WO2021184494A1 - 一种传感器的制备方法、传感器以及传感器的检测方法 - Google Patents

一种传感器的制备方法、传感器以及传感器的检测方法 Download PDF

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WO2021184494A1
WO2021184494A1 PCT/CN2020/087123 CN2020087123W WO2021184494A1 WO 2021184494 A1 WO2021184494 A1 WO 2021184494A1 CN 2020087123 W CN2020087123 W CN 2020087123W WO 2021184494 A1 WO2021184494 A1 WO 2021184494A1
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sensor
early
frequency
silicon oxide
oxide layer
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French (fr)
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陈达
王璟璟
王鸿飞
张文斌
宋戈
刘运时
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Shandong University of Science and Technology
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/02—Analysing fluids
    • G01N29/036—Analysing fluids by measuring frequency or resonance of acoustic waves
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/22—Details, e.g. general constructional or apparatus details
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/01—Indexing codes associated with the measuring variable
    • G01N2291/014—Resonance or resonant frequency
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/02—Indexing codes associated with the analysed material
    • G01N2291/022—Liquids
    • G01N2291/0228—Aqueous liquids

Definitions

  • the present invention belongs to the technical field of instant testing, and particularly relates to a method for preparing a sensor for detecting early markers of heart damage, a sensor prepared by the preparation method, and a detection method for the sensor.
  • Cardiovascular disease is one of the most serious diseases that endanger human health and life. Among them, acute myocardial infarction is the most common and most dangerous. Early diagnosis and treatment of acute myocardial infarction is the key to reducing its mortality and improving patient prognosis. Early markers of heart damage are important detection indicators for clinical diagnosis of heart diseases such as myocardial infarction, myocardial ischemia, and heart failure.
  • the early markers of heart damage mainly include creatine kinase MB isoenzyme (CK-MB), cardiac troponin (cTn), heart-shaped fatty acid binding protein (h-FABP), B-type natriuretic peptide (BNP) and so on.
  • CK-MB creatine kinase MB isoenzyme
  • cTn cardiac troponin
  • h-FABP heart-shaped fatty acid binding protein
  • BNP B-type natriuretic peptide
  • most of the early markers of heart damage detected by routine laboratories are based on chemiluminescence, enzyme-linked immunosorbent assay (ELISA) and immunoturbidimetric method. Although these methods can provide accurate, reliable, and quality-controlled results, they require complex equipment, milliliters of samples, and professional operations.
  • POCT point-of-care testing
  • Patent Document 1 discloses a biochip and a detection method for the detection of five myocardial markers, including a biosensor, which is a wafer platform and a spot antibody coated on the wafer platform.
  • the spot antibody can be coupled with magnetic beads.
  • the conjugated antibody and the marker protein form an immune complex, and the concentration of the marker protein is determined by measuring the strength of the magnetoresistance signal on the complex on the biosensor.
  • Patent Document 2 discloses a microfluidic biochip and detection method of magnetic particles for myocardial infarction and heart failure.
  • the marker protein forms an immune complex, and the concentration of the marker protein is determined by measuring the strength of the complex magnetoresistance signal on the wafer platform.
  • Patent Document 3 discloses a method for preparing a label-free electrochemical sensor for cardiac troponin I and a method for detecting cTnI.
  • a new label-free electrochemical sensor is constructed by combining electrochemically active substances on site with biological immune reactions. The sensor specifically reacts the sensor with the target molecule (cardiac marker cTnI) to obtain a cardiac marker antigen-antibody binding layer, which causes electrochemical activity perturbation and makes the output electrochemical signal produce regular changes.
  • Patent Document 4 discloses a method for preparing a ferrocene-based covalent organic framework modified electrode and a method for electrochemically detecting troponin. This invention patent application provides a ferrocene with high selectivity and high detection sensitivity Preparation method of base covalent organic framework modified electrode and its application in electrochemical sensor.
  • Patent Document 1 Publication number: CN 108845146 A, publication date: November 20, 2018;
  • Patent Document 2 Publication number: CN 108663525 A, publication date: October 16, 2018;
  • Patent Document 3 Publication number: CN 110161100 A, publication date: August 23, 2019;
  • Patent Document 4 Publication number: CN 110044987 A, publication date: July 23, 2019.
  • the device size is large, and it is difficult to form a miniature integrated test system; (2) The test of magnetoresistance or electrochemical detection principle is easily affected by the dielectric and magnetic properties of the liquid test sample itself, resulting in the final The test result is inaccurate.
  • One of the objectives of the present invention is to provide a method for preparing a sensor for detecting early markers of heart damage, so as to produce a sensor capable of detecting early markers of heart damage.
  • a method for preparing a sensor for detecting early markers of heart damage includes the following steps:
  • the piezoelectric film sensor includes a diaphragm type piezoelectric film sensor, a solid assembly type piezoelectric film sensor with an acoustic reflection layer, or an air gap structure piezoelectric film sensor.
  • the silicon oxide layer is obtained by magnetron sputtering deposition.
  • the sidewall of the micro runner is made of SU8 negative glue, polydimethylsiloxane or polyimide material, and is made by ordinary photolithography, soft photolithography or nanoimprinting methods;
  • the height of the side wall of the runner is 1-5 mm.
  • step IV the surface of the glass cover and the side wall of the micro flow channel are treated with particles such as oxygen before the glass cover is set.
