王 鹏，贾芸芳，徐红梅，王中荣，范清杰*

（1.天津市兰力科化学电子高技术有限公司，天津300384）（2.南开大学电子信息与光学工程学院，天津300071）

0 引言

石墨烯是一种二维碳材料，与零维碳材料-富勒烯[1]、一维碳纳米管[2]、三维碳材料(金刚石、石墨)一起被统称为碳的同素异形体。与一维和三维碳材料相比，石墨烯不仅出现得晚，而且其存在性曾是历史上备受争议的话题[3-5]，直到2004年，Geim和Novoselov采用机械剥离方法发现了稳定、独立存在的单层石墨烯[6]，石墨烯的存在才真正得到认可。它的存在被解释为：从三维结构中剥离出来的二维结构，由于石墨烯表面具有轻微的褶皱，使其具有自发的稳定性；石墨烯在三维方向上的弯曲(侧面观察大约10 nm)导致弹性能增加的同时抑制了热振动，当处于较高温度时，可以使自由能降到最低限，从而使其能够自由、稳定地存在[7-8]。

石墨烯目前已在高速器件[9-12]、储能器件[13-14]、柔性器件[15-16]、生化传感器[17]等多方面开展了应用研究，表现出很好的前景；该文主要结合生化传感器发展趋势，对石墨烯及其衍生物在生化传感器中的作用进行综述分析。

1 生化传感器的简介

生化传感器是指能够响应生物、化学量，并按一定规律将其转换成可用信号(光信号、电信号等)的器件或装置。在结构上主要由两部分组成：1）感受器，通常为含有生化活性物质、具有特异性识别能力的敏感膜；2）转换器，将敏感膜感知的生化信息转换为可测量的光信号或电信号[18]。提高生化传感器灵敏性的研究主要集中在感受器、转换器以及二者衔接三个方面。

纳米材料及其与导电聚合物、生物探针相结合是感受器研究的主流趋势，如：TiO2[19]、Co3O4[20]、CuO[21]和Cu2O[22]等纳米金属氧化物作为感受器，可提高对H2O2的灵敏度；导电聚合物与碳纳米管结合可提高氨气的灵敏度[23]，导电聚合物与石墨烯结合，可提高对DNA的灵敏度[24]；单链DNA与纳米金粒子结合[25]，酶和碳纳米管结合[26]，适配子与石墨烯相结合[27]，分别可提高对互补DNA、葡萄糖以及待测细胞的灵敏度。

利用新型电子材料来提高转换器的信号强度则是转换器研究的方向，如，碳纳米管、石墨烯为沟道材料的场效应晶体管 （Field Effect Transistor，FET），可提高对DNA[28-29]、蛋白质[30-31]以及葡萄糖[32-33]的响应强度；在荧光共振能量转移(fluorescence resonance energy transfer，FRET)型生化传感器中，采用量子点取代荧光标记物，可实现将H2O2[34]和氰离子[35]浓度等生化信息转化为荧光信号，通过对荧光强度的测量实现定量检测。

在构建感受器与转换器间敏感界面的研究中，则主要围绕促进感受器与转换器之间电荷传输速率和提高转换器表面感受器的固定效率两方面展开。CNTs、碳量子点、纳米碳纤维、纳米金刚石、富勒烯和石墨烯等新型碳材料可作为探针载体，提高探针在玻碳电极 （Glassy Carbon Electrode，GCE）上的固定效率[36]；应用石墨烯、CNTs可以实现促进葡萄糖氧化酶活性中心[37-38]，DNA探针[39-40]与GCE之间的电子传递。

由此可见，促进感受器与转换器之间的电荷传输、提高感受器在转换器上的固定效率、提高转换器的信号强度是生化传感器发展的重要需求，新型电子材料石墨烯的出现，使同时满足生化传感器的这三个需求成为可能。

2 石墨烯结构与电学特性

石墨烯具有独特的结构和优良的电学特性，为改善生化传感器灵敏性奠定了优良的物质基础。

单层石墨烯由碳原子依靠共价键相互连接形成完美的六边形结构，其厚度仅有0.335 nm，约为头发半径的20万分之一，是目前已知最薄的晶体材料；具有较高的比表面积[41]，理论上可达到2630 m2/g，即使在实际制备过程中发生团聚或产生结构缺陷，石墨烯的比表面积也约为700 m2/g，仍远高于大部分纳米材料，比如：碳纳米管[42]以及Al2O3和CeO2等金属纳米粒子[43]；这种高比表面积的特性，使其更容易与其他材料充分接触，对各种原子或者分子具有较强的吸附能力[44]。

石墨烯中每个碳原子有4个价电子，其中3个价电子以sp2杂化方式形成σ键，最后一个p轨道价电子形成π键，π键电子是可自由移动的载流子，浓度约为1013cm-2，石墨烯具有极低的电阻率，约为 1.59×10-6Ω·cm[45]，载流子迁移率约为1.5×105cm2/V·s[46]；石墨烯是一种零带隙半导体或者半金属，三维能带结构如图1所示，其中导带和价带相交于狄拉克点，研究显示狄拉克点的位置可被外加偏压调节，表现出双极特性[47]。

