WO2019192125A1 - 一种基于声表面波模式的生物传感器及其检测方法 - Google Patents

一种基于声表面波模式的生物传感器及其检测方法 Download PDF

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WO2019192125A1
WO2019192125A1 PCT/CN2018/100808 CN2018100808W WO2019192125A1 WO 2019192125 A1 WO2019192125 A1 WO 2019192125A1 CN 2018100808 W CN2018100808 W CN 2018100808W WO 2019192125 A1 WO2019192125 A1 WO 2019192125A1
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wave mode
surface acoustic
acoustic wave
liquid sample
substrate
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PCT/CN2018/100808
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English (en)
French (fr)
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付琛
罗景庭
全傲杰
范平
张东平
梁广兴
郑壮豪
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深圳大学
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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
    • G01N29/22—Details, e.g. general constructional or apparatus details
    • G01N29/222—Constructional or flow details for analysing fluids
    • 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
    • G01N29/022—Fluid sensors based on microsensors, e.g. quartz crystal-microbalance [QCM], surface acoustic wave [SAW] devices, tuning forks, cantilevers, flexural plate wave [FPW] devices
    • 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
    • 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
    • G01N29/24—Probes
    • G01N29/2462—Probes with waveguides, e.g. SAW devices
    • 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
    • G01N2291/024—Mixtures
    • G01N2291/02466—Biological material, e.g. blood
    • 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
    • G01N2291/04—Wave modes and trajectories
    • G01N2291/042—Wave modes
    • G01N2291/0423—Surface waves, e.g. Rayleigh waves, Love waves

Definitions

  • the invention relates to the field of novel electronic devices and biotechnology, and in particular to a biosensor based on a surface acoustic wave mode and a detection method thereof.
  • SAWB Surface Acoustic Wave Biosensor
  • IDT interdigital transducer
  • a sensitive membrane 12 with highly selective biofunctional substances (such as proteins, DNA, pathogens, cells, viruses, etc.) to form a sensitive area, sensitive when the substance to be tested is physically adsorbed or chemically reacted in the sensitive area
  • the mass load of the zone changes, and the surface acoustic wave parameters of the device also change, thereby detecting the substance to be tested and its content.
  • SAWB has the advantages of convenient detection, low cost and high sensitivity.
  • Love Wave SAWB containing a waveguide layer is very sensitive to changes in boundary conditions on the surface of the waveguide layer because its energy is mainly concentrated in the crystal surface and the waveguide, and high sensitivity can be achieved.
  • the biological reaction process occurring in the biosensor always involves the mixing of the reactants.
  • the rapid and uniform mixing of the reactants in the microfluidic channel of the chip plays an important role in the detection performance of the chip.
  • the main mixing mechanism in this process is natural diffusion, but since the diffusion coefficient of macromolecules or particles suspended in the liquid is low, the simple diffusion process is a slow and inefficient process, so it is subject to reaction in practical applications.
  • the diffusion efficiency of the material has caused the current response speed of most biosensors to be unsatisfactory.
  • SAWB is mainly in the phase of principle verification evaluation and initial test, and has not yet achieved successful commercialization.
  • sample to be tested blood, plasma or urine, etc.
  • sample to be tested contains various macromolecules in addition to the analyte to be tested, the non-target protein or the non-specific binding interference between the molecule and the sensitive membrane will not only increase. Background noise can even lead to false positive test results, and direct detection of body fluid samples is not possible, which becomes an important challenge for biosensor chips.
  • the object of the present invention is to provide a user with a surface acoustic wave mode based biosensor and a detection method thereof, which overcome the defects in the prior art.
  • the first embodiment provided by the present invention is: a surface acoustic wave mode based biosensor, comprising:
  • a piezoelectric substrate or a substrate composed of a piezoelectric material a piezoelectric substrate or a substrate composed of a piezoelectric material
  • At least one pair of interdigital transducers disposed on the piezoelectric substrate or substrate;
  • a microchannel liquid pool for biological reaction disposed between the input transducer and the output transducer of the interdigital transducer;
  • the interdigital transducers When detecting the liquid sample, the interdigital transducers respectively arrange at least one surface acoustic wave mode for microfluidizing and stirring the liquid sample to be detected in the sensing channel and the excitation channel, and outputting for A frequency signal of the physical properties of the liquid sample to be detected is analyzed.
  • the sensing channel and the direction of the surface acoustic wave mode disposed in the excitation channel are at an angle.
  • the sensing channel is arranged in a horizontal shear surface wave mode in the X-axis direction; and the excitation channel is arranged in a Rayleigh wave mode in the Y-axis direction.
  • a waveguide layer is further disposed above the piezoelectric substrate, and the horizontal shear surface wave mode in the X-axis direction is converted into a Love wave mode.
