CN113493558A - 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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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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block
parts
triblock copolymer
molecular weight
chain extender
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于非
童晶晶
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Microtech Medical Hangzhou Co Ltd
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Microtech Medical Hangzhou Co Ltd
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Priority to CN202010192423.3A priority Critical patent/CN113493558A/zh
Priority to PCT/CN2020/135162 priority patent/WO2021184843A1/zh
Publication of CN113493558A publication Critical patent/CN113493558A/zh
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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 BDA0002416391350000031
Figure BDA0002416391350000041
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：
Figure BDA0002416391350000042
Figure BDA0002416391350000043
Figure BDA0002416391350000051
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 BDA0002416391350000081
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***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 FDA0002416391340000011
Figure FDA0002416391340000021
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：
Figure FDA0002416391340000022
Figure FDA0002416391340000031
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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