2.实验内容
将传感器置于葡萄糖的磷酸盐缓冲液中测量对葡萄糖浓度变化的响应。
3.实验结果
厚度为6μm的无多孔结构高分子膜生物传感器无法对溶液中葡萄糖的浓度变化产生响应，如图3；而多孔高分子半透膜生物传感器对溶液中葡萄糖的浓度变化产生快速响应，如图4。
在上述溶胀度对比实验中，多孔高分子膜的溶胀度提高较少，其提高程度并不能显著提升葡萄糖在半透膜中的扩散速度。在不同厚度有多孔与无多孔结构高分子半透膜制生物传感器对葡萄糖浓度变化的响应对比实验中，即使有多孔结构的高分子半透膜厚度是无多孔结构高分子膜的2倍，具有多孔结构的高分子半透膜仍然能够显著提高葡萄糖的扩散能力，保证生物传感器的响应能力。

Claims (10)

  1. 一种多孔高分子半透膜的制备方法，其特征在于，包括如下步骤：将疏水性聚降冰片烯类高分子与含硫醇官能团的亲水性小分子交联剂在可同时溶解二者的溶剂中溶解混合，得涂膜溶液；在生物传感器电极表面进行涂膜，干燥、此过程中疏水性成分与亲水性成分产生相分离，之后成膜进行交联后移除未反应亲水性小分子交联剂，再次干燥制得多孔高分子半透膜。
  2. 根据权利要求1所述多孔高分子半透膜的制备方法，其特征在于：所述疏水性聚降冰片烯类高分子的结构式如下：
    Figure PCTCN2021117123-appb-100001
    其中Z为CH 2、CH 2CH 2、O、S、N-R 4或C＝C(R 5R 6)中的一种；Y为O、S、NH中的一种；R 1为H、直链/含支链/环状烃基、含脂类/醚类的基团或
    Figure PCTCN2021117123-appb-100002
    中的一种；R 2、R 3为直链/含支链/环状烃基、
    Figure PCTCN2021117123-appb-100003
    中的一种，R 2与R 3可相同或不同；R 4为直链/含支链/环状烃基中的一种；R 5、R 6为H或烷基，R 5与R 6可相同或不同；n＝1-10，R 7、R 8、R 9为H或烷基，R 7与R 8与R 9可相同或不同；所述聚降冰片烯类高分子的分子量为10000g/mol–2000000g/mol；所述亲水性小分子交联剂含2个以上硫醇官能团。
  3. 根据权利要求2所述多孔高分子半透膜的制备方法，其特征在于：所述聚降冰片烯类高分子的分子量为200000g/mol–1000000g/mol；所述亲水性小分子交联剂含2-4个硫醇官能团。
  4. 根据权利要求3所述多孔高分子半透膜的制备方法，其特征在于：所述含2个硫醇官能团的小分子交联剂结构式为：
    Figure PCTCN2021117123-appb-100004
    中的一种，其中n＝1-10；
    所述含3个硫醇官能团的小分子交联剂结构式为：
    Figure PCTCN2021117123-appb-100005
    其中n＝1-10,m＝0-5，各个硫醇支链的长度可相同，也可不同；
    所述含4个硫醇官能团的小分子交联剂结构式为：
    Figure PCTCN2021117123-appb-100006
    其中n＝1-10，各个硫醇支链的长度可相同，也可不同。
  5. 根据权利要求1所述多孔高分子半透膜的制备方法，其特征在于：所述疏水性聚降冰片烯类高分子与亲水性小分子交联剂的用量比例按照C＝C:-SH摩尔比为10∶1至1∶20；所述溶剂为四氢呋喃、乙醇、丙醇、异丙醇、丁醇、乙二醇、水中的一种或者任意两种的混合物；所述涂膜溶液中疏水性聚降冰片烯类高分子的质量浓度为1％-25％。
  6. 根据权利要求1所述多孔高分子半透膜的制备方法，其特征在于：所述涂膜为提拉涂膜、旋转涂膜、刮刀涂膜或喷涂；所述涂膜过程的环境温度为15-60℃；所述两次干燥均为在15-80℃环境中干燥1min-2h。
  7. 根据权利要求6所述多孔高分子半透膜的制备方法，其特征在于：所述涂膜过程的环境温度为25-50℃；第一次干燥后将膜放置于气态溶剂环境中进一步促进疏水性成分与亲水性成分的相分离，所述气态溶剂为溶解疏水性聚降冰片烯类高分子所用的溶剂。
  8. 根据权利要求1所述多孔高分子半透膜的制备方法，其特征在于：所述交联为将覆于生物传感器电极表面的高分子半透膜进行UV交联或加热交联；所述UV交联波长为250-400nm；所述加热交联为50-80℃下反应0.5-4小时。
  9. 如权利要求1-8任一项所述方法制得的多孔高分子半透膜。
  10. 根据权利要求9所述的多孔高分子半透膜，其特征在于：膜厚度为200nm-100μm。
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