  • step V the assembly process of the early marker antibody of heart damage is as follows:
  • the heart injury early marker antibody assembled on the surface of the silicon oxide layer in the microchannel includes creatine kinase MB isoenzyme, cardiac troponin, heart-shaped fatty acid binding protein or B-type natriuretic peptide antibody .
  • the second objective of the present invention is to provide a sensor for detecting early markers of heart damage.
  • the sensor has a small size, and the sensor can effectively improve the detection accuracy of the concentration of early markers of heart damage.
  • a sensor for detecting early markers of heart damage which is prepared by the above-mentioned sensor preparation method.
  • the third object of the present invention is to provide a sensor detection method for early detection of cardiac injury markers, so as to realize the real-time measurement of the concentration of the early markers of cardiac injury.
  • a sensor detection method for early detection of cardiac injury markers based on the above-mentioned sensor
  • the detection method of the sensor includes the following steps:
  • the frequency shift value the frequency baseline value-the stable value of the resonance frequency
  • step s6 Compare the concentration calibration curve in step s3 to obtain the concentration of the early markers of heart damage corresponding to the sensor response.
  • step s2 after each passage of serum standard solutions of different concentrations of early markers of cardiac injury, it is necessary to use sodium lauryl sulfate to restore the sensor after the adsorption of the antibodies of the early markers of cardiac injury.
  • the present invention proposes a method for preparing a sensor for the detection of early markers of cardiac injury.
  • the sensor prepared by this method (because the piezoelectric thin film resonator is small in size, only on the order of millimeters) has a relatively small size. Small, conducive to the use of semiconductor technology for large-scale and low-cost manufacturing, and can be integrated into wearable electronic devices or other small electronic devices.
  • the sensor prepared by the above method is based on the principle of quality sensitivity to detect the early markers of heart injury, which reduces the interference of the liquid sample itself, and is beneficial to improve the accuracy of the early marker detection of heart injury; in addition, the present invention also proposes a method based on the above The detection method of the sensor prepared by the method is conducive to real-time measurement of early markers of heart damage.
  • Fig. 1 is a flow chart of a method for preparing a sensor for detecting early markers of heart damage in Example 1 of the present invention
  • FIG. 2 is a schematic diagram of the structure of the piezoelectric film sensor in Embodiment 1 of the present invention.
  • Example 3 is a schematic diagram of the assembly of the sensor used for early marker detection of heart damage in Example 1 of the present invention.
  • FIG. 4 is a schematic structural diagram of a sensor used for early detection of markers of heart injury in Embodiment 2 of the present invention.
  • FIG. 5 is a flowchart of a detection method of a sensor for detecting early markers of heart damage in Embodiment 3 of the present invention.
  • Example 6 is a frequency-time curve diagram of the sensor used for early detection of cardiac injury markers in Example 3 of the present invention to pure serum and a serum standard solution of cardiac troponin (cTnI), an early marker of cardiac injury;
  • cTnI cardiac troponin
  • Fig. 7 is a graph showing the concentration calibration curve of cardiac troponin (cTnI) in Example 3 of the present invention.
  • FIG. 8 is a schematic diagram of the results of measurement comparison between the detection method in Example 3 of the present invention and the conventional chemiluminescence method.
  • 101-piezoelectric layer 101-piezoelectric layer, 102-upper electrode, 103-lower electrode, 104-support layer, 105-silicon substrate, 106-silicon oxide layer, 107-micro channel sidewall, 108-glass cover plate;
  • 109-Antibody for early markers of heart injury 110-Acoustic reflection layer, 111-Air gap, 112-Micro channel.
  • This embodiment 1 describes a method for preparing a sensor for detecting early markers of heart damage.
  • the preparation method of the sensor includes the following steps:
  • the piezoelectric thin film sensor prepared in the first embodiment is, for example, a diaphragm type piezoelectric thin film sensor, as shown in FIG. 2(a).
  • the sensor uses an aluminum nitride film as the piezoelectric layer 101, the c-axis has an inclination angle of 24 degrees with the vertical direction, and the thickness is 1 micron.
  • the upper electrode 102 is made of gold, and the lower electrode 103 is made of tungsten, and both have a thickness of 100 nanometers.
  • the support layer 104 is a silicon nitride film with a thickness of 800 nanometers.
  • the silicon substrate 105 under the sonic oscillation area is completely etched to form a diaphragm structure.
  • the piezoelectric film sensor made in this embodiment 1 can also be a solid assembly type piezoelectric film sensor with an acoustic reflection layer, as shown in Fig. 2(b), or an air gap type structure piezoelectric film sensor, as shown in Fig. As shown in 2(c).
  • the symbol 110 indicates the acoustic reflection layer
  • the symbol 111 indicates an air gap.
  • a diaphragm type piezoelectric film sensor is taken as an example to specifically describe the preparation process of the sensor in the first embodiment.
  • the silicon oxide layer 106 is obtained by a magnetron sputtering deposition method, and the deposition thickness is 200 nanometers.
  • the function of the silicon oxide layer 106 is to provide a hydroxyl surface for assembling sensitive antibodies, while isolating the test liquid from the electrode.
  • the sidewall 107 of the micro-channel is preferably made of polydimethylsiloxane (PDMS), using ordinary photoresist as a template, and fabricated by a soft photolithography method.
  • PDMS polydimethylsiloxane
  • the side wall 107 of the micro flow channel can also be made of SU8 negative glue or polyimide (PI) material.
