Carbon Nanotube Field-Effect Transistor Biosensor with an Enlarged Gate Area for Ultra-Sensitive Detection of a Lung Cancer Biomarker
碳纳米管场效应晶体管生物传感器，具有扩大的栅极面积，用于超灵敏检测肺癌生物标志物
- Luyao Li 李璐瑶Luyao LiHunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, ChinaMore by Luyao Li
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- Xiaofeng Liu 刘晓峰Xiaofeng LiuHunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, ChinaMore by Xiaofeng Liu
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- Tongye Wei 魏彤业Tongye WeiHunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, ChinaMore by Tongye Wei
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- Kemin Wang 王克敏Kemin WangHunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, ChinaMore by Kemin Wang
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- Zijun Zhao 赵子军Zijun ZhaoHunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, ChinaMore by Zijun Zhao
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- Juexian Cao 曹觉贤Juexian CaoHunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, ChinaMore by Juexian Cao
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- Yiwei Liu* 刘一伟*Yiwei Liu*Email: yiweiliu@xtu.edu.cnHunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, ChinaMore by Yiwei Liu
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- Zhiyong Zhang* 张志勇*Zhiyong Zhang*Email: zyzhang@pku.edu.cnHunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, ChinaKey Laboratory for the Physics and Chemistry of Nanodevices and Center for Carbon-based Electronics, School of Electronics, Peking University, Beijing 100871, ChinaMore by Zhiyong Zhang
Cite this: ACS Appl. Mater. Interfaces 2023, 15, 22, 27299–27306
引用： ACS Appl. Mater.接口2023， 15， 22， 27299–27306
引用： ACS Appl. Mater.接口2023， 15， 22， 27299–27306
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Abstract 抽象
Carcinoembryonic antigen (CEA) is a recognized biomarker for lung cancer and can be used for early detection. However, the clinical value of CEA is not fully realized due to the rigorous requirement for high-sensitivity and wide-range detection methods. Field-effect transistor (FET) biosensors, as one of the potentially powerful platforms, may detect CEA with a significantly higher sensitivity than conventional clinical testing equipment, while their sensitivity and detection range for CEA are far below the requirement for early detection. Here, we construct a floating gate FET biosensor to detect CEA based on a semiconducting carbon nanotube (CNT) film combined with an undulating yttrium oxide (Y2O3) dielectric layer as the biosensing interface. Utilizing an undulating biosensing interface, the proposed device showed a wider detection range and optimized sensitivity and detection limit, which benefited from an increase of probe-binding sites on the sensing interface and an increase of electric double-layer capacitance, respectively. The outcomes of analytical studies confirm that the undulating Y2O3 provided the desired biosensing surface for probe immobilization and performance optimization of a CNT-FET biosensor toward CEA including a wide detection range from 1 fg/mL to 1 ng/mL, good linearity, and high sensitivity of 72 ag/mL. More crucially, the sensing platform can function normally in the complicated environment of fetal bovine serum, indicating its great promise for early lung cancer screening.
癌胚抗原 （CEA） 是公认的肺癌生物标志物，可用于早期检测。然而，由于对高灵敏度和广范围检测方法的严格要求，CEA的临床价值尚未充分实现。场效应晶体管（FET）生物传感器作为潜在的强大平台之一，可以以比传统临床检测设备更高的灵敏度检测CEA，而其对CEA的灵敏度和检测范围远低于早期检测的要求。本文构建了一种浮栅FET生物传感器，以半导体碳纳米管（CNT）薄膜结合起伏的氧化钇（Y 2 O 3 ）介电层作为生物传感界面来检测CEA。利用起伏的生物传感界面，该器件显示出更宽的检测范围和优化的灵敏度和检测限，分别受益于传感界面上探针结合位点的增加和双电层电容的增加。分析研究结果证实，起伏的 Y 2 O 3 为探针固定和 CNT-FET 生物传感器针对 CEA 的性能优化提供了所需的生物传感表面，包括从 1 fg/mL 到 1 ng/mL 的宽检测范围、良好的线性度和 72 ag/mL 的高灵敏度。更关键的是，该传感平台能够在胎牛血清的复杂环境中正常工作，表明其在早期肺癌筛查方面具有广阔的前景。
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Introduction 介绍
Lung cancer remains the leading cause of cancer-related death. There were 19.3 million new cancer cases and 10 million deaths worldwide by 2020, among which an estimated 1.8 million deaths (18%) were due to lung cancer. (1,2) Early diagnosis and treatment are considered critical to lowering lung cancer morbidity and mortality, and the 5 year survival rate for I-stage lung cancer patients can reach 90%. (3,4) However, early-stage cancer tissue is difficult to detect, and conventional clinical diagnosis methods, including bronchoscopy after chest X-ray, (5,6) cytology after sputum analysis, (7−10) and low-dose computed tomography (11,12) cannot meet accurate detection requirements. Recently, many clinical cases have confirmed that some proteins [e.g., carcinoembryonic antigen (CEA)] or cytokines (13−17) in the serum of lung cancer patients, even at the early stage, are called serum tumor biomarkers, the abundance of which is related to the development status of lung cancer, and its types relate to different histological subtypes. (18,19) In this regard, accurate quantification of serum tumor biomarkers will provide a new method for the painless and non-invasive diagnosis of lung cancer. Nevertheless, the accurate identification of trace biomarkers in complex serum environments has always been difficult. Although there are some routine methods in clinical diagnosis for CEA, such as chemiluminescence immunoassay, radioimmunoassay (RIA), and many other sensitive electrochemical biosensor strategies, (20−23) these methods have some drawbacks, such as the need for labeling and complex sample pre-treatment process or the requirement for higher laboratory conditions and expensive equipment.
肺癌仍然是癌症相关死亡的主要原因。到 2020 年，全球有 1930 万新发癌症病例和 1000 万人死亡，其中估计有 180 万人 （18%） 死于肺癌。（1,2）早期诊断和治疗被认为对降低肺癌发病率和死亡率至关重要，I期肺癌患者的5年生存率可达90%。（3,4）然而，早期癌症组织难以检测，传统的临床诊断方法，包括胸部X光检查后的支气管镜检查、（5,6）痰液分析后的细胞学检查、（7−10）和低剂量计算机断层扫描（11,12）不能满足准确的检测要求。最近，许多临床病例证实，肺癌患者血清中的一些蛋白质[例如癌胚抗原（CEA）]或细胞因子（13−17）即使在早期也被称为血清肿瘤生物标志物，其丰度与肺癌的发展状况有关，其类型与不同的组织学亚型有关。（18,19）在这方面，血清肿瘤生物标志物的精准定量将为肺癌的无痛无创诊断提供一种新的方法。然而，在复杂的血清环境中准确鉴定痕量生物标志物一直很困难。尽管CEA的临床诊断中有一些常规方法，如化学发光免疫测定、放射免疫测定（RIA）和许多其他灵敏的电化学生物传感器策略（20−23），但这些方法存在一些缺点，例如需要标记和复杂的样品预处理过程，或者需要更高的实验室条件和昂贵的设备。
肺癌仍然是癌症相关死亡的主要原因。到 2020 年，全球有 1930 万新发癌症病例和 1000 万人死亡，其中估计有 180 万人 （18%） 死于肺癌。（1,2）早期诊断和治疗被认为对降低肺癌发病率和死亡率至关重要，I期肺癌患者的5年生存率可达90%。（3,4）然而，早期癌症组织难以检测，传统的临床诊断方法，包括胸部X光检查后的支气管镜检查、（5,6）痰液分析后的细胞学检查、（7−10）和低剂量计算机断层扫描（11,12）不能满足准确的检测要求。最近，许多临床病例证实，肺癌患者血清中的一些蛋白质[例如癌胚抗原（CEA）]或细胞因子（13−17）即使在早期也被称为血清肿瘤生物标志物，其丰度与肺癌的发展状况有关，其类型与不同的组织学亚型有关。（18,19）在这方面，血清肿瘤生物标志物的精准定量将为肺癌的无痛无创诊断提供一种新的方法。然而，在复杂的血清环境中准确鉴定痕量生物标志物一直很困难。尽管CEA的临床诊断中有一些常规方法，如化学发光免疫测定、放射免疫测定（RIA）和许多其他灵敏的电化学生物传感器策略（20−23），但这些方法存在一些缺点，例如需要标记和复杂的样品预处理过程，或者需要更高的实验室条件和昂贵的设备。
FET-based biosensors are emerging detection technologies with inherent advantages, such as high sensitivity, (24−30) quick response, (31) label-free operation, (24,32) and scale integration. (33) Through electrostatic coupling between charged biomolecular and semiconductor channels, the concentration information of target biomolecules can be detected with high sensitivity and transmitted in readable electrical signals. Among various nanomaterials, semiconducting carbon nanotube (s-CNT) film has the advantages of ultra-high mobility, size compatibility with biomolecules, and good biocompatibility, (34−36) which makes it a good candidate for high-performance FET biosensors and has attracted extensive interest. However, the high sensitivity of FET biosensors is always accompanied by low anti-interference ability, which is especially obvious in complex serum samples. Researchers have tried a variety of anti-interference strategies, such as extended gates, (37) floating gates (FG), (36) and so on, by wrapping the semiconductor channel with insulating dielectric materials to avoid direct contact with the detection sample. Nevertheless, such methods inevitably increase the physical distance between the channel and the charged biomolecules and screen signaling charges, which is manifested as reduced sensitivity. How to enhance the sensitivity of FG CNT-FET biosensors has always been a major challenge for the application. In addition, the number of probe-binding sites that can be accommodated on the sensing interface determines the linear range of the biosensor and whether the sensor can meet the detection requirements of CEA with different abundance. How to assemble more probe molecules on the micron-sized sensing interfaces is another challenge for FET biosensors to be applied.
基于FET的生物传感器是新兴的检测技术，具有高灵敏度、（24−30）快速响应、（31）无标记操作（24,32）和刻度集成等固有优势。（33）通过带电生物分子和半导体通道之间的静电耦合，可以高灵敏度检测目标生物分子的浓度信息，并以可读的电信号传输。在各种纳米材料中，半导体碳纳米管（s-CNT）薄膜具有超高迁移率、与生物分子尺寸相容、生物相容性好等优点（34−36），是高性能FET生物传感器的良好候选材料，引起了人们的广泛关注。然而，FET生物传感器的高灵敏度总是伴随着低抗干扰能力，这在复杂的血清样品中尤为明显。研究人员尝试了多种抗干扰策略，如扩展栅极、（37）浮动栅极（FG）、（36）等，通过用绝缘介电材料包裹半导体通道，以避免与检测样品直接接触。然而，这种方法不可避免地增加了通道与带电生物分子和屏幕信号电荷之间的物理距离，这表现为灵敏度降低。如何提高FG CNT-FET生物传感器的灵敏度一直是应用的一大挑战。此外，传感界面上可容纳的探针结合位点数量决定了生物传感器的线性范围以及传感器能否满足不同丰度的CEA检测要求。如何在微米级的传感接口上组装更多的探针分子是FET生物传感器应用的另一个挑战。
基于FET的生物传感器是新兴的检测技术，具有高灵敏度、（24−30）快速响应、（31）无标记操作（24,32）和刻度集成等固有优势。（33）通过带电生物分子和半导体通道之间的静电耦合，可以高灵敏度检测目标生物分子的浓度信息，并以可读的电信号传输。在各种纳米材料中，半导体碳纳米管（s-CNT）薄膜具有超高迁移率、与生物分子尺寸相容、生物相容性好等优点（34−36），是高性能FET生物传感器的良好候选材料，引起了人们的广泛关注。然而，FET生物传感器的高灵敏度总是伴随着低抗干扰能力，这在复杂的血清样品中尤为明显。研究人员尝试了多种抗干扰策略，如扩展栅极、（37）浮动栅极（FG）、（36）等，通过用绝缘介电材料包裹半导体通道，以避免与检测样品直接接触。然而，这种方法不可避免地增加了通道与带电生物分子和屏幕信号电荷之间的物理距离，这表现为灵敏度降低。如何提高FG CNT-FET生物传感器的灵敏度一直是应用的一大挑战。此外，传感界面上可容纳的探针结合位点数量决定了生物传感器的线性范围以及传感器能否满足不同丰度的CEA检测要求。如何在微米级的传感接口上组装更多的探针分子是FET生物传感器应用的另一个挑战。
In this work, we introduced dielectric Y2O3 with an undulating morphology on the CNT channel to form the biosensing interface in the FG CNT-FET biosensor. The undulating morphology was confirmed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and high-resolution transmission electron microscopy (HRTEM), manifesting an interface with a larger specific surface area, which contributes to the probe immobilization, thus widening the linear detection range of the FG CNT-FET biosensors. Furthermore, a desired increment of the electric double-layer (EDL) capacitance was realized because of the larger contact area between the dielectric and electrolyte, and, thereby, the sensitivity of the FG CNT-FET biosensors was enhanced. Indeed, superb detection performance has resulted in a limit of detection (LOD) reaching 72 ag/mL in phosphate-buffered saline (PBS) and 155 ag/mL in fetal bovine serum (FBS), as well as a broad linear range from 1 fg/mL to 1 ng/mL both in simulated buffer solution and serum diluent. Using CEA as the model molecule to verify the excellent sensing performance of the undulating sensing interface, CNT-FET biosensor provides a universal platform for the detection of other ultra-low concentrations of biomolecules, indicating great application potential in the early diagnosis of cancer diseases.
在这项工作中，我们在CNT通道上引入了具有起伏形态的介质Y 2 O 3 ，以形成FG CNT-FET生物传感器中的生物传感界面。通过扫描电子显微镜（SEM）、原子力显微镜（AFM）和高分辨率透射电子显微镜（HRTEM）证实了其起伏形貌，表现出具有较大比表面积的界面，有助于探针固定，从而拓宽了FG CNT-FET生物传感器的线性检测范围。此外，由于电介质和电解质之间的接触面积更大，因此实现了双电层（EDL）电容的预期增量，从而增强了FG CNT-FET 生物传感器的灵敏度。事实上，卓越的检测性能使得磷酸盐缓冲盐水 （PBS） 的检测限 （LOD） 达到 72 ag/mL，胎牛血清 （FBS） 的检测限 （LOD） 达到 155 ag/mL，模拟缓冲液和血清稀释液的线性范围也从 1 fg/mL 到 1 ng/mL。CNT-FET生物传感器以CEA为模型分子，验证了起伏传感接口优异的传感性能，为其他超低浓度生物分子的检测提供了通用平台，在癌症疾病的早期诊断中具有巨大的应用潜力。
在这项工作中，我们在CNT通道上引入了具有起伏形态的介质Y 2 O 3 ，以形成FG CNT-FET生物传感器中的生物传感界面。通过扫描电子显微镜（SEM）、原子力显微镜（AFM）和高分辨率透射电子显微镜（HRTEM）证实了其起伏形貌，表现出具有较大比表面积的界面，有助于探针固定，从而拓宽了FG CNT-FET生物传感器的线性检测范围。此外，由于电介质和电解质之间的接触面积更大，因此实现了双电层（EDL）电容的预期增量，从而增强了FG CNT-FET 生物传感器的灵敏度。事实上，卓越的检测性能使得磷酸盐缓冲盐水 （PBS） 的检测限 （LOD） 达到 72 ag/mL，胎牛血清 （FBS） 的检测限 （LOD） 达到 155 ag/mL，模拟缓冲液和血清稀释液的线性范围也从 1 fg/mL 到 1 ng/mL。CNT-FET生物传感器以CEA为模型分子，验证了起伏传感接口优异的传感性能，为其他超低浓度生物分子的检测提供了通用平台，在癌症疾病的早期诊断中具有巨大的应用潜力。
Experimental Section 实验部分
Chemicals and Materials 化学品和材料
Monoclonal carcinoembryonic antibody (anti-CEA) and CEA were purchased from Abcam Co. Ltd. (UK). Thioglycolic acid (TGA, >95%), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC, 98%), N-hydroxysuccinimide (NHS, 98.5%), and bovine serum albumin (BSA) were provided by Sangon Biotech (Shanghai, China). FBS, Serpin peptidase inhibitor, clade B (ovalbumin), and member 3 Antigen (SERPINB3 Antigen, >85%) were also acquired from Sangon Biotech Co. Ltd. (Shanghai China). CYFRA21-1 (Cytokeratin Fragment) Antigen, Native (>95%) was purchased from EastCoast Bio (USA). Human serum albumin (HSA) and Human serum immunoglobulins (IgG) were purchased from Sigma-Aldrich Co. Ltd. (Shanghai, China). All other chemical reagents used were of electronic grade. The deionized water (18 MΩ/cm) was obtained from a Milli-Q water purification system.
单克隆癌胚抗体（anti-CEA）和CEA购自Abcam Co. Ltd.（英国）。巯基乙醇酸（TGA，>95%）、1-乙基-3-（3-二甲氨基丙基）碳二亚胺盐酸盐（EDC，98%）、N-羟基琥珀酰亚胺（NHS，98.5%）和牛血清白蛋白（BSA）由Sangon Biotech（中国上海）提供。FBS、Serpin肽酶抑制剂、进化枝B（卵清蛋白）和成员3抗原（SERPINB3抗原，>85%）也购自Sangon Biotech Co.， Ltd.（中国上海）。CYFRA21-1（细胞角蛋白片段）抗原，天然 （>95%） 购自 EastCoast Bio（美国）。人血清白蛋白（HSA）和人血清免疫球蛋白（IgG）购自Sigma-Aldrich Co. Ltd.（中国上海）。使用的所有其他化学试剂均为电子级。去离子水（18 MΩ/cm）是从Milli-Q水净化系统获得的。
单克隆癌胚抗体（anti-CEA）和CEA购自Abcam Co. Ltd.（英国）。巯基乙醇酸（TGA，>95%）、1-乙基-3-（3-二甲氨基丙基）碳二亚胺盐酸盐（EDC，98%）、N-羟基琥珀酰亚胺（NHS，98.5%）和牛血清白蛋白（BSA）由Sangon Biotech（中国上海）提供。FBS、Serpin肽酶抑制剂、进化枝B（卵清蛋白）和成员3抗原（SERPINB3抗原，>85%）也购自Sangon Biotech Co.， Ltd.（中国上海）。CYFRA21-1（细胞角蛋白片段）抗原，天然 （>95%） 购自 EastCoast Bio（美国）。人血清白蛋白（HSA）和人血清免疫球蛋白（IgG）购自Sigma-Aldrich Co. Ltd.（中国上海）。使用的所有其他化学试剂均为电子级。去离子水（18 MΩ/cm）是从Milli-Q水净化系统获得的。
Instruments 仪器
The CNT-FET device was prepared with the following equipment: UV lithography machine (EV Group EVG 610, Austria), electron beam evaporation (DE Technology. Inc DE400DHL-EBEAM, Beijing, China), and reactive ion etching (RIE) (Leuven Instruments Co. Ltd LCCP-200A, Jiangsu, China). All electrical tests on FG type CNT-FET devices were performed using a Semiconductor characteristic analyzer (Keithley 4200A-SCS, America) and a probe stage [Form Factor (Cascade) MPS150, America]. The capacitance measurements were achieved by an electrochemical workstation (CHI 660E, Shanghai Chenhua Instruments Co, China). The surface morphology of the Y2O3 was characterized using AFM (Dimension Icon AFM). SEM (ZEISS Sigma 500, Germany) and HRTEM (Thermo Fisher Scientific, Titan Themis Z, America) were used for the surface and structural characterization of the devices.
