WO2019096011A1 - 一种基于mos管的双栅极调控超高灵敏度生物传感器 - Google Patents

一种基于mos管的双栅极调控超高灵敏度生物传感器 Download PDF

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WO2019096011A1
WO2019096011A1 PCT/CN2018/113289 CN2018113289W WO2019096011A1 WO 2019096011 A1 WO2019096011 A1 WO 2019096011A1 CN 2018113289 W CN2018113289 W CN 2018113289W WO 2019096011 A1 WO2019096011 A1 WO 2019096011A1
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layer
silicon
gate
shaped electrode
biosensor
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PCT/CN2018/113289
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English (en)
French (fr)
Inventor
王彤
姜岩峰
张烨
陈航
孙加林
李航
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无锡市人民医院
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Priority to US16/482,266 priority Critical patent/US10935551B2/en
Publication of WO2019096011A1 publication Critical patent/WO2019096011A1/zh

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    • H01L21/302—Treatment of semiconductor bodies using processes or apparatus not provided for in groups H01L21/20 - H01L21/26 to change their surface-physical characteristics or shape, e.g. etching, polishing, cutting
    • H01L21/306—Chemical or electrical treatment, e.g. electrolytic etching
    • H01L21/3065—Plasma etching; Reactive-ion etching
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
    • H01L21/00—Processes or apparatus adapted for the manufacture or treatment of semiconductor or solid state devices or of parts thereof
    • H01L21/02—Manufacture or treatment of semiconductor devices or of parts thereof
    • H01L21/04—Manufacture or treatment of semiconductor devices or of parts thereof the devices having at least one potential-jump barrier or surface barrier, e.g. PN junction, depletion layer or carrier concentration layer
    • H01L21/18—Manufacture or treatment of semiconductor devices or of parts thereof the devices having at least one potential-jump barrier or surface barrier, e.g. PN junction, depletion layer or carrier concentration layer the devices having semiconductor bodies comprising elements of Group IV of the Periodic System or AIIIBV compounds with or without impurities, e.g. doping materials
    • H01L21/30—Treatment of semiconductor bodies using processes or apparatus not provided for in groups H01L21/20 - H01L21/26
    • H01L21/302—Treatment of semiconductor bodies using processes or apparatus not provided for in groups H01L21/20 - H01L21/26 to change their surface-physical characteristics or shape, e.g. etching, polishing, cutting
    • H01L21/306—Chemical or electrical treatment, e.g. electrolytic etching
    • H01L21/308—Chemical or electrical treatment, e.g. electrolytic etching using masks