图1 石墨烯在三维状态下的能带结构图[47]Fig.1 The energy band structure of graphene in three dimensions

GO携带大量含氧基团，分子空间结构如图2所示。根据Lerf-Klinowski模型[48]和Rourke-Wilson模型[49]，GO具有与石墨烯相似的片层结构，GO的片层内部，仍保留了石墨烯完美的六边形结构，这使得GO具有一定的导电能力，GO片层之间存在通过π-π键共轭作用相互粘附，如图2b所示[50]，这说明GO片层之间仍存在载流子输运通道；更重要的是，GO片层边缘存在大量含氧基团，如羟基（-COOH）和环氧基（-O=O-），为生物功能化提供了活性位点。

图2 GO 结构的 Lerf-Klinowski模型[48]（a）和 Rourke-Wilson 模型[49]（b）Fig.2 Lerf-Klinowski model(a)and Rourke-Wilson model(b)of GO structure

从GO的结构可见，GO上含氧基团为功能基团（如ssDNA、抗体等）的固定提供了活性位点。例如，当功能基团存在氨基（-NH2）时，可与GO边缘-COOH形成共价键，从而将功能基团嫁接在GO上。但是，由于含氧基团的引入，π键电子减少，从而使GO表现出较大的表面电阻Rs（与本征石墨烯相比）[51]，这不利于GO表面功能基团与GO片层之间的载流子传输，因而不利于增强传感器输出信号。还原GO（reduced GO，rGO）可使GO上部分含氧基团脱落，rGO的Rs可以下降几个到十几个数量级[52]，但是，rGO上仍有残留含氧基团和结构缺陷，使其Rs仍明显高于石墨烯[53]。

由此可见，rGO的石墨烯形态，既保证了功能基团在石墨烯传感器表面的固定，又能使功能基团与GO之间载流子输运具有较低的电阻。

3 石墨烯在生化传感器中的作用

3.1 增强生物探针与转换器之间的电子传输

采用循环伏安法和交流阻抗法，对比分析聚苯胺、还原氧化石墨烯 (reduced graphene oxide，rGO)和DNA探针修饰的GCE型DNA传感器，结果表明修饰rGO的GCE响应电流大、阻抗小，证明了rGO具有促进DNA探针与电极之间电子传输的作用[54]。rGO、石墨修饰和空GCE三种情况的对比实验显示[55]，rGO修饰的GCE对不同碱基均具有最大的响应电流，证明了rGO有助于加快电极与DNA碱基的电子转移。

蛋白质型生化传感器中氧化还原蛋白的电子转移是生化响应的核心，石墨烯对氧化还原蛋白具有不可逆的吸附性能以及良好的电子传递能力，是促进蛋白质电子转移的理想材料[56]。GO对蛋白质电荷转移性能影响的研究显示[57]，只有GO与蛋白质混合物修饰的GCE才可以清晰地观察到氧化还原峰，而未加入GO的GCE则相对较小。在壳聚糖GCE型血红蛋白质传感器研究中发现，石墨烯具有促进蛋白质与电极间的电子转移的作用[58]；基于rGO和ZnO杂化物的谷胱甘肽生化传感器研究显示[59]，rGO可促进谷胱甘肽与电极间电荷传输，使得rGO修饰的电极光电流成倍增长。

葡萄糖电化学传感器中，利用石墨烯特殊的电子传输性质可实现葡萄糖氧化酶与电极之间的直接电子转移。例如，GO修饰的Pt电极可促进葡萄糖氧化酶与电极间电子转移[60]；对石墨烯和纳米银复合物修饰的葡萄糖氧化酶GCE研究表明[61]，石墨烯的加入可促进葡萄糖氧化酶和GCE间的电荷转移；同时，采用滴涂法制备石墨烯-葡萄糖氧化酶GCE传感器，也显示增强氧化还原峰的特性，实验计算显示葡萄糖氧化酶与电极间的电子转移速率约为2.68 s-1[62]。

3.2 增强生物探针固定量

由于石墨烯具有大比表面积，通过石墨烯的修饰的电极可以获得更高的比表面积，进而提高探针在其表面的负载量[63]。Lin等[64]通过石墨烯与DNA之间的π-π键相互作用，实现GCE表面DNA功能化，有效地提高了电极表面DNA探针的固定量。利用石墨烯和免疫功能化的纳米碳球，基于双重信号放大策略制备了用于甲胎蛋白(Alpha fetal protein，AFP)检测的免疫传感器[65]，由于石墨烯的大比表面积有效提高了抗体在传感器表面的固定量，与未修饰石墨烯的免疫传感器进行对比，该免疫传感器的检测信号强度增大了7倍。

