CN104434131A - 一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备方法及其应用 - Google Patents
一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备方法及其应用 Download PDFInfo
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- A61B5/14503—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
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- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
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Abstract
本发明为一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备,该方法首先用氨基硅烷偶联剂改性石英晶振片表面,然后以丙烯酰胺基苯硼酸为单体,N,N-亚甲基双丙烯酰胺为交联剂,通过紫外光引发聚合在晶振片表面合成薄膜。本发明的基于金表面硼酸类葡萄糖敏感型印迹水凝胶具有优异的生物性相容性,可用于植入人体,实验血糖的连续检测。
Description
技术领域
本发明涉及一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备,特别是其具备优异的生物相容性,可有望植入人体,实现葡萄糖的连续检测。
背景技术
糖尿病作为仅次于心血管病和癌症的第三大危险疾病,已严重威胁到人类的健康。做好I型、II 型、妊娠糖尿病及其他特殊类型的血糖监测工作,有利于糖尿病患者在整个治疗周期中,了解自身情况并及时对症下药,这对于糖尿病的预防与控制具有及其重要的意义。
目前,由于常规的生化分析法和快速血糖仪这种有创或微创技术不能动态连续检测患者的血糖而得不到更接近真实情况。因此,动态血糖监测系统(CGMS)应运而生,CGMS是一个微创血糖监测系统,通过检测皮下组织间液的葡萄糖浓度而反映血糖水平,它可不间断地监测病人1天中的每时每刻的血糖值。目前,市售血糖仪主要以基于葡萄糖氧化酶检测的电化学方法为主,使用寿命一般为3 ~ 5天,最长为7天左右。
葡萄糖敏感型薄膜是利用新型智能水凝胶原理,通过识别环境中葡萄糖分子而产生刺激响应,继而发生膨胀、收缩或者溶胶-凝胶相转变等响应。该材料有望在未来应用于葡萄糖的连续检测。此外,糖敏薄膜材料还具有良好的生物相容性,是一种极具潜力的生物活性材料。葡萄糖敏感型水凝胶薄膜引起特有的糖敏特性及良好的生物活性,目前已得到研究者的广泛关注。(Kathryn E. S. Dean, Adrian M. Horgan, Alexander J. Marshall, et al. Selective holographic detection of glucose using tertiary amines, Chem. Commun, 2006, 3507-3509)。
如上述方法通常会存在如下问题:(1)传统的高分子成膜材料其生物相容性差,对宿主会造成一定的损害。(2)在基体上合成的薄膜容易脱落。(3)基于葡萄糖氧化酶方法的传感器使用寿命较短。
发明内容
本发明为了解决现有在实时检测葡萄糖时所存在的技术问题,选取丙烯酰胺基苯硼酸作为葡萄糖的识别基团,提供了一种基于石英晶振片上的葡萄糖敏感薄膜。对所合成的材料进行体内生物性检测,初步评价了其作为医学植入物的安全性。该方法首先用氨基硅烷偶联剂改性石英晶振片表面,然后以丙烯酰胺基苯硼酸为单体,N,N-亚甲基双丙烯酰胺为交联剂,通过紫外光引发聚合在晶振片表面合成薄膜。