  • the piezoelectric substrate is a piezoelectric crystal substrate; the piezoelectric crystal substrate is made of 36-42° YX lithium niobate, 41YX° lithium niobate, ST quartz, and AT quartz.
  • the substrate is composed of silicon wafer or sapphire, and further comprises one or more piezoelectric films on the surface thereof.
  • the shape of the interdigital transducer is an arc shape.
  • the second embodiment provided by the present invention is: a method for detecting a biosensor, comprising the following steps:
  • the liquid sample to be tested is placed in the microchannel liquid pool, and the biological function film located in the microchannel liquid pool adsorbs the liquid sample to be detected;
  • At least one surface acoustic wave mode is arranged in the sensing channel and the excitation channel to perform microflow and agitation of the liquid sample to be tested;
  • the frequency signals outputted in the sensing channel and the excitation channel are respectively obtained, and the obtained frequency signal is analyzed to obtain the physical properties of the liquid sample to be detected.
  • the sensing channel is arranged in a horizontal shear surface wave mode in the X-axis direction; and the excitation channel is arranged in a Rayleigh wave mode in the Y-axis direction.
  • the frequency of the Rayleigh wave mode is set at 1 to 20 MHz
  • the period of the interdigital transducer is set to 0.1 to 1 mm
  • the frequency of the horizontal shear surface wave mode or the Love wave mode is designed to be 150 to 500 MHz.
  • the period of the interdigital transducer is 10 to 40 ⁇ m; the aperture of the interdigital transducer is 0.4 to 4 mm.
  • the present invention provides a biosensor based on a surface acoustic wave mode and a detection method thereof, which are disposed on the interdigital transducer by a piezoelectric substrate or a substrate composed of a piezoelectric material, an interdigital transducer Between the input transducer and the output transducer, a microchannel liquid pool for biological reaction, and a biological function membrane for adsorbing the liquid sample to be detected in the microchannel liquid pool; At the time, the interdigital transducers respectively arrange at least one surface acoustic wave mode for microfluiding and stirring the liquid sample to be detected in the sensing channel and the excitation channel, and output for analyzing the to-be-tested A frequency signal that detects the physical properties of a liquid sample.
  • the biosensor and the detection method thereof disclosed by the invention increase the surface wave of a Rayleigh mode in the vertical direction of the sensing channel to excite the liquid flow, stir to eliminate, and overcome the above problems, thereby realizing the biological detection function against non-specific interference and rapid response. .
  • FIG. 1 is a schematic structural view of a biosensor in the prior art
  • FIG. 2 is a schematic structural view of a surface acoustic wave mode based biosensor provided by the present invention
  • FIG. 3 is a schematic diagram showing the structure of an IDT of the dual surface acoustic wave mode sensor of the present invention
  • FIG. 4 is a schematic view showing a unidirectional structure of the transducer of the present invention.
  • Figure 5 is a schematic view showing the arc structure adopted by the transducer of the present invention.
  • Fig. 6 is a flow chart showing the steps of the method for detecting the biosensor of the present invention.
  • the utility model can overcome the fact that the existing surface acoustic wave biosensor is subject to the diffusion efficiency of the reactant in practical applications, and the response speed is not ideal.
  • the non-target protein or the non-specific binding of the molecule to the sensitive membrane interferes, it not only increases the background noise, but also leads to the false positive test result, and cannot directly directly perform the body fluid sample. Detection.
  • Detection By adding a Rayleigh mode surface wave in the vertical direction of the sensing channel to stimulate liquid flow and agitation to eliminate and overcome the above problems, the biodetection function against non-specific interference and rapid response is realized.
  • the first embodiment provided by the present invention is a surface acoustic wave mode based biosensor, as shown in FIG. 2, comprising: a piezoelectric substrate or a substrate 21 composed of a piezoelectric material; At least one pair of interdigital transducers 24 on the substrate 21; a microchannel reservoir 26 for biological reaction disposed between the input transducer and the output transducer of the interdigital transducer 24; a biofunctional membrane 25 for adsorbing the liquid sample to be detected in the microchannel liquid pool 26; at least one of the interdigital transducers 24 is disposed in the sensing channel and the excitation channel when detecting the liquid sample A surface acoustic wave mode for performing microfluidization and agitation of the liquid sample to be detected, and outputting a frequency signal for analyzing physical properties of the liquid sample to be detected.
  • the biosensor provided by the present invention comprises: a piezoelectric substrate or a substrate composed of a piezoelectric material.
  • the piezoelectric substrate or the substrate material provided in the present invention is a piezoelectric single wafer satisfying specific conditions or various A piezoelectric thin film material that grows on a substrate and satisfies specific conditions.
  • the specific conditions are that Rayleigh wave and SH-SAW wave can exist and be excited separately.
  • the material includes: 36-42°YX lithium niobate, 41YX° lithium niobate, ST quartz, AT quartz, [ 1120] ZnO, [1120] AlN.
