WO2022047847A1 - 一种局域表面等离子体激元共振生物芯片、其制造方法、包含其的生物传感系统及其应用 - Google Patents

一种局域表面等离子体激元共振生物芯片、其制造方法、包含其的生物传感系统及其应用 Download PDF

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WO2022047847A1
WO2022047847A1 PCT/CN2020/116724 CN2020116724W WO2022047847A1 WO 2022047847 A1 WO2022047847 A1 WO 2022047847A1 CN 2020116724 W CN2020116724 W CN 2020116724W WO 2022047847 A1 WO2022047847 A1 WO 2022047847A1
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optical waveguide
plasmon resonance
biochip according
substrate
resonance biochip
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PCT/CN2020/116724
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French (fr)
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吴兆鹏
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科竟达生物科技有限公司
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/41—Refractivity; Phase-affecting properties, e.g. optical path length
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/55—Specular reflectivity
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
    • G02B6/10—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings of the optical waveguide type
    • G02B6/12—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings of the optical waveguide type of the integrated circuit kind
    • G02B6/122—Basic optical elements, e.g. light-guiding paths
    • G02B6/1226—Basic optical elements, e.g. light-guiding paths involving surface plasmon interaction
    • G—PHYSICS
    • G02—OPTICS
    • G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
    • G02B6/00—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings
    • G02B6/10—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings of the optical waveguide type
    • G02B6/12—Light guides; Structural details of arrangements comprising light guides and other optical elements, e.g. couplings of the optical waveguide type of the integrated circuit kind
    • G02B6/122—Basic optical elements, e.g. light-guiding paths
    • G02B6/1228—Tapered waveguides, e.g. integrated spot-size transformers

Definitions

  • the invention relates to the field of biosensing, in particular to a localized surface plasmon resonance biochip, a manufacturing method thereof, a biosensing system comprising the same, and applications thereof.
  • SPR localized surface plasmon resonance with nanostructures
  • SPR plasmon resonance
  • Existing SPR biosensors are mostly based on silver, gold, or silver-gold alloys as plasmonic support materials to excite collective oscillations of electron clouds.
  • Gold is generally chemically inert and is the material of choice for established functionalization schemes.
  • gold as a plasmon support material suffers from two drawbacks, (i) the gold material itself is expensive; and (ii) the thickness of the gold film is as high as about 50 nm, and the fabrication of gold-based resonant biochips is expensive; these defects prevent gold Widespread use of SPR-based biosensors. Based on this, there is an urgent need in the art for a chip structure and a method for manufacturing the same that can replace or reduce the use of gold materials and reduce the manufacturing cost of biochips.
  • TiN plasmonic titanium nitride
  • BMNIs gold-silver bimetallic nano-islands
  • LSPR biosensing with TiN nanopores achieves a resolution of 9 ⁇ 10-8 RIU, which is comparable to that of AuNIs and BMNIs.
  • biotinylated antibodies enables the function of titanium nitride to be directly realized, so compared to gold, titanium nitride can reduce the number of chemicals involved and improve detection accuracy.
  • titanium nitride material instead of gold material can not only achieve basically the same resolution, but also further reduce the manufacturing cost of plasmonic biochips and improve the detection accuracy of fluid samples.
  • the purpose of the present invention is to provide a localized surface plasmon resonance biochip that can not only reduce the manufacturing cost, improve the detection accuracy, but also meet the requirements of high-throughput and rapid detection, and a manufacturing method thereof.
  • the technical scheme of the present invention is:
  • the present invention provides a localized surface plasmon resonance biochip, comprising: (1) a transparent substrate that allows light to pass through; (2) a plurality of optical waveguides disposed in the middle of the substrate, The plurality of optical waveguides constitute an optical waveguide array; (3) titanium nitride nanocubes disposed on the side surfaces of each of the optical waveguides; (4) a plurality of microfluidic channels disposed on the substrate.
  • the constituent material of the substrate may be one or more of PMMA, PC, PS, and BK7 glass, more preferably a polymer of PMMA or PC, and most preferably a polymer of PMMA.
  • the substrate allows certain wavelengths of light to pass through, so that the properties, types and concentrations of the fluid sample can be determined by measuring the refractive index of the light.
  • the substrate allows transmission of light having a wavelength of 400-1200 nanometers, more preferably light having a wavelength of 600-900 nanometers.
  • the substrate comprises an upper portion, a middle portion and a lower portion, which may be composed of the same or different materials, more preferably composed of the same material.
  • the material of the optical waveguide is at least the same as the material of the middle portion of the substrate on which the optical waveguide is arranged, and more preferably both are PMMA polymer materials.
  • the diameter of the optical waveguide is on the order of micrometers, more preferably 100-500 micrometers, most preferably about 200 micrometers; the height of the optical waveguide is 1000-5000 micrometers, more preferably about 1500 micrometers; The distance between adjacent optical waveguides is on the order of microns, more preferably about 100-500 microns, and most preferably about 200 microns.
  • the number of the optical waveguides is 2-61, more preferably 7-37, and most preferably 19.
  • the number of optical waveguide arrays composed of the optical waveguides is 8-128, more preferably 32-96, and most preferably 64.
  • the optical waveguide is a cylindrical body, more preferably a cylinder; the top and bottom of the optical waveguide are tapered surfaces, more preferably concave tapered surfaces.