CNT-FET器件采用以下设备制备：UV光刻机（EV Group EVG 610，奥地利），电子束蒸发（DE Technology.Inc DE400DHL-EBEAM，中国北京）和反应离子蚀刻（RIE）（鲁汶仪器有限公司LCCP-200A，中国江苏）。FG 型 CNT-FET 器件的所有电气测试均使用半导体特性分析仪（Keithley 4200A-SCS，美国）和探头台 [Form Factor （Cascade） MPS150， America] 进行。电容测量是通过电化学工作站（CHI 660E，上海晨华仪器有限公司，中国）完成的。使用AFM（Dimension Icon AFM）表征了Y 2 O 3 的表面形貌。SEM（蔡司 Sigma 500，德国）和 HRTEM（赛默飞世尔科技，Titan Themis Z，美国）用于设备的表面和结构表征。
CNT-FET器件采用以下设备制备：UV光刻机（EV Group EVG 610，奥地利），电子束蒸发（DE Technology.Inc DE400DHL-EBEAM，中国北京）和反应离子蚀刻（RIE）（鲁汶仪器有限公司LCCP-200A，中国江苏）。FG 型 CNT-FET 器件的所有电气测试均使用半导体特性分析仪（Keithley 4200A-SCS，美国）和探头台 [Form Factor （Cascade） MPS150， America] 进行。电容测量是通过电化学工作站（CHI 660E，上海晨华仪器有限公司，中国）完成的。使用AFM（Dimension Icon AFM）表征了Y 2 O 3 的表面形貌。SEM（蔡司 Sigma 500，德国）和 HRTEM（赛默飞世尔科技，Titan Themis Z，美国）用于设备的表面和结构表征。
Fabrication of CNT-FET Devices with Undulating Y2O3 Interfaces
具有波浪 Y 2 O 3 接口的 CNT-FET 器件的制造
The preparation process of the undulating Y2O3 interface CNT-FET is shown in Figure S1 I–VI. The source-drain electrode region was formed by UV lithography on a Si/SiO2 substrate, and then the Ti/Pd/Au electrode (Ti/Pd/Au = 0.6/20/60 nm) was prepared by electron beam vapor deposition. Subsequently, the excess CNT outside the source-drain electrode was etched off by RIE. The dielectric gate layer was vaporized at 3 nm yttrium, which was oxidized into Y2O3 and exposed to air for 30 min on a hot plate at 270 °C. To prepare the undulating Y2O3 interface, the device was immersed in the electrolyte (0.1× PBS) and then treated with electro-corrosion under −1.5 V gate voltage. It should be noted here that an undulating Y2O3 interface device was prepared for comparison, and to avoid possible electro-corrosion during the electrical measuring process, all the testing was implemented in the 0.01× PBS solution with less than −0.6 V gate voltage. The Au nanoparticles (Au NPs) as the linker between the sensing surface and the antibody were prepared directly by thermal vapor deposition using an electron beam coater. The prepared CNT-FET devices were passivated with photoresist S1813 and stored in a vacuum environment.
起伏的Y 2 O 3 界面CNT-FET的制备过程如图S1 I–VI所示。在Si/SiO 2 衬底上采用UV光刻法形成源漏电极区，然后采用电子束气相沉积法制备Ti/Pd/Au电极（Ti/Pd/Au = 0.6/20/60 nm）。随后，RIE将源极-漏极外过量的CNT蚀刻掉。介电栅极层在3nm钇下汽化，钇被氧化成Y 2 O 3 ，并在270°C的热板上暴露于空气中30分钟。 为了制备起伏的Y 2 O 3 界面，将器件浸入电解液（0.1× PBS）中，然后在−1.5 V栅极电压下进行电腐蚀处理。这里应该注意的是，准备了一个起伏的Y 2 O 3 接口器件进行比较，为了避免在电气测量过程中可能发生的电腐蚀，所有测试都是在0.01× PBS溶液中进行的，栅极电压小于−0.6 V。使用电子束涂布机直接通过热气相沉积制备了作为传感表面与抗体之间的连接体的Au纳米颗粒（Au NPs）。制备的CNT-FET器件用光刻胶S1813钝化，并储存在真空环境中。
起伏的Y 2 O 3 界面CNT-FET的制备过程如图S1 I–VI所示。在Si/SiO 2 衬底上采用UV光刻法形成源漏电极区，然后采用电子束气相沉积法制备Ti/Pd/Au电极（Ti/Pd/Au = 0.6/20/60 nm）。随后，RIE将源极-漏极外过量的CNT蚀刻掉。介电栅极层在3nm钇下汽化，钇被氧化成Y 2 O 3 ，并在270°C的热板上暴露于空气中30分钟。 为了制备起伏的Y 2 O 3 界面，将器件浸入电解液（0.1× PBS）中，然后在−1.5 V栅极电压下进行电腐蚀处理。这里应该注意的是，准备了一个起伏的Y 2 O 3 接口器件进行比较，为了避免在电气测量过程中可能发生的电腐蚀，所有测试都是在0.01× PBS溶液中进行的，栅极电压小于−0.6 V。使用电子束涂布机直接通过热气相沉积制备了作为传感表面与抗体之间的连接体的Au纳米颗粒（Au NPs）。制备的CNT-FET器件用光刻胶S1813钝化，并储存在真空环境中。
Antibody Immobilization on the CNT-FET Devices
CNT-FET设备上的抗体固定化
For the immobilization of CEA antibody on CNTs, based on the previous method, (38) the following steps need to be completed (Figure S1 VII–IX). In detail, 10 μL of TGA solution (10 mM) was first dropped onto each of the surfaces of the prepared CNT-FET devices and incubated overnight at room temperature, ensuring that the TGA was immobilized on the surface of AuNPs by forming an Au–S bond. Then, the devices were washed with 1× PBS solution and deionized water and dried under nitrogen. Next, the mixture (equal volume mixture of 0.4 M EDC and 0.1 M NHS) was incubated on the above CNT-FET devices for 30 min at 4 °C to activate the carboxyl group of TGA, then washed repeatedly and dried under nitrogen. Consequently, 10 μL of the anti-CEA solution (100 μg/mL) was introduced into the CNT-FET devices and incubated overnight at 4 °C. After washing with the PBS solution containing 0.2% SDS, 1× PBS, and deionized water, BSA solution (0.1%) was added to the above CNT-FET devices to block the nonspecific binding sites. Finally, the functionalized CNT-FET devices were washed with 1× PBS and deionized water and dried under nitrogen.
为了在CNT上固定CEA抗体，基于先前的方法，（38）需要完成以下步骤（图S1 VII-IX）。详细地说，首先将 10 μL TGA 溶液 （10 mM） 滴到制备的 CNT-FET 器件的每个表面上，并在室温下孵育过夜，确保 TGA 通过形成 Au-S 键固定在 AuNP 表面。然后，用1× PBS溶液和去离子水洗涤器件，并在氮气下干燥。接下来，将混合物（0.4 M EDC和0.1 M NHS的等体积混合物）在上述CNT-FET装置上在4°C下孵育30分钟以活化TGA的羧基，然后反复洗涤并在氮气下干燥。因此，将 10 μL 抗 CEA 溶液 （100 μg/mL） 引入 CNT-FET 器件并在 4 °C 下孵育过夜。 用含有0.2%SDS、1× PBS的PBS溶液和去离子水洗涤后，将BSA溶液（0.1%）加入上述CNT-FET器件中，以阻断非特异性结合位点。最后，用1× PBS和去离子水洗涤功能化的CNT-FET器件，并在氮气下干燥。
为了在CNT上固定CEA抗体，基于先前的方法，（38）需要完成以下步骤（图S1 VII-IX）。详细地说，首先将 10 μL TGA 溶液 （10 mM） 滴到制备的 CNT-FET 器件的每个表面上，并在室温下孵育过夜，确保 TGA 通过形成 Au-S 键固定在 AuNP 表面。然后，用1× PBS溶液和去离子水洗涤器件，并在氮气下干燥。接下来，将混合物（0.4 M EDC和0.1 M NHS的等体积混合物）在上述CNT-FET装置上在4°C下孵育30分钟以活化TGA的羧基，然后反复洗涤并在氮气下干燥。因此，将 10 μL 抗 CEA 溶液 （100 μg/mL） 引入 CNT-FET 器件并在 4 °C 下孵育过夜。 用含有0.2%SDS、1× PBS的PBS溶液和去离子水洗涤后，将BSA溶液（0.1%）加入上述CNT-FET器件中，以阻断非特异性结合位点。最后，用1× PBS和去离子水洗涤功能化的CNT-FET器件，并在氮气下干燥。
Detection of CEA CEA检测
The CEA solution with different concentrations (1 fg/mL to 1 ng/mL) was dropped onto the CNT-FET devices and incubated for 1 h at room temperature. Subsequently, the CNT-FET devices were repeatedly cleaned with PBS solution and deionized water, and dried under nitrogen. Then, the transfer characteristic curves were recorded using the Keithley 4200A-SCS device with 0.01× PBS (pH 7.4) as the FG, a silver wire (0.4 mm diameter) as the reference electrode, and a constant bias (Vds = −0.1 V) in all transfer curve tests. In addition, the proposed CNT-FET biosensors were also performed for CEA detection in FBS samples. Different concentrations of CEA were first introduced into the serum samples to obtain CEA-spiked FBS samples (10%). The detection of CEA in FBS samples followed the above procedures in the buffer.
将不同浓度（1 fg/mL 至 1 ng/mL）的 CEA 溶液滴入 CNT-FET 器件并在室温下孵育 1 小时。随后，用PBS溶液和去离子水反复清洗CNT-FET器件，并在氮气下干燥。然后，使用Keithley 4200A-SCS器件记录转移特性曲线，其中0.01× PBS（pH 7.4）作为FG，银线（直径0.4 mm）作为参比电极，在所有传输曲线测试中采用恒定偏置（V ds = −0.1 V）。此外，还对所提出的CNT-FET生物传感器进行了FBS样品的CEA检测。首先将不同浓度的 CEA 引入血清样本中，以获得 CEA 加标的 FBS 样品 （10%）。FBS样品中CEA的检测遵循上述程序在缓冲液中。
将不同浓度（1 fg/mL 至 1 ng/mL）的 CEA 溶液滴入 CNT-FET 器件并在室温下孵育 1 小时。随后，用PBS溶液和去离子水反复清洗CNT-FET器件，并在氮气下干燥。然后，使用Keithley 4200A-SCS器件记录转移特性曲线，其中0.01× PBS（pH 7.4）作为FG，银线（直径0.4 mm）作为参比电极，在所有传输曲线测试中采用恒定偏置（V ds = −0.1 V）。此外，还对所提出的CNT-FET生物传感器进行了FBS样品的CEA检测。首先将不同浓度的 CEA 引入血清样本中，以获得 CEA 加标的 FBS 样品 （10%）。FBS样品中CEA的检测遵循上述程序在缓冲液中。
Capacitance Measurements 电容测量
The capacitance measurement of this FG CNT-FET device with an undulating or flat Y2O3 dielectric layer was performed based on another group’s work (39) and the schematic of the testing is displayed in Figure S2. Cyclic voltammetry (CV) was chosen for the characterization method, through an electrochemical workstation (CHI 660E, Shanghai Chenhua, China) with three electrodes, including a reference, counter, and working electrodes. Here, silver chloride (Ag/AgCl), platinum (Pt), and gold electrodes with an attached Y2O3 layer were used as the reference, counter, and working electrodes, respectively.
该FG CNT-FET器件具有起伏或平坦的YO 2 3 介质层，其电容测量基于另一组的工作（39），测试示意图如图S2所示。选择循环伏安法（CV）作为表征方法，通过电化学工作站（CHI 660E，中国上海晨华）具有三个电极，包括参比电极、计数器电极和工作电极。在这里，氯化银 （Ag/AgCl）、铂 （Pt） 和带有 Y 2 O 3 层的金电极分别用作参比电极、计数器电极和工作电极。
该FG CNT-FET器件具有起伏或平坦的YO 2 3 介质层，其电容测量基于另一组的工作（39），测试示意图如图S2所示。选择循环伏安法（CV）作为表征方法，通过电化学工作站（CHI 660E，中国上海晨华）具有三个电极，包括参比电极、计数器电极和工作电极。在这里，氯化银 （Ag/AgCl）、铂 （Pt） 和带有 Y 2 O 3 层的金电极分别用作参比电极、计数器电极和工作电极。
The final results reported were averaged relative responses of eight devices with standard deviation (SD) as error bars. The number of devices (n) tested for each experiment was specified in the figure.
报告的最终结果是以标准差 （SD） 为误差线的 8 个设备的平均相对响应。图中指定了每个实验测试的设备数量（n）。
报告的最终结果是以标准差 （SD） 为误差线的 8 个设备的平均相对响应。图中指定了每个实验测试的设备数量（n）。
Results and Discussion 结果与讨论
Device Structure and Sensing Mechanism
器件结构及传感机理
The schematic diagram of the undulating FG CNT-FET biosensor device is shown in Figure 1a, which presents a typical FG CNT-FET device with an undulating biosensing interface. Figure 1b shows each component of a single CNT-FET device. The SEM displays the CNT uniformly deposited on the substrate, with a channel length of 20 μm and a channel width of 40 μm shown between the source and drain electrodes. Moreover, the 3D AFM image shows the true morphology of undulating Y2O3. The current of a CNT-FET decreases significantly after adding undulating Y2O3 as a biosensing interface (Figure S3) mainly because of the increase in the equivalent gate capacitance caused by the presence of Y2O3. The sensing mechanism indicated in Figure 1c can be explained utilizing bandgap theory, being consistent with traditional FG CNT-FET biosensors. This demonstrated that the undulating interface had no local effect on the energy band of the CNT channel. CEA has an isoelectric point lower than the pH of the test environment, so it has a negative charge. In the case of the p-channel CNT-FET, negatively charged biomolecules adsorb at the sensor interface, causing the band to bend upward and holes to accumulate in the CNT channel, resulting in an increase in the current observed at CNT-FET. It should be noted here that although the differences in the gate dielectric thickness in the local area cause a difference in carrier concentration, the following carrier diffusion process would eliminate this difference. The electrical properties of the CNT-FETs are displayed in Figure 1d. The transfer characteristic curve exhibited p-channel FET characteristics with a current on/off ratio as high as 105 and a subthreshold slope up to 80 mV/dec, indicating perfect semiconductor purity of the CNT channel and excellent gate efficiency of this FG transistor. The room-temperature output characteristic curve (Figure 1e) displayed the linear variation of current with voltage, indicating the well-Ohmic contact between the CNT channel and the metal electrode. The same bias measurements (Figure 1f) showed that the device could provide long-term stability for sensor applications.
起伏的FG CNT-FET生物传感器器件示意图如图1A所示，该器件是具有起伏生物传感接口的典型FG CNT-FET器件。图1b显示了单个CNT-FET器件的每个组件。SEM显示均匀沉积在基板上的碳纳米管，源极和漏极之间的沟道长度为20 μm，沟道宽度为40 μm。此外，3D AFM图像显示了起伏的Y 2 O 3 的真实形态。添加起伏的Y 2 O 3 作为生物传感界面后，CNT-FET的电流显着降低（图S3），主要是因为YO 2 3 的存在导致等效栅极电容的增加。图1c所示的传感机制可以用带隙理论来解释，与传统的FG CNT-FET 生物传感器一致。这说明起伏界面对CNT通道的能带没有局部影响。CEA的等电点低于测试环境的pH值，因此它带有负电荷。在p沟道CNT-FET的情况下，带负电荷的生物分子吸附在传感器界面处，导致条带向上弯曲，空穴积聚在CNT沟道中，导致在CNT-FET处观察到的电流增加。这里应该注意的是，尽管局部区域栅极介电厚度的差异会导致载流子浓度的差异，但以下载流子扩散过程将消除这种差异。CNT-FET的电气特性如图1d所示。 传输特性曲线表现出p沟道FET特性，电流开/关比高达10 5 ，亚阈值斜率高达80 mV/dec，表明该FG晶体管具有完美的半导体纯度和出色的栅极效率。室温输出特性曲线（图1e）显示了电流随电压的线性变化，表明CNT通道与金属电极之间的良好欧姆接触。相同的偏置测量（图1f）表明，该器件可以为传感器应用提供长期稳定性。
起伏的FG CNT-FET生物传感器器件示意图如图1A所示，该器件是具有起伏生物传感接口的典型FG CNT-FET器件。图1b显示了单个CNT-FET器件的每个组件。SEM显示均匀沉积在基板上的碳纳米管，源极和漏极之间的沟道长度为20 μm，沟道宽度为40 μm。此外，3D AFM图像显示了起伏的Y 2 O 3 的真实形态。添加起伏的Y 2 O 3 作为生物传感界面后，CNT-FET的电流显着降低（图S3），主要是因为YO 2 3 的存在导致等效栅极电容的增加。图1c所示的传感机制可以用带隙理论来解释，与传统的FG CNT-FET 生物传感器一致。这说明起伏界面对CNT通道的能带没有局部影响。CEA的等电点低于测试环境的pH值，因此它带有负电荷。在p沟道CNT-FET的情况下，带负电荷的生物分子吸附在传感器界面处，导致条带向上弯曲，空穴积聚在CNT沟道中，导致在CNT-FET处观察到的电流增加。这里应该注意的是，尽管局部区域栅极介电厚度的差异会导致载流子浓度的差异，但以下载流子扩散过程将消除这种差异。CNT-FET的电气特性如图1d所示。 传输特性曲线表现出p沟道FET特性，电流开/关比高达10 5 ，亚阈值斜率高达80 mV/dec，表明该FG晶体管具有完美的半导体纯度和出色的栅极效率。室温输出特性曲线（图1e）显示了电流随电压的线性变化，表明CNT通道与金属电极之间的良好欧姆接触。相同的偏置测量（图1f）表明，该器件可以为传感器应用提供长期稳定性。
Figure 1 图1
Figure 1. (a) Schematic diagram of the three-dimensional undulating FG CNT-FET biosensor. (b) SEM and AFM images of a CNT-FET biosensor with the major sensing regions and morphology of the undulating Y2O3. (c) Changes of the energy band diagram of sensors with undulating Y2O3 structures before (blue curve) and after (red curve) the introduction of biomolecules. (d) Transfer characteristics of an undulating FG CNT- FET. (e) Output properties of an undulating FG CNT-FET. (f) Transfer characteristics of an undulating FG CNT-FET at different times under the same bias voltage.
图 1.（a） 三维起伏FG CNT-FET生物传感器示意图。（b） CNT-FET生物传感器的SEM和AFM图像，以及起伏的Y 2 O 3 的主要感应区域和形态。（c）在引入生物分子之前（蓝色曲线）和之后（红色曲线）具有起伏的Y 2 O 3 结构的传感器的能带图的变化。（d） 起伏FG CNT-FET的转移特性。（e） 波动FG CNT-FET的输出特性。（f） 在相同偏置电压下不同时间波动的FG CNT-FET的传输特性。
The micromorphology of the undulating interface was represented by SEM, HRTEM, and AFM. First, the top view images of flat and undulating Y2O3 on the CNT were observed by SEM, as shown in Figure 2a,b. The inset images depict a cross-section of the two interfaces captured with HRTEM. The Y2O3 thin film was able to densely wrap the CNT surface before electrochemical corrosion, revealing a continuous polycrystalline structure with densely arranged atoms. Only the irregular morphology signs can be observed after corrosion, and the HRTEM image indicates a clear undulating contour of the Y2O3 thin film. It should be noted that the network CNT under the Y2O3 cannot be recognized in HRTEM because it appears network-like and cannot be sliced completely perpendicular to the direction of the CNT during the dual-beam focused ion beam-SEM (FIB-SEM) preparation, and the CNT was proven to be real by mapping analysis (Figure S4). The AFM images revealed the interface morphology in a wider field of view, indicating interfacial topography fluctuations of 12.52 ± 3.79 and 2.59 ± 1.35 nm (Figure S5) for the undulating and flat Y2O3 samples, respectively. Although it is difficult to calculate the difference in specific surface area between the two interfaces, we can find out that the undulating interface has a larger specific surface area than the flat interface.
