CN116735881B - 一种有机场效应晶体管生物传感器及其制备方法和应用 - Google Patents
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Abstract
本发明公开了一种有机场效应晶体管生物传感器,包括衬底、有机半导体薄膜、源电极、漏电极和延长栅电极;源电极、漏电极和延长栅电极之间直接通过导电线相连;延长栅电极上修饰有纳米碳点;纳米碳点上接枝有重组蛋白A;重组蛋白A上接枝有敏感探针。该有机场效应晶体管生物传感器采用延长栅电极,避免检测溶液环境对传感器性能造成的影响,提高了传感器的稳定性。与此同时,纳米碳点的高比表面积可以暴露出更多的结合位点,提升检测灵敏度。
Description
技术领域
本发明涉及生物传感器技术领域,特别是涉及一种有机场效应晶体管生物传感器及其制备方法和应用。
背景技术
癌症是人类面临的重大公共安全问题之一,其对人们的生活质量和生命安全有着不可估量的影响。目前而言,对大多数癌症并没有完全可靠的治疗方法,但大多数癌症在早期发展阶段以现有的治疗手段均可以取得较高的治愈率,因此如果能够及早检测到癌症标志物,做到早发现、早治疗,这会极大的降低死亡率。
基于有机场效应晶体管(OFETs)固有的信号放大能力使其作为生物传感器平台具有巨大的潜力,可以将生物分子信息直接转化为可检测的电信号。通过化学和生物基团的修饰,这些生物传感器可以实现特异性检测,在葡萄糖、蛋白质、离子浓度、DNA等方面取得了重大进展。
对于传统的OFETs,通常利用对OFETs功能化实现对分析物的特异性识别,该识别过程可以通过电荷掺杂和捕获诱发器件电信号的变化得到。例如有机半导体可以通过侧链工程直接功能化,用于生物传感,有机材料的功能化使其能够通过有机合成反应将生物官能团或结合位点通过共价相互作用实现生物敏感探针高效固定。然而,新引入的结合位点可能会对π-π相互作用产生影响,导致电荷传输途径受损且合成过程耗时复杂。此外,也有研究者通过将混合膜作为OFETs生物传感器的通道,增强生物传感器层与目标分析物之间相互作用的方法,以实现高效的生物检测。然而,在双层膜中的上层传感层可能会在制备过程中影响有机通道的形态和陷阱态,造成器件性能的降低。另外,在生物检测中,大多数有机半导体暴露于潮湿环境时性能会迅速衰减。综上这些因素都会影响检测的灵敏度和稳定性。
因此,急需开发灵敏度更高,操作更简便,适用范围更广的低成本有机场效应晶体管生物传感器以实现对癌症标志物的检测评估及早期预警的普及化。
发明内容
本发明的目的是针对现有OFETs生物传感器存在的稳定性差及灵敏度低的技术缺陷,而提供一种有机场效应晶体管生物传感器,该有机场效应晶体管生物传感器在延长栅有机场效应晶体管基础上修饰纳米碳点,提高了生物传感器存在的稳定性和灵敏度。
本发明的另一个目的,是提供上述有机场效应晶体管生物传感器的制备方法。
本发明的另一个目的,是提供上述有机场效应晶体管生物传感器在癌症标志物检测中的应用。
为实现本发明的目的所采用的技术方案是:
一种有机场效应晶体管生物传感器,包括衬底、有机半导体薄膜、源、漏电极和延长栅电极;所述衬底包括基底和介电层;
所述源漏电极与所述延长栅电极之间通过导电线相连;
所述延长栅电极上修饰有纳米碳点;所述纳米碳点上接枝有重组蛋白A;
所述重组蛋白A上接枝有敏感探针。
在上述技术方案中,所述纳米碳点上带有巯基官能团和羧基官能团;其中巯基官能团用于将所述纳米碳点接枝在所述延长栅电极上;所述羧基官能团用于接枝重组蛋白A。