  • the microchannel reaction cell can be composed of inorganic materials (such as single crystal silicon, quartz, glass, metal) and organic polymers (such as polymethyl methacrylate PMMA, polycarbonate PC, polydimethylsiloxane PDMS, ring). Oxygen resin, etc.).
  • inorganic materials such as single crystal silicon, quartz, glass, metal
  • organic polymers such as polymethyl methacrylate PMMA, polycarbonate PC, polydimethylsiloxane PDMS, ring). Oxygen resin, etc.).
  • the interdigital transducers can be fabricated onto the substrate surface using microfabrication lithography using gold, aluminum, and other metallic materials.
  • the interdigital transducers can be designed in a bidirectional, unidirectional configuration and pumped to the interdigital transducers. Refers to weighting or apodization weighting to achieve the control of surface acoustic waves.
  • the piezoelectric substrate is a piezoelectric crystal substrate; the piezoelectric crystal substrate is made of 36-42° YX lithium niobate, 41YX° lithium niobate, ST quartz, and AT quartz.
  • the substrate is composed of a silicon wafer and sapphire, and further includes one or more piezoelectric films on its surface.
  • biosensor will be further described by the specific manufacturing method of the biosensor provided by the present invention.
  • the first step is to design the substrate or substrate and make the IDT.
  • Piezoelectric substrate materials include: 36-42° YX lithium niobate, 41YX° lithium niobate, ST quartz, AT quartz, by etching or stripping, by electron beam evaporation, magnetron sputtering, CVD, atomic layer
  • the process is formed to obtain the shape of a metallization layer of the interdigital transducer, the material of the interdigital transducer comprising a metal element or alloy selected from the group consisting of aluminum, gold, copper, nickel, chromium, zinc, platinum, and a metal layer.
  • the thickness is between 80 and 200 nm.
  • One or more layers of [1120] ZnO, [1120]AlN piezoelectric film were grown on the substrate by magnetron sputtering using a silicon or sapphire substrate.
  • An interdigital transducer was prepared on its surface using a stripping method.
  • the PDMS is packaged into a biosensor.
  • the male mold of the channel portion is formed by photolithography and etching.
  • the material of the male mold is silicon material, glass, epoxy-based SU-8 photoresist.
  • the biosensor provided by the invention increases the reaction process of the liquid sample in the reaction cell by separately arranging different surface acoustic wave modes in the sensing channel and the excitation channel, respectively, and at the same time can remove non-specific adsorption interference.
  • the surface acoustic wave modes arranged in the sensing channel and the excitation channel are two different surface acoustic wave modes, and the propagation directions of the two surface acoustic wave modes may be set to be parallel, or the excitation channel may be arranged.
  • the transmitted surface acoustic wave mode has a certain angle with the surface acoustic wave mode in the sensing channel.
  • the directions of the two surface acoustic wave modes are perpendicular to each other, The best mixing results can be achieved.
  • a pair of interdigital transducers in the Y direction may be used to excite a Rayleigh wave mode, the energy of which is coupled to the liquid sample to be detected, and by controlling the energy of the excitation signal, Causing microfluidic and agitation of the liquid;
  • a pair of interdigital transducers in the X direction are arranged in a delay line structure of the SH-SAW wave mode (horizontal shear surface wave), the energy is concentrated on the surface of the substrate, and no liquid is lost In the middle, the SH-SAW wave is disturbed by molecules such as bio-functionalized material adsorption proteins, and the information is sent to the output transducer, and the differential frequency signal is used as the final output through the two sensing channels to obtain the measured object. Quantitative testing.
  • a waveguide layer is further disposed above the piezoelectric substrate, and the horizontal shear surface wave mode in the X-axis direction is converted into a Love wave mode.
  • the waveguide layer may utilize an organic or inorganic material having a shear wave velocity less than that of the substrate.
  • a 0.5 to 10 ⁇ m silicon dioxide film may be prepared by magnetron sputtering or PECVD on the surface of the prepared surface acoustic wave device, or a 0.5 to 2 ⁇ m polymer may be grown by spin coating.
  • the waveguide layer converts the SH-SAW wave into a more sensitive Love wave.
  • an IDT 33 that excites Rayleigh waves is arranged in the Y direction.
  • the Rayleigh wave 31 of the energy condition propagates along the Y direction, when the Rayleigh wave encounters the microchannel liquid pool.
  • the energy will be coupled into the liquid to be detected in the pool, causing a change in the sound pressure within the liquid sample, causing the liquid sample to flow inside the microchannel tank.
  • Two sensing IDTs are arranged in the X direction, and the SH-SAW or Love wave 32 is excited by the input transducer, and its energy is directly transmitted to the output transducer through the surface of the substrate without being coupled into the liquid.
  • One of the channels 34 is provided with a biofunctional membrane in the reaction cell, which is capable of adsorbing the reactants and causing perturbation to 32.