起伏界面的微观形貌由SEM、HRTEM和AFM表示。首先，通过SEM观察CNT上平坦起伏的Y 2 O 3 的顶视图图像，如图2a，b所示。插图描绘了使用 HRTEM 捕获的两个界面的横截面。在电化学腐蚀之前，Y 2 O 3 薄膜能够密集包裹CNT表面，显示出具有密集排列原子的连续多晶结构。腐蚀后只能观察到不规则的形貌征象，HRTEM图像显示Y 2 O 3 薄膜有清晰的起伏轮廓。需要注意的是，在双束聚焦离子束-SEM（FIB-SEM）制备过程中，由于在双束聚焦离子束-SEM（FIB-SEM）制备过程中，Y 2 O 3 下的网络CNT无法被识别，因为它看起来像网络一样，不能完全垂直于CNT的方向进行切片，并且通过映射分析证明了CNT是真实的（图S4）。AFM图像揭示了更宽视场的界面形貌，表明起伏和平坦的Y 2 O 3 样品的界面形貌波动分别为12.52±3.79和2.59±1.35 nm（图S5）。虽然很难计算出两个界面之间比表面积的差异，但我们可以发现，起伏界面比平面界面具有更大的比表面积。
起伏界面的微观形貌由SEM、HRTEM和AFM表示。首先，通过SEM观察CNT上平坦起伏的Y 2 O 3 的顶视图图像，如图2a，b所示。插图描绘了使用 HRTEM 捕获的两个界面的横截面。在电化学腐蚀之前，Y 2 O 3 薄膜能够密集包裹CNT表面，显示出具有密集排列原子的连续多晶结构。腐蚀后只能观察到不规则的形貌征象，HRTEM图像显示Y 2 O 3 薄膜有清晰的起伏轮廓。需要注意的是，在双束聚焦离子束-SEM（FIB-SEM）制备过程中，由于在双束聚焦离子束-SEM（FIB-SEM）制备过程中，Y 2 O 3 下的网络CNT无法被识别，因为它看起来像网络一样，不能完全垂直于CNT的方向进行切片，并且通过映射分析证明了CNT是真实的（图S4）。AFM图像揭示了更宽视场的界面形貌，表明起伏和平坦的Y 2 O 3 样品的界面形貌波动分别为12.52±3.79和2.59±1.35 nm（图S5）。虽然很难计算出两个界面之间比表面积的差异，但我们可以发现，起伏界面比平面界面具有更大的比表面积。
Figure 2 图2
Figure 2. Morphology characterizations of biosensing interfaces. SEM images of (a) flattened and (b) corroded Y2O3 layer. Inset: Flat and undulating Y2O3 taken by HRTEM. (c,d) AFM images of the cross-section of flattened and undulating Y2O3 layers.
图2.生物传感界面的形态学表征。（a）扁平和（b）腐蚀的Y 2 O 3 层的SEM图像。插图：HRTEM拍摄的平坦起伏的Y 2 O 3 。（c，d）扁平和起伏的 Y 2 O 3 层横截面的 AFM 图像。
To verify whether the undulating Y2O3 can contribute to the immobilization of probes, we tested and counted the number of Au NPs on flat and undulating Y2O3 surfaces and the fluorescence intensity of adsorbed fluorescent-labeled CEA antibodies. More Au NPs provide more binding sites for antibody immobilization, and fluorescence intensity analysis can also demonstrate that the undulating Y2O3 interface adsorbs more antibodies. Moreover, we tested and compared the transfer characteristic curves of the CNT-FET device with flat and undulating Y2O3 before and after probe assembly, as shown in Figure 3a,b. The change of the threshold voltage (ΔVth) was extracted and statistically plotted in the inset chart. Based on the response mechanism of the CNT-FET biosensor and Langmuir adsorption isotherms model, ΔVth is positively correlated with the number of molecules adsorbed on the sensing interface. It should be noted here that the change of the channel current cannot reflect the difference in the number of adsorbed molecules on the two interfaces, which is due to the difference in the gate efficiency of the two FET devices. These results showed that the ΔVth of the undulating Y2O3 device is twice that of the flat Y2O3 device, demonstrating twice the number of assembled probes in the undulating interface compared to the flat interface. By combining this with the microscope characterization, we can attribute the optimization of probe immobilization to the increment of the specific surface area of the biosensing interface.
为了验证起伏的 Y 2 O 3 是否有助于探针的固定，我们测试并计算了平坦和起伏的 Y 2 O 3 表面上的 Au NP 数量以及吸附荧光标记的 CEA 抗体的荧光强度。更多的Au NPs为抗体固定提供了更多的结合位点，荧光强度分析也可以证明起伏的Y 2 O 3 界面吸附更多的抗体。此外，我们测试并比较了 CNT-FET 器件在探头组装前后平坦起伏的 Y 2 O 3 的传输特性曲线，如图 3a、b 所示。提取阈值电压（ΔV th ）的变化，并在插图中统计绘制。基于CNT-FET生物传感器和Langmuir吸附等温线模型的响应机制，ΔV th 与吸附在传感界面上的分子数量呈正相关。这里需要注意的是，沟道电流的变化并不能反映两个界面上吸附分子数量的差异，这是由于两个FET器件的栅极效率不同所致。结果表明，起伏 Y 2 O 器件的 ΔV th 是扁平 Y 2 O 3 器件的 2 倍，与扁平界面相比，波起伏界面中的组装探头数量是其两 3 倍。通过将其与显微镜表征相结合，我们可以将探针固定化的优化归因于生物传感界面比表面积的增加。
为了验证起伏的 Y 2 O 3 是否有助于探针的固定，我们测试并计算了平坦和起伏的 Y 2 O 3 表面上的 Au NP 数量以及吸附荧光标记的 CEA 抗体的荧光强度。更多的Au NPs为抗体固定提供了更多的结合位点，荧光强度分析也可以证明起伏的Y 2 O 3 界面吸附更多的抗体。此外，我们测试并比较了 CNT-FET 器件在探头组装前后平坦起伏的 Y 2 O 3 的传输特性曲线，如图 3a、b 所示。提取阈值电压（ΔV th ）的变化，并在插图中统计绘制。基于CNT-FET生物传感器和Langmuir吸附等温线模型的响应机制，ΔV th 与吸附在传感界面上的分子数量呈正相关。这里需要注意的是，沟道电流的变化并不能反映两个界面上吸附分子数量的差异，这是由于两个FET器件的栅极效率不同所致。结果表明，起伏 Y 2 O 器件的 ΔV th 是扁平 Y 2 O 3 器件的 2 倍，与扁平界面相比，波起伏界面中的组装探头数量是其两 3 倍。通过将其与显微镜表征相结合，我们可以将探针固定化的优化归因于生物传感界面比表面积的增加。
Figure 3 图3
Figure 3. Transfer characteristics of flat (a) and undulating (b) biosensing interfaces before (red curve) and after (blue curve) introduction of the antibodies. Insets: The threshold voltage shift (ΔVth) after the introduction of antibodies for eight groups of FET devices at different biosensing interfaces. The total capacitance of (c) flat and (d) undulating Y2O3 (scanning speed of 20, 50, 80, 120, and 200 mV/s, respectively).
图3.平坦（a）和起伏（b）生物传感界面在（红色曲线）和之后（蓝色曲线）引入抗体的转移特性。插图：在不同生物传感界面上为八组 FET 器件引入抗体后的阈值电压偏移 （ΔV th ）。（c）平坦和（d）起伏的Y 2 O 3 的总电容（扫描速度分别为20、50、80、120和200 mV/s）。
More importantly, a change in surface morphology can induce an extra EDL capacitance increment. The capacitance was measured by CV (the experimental setup diagram is shown in Figure S2), which was utilized to determine the normalized total capacitance of the FG CNT-FET biosensors with undulating and flat sensing areas, as shown in Figure 3c,d, respectively. This indicated that the total capacitance of the undulating device was increased by 50%. The total capacitance or gate capacitance Cgate is composed of three capacitances connected in series: the quantum capacitance CQ, (40,41) the gate oxide layer capacitance Cox, and the electrical double layer capacitance CEDL at the Y2O3 interface in contact with the electrolyte solution, the equivalent circuit diagram is shown in Figure S7. It is very difficult to precisely capture or distinguish these three capacitances; however, this study focused more on the differences in total capacitances between these two types of devices. According to previous works, (40,41) the CQ originated from the finite density of states in the CNT channel and the extra energy required to pump carriers to the states with high energy, which depends on the dielectric constant and thickness of the oxide layer, and the CEDL is primarily determined by the specific surface area of the solid–liquid interface. Considering both flat and undulating interface devices consisting of the same CNT and Y2O3 materials and the obvious difference in surface morphology, the increment in the total capacitance mainly derives from the larger specific surface area of the undulating interface.
更重要的是，表面形态的变化会引起额外的EDL电容增量。电容通过CV测量（实验设置图如图S2所示），用于确定具有起伏和平坦传感区域的FG CNT-FET生物传感器的归一化总电容，分别如图3c，d所示。这表明起伏器件的总电容增加了50%。总电容或栅极电容C gate 由三个电容串联而成：量子电容C Q 、栅极氧化层 ox 电容C、双电层电容C EDL 在Y 2 O 3 界面处与电解质溶液接触，等效电路图如图S7所示。要精确捕获或区分这三个电容是非常困难的;然而，这项研究更多地关注这两种器件之间总电容的差异。根据以往的研究，（40,41）C Q 起源于CNT通道中的有限态密度以及将载流子泵送到高能态所需的额外能量，这取决于氧化层的介电常数和厚度，而C EDL 主要由固液界面的比表面积决定。考虑到由相同的CNT和Y 2 O 3 材料组成的平面和起伏界面器件以及表面形貌的明显差异，总电容的增加主要来源于起伏界面的比表面积越大。
更重要的是，表面形态的变化会引起额外的EDL电容增量。电容通过CV测量（实验设置图如图S2所示），用于确定具有起伏和平坦传感区域的FG CNT-FET生物传感器的归一化总电容，分别如图3c，d所示。这表明起伏器件的总电容增加了50%。总电容或栅极电容C gate 由三个电容串联而成：量子电容C Q 、栅极氧化层 ox 电容C、双电层电容C EDL 在Y 2 O 3 界面处与电解质溶液接触，等效电路图如图S7所示。要精确捕获或区分这三个电容是非常困难的;然而，这项研究更多地关注这两种器件之间总电容的差异。根据以往的研究，（40,41）C Q 起源于CNT通道中的有限态密度以及将载流子泵送到高能态所需的额外能量，这取决于氧化层的介电常数和厚度，而C EDL 主要由固液界面的比表面积决定。考虑到由相同的CNT和Y 2 O 3 材料组成的平面和起伏界面器件以及表面形貌的明显差异，总电容的增加主要来源于起伏界面的比表面积越大。
The FET biosensor is a capacitance coupling device whose sensitivity is related to the gate capacitance and can be described by the following formula
FET生物传感器是一种电容耦合器件，其灵敏度与栅极电容有关，可以用以下公式来描述where Vth is the threshold voltage, k is the Boltzmann constant, T is the thermodynamic temperature, q is the electron charge, CQ is the quantum capacitance, Cox is the gate oxide capacitance, and CEDL is the EDL capacitance. Hence, for the undulating interface device, a larger EDL capacitance means a larger carrier (hole) concentration change of the CNT channel achieved under the same field-effect modulation, eventually leading to the sensitivity improvement of the FET biosensor. In addition, the larger specific surface area can endow more sites to accommodate the probe, allowing for more probe-target-specific binding processes and broadening the linear range of the FET biosensor. Therefore, we can deduce that the sensing properties of the undulating Y2O3 CNT-FET biosensor would be better than the flat one.
其中 V th 是阈值电压，k 是玻尔兹曼常数，T 是热力学温度，q 是电子电荷，C Q 是量子电容，C ox 是栅极氧化物电容，C EDL 是 EDL 电容。因此，对于起伏接口器件，EDL电容越大，意味着在相同的场效应调制下，CNT通道的载流子（空穴）浓度变化越大，最终导致FET生物传感器的灵敏度提高。此外，更大的比表面积可以赋予更多的位点来容纳探针，从而允许更多的探针靶标特异性结合过程，并拓宽FET生物传感器的线性范围。因此，我们可以推断出起伏的Y 2 O 3 CNT-FET生物传感器的传感性能会优于扁平的生物传感器。
FET生物传感器是一种电容耦合器件，其灵敏度与栅极电容有关，可以用以下公式来描述
其中 V th 是阈值电压，k 是玻尔兹曼常数，T 是热力学温度，q 是电子电荷，C Q 是量子电容，C ox 是栅极氧化物电容，C EDL 是 EDL 电容。因此，对于起伏接口器件，EDL电容越大，意味着在相同的场效应调制下，CNT通道的载流子（空穴）浓度变化越大，最终导致FET生物传感器的灵敏度提高。此外，更大的比表面积可以赋予更多的位点来容纳探针，从而允许更多的探针靶标特异性结合过程，并拓宽FET生物传感器的线性范围。因此，我们可以推断出起伏的Y 2 O 3 CNT-FET生物传感器的传感性能会优于扁平的生物传感器。
Sensitivity and Specificity
敏感性和特异性
Moreover, to demonstrate the superiority of the undulating interface device, the sensing performance (CEA detection) of the proposed CNT-FET biosensor was measured by the Keithley 4200A-SCS device. The detection mechanism of the proposed CNT-FET biosensor is illustrated in Figure 1c. The AuNPs of the FG can be conveniently modified with the antibodies on the surface and used for CEA detection. We characterized the immobilization of antibodies and binding of antibody-antigen using AFM and electrical measurements (Figure S8). AFM height images (Figure S8a,b) show that, with the addition of the anti-CEA, the surface height increased from 4.48 to 15.2 nm, increasing 10.72 nm, which was consistent with the results in the literature. (25) The root-mean-square roughness of the channel region increases significantly from 1.60 to 5.02 nm. In summary, the CNT-FET biosensor has successfully constructed a specific identification platform to ensure the effectiveness of the CEA detection process. The small changes in height and roughness after antigen and antibody demonstrated in Figure S8c,f are because the antigen is bound to the Fab fragment of the antibody.
此外，为了证明起伏接口器件的优越性，使用Keithley 4200A-SCS器件测量了所提出的CNT-FET生物传感器的传感性能（CEA检测）。所提出的CNT-FET生物传感器的检测机理如图1c所示。FG的AuNPs可以方便地用表面的抗体修饰，并用于CEA检测。我们使用AFM和电测量表征了抗体的固定和抗体-抗原的结合（图S8）。AFM高度图像（图S8a，b）显示，随着抗CEA的加入，表面高度从4.48 nm增加到15.2 nm，增加了10.72 nm，这与文献结果一致。（25） 通道区域的均方根粗糙度从 1.60 nm 显着增加到 5.02 nm。综上所述，CNT-FET生物传感器成功构建了特定的识别平台，保证了CEA检测过程的有效性。图S8c，f所示的抗原和抗体后高度和粗糙度的微小变化是因为抗原与抗体的Fab片段结合。
此外，为了证明起伏接口器件的优越性，使用Keithley 4200A-SCS器件测量了所提出的CNT-FET生物传感器的传感性能（CEA检测）。所提出的CNT-FET生物传感器的检测机理如图1c所示。FG的AuNPs可以方便地用表面的抗体修饰，并用于CEA检测。我们使用AFM和电测量表征了抗体的固定和抗体-抗原的结合（图S8）。AFM高度图像（图S8a，b）显示，随着抗CEA的加入，表面高度从4.48 nm增加到15.2 nm，增加了10.72 nm，这与文献结果一致。（25） 通道区域的均方根粗糙度从 1.60 nm 显着增加到 5.02 nm。综上所述，CNT-FET生物传感器成功构建了特定的识别平台，保证了CEA检测过程的有效性。图S8c，f所示的抗原和抗体后高度和粗糙度的微小变化是因为抗原与抗体的Fab片段结合。
In addition, before attaching CEA to the interface of the functionalized CNT-FET device (see Experimental Section), the device displayed a weak drain–source current (Ids) value, while there was a significant increase in Ids after the specific binding of the negatively charged CEA (in PBS buffer, pH 7.4) and antibodies. Figure 4a,b shows the current responses of the undulating and flat Y2O3 devices with different concentrations of CEA, respectively. For the flat Y2O3 device in low CEA concentration (1–10 fg/mL), it can normally respond to the captured CEA. However, in high concentrations (100 fg/mL to 1 ng/mL), the change of channel current was a bit small, especially in 100 pg/mL and 1 ng/mL, the channel current was almost the same. There are two theoretical explanations for this abnormal result: the saturation of the binding site due to the lack of probes and a steric hindrance effect, both of which reflect the fact that a poor biosensing interface cannot satisfy the requirements of the high-performance biosensor. For the undulating Y2O3 interface CNT-FET biosensor, as shown in Figure 4b, the Ids with the continuous increase in addition of CEA ranging from 1 fg/mL to 1 ng/mL, exhibited excellent sensitivity with a large signal response and a wide linear range. We attributed this performance to CEA detection at the undulating interface of the CNT-FET biosensor. As mentioned above, a larger specific surface area of the biosensing interface can assemble more probes and reduce the steric hindrance effect, thus realizing an expansion of the linear range and a larger EDL capacitance means this device can yield a larger signal response to the captured CEA. In addition, the increment of the captured target can also induce an extra variation of channel current. Figure 4c displays the relationship between the values (ΔI/I0) and the concentration of CEA for the proposed CNT-FET biosensor including the undulating and flat Y2O3 gate interface. Herein, the ΔI (ΔI = Ids – Ids0) value was represented as the change of Ids, where I and I0 were the Ids values of the CNT-FET biosensor in the presence and absence of CEA, respectively. A more intuitive result reflects the improvement of the device’s performance. The signal response in the undulating device reached 300% with good linearity from 1 fg/mL to 1 ng/mL CEA, manifesting a considerable performance boost compared with the flat device. Furthermore, a lower LOD can be calibrated for the optimized device as low as 72 ag/mL. The detection limit and linear range were also compared to those of previous reports (Figure S9 and Table S1), showing that the proposed CNT-FET biosensor with an undulating interface had excellent sensitivity and a wide linear range to CEA.