Definitions

  • the invention relates to the technical field of biological materials detection, in particular to a high success rate preparation and a using method of an ultra-high sensitivity biosensor based on a MOS tube.
  • the clinically widely used method for detecting tumor markers is a classical ELISA method, but its clinical application is limited to a certain extent due to its high requirements for detection environment, strong subjectivity, and low sensitivity.
  • the rapid development of nanometer (nm) technology has brought new ideas for the detection of tumor markers.
  • MOS tube Metal Oxide semiconductor biosensors can directly convert the target molecule to the surface of the device into electrical signals. As a sensor with good sensitivity and specificity, it is of great significance for improving the quality of human life.
  • a first object of the present invention is to provide a method for fabricating an ultra-high sensitivity biosensor based on a MOS tube, which can realize rapid and efficient detection of tumor-related markers on the basis of improving the traditional sensor processing technology, and is simple in operation and low in cost.
  • a second object of the present invention is to provide an application of the above biochip.
  • the working principle of the sensor is related to the specific binding of the antigen chain antibody through the linker chain; the specific binding causes the change of the electrical signal to be captured by the electrical test system connected by the probe station, thereby realizing the tumor marker in the sample.
  • Low concentration, immediate detection; the sample can be whole blood, serum or buffer solution.
  • a MOS tube-based biosensor, a mutual bonding detection system and a micro flow channel system comprising a substrate (8) and an ion implantation layer (7) laid on the substrate (8), Two sets of U-shaped electrode groups facing away from each other are disposed on the ion implantation layer (7); the two wings of the U-shaped electrode group are source-drain electrodes (1), (4), and a bottom of the U-shaped electrode group is connected a top gate (3), the U-shaped electrode group is internally provided with a surface gate (2) parallel to the top gate (3) and not connected to the U-shaped electrode group;
  • the source/drain electrodes (1) and (4) are composed of a silicon layer (10), an oxide layer (9) and a metal layer (6) in this order from the ion implantation layer (7);
  • the bottom of the U-shaped electrode is connected to the source and drain electrodes (1), (4) is a silicon nanowire (5); the silicon nanowire (5) is constructed by ultraviolet lithography and NLD etching; silicon nanowires ( 5) has a length of 10 nm to 100 um, a width of 10 nm to 5 um, and a thickness of 10 nm to 500 nm;
  • the two-wing source-drain electrodes (1), (4) and the surface gate (2) and the top gate (3) of the U-shaped electrode group are each wrapped with a passivation layer (11), and only the electrodes and the gate are exposed.
  • the end of the pole and the silicon nanowire (5) is not limited.
  • the applicant also provides a method for preparing a MOS tube-based biosensor, comprising the following steps:
  • the step (1) comprises the following steps:
  • A surface silicon thinning: cleaning silicon wafer, in the oxidation furnace through dry oxygen - wet oxygen - dry oxygen 900-1100 ° C high temperature oxidation for 1-10 hours; then use BOE rinse to remove the SiO 2 layer, the surface layer of silicon Reduction to 10-100 nm, obtaining a silicon layer (10);
  • nanowire patterns were obtained by exposure and development by ultraviolet stepper, and a layer of 10-1000 nm chromium was plated on the pattern region by magnetron sputtering, using NLD engraving. Etching the entire etching, removing Si and SiO 2 in the non-pattern area, exposing the substrate (8);
  • Ion implantation full-layer ion implantation, the exposed substrate (8) is turned on, and the surface gate (2) is prepared for later introduction; wherein the implanted ions are nitrogen, phosphorus or arsenic As, and the implantation dose is 1e14-1e20/ Cm 2 , the implantation energy is 10 keV-1 MeV, and the ion implantation layer (7) is obtained;
  • E source (1), drain (4), surface gate (2), top gate (3) pattern preparation: uniform coating of a layer of photoresist on the surface of SOI wafer, using UV lithography
  • the engraving method prepares a pattern of a source (1), a drain (4), a surface gate (2), and a top gate (3) at a specific position, and deposits Ti/Au/ on the surface of the substrate (8) by a thin film deposition technique.
  • the Ti three-layer metal is a metal layer (6) having a thickness selected from the group consisting of 1-10 nm/10-200 nm/1-10 nm, and finally stripped to obtain an electrode pattern;
  • ohmic contact preparation using a rapid annealing furnace, under nitrogen protection, rapidly heating to 350-500 degrees to maintain 1-100 seconds to cool down, to build ohmic contact between the electrode and the silicon nanowire (5);
  • Preparation of passivation layer (11) uniformly coating an electron beam photoresist on the surface of the SOI silicon wafer of the substrate (8), preparing a passivation layer by ultraviolet lithography, and using a thin film deposition technique on the substrate (8) A SiO 2 /SiN x double-layer film is deposited on the surface, the thickness is selected from 10 to 1000 nm/10 to 500 nm, and a passivation layer (11) is obtained by a stripping technique.
  • the thin film deposition technique can employ magnetron sputtering.
  • the passivation layer (11) is for preventing leakage.
  • the step (2) comprises the following steps:
  • the silane treatment of the silicon wafer is performed to make the surface exhibit super-hydrophobic property to facilitate the stripping of the subsequent micro-channel material; the polydimethylsiloxane PDMS or SU-8 glue is applied to the surface of the silicon wafer and cured; After curing, the PDMS is peeled off from the surface of the silicon wafer;
  • the step (3) comprises the following steps:
  • micro-channel system and the substrate (8) of the detection system are surface-treated by an oxygen plasma system to obtain a super-hydrophilic surface, and then the two are aligned and bonded to complete the preparation of the biosensor.
  • the material of the microchannel is polydimethylsiloxane PDMS or SU-8 glue.
  • the Applicant also provides a method of detecting a tumor marker using the biosensor described, comprising the steps of:
  • the modification of the antibody protein the micro-channel pathway is connected, and the antibody of 1-1000 ⁇ g/ml is passed through the solution at room temperature by using a syringe pump or a peristaltic pump, and the surface of the silicon nanowire (5) is retained, and the modification time is less than 0.1-10 hours;
  • the biosensor is washed with an immunostaining washing solution/PBST solution and nitrogen gas. The purpose of these operations is to modify the corresponding antibody of the target tumor marker on the silicon nanowire (5) of the biosensor;
  • the PBS solution is passed through the microchannel system for 1-100 minutes by a syringe pump or a peristaltic pump, and the flow rate is 0.001-100 ml/min, and the basic current value is obtained.
  • the sample to be tested is slowly transported to the silicon nanowire (5) region of the biosensor and left for a few minutes, so that the target tumor marker in the sample to be tested is fully combined with the antibody protein, and the solution is continued by using a syringe pump or a peristaltic pump. Delivery to the microchannel outlet;
  • C. Detection During the delivery process, the C-V mode is used and the electrical analyzer captures changes in electrical signals relative to the baseline.
  • the tumor markers include alpha-fetoprotein AFP, carcinoembryonic antigen CEA tumor markers.
  • the invention uses a novel tumor detection method, and the advantage of the method C-V detection method is that it is simple, super sensitive, and resistant to strong interference.
  • This method detects changes in capacitance in the channel during antigen-antibody binding. For example, when an antibody binds to a negatively charged antigenic protein, the total amount of charge accumulated in the channel increases due to charge adsorption, and in the case of a certain nanobelt area, the capacitance is eventually increased. The capacitance value is more stable than other electrical signals, and the detected curve is smoother. Even if it is not in the electromagnetic shielding box, good detection results can be obtained. In terms of detection sensitivity, the lowest detectable concentration is in the range of 1fg/ml ⁇ 1ng/ml. Sample inside.
  • the silicon nanobelt in the present invention is prepared by ultraviolet lithography combined with NLD etching. Compared with the previous wet etching process, the nanowire has a great improvement in roughness, width and success rate.
  • the source, drain, and double gate metals are Ti/Au/Ti three-layer metals, and the rapid annealing conditions are rapidly increased to 350-500 ° C for about 1-100 seconds to cool down, greatly reducing the annealing process.
  • the disconnection rate of silicon nanoribbons is obtained by the method of ultraviolet lithography combined with the stripping technique, which avoids the uncontrollable damage of the chip by etching and etching in the prior process. Thereby directly reducing the MOS based tube (Metal Oxide semiconductor) The processing and use cost of biosensors.
  • the present invention uses a MOS based tube (Metal Oxide semiconductor's biosensor directly converts the binding of multiple target molecules to the surface of the device directly into an electrical signal, exhibiting excellent sensitivity and specificity, while enabling multi-marker detection of a single sample. It is of great significance for improving the quality of human life. At the same time, the introduction of double gate greatly improves the regulation of gate-to-source leakage current and enhances the sensitivity of the device.