  • another channel 35 there is no biofunctional membrane in the reaction cell, and no liquid sample to be detected is adsorbed. Due to environmental influences, humidity, temperature and the like have almost the same effect on the signals of the two channels, so signals through channel 34 and channel 35 are passed.
  • the shift of the surface acoustic wave frequency due to the adsorption of the liquid sample to be tested can be obtained.
  • the adsorption process of the liquid sample to be tested is a slow and inefficient process, and the microfluidic flow inside the liquid caused by the Rayleigh wave 31 can significantly increase the adsorption process.
  • the non-specific substance adsorbed by the biofunctional membrane is washed away by increasing the energy of the channel 31.
  • the surface wave is excited and propagated in one direction, the other direction is suppressed, the IDT insertion loss is reduced, and the amplitude of the excitation surface acoustic wave can also be increased.
  • the interdigital transducer can also adopt an arc structure, which can focus the Rayleigh wave on a desired position in the liquid pool to achieve better driving and stirring effect. .
  • the surface acoustic wave mode-based biosensor provided by the invention is based on the SH-SAW of the existing surface acoustic wave biosensor for liquid environment sensing, and a surface acoustic wave of a Rayleigh wave mode is added in the vertical direction to drive
  • the microfluidics in the liquid achieve the purpose of accelerating the biological reaction process and flushing non-specific binding interference, and the distribution, morphology and energy of the Rayleigh wave can be controlled by the design of the device. Since this process does not require any other chemicals to be applied to the sample reaction process, it does not cause interference and false response to the reaction process, and the cost is low.
  • the second embodiment provided by the present invention is a method for detecting a biosensor, as shown in FIG. 6, comprising the following steps:
  • the liquid sample to be detected is placed in the microchannel liquid pool, and the biological function film located in the microchannel liquid pool adsorbs the liquid sample to be detected.
  • At least one surface acoustic wave mode is arranged in the sensing channel and the excitation channel to perform microflow and agitation of the liquid sample to be tested.
  • the two different surface acoustic wave modes are a horizontal shear surface wave mode or a Love wave mode in the X-axis direction, and a Rayleigh wave mode in the Y-axis direction.
  • the above detection method provided by the present invention utilizes a mutually perpendicular Rayleigh wave and a Shear Horizontal SAW (SH-SAW)/Love wave double surface acoustic wave (surface acoustic wave,
  • SH-SAW Shear Horizontal SAW
  • Love wave double surface acoustic wave surface acoustic wave
  • the surface acoustic wave biosensor structure of the SAW) mode in particular, simultaneously excites Rayleigh and SH-SAW mode sensors on the same substrate, on the one hand based on the SH-SAW mode high sensitivity sensing, and on the other hand Rayleigh
  • the mode surface acoustic wave is used to agitate the biological sample in the reaction bath to speed up the sample reaction process and eliminate non-specific adsorption interference, thereby improving biosensor performance.
  • the frequency of the Rayleigh wave mode is set at 1 to 20 MHz
  • the period of the interdigital transducer is set to 0.1 to 1 mm
  • the frequency of the horizontal shear surface wave mode or the Love wave mode is designed to be 150 to 500 MHz.
  • the period of the interdigital transducer is 10 to 40 ⁇ m; the aperture of the interdigital transducer is 0.4 to 4 mm.
  • the invention provides a surface acoustic wave mode based biosensor and a detection method thereof, which are arranged on the input of the interdigital transducer by a piezoelectric substrate or a substrate composed of a piezoelectric material and an interdigital transducer.
  • the interdigital transducer Obtaining at least two different frequency signals outputted from the sensing channel and the excitation channel by exciting at least one different surface acoustic wave mode in the sensing channel and the excitation channel when detecting the liquid sample, and acquiring the obtained frequency signal The analysis is performed to obtain the detection result of the liquid sample to be tested.
  • the biosensor and the detection method thereof disclosed by the invention add a Rayleigh mode surface wave to stimulate the liquid flow and agitation in the vertical direction of the sensing channel to eliminate and overcome the above problems, thereby realizing the biological detection function against non-specific interference and rapid response. .