此外，在将CEA连接到功能化CNT-FET器件的接口（参见实验部分）之前，该器件显示出微弱的漏源电流（I ds ）值，而在带负电荷的CEA（在PBS缓冲液中，pH 7.4）和抗体特异性结合后，I ds 值显着增加。图4a，b分别显示了不同浓度CEA的起伏和扁平Y 2 O 3 器件的电流响应。对于低 CEA 浓度 （1–10 fg/mL） 的扁平 Y 2 O 3 器件，它通常可以响应捕获的 CEA。然而，在高浓度（100 fg/mL至1 ng/mL）下，沟道电流的变化有点小，特别是在100 pg/mL和1 ng/mL时，沟道电流几乎相同。对于这种异常结果，有两种理论解释：由于缺乏探针导致的结合位点饱和和空间位阻效应，这两者都反映了一个事实，即不良的生物传感界面无法满足高性能生物传感器的要求。对于起伏的Y 2 O 3 界面CNT-FET生物传感器，如图4b所示，CEA添加量从1 fg/mL到1 ng/mL的连续增加，I ds 表现出优异的灵敏度，信号响应大，线性范围宽。我们将这种性能归因于CNT-FET生物传感器起伏界面处的CEA检测。如上所述，生物传感接口的比表面积越大，可以组装更多的探头，降低空间位阻效应，从而实现线性范围的扩展，而更大的EDL电容意味着该器件可以对捕获的CEA产生更大的信号响应。 此外，捕获目标的增量也会引起沟道电流的额外变化。图4c显示了所提出的CNT-FET生物传感器（包括起伏和平坦的Y 2 O 3 栅极接口）的值（ΔI/I 0 ）与CEA浓度之间的关系。本文中，ΔI （ΔI = I ds – I ds0 ） 值表示为 I ds 的变化，其中 I 和 I 0 分别是 CNT-FET 生物传感器在存在和不存在 CEA 时的 I ds 值。更直观的结果反映了设备性能的改进。起伏器件的信号响应达到300%，在1 fg/mL至1 ng/mL CEA范围内具有良好的线性度，与平面器件相比，性能得到了显著提升。此外，针对优化的器件，可以校准低至 72 ag/mL 的较低 LOD。还比较了先前报道的检测限和线性范围（图S9和表S1），表明所提出的具有起伏界面的CNT-FET生物传感器对CEA具有优异的灵敏度和较宽的线性范围。
此外，在将CEA连接到功能化CNT-FET器件的接口（参见实验部分）之前，该器件显示出微弱的漏源电流（I ds ）值，而在带负电荷的CEA（在PBS缓冲液中，pH 7.4）和抗体特异性结合后，I ds 值显着增加。图4a，b分别显示了不同浓度CEA的起伏和扁平Y 2 O 3 器件的电流响应。对于低 CEA 浓度 （1–10 fg/mL） 的扁平 Y 2 O 3 器件，它通常可以响应捕获的 CEA。然而，在高浓度（100 fg/mL至1 ng/mL）下，沟道电流的变化有点小，特别是在100 pg/mL和1 ng/mL时，沟道电流几乎相同。对于这种异常结果，有两种理论解释：由于缺乏探针导致的结合位点饱和和空间位阻效应，这两者都反映了一个事实，即不良的生物传感界面无法满足高性能生物传感器的要求。对于起伏的Y 2 O 3 界面CNT-FET生物传感器，如图4b所示，CEA添加量从1 fg/mL到1 ng/mL的连续增加，I ds 表现出优异的灵敏度，信号响应大，线性范围宽。我们将这种性能归因于CNT-FET生物传感器起伏界面处的CEA检测。如上所述，生物传感接口的比表面积越大，可以组装更多的探头，降低空间位阻效应，从而实现线性范围的扩展，而更大的EDL电容意味着该器件可以对捕获的CEA产生更大的信号响应。 此外，捕获目标的增量也会引起沟道电流的额外变化。图4c显示了所提出的CNT-FET生物传感器（包括起伏和平坦的Y 2 O 3 栅极接口）的值（ΔI/I 0 ）与CEA浓度之间的关系。本文中，ΔI （ΔI = I ds – I ds0 ） 值表示为 I ds 的变化，其中 I 和 I 0 分别是 CNT-FET 生物传感器在存在和不存在 CEA 时的 I ds 值。更直观的结果反映了设备性能的改进。起伏器件的信号响应达到300%，在1 fg/mL至1 ng/mL CEA范围内具有良好的线性度，与平面器件相比，性能得到了显著提升。此外，针对优化的器件，可以校准低至 72 ag/mL 的较低 LOD。还比较了先前报道的检测限和线性范围（图S9和表S1），表明所提出的具有起伏界面的CNT-FET生物传感器对CEA具有优异的灵敏度和较宽的线性范围。
Figure 4 图4
Figure 4. Comparison of proposed CNT-FET biosensor with different gate interfaces for CEA detection. (a) The transfer curve evolution of the CNT-FET biosensor with a flat interface was recorded after the introduction of various CEA concentrations ranging from 1 fg/mL to 1 ng/mL. (b) Transfer curve evolution of the CNT-FET biosensor with an undulating interface corresponding to different CEA concentrations (0, 1 fg/mL, 10 fg/mL, 100 fg/mL, 1 pg/mL, 10 pg/mL, 100 pg/mL, and 1 ng/mL). (c) Calibration curves of the value (ΔI/I0) vs CEA concentration using our proposed FET biosensor with the undulating interface (red) or flat interface (blue). (d) Selectivity investigation of the proposed CNT-FET biosensor. The final concentration of CEA was 100 pg/mL, while the concentration of other proteins was 1 ng/mL. The error bars represent the SD of eight different devices (n = 8).
图4.所提出的CNT-FET生物传感器与用于CEA检测的不同栅极接口的比较。（a） 在引入从1 fg/mL到1 ng/mL的各种CEA浓度后，记录了具有平坦界面的CNT-FET生物传感器的转移曲线演变。（b） 具有对应于不同 CEA 浓度（0、1 fg/mL、10 fg/mL、100 fg/mL、1 pg/mL、10 pg/mL、100 pg/mL 和 1 ng/mL）的起伏界面的 CNT-FET 生物传感器的转移曲线演变。（c） 使用我们提出的具有起伏界面（红色）或平坦界面（蓝色）的 FET 生物传感器的值 （ΔI/I 0 ） 与 CEA 浓度的校准曲线。（d） 拟议的CNT-FET生物传感器的选择性研究。CEA的最终浓度为100 pg/mL，而其他蛋白质的浓度为1 ng/mL。误差线表示八种不同器件的 SD （n = 8）。
To evaluate the specificity of the proposed CNT-FET biosensor for CEA detection, the effect of other proteins including squamous cell carcinoma antigen cytokeratin 19 fragments (CYFRA21-1), immunoglobulin G (IgG), and HSA were investigated. The concentration of other proteins was 1 ng/mL, whereas that the concentration of CEA was 100 pg/mL. Compared to the blank sample, the response showed significant changes (more than 260%) in the presence of CEA (100 pg/mL). Nevertheless, the response was negligible (less than 55%) in the presence of other proteins at 10 times the CEA concentration (Figure 4d), attributing to the specific binding of CEA and antibodies. The results illustrated that other proteins had a weak effect in the performed assay, suggesting that the proposed CNT-FET biosensor has excellent selectivity for CEA detection.
为了评估所提出的CNT-FET生物传感器在CEA检测中的特异性，研究了其他蛋白质的影响，包括鳞状细胞癌抗原细胞角蛋白19片段（CYFRA21-1）、免疫球蛋白G（IgG）和HSA。其他蛋白质的浓度为 1 ng/mL，而 CEA 的浓度为 100 pg/mL。与空白样品相比，在CEA存在下（100 pg/mL）下，响应显示出显着变化（超过260%）。然而，在CEA浓度为10倍的其他蛋白质存在下，反应可以忽略不计（小于55%），这归因于CEA和抗体的特异性结合。结果表明，其他蛋白质在所进行的测定中具有较弱的作用，表明所提出的CNT-FET生物传感器对CEA检测具有优异的选择性。
为了评估所提出的CNT-FET生物传感器在CEA检测中的特异性，研究了其他蛋白质的影响，包括鳞状细胞癌抗原细胞角蛋白19片段（CYFRA21-1）、免疫球蛋白G（IgG）和HSA。其他蛋白质的浓度为 1 ng/mL，而 CEA 的浓度为 100 pg/mL。与空白样品相比，在CEA存在下（100 pg/mL）下，响应显示出显着变化（超过260%）。然而，在CEA浓度为10倍的其他蛋白质存在下，反应可以忽略不计（小于55%），这归因于CEA和抗体的特异性结合。结果表明，其他蛋白质在所进行的测定中具有较弱的作用，表明所提出的CNT-FET生物传感器对CEA检测具有优异的选择性。
FBS Samples Analysis FBS样品分析
To explore the ability of the CNT-FET biosensor to detect CEA in a complex system, FBS samples were used as model substrates. The spiked FBS samples (10%) with different concentrations of CEA were directly detected without any other operation. As shown in Figure 5a, similar to the buffer, the Ids value increased as the CEA concentration increased from 0 to 1 ng/mL. Moreover, the corresponding linear graph between the ΔI/I0 value and CEA concentration is displayed in Figure 5b. The linear regression curve was ΔI/I0 = 50.4151 + 48.4289 lg x with great linearity (R2 = 0.9983), and CEA could be detected at as low as 155 ag/mL. It is lower than the clinical cut-off CEA concentration, (42) demonstrating that the proposed CNT-FET biosensor with an undulating interface may be a promising way for CEA detection in clinical diagnosis.
为了探索CNT-FET生物传感器在复杂系统中检测CEA的能力，使用FBS样品作为模型底物。直接检测不同浓度CEA的加标FBS样品（10%），无需任何其他操作。如图5a所示，与缓冲液类似，随着CEA浓度从0 ng/mL增加到1 ng/mL，I ds 值增加。此外，ΔI/I 0 值和CEA浓度之间的相应线性图如图5b所示。线性回归曲线为ΔI/I 0 = 50.4151 + 48.4289 lg x，线性度高（R 2 = 0.9983），CEA检测低至155 ag/mL。它低于临床临界CEA浓度（42），表明所提出的具有起伏界面的CNT-FET生物传感器可能是临床诊断中CEA检测的一种有前途的方法。
为了探索CNT-FET生物传感器在复杂系统中检测CEA的能力，使用FBS样品作为模型底物。直接检测不同浓度CEA的加标FBS样品（10%），无需任何其他操作。如图5a所示，与缓冲液类似，随着CEA浓度从0 ng/mL增加到1 ng/mL，I ds 值增加。此外，ΔI/I 0 值和CEA浓度之间的相应线性图如图5b所示。线性回归曲线为ΔI/I 0 = 50.4151 + 48.4289 lg x，线性度高（R 2 = 0.9983），CEA检测低至155 ag/mL。它低于临床临界CEA浓度（42），表明所提出的具有起伏界面的CNT-FET生物传感器可能是临床诊断中CEA检测的一种有前途的方法。
Figure 5 图5
Figure 5. Detection of CEA via proposed CNT-FET biosensor with an undulating interface in the real sample. (a) Transfer curve evolution of the CNT-FET biosensor was recorded after the introduction of various target concentrations in a 10% FBS sample ranging from 1 fg/mL to 1 ng/mL. (b) Calibration curves of ΔI/I0 values as the concentration of CEA increased. The error bars represent the SD of eight different devices (n = 8).
图5.通过所提出的具有起伏界面的CNT-FET生物传感器在真实样品中检测CEA。（a） 在10%FBS样品中引入各种目标浓度后，记录了CNT-FET生物传感器的转移曲线演变，范围为1 fg/mL至1 ng/mL。（b） 随着CEA浓度的增加，ΔI/I 0 值的校准曲线。误差线表示八种不同器件的 SD （n = 8）。
In summary, this work developed FG CNT-FET biosensors with undulating Y2O3 sensing interfaces for the ultra-highly sensitivity and wide linear range detection of CEA. The microscopic and electrical characterization results intuitively showed that the undulating interface improved the specific surface area of the dielectric–electrolyte interface, thereby increasing the number of modified antibodies for boarding the detection range of FG CNT-FET biosensors. Furthermore, the sensitivity of FG CNT-FET was also enhanced resulting from the increment of the specific surface area of the dielectric–electrolyte interface and caused an increase of the EDL capacitance. The detection limit of the proposed CNT-FET biosensor was calculated to be 72 ag/mL in PBS, with a wide linear range of 1 fg/mL to 1 ng/mL. In addition, the proposed CNT-FET biosensor performed well in serum samples and can be used for other target assays by simply changing the appropriate recognition probe. As a result, this device has enormous potential as a general and highly sensitive method for detecting other targets and for practical applications in early-stage cancer diagnosis.
综上所述，本工作开发了具有起伏YO 2 3 传感接口的FG CNT-FET生物传感器，用于CEA的超高灵敏度和宽线性范围检测。显微和电学表征结果直观地表明，起伏界面改善了介电-电解质界面的比表面积，从而增加了FG CNT-FET 生物传感器检测范围的修饰抗体数量。此外，由于介电-电解质界面比表面积的增加，FG CNT-FET的灵敏度也得到了提高，并导致了EDL电容的增加。所提出的CNT-FET生物传感器在PBS中的检测限为72 ag/mL，线性范围为1 fg/mL至1 ng/mL。此外，所提出的CNT-FET生物传感器在血清样品中表现良好，只需更换适当的识别探针即可用于其他靶标检测。因此，该设备具有巨大的潜力，可作为检测其他靶标的通用且高度灵敏的方法，并在早期癌症诊断中实际应用。
综上所述，本工作开发了具有起伏YO 2 3 传感接口的FG CNT-FET生物传感器，用于CEA的超高灵敏度和宽线性范围检测。显微和电学表征结果直观地表明，起伏界面改善了介电-电解质界面的比表面积，从而增加了FG CNT-FET 生物传感器检测范围的修饰抗体数量。此外，由于介电-电解质界面比表面积的增加，FG CNT-FET的灵敏度也得到了提高，并导致了EDL电容的增加。所提出的CNT-FET生物传感器在PBS中的检测限为72 ag/mL，线性范围为1 fg/mL至1 ng/mL。此外，所提出的CNT-FET生物传感器在血清样品中表现良好，只需更换适当的识别探针即可用于其他靶标检测。因此，该设备具有巨大的潜力，可作为检测其他靶标的通用且高度灵敏的方法，并在早期癌症诊断中实际应用。
Supporting Information 支持信息
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CNT-FET device preparation and surface functionalization process, schematic of CV for capacitance measurement setup, the device electrical properties before and after adding undulating Y2O3, mapping analysis of CNT-FET device, AFM images of flat and undulating interface with height fluctuations, SEM and fluorescence images of flat and undulating Y2O3, equivalent capacitive circuits of undulating structure transistorized biosensor, surface morphology, height variation and electrical properties of CNT-FET biosensors, comparison with previous methods for CEA detection (PDF)
CNT-FET器件制备及表面功能化工艺、电容测量设置CV示意图、添加起伏Y 2 O 3 前后的器件电学特性、CNT-FET器件映射分析、高度波动的平面和起伏界面AFM图像、平坦和起伏Y 2 O 3 的SEM和荧光图像、起伏结构晶体管生物传感器的等效电容电路、CNT-FET生物传感器的表面形貌、高度变化和电学性能，与以往CEA检测方法的比较 （PDF）
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Author Information 作者信息
- Yiwei Liu - Hunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, China;
https://orcid.org/0000-0001-7416-4452;
Yiwei Liu - 湘潭大学湖南省先进传感与信息技术研究院，中国湖南411105; https://orcid.org/0000-0001-7416-4452;电子邮件： yiweiliu@xtu.edu.cn - Zhiyong Zhang - Hunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, China; Key Laboratory for the Physics and Chemistry of Nanodevices and Center for Carbon-based Electronics, School of Electronics, Peking University, Beijing 100871, China;https://orcid.org/0000-0003-1622-3447;
Zhiyong Zhang - 湘潭大学湖南省先进传感与信息技术研究院，中国湖南411105;北京大学电子学院纳米器件理化重点实验室和碳基电子中心， 北京100871; https://orcid.org/0000-0003-1622-3447;电子邮件： zyzhang@pku.edu.cn
- Xiaofeng Liu - Hunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, China;https://orcid.org/0000-0002-0447-5658
Xiaofeng Liu - 湘潭大学湖南省先进传感与信息技术研究院，中国湖南411105; https://orcid.org/0000-0002-0447-5658 - Tongye Wei - Hunan Institute of Advanced Sensing and Information Technology, Xiangtan University, Hunan 411105, China;https://orcid.org/0000-0001-7232-8644
魏同业 - 湘潭大学湖南省先进传感与信息技术研究院，湖南411105; https://orcid.org/0000-0001-7232-8644
L.L. and X.L. contributed equally to this work. Z.Z. and Y.L. supervised and designed the project. L.L., K.W., and Z.Z. fabricated the devices. L.L. and X.L. completed the sensing experiment. T.W. performed CV testing and data analysis. L.L, X.L., and Y.L. analyzed the experimental data and co-wrote the manuscript. All of the authors discussed the results and commented on the manuscript.
L.L.和X.L.对这项工作做出了同等贡献。Z.Z.和Y.L.监督并设计了该项目。L.L.、K.W. 和 Z.Z. 制造了这些设备。L.L.和X.L.完成了传感实验。T.W.进行了CV测试和数据分析。L.L.、X.L. 和 Y.L. 分析了实验数据并共同撰写了手稿。所有作者都讨论了结果并评论了手稿。
Acknowledgments 确认
This work is supported by the National Natural Science Foundation of China (62225101 and 22204136) and the Natural Science Foundation of Hunan Province China (grant no. 2021JJ40543).
这项工作得到了国家自然科学基金（62225101和22204136）和中国湖南省自然科学基金（批准号：2021JJ40543）的支持。
This article references 42 other publications.
本文参考了其他 42 篇出版物。
- 1Cao, W.; Chen, H. D.; Yu, Y. W.; Li, N.; Chen, W. Q. Changing Profiles of Cancer Burden Worldwide and in China: a Secondary Analysis of the Global Cancer Statistics. China Med. J. 2021, 134, 783– 791, DOI: 10.1097/cm9.0000000000001474
1曹，W.;陈，H.D.;俞玉华;李，N.;Chen， W. Q.全球和中国癌症负担的变化概况：全球癌症统计数据的二次分析。中华医学杂志 2021， 134， 783– 791， DOI： 10.1097/cm9.00000000000001474 - 2Sung, H.; Ferlay, J.; Siegel, R. L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. Ca-Cancer J. Clin. 2021, 71, 209– 249, DOI: 10.3322/caac.21660Google Scholar Google 学术搜索2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3srpsVKnug%253D%253D&md5=f3e54fabe5ac5f2397292bf9a97ce5bfGlobal Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 CountriesSung Hyuna; Siegel Rebecca L; Jemal Ahmedin; Ferlay Jacques; Laversanne Mathieu; Soerjomataram Isabelle; Bray FreddieCA: a cancer journal for clinicians (2021), 71 (3), 209-249 ISSN:.This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
2宋，H.;费莱，J.;西格尔，RL;拉弗桑，M.;Soerjomataram，I.;杰马尔，A.;Bray， F.2020 年全球癌症统计：GLOBOCAN 对全球 185 个国家/地区 36 种癌症的发病率和死亡率的估计。Ca-癌症 J. 克林。2021， 71， 209– 249， DOI： 10.3322/caac.21660 - 3Guo, H.; Zhao, L.; Zhu, J.; Chen, P.; Wang, H.; Jiang, M.; Liu, X.; Sun, H.; Zhao, W.; Zheng, Z. Microbes in Lung Cancer Initiation, Treatment, and Outcome: Boon or Bane?. Semin. Cancer Biol. 2022, 86, 1190– 1206, DOI: 10.1016/j.semcancer.2021.05.025Google Scholar Google 学术搜索3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtlajs7zO&md5=9127ca5b98d5b9478d37092214da0061Microbes in lung cancer initiation, treatment, and outcome: Boon or baneGuo, Haoyue; Zhao, Lishu; Zhu, Junjie; Chen, Peixin; Wang, Hao; Jiang, Minlin; Liu, Xiaogang; Sun, Hui; Zhao, Wencheng; Zheng, Zixuan; Li, Wei; Chen, Bin; Fang, Qiyu; Yang, Menghang; He, Yayi; Yang, YangSeminars in Cancer Biology (2022), 86 (Part_2), 1190-1206CODEN: SECBE7; ISSN:1044-579X. (Elsevier Ltd.)A review. Lung cancer is the top reason for cancer-related deaths worldwide. The 5-yr overall survival rate of lung cancer is approx. 20% due to the delayed diagnosis and low response rate to regular treatments. Microbiota, both host-microbiota and alien pathogenic microbiota, have been investigated to be involved in a complicated and contradictory relationship with lung cancer initiation, treatments, and prognosis. Disorders of certain host-microbiota and pathogen infection are assocd. with the risk of lung cancers based on epidemiol. evidence, and antibiotics (ATBs) could dramatically impair anti-cancer treatment efficacy, including chemotherapy and immunotherapy. Moreover, probiotics and microbe-mediated drugs are potential approaches to enhance regular anti-tumor treatments. Therefore, the knowledge of the complex dual effect of microbes on lung cancer is beneficial to take their essence and remove their dross. This review offers insight into the current trends and advancements in microbiota or microbial components related to lung cancer.