  • the titanium nitride nanocubes are dispersed and immobilized on the surface of the optical waveguide array by wet chemistry and UV curing techniques.
  • the titanium nitride nanocubes are about 40 to 50 nanometers in size, more preferably about 45 nanometers.
  • the microfluidic channel is divided into an inlet section, a transmission section and an outlet section, and the fluid sample for detection flows in from the inlet section, flows through the optical waveguide of the transmission section, and flows out from the outlet section.
  • the number of said microfluidic channels is the same as the number of optical waveguide arrays, 8-128, more preferably 32-96, and most preferably 64.
  • each microfluidic channel can independently detect the same or different fluid samples.
  • the present invention provides a method for fabricating the above-mentioned localized surface plasmon resonance biochip, comprising: (1) providing a base material; (2) generating an underlying microfluidic channel; (3) ) generating a middle layer optical waveguide and an optical waveguide array; (4) an upper layer microfluidic channel; (5) dispersing and immobilizing titanium nitride nanocubes on the side surfaces of the optical waveguide.
  • the microfluidic channels, optical waveguides and optical waveguide arrays in steps (2) to (4) are all formed by 3D printing.
  • titanium nitride nanocubes are dispersed and immobilized on the side surfaces of the optical waveguide by wet chemical methods and UV curing techniques.
  • the present invention provides a biosensing system comprising the above-described localized surface plasmon resonance biochip.
  • the present invention also provides the use of the above-mentioned localized surface plasmon resonance biochip or a biosensing system comprising the chip for fluid sample detection.
  • titanium nitride nanomaterials instead of gold materials and forming an optical waveguide array with titanium nitride nanocubes in the middle of the substrate not only ensures the resolution but also significantly reduces the material cost; in addition, titanium nitride can reduce the number of involved The number of chemical substances increases the detection accuracy.
  • micron-scale optical waveguide arrays and multiple independent microfluidic channels increases the number of detection channels of the LSPR system, improves parallel processing capabilities, and meets the needs of high-throughput and rapid detection.
  • the number of optical waveguides should be appropriate, too little will lead to a reduction in the number of detection channels, and too much will hinder the free flow of the fluid sample.
  • the top and bottom of the optical waveguide are designed with tapered surfaces, which can not only miniaturize the related components of the optical waveguide, but also satisfy the incidence angle of the titanium nitride nanocube to generate resonance, thereby improving the measurement accuracy of the refractive index change and improving the sample detection. accuracy.
  • PMMA and PC polymers can not only achieve basically the same refractive index as BK7 glass, but also self-assemble with titanium nitride nanocubes and fix them on the optical waveguides through chemical bonds, which is convenient for manufacturing and improving. Increased manufacturing efficiency and reduced costs.
  • the technical solution of the present invention can not only reduce the manufacturing cost and improve the detection accuracy, but also meet the requirements of high-throughput rapid detection.
  • Figure 1 shows the structure of a gold-based SPR biochip in the prior art.
  • Figures 2a-2e are a front view (Figure 2a), a top view ( Figures 2b-2c), a bottom view ( Figure 2d), and a perspective view ( Figure 2e) of a biochip with an optical waveguide array of the present invention, wherein the substrate is shown , the positional relationship between the optical waveguide array and the microfluidic channel.
  • FIG. 3 shows the arrangement of the titanium nitride nanocubes of the present invention on the side surface of the optical waveguide.
  • Figure 4 shows the inlet, delivery and outlet sections of the microfluidic channel of the present invention.
  • Figure 5 shows the schematic diagram of the fluid sample to be detected flowing through the microfluidic channel and the optical waveguide array with arrows.
  • Figures 6a-6e show a schematic embodiment of the constituent materials of the base, wherein Figure 6a shows that the upper, middle and lower parts of the base use the same material; Figure 6b shows that the upper and lower parts of the base use the same material, and the middle part uses another A different material; Fig. 6c shows that the upper and middle parts of the base are made of the same material, and the lower part is made of different materials; Fig. 6d shows that the middle and lower parts of the base are made of the same material, and the upper part is made of another different material; Fig. 6e shows the base The upper, middle and lower parts are made of three different materials.
  • Figure 7 shows a schematic preferred embodiment of an optical waveguide, wherein the optical waveguide is cylindrical and the top and bottom of the optical waveguide are concave conical surfaces.
  • FIG. 8 shows an optical path diagram of light entering and exiting on an optical waveguide.
  • Figure 9 shows a top view of the arrangement of optical waveguides in an optical waveguide array.
  • FIG. 10 shows a schematic flow chart of manufacturing the biochip of the present invention.
  • FIG. 1 the structure of a gold-based SPR biochip in the prior art is shown, in which a thicker gold film is deposited on a substrate.
  • a chip structure arrangement in the prior art needs to use a lot of gold materials, and the manufacturing cost is high, which hinders the wide application of gold-based SPR biochips.
  • the biochip of the present invention includes: a substrate, an optical waveguide and an optical waveguide array arranged in the middle of the substrate, and a plurality of microfluidic channels arranged on the substrate.
  • the optical waveguide array is arranged in the middle of the substrate, and the microfluidic channels are arranged in the upper, middle and lower parts of the substrate.