在上述技术方案中,所述源漏电极的厚度为20-40nm。
在上述技术方案中,所述延长栅电极包括钛层和金层;其中,钛层厚度为5nm,金层厚度为30-80nm。
本发明的另一方面,上述有机场效应晶体管生物传感器的制备方法,包括以下步骤:
步骤1:清洗衬底
依次使用超纯水、丙酮和异丙醇对衬底进行超声清洗;
步骤2:界面修饰
首先在氧气环境下用等离子体对衬底进行处理;然后用十八烷基三氯硅烷对衬底进行修饰;
步骤3:形成有机半导体薄膜
首先配制PDBT-co-TT聚合溶液并加热搅拌,然后将溶解好的PDBT-co-TT聚合溶液旋涂于界面修饰后的的衬底上,最后退火形成有机半导体薄膜;
步骤4:制备源漏电极
使用透射电镜铜网作为掩模版,在有机半导体薄膜上沉积20-40nm的金,从而得到源漏电极;
步骤5:制备延长栅电极
使用透射电镜镍网作为掩模版,在玻璃基底上先后沉积5nm的钛和30-80nm的金,从而得到延长栅电极;
将源漏电极和延长栅电极之间通过导电线相连;
步骤6:修饰纳米碳点
首先在延长栅电极上通过分子自组装修饰纳米碳点,然后在纳米碳点上接枝重组蛋白A,最后将敏感探针接枝到重组蛋白A上,构建有机场效应晶体管生物传感器。
在上述技术方案中,所述纳米碳点的制备方法为,
首先,将柠檬酸和L-半胱氨酸混合,加入水中,加热搅拌溶解,形成乳白色液体;
然后,将所得乳白色液体在高压反应釜中,加热反应得到棕褐色液体;
然后,向反应后的棕褐色液体中加入NaOH溶液和去离子水,离心去除沉淀物;
最后,将离心液过滤,滤液干燥得纳米碳点。
在上述技术方案中,步骤6中,
首先,将纳米碳点配制成浓度为0.3-1mg/mL的纳米碳点溶液,并孵育在延长栅电极上,于室温下静置修饰3h;
然后,利用EDC/NHS活化纳米碳点上的羧基1h,用磷酸缓冲盐溶液冲洗表面3-5次,将蛋白A孵育在纳米碳点上;用磷酸缓冲盐溶液冲洗所述表面3-5次;
最后,将敏感探针滴加在修饰后的延长栅电极表面,并于室温孵化1h。
本发明的另一方面,上述有机场效应晶体管生物传感器在癌症标志物检测中的应用。
在上述技术方案中,所述敏感探针为待测癌症标志物分子所对应的抗体分子。
在上述技术方案中,检测步骤包括:
步骤a:用磷酸缓冲盐溶液冲洗延长栅电极的表面,于室温干燥后测试所述有机场效应晶体管生物传感器的转移曲线,并得到输出信号电流的数值I0;
步骤b:将待测溶液滴加在延长栅电极的表面,于室温孵化1-2h后室温干燥,测试转移曲线并得到输出信号电流的数值I;
步骤c:计算△IDS=(I-I0)/I0作为传感输出信号。
与现有技术相比,本发明的有益效果是:
1.本发明提供的有机场效应晶体管生物传感器,该有机场效应晶体管生物传感器采用延长栅电极,避免检测溶液环境对传感器性能造成的影响,提高了传感器的稳定性。
2.本发明提供的有机场效应晶体管生物传感器,根据不同物质和官能团之间亲和力的差异以及纳米碳点表面易修饰的特点,设计合成了带有巯基和羧基官能团的纳米碳点。纳米碳点的巯基可以通过分子自组装接枝在金栅电极上,另外丰富的羧基官能团有效提升了敏感探针接枝的稳定性,可以进一步提高样品检测的重复性。纳米碳点的高比表面积可以暴露出更多的结合位点,提升检测灵敏度。与此同时,通过在生物检测中引入His标记的重组蛋白A,减少了敏感探针(抗体片段)随机结合造成的立体阻碍效应,使抗体片段可以定向有序排列,达到提高稳定性和灵敏度的目的。
3.本发明提供的有机场效应晶体管生物传感器在癌症标志物检测中的应用,与其他检测方法相比,由于其体积小、操作简便、灵敏度高、可靠性强,有望成为检测各种生物分子的高性能传感平台。