  • the manufacturing process of the sidewall 107 of the micro-channel also includes, for example, ordinary photolithography or nanoimprinting methods.
  • the height of the side wall 107 of the micro flow channel is 1-5 mm, for example, the value may be 2 mm.
  • a glass cover 108 is provided on the upper surface of the side wall 107 of the micro channel to form a micro channel, as shown in Figure 3(d).
  • the surface of the glass cover and the sidewall of the micro flow channel need to be treated with particles such as oxygen
  • the processing power density is 1 watt/cm2
  • the oxygen atmosphere pressure is 20 Pa
  • the processing time is 10 minutes.
  • the effect of the surface treatment of particles such as oxygen is to ensure the connection effect between the side wall 107 of the micro flow channel and the glass cover 108, to ensure the reliability of the use of the micro flow channel, and to avoid the leakage of the solution in the micro flow channel.
  • the function of designing the micro flow channel on the piezoelectric thin film sensor in the first embodiment is to enable the sensor prepared by this method to perform real-time continuity measurement of the sample solution to be tested into the micro flow channel based on the principle of mass sensitivity. It is helpful to ensure the accuracy of the measurement results, and at the same time, it is helpful to replace the solution and realize the rapid measurement of the sample (no need to wait for drying).
  • cardiac troponin Take cardiac troponin as an example to illustrate the assembly process of the early marker antibodies of cardiac injury, as follows:
  • deionized water and ethanol are introduced into the micro flow channel 112 to clean the surface.
  • APTES aminopropyltriethoxysilane
  • a 5% aqueous solution of glutaraldehyde was further introduced for 30 minutes to modify the surface of the amino group with aldehyde groups.
  • bovine serum albumin (BSA) solution in PBS was used to block unbound aldehyde groups for 30 minutes, minimizing non-specific binding effects.
  • CK-MB creatine kinase MB isoenzyme
  • h-FABP heart-shaped fatty acid binding protein
  • BNP B-type natriuretic peptide
  • Example 1 Through the preparation method in Example 1, a sensor for early marker detection of heart damage can be prepared.
  • the size of the sensor manufactured in the first embodiment is small, it is advantageous for large-scale and low-cost manufacturing using semiconductor technology, and can be integrated into wearable electronic devices or other small electronic devices.
  • the senor prepared in Example 1 detects early markers of heart injury based on the principle of quality sensitivity, which is beneficial to reduce the interference of the liquid sample itself, thereby improving the accuracy of early marker detection of heart injury.
  • This embodiment 2 describes a sensor for early detection of cardiac injury markers, and the sensor is prepared based on the preparation method of the sensor for early detection of cardiac injury markers in the above-mentioned embodiment 1.
  • the senor includes a piezoelectric thin film sensor, a silicon oxide layer 106, a sidewall 107 of the micro channel, a glass cover 108, and an antibody 109 that is an early marker of cardiac injury.
  • the silicon oxide layer 106 is located on the surface of the upper electrode 102 of the piezoelectric film sensor.
  • the sidewall 107 of the micro channel is disposed on the surface of the silicon oxide layer 106.
  • the glass cover 108 covers the upper surface of the side wall 107 of the micro channel and is connected to the side wall 107 of the micro channel to form the micro channel 112.
  • the antibody 109 a marker of early cardiac injury, is assembled on the surface of the silicon oxide layer 106 in the microfluidic channel.
  • the heart injury early marker antibody 109 in this example 2 includes creatine kinase MB isoenzyme (CK-MB), cardiac troponin (cTnI), heart-shaped fatty acid binding protein (h-FABP), or B-type sodium urine Antibodies such as peptide (BNP).
  • CK-MB creatine kinase MB isoenzyme
  • cTnI cardiac troponin
  • h-FABP heart-shaped fatty acid binding protein
  • BNP B-type sodium urine Antibodies such as peptide
  • Embodiment 1 the advantages of the sensor in Embodiment 2 have been described in more detail, and will not be repeated here.
  • Embodiment 2 can also assemble different sensitive (ie early markers of heart damage) antibodies for different sensors to form a sensor array, which can simultaneously detect multiple early markers of heart damage.
  • This embodiment 3 describes a detection method of a sensor for early detection of cardiac injury markers, and the detection method is implemented based on the sensor for early detection of cardiac damage markers described in the above-mentioned embodiment 2.
  • cardiac troponin as an example to illustrate the detection process of early markers of cardiac injury.
  • the detection method of the sensor for detecting early markers of heart damage includes the following steps:
  • the inlet and outlet of the microchannel 112 use injection needles to input and output liquid samples respectively, and the liquid samples are injected through a syringe pump and a flow pump, and a network analyzer or a frequency measuring circuit is used to measure the frequency of the resonator.
  • the resonator frequency of the thin film sensor drops significantly, and the steady state resonant frequency should be taken as the frequency baseline, as shown in Figure 6. .
  • the serum standard solution concentration of cardiac troponin (cTnI) shown in FIG. 6 is 0.1 ng/ml.
  • SDS sodium dodecyl sulfate
  • this embodiment 3 is not limited to the use of SDS, and other liquids with the same or similar functions as SDS can be used to restore the sensor after the absorption of the antibody of the early marker of heart injury, so that the sensor can be reused.
  • the square represents the data points obtained by the actual test (the line above and below the square represents the standard deviation of the 5 measurements), and the dashed line represents the linear fit to the test result.