本发明的技术方案为:一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备,包括如下步骤:(1)晶振片表面预处理:将金片置于配置好的皮尔试剂中,超声10 ~ 60 min,然后分别用丙酮、乙醇、二次蒸馏水超声清洗2 ~ 20 min,N2吹干;其中,皮尔试剂的配置为浓H2SO4:H2O2=5 ~ 10 : 3(V : V);(2)氨基化:将一定量的硅烷偶联剂溶解于溶剂中,将处理过的晶振片置于上述溶液中,N2气氛,在50 ~ 110 ℃反应5 ~ 12 h后,依次用无水乙醇和二次蒸馏水将金片冲净,N2吹干;其中,硅烷偶联剂的浓度= 2 ~ 5 mmol/L;(3)聚合:将3-丙烯酰胺基苯硼酸、交联剂、引发剂、丙烯酰胺和加入到溶剂中,混合均匀后,取5 ~ 50 uL的混合液均匀地涂在步骤(2)中所述的晶振片上,置于匀胶机上,转速3000 ~ 6000r/min,然后于紫外灯下光引发聚合5 ~ 60 min,反应完后用溶剂反复洗涤,洗去未反应物。其中,3-丙烯酰胺基苯硼酸、交联剂、引发剂和丙烯酰胺的浓度分别为50 ~ 100、100 ~ 200、0.2 ~ 0.5 mmol/L、10 ~ 50 mmol/L。
所述的步骤(1)中石英晶振片的直径为2 ~ 20min,标准频率为5或6MHz的一种。
所述的步骤(2)中硅烷偶联剂为3-氨丙基三甲氧基硅烷、3-氨丙基三乙氧基硅烷、γ-氨丙基甲基二乙氧基硅烷和N-2-氨乙基-3-氨丙基甲基二甲氧基硅烷中的一种。
所述的步骤(2)中溶剂为乙醇、甲苯和乙醇:蒸馏水=1:1(V : V=1 : 1)中的一种。
所述的步骤(3)中紫外光的波长范围为250 ~ 400 nm,紫外光的照射强度为1 ~ 100 W/m2。
所述的步骤(3)中引发剂为二苯基乙二酮﹑2,2-二乙氧基苯乙酮﹑a,a-二甲氧基-a-苯基苯乙酮﹑2,4,6-三甲基二苯甲酮和2,4-二乙基硫杂蒽酮中的一种。
所述的步骤(3)中洗涤所用的溶剂是乙醇﹑丙酮﹑异丙醇和二甲基亚砜中的一种或几种。
与现有技术相比,本发明的优点是:(1)其作为医学植入物具有良好的生物安全性。(2)所合成的材料植入后15天未见薄膜脱落。(3)该产品经过后续研究,有望植入人体,实现对葡萄糖的连续监测,大大地延长了使用寿命。
附图说明
图1为本发明中体外细胞毒性实验中晶振片与对照组的显微镜图。
图2为本发明中植入小鼠一周后晶振片周围组织切片和对照组组织切片的显微镜图(常规石蜡包埋后,切片,HE染色)。
图3为本发明中体外细胞毒性实验(48 h)中晶振片与对照组的细胞增值率与抑制率表。
图4为晶振片植入小鼠后的日常症状(以第三天为例)。
具体实施方式
以下结合实施例对本发明作进一步说明,但本发明并不局限于此。
实施例1:(1)晶振片表面预处理:将晶振片置于配置好的皮尔试剂(Piranha)中,超声15 min,然后分别用丙酮、乙醇、二次蒸馏水超声清洗10 min,N2吹干;其中,皮尔试剂的配置为浓H2SO4:H2O2=5 : 3(V:V);(2)氨基化:将3-氨丙基三甲氧基硅烷溶解于甲苯中,将处理过的晶振片置于上述溶液中,N2气氛,在110 ℃反应12 h后,依次用无水乙醇和二次蒸馏水将金片冲净,N2吹干;其中,硅烷偶联剂的浓度为3 mmol/L;(3)聚合:将3-丙烯酰胺基苯硼酸、交联剂、引发剂、丙烯酰胺和加入到溶剂中,混合均匀后,取10 uL的混合液均匀地涂在步骤(2)中所述的晶振片上,置于匀胶机上,转速3000 r/min,然后于紫外灯下光引发聚合10 min,反应完后用溶剂反复洗涤,洗去未反应物。其中,葡萄糖、丙烯酰胺基苯硼酸、N,N-亚甲基双丙烯酰胺、引发剂的浓度分别为30、50、150、0.2 mmol/L。