  • MOS based tube Metal Oxide semiconductor's biosensor directly converts the binding of multiple target molecules to the surface of the device directly into an electrical signal, exhibiting excellent sensitivity and specificity, while enabling multi-marker detection of a single sample. It is of great significance for improving the quality of human life.
  • the introduction of double gate greatly improves the regulation of gate-to-source leakage current and enhances the sensitivity of the device.
  • the biochip of the invention adapts to the whole blood sample, can avoid the loss of tumor markers caused by the sample pretreatment process, and can meet the needs of subsequent detection applications.
  • FIG. 1 is a structural diagram of a double-gate regulated ultra-high sensitivity biosensor based on a MOS tube;
  • Figure 2 is a schematic diagram of the modification of the surface of the silicon nanoribbon antibody: 13-hydroxyl, 14-Linker strand, 15-antibody corresponding to the tumor marker.
  • Fig. 3 is a diagram showing the effect of microchannel modification; wherein (a) the device is synchronously modified by the green fluorescent protein and the red fluorescent protein respectively through the microchannel system; (b) the negative reference only after passing the fluorescent protein alone A small amount of non-specific adsorption of red fluorescent protein was seen.
  • Figure 4 shows the non-specific adsorption of the microfluidic system after passing the green fluorescent protein; (a) the non-specific adsorption of the microfluidic system not blocked with BSA after passing the green fluorescent protein; (b) the utilization of BSA The non-specific adsorption of the closed microchannel system after passing the green fluorescent protein.
  • Figure 5 shows the sensor's real-time detection of the output transfer signal for solutions at different pH values.
  • Figure 6 shows the real-time monitoring of different concentrations of AFP in serum by the sensor.
  • Figure 7 shows the real-time monitoring of different concentrations of CEA in serum by the sensor.
  • the present invention provides a MOS tube-based biosensor, a mutual bonding detection system and a micro flow channel system, the detection system including a substrate 8 and an ion implantation layer 7 laid on the substrate 8 .
  • the ion implantation layer 7 is provided with two sets of U-shaped electrode groups facing away from each other; the two wings of the U-shaped electrode group are source and drain electrodes 1, 4, and a top gate 3 is connected to the bottom of the U-shaped electrode group.
  • the U-shaped electrode group is internally provided with a surface gate 2 which is parallel to the top gate 3 and is not connected to the U-shaped electrode group;
  • the source/drain electrodes 1, 4 and the top gate 3 are sequentially composed of a silicon layer 10, an oxide layer 9, and a metal layer 6 from the ion implantation layer 7 in order;
  • the bottom of the U-shaped electrode is connected to the source and drain electrodes 1 and 4 as a silicon nanowire 5;
  • the silicon nanowire 5 is formed by ultraviolet lithography and NLD etching;
  • the length of the silicon nanowire 5 is 10 nm to 100 um, and the width is 10nm ⁇ 5um, thickness 10nm ⁇ 500nm;
  • the two-wing source-drain electrodes 1, 4 of the U-shaped electrode group and the surface gate 2 and the top gate 3 are externally wrapped with a passivation layer 11 (not shown in FIG. 1), and only the electrodes and the gate are exposed. End and silicon nanowires 5.
  • the method for preparing a MOS tube-based biosensor provided by the invention comprises the following steps:
  • A surface silicon thinning: cleaning silicon wafer, in the oxidation furnace through dry oxygen - wet oxygen - dry oxygen 900-1100 ° C high temperature oxidation for 1-10 hours; then use BOE rinse to remove the SiO 2 layer, the surface layer of silicon Reduced to 10-100nm, the silicon layer 10 is obtained;
  • Ion implantation full-layer ion implantation, the exposed substrate 8 is turned on, and the surface gate 2 is prepared for later introduction; wherein the implanted ions are nitrogen, phosphorus or arsenic As, the implantation dose is 1e14-1e20/cm 2 , and the injection is performed. The energy is 10 keV-1 MeV, and the ion implantation layer 7 is obtained;
  • oxide layer 9 on the silicon nanowire 5 a 1-100 nm thick SiO 2 is grown in a portion of the silicon nanowire 5 by a MA6 ultraviolet lithography machine and PECVD, where the lead gate 3 is subsequently taken out;
  • source 1, drain 4, surface gate 2, top gate 3 pattern preparation uniformly coating a layer of photoresist on the surface of the SOI wafer, using ultraviolet lithography engraving method to prepare the source at a specific position 1.
  • the pattern of the drain 4, the surface gate 2, and the top gate 3 is deposited by depositing a Ti/Au/Ti three-layer metal on the surface of the substrate 8 by a thin film deposition technique, that is, a metal layer 6 having a thickness selected from the group consisting of 1-10 nm/ 10-200nm / 1-10nm, finally stripped to obtain the electrode pattern;
  • Preparation of passivation layer 11 uniformly coating an electron beam photoresist on the surface of the SOI silicon wafer of the substrate 8, preparing a passivation layer by ultraviolet lithography, and depositing SiO on the surface of the substrate 8 by a thin film deposition technique.
  • the thin film deposition technique can employ magnetron sputtering.
  • the substrate 8 of the biosensor uses an SOI wafer.
  • the silane treatment of the silicon wafer is performed to make the surface exhibit super-hydrophobic property to facilitate the stripping of the subsequent micro-channel material; the polydimethylsiloxane PDMS or SU-8 glue is applied to the surface of the silicon wafer and cured; After curing, the PDMS is peeled off from the surface of the silicon wafer;
  • Linker chain Firstly, the detection system after 1-10 min treatment with oxygen plasma is placed in 1-10 wt% APTES anhydrous ethanol solution for 1-100 min, dried by nitrogen and heated at 80-200 °C. -10h, further put into a 1-10wt% glutaraldehyde deionized water solution for 0.1-10 hours, nitrogen drying;
  • the biosensor can be prepared by sexual bonding.
  • FIG. 2 shows a schematic diagram of antibody protein and biosensor modification.
  • 14 is the antibody protein
  • 13 is a series of Linker chains
  • 12 is the OH- of the sensor surface after oxygen plasma treatment. It can be found that the antibody protein passes the chemistry.
  • the Linker chain is firmly tied to the biosensor.
  • the microchannels were first sealed on the surface of the device by irreversible sealing, and the green and red fluorescent proteins were modified on the surface of the device by the microchannel system. It can be seen that there is no leakage between the two microchannels, and both green and red fluorescent proteins are well modified to the surface of the device, as shown in Figure 3.
  • Figure 4 shows the non-specific adsorption of proteins by the microfluidic system using green fluorescent protein after blocking the microchannel with BSA.
  • the closed microfluidic system can be found.
  • the non-specific adsorption of proteins is significantly reduced.
  • the success rate of the above method for preparing a MOS tube-based biosensor can reach more than 90%.
  • Example 2 Trace, immediate detection of alpha fetoprotein (AFP), carcinoembryonic antigen ( CEA):
  • the modification of the antibody protein the micro-channel pathway is connected, and the antibody of 1-1000 ⁇ g/ml is passed through the surface of the silicon nanowire 5 at a normal temperature by a syringe pump or a peristaltic pump, and the modification time is less than 0.1-10 hours;
  • the dye washing solution/PBST solution is washed and the biosensor is blown dry with nitrogen. The purpose of these operations is to modify the corresponding antibody of the target tumor marker on the silicon nanowire 5 of the biosensor;
  • the PBS solution is passed through the microchannel system for 1-100 minutes by a syringe pump or a peristaltic pump, and the flow rate is 0.001-100 ml/min, and the basic current value is obtained.
  • the sample to be tested is slowly delivered to the silicon nanowire 5 region of the biosensor and stays for a few minutes, so that the target tumor marker in the sample to be tested is fully combined with the antibody protein, and the solution is continuously delivered to the syringe pump or peristaltic pump to the solution.
  • Microchannel outlet
  • the tumor markers include alpha-fetoprotein AFP, carcinoembryonic antigen CEA tumor markers.
  • Figure 5 shows the detection of different pH solutions by nanodevices. It can be seen that a MOS tube-based ultra-high sensitivity biosensor can stably respond to solutions of different pH values.
  • a MOS tube-based ultra-high sensitivity biosensor can stably respond to solutions of different pH values.
  • serum samples containing different concentrations of AFP and CEA obtained the following curves ( Figures 6, 7). It can be seen from the figure that as the concentration of the sample to be tested gradually increases, the detected capacitance value also shows a significant upward trend, and the detection range is as low as 1 fg/ml-1 ng/ml, spanning six orders of magnitude.
  • the present invention has achieved detection of a series of clinically common tumor markers, including AFP, CEA, CA125, PSA, ⁇ 2-MG, NES, SCC, etc., and diseases involved include liver cancer, gastric cancer, and colorectal cancer. , a series of tumors such as breast cancer, lung cancer and cervical cancer.
  • biomolecular enrichment system which can purify the antigen protein we need from whole blood to achieve efficient detection. It works by using a custom-made photolysis magnetic bead that adsorbs antigenic proteins in whole blood, then centrifuges to remove supernatants to obtain precipitated antigen-bearing magnetic beads, and finally separates the antigenic proteins and photocleavage beads by illumination. This biomolecular enrichment system will be described in detail in our other patent and will not be repeated here.