  • upper and lower only refer to relative directions, and they can be used interchangeably; the shape and structure of the microfluidic channel are for illustration, not limitation, as long as the fluid sample can be injected into the The sample can be flowed through the optical waveguide and the optical waveguide array, and the sample can be taken out for detection.
  • titanium nitride nanocubes are shown arranged on the side surfaces of the optical waveguide.
  • inlet section delivery section and outlet section of the microfluidic channel of the present invention.
  • outlet section are only relative expressions for the direction of fluid flow, and the two can be used interchangeably.
  • the inlet section, the transmission section, and the outlet section are only relative divisions of the microfluidic channel, and do not limit the structure of the microfluidic channel.
  • FIG. 5 a schematic route diagram of a fluid sample to be detected flowing through the microfluidic channel of FIG. 4 is shown with arrows.
  • arrows refer to relative directions, which are not limited to flow in this direction, as long as the fluid sample can flow through the optical waveguide and the optical waveguide array.
  • FIG. 6a shows that the upper, middle and lower parts of the substrate are made of the same material PMMA;
  • Fig. 6b shows that the upper and lower parts of the base are made of the same material PC, and the middle part is made of another different material PMMA;
  • the same material PMMA is used in the middle part, and PC is used in the lower part;
  • Figure 6d shows that the middle part and the lower part of the base use the same material PMMA, and the upper part uses another different material PC;
  • Figure 6e shows that the upper part, middle part, and lower part of the base use respectively PC, PMMA, PS three different materials.
  • PMMA is polymethyl methacrylate
  • PC is polydimethylsiloxane
  • PS is polycarbonate
  • the substrate is made of a transparent material, such as one or more of PMMA, PC, PS, and BK7 glass.
  • the substrate may comprise an upper portion, a middle portion and a lower portion, which may be composed of the same or different materials, more preferably composed of the same material.
  • optical waveguide is a cylinder, and the top and bottom of the optical waveguide are shown as concave conical surfaces.
  • the optical waveguide can also be in other suitable shapes, and its top and bottom can also be convex cones, as long as the refractive index of incident light can be accurately measured.
  • an optical path diagram of light entering and exiting the optical waveguide is shown by arrows.
  • the light path diagram is only a schematic diagram, and it is not limited that light must be incident from below, and light can also be incident from above and exit from below.
  • FIG. 9 a schematic embodiment of the arrangement of the optical waveguides in each optical waveguide array is shown. Those skilled in the art should understand that the arrangement of the optical waveguides in each optical waveguide array may be the same or different.
  • the method for fabricating the localized surface plasmon resonance biochip described herein includes: (1) providing a base material; (2) generating a lower layer microfluidic channel; (3) generating a middle layer optical waveguide and an optical waveguide array; (4) ) generating the upper microfluidic channel; (5) dispersing and fixing titanium nitride nanocubes on the side surface of the optical waveguide, thereby preparing the biochip of the present invention.
  • steps (2) to (4) is not limited.
  • the preferred embodiment is to use 3D printing to generate microfluidic channels, optical waveguides, and optical waveguide arrays.
  • the preferred embodiment is to manufacture the biochips of the present invention by wet chemical methods and UV curing techniques.
  • those skilled in the art can also use any other known technology or method to manufacture the biochip of the present invention.
  • the localized surface plasmon resonance biochip of the present invention can be applied to a biosensing system, and the biochip or a biosensing system including the biochip can be used for fluid sample detection.
  • the principle of detecting the concentration of the fluid sample in this embodiment is that when the optical waveguide array is irradiated with light, the surface plasmon resonance of the titanium nitride nanocube will be excited.
  • the resonance is divided into the radial polarization component TM polarization and the annular polarization component TE polarization. Since the surface plasmon resonance of the titanium nitride nanocube only affects the TM polarization and has no effect on the TE polarization, the radial polarization can be adjusted by the phase shift device.
  • the phase-shift of the polarized components in the direction and the circular direction is carried out, and the differential phase value of the two polarization directions is obtained.
  • the magnitude of the differential phase value is related to the refractive index around the titanium nitride nanocube, which in turn is related to the concentration of the target captured by the receptor (the fluid sample in this example).
  • the molecular weight of each biological target Different, its refractive index is also different, so the concentration of different fluid samples can be obtained through the measured differential phase value or the differential phase change value calculated based on this.
  • Exemplary detection methods are as follows:
  • a PBS solution containing human IgG antibody is used as a fluid sample, and the structure of the biochip of the present invention shown in FIG. 4 is exemplified.
  • This example serves to exemplarily detect the concentration of human IgG antibodies in different fluid samples. It should be understood that the method steps, reagents, concentrations, flow rates, time, instruments, equipment, etc. used in this embodiment are all examples, and those skilled in the art can adjust the steps, reagents, Concentration, flow rate, time, instruments, equipment, etc.
  • the 0.1 ⁇ g/ml human IgG antigen diluted in PBS was immobilized on the titanium nitride nanocubes at a constant flow rate of 5 ⁇ ml/min for 5 minutes, so that the human IgG antigen was adsorbed by the titanium nitride nanocubes. Subsequently, excess human IgG antigen was washed away with PBS solution. Thereafter, the non-specific binding sites of the titanium nitride nanocubes were blocked with 0.1 mM ethanolamine (EA) in PBS for about 30 seconds to prevent non-specific interactions between the titanium nitride nanocubes and the IgG antibody. Excess ethanolamine EA was then rinsed off with PBS solution. So far, the functionalized adsorption is completed.