  • the concentration of cardiac troponin (cTnI) has an approximately linear relationship with its frequency shift value.
  • the frequency shift value the frequency baseline value-the stable value of the resonance frequency.
  • the serum sample to be tested in Example 3 is a human blood sample obtained through a standard blood sampling process.
  • step s6 Compare the concentration calibration curve in step s3 to obtain the cardiac troponin (cTnI) concentration corresponding to the sensor response.
  • the above process is the detection method of cardiac troponin (cTnI) concentration.
  • CK-MB creatine kinase MB isoenzyme
  • h-FABP heart-shaped fatty acid binding protein
  • BNP B-type natriuretic peptide
  • This example 3 is beneficial to realize the real-time dynamic detection of the early markers of heart damage, and the detection results are accurate and reliable.
  • the specific principle analysis is as follows: the liquid flowing in the test can wash away the substances that are not bound to the antibody on the sensor surface, thereby reducing the surface of the sensor. The non-specific adsorption, thereby improving accuracy.
  • the microfluidic channel has a fixed channel and cavity volume, so that the volume of the sample entering the sensitive area of the sensor can be accurately controlled, which improves the reliability and repeatability of the test.
  • the piezoelectric thin-film resonator is manufactured using silicon semiconductor technology, it can be integrated into a micro integrated test system.
  • the dynamic measurement of flowing liquid can achieve continuity and automatic measurement with other components (such as blood separation, centrifugation, etc.), and after one measurement is completed , Can pass in a new liquid (such as SDS) to clear the surface, to achieve multiple automatic repeated measurement.
  • this Example 3 also compared the results of the detection by the method of the present invention with the results of the conventional chemiluminescence method, and the comparison results are shown in FIG. 8. Among them, the square represents the detection result of the data point obtained in the actual test, and the dotted line represents the result of linear fitting to the test result. By comparing the detection result of the method of the present invention with the result obtained by the conventional chemiluminescence method, the results are consistent, indicating that the detection accuracy of the detection method in Example 3 of the present invention is better.