Abstract

一种基于MOS管的双栅极调控超高灵敏度生物传感器，包括互相键合的检测系统与微流道系统，检测系统包括衬底（8）以及平铺于衬底（8）上方的离子注入层（7），离子注入层（7）上设置两组背对的U型电极组；U型电极组的两翼为源漏电极（1）、（4），U型电极组的底部连出一条顶层栅极（3），内部设置一条与顶层栅极（3）平行、且不与U型电极组相连的表面栅极（2）。该传感器使用SOI片加工制备，通过离子注入技术实现了独特的双栅极控制结构，传感器由紫外光刻联合NLD刻蚀法制备而成，实现了肿瘤标志物的微量、即时、免标记检测。与常见的检测电流或电导的传感器相比，该传感器检测抗原抗体结合过程中沟道中电容的变化。利用该传感器的检测方法更加稳定、抗干扰性强，能满足在检测范围和敏感度方面的需求，尤在检测灵敏度方面表现极其突出，可以检测浓度在1fg/ml～1ng/ml范围内的样本。

Description

一种基于MOS管的双栅极调控超高灵敏度生物传感器 技术领域
本发明涉及生物材料检测技术领域，尤其是涉及一种基于MOS管的超高灵敏度生物传感器的高成功率制备及其使用方法。
 背景技术
恶性肿瘤是目前威胁人类健康的重大疾病之一，但是多数肿瘤出现临床表现都是处于晚期阶段，因而对其早期、快速、灵敏的诊断是提高人类生存质量的重要途径。目前临床上肿瘤发病的监控方法主要依靠影像学检查和肿瘤标志物检测。影像学检查由于分辨率和放射风险往往无法做到长期的随访。肿瘤标志物的检测虽然操作较为简便，但是肿瘤标志物检测的灵敏度和特异性成为限制其应用的重要因素。因而为肿瘤发病的风险判断和早期诊断寻找一个简单、准确检测方法成为提高人类生存质量的重要研究方向。
目前临床上广泛采用的肿瘤标志物检测方法是经典的ELISA法，但由于其对于检测环境的要求高、检测主观性强、灵敏度低等特性一定程度上限制了临床运用。纳米（nanometer，nm）技术的迅速发展，为检测肿瘤标记物的检测方法带来了新思路。其中基于MOS管（Metal oxide semiconductor）的生物传感器因其可以直接将目标分子与器件表面的结合直接转化为电信号，作为一种灵敏性和特异性都较好的传感器，对于提高人类生存质量具有十分重大的意义。
 技术问题
但是传统的湿法腐蚀制备硅纳米带的工艺，由于腐蚀速率的不可控性导致器件性能不稳定，获得的硅纳米带的宽度也不可控，最终使得成本大大增加，从而很大程度上限制了超高灵敏度生物传感器的广泛应用。因此，开发出一种高成功率超高灵敏度生物传感器的制备具有重要的应用价值。
 技术解决方案
针对现有技术存在的上述问题，本申请提供了一种基于MOS管的双栅极调控超高灵敏度生物传感器。本发明的第一个目的是提供一种基于MOS管的超高灵敏度生物传感器的制作方法，在改进传统传感器加工工艺的基础上实现肿瘤相关标记物的快速、高效检测，且操作简单，成本低廉。本发明的第二个目的是提供了上述生物芯片的应用。
本传感器的工作原理与抗原抗体之间通过linker链的特异性结合有关；所述特异性结合引起电学信号的改变可被探针台连接的电学测试系统捕捉到，从而实现了样本中肿瘤标志物低浓度、即时的检测；所述样本可为全血、血清或缓冲溶液。
本发明的技术方案如下：
一种基于MOS管的生物传感器，互相键合的检测系统与微流道系统，所述检测系统包括衬底（8）以及平铺于衬底（8）上方的离子注入层（7），所述离子注入层（7）上设置两组背对的U型电极组；所述U型电极组的两翼为源漏电极（1）、（4），所述U型电极组的底部连出一条顶层栅极（3），所述U型电极组内部设置一条与顶层栅极（3）平行、且不与U型电极组相连的表面栅极（2）；
所述源漏电极（1）、（4）从离子注入层（7）向上依次由硅层（10）、氧化层（9）及金属层（6）组成；
所述U型电极底部连接源漏电极（1）、（4）的为硅纳米线（5）；所述硅纳米线（5）通过紫外光刻及NLD刻蚀构建而成；硅纳米线（5）的长度为10nm~100um，宽度为10nm~5um，厚度为10nm~500nm；
所述U型电极组的两翼源漏电极（1）、（4）以及所述表面栅极（2）、顶层栅极（3）外部均包裹钝化层（11），仅裸露各电极、栅极的端部及硅纳米线（5）。
本申请人还提供了基于MOS管的生物传感器的制备方法，包括如下步骤：
（一）检测系统的制备；
（二）微流道的制备；
（三）检测系统与微流道系统的键合。
所述步骤（一）包含以下工序：
A、表层硅减薄：清洗硅片，在氧化炉中通过干氧——湿氧——干氧900-1100℃高温氧化1-10个小时；再用BOE漂洗去掉SiO 2层，将表层硅减至10-100nm，得到硅层（10）；
B、硅纳米线（5）的制备：通过紫外步进式光刻机曝光显影得到纳米线图形，用磁控溅射在图形区域镀上一层10-1000nm的铬作为掩膜，使用NLD刻蚀法整体刻蚀，去除非图形区域的Si和SiO 2，暴露出衬底（8）；
C、离子注入：全层离子注入，使暴露的衬底（8）导通，为后面引出表面栅极（2）做准备；其中注入离子为氮、磷或砷As，注入剂量1e14-1e20/cm 2，注入能量为10 keV-1 MeV，得到离子注入层（7）；
D、硅纳米线（5）上氧化层（9）的构建：通过MA6紫外光刻机及PECVD在硅纳米线（5）部分区域生长1-100nm厚的SiO 2，此处为后面引出顶层栅极（3）做准备；
E、源极（1）、漏极（4）、表面栅极（2）、顶层栅极（3）图形的制备：在SOI硅片表面均匀涂覆一层光刻胶，利用紫外光刻套刻方法在特定位置制备源极（1）、漏极（4）、表面栅极（2）、顶层栅极（3）的图形，利用薄膜沉积技术在衬底（8）表面沉积Ti/Au/Ti三层金属，即为金属层（6），厚度选自1-10nm/10-200nm/1-10nm，最后剥离即可得到电极图形；
F、欧姆接触的制备：利用快速退火炉，在氮气保护下，迅速升温至350-500度维持1-100秒降温，构建电极与硅纳米线（5）之间的欧姆接触；
G、钝化层（11）的制备：在衬底（8）的SOI硅片表面均匀涂覆一层电子束光刻胶，利用紫外光刻方法制备钝化层，利用薄膜沉积技术在衬底（8）表面沉积SiO 2/SiN x双层薄膜，厚度选自10-1000nm/10-500nm，结合剥离技术获得钝化层（11）。所述薄膜沉积技术，可以采用磁控溅射。钝化层（11）是为了防止漏电。