Abstract

一种基于声表面波模式的生物传感器及其检测方法，通过压电基底或者由压电材料组成的衬底（21）、叉指换能器（24）；设置在叉指换能器（24）的输入换能器与输出换能器之间，用于生物反应的微通道液池（26）；以及位于微通道液池（26）内用于吸附待检测液体样品的生物功能膜（25）；在检测液体样品时，叉指换能器（24）分别在传感通道和激励通道中布置至少一种用于对待检测液体样品进行微流和搅拌的声表面波模式，并输出用于分析待检测液体样品物理属性的频率信号。该生物传感器及其检测方法，通过传感通道垂直方向增加一道瑞利表面波激励液体流动、搅拌，从而实现抗非特异性干扰和快速响应的生物检测功能。

Description

一种基于声表面波模式的生物传感器及其检测方法 技术领域
本发明涉及新型电子器件和生物技术领域，尤其涉及的是一种基于声表面波模式的生物传感器及其检测方法。
背景技术
声表面波生物传感器(Surface Acoustic Wave Biosensor,SAWB，SAWB)是近年来发展起来的一类新型无标记声学MEMS生物传感器。其结构如图1所示，由制作在具有压电性能的基片11表面的叉指换能器13(Interdigital transducer,IDT)激发和接收声表面波，通过在声表面波的传播路径上上涂一层有高选择性的生物功能化物质(如蛋白质、DNA、病原体、细胞、病毒等)的敏感膜12，构成敏感区，当待测物质在敏感区发生物理吸附或化学反应时，敏感区的质量负载就会发生变化，器件的声表面波参数也随之变化，从而检测出待测物质及其含量。SAWB与其他传统的生物检测技术相比较具有检测方便、成本低、灵敏度高等优点。特别是含有波导层的Love波SAWB，由于其能量主要集中在晶体表面和波导之中，它对波导层表面的边界条件变化非常敏感，可以达到很高的灵敏度。
但是在生物传感器中发生的生物反应过程总是涉及到反应物的混合，通常对于生物芯片而言，反应物在芯片微流通道中快速、均匀地混合对芯片的检测性能起着重要的作用。在此过程中的主要混合机制是自然扩散，但是由于悬浮在液体中的大分子或者颗粒的扩散系数低，因此单纯地扩散过程是一个缓慢而且低效的过程，所以在实际应用中受制于反应物扩散效率底，造成了目前大部分生物传感器响应速度不理想；另一方面，SAWB主要处于原理验证评估和初次试验测试阶段，还没有真正实现成功的商业化。这主要是由于当待测样本(血液，血浆或尿液等)除了待测分析物之外，还含有各种大分子时，非目标蛋白或者分子与敏感膜的非特异结合干扰不但会增大背景噪声，甚至会导致假阳性测试结果，无法直接对体液样品进行直接检测，成为生物传感器芯片面临一个重要的挑战。
因此，现有技术有待于进一步的改进。
发明内容
鉴于上述现有技术中的不足之处，本发明的目的在于为用户提供一种基于声表面波模式的生物传感器及其检测方法，克服现有技术中缺陷。
本发明提供的第一实施例为：一种基于声表面波模式的生物传感器，其中，包括：
压电基底或者由压电材料组成的衬底；
设置在所述压电基底或者衬底上的至少一对叉指换能器；
设置在所述叉指换能器的输入换能器与输出换能器之间，用于生物反应的微通道液池；
以及位于所述微通道液池内用于吸附所述待检测液体样品的生物功能膜；
在检测液体样品时，所述叉指换能器分别在传感通道和激励通道中布置至少一种用于对所述待检测液体样品进行微流和搅拌的声表面波模式，并输出用于分析所述待检测液体样品物理属性的频率信号。
可选的，所述传感通道和激励通道中布置的声表面波模式的方向之间呈一定角度。
可选的，所述传感通道中布置为位于X轴方向的水平剪切表面波模式；所述激励通道中布置的为位于Y轴方向的瑞利波模式。
可选的，所述压电基底上方还设置有波导层，所述位于X轴方向水平剪切表面波模式转化成Love波模式。
可选的，所述压电基底为压电晶体基底；所述压电晶体基底的材料为：36～42°YX钽酸锂，41YX°铌酸锂，ST石英，AT石英。
可选的，所述衬底由硅片或蓝宝石组成，其表面上还包括一层或多层的压电薄膜。
可选的，所述叉指换能器的形状为弧线型。
本发明提供的第二实施例为：一种生物传感器的检测方法，其中，包括以下步骤：
将待检测液体样品放入微通道液池内，位于微通道液池内的生物功能膜对所述待检测液体样品进行吸附；
控制叉指换能器检测液体样品时，分别在传感通道和激励通道中布置至少一种声表面波模式对待测液体样品进行微流和搅拌；
分别获取传感通道和激励通道内输出的频率信号，对获取到的频率信号进行分析，得到待检测液体样品的物理属性。
可选的，所述传感通道中布置为位于X轴方向的水平剪切表面波模式；所述激励通道中布置的为位于Y轴方向的瑞利波模式。