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Abstract

一种用于心脏损伤早期标志物检测的传感器的制备方法、通过该制备方法制得的传感器以及该传感器的检测方法。该制备方法包括：I. 制备压电薄膜传感器；II. 在压电薄膜传感器的上电极表面沉积氧化硅层；III. 在氧化硅层的表面制作微流道侧壁；IV. 在微流道侧壁的上表面设置玻璃盖板，形成微流道；V. 在微流道内氧化硅层的表面组装心脏损伤早期标志物抗体。该制得的传感器，基于质量敏感原理进行检测，降低了干扰，利于提高检测的精度，且尺寸较小。

Description

一种传感器的制备方法、传感器以及传感器的检测方法 技术领域
本发明属于即时检验技术领域，特别涉及一种用于心脏损伤早期标志物检测的传感器的制备方法、通过所述制备方法制得的传感器以及所述传感器的检测方法。
 背景技术
心血管疾病是危害人类健康及生命的最严重疾病之一。其中，急性心肌梗死最常见、最危险。尽早诊断和治疗急性心肌梗死是降低其死亡率和改善患者预后的关键。心脏损伤早期标志物是临床诊断心肌梗死、心肌缺血、心衰等心脏疾病的重要检测指标。
心脏损伤早期标志物主要包括肌酸激酶MB同工酶(CK-MB)、心肌肌钙蛋白(cTn)、心型脂肪酸结合蛋白（h-FABP）、B型尿钠肽(BNP)等。目前，大多数常规实验室检测的心脏损伤早期标志物是基于化学发光、酶联免疫吸附法(ELISA)和免疫比浊法。虽然这些方法能够提供精确、可靠和质量控制的结果，但需要复杂的设备、毫升体积的样品和专业操作。
近年来，随着即时检验 (point-of-care testing，简称POCT)技术的兴起，医学行为发生了革命性的变化。POCT设备的分析时间短，样品消耗量低，对急性心肌梗死等危急重大疾病的诊断具有重要意义。目前，已经开发出多种有希望用于检测心脏生物标志物的POCT心脏损伤早期标志物传感器，包括电化学、磁学、荧光等多种原理。例如：
专利文献1公开了一种用于心肌五项标志物检测的生物芯片、检测方法，包括生物传感器，为晶元平台以及晶元平台上包被的点样抗体，点样抗体能够与磁珠偶联抗体和标志物蛋白形成免疫复合物，通过测定生物传感器上复合物上磁阻信号强弱判断标志物蛋白浓度。
专利文献2公开了一种心梗心衰磁微粒微流控生物芯片、检测方法，包括具有微流通道的PCB板，微流通道内设置有生物传感器，点样抗体能够与磁珠偶联抗体和标志物蛋白形成免疫复合物，通过测定晶元平台上复合物磁阻信号强弱判断标志物蛋白浓度。
专利文献3公开了一种心肌肌钙蛋白I的免标记电化学传感器制备方法及对cTnI的检测方法，通过现场制备具有电化学活性的物质与生物免疫反应相结合构建了新型的免标记型的传感器，将传感器与目标分子（心脏标志物cTnI）进行特异性反应，得到心脏标志物抗原-抗体结合层，从而引起电化学活性扰动，使输出的电化学信号产生规律性变化。
专利文献4公开了一种二茂铁基共价有机框架修饰电极的制备方法及其电化学检测肌钙蛋白的方法，该发明专利申请提供一种选择性高、检测灵敏度较高的二茂铁基共价有机框架修饰电极的制备方法及其在电化学传感器上的应用。
现有技术文献
专利文献
专利文献1：公开号为：CN 108845146 A，公开日期：2018年11月20日；
专利文献2：公开号为：CN 108663525 A，公开日期：2018年10月16日；
专利文献3：公开号为：CN 110161100 A，公开日期：2019年08月23日；
专利文献4：公开号为：CN 110044987 A，公开日期：2019年07月23日。
 技术问题
然而，以上基于电化学、磁学或荧光等原理的技术方案存在如下缺陷：
(1)、器件尺寸较大，且很难形成微型集成测试系统；(2)、磁阻或电化学检测原理的测试容易受到液体测试样品本身的介电性和磁学性质影响，导致最终的检测结果不准确。
 技术解决方案
本发明的目的之一在于提出一种用于心脏损伤早期标志物检测的传感器的制备方法，以便制得能够进行心脏损伤早期标志物检测的传感器。
本发明为了实现上述目的，采用如下技术方案：
一种用于心脏损伤早期标志物检测的传感器的制备方法，包括如下步骤：
I. 制备压电薄膜传感器；
II. 在压电薄膜传感器的上电极表面沉积氧化硅层；
III. 在氧化硅层的表面制作微流道侧壁；
IV. 在微流道侧壁的上表面设置玻璃盖板，形成微流道；
V. 在微流道内氧化硅层的表面组装心脏损伤早期标志物抗体。
优选地，步骤I中，压电薄膜传感器包括横膈膜型压电薄膜传感器、具有声反射层的固体装配型压电薄膜传感器、或空气隙型结构压电薄膜传感器。
优选地，步骤II中，氧化硅层采用磁控溅射沉积的方法得到。
优选地，步骤III中，微流道侧壁选用SU8负胶、聚二甲基硅氧烷或聚酰亚胺材料，并采用普通光刻、软光刻或纳米压印方法制作而成；微流道侧壁的高度为1-5毫米。
优选地，步骤IV中，在设置玻璃盖板之前将玻璃盖板和微流道侧壁表面使用氧等粒子处理。
优选地，步骤V中，心脏损伤早期标志物抗体的组装过程如下：
首先在微流道中通入去离子水和乙醇清洗表面；
然后通入氨丙基三乙氧基硅烷的乙醇溶液，与氧化硅层的羟基相互作用形成氨基表面；