  • EA 0.1 mM ethanolamine
  • Phosphate buffered saline was introduced into the optical waveguide array, rinsed and stabilized for 3 minutes to create baseline values.
  • the baseline value here refers to the differential phase value of the TM and TE polarized light generated by irradiating the optical waveguide array with a 633 nm laser to excite the surface resonance of the titanium nitride nanocube when the sample is a phosphate buffered saline solution.
  • Human IgG antibodies were prepared with different concentrations in PBS, namely 1OfM, 100fM, 1 pM, 10 pM, 100 pM, 1 nM and 10 nM. Multiple fluid samples containing different concentrations of human IgG antibodies were introduced from different microfluidic channel inlets at a rate of 5 ⁇ l/min, flowed through the optical waveguide and the optical waveguide array for about 10 minutes, and then exited from their corresponding microfluidic channels. outflow.
  • each optical waveguide array through which the above sample flows to excite the surface plasmon resonance of titanium nitride nanocubes; the radial and annular polarization components are phase-shifted by a liquid crystal phase-shift device to obtain two polarization directions
  • the difference phase change value is obtained by subtracting the above-mentioned baseline value of the PBS solution from the obtained differential phase value. A one-to-one correspondence is established between this known concentration and the resulting differential phase change, thereby establishing a calibration curve.
  • R 2 refers to the coefficient of determination (also known as the coefficient of determination) of a statistic that measures the goodness of fit
  • the goodness of fit refers to the degree of fit of the regression line to the observed value.
  • the maximum value of R2 is 1 . The closer the value of R 2 is to 1, the better the fit of the regression line to the observed values; on the contrary, the smaller the value of R 2 is, the worse the fit of the regression line to the observed values.
  • the LOD (limit of detection) of the detected human IgG is ⁇ 0.1 pM. This is up to an order of magnitude superior to the LOD reported in the prior art. This improvement in detection accuracy is attributed to the multiple total reflections and resonances of the TM-polarized light in the optical waveguide, so the LSPR phase is amplified. In the prism coupler, however, the TM polarized light resonates with the nanostructure through only one total reflection, so there is no phase amplification, resulting in insufficient measurement accuracy.
  • this example shows that the biochip of the present invention can be applied to the detection of fluid samples, which can not only achieve high-throughput and rapid detection, but also achieve very high detection accuracy.
  • Those skilled in the art should understand that other nano-wavelength light irradiation can be used, as long as the resonance excited by the incident light can be divided into radial polarization and annular polarization;
  • the differential phase value and refractive index can be calculated using any known method.

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Abstract

一种局域表面等离子体激元共振生物芯片，包括：（1）基底，（2）设置在基底中部的多个光波导，多个光波导组成光波导阵列，（3）设置在每个光波导的侧表面上的氮化钛纳米立方体，（4）设置在基底中的多个微流体通道。还提供了生物芯片的制造方法、包含生物芯片的生物传感系统，及其应用。既能够降低制造成本、提高检测精度，还满足高通量快速检测的需求。