附图说明
图1所示为实施例1制备的纳米碳点的紫外表征图谱;
图2所示为实施例1制备的纳米碳点在自然光(左)和365nmUV光(右)照射下获得的图片;
图3所示为实施例1制备的纳米碳点的荧光表征光谱;
图4所示为实施例1制备的纳米碳点的红外光谱;
图5所示为实施例1制备的纳米碳点的透射电子显微镜(TEM)表征图;
图6所示为实施例1制备的纳米碳点的X射线光电子能谱(XPS)表征图;
图7a所示为实施例2制备的有机场效应晶体管生物传感器的结构示意图;
图7b所示为延长栅电极的修饰流程图;
图8所示为实施例2制备的EG-OFET的转移曲线(a)和输出曲线(b);
图9所示为纳米碳点修饰前后延长栅电极的接触角变化;
图10所示为修饰纳米碳点前后EG-OFET的转移曲线表征图;
图11所示为接枝抗体前后的原子力显微镜(AFM)表征;
图12所示为有无纳米碳点修饰的EG-OFET接枝抗体前后的XPS表征图(黑线为接枝抗体前,红线为接枝抗体后);
图13所示为延长栅电极的共聚焦激光扫描显微镜(CLSM)表征图;
其中,a为无荧光抗体;b为无纳米碳点修饰直接接枝抗体;c为纳米碳点修饰后接枝抗体;
图14所示为实施例2制备的有机场效应晶体管生物传感器对于不同浓度的CEA生物标志物的ISD电信号的传感行为;
图15a所示为实施例2制备的有机场效应晶体管生物传感器针对不同抗体的Ids电信号的传感行为;
图15b所示为实施例2制备的有机场效应晶体管生物传感器暴露于不同浓度的CEA的Ids电信号的良好线性拟合曲线。
具体实施方式
以下结合具体实施例对本发明作进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1
本实施例介绍纳米碳点的制备及表征。
所述纳米碳点通过水热法合成,反应式如下:
具体制备方法包括以下步骤:
步骤1:将1.83克柠檬酸和1.0克L-半胱氨酸混合,加入5mL水搅拌溶解,在70℃下加热12小时,形成乳白色液体;
步骤2:将上述乳白色液体加到高压反应釜中,在200℃下反应3h(以10℃/min的速度升温加热),得到棕褐色液体;
步骤3:在反应后的棕褐色溶液中加入300μL的1mol/L的NaOH溶液和20mL的去离子水,在6000rpm下离心20min,去除沉淀物;
步骤4:将离心液用孔径为0.22μm的针式过滤器过滤掉大的纳米颗粒,滤液在真空烘箱中于80℃下干燥得到纳米碳点固体。
通过紫外光谱仪对制备所得的纳米碳点进行表征,如图1所示,在242和345nm处有两个典型的UV/vis吸收峰,而反应物柠檬酸的吸收峰在230nm以下,L-半胱氨酸的吸收在230nm以上非常弱,表明纳米碳点CDs的合成成功。
制备所得的纳米碳点具有荧光,而且即使在很低的浓度下,在紫外光照射下发出非常明亮的蓝光,如图2所示。
通过荧光光谱仪对制备所得的纳米碳点进行表征,如图3所示,纳米碳点水溶液的最大激发波长位于345nm,这与紫外测量数据一致,发射波长为436nm。
通过红外光谱仪对制备所得的纳米碳点进行表征,如图4所示,位于3403cm-1和2543cm-1的峰对应O-H和S-H,位于1702cm-1的峰表示存在C=O拉伸振动。C-O和C-S的拉伸振动分别出现在1180cm-1和1124cm-1,位于1396cm-1的峰认为是-COOH基团。
通过透射电子显微镜对制备所得的纳米碳点进行表征,如图5所示,合成的纳米碳点是球形的纳米颗粒,分布均匀,直径小于10nm。