进一步通入戊二醛水溶液进行醛基改性；
再通入心脏损伤早期标志物抗体的磷酸盐缓冲液溶液，进行抗体的共价结合；
最后通入牛血清蛋白的磷酸盐缓冲液溶液阻断未结合的醛基。
优选地，步骤V中，在微流道内氧化硅层的表面组装的心脏损伤早期标志物抗体包括肌酸激酶MB同工酶、心肌肌钙蛋白、心型脂肪酸结合蛋白或B型尿钠肽抗体。
本发明的目的之二在于提出一种用于心脏损伤早期标志物检测的传感器，该传感器的尺寸较小，利用该传感器能够有效提高心脏损伤早期标志物浓度的检测精度。
本发明为了实现上述目的，采用如下技术方案：
一种用于心脏损伤早期标志物检测的传感器，其是通过上述传感器的制备方法制得的。
本发明的目的之三在于提出一种用于心脏损伤早期标志物检测的传感器的检测方法，以便实现对心脏损伤早期标志物浓度的实时测量。
本发明为了实现上述目的，采用如下技术方案：
一种用于心脏损伤早期标志物检测的传感器的检测方法，基于上面提到的传感器；
该传感器的检测方法包括如下步骤：
s1. 在微流道中通入纯血清样品，测量压电薄膜谐振器的谐振频率；
将谐振器处于稳定状态时的谐振频率作为测量的频率基线；
s2. 在微流道中依次通入含有不同浓度心脏损伤早期标志物的血清标准溶液，并持续测量压电薄膜谐振器在不同浓度心脏损伤早期标志物的血清标准溶液下的谐振频率；
通过以上过程依次得到多个谐振频率随时间的变化曲线；
s3. 取各个变化曲线中谐振频率的稳定值，然后分别与频率基线进行比较，将频率移动值作为传感器的响应，得到该传感器对心脏损伤早期标志物的浓度校正曲线；
其中，频率移动值=频率基线值-谐振频率的稳定值；
s4. 在微流道中通入待测血清样品；
s5. 持续测量压电薄膜谐振器的谐振频率，得到谐振频率随时间的变化曲线，取该变化曲线上的频率稳定值，并与频率基线比较，以频率移动值作为传感器响应；
s6. 对照步骤s3中的浓度校正曲线，获得传感器响应对应的心脏损伤早期标志物浓度。
优选地，步骤s2中，在每次通入不同浓度心脏损伤早期标志物的血清标准溶液之后，均需要使用十二烷基硫酸钠恢复心脏损伤早期标志物抗体吸附后的传感器。
 有益效果
如上所述，本发明提出了一种用于心脏损伤早期标志物检测的传感器的制备方法，通过该方法制得的传感器（由于压电薄膜谐振器尺寸较小，仅为毫米量级）尺寸较小，利于采用半导体工艺进行大规模及低成本制造，可集成于可穿戴电子设备或其他小型电子设备中。通过上述方法制得的传感器，基于质量敏感原理进行心脏损伤早期标志物检测，降低了液体样品本身的干扰，利于提高心脏损伤早期标志物检测的精度；此外，本发明还提出了一种基于上述方法制得的传感器的检测方法，利于实现对心脏损伤早期标志物的实时测量。
 附图说明
图1为本发明实施例1中用于心脏损伤早期标志物检测的传感器的制备方法的流程框图；
图2为本发明实施例1中压电薄膜传感器的结构示意图；
图3为本发明实施例1中用于心脏损伤早期标志物检测的传感器的组装示意图；
图4为本发明实施例2中用于心脏损伤早期标志物检测的传感器的结构示意图；
图5为本发明实施例3中用于心脏损伤早期标志物检测的传感器的检测方法的流程框图；
图6为本发明实施例3中用于心脏损伤早期标志物检测的传感器对纯血清和心脏损伤早期标志物心肌肌钙蛋白(cTnI)的血清标准溶液的频率-时间曲线图；
图7为本发明实施例3中对心肌肌钙蛋白(cTnI)的浓度校正曲线图。
图8为采用本发明实施例3中的检测方法与常规化学发光法进行测量对照的结果示意图。
其中，101-压电层，102-上电极，103-下电极，104-支撑层，105-硅衬底，106-氧化硅层，107-微流道侧壁，108-玻璃盖板；
109-心脏损伤早期标志物抗体，110-声反射层，111-空气隙，112-微流道。
 本发明的实施方式
下面结合附图以及具体实施方式对本发明作进一步详细说明：
实施例1
本实施例1述及了一种用于心脏损伤早期标志物检测的传感器的制备方法。
如图1所示，该传感器的制备方法包括如下步骤：
I. 制备压电薄膜传感器。
本实施例1制得的压电薄膜传感器例如是横膈膜型压电薄膜传感器，如图2(a)所示。
该传感器采用氮化铝薄膜为压电层101，c轴与垂直方向具有倾角24度，厚度为1微米。上电极102为金材料，下电极103为钨材料，厚度均为100纳米。
支撑层104为氮化硅薄膜，厚度为800纳米。
声波震荡区域下方的硅衬底105被完全刻蚀形成横膈膜结构。
当然，本实施例1制得的压电薄膜传感器还可以是具有声反射层的固体装配型压电薄膜传感器，如图2(b)所示，或空气隙型结构压电薄膜传感器，如图2(c)所示。
其中，图2(b)中，标记110表示声反射层，图2(c)中，标记111表示空气隙。
下面以横膈膜型压电薄膜传感器为例具体说明本实施例1中传感器的制备过程。
II. 在制得的压电薄膜传感器（如图3(a)中示出了一种横膈膜型压电薄膜传感器）的上电极表面沉积氧化硅层106，如图3(b)所示。
该氧化硅层106是采用磁控溅射沉积的方法得到的，沉积厚度为200纳米。
氧化硅层106的作用是为组装敏感抗体提供羟基表面，同时隔离测试液体与电极。
III. 在氧化硅层106的表面制作微流道侧壁107，如图3(c)所示。由图3(c)可知，本实施例1制得的微流道侧壁107有两个，且均位于氧化硅层106的表面。
微流道侧壁107优选采用聚二甲基硅氧烷（PDMS），采用普通光刻胶为模板，软光刻法制作而成。当然，微流道侧壁107还可以选用SU8负胶或聚酰亚胺（PI）材料等。
微流道侧壁107的制作工艺例如还包括普通光刻或纳米压印方法等。
微流道侧壁107的高度1-5毫米，例如可以取值为2毫米。