3郭华;赵玲玲;朱杰;陈，P.;王旭东;江，M.;刘旭;孙，H.;赵旭;Zheng， Z.肺癌的起始、治疗和结果中的微生物：恩惠还是祸根？.。癌症生物学 2022， 86， 1190– 1206， DOI： 10.1016/j.semcancer.2021.05.025 - 4Khan, P.; Siddiqui, J. A.; Lakshmanan, I.; Ganti, A. K.; Salgia, R.; Jain, M.; Batra, S. K.; Nasser, M. W. RNA-Based Therapies: a Cog in the Wheel of Lung Cancer Defense. Mol. Cancer 2021, 20, 54, DOI: 10.1186/s12943-021-01338-2Google Scholar Google 学术搜索4https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXht1Sms73I&md5=e7c21faba2df89bb0bf7f35c8bd48971RNA-based therapies: A cog in the wheel of lung cancer defenseKhan, Parvez; Siddiqui, Jawed Akhtar; Lakshmanan, Imayavaramban; Ganti, Apar Kishor; Salgia, Ravi; Jain, Maneesh; Batra, Surinder Kumar; Nasser, Mohd WasimMolecular Cancer (2021), 20 (1), 54CODEN: MCOACG; ISSN:1476-4598. (BioMed Central Ltd.)A review. Lung cancer (LC) is a heterogeneous disease consisting mainly of two subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and remains the leading cause of death worldwide. Despite recent advances in therapies, the overall 5-yr survival rate of LC remains less than 20%. The efficacy of current therapeutic approaches is compromised by inherent or acquired drug-resistance and severe off-target effects. Therefore, the identification and development of innovative and effective therapeutic approaches are critically desired for LC. The development of RNA-mediated gene inhibition technologies was a turning point in the field of RNA biol. The crit. regulatory role of different RNAs in multiple cancer pathways makes them a rich source of targets and innovative tools for developing anticancer therapies. The identification of antisense sequences, short interfering RNAs (siRNAs), microRNAs (miRNAs or miRs), anti-miRs, and mRNA-based platforms holds great promise in preclin. and early clin. evaluation against LC. In the last decade, RNA-based therapies have substantially expanded and tested in clin. trials for multiple malignancies, including LC. This article describes the current understanding of various aspects of RNA-based therapeutics, including modern platforms, modifications, and combinations with chemo-/immunotherapies that have translational potential for LC therapies.
4汗，P.;西迪基，JA;拉克什马南，I.;甘蒂，AK;萨尔吉亚，R.;耆那教，M.;巴特拉，SK;Nasser， M. W.RNA 基于疗法：肺癌防御车轮上的齿轮。分子癌症 2021， 20， 54， DOI： 10.1186/s12943-021-01338-2 - 5Foley, R. W.; Nassour, V.; Oliver, H. C.; Hall, T.; Masani, V.; Robinson, G.; Rodrigues, J. C. L.; Hudson, B. J. Chest X-Ray in Suspected Lung Cancer is Harmful. Eur. Radiol. 2021, 31, 6269– 6274, DOI: 10.1007/s00330-021-07708-0Google Scholar Google 学术搜索5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3srntl2hsA%253D%253D&md5=e4d56865de4a6fcb33eb5ef899962ee4Chest X-ray in suspected lung cancer is harmfulFoley Robert W; Oliver Helen C; Hall Toby; Robinson Graham; Rodrigues Jonathan C L; Hudson Benjamin J; Nassour Vanessa; Masani VidanEuropean radiology (2021), 31 (8), 6269-6274 ISSN:.OBJECTIVES: The aim of this study was to analyse the use of the chest radiograph (CXR) as the first-line investigation in primary care patients with suspected lung cancer. METHODS: Of 16,945 primary care referral CXRs (June 2018 to May 2019), 1,488 were referred for suspected lung cancer. CXRs were coded as follows: CX1, normal but a CT scan is recommended to exclude malignancy; CX2, alternative diagnosis; or CX3, suspicious for cancer. Kaplan-Meier survival analysis was undertaken by stratifying patients according to their CX code. RESULTS: In the study period, there were 101 lung cancer diagnoses via a primary care CXR pathway. Only 10% of patients with a normal CXR (CX1) underwent subsequent CT and there was a significant delay in lung cancer diagnosis in these patients (p < 0.001). Lung cancer was diagnosed at an advanced stage in 50% of CX1 patients, 38% of CX2 patients and 57% of CX3 patients (p = 0.26). There was no survival difference between CX codes (p = 0.42). CONCLUSION: Chest radiography in the investigation of patients with suspected lung cancer may be harmful. This strategy may falsely reassure in the case of a normal CXR and prioritises resources to advanced disease. KEY POINTS: • Half of all lung cancer diagnoses in a 1-year period are first investigated with a chest X-ray. • A normal chest X-ray report leads to a significant delay in the diagnosis of lung cancer. • The majority of patients with a normal or abnormal chest X-ray have advanced disease at diagnosis and there is no difference in survival outcomes based on the chest X-ray findings.
5弗利，R.W.;纳苏尔，V.;奥利弗，HC;霍尔，T.;马萨尼，V.;罗宾逊，G.;罗德里格斯，JCL;Hudson， B. J.疑似肺癌的胸部X光检查是有害的。Eur. Radiol.2021， 31， 6269– 6274， DOI： 10.1007/s00330-021-07708-0 - 6Welch, H. G.; Black, W. C. Overdiagnosis in Cancer. J. Natl. Cancer Inst. 2010, 102, 605– 613, DOI: 10.1093/jnci/djq099Google Scholar Google 学术搜索6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3czhtVKmuw%253D%253D&md5=b5aa450b34dc9086342220797c638eb9Overdiagnosis in cancerWelch H Gilbert; Black William CJournal of the National Cancer Institute (2010), 102 (9), 605-13 ISSN:.This article summarizes the phenomenon of cancer overdiagnosis-the diagnosis of a "cancer" that would otherwise not go on to cause symptoms or death. We describe the two prerequisites for cancer overdiagnosis to occur: the existence of a silent disease reservoir and activities leading to its detection (particularly cancer screening). We estimated the magnitude of overdiagnosis from randomized trials: about 25% of mammographically detected breast cancers, 50% of chest x-ray and/or sputum-detected lung cancers, and 60% of prostate-specific antigen-detected prostate cancers. We also review data from observational studies and population-based cancer statistics suggesting overdiagnosis in computed tomography-detected lung cancer, neuroblastoma, thyroid cancer, melanoma, and kidney cancer. To address the problem, patients must be adequately informed of the nature and the magnitude of the trade-off involved with early cancer detection. Equally important, researchers need to work to develop better estimates of the magnitude of overdiagnosis and develop clinical strategies to help minimize it.
6韦尔奇，HG;Black， W. C.癌症过度诊断。国家癌症研究所 2010， 102， 605– 613， DOI： 10.1093/jnci/djq099 - 7D’Urso, V.; Doneddu, V.; Marchesi, I.; Collodoro, A.; Pirina, P.; Giordano, A.; Bagella, L. Sputum Analysis: Non-Invasive Early Lung Cancer Detection. J. Cell. Physiol. 2013, 228, 945– 951, DOI: 10.1002/jcp.24263Google Scholar Google 学术搜索7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVKmtLw%253D&md5=d3ad36632a46551ec717e442a05a35feSputum analysis: Non-invasive early lung cancer detectionD'Urso, Vittorio; Doneddu, Valentina; Marchesi, Irene; Collodoro, Angelo; Pirina, Pietro; Giordano, Antonio; Bagella, LuigiJournal of Cellular Physiology (2013), 228 (5), 945-951CODEN: JCLLAX; ISSN:0021-9541. (Wiley-Blackwell)Lung cancer is the leading cause of cancer-related deaths over the world, characterized by a very high mortality rate. Mol. technique development tries to focus on early detection of cancers by studying mol. alterations that characterize cancer cells. Worldwide lung cancer research has focused on an ever-increasing no. of mol. elements of carcinogenesis at genetic, epigenetic and protein levels. The non-invasiveness is the characteristic that all clin. trials on cancer detection should have. Abnormal chest imaging and/or non-specific symptoms are initial signals of lung cancer that appear in an advanced stage of disease. This fact represents the cause of the low 5-yr survival rate: over 90% of patients dying within 5 years of diagnosis. Since smokers have higher quantity of sputum contg. exfoliated cells from the bronchial tree, and the sputum represents the most easily accessible biol. fluid and its collection is non-invasive, anal. of this sample represents a good area of research in early lung cancer diagnosis. Continued cigarette smoking is the cause of chronic obstructive pulmonary disease (COPD), with an estd. attributable risk factor exceeding 80% in smoking affected individuals. Lung cancer is found in 40-70% of patients with COPD, particularly in severe disease, and it is a common cause of death in these patients. A large prospective trial of almost half a million non-smokers showed as lung cancer is also common in patients with COPD who have never smoked. This review describes issues related to early lung cancer screening using non-invasive methods. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
7D'Urso，V.;多内杜，V.;马尔凯西，I.;科洛多罗，A.;皮里纳，P.;佐丹奴，A.;Bagella，L.Sputum 分析：非侵入性早期肺癌检测。J.细胞。生理学 2013， 228， 945– 951， DOI： 10.1002/jcp.24263 - 8Kemp, R. A.; Reinders, D. M.; Turic, B. Detection of Lung Cancer by Automated Sputum Cytometry. J. Thorac. Oncol. 2007, 2, 993– 1000, DOI: 10.1097/jto.0b013e318158d488Google Scholar Google 学术搜索8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2snltFansw%253D%253D&md5=93b1aca0d22b4a5cf8416064ef8f379eDetection of lung cancer by automated sputum cytometryKemp Roger A; Reinders Daniel M; Turic BojanaJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2007), 2 (11), 993-1000 ISSN:.INTRODUCTION: Biomarkers may prove to be valuable tools to manage those at risk of lung cancer. Sputum analysis using DNA cytometry has shown promise, but an automated, objective sputum analysis test has yet to be developed. This study evaluated the performance characteristics of the LungSign test for lung cancer and compared them to conventional cytology METHODS: A multicenter validation trial was conducted in which sputum specimens were prospectively collected from subjects suspected of having lung cancer during diagnostic workup. Specimens were placed on slides, DNA stained using Feulgen thionin, and analyzed using an automated cytometry-based scoring system. Smears were also prepared from the sputum specimens, stained by the Papanicolaou procedure, and analyzed using conventional cytology. LungSign scores and conventional cytology results were compared with the subject diagnoses. RESULTS: A total of 1235 high-risk subjects were enrolled at nine clinical sites. Of 1123 subjects included for analysis, 370 were found to have lung cancer--a 33% prevalence. The a priori selected LungSign score threshold detected 40% of all lung cancers and 35% of stage I lung cancers with 91% specificity. Test performance was statistically equivalent across cancer stages, histologic types, and localizations for 330 analyzable lung cancer subjects. LungSign receiver operating characteristic area under the curve measure for the test was 0.692. Conventional cytology detected 16% of lung cancers with 99% specificity. CONCLUSIONS: DNA cytometry of sputum using the LungSign test detects stage I lung cancer and may provide a new tool to manage high-risk individuals.
8肯普，RA;莱因德斯，DM;Turic，B.通过自动痰细胞术检测肺癌。J.胸腔。肿瘤。2007， 2， 993– 1000， DOI： 10.1097/jto.0b013e318158d488 - 9Xie, X.; Wu, J.; Guo, B.; Wang, L.; Deng, H.; Lin, X.; Liu, M.; Qin, Y.; Luo, W.; Yang, Y. Comprehensive Characterization Reveals Sputum Supernatant as a Valuable Alternative Liquid Biopsy for Genome Profiling in Advanced Non-Small Cell Lung Cancer. Respir. Res. 2022, 23, 175, DOI: 10.1186/s12931-022-02097-4Google Scholar Google 学术搜索9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhvVOis7vP&md5=a6a2b748be06f34de5c0772e324907a6Comprehensive characterization reveals sputum supernatant as a valuable alternative liquid biopsy for genome profiling in advanced non-small cell lung cancerXie, Xiaohong; Wu, Jianhui; Guo, Bingpeng; Wang, Liqiang; Deng, Haiyi; Lin, Xinqing; Liu, Ming; Qin, Yinyin; Luo, Wei; Yang, Yilin; Zou, Xiao; Hou, Ting; Xiang, Jianxing; Chen, Zhange; Zhou, ChengzhiRespiratory Research (2022), 23 (1), 175CODEN: RREEBZ; ISSN:1465-993X. (BioMed Central Ltd.)Sputum biopsies offer unique advantages such as non-invasiveness and convenient collection. The one investigation so far on sputum for genome profiling in advanced non-small cell lung cancer (aNSCLC) suggested promising performance. However, it remains undefined whether clinicohistol. characteristics were assocd. with performance and how this knowledge could help guide choice of liq. biopsy. Targeted sequencing with a 520-gene panel was performed on prospectively collected matched tumor tissue (TIS), plasma (PLA), and sputum supernatant (SPU) from 71 aNSCLC patients (NCT05034445). Genomic alteration detection was characterized in a series of aspects and interrogated for assocn. with 14 clinicohistol. features. Nomograms were constructed with logistic regression for predicting the liq. biopsy type with greater sensitivity. Compared with PLA, SPU showed comparable quality control metrics, mutation detection rate (SPU: 67.6%, PLA: 70.4%), concordance with tumor tissue (67.6% vs. 73.2%), and correlation with tissue-based tumor mutation burden levels (r = 0.92 vs. 0.94). For driver alterations, detection was less sensitive with SPU (50.0%) than PLA (63.5%) in the entire cohort but similarly or more sensitive in patients with centrally located lung tumors or smoking history or for altered ALK or KRAS. Two nomograms were constructed and enabled predicting the probability of superior sensitivity with SPU with moderate to borderline high accuracy. In addn. to demonstrating comparable performance in multiple aspects, this study is the first to propose nomograms for choosing liq. biopsy based on clinicohistol. characteristics. Future research is warranted to delineate the clin. utility of sputum for genome profiling.
9谢，X.;吴，J.;郭斌;王玲玲;邓，H.;林，X.;刘，M.;秦彦;罗，W.;Yang， Y.综合表征揭示了痰上清液是晚期非小细胞肺癌基因组分析的有价值的替代液体活检。呼吸。第 2022 号决议， 23， 175， DOI： 10.1186/s12931-022-02097-4 - 10Hubers, A. J.; Prinsen, C. F.; Sozzi, G.; Witte, B. I.; Thunnissen, E. Molecular Sputum Analysis for the Diagnosis of Lung Cancer. Br. J. Cancer 2013, 109, 530– 537, DOI: 10.1038/bjc.2013.393Google Scholar Google 学术搜索10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Ghs7fJ&md5=ebe066cae0b60699737b003f5693c1eeMolecular sputum analysis for the diagnosis of lung cancerHubers, A. J.; Prinsen, C. F. M.; Sozzi, G.; Witte, B. I.; Thunnissen, E.British Journal of Cancer (2013), 109 (3), 530-537CODEN: BJCAAI; ISSN:0007-0920. (Nature Publishing Group)A review. Lung cancer is the leading cause of cancer mortality rate worldwide, mainly because of the presence of metastatic disease at the time of diagnosis. Early detection of lung cancer improves prognosis, and towards this end, large screening trials in high-risk individuals have been conducted since the past century. Despite all efforts, the need for novel (complementary) lung cancer diagnostic and screening methods still exists. In this review, we focus on the assessment of lung cancer-related biomarkers in sputum in the past decennium. Besides cytol., mutation and microRNA anal., special attention has been paid to DNA promoter hypermethylation, of which all available literature is summarised without time restriction. A model is proposed to aid in the distinction between diagnostic and risk markers. Research on the use of sputum for non-invasive detection of early-stage lung cancer has brought new insights and advanced mol. techniques. The sputum shows a promising potential for routine diagnostic and possibly screening purposes. British Journal of Cancer (2013) 109, 530-537; doi:10.1038/bjc.2013.393 www.bjcancer.com Published online 18 July 2013.
10胡伯斯，AJ;普林森，CF;索齐，G.;维特，BI;Thunnissen，用于肺癌诊断的分子痰液分析。癌症杂志 2013， 109， 530– 537， DOI： 10.1038/bjc.2013.393 - 11Gierada, D. S.; Pinsky, P.; Nath, H.; Chiles, C.; Duan, F.; Aberle, D. R. Projected Outcomes Using Different Nodule Sizes to Define a Positive CT Lung Cancer Screening Examination. J. Natl. Cancer Inst. 2014, 106, dju284, DOI: 10.1093/jnci/dju284
11吉拉达，DS;平斯基，P.;纳特，H.;智利，C.;段，F.;Aberle， D. R.使用不同结节大小来定义阳性 CT 肺癌筛查检查的预测结果。国家癌症研究所 2014， 106， dju284， DOI： 10.1093/jnci/dju284 - 12Veronesi, G.; Maisonneuve, P.; Spaggiari, L.; Rampinelli, C.; Pardolesi, A.; Bertolotti, R.; Filippi, N.; Bellomi, M. Diagnostic Performance of Low-Dose Computed Tomography Screening for Lung Cancer over Five Years. J. Thorac. Oncol. 2014, 9, 935– 939, DOI: 10.1097/jto.0000000000000200Google Scholar Google 学术搜索12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfhsVChtw%253D%253D&md5=7c7fe4a54ff3ea070108a4f27b8c47dcDiagnostic performance of low-dose computed tomography screening for lung cancer over five yearsVeronesi Giulia; Maisonneuve Patrick; Spaggiari Lorenzo; Rampinelli Cristiano; Pardolesi Alessandro; Bertolotti Raffaella; Filippi Niccolo; Bellomi MassimoJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2014), 9 (7), 935-939 ISSN:.INTRODUCTION: Low-dose computed tomography (LD-CT) screening can reduce lung cancer mortality; however, it is essential to improve nodule management protocols. We analyze the performance of the diagnostic protocol of the Continuous Observation of SMOking Subjects single-center screening study, after long-term follow-up. METHODS: Between 2004 and 2005, 5203 asymptomatic high-risk individuals (≥20 pack-years, aged 50 years or older) were enrolled to undergo annual LD-CT for 5 years. Nodules 5 mm or smaller underwent repeat LD-CT a year later. Nodules larger than 5.0 mm and 8.0 mm or smaller received LD-CT 3 to 6 months later. Nodules larger than 8.0 mm or growing underwent CT-positron emission tomography. True positives were any stage prevalent lung cancer, progressing nodules diagnosed at stage 1, localized multifocal cancer, or new nodules diagnosed at any stage. False negatives were progressing nodules diagnosed at stage >1. False positives were benign nodules resected surgically. RESULTS: Compliance was 79% over 5 years; 175 primary lung cancers were detected (0.76% per year), 136 (77.7%) were N0M0 and three were interval cancers. Eleven second primary lung cancers were diagnosed. Resectability was 87.4%; postoperative mortality 0.6%. Recall was 6.4% overall, 10.1% at baseline. False negatives were 14 of 175 (8%). Protocol sensitivity was 158 of 175 (90%); specificity 4994 of 5028 (99.4%); positive predictive value was 158 of 187 (84.5%); and negative predictive value was 4994 of 5016 (99.7%). Twenty-nine of 204 (14.2%) benign lesions were diagnosed surgically. Five-year overall and cancer-specific survival were 78% (95% confidence interval, 72-84) and 82% (95% confidence interval, 76%-88%) respectively. CONCLUSIONS: The performance of the CT protocol was satisfactory with an acceptable number of benign lesions biopsied surgically, low recall rate, and good oncological outcomes. However, interval and advanced cancers, and misdiagnoses, need to be reduced, perhaps by risk modeling and use of serum markers.