图1为体外细胞毒性实验中植入晶振片与两个对照组的显微镜图,从图中可以用看出细胞形态与对照组无差异,无细胞脱落,溶解现象,细胞形态正常,细胞膜完整。计分为0,即无细胞毒性。图3体外细胞毒性实验(48 h)中晶振片与对照组的细胞增值率与抑制率表,从表中可以看出实验组细胞相对增殖率均>90%,反应为1级,合格。图4为晶振片植入小鼠后的日常症状(以第三天为例),可以看出植入后小鼠并无异常现象发生,并且7d内观察动物正常,无死亡现象,取材时晶振片外观无变化,薄膜未脱离,无覆盖。图2为发明中植入小鼠一周后晶振片周围组织切片和对照组组织切片的显微镜图(常规石蜡包埋后,切片,HE染色),可以看出组织形态正常,未见炎症细胞浸润。
实施例2:(1)晶振片表面预处理:将晶振片置于配置好的皮尔试剂(Piranha)中,超声30 min,然后分别用丙酮、乙醇、二次蒸馏水超声清洗10 min,N2吹干;其中,皮尔试剂的配置为浓H2SO4:H2O2=7 : 3(V:V);(2)氨基化:将一定量的3-氨丙级三乙氧基硅烷溶解于乙醇中,将处理过的晶振片置于上述溶液中,N2气氛,在78 ℃反应5 h后,依次用无水乙醇和二次蒸馏水将晶振片冲净,N2吹干;其中,硅烷偶联剂的浓度为5 mmol/L;(3)聚合:将3-丙烯酰胺基苯硼酸、交联剂、引发剂、丙烯酰胺和加入到溶剂中,混合均匀后,取20 uL的混合液均匀地涂在步骤(2)中所述的晶振片上,置于匀胶机上,转速5000 r/min,然后于紫外灯下光引发聚合50 min,反应完后用溶剂反复洗涤,洗去未反应物。其中,葡萄糖、丙烯酰胺基苯硼酸、N,N-亚甲基双丙烯酰胺、引发剂的浓度分别为20、50、150、0.3 mmol/L。
实施例3:(1)晶振片表面预处理:将镀金硅片置于配置好的皮尔试剂(Piranha)中,超声60 min,然后分别用丙酮、乙醇、二次蒸馏水超声清洗10 min,N2吹干;其中,皮尔试剂的配置为浓H2SO4:H2O2=4 : 3(V:V);(2)氨基化:将一定量的γ-氨丙基甲基二乙氧基硅烷溶解于体积比为1:1的乙醇和蒸馏水中,将处理过的晶振片置于上述溶液中,N2气氛,在50 ℃反应12 h后,依次用无水乙醇和二次蒸馏水将晶振片冲净,N2吹干;其中,γ-氨丙基甲基二乙氧基硅烷的浓度=4 mmol/L;(3)聚合:将3-丙烯酰胺基苯硼酸、交联剂、引发剂、丙烯酰胺和加入到溶剂中,混合均匀后,取30 uL的混合液均匀地涂在步骤(2)中所述的晶振片上,置于匀胶机上,转速6000 r/min,然后于紫外灯下光引发聚合5 min,反应完后用溶剂反复洗涤,洗去未反应物。其中,葡萄糖、丙烯酰胺基苯硼酸、N,N-亚甲基双丙烯酰胺、引发剂的浓度分别为20、50、100、0.3 mmol/L。
实施例4:(1)晶振片表面预处理:将金金属片置于配置好的皮尔试剂(Piranha)中,超声20 min,然后分别用丙酮、乙醇、二次蒸馏水超声清洗10 min,N2吹干;其中,皮尔试剂的配置为浓H2SO4:H2O2=7 : 3(V:V);(2)氨基化:将一定量的N-2-氨乙基-3-氨丙基甲基二甲氧基硅烷溶解于甲苯中,将处理过的晶振片置于上述溶液中,N2气氛,在110 ℃反应12 h后,依次用无水乙醇和二次蒸馏水将晶振片冲净,N2吹干;其中,硅烷偶联剂的浓度= 2.5 mmol/L;(3)聚合:将3-丙烯酰胺基苯硼酸、交联剂、引发剂、丙烯酰胺和加入到溶剂中,混合均匀后,取25 uL的混合液均匀地涂在步骤(2)中所述的晶振片上,置于匀胶机上,转速5000 r/min,然后于紫外灯下光引发聚合30 min,反应完后用溶剂反复洗涤,洗去未反应物。其中,葡萄糖、丙烯酰胺基苯硼酸、N,N-亚甲基双丙烯酰胺、引发剂的浓度分别为50、80、100、0.2 mmol/L。