IV. 在微流道侧壁107的上表面设置玻璃盖板108，形成微流道，如图3(d)所示。
其中，在设置玻璃盖板108之前，需要将玻璃盖板和微流道侧壁表面使用氧等粒子处理，处理功率密度为1瓦/平方厘米，氧气的气氛压强为20Pa，处理时间10分钟。
氧等粒子表面处理的作用在于，保证微流道侧壁107与玻璃盖板108之间的连接效果，保证微流道的使用可靠性，同时避免微流道中的溶液出现泄漏。
本实施例1在压电薄膜传感器上设计微流道的作用在于：使得该方法制得的传感器，能够基于质量敏感原理对通入到微流道内的待测样品溶液进行实时的连续性测量，利于保证测量结果的精确性，同时利于更换溶液，实现样品的快速测量（不需要等干燥）。
V. 在微流道内氧化硅层106的表面组装心脏损伤早期标志物抗体109，如图3(e)所示。
以心肌肌钙蛋白为例说明心脏损伤早期标志物抗体的组装过程，具体如下：
首先在微流道112中通入去离子水和乙醇清洗表面。
然后通入氨丙基三乙氧基硅烷（APTES）浓度2%的乙醇溶液并浸泡60分钟。由于APTES的硅烷基团与氧化硅层的羟基相互作用，形成氨基表面。
进一步通入戊二醛5%的水溶液30分钟，对氨基表面进行醛基改性。
再通入10微克/毫升的心肌肌钙蛋白（cTnI）的磷酸盐缓冲液（PBS）溶液2小时，进行抗体的共价结合。
最后通入0.1%牛血清蛋白（BSA）的PBS溶液阻断未结合的醛基30分钟，使得非特异性结合效应最小化。通过以上过程，实现了心肌肌钙蛋白抗体的组装过程。
组装肌酸激酶MB同工酶(CK-MB)、心型脂肪酸结合蛋白（h-FABP）、以及B型尿钠肽(BNP)等其他心脏损伤早期标志物抗体的方法与上述方法相同，此处不再赘述。
通过本实施例1中制备方法能够制得用于心脏损伤早期标志物检测的传感器。
由于本实施例1制得的传感器尺寸较小，因而利于采用半导体工艺进行大规模及低成本制造，可集成于可穿戴电子设备或其他小型电子设备中。
此外，本实施例1制得的传感器，基于质量敏感原理进行心脏损伤早期标志物检测，利于降低液体样品本身的干扰，从而提高心脏损伤早期标志物检测的精度。
实施例2
本实施例2述及了一种用于心脏损伤早期标志物检测的传感器，该传感器基于上述实施例1中用于心脏损伤早期标志物检测的传感器的制备方法制得的。
如图4所示，该传感器包括压电薄膜传感器、氧化硅层106、微流道侧壁107、玻璃盖板108以及心脏损伤早期标志物抗体109。
其中，氧化硅层106位于压电薄膜传感器的上电极102表面。
微流道侧壁107设置于氧化硅层106表面。
玻璃盖板108覆盖于微流道侧壁107的上表面并与微流道侧壁107连接，形成微流道112。
心脏损伤早期标志物抗体109组装于微流道内氧化硅层106的表面。
本实施例2中的心脏损伤早期标志物抗体109包括肌酸激酶MB同工酶(CK-MB)、心肌肌钙蛋白（cTnI）、心型脂肪酸结合蛋白（h-FABP）或B型尿钠肽(BNP)等抗体。
在实施例1中已对本实施例2中传感器的优点做了比较详细的描述，此处不再赘述。
本实施例2还可以针对不同的传感器分别组装不同的敏感（即心脏损伤早期标志物）抗体，组成传感器阵列，能够同时对多种心脏损伤早期标志物进行联合检测。
实施例3
本实施例3述及了一种用于心脏损伤早期标志物检测的传感器的检测方法，该检测方法基于上述实施例2中述及的用于心脏损伤早期标志物检测的传感器实现。
下面以心肌肌钙蛋白为例说明心脏损伤早期标志物的检测过程。
如图5所示，用于心脏损伤早期标志物检测的传感器的检测方法，包括如下步骤：
s1. 在微流道112中通入纯血清样品，测量压电薄膜谐振器的谐振频率。
其中，微流道112的进口和出口分别使用注射针头进行液体样品的输入和输出，并通过注射泵、流动泵注入液体样品，使用网络分析仪或频率测量电路测量谐振器频率。
由于质量和阻尼负载，通入液体（此处是指上面提到的纯血清样品）后，薄膜传感器的谐振器频率有明显下降，应取稳定状态的谐振频率为频率基线，如图6所示。
s2. 在微流道112中依次通入含有不同浓度心肌肌钙蛋白（cTnI）的血清标准溶液，由于抗体和抗原发生反应，因此，谐振器的谐振频率会逐渐下降并稳定，如图6所示。
持续测量谐振器在不同浓度心脏损伤早期标志物的血清标准溶液下的谐振频率。
由于每次通入一定浓度的心肌肌钙蛋白（cTnI）的血清标准溶液，均会得到一组频率随时间的变化曲线，因此通过以上过程能够依次得到多个谐振频率随时间的变化曲线。
在图6中示出的心肌肌钙蛋白（cTnI）的血清标准溶液浓度为0.1ng/ml。
在每次通入不同浓度心肌肌钙蛋白（cTnI）的血清标准溶液之后，均需要使用1%的十二烷基硫酸钠（SDS）恢复心脏损伤早期标志物抗体吸附后的传感器，使传感器可重复使用。
当然，本实施例3也并不局限于使用SDS，还可以采用其他与SDS有相同或相近功能的液体恢复心脏损伤早期标志物抗体吸附后的传感器，使传感器可重复使用。
s3. 取各个变化曲线中谐振频率的稳定值，然后分别与频率基线比较，将频率移动值作为传感器的响应，得到该传感器对心脏损伤早期标志物的浓度校正曲线，如图7所示。
其中，方块表示实际测试获得的数据点（方块上下的线表示为5次测量的标准差），虚线表示对测试结果的线性拟合。由图7可知，在对数坐标系下，心肌肌钙蛋白（cTnI）的浓度与其频率移动值呈近似线性关系。其中，频率移动值=频率基线值-谐振频率的稳定值。
s4. 在微流道中通入待测血清样品。
本实施例3中的待测血清样品为通过标准采血过程获得的人血样本。
s5. 持续测量压电薄膜谐振器的谐振频率，得到谐振频率随时间的变化曲线，取该变化曲线上的频率稳定值，并与频率基线比较，以频率移动值作为传感器响应。