Description

一种局域表面等离子体激元共振生物芯片、其制造方法、包含其的生物传感系统及其应用 技术领域
本发明涉及生物传感领域，特别是涉及一种局域表面等离子体激元共振生物芯片、其制造方法、包含其的生物传感系统及其应用等领域。
背景技术
基于纳米技术的先进版本称为具有纳米结构的局域表面等离振子共振(LSPR)，是一种建立在等离振子共振(SPR)无标记生物传感的技术。现有的SPR生物传感器大都基于银、金或银-金合金作为等离激元支持材料，以激发电子云的集体振荡。金通常是化学惰性的，是已建立的功能化方案的材料选择。然而，金作为等离激元支持材料存在两个缺陷，(i)金材料本身昂贵；和(ii)金膜的厚度高达约50nm，基于金的共振生物芯片制造成本高昂；这些缺陷妨碍了金基SPR生物传感器的广泛使用。基于此，本领域急需一种能够代替或减少金材料使用、且降低生物芯片制造成本的芯片结构及其制造方法。
本发明人发现等离子氮化钛(TiN)材料可替代金材料用于无标记生物传感应用中，氮化钛材料的分辨率约为2×10 -7折射率单位(RIU)，与金纳米岛或金银双金属纳米岛(BMNIs)的分辨率几乎相同。牺牲热缩锡模板对薄膜进行进一步修饰，以在玻璃上形成氮化钛的纳米通孔。带有TiN纳米孔的LSPR生物传感实现了9×10 -8RIU的分辨率，与AuNIs和BMNIs的分辨率相当。此外，使用生物素化抗体可以使氮化钛的功能直接实现，因此与金相比，氮化钛可以减少涉及的化学物质的数量，提高检测精度。综上，使用氮化钛材料代替金材料不但可实现基本相同的分辨率，还可进一步降低等离激元生物芯片的制造成本、提高流体样品的检测精度。
尽管等离子材料的发展和固有的无标记优势，但现有的SPR设备在并行检测通道的数量上也受到限制。即使使用系统制造商提供的已建立的最先进的型号，即
Figure PCTCN2020116724-appb-000001
等，通常也仅包含四 至八个通道。这远远不能满足高通量快速检测生物样品的需求。SPR系统中检测信道数量有限的原因是使用衰减全反射(ATR)配置。使用ATR配置将入射角调整到70度以上，导致反射的图像太小而无法以高保真度聚焦在焦点上，因此只能用于多路传输的区域非常有限。SPR系统的检测信道数量不足，导致并行处理能力受到极大限制，无法满足高通量快速检测生物样品的需求。因此，急需一种既能够降低制造成本、提高检测精度同时还满足高通量快速检测需求的LSPR共振生物芯片及其制造方法。
发明内容
为了克服现有技术的不足，本发明的目的在于：提供一种既能够降低制造成本、提高检测精度同时还满足高通量快速检测需求的局域表面等离子体激元共振生物芯片，其制造方法、包含其的生物传感系统及其应用。
为实现上述目的，本发明的技术方案是：
在一个方面，本发明提供一种局域表面等离子体激元共振生物芯片，其包括：(1)透明基底，其允许光透过；(2)设置在所述基底中部的多个光波导，所述多个光波导组成光波导阵列；(3)设置在每个所述光波导的侧表面上的氮化钛纳米立方体；(4)设置在基底的多个微流体通道。
在优选的实施方案中，所述基底的组成材料可以为PMMA、PC、PS、BK7玻璃中的一种或多种，更优选PMMA或PC的聚合物，最优选为PMMA聚合物。
其中，基底允许一定波长的光透过，以便通过测量光的折射率来流体样品的性质、种类及浓度。在优选的实施方案中，所述基底允许400-1200纳米波长的光透过，更优选600-900纳米波长的光透过。
在优选的实施方案中，所述基底包括上部、中部和下部，所述上部、中部、下部可以由相同的或不同的材料组成，更优选由相同的材料组成。
在优选的实施方案中，所述光波导的材料至少与设置所述光波导的基底中部的材料相同，更优选都为PMMA聚合物材料。
在优选的实施方案中，所述光波导的直径为微米量级，更优选100-500微米，最优选约200微米；所述光波导的高度为1000-5000微米，更优选约1500微米；相邻光波导之间的距离为微米量级，更优选约100-500微米，最优选约200微米。
在优选的实施方案中，所述光波导的数量为2-61个，更优选7-37个，最优选19个。
在优选的实施方案中，所述光波导组成的光波导阵列数量为8-128个，更优选32-96个，最优选64个。
在优选的实施方案中，所述光波导为柱状体，更优选为圆柱体；所述光波导的顶部和底部为锥面，更优选为内凹的锥面。
在优选的实施方案中，所述氮化钛纳米立方体通过湿化学法和紫外线固化技术在光波导阵列的表面上分散并固定。
在优选的实施方案中，所述氮化钛纳米立方体的大小为约40至50纳米，更优选约45纳米。
在优选的实施方案中，所述微流体通道分为入口段、传送段和出口段，用于检测的流体样品由入口段流入、流经传送段的光波导、由出口段流出。
在优选的实施方案中，所述微流体通道的数量与光波导阵列的数量相同，为8-128个，更优选32-96个，最优选64个。
其中，各个微流体通道可以独立地检测相同或不同的流体样品。
在又一个方面，本发明提供一种制造上文所述的局域表面等离子体激元共振生物芯片的方法，其包括：(1)提供基底材料；(2)生成下层微流体通道；(3)生成中层光波导和光波导阵列；(4)上层微流体通道；(5)在所述光波导的侧表面上分散并固定氮化钛纳米立方体。
其中，上述方法中，步骤(2)至(4)之间的顺序不受限制。
在优选的实施方案中，上述方法中，步骤(2)至(4)中的所述微流体通道、光波导和光波导阵列均通过3D打印成型。
在优选的实施方案中，通过湿化学法和紫外线固化技术在所述光波导的侧表面上分散并固定氮化钛纳米立方体。
在又一个方面，本发明提供一种生物传感系统，其包含上文所述的局域表面等离子体激元共振生物芯片。
在又一个方面，本发明还提供上文所述的局域表面等离子体激元共振生物芯片或包含该芯片的生物传感系统用于流体样品检测中的用途。
本发明的有益效果在于：
1、使用氮化钛纳米材料代替金材料同时采用在基底中部形成带有氮化钛纳米立方体的光波导阵列，不但保证了分辨率同时还显著降低了材料成本；另外，氮化钛可以减少涉及的化学物质的数量，提高了检测精度。
2、使用微米量级的光波导阵列和多个独立的微流体通道，增加了LSPR系统的检测信道数量，提高了并行处理能力、满足了高通量快速检测的需求。光波导的数量应适当，过少会导致检测信道数量减少，过多会阻碍流体样品自由流动。
3、光波导顶部和底部采用锥面设计，不但可使光波导相关器件小型化，而且满足氮化钛纳米立方体产生共振的入射角度，从而提高了折射率变化测量的精确度，提高了样品检测的精度。
4、PMMA、PC聚合物作为光波导的组成材料，不但可以实现与BK7玻璃等基本相同的折射率，而且还能与氮化钛纳米立方体通过化学键自组装固定在光波导上，方便制造、提高了制造效率且降低了成本。
5、通过3D打印聚合物基底材料使其生成微流体通道、光波导及光波导阵列，极大地节省了工序，提高了制造效率，适合大规模应用。
综上，本发明的技术方案不但能够降低制造成本、提高检测精度，还能满足高通量快速检测的需求。
附图说明
以下结合附图和实施例对本发明作进一步详细描述，需要指出的是，以下所述实施例或实施方案旨在便于对本发明的理解，而非限制。
图1示出了现有技术中金基SPR生物芯片的结构。
图2a-2e为本发明的带有光波导阵列的生物芯片的正视图(图2a)、俯视图(图2b-2c)、仰视图(图2d)、立体图(图2e)，其中示出了基底、光波导阵列、微流体通道三者之间的位置关系。
图3示出了本发明的氮化钛纳米立方体在光波导侧表面的布置。
图4示出了本发明的微流体通道的入口段、传送段和出口段。
图5用箭头示出了待检测的流体样品流经微流体通道以及光波导阵列的示意图.