所述步骤（二）包含以下工序：
A、依次使用丙酮、异丙醇以及超纯水对硅片进行超声清洗各5-15分钟，利用匀胶台在表面涂覆一层光刻胶，涂覆厚度为2-10μm，利用紫外光刻获得微流道光刻胶图案；利用深硅刻蚀对硅片进行刻蚀，刻蚀深度100-150μm；
B、对硅片进行氟硅烷处理，使表面呈现超疏水性质以便于后续微流道材料的剥离；将聚二甲基硅氧烷PDMS或SU-8胶涂覆到硅片表面并固化处理；固化后将PDMS去硅片表面剥离下来；
C、利用打孔器在PDMS或SU-8胶表面打孔，获得微流道进口与出口，二者之间的区域则为微流道系统中的通路。
所述步骤（三）包含以下工序：
利用氧等离子体系统对微流道系统以及检测系统的衬底（8）进行表面处理，获得超亲水的表面，然后将二者对准键合即可完成生物传感器的制备。
所述微流道的材料为聚二甲基硅氧烷PDMS或SU-8胶。
本申请人还提供了利用所述的生物传感器检测肿瘤标志物的方法，包括以下步骤：
A、抗体蛋白的修饰：连接微流道通路，利用注射泵或蠕动泵将1-1000μg/ml的抗体于常温下通过并停留硅纳米线（5）表面，修饰时间小于0.1-10小时；随后用免疫染色洗涤液/PBST溶液清洗、氮气吹干生物传感器，这些操作的目的是在生物传感器的硅纳米线（5）上修饰目标肿瘤标志物相应的抗体；
B、分析：在探针台上完成固定、扎针、连接通路操作后，利用注射泵或蠕动泵将PBS溶液通过微流道系统1-100分钟，流速0.001-100ml/min，获得基础电流值，再将待测样本缓慢输送至生物传感器的硅纳米线（5）区域并停留数分钟，以使待测样本中的目标肿瘤标志物与抗体打蛋白充分结合，继续利用注射泵或蠕动泵将溶液输送至微流道出口；
C、检测：在输送过程中，使用C-V模式，电学分析仪捕获相对于基线电学信号的改变。
所述肿瘤标志物包括甲胎蛋白AFP、癌胚抗原CEA肿瘤标志物。
 有益效果
本发明使用了一种全新的肿瘤检测方法，这种方法为C-V检测法的优点在于简便、超高敏感、抗强干扰。这种方法检测的是抗原抗体结合过程中沟道中电容的变化。比如，当抗体与带负电的抗原蛋白结合，沟道中积聚的总电荷数由于电荷吸附作用就会增加，在纳米带面积一定的情况下，最终导致电容的增加。电容值相比于其他电学信号更稳定，检测到的曲线更加平滑，即使不在电磁屏蔽箱中也能获得良好的检测结果，在检测灵敏度方面，最低可以检测浓度在1fg/ml~1ng/ml范围内的样本。
本发明中硅纳米带是紫外光刻联合NLD刻蚀法制备。与既往的湿法腐蚀工艺相比，在纳米线的粗糙度、宽度、成功率方面具有极大提高。源极、漏极、双栅极的金属为Ti/Au/Ti三层金属，并且快速退火的条件为迅速升至350-500℃维持1-100秒左右便降温，极大降低了退火过程中硅纳米带的断线率。钝化层的制备利用紫外光刻结合剥离技术的方法获得，避免了既往工艺中刻蚀加腐蚀对于芯片不可控的损害。从而直接降低了基于MOS管（Metal oxide semiconductor）生物传感器的加工及使用成本。
本发明通过使用基于MOS管（Metal oxide semiconductor）的生物传感器可以直接将多种目标分子与器件表面的结合直接转化为电信号，表现出优异的灵敏性和特异性，同时实现了单个样本的多标志物检测。对于提高人类生存质量具有十分重大的意义。同时双栅的引入极大提高了栅压对源漏电流的调控作用，增强了器件的敏感性。
本发明所涉及的生物芯片适应全血样本，可避免因样本前处理过程而造成肿瘤标志物的损失，能够满足后续检测应用需求。
 附图说明
图1为本基于MOS管的双栅极调控超高灵敏度生物传感器的结构图；
图中，1、4：源漏电极，2：表面栅极，3：顶层栅极，5：纳米线，6：金属层，7：离子注入层，8：衬底，9：氧化层，10：硅层；钝化层11未标出。
图2为硅纳米带表面抗体修饰示意图：13-羟基，14-Linker链，15-对应于肿瘤标志物的抗体。
图3为微流道修饰效果图；其中(a)为分别用绿色荧光蛋白和用红色荧光蛋白通过微流道体系对器件进行同步修饰；(b)为仅单纯通过荧光蛋白后的阴性参照可以看到红色荧光蛋白的少量非特异性吸附。
图4为微流道系统通过绿色荧光蛋白后的非特异吸附情况；其中 (a)为未用BSA封闭的微流道系统在通过绿色荧光蛋白后的非特异性吸附情况；(b)为利用BSA封闭的微流道系统在通过绿色荧光蛋白后的非特异性吸附情况。
图5为本传感器对于在不同PH值溶液的输出转移信号的实时检测。
图6为本传感器对于血清中的不同浓度的AFP的实时监测。
图7为本传感器对于血清中的不同浓度的CEA的实时监测。
 本发明的实施方式
实施例1：本发明传感器的制备
如图1所示，本发明提供的基于MOS管的生物传感器，互相键合的检测系统与微流道系统，所述检测系统包括衬底8以及平铺于衬底8上方的离子注入层7，所述离子注入层7上设置两组背对的U型电极组；所述U型电极组的两翼为源漏电极1、4，所述U型电极组的底部连出一条顶层栅极3，所述U型电极组内部设置一条与顶层栅极3平行、且不与U型电极组相连的表面栅极2；
所述源漏电极1、4及顶层栅极3从离子注入层7向上依次由硅层10、氧化层9及金属层6组成；
所述U型电极底部连接源漏电极1、4的为硅纳米线5；所述硅纳米线5通过紫外光刻及NLD刻蚀构建而成；硅纳米线5的长度为10nm~100um，宽度为10nm~5um，厚度为10nm~500nm；
所述U型电极组的两翼源漏电极1、4以及所述表面栅极2、顶层栅极3外部均包裹钝化层11（图1中未画出），仅裸露各电极、栅极的端部及硅纳米线5。
本发明所提供的基于MOS管的生物传感器的制备方法，包括如下步骤：
（一）检测系统的制备；
A、表层硅减薄：清洗硅片，在氧化炉中通过干氧——湿氧——干氧900-1100℃高温氧化1-10个小时；再用BOE漂洗去掉SiO 2层，将表层硅减至10-100nm，得到硅层10；