通过X射线光电子能谱(XPS)光谱对制备所得的纳米碳点进行表征,如图6所示,表明合成的碳点主要由碳、氧、氮和硫元素组成。
以上表征均能证明纳米碳点CDs的合成成功。
实施例2
一种有机场效应晶体管生物传感器的制备方法,包括以下步骤:
步骤1:清洗衬底
本申请中,所述衬底为中国电子科技集团公司生产的含300nm SiO2层的N掺杂硅晶片,既包含了硅基底也包含了SiO2介电层。
首先用超纯水(电阻率为18.2MΩcm)超声10min去除衬底表面易于清洗的灰尘,然后用丙酮超声10min去除衬底表面难以清洗的灰尘,最后用异丙醇超声10min进行最后的清洗;
步骤2:界面修饰
首先在氧气环境下用等离子体对衬底处理10min,功率为100W;然后将衬底放置在OTS修饰溶液中(OTS修饰溶液中,正庚烷和OTS的体积比为1000:1),于室温下静置修饰3h,接着取出衬底依次放入含有正己烷溶液、三氯甲烷溶液、异丙醇溶液的烧杯中超声处理10min;
步骤3:形成有机半导体薄膜
首先将PDBT-co-TT聚合物溶于氯苯有机溶剂配制成浓度为10mg/mL的PDBT-co-TT聚合溶液,并于90℃的热台上进行加热搅拌15h;然后将溶解好的PDBT-co-TT聚合溶液以4000rpm旋涂于步骤2界面修饰后的衬底上;最后于热台170℃退火10min形成有机半导体薄膜;
步骤4:制备源漏电极
使用透射电镜铜网作为掩模版,在有机半导体薄膜上使用金属真空镀膜仪以s-1沉积沉积30nm的金,从而得到源漏电极;其中掩膜版的宽长比W/L=7.2;
步骤5:制备延长栅电极
用玻璃作为基底,通过水、丙酮和异丙醇溶液进行清洗,然后使用透射电镜镍网作为掩模版,在清洗后的玻璃基底上使用金属真空镀膜仪以s-1先后沉积5nm的钛和50nm的金,从而得到延长栅电极;
如图7a所示,源漏电极和延长栅电极之间直接通过导电线相连,组成有机场效应晶体管(EG-OFETs),并通过Keithley 4200SCS半导体参数分析仪进行电学性能的表征。表征结果如图8所示,转移曲线表明,载流子的数量可以通过外部施加的栅压Vg控制,即具有栅极可调的空穴电荷传输特性;输出曲线表现出从线性状态到饱和状态的清晰过渡,饱和电流几乎平坦。
步骤6:修饰纳米碳点
首先在延长栅电极上通过分子自组装修饰纳米碳点,然后在纳米碳点上接枝重组蛋白A,最后将待测癌症标志物分子所对应的抗体作为敏感探针接枝到重组蛋白A上,构建有机场效应晶体管生物传感器。
具体来说,纳米碳点在延长栅电极上的分子自组装过程为:步骤1):称取0.5mg纳米碳点溶于1mL去离子水中配制成浓度为0.5mg/mL的纳米碳点溶液;取5μL纳米碳点溶液滴在延长栅电极上室温下孵育3h。通过接触角对纳米碳点修饰前后的延长栅电极进行表征。如图9所示,带有巯基的纳米碳点和金延长栅电极很容易通过分子自组装形成金硫键。在分子自组装前后,水在金延长栅电极上的接触角从76.9°变为60.5°,表明纳米碳点分子自组装的成功形成。通过电学性能测试对纳米碳点修饰前后的延长栅有机场效应晶体管进行表征,如图10所示,纳米碳点修饰前后延长栅有机场效应晶体管性能几乎无变化,表明纳米碳点的固定对延长栅有机场效应晶体管性能几乎无影响。
纳米碳点分子自组装成功后,利用EDC/NHS活化纳米碳点上的羧基1h,用磷酸缓冲盐溶液冲洗表面3次,将重组蛋白A孵育在纳米碳点上;用磷酸缓冲盐溶液冲洗所述表面3次;最后,将50μg/mL敏感探针(CEA抗体)滴加在修饰后的延长栅电极表面,并于室温20~25℃孵化1小时。通过原子力显微镜(AFM)对接枝抗体前后高度和粗糙度进行表征,如图11所示,AFM高度图像显示,随着抗体的加入,高度增加了约8nm,这与CEA抗体的尺寸相似,在固定抗体前后,生物传感器识别层表面的均方根粗糙度的增加也表明CEA抗体的成功固定。