图6a-6e示出了基底组成材料的示意性实施方案，其中图6a示出了基底 的上部、中部、下部采用相同材料；图6b示出了基底的上部、下部采用相同材料，中部采用另一不同材料；图6c示出了基底的上部、中部采用相同材料，下部采用不同材料；图6d示出了基底的中部、下部采用相同材料，上部采用另一不同材料；图6e示出了基底的上部、中部、下部采用三种不同的材料。
图7示出了光波导的示意性优选实施方案，其中光波导为圆柱形，光波导的顶部和底部为内凹的锥面。
图8示出了光在光波导上入射、出射的光路图。
图9示出了一个光波导阵列中光波导布置的俯视图。
图10示出了制造本发明的生物芯片的示意性流程图。
具体实施方式
根据需要，本文公开了本发明的详细实施方案。然而，本领域技术人员应该理解，所公开的详细实施方案仅仅是本发明的示例，本发明可以以各种适当的形式实施。因此，在此公开的具体结构和功能细节不应被解释为限制，而是作为权利要求的基础和用于教导本领域技术人员在任何适当的布置、结构或系统中以各种方式实施本发明的基础。
参照图1，示出了现有技术中金基SPR生物芯片的结构，其中在基底上沉积较厚的金膜。现有技术的这种芯片结构布置需要使用较多的金材料，制造成本高昂，阻碍了金基SPR生物芯片的广泛应用。
图2至图9示出了本发明的生物芯片的结构、基底材料的布置、光波导的布置、形状以及微流体通道在基底的布置。本领域技术人员应理解，附图所示的结构、材料、布置、形状以及其他特征均用于示意，而非限制。
参照图2a至2e，示出了本发明的生物芯片结构的优选实施方案的正视图(图2a)、俯视图(图2b-2c)、仰视图(图2d)、立体图(图2e)。本发明的生物芯片包括：基底、设置在基底中部的光波导及光波导阵列以及设置在基底的多个微流体通道。附图中，光波导阵列设置在基底的中部，微流体通道设置在基底的上部、中部和下部。本领域技术人员应理解，“上部”和“下部”仅仅指相对方向，两者之间可以互换使用；微流体通道的形状及结构均用于示意，而非限制，只要能够使流体样品入样、流经光波导以及光波导阵列、出样用于检测即可。
参照图3，示出了氮化钛纳米立方体布置在光波导的侧表面上。
参照图4，本发明的微流体通道的入口段、传送段和出口段。本领域技术人员应理解，“入口”和“出口”仅是对流体流经方向的相对表述，两者可以互换使用。入口段、传送段、出口段也只是微流体通道的相对划分，并不限制微流体通道的结构。
参照图5，用箭头示出了待检测的流体样品流经图4的微流体通道的示意性路线图。本领域技术人员应理解，图中箭头指的是相对方向，并不限制必须沿该方向流动，只要流体样品能够流经光波导以及光波导阵列均可。
参照图6a-6e，示出了基底各部分的组成的示意性方案。其中图6a示出了基底的上部、中部、下部采用相同材料PMMA；图6b示出了基底的上部、下部采用相同材料PC，中部采用另一不同材料PMMA；图6c示出了基底的上部、中部采用相同材料PMMA，下部采用不同材料PC；图6d示出了基底采用的中部、下部采用相同材料PMMA，上部采用另一不同材料PC；图6e示出了基底的上部、中部、下部分别采用PC、PMMA、PS三种不同的材料。其中，PMMA是聚甲基丙烯酸甲酯；PC是聚二甲基硅氧烷；PS是聚碳酸酯。本领域技术人员应理解，基底由透明材料构成，例如可以为PMMA、PC、PS、BK7玻璃中的一种或多种。基底可以包括上部、中部和下部，所述上部、中部、下部可以由相同的或不同的材料组成，更优选由相同的材料组成。
参照图7，示出了光波导的优选实施方案。其中光波导为圆柱体，示出了光波导的顶部和底部为内凹的锥面。本领域技术人员应理解，光波导也可以为其他合适的形状，其顶部和底部也可以为外凸的锥面，只要能够将入射的光的折射率精确测量即可。
参照图8，用箭头示出了光在光波导上入射、出射的光路图。本领域技术人员应理解，该光路图只是示意，并不限制光必须从下方入射，也可以从上方入射、下方出射。
参照图9，示出了每个光波导阵列中光波导的布置的示意性实施方案。本领域技术人员应理解，每个光波导阵列中光波导的布置可以相同、也可以不同。
参照图10，示出了制造本发明的生物芯片的一个优选实施方案的流程图。制造本文所述的局域表面等离子体激元共振生物芯片的方法，其包括：(1)提 供基底材料；(2)生成下层微流体通道；(3)生成中层光波导和光波导阵列；(4)生成上层微流体通道；(5)在所述光波导的侧表面上分散并固定氮化钛纳米立方体，由此制得本发明的生物芯片。本领域技术人员应理解，步骤(2)至(4)之间的顺序不受限制。对于本发明特定的聚合物基底材料而言，优选的实施方案是采用3D打印生成微流体通道、光波导和光波导阵列。对于本发明特定的聚合物基底材料和氮化钛纳米立方体而言，优选的实施方案是通过湿化学法和紫外线固化技术制造本发明的生物芯片。当然，本领域技术人员也可以采用任何其他已知的技术或方法来制造本发明的生物芯片。