可选的，所述瑞利波模式的频率设置在1～20MHz，叉指换能器的周期设置为0.1～1mm；所述水平剪切表面波模式或Love波模式的频率设计在150～500MHz，叉指换能器的周期10～40μm；所述叉指换能器的孔径为0.4～4mm。
有益效果：本发明提供了一种基于声表面波模式的生物传感器及其检测方法，通过压电基底或者由压电材料组成的衬底、叉指换能器，设置在所述叉指换能器的输入换能器与输出换能器之间，用于生物反应的微通道液池，以及位于所述微通道液池内用于吸附所述待检测液体样品的生物功能膜；在检测液体样品时，所述叉指换能器分别在传感通道和激励通道中布置至少一种用于对所述待检测液体样品进行微流和搅拌的声表面波模式，并输出用于分析所述待检测液体样品物理属性的频率信号。本发明所公开的生物传感器及其检测方法，通过传感通道垂直方向增加一道Rayleigh模式的表面波激励液体流动，搅拌来消除，克服以上问题，从而实现抗非特异性干扰和快速响应的生物检测功能。
附图说明
图1是现有技术中生物传感器的结构示意图；
图2是本发明所提供的基于声表面波模式的生物传感器的结构示意图；
图3是本发明所述双声表面波模式传感器的IDT结构示意图；
图4是本发明所述换能器采用单向结构示意图；
图5是本发明所述的换能器采用的弧形结构示意图；
图6是本发明所述的生物传感器的检测方法步骤流程图。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚、明确，以下参照附图并举实施例对本发明进一步详细说明。应当理解，此处所描述的具体实施例仅仅用于解释本发明，并不用于限定本发明。
本发明的目的在于提供一种高特异性和快速响应的声表面波生物传感器。其能够克服现有声表面波生物传感器在实际应用中受制于反应物扩散效率底，造成的响应速度不理想。另外在待测样品中存在各种大分子时，非目标蛋白或者分子与敏感膜的非特异结合干扰时，不但会增大背景噪声，甚至会导致假阳性测试结 果，无法直接对体液样品进行直接检测。通过在传感通道垂直方向增加一道瑞利模式的表面波激励液体流动、搅拌来消除、克服以上问题，从而实现抗非特异性干扰和快速响应的生物检测功能。
本发明提供的第一实施例为一种基于声表面波模式的生物传感器，如图2所示，包括：压电基底或者由压电材料组成的衬底21；设置在所述压电基底或者衬底21上的至少一对叉指换能器24；设置在所述叉指换能器24的输入换能器与输出换能器之间，用于生物反应的微通道液池26；以及位于所述微通道液池26内用于吸附所述待检测液体样品的生物功能膜25；在检测液体样品时，所述叉指换能器24分别在传感通道和激励通道中布置至少一种用于对所述待检测液体样品进行微流和搅拌的声表面波模式，并输出用于分析所述待检测液体样品物理属性的频率信号。
本发明所提供的生物传感器包括：压电基底或者压电材料组成的衬底，具体的，本发明中所提供的压电基底或者衬底材料是满足特定条件的压电单晶片或者是各种衬底上生长的满足特定条件的压电薄膜材料。特定条件是能分别存在和激励Rayleigh波和SH-SAW波，当其为压电基底时，其材料包括：36～42°YX钽酸锂，41YX°铌酸锂，ST石英，AT石英，[1120]ZnO,[1120]AlN。
微通道反应池可以采用包括无机材料〔如单晶硅、石英、玻璃、金属〕和有机聚合物(如聚甲基丙烯酸甲酯PMMA、聚碳酸酯PC、聚二甲基硅氧烷PDMS、环氧树酯等)。
叉指换能器可以采用金、铝和其他金属材料利用微加工光刻工艺制备到基片表面，叉指换能器的设计可以采用双向，单向结构，并且对叉指换能器进行抽指加权或者变迹加权来实现声表面波的调控。
可选的，所述压电基底为压电晶体基底；所述压电晶体基底的材料为：36～42°YX钽酸锂，41YX°铌酸锂，ST石英，AT石英。所述衬底由硅片和蓝宝石组成，其表面上还包括一层或多层的压电薄膜。
下面，以本发明提供的生物传感器具体的制造方法对所述生物传感器做进一步的说明。
第一步，设计基底或衬底和制作IDT。
以所述生物传感器采用压电晶体基底的方案为例；
压电基底的材料包括：36～42°YX钽酸锂，41YX°铌酸锂，ST石英，AT石英，使用刻蚀或者剥离的方法，通过电子束蒸发、磁控溅射、CVD、原子层等工艺形成得到叉指换能器的金属化层的形状，所述叉指换能器的材料包括选自铝、金、铜、镍、铬、锌、铂的金属单质或者合金，金属层的厚度在80～200nm。
第二种，以所述生物传感器采用压电材料做衬底的方案为例；
采用硅片或者蓝宝石衬底的方案，通过磁控溅射在衬底上生长一层或者多层的[1120]ZnO,[1120]AlN压电薄膜。使用剥离的方法在其表面制备叉指换能器。