壳聚糖、葡萄糖氧化酶/壳聚糖、壳聚糖/石墨烯、葡萄糖氧化酶/壳聚糖/石墨烯混合物修饰GCE的电化学研究显示，含有石墨烯的混合物修饰电极的响应电流较大，葡萄糖氧化酶在含有石墨烯的GCE表面的负载量可达到1.12×10-9mol/cm2[66]。

Fe2O3和rGO修饰GCE的亚硝酸盐生化传感器[67]，与 MnO2、Au/ZnO/MWCNTs 等材料修饰的GCE对比显示，由于石墨烯提高电极表面Fe2O3负载量，其对亚硝酸盐具有催化活性，从而改善了传感器对亚硝酸盐检测灵敏性，使得该传感器对亚硝酸盐检测响应电流明显较大。

GO上羧基基团与DNA探针3'末端的氨基发生酰胺反应，将DNA探针在光寻址电位传感器 （LightAddressable Potentiometric Sensor，LAPS），表面，制备出用于DNA检测的石墨烯-LAPS(graphene modified LAPS，G-LAPS)生化传感器[68]。该传感器对互补DNA的响应电流明显大于未修饰GO的LAPS传感器，结合XPS表面分析表明GO的修饰作用，增加了LAPS表面DNA探针的固定量，从而增强了LAPS对DNA的响应强度。

羧基化GO（GO-COOH）对GCE修饰作用的研究也表明[69]，GO-COOH中-COOH基团可以以共价键方式连接ssDNA探针，增加了GCE上DNA探针固定量，与未修饰GO-COOH的GCE相比，其交流阻抗谱曲线半径明显减小。

3.3 直接作为转换器

石墨烯及其衍生物作为转换器，主要是将被测物信息转换为可测量的光信号或电信号，作为转换器典型的应用主要在FRET型和石墨烯场效应晶体管(graphene field effect transistor，GFET)型生化传感器中。

FRET型石墨烯生化传感器是以GO荧光特性为基础。在GO制备过程中，其表面和边沿携带大量含氧基团，破坏了石墨烯的大π键，使其具有光致发光的特性，可在较宽的范围内(近红外到紫外)发出荧光[70-71]。GO作为能量受体[72]，通过π-π作用与其接触的荧光基团发生能量转移导致荧光猝灭，实现生化量与光学量的转换。

基于GO荧光特性结构的多巴胺生化传感器[73]，多巴胺以π-π键吸附到GO表面，使GO荧光猝灭，且随着多巴胺浓度逐渐增大，GO荧光强度降低。基于GO荧光特性的轮状病毒检测的FRET免疫传感器[74]，通过在GO表面修饰轮状病毒的一级抗体，用于捕获感染了轮状病毒的细胞，用修饰纳米金的二级抗体与轮状病毒再次结合形成三明治结构，纳米金可以猝灭GO荧光，从而实现对轮状病毒的检测。GO荧光猝灭原理和凝血酶适体相结合的凝血酶FRET生化传感器[75]， 最低检测限为31.3 pmol/L，相对于基于CNTs的FRET低两个数量级。

GFET型生化传感器以石墨烯作为FET的导电沟道，通过离子、分子的吸附或脱落影响石墨烯电荷密度和类型[76-78]，从而实现通过GFET输出电信号的变化检测生化量检测。将DNA探针固定于石墨烯表面形成DNA-GFET传感器[79]，DNA探针与其互补DNA杂交形成石墨烯掺杂效应，使得GFET沟道载流子浓度发生变化，从而使源漏电流发生改变。蛋白质GFET传感器[80]，则利用蛋白质吸附导致GFET响应输出改变，实现蛋白质浓度的直接电学检测。葡萄糖-GFET生化传感器[81]则通过固定在石墨烯上的葡萄糖氧化酶催化葡萄糖氧化产生H2O2并吸附在石墨烯表面，使GFET沟道电导发生变化，实现对葡萄糖的快速检测。

以离子选择透过性膜修饰GFET形成多离子（Na+、K+、Ca2+、H+）GFET 传感器阵列[82]，实现对多离子高效并行检测。基于悬浮单晶石墨烯的FET型生化传感器用于三种肿瘤标记物检测(ANXA2，VEGF和ENO1)[83]，该传感器避免了来自基底晶界与散射对石墨烯的影响，提升了GFET导电沟道内载流子传输速率，更加高效的实现生化量与电学量的转换，最低检测限可达0.1 pg/mL。

4 结论

石墨烯具有极高的电子迁移率，即可有效的提高感受器与转换器间电荷传输速率，又可用于研制GFET型生化传感器；同时，石墨烯片层结构具有极大比表面积可提高转换器表面生物探针的固定量，有助于提高生化传感器的响应强度和响应范围；最后，石墨烯衍生物富含羧基、羟基等含氧基团，可作为多种生物探针的固定位点，使其成为多种生化响应机制的载体。综上所述，石墨烯及其衍生物在构建高灵敏度、多功能型生化传感器方面具有极大的潜力。

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