12维罗内西，G.;Maisonneuve，P.;斯帕吉亚里，L.;兰皮内利，C.;帕尔多莱西，A.;贝尔托洛蒂，R.;菲利皮，N.;Bellomi， M.五年来肺癌低剂量计算机断层扫描筛查的诊断性能。J.胸腔。肿瘤。2014， 9， 935– 939， DOI： 10.1097/jto.0000000000000000200 - 13Altintas, Z.; Tothill, I. Biomarkers and Biosensors for the Early Diagnosis of Lung Cancer. Sens. Actuators, B 2013, 188, 988– 998, DOI: 10.1016/j.snb.2013.07.078Google Scholar Google 学术搜索13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1SgtbbK&md5=961643c4019efbc7aad908ca12bd5820Biomarkers and biosensors for the early diagnosis of lung cancerAltintas, Zeynep; Tothill, IbtisamSensors and Actuators, B: Chemical (2013), 188 (), 988-998CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)A review. Lung cancer shows the highest mortality rate worldwide (1.3 million/yr) with respect to other common cancers as prostate, breast and colon cancer. It is the second most common cancer in men and the third in women (22% of all cancer cases). The treatment of the disease is long and difficult with survival scarcely attains to 5 years. The most crit. point for best prognosis is to diagnose the disease at its early stage. For this aim, divers' methods have been used including chest X-ray, computerized tomog., magnetic resonance imaging, positron emission tomog., sputum cytol. and biopsy. Although some of these methods are not suitable for all people due to the other pathologies that the patient may have. Also since the current diagnostic tools are also expensive and time consuming, hence, a new sensitive and rapid method for screening is necessary for lung cancer detection. With this approach, biosensors as diagnostics tools have provided a promising technol. for the detection of many important disease biomarkers through rapid, sensitive and easy applications. In this paper, lung cancer, state-of-the-art with current diagnostics tools, genetic and protein biomarkers of the disease and emerging biosensor technol. for rapid detection are reviewed.
13阿尔廷塔斯，Z.;Tothill，I.用于肺癌早期诊断的生物标志物和生物传感器。Sens. Actuators， B 2013， 188， 988– 998， DOI： 10.1016/j.snb.2013.07.078 - 14Guida, F.; Sun, N.; Bantis, L. E.; Muller, D. C.; Li, P.; Taguchi, A.; Dhillon, D.; Kundnani, D. L.; Patel, N. J.; Yan, Q. Assessment of Lung Cancer Risk on the Basis of a Biomarker Panel of Circulating Proteins. JAMA Oncol. 2018, 4, e182078 DOI: 10.1001/jamaoncol.2018.2078
14圭达，F.;太阳，N.;班蒂斯，L.E.;穆勒，哥伦比亚特区;李，P.;田口，A.;迪隆，D.;昆德纳尼，DL;新泽西州帕特尔;Yan， Q.基于循环蛋白的生物标志物组评估肺癌风险。美国医学会肿瘤协会（JAMA Oncol）。2018， 4， e182078 DOI： 10.1001/jamaoncol.2018.2078 - 15Sandfeld-Paulsen, B.; Jakobsen, K. R.; Bæk, R.; Folkersen, B. H.; Rasmussen, T. R.; Meldgaard, P.; Varming, K.; Jørgensen, M. M.; Sorensen, B. S. Exosomal Proteins as Diagnostic Biomarkers in Lung Cancer. J. Thorac. Oncol. 2016, 11, 1701– 1710, DOI: 10.1016/j.jtho.2016.05.034Google Scholar Google 学术搜索15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s7jslyisg%253D%253D&md5=18daaee0417b8ddcdbca390792e58befExosomal Proteins as Diagnostic Biomarkers in Lung CancerSandfeld-Paulsen Birgitte; Jakobsen Kristine Raaby; Baek Rikke; Varming Kim; Jorgensen Malene Moller; Folkersen Birgitte Holst; Rasmussen Torben Riis; Meldgaard Peter; Sorensen Boe SandahlJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (2016), 11 (10), 1701-10 ISSN:.INTRODUCTION: Exosomes have been suggested as promising biomarkers in NSCLC because they contain proteins from their originating cells and are readily available in plasma. In this study, we explored the potential of exosome protein profiling in diagnosing lung cancers of all stages and various histological subtypes in patients. METHODS: Plasma was isolated from 581 patients (431 with lung cancer and 150 controls). The extracellular vesicle array was used to phenotype exosomes. The extracellular vesicle array contained 49 antibodies for capturing exosomes. Subsequently, a cocktail of biotin-conjugated CD9, CD81, and CD63 antibodies was used to detect and visualize captured exosomes. Multimarker models were made by combining two or more markers. The optimal multimarker model was evaluated by area under the curve (AUC) and random forests analysis. RESULTS: The markers CD151, CD171, and tetraspanin 8 were the strongest separators of patients with cancer of all histological subtypes versus patients without cancer (CD151: AUC = 0.68, p = 0.0002; CD171: AUC = 0.60, p = 0.0002; and TSPAN8: AUC = 0.60, p = 0.0002). The multimarker models with the largest AUC in the cohort of patients with all lung cancer histological subtypes and in the cohort of patients with adenocarcinoma only covered 10 markers (all cancer: AUC = 0.74 [95% confidence interval: 0.70-0.80]; adenocarcinoma only: AUC = 0.76 [95% confidence interval: 0.70-0.83]). In squamous cell cancer and SCLC, multimarker models did not exceed CD151 as an individual marker in separating patients with cancer from controls. CONCLUSION: We have demonstrated exosome protein profiling to be a promising diagnostic tool in lung cancer independently of stage and histological subtype. Multimarker models could make a fair separation of patients, demonstrating the perspectives of exosome protein profiling as a biomarker.
15桑德菲尔德-保尔森，B.;雅各布森，K.R.;贝克，R.;福克森，BH;拉斯穆森，TR;梅尔德加德，P.;瓦明，K.;约根森，M.M.;Sorensen， BS 外泌体蛋白作为肺癌的诊断生物标志物。J.胸腔。肿瘤。2016， 11， 1701– 1710， DOI： 10.1016/j.jtho.2016.05.034 - 16Seijo, L. M.; Peled, N.; Ajona, D.; Boeri, M.; Field, J. K.; Sozzi, G.; Pio, R.; Zulueta, J. J.; Spira, A.; Massion, P. P. Biomarkers in Lung Cancer Screening: Achievements, Promises, and Challenges. J. Thorac. Oncol. 2019, 14, 343– 357, DOI: 10.1016/j.jtho.2018.11.023Google Scholar Google 学术搜索16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFemtLbN&md5=c9bcd3b12f324a45c17de4e22b406a87Biomarkers in Lung Cancer Screening: Achievements, Promises, and ChallengesSeijo, Luis M.; Peled, Nir; Ajona, Daniel; Boeri, Mattia; Field, John K.; Sozzi, Gabriella; Pio, Ruben; Zulueta, Javier J.; Spira, Avrum; Massion, Pierre P.; Mazzone, Peter J.; Montuenga, Luis M.Journal of Thoracic Oncology (2019), 14 (3), 343-357CODEN: JTOOB7; ISSN:1556-1380. (Elsevier)The present review is an update of the research and development efforts regarding the use of mol. biomarkers in the lung cancer screening setting. The two main unmet clin. needs, namely, the refinement of risk to improve the selection of individuals undergoing screening and the characterization of undetd. nodules found during the computed tomog.-based screening process are the object of the biomarkers described in the present review. We first propose some principles to optimize lung cancer biomarker discovery projects. Then, we summarize the discovery and developmental status of currently promising mol. candidates, such as autoantibodies, complement fragments, microRNAs, circulating tumor DNA, DNA methylation, blood protein profiling, or RNA airway or nasal signatures. We also mention other emerging biomarkers or new technologies to follow, such as exhaled breath biomarkers, metabolomics, sputum cell imaging, genetic predisposition studies, and the integration of next-generation sequencing into study of circulating DNA. We also underline the importance of integrating different mol. technologies together with imaging, radiomics, and artificial intelligence. We list a no. of completed, ongoing, or planned trials to show the clin. utility of mol. biomarkers. Finally, we comment on future research challenges in the field of biomarkers in the context of lung cancer screening and propose a design of a trial to test the clin. utility of one or several candidate biomarkers.
16Seijo，L.M.;佩莱德，N.;阿约纳，D.;博埃里，M.;菲尔德，JK;索齐，G.;皮奥，R.;祖卢埃塔，JJ;斯皮拉，A.;Massion， P. P.肺癌筛查中的生物标志物：成就、承诺和挑战。J.胸腔。肿瘤。2019， 14， 343– 357， DOI： 10.1016/j.jtho.2018.11.023 - 17Yang, G.; Xiao, Z.; Tang, C.; Deng, Y.; Huang, H.; He, Z. Recent Advances in Biosensor for Detection of Lung Cancer Biomarkers. Biosens. Bioelectron. 2019, 141, 111416, DOI: 10.1016/j.bios.2019.111416Google Scholar Google 学术搜索17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlSls7zE&md5=efc2e1527c681f2e70f556fd76b6b3d5Recent advances in biosensor for detection of lung cancer biomarkersYang, Gaojian; Xiao, Ziqi; Tang, Congli; Deng, Yan; Huang, Hao; He, ZiyuBiosensors & Bioelectronics (2019), 141 (), 111416CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)A review. Lung cancer is primary cancer threatening human life worldwide with the highest mortality rate. The early detection of lung cancer plays a crit. role in the early diagnosis and subsequent treatment. However, the conventional methodologies limit the applications due to the low sensitivity, being expensive, and invasive procedure. Tumor markers as biochem. parameters can reflect cancer occurrence and progression, which show sensitivity, convenience, and low cost in developing biosensors, and act as good candidates for fabricating biosensors of detecting lung cancer. This review describes various biosensors (2013-2019) for detection of lung cancer biomarkers. Firstly, the various reported tumor markers of lung cancer are briefly described. Then, the advancements of designing biosensors for sensitive, stable, and selective identification of lung cancer biomarkers are systematically provided, with a specific focus on the main clin. biomarkers such as neuron-specific enolase (NSE), cytokeratin 19 fragment (CYFRA 21-1). Finally, the recent challenges and further opportunities for developing effective biosensors for early diagnosis of lung cancer are discussed.
17杨，G.;肖，Z.;唐，C.;邓，Y.;黄，H.;用于检测肺癌生物标志物的生物传感器的最新进展.生物sens。生物电子。2019， 141， 111416， DOI： 10.1016/j.bios.2019.111416 - 18Jiao, Z.; Cao, S.; Li, J.; Hu, N.; Gong, Y.; Wang, L.; Jin, S. Clinical Associations of Preoperative and Postoperative Serum CEA and Lung Cancer Outcome. Front. Mol. Biosci. 2021, 8, 686313, DOI: 10.3389/fmolb.2021.686313Google Scholar Google 学术搜索18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB2cfjtFWjtA%253D%253D&md5=88b716443ebaa1f4db45d702d904eeeaClinical Associations of Preoperative and Postoperative Serum CEA and Lung Cancer OutcomeJiao Zonglin; Gong Yinghui; Wang Linduo; Cao Shoubo; Li Jianhua; Hu Nan; Jin ShiFrontiers in molecular biosciences (2021), 8 (), 686313 ISSN:2296-889X.Background: Serum carcinoembryonic antigen (CEA), a classic tumour marker, is widely used in lung cancer in clinical practice. Nevertheless, few studies have elucidated the influence of dynamic changes in CEA in the perioperative phases, as a prognostic indicator, on lung cancer prognosis. Methods: This retrospective cohort analysis included consecutive patients with stage I-III lung cancer who underwent curative resection between December 2010 and December 2014. The patients were grouped into three cohorts: group A included patients with normal preoperative CEA, group B included patients with elevated preoperative CEA but normal postoperative CEA, and group C included patients with elevated preoperative and postoperative CEA. Five-year overall survival (OS) was estimated by Kaplan-Meier analysis (log-rank test). Multivariate analyses were performed with Cox proportional hazard regression. Results: A total of 1662 patients with stage I-III lung cancer were enrolled in our study. Patients with normal preoperative CEA had 15.9 and 20.1% better 3- and 5-year OS rates than the cohort with elevated preoperative CEA (p < 0.001). Furthermore, group C had 36.0 and 26.6% lower 5-year OS rates (n = 74, 32.4%) than group A (n = 1188, 68.4%) and group B (n = 139, 59.0%) (p < 0.001). Group B had poorer OS than group A (p = 0.016). For patients with different pathological TNM stages, subgroup analyses showed that group C had the shortest OS in stages I and II (p < 0.05), and patients with a post-preoperative CEA increment had poorer OS than those without an increment (p = 0.029). Multivariate analyses suggested that group C (HR = 2.0, 95% CI, 1.5-2.7, p < 0.001) rather than the group with normalized postoperative CEA (HR = 1.2, 95% CI, 0.9-1.5, p = 0.270) was an independent prognostic factor. In subgroup analysis of adenocarcinoma (ADC), survival analyses suggested that group C predicted a worse prognosis. Multivariate analysis of ADC indicated that group C was an independent adverse prognostic factor (HR = 1.9, 95% CI, 1.4-2.7, p < 0.001). Conclusions: Combined elevated preoperative and postoperative CEA is an independent adverse prognostic factor for stage I-III lung adenocarcinoma. Additionally, routine perioperative detection of serum CEA can yield valuable prognostic information for patients after lung cancer surgery.
18焦Z.;曹曹曹;李，J.;胡，N.;龚婷婷;王玲玲;Jin， S.术前和术后血清CEA与肺癌结果的临床关联。前面。分子生物科学。2021， 8， 686313， DOI： 10.3389/fmolb.2021.686313 - 19Dal Bello, M. G.; Filiberti, R. A.; Alama, A.; Orengo, A. M.; Mussap, M.; Coco, S.; Vanni, I.; Boccardo, S.; Rijavec, E.; Genova, C. The Role of CEA, CYFRA21-1 and NSE in Monitoring Tumor Response to Nivolumab in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients. J. Transl. Med. 2019, 17, 74, DOI: 10.1186/s12967-019-1828-0Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cbitVaisw%253D%253D&md5=3c5d833184b1e3eb7c050c67309bbc98The role of CEA, CYFRA21-1 and NSE in monitoring tumor response to Nivolumab in advanced non-small cell lung cancer (NSCLC) patientsDal Bello M G; Alama A; Coco S; Vanni I; Boccardo S; Rijavec E; Genova C; Biello F; Barletta G; Rossi G; Tagliamento M; Maggioni C; Filiberti R A; Orengo A M; Mussap M; Genova C; Grossi FJournal of translational medicine (2019), 17 (1), 74 ISSN:.BACKGROUND: CEA, CYFRA21-1 and NSE are tumor markers used for monitoring the response to chemotherapy in advanced adenocarcinoma, squamous cell carcinoma and small-cell lung cancer, respectively. Their role in cancer immunotherapy needs to be elucidated. METHODS: Patients with advanced non-small cell lung cancer (NSCLC) were treated with nivolumab 3 mg/kg every 2 weeks within the Italian Nivolumab Expanded Access Program. Blood samples were collected at baseline, at each cycle up to cycle 5 and then every two cycles until patient's withdrawn from the study. All patients underwent a CT-scan after every 4 cycles of treatment and responses were classified according to RECIST 1.1. The biomarkers serum levels were measured with a chemiluminescent microparticle immunoassay for CEA and with an immuno radiometric assay for CYFRA21-1 and NSE. The markers values at baseline and after 4 cycles were used to analyze the relationship between their variation over baseline and the tumor response, evaluated as disease control rate (DCR: CR + PR + SD), and survival (PFS and OS). RESULTS: A total of 70 patients were evaluable for the analysis. Overall, a disease control was obtained in 24 patients (35.8%, 4 PR + 20 SD). After 4 cycles of nivolumab a CEA or CYFRA21-1 reduction ≥ 20% over the baseline was significantly associated with DCR (CEA, p = 0.021; CYFRA21-1, p < 0.001), PFS (CEA, p = 0.028; CYFRA21-1, p < 0.001) and OS (CEA, p = 0.026; CYFRA21-1, p = 0.019). Multivariate analysis confirmed the ability of CYFRA21-1 reduction ≥ 20% to predict DCR (p = 0.002) and PFS (p < 0.001). CONCLUSION: The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab.
- 20Chen, Y.; Deng, W.; Tan, Y.; Xie, Q. CdS Quantum-Dots-Decorated V2O5 Nanosheets as Chemically Etchable Active Materials for Sensitive Photoelectrochemical Immunoassay of Carcinoembryonic Antigen. ACS Appl. Mater. Interfaces 2020, 12, 29066– 29073, DOI: 10.1021/acsami.0c06793Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFWms7bP&md5=0431c7ddb5c964b41a1c3faa6f5ee114CdS Quantum-Dots-Decorated V2O5 Nanosheets as Chemically Etchable Active Materials for Sensitive Photoelectrochemical Immunoassay of Carcinoembryonic AntigenChen, Yanqun; Deng, Wenfang; Tan, Yueming; Xie, QingjiACS Applied Materials & Interfaces (2020), 12 (26), 29066-29073CODEN: AAMICK; ISSN:1944-8244. (American Chemical Society)The authors report here CdS quantum-dots (QDs)-decorated V2O5 nanosheets as high-performance and chem. etchable photoelec. active materials for constructing a photoelectrochem. (PEC) immunoassay platform. CdS QDs-decorated V2O5 nanosheets as new photoelec. materials can show superior photocurrent to V2O5 nanosheets and CdS QDs under visible-light irradn. because of the promoted photogenerated electron-hole sepn. and the increased visible-light absorption. V2O5 nanosheets can be etched by ascorbic acid (AA) because of the redn. of V2O5 to V4+, and the photocurrent of CdS/V2O5-nanocomposite-modified indium tin oxide electrode decreases significantly after being etched by AA. Inspired by this phenomenon, a PEC immunoassay platform is constructed for carcinoembryonic antigen (CEA) detection by using CdS/V2O5 nanocomposite as the photoelec. material and AA-encapsulated liposome immunonanocapsules as labels. The linear detection range for detecting CEA is from 0.5 pg mL-1 to 1 ng mL-1, with a limit of detection of 0.1 pg mL-1. The proposed method also shows good selectivity, excellent reproducibility, and satisfactory recovery in detection of CEA in human serum samples. The authors believe that this work will lay the foundation for the future development of V2O5-based materials for PEC anal., and also provide a reasonable design and implementation for the development of PEC immunoassay.
- 21Su, S.; Sun, Q.; Wan, L.; Gu, X.; Zhu, D.; Zhou, Y.; Chao, J.; Wang, L. Ultrasensitive Analysis of Carcinoembryonic Antigen Based on MoS2-Based Electrochemical Immunosensor with Triple Signal Amplification. Biosens. Bioelectron. 2019, 140, 111353, DOI: 10.1016/j.bios.2019.111353Google Scholar Google 学术搜索21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVKis7bP&md5=5dc2f52fc5dcc7608efb764924df33d8Ultrasensitive analysis of carcinoembryonic antigen based on MoS2-based electrochemical immunosensor with triple signal amplificationSu, Shao; Sun, Qian; Wan, Ling; Gu, Xiaodan; Zhu, Dan; Zhou, Yi; Chao, Jie; Wang, LianhuiBiosensors & Bioelectronics (2019), 140 (), 111353CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)Ultrasensitive detection of cancer biomarkers has shown great promise for precision medicine. Here, a triple signal amplification strategy was developed for anal. of carcinoembryonic antigen (CEA) by using MoS2-based nanocomposites. Gold nanoparticles-decorated molybdenum disulfide nanocomposite (MoS2-AuNPs) was used to construct the modified electrode and nanoprobe, which could efficiently amplify electrochem. signal due to its large surface area and high catalytic ability. Horseradish peroxidase (HRP)-labeled carcinoembryonic monoclonal antibody (anti-CEA) and HRP were used to co-construct the MoS2-based nanoprobe, which could further amplify the electrochem. signal by catalyzing o-phenylenediamine (o-PD) in the presence of hydrogen peroxide (H2O2). Expectedly, an excellent anal. performance for CEA detection was obtained, such as wide detection range (10 fg mL-1-1 ng mL-1), ultralow detection limit (1.2 fg mL-1), high selectivity and good stability, suggesting this immunosensor could detect CEA in real samples.