本发明的局域表面等离子体激元共振生物芯片可以应用于生物传感系统中，该生物芯片或包含其的生物传感系统可以用于流体样品检测。
本实施例检测流体样品浓度的原理在于：使用光照射光波导阵列时，会激发氮化钛纳米立方体表面等离子体共振。共振分为径向偏振分量TM偏振和环向偏振分量TE偏振，由于氮化钛纳米立方体表面等离子体共振只对TM偏振起作用，而对TE偏振没有任何影响，因此通过相移设备可对径向和环向偏振分量进行移相，由此得出两个偏振方向的差分相位值。已知差分相位值的大小与氮化钛纳米立方体周边的折射率相关，而折射率又与受体捕获的靶标物(本实施例中为流体样品)的浓度有关，每种生物靶标物的分子不同，其折射率也不同，因此通过测量的差分相位值或基于此计算的差分相位变化值可以得到不同流体样品的浓度。
示例性检测方法如下：
以含人IgG抗体的PBS溶液作为流体样品、以图4所示的本发明生物芯片结构来例示。本实施例用于示例性地检测不同流体样品中人IgG抗体的浓度。应理解，本实施例中所用的方法步骤、试剂、浓度、流速、时间、仪器、设备等均为示例，本领域技术人员能够根据待测的流体样品及检测目的来调整所用的步骤、试剂、浓度、流速、时间、仪器、设备等。
(1)功能化吸附
将以PBS稀释的0.1μg/ml人IgG抗原以5μml/min的恒定流速固定在氮化钛纳米立方体上5分钟，使人IgG抗原被氮化钛纳米立方体吸附。随后，使用PBS溶液冲洗掉过量的人IgG抗原。此后，采用PBS中0.1mM的乙醇胺 (EA)封闭氮化钛纳米立方体的非特异性结合位点约30秒钟，以防止氮化钛纳米立方体和IgG抗体之间的非特异性相互作用。然后用PBS溶液冲洗掉过量的乙醇胺EA。至此，功能化吸附完成。
(2)创建基线值
将磷酸缓冲盐溶液(PBS)引入光波导阵列，冲洗并稳定3分钟，用以创建基线值。此处的基线值是指，样品为磷酸缓冲盐溶液时，使用633纳米激光照射光波导阵列激发氮化钛纳米方体的表面共振，所产生的TM和TE偏振光的差分相位值。
(3)建立标定曲线
制备在PBS中具有不同浓度的人IgG抗体，即10fM、100fM、1pM、10pM、100pM、1nM和10nM。将含不同浓度的含人IgG抗体的多份流体样品以5μl/min的速率从不同的微流体通道入口引入，流经光波导及光波导阵列大约10分钟，然后从各自对应的微流体通道出口流出。
使用633纳米激光照射上述样品流经的每一个光波导阵列，激发氮化钛纳米立方体表面等离子体共振；通过液晶相移设备对径向和环向偏振分量进行移相，得出两个偏振方向的差分相位值。以PBS溶液的上述基线值与得到的差分相位值进行相减，得到差分相位变化值。用该已知浓度和得出的差分相位变化之间建立一一对应关系，由此建立标定曲线。
经检测，IgG抗体浓度为10fM、100fM、1pM、10pM、100pM、1nM和10nM时，各自对应的差分相位变化值分别为0.04弧度、0.12弧度、0.27弧度、1.45弧度、2.19弧度、2.78弧度和2.91弧度。由此建立的线性回归拟合表明，线性关系为y＝0.115x+1.433(R 2为0.96)。其中x是以10为底的对数IgG浓度，y是差分相位值。此处的R 2指的是度量拟合优度的统计量的可决系数(亦称确定系数)，拟合优度(Goodness of Fit)是指回归直线对观测值的拟合程度。R 2最大值为1。R 2的值越接近1，说明回归直线对观测值的拟合程度越好；反之，R 2的值越小，说明回归直线对观测值的拟合程度越差。
(4)检测待测样品的浓度
先用与上述(1)中相同的步骤进行功能性吸附，并以与上述(2)中相同的步骤建立PBS溶液的基线值。
之后，将未知浓度的含人IgG抗体的多份流体样品以5μl/min的速率从不同的微流体通道入口引入，流经光波导及光波导阵列大约10分钟，然后从各自对应的微流体通道出口流出。
使用与建立标定曲线相同的633纳米激光照射上述样品流经的每一个光波导阵列，激发氮化钛纳米立方体表面等离子体共振；通过液晶相移设备对径向和环向偏振分量进行移相，得出两个偏振方向的差分相位值。以PBS溶液的基线值与得到的差分相位值进行相减，得到差分相位变化值。将得到的差分相位变化值代入到上述的线性关系式y＝0.115x+1.433中，其中x是以10为底的对数IgG浓度，y是差分相位值，由此得到待测样品的浓度。