s6. 对照步骤s3中的浓度校正曲线，获得传感器响应对应的心肌肌钙蛋白（cTnI）浓度。
以上过程为心肌肌钙蛋白（cTnI）浓度的检测方法。
对于肌酸激酶MB同工酶(CK-MB)、心型脂肪酸结合蛋白（h-FABP）、以及B型尿钠肽(BNP)等其他心脏损伤早期标志物的检测过程与上述方法相同，此处不再赘述。
本实施例3利于实现对心脏损伤早期标志物的实时动态检测，且检测结果精确可靠，具体原理分析如下：测试中流动的液体能够将没有结合在传感器表面抗体的物质冲走，从而降低传感器表面的非特异性吸附，从而提高准确性。另外，微流道具有固定的通道和腔体体积，从而能够精确控制进入传感器敏感区的样品体积，使测试的可靠性和重复性提高。
由于压电薄膜谐振器采用硅半导体工艺制造，可以集成于微型集成测试系统中，流动液体动态测量能够实现与其他组件（如血液分离、离心等）的连续性、自动化测量，并且一次测量完成后，可通入新的液体（例如SDS）清除表面后，实现多次自动化反复测量。
此外，本实施例3还对采用本发明方法进行检测的结果与常规化学发光法结果进行了对照，对照结果如图8所示。其中，方块表示实际测试获得的数据点的检测结果，虚线表示对测试结果的线性拟合的结果。通过将本发明方法检测的结果与常规化学发光法得到的结果进行对照，结果呈现一致性，表明本发明实施例3中的检测方法的检测准确性较好。
当然，以上说明仅仅为本发明的较佳实施例，本发明并不限于列举上述实施例，应当说明的是，任何熟悉本领域的技术人员在本说明书的教导下，所做出的所有等同替代、明显变形形式，均落在本说明书的实质范围之内，理应受到本发明的保护。

Claims (10)

  1. 一种用于心脏损伤早期标志物检测的传感器的制备方法，其特征在于，
    包括如下步骤：
    I. 制备压电薄膜传感器；
    II. 在所述压电薄膜传感器的上电极表面沉积氧化硅层；
    III. 在所述氧化硅层的表面制作微流道侧壁；
    IV. 在所述微流道侧壁的上表面设置玻璃盖板，形成微流道；
    V. 在所述微流道内氧化硅层的表面组装心脏损伤早期标志物抗体。
  2. 根据权利要求1所述的传感器的制备方法，其特征在于，
    所述步骤I中，压电薄膜传感器包括横膈膜型压电薄膜传感器、具有声反射层的固体装配型压电薄膜传感器、或空气隙型结构压电薄膜传感器。
  3. 根据权利要求1所述的传感器的制备方法，其特征在于，
    所述步骤II中，氧化硅层采用磁控溅射沉积的方法得到。
  4. 根据权利要求1所述的传感器的制备方法，其特征在于，
    所述步骤III中，微流道侧壁选用SU8负胶、聚二甲基硅氧烷或聚酰亚胺材料，并采用普通光刻、软光刻或纳米压印方法制作而成；微流道侧壁的高度为1-5毫米。
  5. 根据权利要求1所述的传感器的制备方法，其特征在于，
    所述步骤IV中，在设置玻璃盖板之前，将玻璃盖板和微流道侧壁表面使用氧等粒子处理。
  6. 根据权利要求1所述的传感器的制备方法，其特征在于，
    所述步骤V中，心脏损伤早期标志物抗体的组装过程如下：
    首先在所述微流道中通入去离子水和乙醇清洗表面；
    然后通入氨丙基三乙氧基硅烷的乙醇溶液，与氧化硅层的羟基相互作用形成氨基表面；
    进一步通入戊二醛水溶液进行醛基改性；
    再通入心脏损伤早期标志物抗体的磷酸盐缓冲液溶液，进行抗体的共价结合；
    最后通入牛血清蛋白的磷酸盐缓冲液溶液阻断未结合的醛基。
  7. 根据权利要求1所述的传感器的制备方法，其特征在于，
    所述步骤V中，在微流道内氧化硅层的表面组装的心脏损伤早期标志物抗体包括肌酸激酶MB同工酶、心肌肌钙蛋白、心型脂肪酸结合蛋白或B型尿钠肽抗体。
  8. 一种用于心脏损伤早期标志物检测的传感器，其特征在于，
    所述传感器是采用上述权利要求1至7中任一项所述的传感器的制备方法制得的。
  9. 一种用于心脏损伤早期标志物检测的传感器的检测方法，基于上述权利要求8所述的用于心脏损伤早期标志物检测的传感器，其特征在于，
    所述传感器的检测方法包括如下步骤：
    s1. 在所述微流道中通入纯血清样品，测量压电薄膜谐振器的谐振频率；
    将谐振器处于稳定状态时的谐振频率作为测量的频率基线；
    s2. 在微流道中依次通入含有不同浓度心脏损伤早期标志物的血清标准溶液，并持续测量压电薄膜谐振器在不同浓度心脏损伤早期标志物的血清标准溶液下的谐振频率；
    通过以上过程依次得到多个谐振频率随时间的变化曲线；
    s3. 取各个变化曲线中谐振频率的稳定值，然后分别与频率基线进行比较，将频率移动值作为传感器的响应，得到该传感器对心脏损伤早期标志物的浓度校正曲线；
    其中，频率移动值=频率基线值-谐振频率的稳定值；
    s4. 在微流道中通入待测血清样品；
    s5. 持续测量压电薄膜谐振器的谐振频率，得到谐振频率随时间的变化曲线，取该变化曲线上的频率稳定值，并与频率基线比较，以频率移动值作为传感器响应；
    s6. 对照步骤s3中的浓度校正曲线，获得传感器响应对应的心脏损伤早期标志物浓度。
  10. 根据权利要求9所述的传感器的检测方法，其特征在于，
    所述步骤s2中，在每次通入不同浓度心脏损伤早期标志物的血清标准溶液之后，均需要使用十二烷基硫酸钠恢复心脏损伤早期标志物抗体吸附后的传感器。
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