21苏，S.;孙，Q.;万，L.;顾，X.;朱，D.;周，Y.;赵，J.;Wang， L.基于MoS 2 的三重信号放大电化学免疫传感器的癌胚抗原超灵敏分析.生物sens。生物电子。2019， 140， 111353， DOI： 10.1016/j.bios.2019.111353 - 22Hong, W.; Lee, S.; Cho, Y. Dual-Responsive Immunosensor that Combines Colorimetric Recognition and Electrochemical Response for Ultrasensitive Detection of Cancer Biomarkers. Biosens. Bioelectron. 2016, 86, 920– 926, DOI: 10.1016/j.bios.2016.07.014Google Scholar Google 学术搜索22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlWnsr3E&md5=aacb9e6d2868d82208e78e07ccd62d1fDual-responsive immunosensor that combines colorimetric recognition and electrochemical response for ultrasensitive detection of cancer biomarkersHong, Wooyoung; Lee, Sooyeon; Cho, YoungnamBiosensors & Bioelectronics (2016), 86 (), 920-926CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)We developed a nanoroughened, biotin-doped polypyrrole immunosensor for the detection of tumor markers through dual-signal (electrochem. and colorimetric) channels, electrochem. and colorimetric, that demonstrates remarkable anal. performance. A rapid, one-step elec. field-mediated method was employed to fabricate the immunosensor with nanoscale roughness by simply modulating the applied elec. potential. We demonstrated the successful detection of three tumor markers (CA125, CEA, and PSA) via the double enzymic signal amplifications in the presence of a target antigen, ultimately leading to desired diagnostic accuracy and reliability. The addn. of multiple horseradish peroxidase (HRP)- and antibody-labeled nanoparticles greatly amplified the signal and simplified the measurement of cancer biomarker proteins by sequentially magnifying electrochem. and colorimetric signals in a single platform. The two parallel assays performed using the proposed immunosensor have yielded highly consistent and reproducible results. Addnl., for the anal. of plasma samples in a clin. setting, the values obtained with our immunosensor were validated by correlating the results with those of a std. RIA (RIA), which obtained very similar clin. valid responses.
22洪，W.;李，S.;Cho， Y.双响应式免疫传感器，结合了比色识别和电化学反应，用于癌症生物标志物的超灵敏检测。生物sens。生物电子。2016， 86， 920– 926， DOI： 10.1016/j.bios.2016.07.014 - 23Meneghel, L.; Ruffatti, A.; Gavasso, S.; Tonello, M.; Mattia, E.; Spiezia, L.; Campello, E.; Hoxha, A.; Fedrigo, M.; Punzi, L. The Clinical Performance of a Chemiluminescent Immunoassay in Detecting Anti-Cardiolipin and Anti-β2 Glycoprotein I Antibodies. A Comparison with a Homemade ELISA Method. Clin. Chem. Lab. Med. 2015, 53, 1083– 1089, DOI: 10.1515/cclm-2014-0925Google Scholar Google 学术搜索23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXps1SmsrY%253D&md5=14efcedf1b6ac5c344989b8a3533db59The clinical performance of a chemiluminescent immunoassay in detecting anti-cardiolipin and anti-β2 glycoprotein I antibodies. A comparison with a homemade ELISA methodMeneghel, Lauro; Ruffatti, Amelia; Gavasso, Sabrina; Tonello, Marta; Mattia, Elena; Spiezia, Luca; Campello, Elena; Hoxha, Ariela; Fedrigo, Marny; Punzi, Leonardo; Simioni, PaoloClinical Chemistry and Laboratory Medicine (2015), 53 (7), 1083-1089CODEN: CCLMFW; ISSN:1434-6621. (Walter de Gruyter GmbH)Background: Fully automated chemiluminescence immunoassays (CLIAs) are emerging technologies for the detection of anti-cardiolipin (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies for anti-phospholipid syndrome (APS) classification, which is commonly based on an ELISA (ELISA) test result. CLIA and a homemade ELISA were used in this study to detect these antibodies, and their performances were compared. Methods: Sera were collected from 104 patients with primary APS, 88 seroneg. subjects who met the clin. but not the lab. criteria for APS, and 150 control subjects. IgG/IgM aCL and IgG/IgM anti-β2GPI antibodies were detd. in the sera using a CLIA (HemosIL AcuStar) and a homemade ELISA. Results: CLIA had a significantly lower comparative sensitivity for IgM aCL and IgG/IgM IgG anti-β2GPI antibodies; its comparative specificity was higher with respect to ELISA for IgM aCL and IgM anti-β2GPI antibodies. The two techniques showed a high, significant agreement (p<0.001) and a significant titer correlation (p<0.001). CLIA also detected IgG/IgM aCL and IgG anti-β2GPI antibodies in the seroneg. patients. There was a significantly higher prevalence of IgG aCL and IgG anti-β2GPI antibodies (p<0.001 and p=0.01, resp.) in those patients with respect to that in the control population. Conclusions: Despite a lower comparative sensitivity, CLIA showed a higher comparative specificity for some aPL and a good level of agreement and correlation with a homemade ELISA. CLIA also detected some aCL and anti-β2GPI antibodies in the seroneg. patients not usually identified by homemade ELISA.
23梅内盖尔，L.;鲁法蒂，A.;加瓦索，S.;托内洛，M.;马蒂亚，E.;斯皮齐亚，L.;坎佩洛，E.;霍查，A.;费德里戈，M.;Punzi， L.化学发光免疫测定法在检测抗心磷脂和抗β 2 糖蛋白 I 抗体方面的临床表现。与自制ELISA方法的比较。克林。化学实验室医学 2015， 53， 1083– 1089， DOI： 10.1515/cclm-2014-0925 - 24Sun, C.; Feng, G.; Song, Y.; Cheng, S.; Lei, S.; Hu, W. Single Molecule Level and Label-Free Determination of Multibiomarkers with an Organic Field-Effect Transistor Platform in Early Cancer Diagnosis. Anal. Chem. 2022, 94, 6615– 6620, DOI: 10.1021/acs.analchem.2c00897Google Scholar Google 学术搜索24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhtVClsbfJ&md5=b8dfbd6962978d92c0f09a4cbcd2a5d4Single Molecule Level and Label-Free Determination of Multibiomarkers with an Organic Field-Effect Transistor Platform in Early Cancer DiagnosisSun, Chenfang; Feng, Guangyuan; Song, Yaru; Cheng, Shanshan; Lei, Shengbin; Hu, WenpingAnalytical Chemistry (Washington, DC, United States) (2022), 94 (17), 6615-6620CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)The single mol. level detn. with a transistor (SiMoT) platform has attracted considerable attention in the recognition of various ultralow abundance biomols., while complicated labeling and testing processes limit its further applications. Recently, org. field-effect transistor (OFET)-based biosensors are good candidates for constructing an advanced label-free SiMoT platform due to their facile fabrication process, rapid response time, and low sample vol. with a wide range of detection. However, the sensitivity of most OFET-based biosensors is in the order of nM and pM, which cannot meet the detection requirements of ultralow abundance protein. Herein, a label-free SiMoT platform is demonstrated by integrating pillar[n]arene as a signal amplifier, and the detection limit can reach 4.75 aM. Besides, by simultaneous detn. of α-fetoprotein, carcinoembryonic antigen, and prostate antigen, the proposed multiplexed OFET-based SiMoT platform provides a key step in reliable early cancer diagnosis.
24太阳，C.;冯，G.;宋，Y.;程淑贞;雷磊;胡，W.使用有机场效应晶体管平台在早期癌症诊断中多生物标志物的单分子水平和无标记测定。分析化学 2022， 94， 6615– 6620， DOI： 10.1021/acs.analchem.2c00897 - 25Wang, X.; Sun, C.; Zhang, C.; Cheng, S.; Hu, W. Organic Field-Effect Transistor-Based Biosensors with Enhanced Sensitivity and Reliability under Illumination for Carcinoembryonic Antigen Bioassay. Anal. Chem. 2021, 93, 15167– 15174, DOI: 10.1021/acs.analchem.1c03683Google Scholar Google 学术搜索25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXitlGkt77M&md5=f6bcee0c50550069606db1a0a46d8dc9Organic Field-Effect Transistor-Based Biosensors with Enhanced Sensitivity and Reliability under Illumination for Carcinoembryonic Antigen BioassayWang, Xue; Sun, Chenfang; Zhang, Congcong; Cheng, Shanshan; Hu, WenpingAnalytical Chemistry (Washington, DC, United States) (2021), 93 (45), 15167-15174CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)Achieving biosensors of high sensitivity and reliability is extremely significant for early diagnosis and treatment of tumor diseases. Herein, a novel org. field-effect transistor (OFET)-based biosensor was developed and applied for carcinoembryonic antigen (CEA) bioassay. This OFET-based biosensor can respond sensitively to the antigen-antibody immune-recognition reaction under illumination and darkness, resp., thereby generating elec. signal changes of source-drain current (IDS) and threshold voltage (Vth). The OFET-based biosensor exhibits detection limits for CEA detection of 0.5 and 0.2 pM, resp., using IDS and Vth as the response signals under darkness. When a specific intensity of light is applied, light will influence the charge-carrier transport process in the conductive channel, thus causing biosignals to turn into higher elec. signal changes of photocurrent and threshold voltage under illumination. Compared with the detection results in the dark, the biosensor exhibits higher sensitivity for CEA detection under illumination with detection limits of 13.5 and 16.9 fM. Also, multisignal outputs effectively improve the reliability of the biosensor for CEA detection. Consequently, with powerful detection functions, this OFET-based biosensor is expected to become a high-performance biosensing platform for the detection of various biol. substances in the future.
25王旭;孙，C.;张，C.;程淑贞;胡， W.基于有机场效应晶体管的生物传感器，在钙胚抗原生物测定的照明下具有增强的灵敏度和可靠性。分析化学 2021， 93， 15167– 15174， DOI： 10.1021/acs.analchem.1c03683 - 26Liu, J.; Chen, X.; Wang, Q.; Xiao, M.; Zhong, D.; Sun, W.; Zhang, G.; Zhang, Z. Ultrasensitive Monolayer MoS2 Field-Effect Transistor Based DNA Sensors for Screening of Down Syndrome. Nano Lett. 2019, 19, 1437– 1444, DOI: 10.1021/acs.nanolett.8b03818Google Scholar Google 学术搜索26https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivVSgtrw%253D&md5=14863eb703d060fa57bf44fd44db9cc2Ultrasensitive Monolayer MoS2 Field-Effect Transistor Based DNA Sensors for Screening of Down SyndromeLiu, Jingxia; Chen, Xihua; Wang, Qinqin; Xiao, Mengmeng; Zhong, Donglai; Sun, Wei; Zhang, Guangyu; Zhang, ZhiyongNano Letters (2019), 19 (3), 1437-1444CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)Field-effect transistor (FET) biosensors based on low-dimensional materials present the advantages of low cost, high speed, small size, and excellent compatibility with integrated circuits (ICs). In this work, the authors fabricated highly sensitive FET-based DNA biosensors based on chem. vapor deposition (CVD)-grown monolayer MoS2 films in batches and explored their application in noninvasive prenatal testing (NIPT) for trisomy 21 syndrome. Specifically, MoS2 was functionalized with gold nanoparticles (Au NPs) of an optimized size and at an ideal d., and then, probe DNAs for the specific capture of target DNAs were immobilized on the nanoparticles. The fabricated FET biosensors are able to reliably detect target DNA fragments (chromosome 21 or 13) with a detection limit below 100 aM, a high response up to 240%, and a high specificity, which satisfy the requirement for the screening of Down syndrome. In addn., a real-time test was conducted to show that the biosensor clearly responds to the target DNA at concns. as low as 1 fM. The approach shows the potential for detecting the over-expression of chromosome 21 in the peripheral blood of pregnant women and achieving Down syndrome screening.
26刘婷婷;陈旭;王，Q.;肖，M.;钟，D.;孙，W.;张，G.;Zhang， Z.基于超灵敏单层MoS 2 场效应晶体管的DNA传感器，用于唐氏综合症的筛查。纳米杂志 2019， 19， 1437– 1444， DOI： 10.1021/acs.nanolett.8b03818 - 27Park, H.; Baek, S.; Sen, A.; Jung, B.; Shim, J.; Park, Y. C.; Lee, L. P.; Kim, Y. J.; Kim, S. Ultrasensitive and Selective Field-Effect Transistor-Based Biosensor Created by Rings of MoS2 Nanopores. ACS Nano 2022, 16, 1826– 1835, DOI: 10.1021/acsnano.1c08255Google Scholar Google 学术搜索27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXivVCgsr3M&md5=7ffbee6d229e9cc8f9bc0d50741c3f58Ultrasensitive and Selective Field-Effect Transistor-Based Biosensor Created by Rings of MoS2 NanoporesPark, Heekyeong; Baek, Seungho; Sen, Anamika; Jung, Bongjin; Shim, Junoh; Park, Yun Chang; Lee, Luke P.; Kim, Young Jun; Kim, SunkookACS Nano (2022), 16 (2), 1826-1835CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)The ubiquitous field-effect transistor (FET) is widely used in modern digital integrated circuits, computers, communications, sensors, and other applications. However, reliable biol. FET (bio-FET) is not available in real life due to the rigorous requirement for highly sensitive and selective bio-FET fabrication, which remains a challenging task. Here, we report an ultrasensitive and selective bio-FET created by the nanorings of molybdenum disulfide (MoS2) nanopores inspired by nuclear pore complexes. We characterize the nanoring of MoS2 nanopores by scanning transmission electron microscopy, Raman, and XPS spectra. After fabricating MoS2 nanopore rings-based bio-FET, we confirm edge-selective functionalization by the gold nanoparticle tethering test and the change of elec. signal of the bio-FET. Ultrahigh sensitivity of the MoS2 nanopore edge rings-based bio-FET (limit of detection of 1 ag/mL) and high selectivity are accomplished by effective coupling of the aptamers on the nanorings of the MoS2 nanopore edge for cortisol detection. We believe that MoS2 nanopore edge rings-based bio-FET would provide platforms for everyday biosensors with ultrahigh sensitivity and selectivity.
27帕克，H.;白，S.;森，A.;荣格，B.;希姆，J.;帕克，Y.C.;李，LP;金，Y.J.;Kim， S.由MoS 2 纳米孔环产生的基于超灵敏和选择性场效应晶体管的生物传感器。ACS Nano 2022， 16， 1826– 1835， DOI： 10.1021/acsnano.1c08255 - 28Zhang, N.; Zhang, Z.; Zhang, Q.; Wei, Q.; Zhang, J.; Tang, S.; Lv, C.; Wang, Y.; Zhao, H.; Wei, F. O2 Plasma Treated Biosensor for Enhancing Detection Sensitivity of Sulfadiazine in a High-k HfO2 Coated Silicon Nanowire Array. Sens. Actuators, B 2020, 306, 127464, DOI: 10.1016/j.snb.2019.127464Google Scholar Google 学术搜索28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXisVKru7%252FI&md5=dcb2d05d7e46cd37235ab8db6448792fO2 plasma treated biosensor for enhancing detection sensitivity of sulfadiazine in a high-κ HfO2 coated silicon nanowire arrayZhang, Nan; Zhang, Zhaohao; Zhang, Qingzhu; Wei, Qianhui; Zhang, Jing; Tang, Siqi; Lv, Chunguang; Wang, Yanrong; Zhao, Hongbin; Wei, Feng; Yan, Jiang; Baklanov, Mikhail; Yin, Huaxiang; Wang, Wenwu; Tu, HailingSensors and Actuators, B: Chemical (2020), 306 (), 127464CODEN: SABCEB; ISSN:0925-4005. (Elsevier B.V.)In this paper, highly uniform silicon nanowire (SiNW) arrays (∼30 nm in diam.) used as FET biosensors are fabricated by using a CMOS-compatible spacer image transfer (SIT) technol. with high efficiency compared with conventional electron beam (E-beam) lithog. An effective biochem. sensing approach that treated with optimization of O2 plasma on the SiNW biosensors coated with a 10 nm HfO2 high dielec. const. (high κ) film is demonstrated to enhance immobilization of antibodies. Furthermore, water contact angle (WCA) measurements verify that the increased no. of hydroxyl groups (-OH) on the HfO2 surfaces treated with O2 plasma reaches or surpasses that on a conventional SiO2 surface. Therefore, it is obsd. that the IDS/I0 is enlarged by 3.15 times compared with that of the HfO2 surface without O2 plasma treatment. In addn., real-time and label-free detection of sulfadiazine with high sensitivity and specific recognition is successfully achieved using the SiNW FET biosensor with the optimized process. And a 10 pg·mL-1 limit of detection (LOD) is achieved for the SiNW FET biosensor using O2 plasma treatment on an ultrathin HfO2 mentioned above. The proposed O2 plasma treatment on HfO2 provides an effective soln. for future FET biosensors coated with high-κ dielecs.
28张，N.;张志强;张，Q.;魏，Q.;张，J.;唐，S.;吕，C.;王彦;赵旭;Wei， F.O 2 等离子体处理的生物传感器用于提高磺胺嘧啶在高 k HfO 2 涂层硅纳米线阵列中的检测灵敏度。Sens. Actuators， B 2020， 306， 127464， DOI： 10.1016/j.snb.2019.127464 - 29Macchia, E.; Torricelli, F.; Bollella, P.; Sarcina, L.; Tricase, A.; Di Franco, C.; Osterbacka, R.; Kovacs-Vajna, Z. M.; Scamarcio, G.; Torsi, L. Large-Area Interfaces for Single-Molecule Label-free Bioelectronic Detection. Chem. Rev. 2022, 122, 4636– 4699, DOI: 10.1021/acs.chemrev.1c00290Google Scholar Google 学术搜索29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhsl2lsrs%253D&md5=cae9afe5ef559192f87d2468cfd1820eLarge-Area Interfaces for Single-Molecule Label-free Bioelectronic DetectionMacchia, Eleonora; Torricelli, Fabrizio; Bollella, Paolo; Sarcina, Lucia; Tricase, Angelo; Di Franco, Cinzia; Osterbacka, Ronald; Kovacs-Vajna, Zsolt M.; Scamarcio, Gaetano; Torsi, LuisaChemical Reviews (Washington, DC, United States) (2022), 122 (4), 4636-4699CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)A review. Bioelectronic transducing surfaces that are nanometric in size have been the main route to detect single mols. Though enabling the study of rarer events, such methodologies are not suited to assay at concns. below the nanomolar level. Bioelectronic field-effect-transistors with a wide (μm2-mm2) transducing interface are also assumed to be not suited, because the mol. to be detected is orders of magnitude smaller than the transducing surface. Indeed, it is like seeing changes on the surface of a one-kilometer-wide pond when a droplet of water falls on it. However, it is a fact that a no. of large-area transistors have been shown to detect at a limit of detection lower than femtomolar; they are also fast and hence innately suitable for point-of-care applications. This review critically discusses key elements, such as sensing materials, FET-structures, and target mols. that can be selectively assayed. The amplification effects enabling extremely sensitive large-area bioelectronic sensing are also addressed.
29玛奇亚，E.;托里切利，F.;博莱拉，P.;萨奇纳，L.;三大小写，A.;迪佛朗哥，C.;奥斯特巴卡，R.;科瓦奇-瓦伊纳，Z.M.;斯卡马西奥，G.;Torsi， L.用于单分子无标记生物电子检测的大面积界面。Chem. Rev. 2022， 122， 4636– 4699， DOI： 10.1021/acs.chemrev.1c00290 - 30Macchia, E.; Manoli, K.; Holzer, B.; Di Franco, C.; Ghittorelli, M.; Torricelli, F.; Alberga, D.; Mangiatordi, G. F.; Palazzo, G.; Scamarcio, G. Single-Molecule Detection with a Millimetre-Sized Transistor. Nat. Commun. 2018, 9, 3223, DOI: 10.1038/s41467-018-05235-zGoogle Scholar Google 学术搜索30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c7nslymsg%253D%253D&md5=14bad10d52d3b94a7cfe9413523fa803Single-molecule detection with a millimetre-sized transistorMacchia Eleonora; Manoli Kyriaki; Holzer Brigitte; Palazzo Gerardo; Torsi Luisa; Di Franco Cinzia; Scamarcio Gaetano; Ghittorelli Matteo; Torricelli Fabrizio; Alberga Domenico; Mangiatordi Giuseppe Felice; Mangiatordi Giuseppe Felice; Palazzo Gerardo; Torsi Luisa; Scamarcio Gaetano; Torsi LuisaNature communications (2018), 9 (1), 3223 ISSN:.Label-free single-molecule detection has been achieved so far by funnelling a large number of ligands into a sequence of single-binding events with few recognition elements host on nanometric transducers. Such approaches are inherently unable to sense a cue in a bulk milieu. Conceptualizing cells' ability to sense at the physical limit by means of highly-packed recognition elements, a millimetric sized field-effect-transistor is used to detect a single molecule. To this end, the gate is bio-functionalized with a self-assembled-monolayer of 10(12) capturing anti-Immunoglobulin-G and is endowed with a hydrogen-bonding network enabling cooperative interactions. The selective and label-free single molecule IgG detection is strikingly demonstrated in diluted saliva while 15 IgGs are assayed in whole serum. The suggested sensing mechanism, triggered by the affinity binding event, involves a work-function change that is assumed to propagate in the gating-field through the electrostatic hydrogen-bonding network. The proposed immunoassay platform is general and can revolutionize the current approach to protein detection.