第二步，PDMS封装成生物传感器。
用光刻和蚀刻的方法先制出通道部位突起的阳模，阳模的制作材料有硅材料，玻璃，环氧基SU-8光刻胶。通过模塑法，将PDMS及固化剂按1:10的比例混合后的液体注入阳模板上，通过加热固化从负板上剥落下来，后通过等离子体处理，如图2所示，与基片进行键合。
本发明所提供的生物传感器通过分别在传感通道和激励通道中分别布置不同的声表面波模式，增加反应池内的液体样品的反应过程，且同时可以清除非特异性吸附干扰。
可以想到的是，布置在传感通道和激励通道中的声表面波模式为两种不同的声表面波模式，可以设置两种声表面波模式的传播方向相平行，也可以布置激励通道中的传输的声表面波模式与传感通道中的声表面波模式具有一定的角度，较佳的，为了取得更好的微流和搅拌结果，当两种声表面波模式传输的方向相互垂直时，可以取得最佳的搅拌效果。在具体实施时，如图2所示，可以采用在Y方向上的一对叉指换能器激励起瑞利波模式，其能量耦合到待检测液体样品中，通过控制激励信号的能量大小，引起液体的微流和搅拌；在X方向上的一对叉指换能器布置SH-SAW波模式(水平剪切表面波)的延迟线结构，能量集中在基片表面，不会损失到液体中去，SH-SAW波受到生物功能化材料吸附蛋白等分子扰动，并将信息到达输出换能器，并通过两道传感通道进行差分的频率信号作为最终的输出来得到所述被测量物的定量检测。
为了取得更好的效果，可选的，所述压电基底上方还设置有波导层，所述位于X轴方向水平剪切表面波模式转化成Love波模式。实际应用时，根据实际需要决定是否在所述压电基底或者衬底的上方先覆盖一层波导层，将SH-SAW模 式进一步转化成Love波模式来提高灵敏度。波导层可以利用横波速度小于基片的有机或者无机材料。
在具体的制造时，可以采用在制备好的声表面波器件表面采用磁控溅射、PECVD方法制备一层0.5～10μm的二氧化硅薄膜，或者通过旋涂方式生长一层0.5～2μm聚合物波导层，将SH-SAW波转化成灵敏度更高的Love波。
如图3所示，在Y方向上布置有激励瑞利波的IDT 33，在激励满足一定频率，能量条件的瑞利波31沿着Y方向传播，当瑞利波遇到微通道液池时，其能量将会耦合到池内的待检测液体中去，引起液体样品内声压的变化，从而导致液体样品在微通道液池内部形成流动。通过改变IDT 33和微通道液池的设计，可以调控液体流动的形式。在X方向上布置两道传感IDT，都通过输入换能器激励SH-SAW或者Love波32，其能量通过基底表面直接传到输出换能器，不会耦合到液体中去。其中一个通道34的反应池中设置有生物功能膜，能够吸附待反应物，对32产生微扰。另外一个通道35的反应池中没有生物功能膜，不吸附待检测液体样品，由于环境的影响，包括湿度、温度等对两个通道的信号影响几乎一样，因此通过对通道34和通道35的信号进行差分就能得到由于待测液体样品吸附导致的声表面波频率的偏移。在通道34的液池中，待测液体样品的吸附过程是一个缓慢而且低效的过程，通过瑞利波31的引起的液体内部的微流，可以明显增快该吸附过程。在吸附完成后，通过加大通道31的能量，冲洗掉生物功能膜吸附的非特异性物质。
通过采用图4单向结构，增强表面波的沿着一个方向激发和传播，抑制另一个方向，降低IDT插入损耗，也可以提高激励声表面波的幅度。
较佳的，如图5所示，所示叉指换能器还可以采用弧形结构，该弧形结构可以将瑞利波的聚焦在液池中需要的位置，取得更好的驱动搅拌效果。
本发明提供的基于声表面波模式的生物传感器，在现有声表面波生物传感器利用的SH-SAW进行液体环境传感的基础上，在其垂直方向增加一个瑞利波模式的声表面波来驱动液体中的微流，达到加速生物反应过程和冲洗非特异性结合干扰的目的，并且瑞利波的分布、形态和能量大小都可以通过器件的设计来实现控制。由于该过程不需要对样品反应过程施加任何其他的化学物质，不会对反应过程产生干扰和假响应，而且成本低。
本发明提供的第二实施例为一种生物传感器的检测方法，如图6所示，包括以下步骤：
S61，将待检测液体样品放入微通道液池内，位于微通道液池内的生物功能膜对所述待检测液体样品进行吸附。
S62，控制叉指换能器检测液体样品时，分别在传感通道和激励通道中布置至少一种声表面波模式对待测液体样品进行微流和搅拌。
S63，分别获取传感通道和激励通道内输出的频率信号，对获取到的频率信号进行分析，得到待检测液体样品的物理属性。
可选的，所述两种不同的声表面波模式分别为位于X轴方向的水平剪切表面波模式或Love波模式，和位于Y轴方向的瑞利波模式。