对比例
本对比例与实施例2相比,区别在于不接枝纳米碳点,而是将重组蛋白A和敏感探针直接接枝在延长栅电极上。
一种有机场效应晶体管生物传感器的制备方法,步骤1-5与实施例2中步骤1-5相同,在此不做赘述。
步骤6:将重组蛋白A孵育在延长栅电极上;用磷酸缓冲盐溶液冲洗所述表面3次;最后,将50μg/mL敏感探针(CEA抗体)滴加在修饰后的延长栅电极表面,并于室温20~25℃孵化1小时。
通过X射线光电子能谱(XPS)对有无纳米碳点修饰的延长栅电极对敏感探针的接枝情况进行表征,如图12所示,对比了在有纳米碳点(实施例2)和无纳米碳点(对比例)修饰的延长栅电极上固定CEA抗体前后的O1s和N1s峰。在没有纳米碳点修饰的延长栅电极上,接枝抗体前后的N/O峰值没有出现大的变化,而在有纳米碳点修饰的延长栅电极上,接枝抗体前后的N/O峰值出现了明显变化,说明纳米碳点功能化的延长栅电极可以增加敏感探针的固定。
通过共聚焦激光扫描显微镜(CLSM)对纳米碳点修饰前后的延长栅电极对敏感探针的接枝情况进行表征,如图13所示,如a所示,在荧光标记的CEA抗体固定化之前,裸露的延长栅电极上没有荧光,然后将带荧光的CEA抗体固定在延长栅电极上后表现出预期的黄绿色荧光(图b,c)。从图中可以明显看出,没有纳米碳点修饰的延长栅电极显示出少量不均匀的黄绿色荧光,而有纳米碳点修饰的延长栅电极显示出大量均匀的黄绿色荧光。进一步证实了纳米碳点功能化的延长栅电极有助于敏感探针的接枝。
实施例3
本实施例介绍实施例2制备的有机场效应晶体管生物传感器在癌症标志物检测中的应用。
上述有机场效应晶体管生物传感器应用于癌胚抗原癌症标志物分子浓度的检出,包括以下步骤:
步骤a:在接枝有待测癌症标志物分子所对应抗体分子的延长栅电极上,用磷酸缓冲盐(0.01×PBS,pH为7)溶液冲洗延长栅电极的表面3次,于室温干燥至少5s后测试所述有机场效应晶体管生物传感器的转移曲线,并得到输出信号电流的数值I0;
步骤b:将5μL待测溶液滴加在步骤1处理后的延长栅电极的表面,于室温孵化1h后室温干燥至少5s,测试转移曲线并得到输出信号电流的数值I;
步骤c:计算△ISD=(I-I0)/I0作为传感输出信号。
按照上述步骤,分别使用实施例2和对比例制备的有机场效应晶体管生物传感器,对于不同浓度(1000ng/mL,100ng/mL)的CEA生物标志物进行检测,结果如图14所示。在抗原和抗体之间发生特异性免疫反应后,具有纳米碳点修饰的延长栅电极引起了更大的电信号的变化,这同时表明,纳米碳点修饰的延长栅电极可以接枝更多的敏感探针。
图15a所示为实施例2制备的有机场效应晶体管生物传感器在CEA生物标志物检测中的Ids电信号的传感行为。从图中可以看到Ids电信号只对癌胚抗原癌症标志物分子有响应,而对非特异性结合的分子甲胎蛋白AFP、人血清白蛋白HSA以及空白1×PBS溶液响应程度很弱,展现出特异性。
图15b所示为实施例2制备的有机场效应晶体管生物传感器暴露于不同浓度(范围从1μg/mL到10pg/mL)的癌症标志物的Ids电信号的良好线性拟合曲线,检出限为3.3pg/mL,具有较高的灵敏度。
依照本发明内容进行工艺参数调整,均可制备本发明的有机场效应晶体管生物传感器,并表现出与实施例1基本一致的性能。