B、硅纳米线5的制备：依次使用丙酮、异丙醇以及超纯水针对硅片进行超声清洗各5-15分钟，通过紫外步进式光刻机曝光显影得到纳米线图形，用磁控溅射在图形区域镀上一层10-1000nm的铬作为掩膜，使用NLD刻蚀法整体刻蚀，去除非图形区域的Si和SiO 2，暴露出衬底8；
C、离子注入：全层离子注入，使暴露的衬底8导通，为后面引出表面栅极2做准备；其中注入离子为氮、磷或砷As，注入剂量1e14-1e20/cm 2，注入能量为10 keV-1 MeV，得到离子注入层7；
D、硅纳米线5上氧化层9的构建：通过MA6紫外光刻机及PECVD在硅纳米线5部分区域生长1-100nm厚的SiO 2，此处为后面引出顶层栅极3做准备；
E、源极1、漏极4、表面栅极2、顶层栅极3图形的制备：在SOI硅片表面均匀涂覆一层光刻胶，利用紫外光刻套刻方法在特定位置制备源极1、漏极4、表面栅极2、顶层栅极3的图形，利用薄膜沉积技术在衬底8表面沉积Ti/Au/Ti三层金属，即为金属层6，厚度选自1-10nm/10-200nm/1-10nm，最后剥离即可得到电极图形；
F、欧姆接触的制备：利用快速退火炉，在氮气保护下，迅速升温至350-500度维持1-100秒降温，构建电极与硅纳米线5之间的欧姆接触；
G、钝化层11的制备：在衬底8的SOI硅片表面均匀涂覆一层电子束光刻胶，利用紫外光刻方法制备钝化层，利用薄膜沉积技术在衬底8表面沉积SiO 2/SiN x双层薄膜，厚度选自10-1000nm/10-500nm，结合剥离技术获得钝化层11。所述薄膜沉积技术，可以采用磁控溅射。
本生物传感器的衬底8采用SOI硅片。
（二）微流道系统的制备。
A、依次使用丙酮、异丙醇以及超纯水对硅片进行超声清洗各5-15分钟，利用匀胶台在表面涂覆一层光刻胶，涂覆厚度为2-10μm，利用紫外光刻获得微流道光刻胶图案；利用深硅刻蚀对硅片进行刻蚀，刻蚀深度100-150μm；
B、对硅片进行氟硅烷处理，使表面呈现超疏水性质以便于后续微流道材料的剥离；将聚二甲基硅氧烷PDMS或SU-8胶涂覆到硅片表面并固化处理；固化后将PDMS去硅片表面剥离下来；
C、利用打孔器在PDMS或SU-8胶表面打孔，获得微流道进口与出口，二者之间的区域则为微流道系统中的通路。
（三）检测系统与微流道系统的集成：
A、Linker链的构建：首先将采用氧等离子体处理1-10min后的检测系统放入1-10wt%的APTES无水乙醇溶液中反应1-100min，氮气吹干后于80-200℃加热0.1-10h，再放入1-10wt%的戊二醛去离子水溶液中反应0.1-10小时，氮气吹干；
B、PDMS或SU-8微流道与检测系统的封接：对清洁的PDMS或SU-8微流道进行氧等离子体处理1-10min，获得超亲水的表面，立即与检测系统进行不可逆性键合，即可完成生物传感器的制备。
图2所示为抗体蛋白与生物传感器修饰的示意图，图中14即为抗体蛋白，13表示一系列Linker链，12为经过氧等离子体处理后传感器表面的OH-，可以发现，抗体蛋白通过化学Linker链与生物传感器牢牢绑定。
为了验证这种微流道结果的整体修饰效果，首先使用不可逆性封接将这种微流道封接在器件表面，同时分别通过微流道系统在器件表面进行了绿色和红色荧光蛋白的修饰，可以看到两个微流道之间没有发生任何渗漏，同时绿色和红色荧光蛋白都很好的修饰到了器件表面，如图3所示。
BSA对于微流道体系的封闭效果：图4所示在使用BSA对于微流道进行封闭之后利用绿色荧光蛋白检测了微流道体系对于蛋白的非特异性吸附结果可以发现，封闭后微流道系统对于蛋白的非特异性吸附明显下降。
以上方法制备基于MOS管的生物传感器的成功率可达90%以上。
实施例2：甲胎蛋白（AFP）、 癌胚抗原（CEA）的微量、即时检测：
按照下列方法进行检测：
A、抗体蛋白的修饰：连接微流道通路，利用注射泵或蠕动泵将1-1000μg/ml的抗体于常温下通过并停留硅纳米线5表面，修饰时间小于0.1-10小时；随后用免疫染色洗涤液/PBST溶液清洗、氮气吹干生物传感器，这些操作的目的是在生物传感器的硅纳米线5上修饰目标肿瘤标志物相应的抗体；
B、分析：在探针台上完成固定、扎针、连接通路操作后，利用注射泵或蠕动泵将PBS溶液通过微流道系统1-100分钟，流速0.001-100ml/min，获得基础电流值，再将待测样本缓慢输送至生物传感器的硅纳米线5区域并停留数分钟，以使待测样本中的目标肿瘤标志物与抗体打蛋白充分结合，继续利用注射泵或蠕动泵将溶液输送至微流道出口；
C、检测：在输送过程中，使用C-V模式，电学分析仪捕获相对于基线电学信号的改变。所述肿瘤标志物包括甲胎蛋白AFP、癌胚抗原CEA肿瘤标志物。
图5所示的是纳米器件对不同PH值溶液的检测情况。可以看到一种基于MOS管的超高灵敏度生物传感器可以稳定的对不同PH值的溶液即时响应。同时我们对含有不同浓度AFP和CEA的血清样品进行了研究、检测并得到如下曲线（图6、7）。从图中可以看到，随着被检测样品的浓度逐渐增大，检测到的电容值也呈明显上升趋势，检测范围低至1fg/ml-1ng/ml，跨越六个数量级。
目前，本发明已经实现对临床上常见的一系列肿瘤标记物的检测，其中包括AFP、CEA、CA125、PSA、β2-MG、NES、SCC等，涉及到的疾病包括肝癌、胃癌、结直肠癌、乳腺癌、肺癌、子宫颈癌等一系列肿瘤。
值得说明的是，以上所有这些检测都是在全血条件下进行的。众所周知，全血的成分极其复杂，包含了各种各样的蛋白、脂质、氨基酸和缓冲离子等，这对于检测的结果有极大的影响。我们主要通过生物分子富集系统来解决这个难题，这个系统可以从全血中提纯出我们所需要的抗原蛋白，实现高效的检测。它的工作原理是使用一种订制的光裂解磁珠，能够在全血中吸附抗原蛋白，然后离心去上清得到沉淀的带抗原的磁珠，最后光照法分离抗原蛋白和光裂解磁珠。这种生物分子富集系统将会在我们另外一篇专利中详细介绍，这里不再赘述。
以上所述，仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专业的技术人员，在不脱离本发明技术方案范围内，当可利用上述揭示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。