30玛奇亚，E.;马诺利，K.;霍尔泽，B.;迪佛朗哥，C.;吉托雷利，M.;托里切利，F.;阿尔贝加，D.;曼吉亚托迪，GF;帕拉佐，G.;Scamarcio， G.使用毫米级晶体管进行单分子检测。Nat. Commun.2018， 9， 3223， DOI： 10.1038/s41467-018-05235-z - 31Seo, G.; Lee, G.; Kim, M. J.; Baek, S. H.; Choi, M.; Ku, K. B.; Lee, C. S.; Jun, S.; Park, D.; Kim, H. G. Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based Biosensor. ACS Nano 2020, 14, 5135– 5142, DOI: 10.1021/acsnano.0c02823Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnt1SrtrY%253D&md5=735104d0be58eaefaae38aa6f9877459Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor-Based BiosensorSeo, Giwan; Lee, Geonhee; Kim, Mi Jeong; Baek, Seung-Hwa; Choi, Minsuk; Ku, Keun Bon; Lee, Chang-Seop; Jun, Sangmi; Park, Daeui; Kim, Hong Gi; Kim, Seong-Jun; Lee, Jeong-O.; Kim, Bum Tae; Park, Edmond Changkyun; Kim, Seung IlACS Nano (2020), 14 (4), 5135-5142CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Coronavirus disease 2019 (COVID-19) is a newly emerging human infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously called 2019-nCoV). Based on the rapid increase in the rate of human infection, the World Health Organization (WHO) has classified the COVID-19 outbreak as a pandemic. Because no specific drugs or vaccines for COVID-19 are yet available, early diagnosis and management are crucial for contg. the outbreak. Here, we report a field-effect transistor (FET)-based biosensing device for detecting SARS-CoV-2 in clin. samples. The sensor was produced by coating graphene sheets of the FET with a specific antibody against SARS-CoV-2 spike protein. The performance of the sensor was detd. using antigen protein, cultured virus, and nasopharyngeal swab specimens from COVID-19 patients. Our FET device could detect the SARS-CoV-2 spike protein at concns. of 1 fg/mL in phosphate-buffered saline and 100 fg/mL clin. transport medium. In addn., the FET sensor successfully detected SARS-CoV-2 in culture medium (limit of detection [LOD]: 1.6 x 101 pfu/mL) and clin. samples (LOD: 2.42 x 102 copies/mL). Thus, we have successfully fabricated a promising FET biosensor for SARS-CoV-2; our device is a highly sensitive immunol. diagnostic method for COVID-19 that requires no sample pretreatment or labeling.
31徐，G.;李，G.;金，MJ;白，SH;崔，M.;顾，K.B.;李，CS;Jun， S.;朴，D.;Kim， HG 使用基于场效应晶体管的生物传感器快速检测人类鼻咽拭子标本中的 COVID-19 致病病毒 （SARS-CoV-2）。ACS 纳米 2020， 14， 5135– 5142， DOI： 10.1021/acsnano.0c02823 - 32Balasubramanian, K.; Kern, K. 25th Anniversary Article: Label-Free Electrical Biodetection Using Carbon Nanostructures. Adv. Mater. 2014, 26, 1154– 1175, DOI: 10.1002/adma.201304912Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVyjtLs%253D&md5=2a9c425965e0c41de5685ec8c099026c25th Anniversary Article: Label-Free Electrical Biodetection Using Carbon NanostructuresBalasubramanian, Kannan; Kern, KlausAdvanced Materials (Weinheim, Germany) (2014), 26 (8), 1154-1175CODEN: ADVMEW; ISSN:0935-9648. (Wiley-VCH Verlag GmbH & Co. KGaA)A review. Nanostructures are promising candidates for use as active materials for the detection of chem. and biol. species, mainly due to the high surface-to-vol. ratio and the unique phys. properties arising at the nanoscale. Among the various nanostructures, materials comprised of sp2-carbon enjoy a unique position due to the possibility to readily prep. them in various dimensions ranging from 0D, through 1D to 2D. This review focuses on the use of 1D (carbon nanotubes) and 2D (graphene) carbon nanostructures for the detection of biol. relevant mols. A key advantage is the possibility to perform the sensing operation without the use of any labels or complex reaction schemes. Along this spirit, various strategies reported for the label-free elec. detection of biomols. using carbon nanostructures are discussed. With their promise for ultimate sensitivity and the capability to attain high selectivity through controlled chem. functionalization, carbon-based nanobiosensors are expected to open avenues to novel diagnostic tools as well as to obtain new fundamental insight into biomol. interactions down to the single mol. level.
- 33Xu, H.; Zhang, H.; Guo, Z.; Shan, Y.; Wu, S.; Wang, J.; Hu, W.; Liu, H.; Sun, Z.; Luo, C. High-Performance Wafer-Scale MoS2 Transistors toward Practical Application. Small 2018, 14, e1803465 DOI: 10.1002/smll.201803465
- 34Munzer, A. M.; Michael, Z. P.; Star, A. Carbon Nanotubes for the Label-Free Detection of Biomarkers. ACS Nano 2013, 7, 7448– 7453, DOI: 10.1021/nn404544eGoogle Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3sbnvFSrtQ%253D%253D&md5=d3eed324a1568817fdafee8eafc7f9f4Carbon nanotubes for the label-free detection of biomarkersMunzer Alexandra M; Michael Zachary P; Star AlexanderACS nano (2013), 7 (9), 7448-53 ISSN:.Carbon nanotubes (CNTs) have been of high interest because of their potential to complement or to replace current biomedical sensor and assay techniques. By taking advantage of their unique electrical and optical properties, CNTs can be integrated into highly sensitive sensors and probes. We highlight recent advances toward applying CNTs to the biomedical field, focusing on a report by Reuel et al. in this issue of ACS Nano, wherein the inherent near-infrared (NIR) fluorescence of functionalized arrays of single-walled carbon nanotubes (SWNTs) is utilized for detection of several important biological markers.
- 35Chen, R. J.; Bangsaruntip, S.; Drouvalakis, K. A.; Wong Shi Kam, N.; Shim, M.; Li, Y.; Kim, W.; Utz, P. J.; Dai, H. Noncovalent Functionalization of Carbon Nanotubes for Highly Specific Electronic Biosensors. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 4984– 4989, DOI: 10.1073/pnas.0837064100Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjs1yju7o%253D&md5=4e6b6a8764d850e0858cfc63bbb4a4f0Noncovalent functionalization of carbon nanotubes for highly specific electronic biosensorsChen, Robert J.; Bangsaruntip, Sarunya; Drouvalakis, Katerina A.; Kam, Nadine Wong Shi; Shim, Moonsub; Li, Yiming; Kim, Woong; Utz, Paul J.; Dai, HongjieProceedings of the National Academy of Sciences of the United States of America (2003), 100 (9), 4984-4989CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Novel nanomaterials for bioassay applications represent a rapidly progressing field of nanotechnol. and nanobiotechnol. Here, we present an exploration of single-walled carbon nanotubes as a platform for investigating surface-protein and protein-protein binding and developing highly specific electronic biomol. detectors. Nonspecific binding on nanotubes, a phenomenon found with a wide range of proteins, is overcome by immobilization of polyethylene oxide chains. A general approach is then advanced to enable the selective recognition and binding of target proteins by conjugation of their specific receptors to polyethylene oxide-functionalized nanotubes. This scheme, combined with the sensitivity of nanotube electronic devices, enables highly specific electronic sensors for detecting clin. important biomols. such as antibodies assocd. with human autoimmune diseases.
- 36Liang, Y.; Xiao, M.; Wu, D.; Lin, Y.; Liu, L.; He, J.; Zhang, G.; Peng, L. M.; Zhang, Z. Wafer-Scale Uniform Carbon Nanotube Transistors for Ultrasensitive and Label-Free Detection of Disease Biomarkers. ACS Nano 2020, 14, 8866– 8874, DOI: 10.1021/acsnano.0c03523Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXht1alsr%252FJ&md5=68160e66665226f1b17d62aafeb5d4a3Wafer-Scale Uniform Carbon Nanotube Transistors for Ultrasensitive and Label-Free Detection of Disease BiomarkersLiang, Yuqi; Xiao, Mengmeng; Wu, Ding; Lin, Yanxia; Liu, Lijun; He, Jianping; Zhang, Guojun; Peng, Lian-Mao; Zhang, ZhiyongACS Nano (2020), 14 (7), 8866-8874CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)Carbon nanotube (CNT) field-effect transistor (FET)-based biosensors showed great potential for ultrasensitive biomarker detection, but challenges remain, which include unsatisfactory sensitivity, difficulty in stable functionalization, incompatibility with scalable fabrication, and nonuniform performance. Here, the authors describe ultrasensitive, label-free, and stable FET biosensors built on polymer-sorted high-purity semiconducting CNT films with wafer-scale fabrication and high uniformity. With a floating gate (FG) structure using an ultrathin Y2O3 high-κ dielec. layer, the CNT FET biosensors show amplified response and improved sensitivity compared with those sensors without Y2O3, which is attributed to the chem. gate-coupling effect dominating the sensor response. The CNT FG-FETs are modified to selectively detect specific disease biomarkers, namely, DNA sequences and microvesicles, with theor. record detection limits as low as 60 aM and 6 particles/mL, resp. Furthermore, the biosensors exhibit highly uniform performance over the 4 in. wafer as well as superior bias stress stability. The FG CNT FET biosensors could be extended as a universal biosensor platform for the ultrasensitive detection of multiple biol. mols. and applied in highly integrated and multiplexed all CNT-FET-based sensor architectures.
- 37Song, J.; Dailey, J.; Li, H.; Jang, H. J.; Zhang, P.; Wang, J. T.; Everett, A. D.; Katz, H. E. Extended Solution Gate OFET-based Biosensor for Label-free Glial Fibrillary Acidic Protein Detection with Polyethylene Glycol-Containing Bioreceptor Layer. Adv. Funct. Mater. 2017, 27, 1606506, DOI: 10.1002/adfm.201606506Google ScholarThere is no corresponding record for this reference.
- 38Tang, H.; Chen, J.; Nie, L.; Kuang, Y.; Yao, S. A Label-Free Electrochemical Immunoassay for Carcinoembryonic Antigen (CEA) Based on Gold Nanoparticles (AuNPs) and Nonconductive Polymer Film. Biosens. Bioelectron. 2007, 22, 1061– 1067, DOI: 10.1016/j.bios.2006.04.027Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlalsLfL&md5=fe76e004c2d22861fc26e7588ea00394A label-free electrochemical immunoassay for carcinoembryonic antigen (CEA) based on gold nanoparticles (AuNPs) and nonconductive polymer filmTang, Hao; Chen, Jinhua; Nie, Lihua; Kuang, Yafei; Yao, ShouzhuoBiosensors & Bioelectronics (2007), 22 (6), 1061-1067CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)A simple and sensitive label-free electrochem. immunoassay electrode for detection of carcinoembryonic antigen (CEA) has been developed. CEA antibody (CEAAb) was covalently attached on glutathione (GSH) monolayer-modified gold nanoparticle (AuNP) and the resulting CEAAb-AuNP bioconjugates were immobilized on Au electrode by electro-copolymn. with o-aminophenol (OAP). Electrochem. impedance spectroscopy and cyclic voltammetry studies demonstrate that the formation of CEA antibody-antigen complexes increases the electron transfer resistance of [Fe(CN)6]3-/4- redox pair at the poly-OAP/CEAAb-AuNP/Au electrode. The use of CEA antibody-AuNP bioconjugates and poly-OAP film could enhance the sensitivity and anti-nonspecific binding of the resulting immunoassay electrode. The preliminary application of poly-OAP/CEAAb-AuNP/Au electrode for detection of CEA was also evaluated.
- 39Hwang, M. T.; Heiranian, M.; Kim, Y.; You, S.; Leem, J.; Taqieddin, A.; Faramarzi, V.; Jing, Y.; Park, I.; van der Zande, A. M. Ultrasensitive Detection of Nucleic Acids Using Deformed Graphene Channel Field Effect Biosensors. Nat. Commun. 2020, 11, 1543, DOI: 10.1038/s41467-020-15330-9Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlvFGnsbo%253D&md5=d0023071579345f709e79f5035e10c77Ultrasensitive detection of nucleic acids using deformed graphene channel field effect biosensorsHwang, Michael Taeyoung; Heiranian, Mohammad; Kim, Yerim; You, Seungyong; Leem, Juyoung; Taqieddin, Amir; Faramarzi, Vahid; Jing, Yuhang; Park, Insu; van der Zande, Arend M.; Nam, Sungwoo; Aluru, Narayana R.; Bashir, RashidNature Communications (2020), 11 (1), 1543CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)Field-effect transistor (FET)-based biosensors allow label-free detection of biomols. by measuring their intrinsic charges. The detection limit of these sensors is detd. by the Debye screening of the charges from counter ions in solns. Here, we use FETs with a deformed monolayer graphene channel for the detection of nucleic acids. These devices with even millimeter scale channels show an ultra-high sensitivity detection in buffer and human serum sample down to 600 zM and 20 aM, resp., which are ~ 18 and ~ 600 nucleic acid mols. Computational simulations reveal that the nanoscale deformations can form 'elec. hot spots' in the sensing channel which reduce the charge screening at the concave regions. Moreover, the deformed graphene could exhibit a band-gap, allowing an exponential change in the source-drain current from small nos. of charges. Collectively, these phenomena allow for ultrasensitive electronic biomol. detection in millimeter scale structures.
- 40Xia, J.; Chen, F.; Li, J.; Tao, N. Measurement of the Quantum Capacitance of Graphene. Nat. Nanotechnol. 2009, 4, 505– 509, DOI: 10.1038/nnano.2009.177Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXpsFSisbs%253D&md5=52c50cccf922633718c8de20a4de9d69Measurement of the quantum capacitance of grapheneXia, Jilin; Chen, Fang; Li, Jinghong; Tao, NongjianNature Nanotechnology (2009), 4 (8), 505-509CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)Graphene has received widespread attention due to its unique electronic properties. Much of the research conducted so far has focused on electron mobility, which is detd. by scattering from charged impurities and other inhomogeneities. However, another important quantity, the quantum capacitance, was largely overlooked. Here, the authors report a direct measurement of the quantum capacitance of graphene as a function of gate potential using a three-electrode electrochem. configuration. The quantum capacitance has a nonzero min. at the Dirac point and a linear increase on both sides of the min. with relatively small slopes. The authors' findings-which are not predicted by theory for ideal graphene-suggest that charged impurities also influences the quantum capacitance. The authors also measured the capacitance in aq. solns. at different ionic concns., and the authors' results strongly indicate that the long-standing puzzle about the interfacial capacitance in C-based electrodes has a quantum origin.
- 41Xu, H.; Zhang, Z.; Wang, Z.; Wang, S.; Liang, X.; Peng, L. M. Quantum Capacitance Limited Vertical Scaling of Graphene Field-Effect Transistor. ACS Nano 2011, 5, 2340– 2347, DOI: 10.1021/nn200026eGoogle Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXitVSit70%253D&md5=bda1526d9b5a41c9f19c603d0b2f81cbQuantum capacitance limited vertical scaling of graphene field-effect transistorXu, Huilong; Zhang, Zhiyong; Wang, Zhenxing; Wang, Sheng; Liang, Xuelei; Peng, Lian-MaoACS Nano (2011), 5 (3), 2340-2347CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)A high-quality Y2O3 dielec. layer was grown directly on graphene and used to fabricated top-gate graphene field-effect transistors (FETs), and the thickness of the dielec. layer was reduced continuously down to 3.9 nm with an equiv. oxide thickness (EOT) of 1.5 nm and excellent insulativity. By measuring CV characteristics of two graphene FETs with different gate oxide thicknesses, the oxide capacitance and quantum capacitance are retrieved directly from the exptl. CV data without introducing any addnl. fitting process and parameters, yielding a relative dielec. const. of κ = 10 for Y2O3 on graphene and an oxide capacitance of about 2.28 μF/cm2. For a rather large gate voltage range, this oxide capacitance is comparable and sometimes even larger than the quantum capacitance of graphene. Since the total gate capacitance is detd. by the smaller of the oxide and quantum capacitance, our results show that not much further improvement can be gained via further vertical scaling down of the gate oxide, suggesting that Y2O3 may be the ultimate dielec. material for graphene. The Y2O3 gate dielec. layer with EOT of 1.5 nm may also satisfy the ultimate lateral scaling requirement on the gate length of graphene FET and be used effectively to control a graphene FET with a gate length as small as 1 nm.
- 42Zhou, Z. M.; Feng, Z.; Zhou, J.; Fang, B. Y.; Qi, X. X.; Ma, Z. Y.; Liu, B.; Zhao, Y. D.; Hu, X. B. Capillary Electrophoresis-Chemiluminescence Detection for Carcino-embryonic Antigen Based on Aptamer/Graphene Oxide Structure. Biosens. Bioelectron. 2015, 64, 493– 498, DOI: 10.1016/j.bios.2014.09.050Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1ahurbI&md5=0d2f3aa7e24f323bae16aec18c85afe1Capillary electrophoresis-chemiluminescence detection for carcino-embryonic antigen based on aptamer/graphene oxide structureZhou, Zi-Ming; Feng, Zhe; Zhou, Jun; Fang, Bi-Yun; Qi, Xiao-Xiao; Ma, Zhi-Ya; Liu, Bo; Zhao, Yuan-Di; Hu, Xue-BinBiosensors & Bioelectronics (2015), 64 (), 493-498CODEN: BBIOE4; ISSN:0956-5663. (Elsevier B.V.)A new strategy is proposed for detn. of carcino-embryonic antigen (CEA) based on aptamer/graphene oxide (Apt/GO) by capillary electrophoresis-chemiluminescence (CE-CL) detection system. CEA aptamer conjugated with horseradish peroxidase (HRP) firstly mixes with GO, and the CL will be quenched because the stack of HRP-Apt on GO leads to chemiluminescence resonance energy transfer (CRET). When CEA exists, the specific combination of HRP-Apt and CEA can form HRP-Apt-CEA complex, which dissocs. from GO. Then, the CL catalyzed by HRP-Apt-CEA complex can be detected without any CRET, and the content of CEA can be estd. by the CL intensity. It has been proved that the interference issue resulted from free HRP-Apt is solved well by mixing GO firstly with HRP-Apt, which blocks the free HRP-Apt's CL signal due to CL quenching effect of GO; and the interference resulted from GO to CL is also solved by CE, then the sensitivity and accuracy can be greatly improved. Results also showed that the CL intensity had a linear relationship with the concn. of CEA in the range from 0.0654 to 6.54 ng/mL, and the limit of detection was approx. 4.8 pg/mL (S/N=3). This proposed method with high specificity offers a new way for sepn. and detn. of biomol., and has good potential in application of biochem. and bioanal.
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