本发明提供的上述检测方法利用相互垂直的瑞利波(Rayleigh wave)和水平剪切表面波(Shear Horizontal SAW,SH-SAW)/乐甫波(Love wave)的双声表面波(surface acoustic wave,SAW)模式的声表面波生物传感器结构，具体来说在同一基片上同时激励Rayleigh和SH-SAW模式的传感器，一方面在利用SH-SAW模式高灵敏度传感的基础上，另一方面利用Rayleigh模式的声表面波去搅拌反应液池中的生物样品方面，加快样品的反应过程和清除非特异性吸附干扰，从而改善生物传感器性能。
较佳的，所述瑞利波模式的频率设置在1～20MHz，叉指换能器的周期设置为0.1～1mm；所述水平剪切表面波模式或Love波模式的频率设计在150～500MHz，叉指换能器的周期10～40μm；所述叉指换能器的孔径为0.4～4mm。
本发明提供了一种基于声表面波模式的生物传感器及其检测方法，通过压电基底或者由压电材料组成的衬底、叉指换能器，设置在所述叉指换能器的输入换能器与输出换能器之间，用于生物反应的微通道液池，以及位于所述微通道液池内用于吸附所述待检测液体样品的生物功能膜；所述叉指换能器，在检测液体样品时，通过在传感通道和激励通道中激励出至少一种不同的声表面波模式，获取传感通道和激励通道中输出的至少两个频率信号，对获取到的频率信号进行分析，得到待检测液体样品的检测结果。本发明所公开的生物传感器及其检测方法，通过传感通道垂直方向增加一道Rayleigh模式的表面波激励液体流动、搅拌来消除、克服以上问题，从而实现抗非特异性干扰和快速响应的生物检测功能。
可以理解的是，对本领域普通技术人员来说，可以根据本发明的技术方案及其发明构思加以等同替换或改变，而所有这些改变或替换都应属于本发明所附的权利要求的保护范围。

Claims (10)

  1. 一种基于声表面波模式的生物传感器，其特征在于，包括：
    压电基底或者由压电材料组成的衬底；
    设置在所述压电基底或者衬底上的至少一对叉指换能器；
    设置在所述叉指换能器的输入换能器与输出换能器之间，用于生物反应的微通道液池；
    以及位于所述微通道液池内用于吸附所述待检测液体样品的生物功能膜；
    在检测液体样品时，所述叉指换能器分别在传感通道和激励通道中布置至少一种用于对所述待检测液体样品进行微流和搅拌的声表面波模式，并输出用于分析所述待检测液体样品物理属性的频率信号。
  2. 根据权利要求1所述的基于声表面波模式的生物传感器，其特征在于，所述传感通道和激励通道中布置的声表面波模式的方向之间呈一定角度。
  3. 根据权利要求2所述的基于声表面波模式的生物传感器，其特征在于，所述传感通道中布置为位于X轴方向的水平剪切表面波模式；所述激励通道中布置的为位于Y轴方向的瑞利波模式。
  4. 根据权利要求3所述的基于声表面波模式的生物传感器，其特征在于，所述压电基底上方还设置有波导层，所述位于X轴方向水平剪切表面波模式转化成Love波模式。
  5. 根据权利要求1至4任一项所述的基于声表面波模式的生物传感器，其特征在于，所述压电基底为压电晶体基底；
    所述压电晶体基底的材料选自：36～42°YX钽酸锂，41YX°铌酸锂，ST石英，AT石英中的一种或多种。
  6. 根据权利要求1至4任一项所述的基于声表面波模式的生物传感器，其特征在于，所述衬底由硅片或蓝宝石组成，其表面上还包括一层或多层的压电薄膜。
  7. 根据权利要求1至4任一项所述的基于声表面波模式的生物传感器，其特征在于，所述叉指换能器的形状为弧线型。
  8. 一种如权利要求1所述的生物传感器的检测方法，其特征在于，包括以下步骤：
    将待检测液体样品放入微通道液池内，位于微通道液池内的生物功能膜对所述待检测液体样品进行吸附；
    控制叉指换能器检测液体样品时，分别在传感通道和激励通道中布置至少一种声表面波模式对待测液体样品进行微流和搅拌；
    分别获取传感通道和激励通道内输出的频率信号，对获取到的频率信号进行分析，得到待检测液体样品的物理属性。
  9. 根据权利要求8所述的生物传感器的检测方法，其特征在于，所述传感通道中布置为位于X轴方向的水平剪切表面波模式；所述激励通道中布置的为位于Y轴方向的瑞利波模式。
  10. 根据权利要求9所述的生物传感器的检测方法，其特征在于，所述瑞利波模式的频率设置在1～20MHz，叉指换能器的周期设置为0.1～1mm；所述水平剪切表面波模式或Love波模式的频率设计在150～500MHz，叉指换能器的周期10～40μm；所述叉指换能器的孔径为0.4～4mm。
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