另外，当本实施例采用的光波导为顶部和底部的锥面设计时，所检测的人IgG的LOD(检测极限)≥0.1pM。这比现有技术中报告的LOD更优异，高达一个数量级。该检测精度的提高归因于光波导中TM偏振光经过多重全反射和共振，因此LSPR相位得到了放大。而在棱镜耦合器中，TM偏振光仅通过一次全反射与纳米结构发生共振，因此不存在相位放大，导致测量精度不足。
因此，本实施例表明本发明的生物芯片可以应用于流体样片的检测中，不但能实现高通量快速检测，而且还实现了非常高的检测精度。本领域技术人员应理解，可以使用其他纳米波长的光照射，只要入射的光激发的共振可以分为径向偏振和环向偏振即可；可以使用现有的任何相移设备进行移相，也可以使用已知的任何方法计算差分相位值以及折射率。
应当理解，虽然上文已经详细描述了优选实施方案，但是本发明不限于这里描述和示出的材料、结构和特征的布置，这些描述仅仅是本发明的示例性优选实施方案，其可以以各种等同的形式实现。

Claims (17)

  1. 一种局域表面等离子体激元共振生物芯片，其特征在于，包括：(1)透明基底，其允许光透过；(2)设置在所述基底中部的多个光波导，所述多个光波导组成光波导阵列；(3)设置在每个所述光波导的侧表面上的氮化钛纳米立方体；(4)设置在基底的多个微流体通道。
  2. 根据权利要求1所述的等离子体激元共振生物芯片，其特征在于，所述基底的组成材料为PMMA、PC、PS、BK7玻璃中的一种或多种，优选PMMA或PC的聚合物，最优选为PMMA聚合物。
  3. 根据权利要求1所述的等离子体激元共振生物芯片，其特征在于，所述基底允许400至1200纳米波长的光透过，优选允许600-900纳米波长的光透过。
  4. 根据权利要求2所述的等离子体激元共振生物芯片，其特征在于，所述基底包括上部、中部和下部，所述上部、中部、下部是由相同的或不同的材料组成，优选由相同的材料组成。
  5. 根据权利要求4所述的等离子体激元共振生物芯片，其特征在于，所述光波导的材料至少与设置所述光波导的基底中部的材料相同，优选为PMMA聚合物材料。
  6. 根据权利要求1所述的等离子体激元共振生物芯片，其特征在于，所述光波导的直径为微米量级，优选100-500微米，最优选约200微米；所述光波导的高度为1000-3000微米，优选约1500微米；相邻光波导之间的距离为微米量级，优选约100-500微米，最优选约200微米。
  7. 根据权利要求1所述的等离子体激元共振生物芯片，其特征在于，所述光波导为柱状体，优选为圆柱体；所述光波导的顶部和底部为锥面，优选为内凹的锥面。
  8. 根据权利要求1所述的等离子体激元共振生物芯片，其特征在于，所述氮化钛纳米立方体通过湿化学法和紫外线固化技术在光波导阵列的表面上分散并固定。
  9. 根据权利要求1所述的等离子体激元共振生物芯片，其特征在于，所述氮化钛纳米立方体的大小为约40-50纳米，优选为约45纳米。
  10. 根据权利要求1所述的等离子体激元共振生物芯片，其特征在于，所述微流体通道分为入口段、传送段和出口段，用于检测的流体样品由入口段流入、流经传送段的光波导、由出口段流出。
  11. 根据权利要求1所述的等离子体激元共振生物芯片，其特征在于，所述微流体通道的数量与光波导阵列的数量相同。
  12. 根据权利要求1所述的等离子体激元共振生物芯片，其特征在于，各个微流体通道独立地检测相同或不同的流体样品。
  13. 制造权利要求1-12中任一项所述的局域表面等离子体激元共振生物芯片的方法，其包括：(1)提供基底材料；(2)生成下层微流体通道；(3)生成中层光波导和光波导阵列；(4)生成上层微流体通道；(5)在所述光波导的侧表面上分散并固定氮化钛纳米立方体。
  14. 根据权利要求13所述的方法，其特征在于，步骤(2)至(4)中的所述微流体通道、光波导和光波导阵列均通过3D打印成型。
  15. 根据权利要求13所述的方法，其特征在于，通过湿化学法和紫外线固化技术在所述光波导的侧表面上分散并固定氮化钛纳米立方体。
  16. 一种生物传感系统，其包含权利要求1-12中任一项所述的局域表面等离子体激元共振生物芯片。
  17. 权利要求1-12任一项所述的局域表面等离子体激元共振生物芯片或权利要求16所述的生物传感系统用于流体样品检测中的用途。
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