实施例5:(1)晶振片表面预处理:将金金属片置于配置好的皮尔试剂(Piranha)中,超声10 min,然后分别用丙酮、乙醇、二次蒸馏水超声清洗10 min,N2吹干;其中,皮尔试剂的配置为浓H2SO4:H2O2=5 : 3(V:V);(2)氨基化:将一定量的3-氨丙基三乙氧基硅烷溶解于乙醇中,将处理过的晶振片置于上述溶液中,N2气氛,在78 ℃反应12 h后,依次用无水乙醇和二次蒸馏水将晶振片冲净,N2吹干;其中,3-氨丙基三乙氧基硅烷的浓度为5 mmol/L;(3)聚合:将3-丙烯酰胺基苯硼酸、交联剂、引发剂、丙烯酰胺和加入到溶剂中,混合均匀后,取35 uL的混合液均匀地涂在步骤(2)中所述的晶振片上,置于匀胶机上,转速6000 r/min,然后于紫外灯下光引发聚合60 min,反应完后用溶剂反复洗涤,洗去未反应物。其中,葡萄糖、丙烯酰胺基苯硼酸、N,N-亚甲基双丙烯酰胺、引发剂的浓度分别为40、80、150、0.5 mmol/L。
上述实施例用来解释说明本发明,而不是对本发明进行限制,在本发明的精神和权利要求的保护范围内,对本发明作出的任何修改和改变,都落入本发明的保护范围。
Claims (7)
1.一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备,其特征为包括如下步骤:(1)晶振片表面预处理:将金片置于配置好的皮尔试剂中,超声10 ~ 60 min,然后分别用丙酮、乙醇、二次蒸馏水超声清洗2 ~20 min,N2吹干;其中,皮尔试剂的配置为浓H2SO4:H2O2=5 ~ 10 : 3(V : V);(2)氨基化:将一定量的硅烷偶联剂溶解于溶剂中,将处理过的晶振片置于上述溶液中,N2气氛,在50 ~ 110 ℃反应5 ~ 12 h后,依次用无水乙醇和二次蒸馏水将金片冲净,N2吹干;其中,硅烷偶联剂的浓度= 2 ~ 5 mmol/L;(3)聚合:将3-丙烯酰胺基苯硼酸、交联剂、引发剂、丙烯酰胺和加入到溶剂中,混合均匀后,取5 ~ 50 uL的混合液均匀地涂在步骤(2)中所述的晶振片上,置于匀胶机上,转速3000 ~ 6000r/min,然后于紫外灯下光引发聚合5 ~ 60 min,反应完后用溶剂反复洗涤,洗去未反应物,其中,3-丙烯酰胺基苯硼酸、交联剂、引发剂和丙烯酰胺的浓度分别为50 ~ 100、100 ~ 200、0.2 ~ 0.5 mmol/L、10 ~ 50 mmol/L。
2.如权利要求1所述的一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备,其特征为所述的步骤(1)中石英晶振片的直径为5 ~ 20mm,标准频率为5或6MHz的一种。
3.如权利要求1所述的一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备,其特征为所述的步骤(2)中硅烷偶联剂为3-氨丙基三甲氧基硅烷、3-氨丙基三乙氧基硅烷、γ-氨丙基甲基二乙氧基硅烷和N-2-氨乙基-3-氨丙基甲基二甲氧基硅烷中的一种或几种。
4.如权利要求1所述的一一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备,其特征为所述的步骤(2)中溶剂为乙醇、甲苯和乙醇:蒸馏水=1:1(V : V=1 : 1)中的一种。
5.如权利要求1所述的一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备,其特征为所述的步骤(3)中紫外光的波长范围为250 ~ 400 nm,紫外光的照射强度为1 ~ 100 W/cm2。
6.如权利要求1一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备,其特征为所述的步骤(3)中引发剂为二苯基乙二酮﹑2,2-二乙氧基苯乙酮﹑a,a-二甲氧基-a-苯基苯乙酮﹑2,4,6-三甲基二苯甲酮和2,4-二乙基硫杂蒽酮中的一种。
7.如权利要求1一种基于石英晶振片具有优异生物相容性的葡萄糖敏感薄膜的制备,其特征为所述的步骤(3)中洗涤所用的溶剂是乙醇﹑丙酮﹑异丙醇和二甲基亚砜中的一种或两种。
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