以上所述仅是本发明的优选实施方式,应当指出的是,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (9)
1.一种有机场效应晶体管生物传感器,其特征在于,包括衬底、有机半导体薄膜、源漏电极和延长栅电极;
所述源漏电极与所述延长栅电极之间通过导电线相连;
所述延长栅电极上修饰有纳米碳点;所述纳米碳点上接枝有重组蛋白A;
所述重组蛋白A上接枝有敏感探针;
有机场效应晶体管生物传感器的制备方法,包括以下步骤:
步骤1:清洗衬底
依次使用超纯水、丙酮和异丙醇对衬底进行超声清洗;
步骤2:界面修饰
首先在氧气环境下用等离子体对衬底进行处理;然后用十八烷基三氯硅烷对衬底进行修饰;
步骤3:形成有机半导体薄膜
首先配制PDBT-co-TT聚合溶液并加热搅拌,然后将溶解好的PDBT-co-TT聚合溶液旋涂于界面修饰后的的衬底上,最后退火形成有机半导体薄膜;
步骤4:制备源漏电极
使用掩模版,在有机半导体薄膜上沉积金,从而得到源漏电极;
步骤5:制备延长栅电极
使用掩模版,在玻璃基底上先后沉积钛和金,从而得到延长栅电极;
将源漏电极和延长栅电极之间通过导电线相连;
步骤6:修饰纳米碳点
首先在延长栅电极上通过分子自组装修饰纳米碳点,然后在纳米碳点上接枝重组蛋白A,最后将敏感探针接枝到重组蛋白A上,构建有机场效应晶体管生物传感器。
2.如权利要求1所述的有机场效应晶体管生物传感器,其特征在于,所述纳米碳点上带有巯基官能团和羧基官能团;其中巯基官能团用于将所述纳米碳点接枝在所述延长栅电极上;所述羧基官能团用于接枝重组蛋白A。
3.如权利要求1所述的有机场效应晶体管生物传感器,其特征在于,所述源漏电极的厚度为20-40nm。
4.如权利要求1所述的有机场效应晶体管生物传感器,其特征在于,所述延长栅电极包括钛层和金层;
其中,钛层厚度为5nm,金层厚度为30-80nm。
5.如权利要求1所述的有机场效应晶体管生物传感器,其特征在于,所述纳米碳点的制备方法为,
首先,将柠檬酸和L-半胱氨酸混合,加入水中,加热搅拌溶解,形成乳白色液体;
然后,将所得乳白色液体在高压反应釜中,加热反应得到棕褐色液体;
然后,向反应后的棕褐色液体中加入NaOH溶液和去离子水,离心去除沉淀物;
最后,将离心液过滤,滤液干燥得纳米碳点。
6.如权利要求5所述的有机场效应晶体管生物传感器,其特征在于,步骤6中,
首先,将纳米碳点配制成浓度为0.3-1mg/mL的纳米碳点溶液,并孵育在延长栅电极上,于室温下静置修饰3h;
然后,利用EDC/NHS活化纳米碳点上的羧基1h,用磷酸缓冲盐溶液冲洗表面3-5次,将蛋白A孵育在纳米碳点上;用磷酸缓冲盐溶液冲洗所述表面3-5次;
最后,将敏感探针滴加在修饰后的延长栅电极表面,并于室温孵化1h。
7.如权利要求1-6任一项所述的有机场效应晶体管生物传感器在癌症标志物检测中的应用。
8.如权利要求7所述应用,其特征在于,所述敏感探针为待测癌症标志物分子所对应的抗体分子。
9.如权利要求8所述应用,其特征在于,检测步骤包括:
步骤a:用磷酸缓冲盐溶液冲洗延长栅电极的表面,于室温干燥后测试所述有机场效应晶体管生物传感器的转移曲线,并得到输出信号电流的数值I0;
步骤b:将待测溶液滴加在延长栅电极的表面,于室温孵化1-2h后室温干燥,测试转移曲线并得到输出信号电流的数值I;
步骤c:计算△IDS=(I-I0)/I0作为传感输出信号。
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