Claims (8)

  1. 一种基于MOS管的生物传感器，包括互相键合的检测系统与微流道系统，所述检测系统包括衬底（8）以及平铺于衬底（8）上方的离子注入层（7）；其特征在于：
    所述离子注入层（7）上设置两组背对的U型电极组；所述U型电极组的两翼为源漏电极（1）、（4），所述U型电极组的底部连出一条顶层栅极（3），所述U型电极组内部设置一条与顶层栅极（3）平行、且不与U型电极组相连的表面栅极（2）；
    所述源漏电极（1）、（4）从离子注入层（7）向上依次由硅层（10）、氧化层（9）及金属层（6）组成；
    所述U型电极底部连接源漏电极（1）、（4）的为硅纳米线（5）；所述硅纳米线（5）通过紫外光刻及NLD刻蚀构建而成；硅纳米线（5）的长度为10nm~100um，宽度为10nm~5um，厚度为10nm~500nm；
    所述U型电极组的两翼源漏电极（1）、（4）以及所述表面栅极（2）、顶层栅极（3）外部均包裹钝化层（11），仅裸露各电极、栅极的端部及硅纳米线（5）。
  2. 一种基于MOS管的生物传感器的制备方法，其特征在于包括如下步骤：
    （一）检测系统的制备；
    （二）微流道的制备；
    （三）检测系统与微流道系统的键合。
  3. 根据权利要求1或2所述的制备方法，其特征在于：所述步骤（一）包含以下工序：
    A、表层硅减薄：清洗硅片，在氧化炉中通过干氧——湿氧——干氧900-1100℃高温氧化1-10个小时；再用BOE漂洗去掉SiO 2层，将表层硅减至10-100nm，得到硅层（10）；
    B、硅纳米线（5）的制备：通过紫外步进式光刻机曝光显影得到纳米线图形，用磁控溅射在图形区域镀上一层10-1000nm的铬作为掩膜，使用NLD刻蚀法整体刻蚀，去除非图形区域的Si和SiO 2，暴露出衬底（8）；
    C、离子注入：全层离子注入，使暴露的衬底（8）导通，为后面引出表面栅极（2）做准备；其中注入离子为氮、磷或砷As，注入剂量1e14-1e20/cm 2，注入能量为10 keV-1 MeV，得到离子注入层（7）；
    D、硅纳米线（5）上氧化层（9）的构建：通过MA6紫外光刻机及PECVD在硅纳米线（5）部分区域生长1-100nm厚的SiO 2，此处为后面引出顶层栅极（3）做准备；
    E、源极（1）、漏极（4）、表面栅极（2）、顶层栅极（3）图形的制备：在SOI硅片表面均匀涂覆一层光刻胶，利用紫外光刻套刻方法在特定位置制备源极（1）、漏极（4）、表面栅极（2）、顶层栅极（3）的图形，利用薄膜沉积技术在衬底（8）表面沉积Ti/Au/Ti三层金属，即为金属层（6），厚度选自1-10nm/10-200nm/1-10nm，最后剥离即可得到电极图形；
    F、欧姆接触的制备：利用快速退火炉，在氮气保护下，迅速升温至350-500度维持1-100秒降温，构建电极与硅纳米线（5）之间的欧姆接触；
    G、钝化层（11）的制备：在衬底（8）的SOI硅片表面均匀涂覆一层电子束光刻胶，利用紫外光刻方法制备钝化层，利用薄膜沉积技术在衬底（8）表面沉积SiO 2/SiN x双层薄膜，厚度选自10-1000nm/10-500nm，结合剥离技术获得钝化层（11）。
  4. 根据权利要求1或2所述的制备方法，其特征在于：所述步骤（二）包含以下工序：
    A、依次使用丙酮、异丙醇以及超纯水对硅片进行超声清洗各5-15分钟，利用匀胶台在表面涂覆一层光刻胶，涂覆厚度为2-10μm，利用紫外光刻获得微流道光刻胶图案；利用深硅刻蚀对硅片进行刻蚀，刻蚀深度100-150μm；
    B、对硅片进行氟硅烷处理，使表面呈现超疏水性质以便于后续微流道材料的剥离；将聚二甲基硅氧烷PDMS或SU-8胶涂覆到硅片表面并固化处理；固化后将PDMS去硅片表面剥离下来；
    C、利用打孔器在PDMS或SU-8胶表面打孔，获得微流道进口与出口，二者之间的区域则为微流道系统中的通路。
  5. 根据权利要求1或2所述的制备方法，其特征在于：所述步骤（三）包含以下工序：
    利用氧等离子体系统对微流道系统以及检测系统的衬底（8）进行表面处理，获得超亲水的表面，然后将二者对准键合即可完成生物传感器的制备。
  6. 根据权利要求1所述的生物传感器，其特征在于，所述微流道的材料为聚二甲基硅氧烷PDMS或SU-8胶。
  7. 一种利用权利要求1所述的生物传感器检测肿瘤标志物的方法，其特征在于包括以下步骤：
    A、抗体蛋白的修饰：连接微流道通路，利用注射泵或蠕动泵将1-1000μg/ml的抗体于常温下通过并停留硅纳米线（5）表面，修饰时间小于0.1-10小时；随后用免疫染色洗涤液/PBST溶液清洗、氮气吹干生物传感器，这些操作的目的是在生物传感器的硅纳米线（5）上修饰目标肿瘤标志物相应的抗体；
    B、分析：在探针台上完成固定、扎针、连接通路操作后，利用注射泵或蠕动泵将PBS溶液通过微流道系统1-100分钟，流速0.001-100ml/min，获得基础电流值，再将待测样本缓慢输送至生物传感器的硅纳米线（5）区域并停留数分钟，以使待测样本中的目标肿瘤标志物与抗体打蛋白充分结合，继续利用注射泵或蠕动泵将溶液输送至微流道出口；
    C、检测：在输送过程中，使用C-V模式，电学分析仪捕获相对于基线电学信号的改变。
  8. 根据权利要求7所述的方法，其特征在于，所述肿瘤标志物包括甲胎蛋白AFP、癌胚抗原CEA肿瘤标志物。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113514420A (zh) * 2021-04-20 2021-10-19 桂林电子科技大学 一种双u型波导结构的高灵敏度传感器

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108169485B (zh) * 2017-11-20 2019-04-23 无锡市人民医院 一种基于mos管的双栅极调控超高灵敏度生物传感器
CN108957007B (zh) * 2018-07-24 2021-08-17 无锡市人民医院 一种联合透析装置和硅纳米线场效应管的生物传感器
CN109402680B (zh) * 2018-11-02 2021-11-16 徐州晶迪电子有限公司 一种mos晶体管用掩模板材料的制备方法
CN110632304A (zh) * 2019-09-09 2019-12-31 广西华银医学检验所有限公司 一种大肠癌免疫传感器的制备及其检测方法
CN111157762B (zh) * 2020-01-09 2021-09-24 大连理工大学 一种高灵敏度纳米线加速度传感器
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CN111257316A (zh) * 2020-02-11 2020-06-09 军事科学院系统工程研究院卫勤保障技术研究所 一种便携式纳米检测仪
CN111939992A (zh) * 2020-07-23 2020-11-17 侯双 捕获和富集循环肿瘤细胞的微流体系统的制备方法及微流体装置
CN112326758A (zh) * 2020-09-21 2021-02-05 江苏元上分子工程研究中心有限公司 一种硅纳米生物传感器及制备方法和病毒检测方法
CN113960128B (zh) * 2020-12-15 2022-08-23 有研工程技术研究院有限公司 基于钾离子适配体修饰的硅纳米线场效应管生物传感器
CN113048887B (zh) * 2021-03-03 2022-09-30 西北工业大学 一种基于四区域等线宽相位调制光栅的面外位移传感单元
CN113351265B (zh) * 2021-05-26 2022-10-25 西安交通大学 一种基于微导线磁场驱动微流体磁混合的系统的加工方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060166415A1 (en) * 2004-06-07 2006-07-27 Sharp Laboratories Of America, Inc. Two-transistor tri-state inverter
CN101592627A (zh) * 2009-03-19 2009-12-02 苏州纳米技术与纳米仿生研究所 多通道高灵敏生物传感器的制作集成方法
CN102435655A (zh) * 2011-09-05 2012-05-02 湖南大学 基于场效应晶体管的肿瘤诊断仪及其检测方法
CN102951591A (zh) * 2012-11-20 2013-03-06 华中科技大学 一种用于捕获循环肿瘤细胞的微流道结构及其制备方法
CN103558279A (zh) * 2013-11-15 2014-02-05 中国科学院上海微系统与信息技术研究所 一种基于硅纳米线隧穿场效应晶体管的生物传感器及其制备方法
CN107328838A (zh) * 2017-04-13 2017-11-07 南京大学 一种基于双栅极单电子晶体管的电子生物传感器及制备方法
CN108169485A (zh) * 2017-11-20 2018-06-15 无锡市人民医院 一种基于mos管的双栅极调控超高灵敏度生物传感器

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0786420A (ja) * 1993-09-10 1995-03-31 Fujitsu Ltd 半導体装置
CN103681829A (zh) * 2013-12-27 2014-03-26 上海集成电路研发中心有限公司 硅基单电子晶体管结构及其制备方法
CN104779275B (zh) * 2015-04-30 2017-11-28 湖北工业大学 自激励自旋单电子电磁场效应晶体管、制备方法及应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060166415A1 (en) * 2004-06-07 2006-07-27 Sharp Laboratories Of America, Inc. Two-transistor tri-state inverter
CN101592627A (zh) * 2009-03-19 2009-12-02 苏州纳米技术与纳米仿生研究所 多通道高灵敏生物传感器的制作集成方法
CN102435655A (zh) * 2011-09-05 2012-05-02 湖南大学 基于场效应晶体管的肿瘤诊断仪及其检测方法
CN102951591A (zh) * 2012-11-20 2013-03-06 华中科技大学 一种用于捕获循环肿瘤细胞的微流道结构及其制备方法
CN103558279A (zh) * 2013-11-15 2014-02-05 中国科学院上海微系统与信息技术研究所 一种基于硅纳米线隧穿场效应晶体管的生物传感器及其制备方法
CN107328838A (zh) * 2017-04-13 2017-11-07 南京大学 一种基于双栅极单电子晶体管的电子生物传感器及制备方法
CN108169485A (zh) * 2017-11-20 2018-06-15 无锡市人民医院 一种基于mos管的双栅极调控超高灵敏度生物传感器

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113514420A (zh) * 2021-04-20 2021-10-19 桂林电子科技大学 一种双u型波导结构的高灵敏度传感器
CN113514420B (zh) * 2021-04-20 2022-10-04 桂林电子科技大学 一种双u型波导结构的高灵敏度传感器

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