WO2016149980A1 - 变量干预式生物标志物浓度检测方法及装置 - Google Patents

变量干预式生物标志物浓度检测方法及装置 Download PDF

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Publication number
WO2016149980A1
WO2016149980A1 PCT/CN2015/077441 CN2015077441W WO2016149980A1 WO 2016149980 A1 WO2016149980 A1 WO 2016149980A1 CN 2015077441 W CN2015077441 W CN 2015077441W WO 2016149980 A1 WO2016149980 A1 WO 2016149980A1
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Prior art keywords
variable
intervention
light receiving
receiving module
biomarker
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PCT/CN2015/077441
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English (en)
French (fr)
Inventor
张贯京
陈兴明
葛新科
张少鹏
方静芳
克里斯基捏普拉纽克
古列莎艾琳娜
波达别特伊万
高伟明
梁昊原
梁艳妮
周荣
徐之艳
周亮
肖应芬
郑慧华
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Shenzhen Qianhai AnyCheck Information Technology Co Ltd
E Techno Information Technologies Co Ltd
Bio Tech Academy China Co Ltd
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Shenzhen Qianhai AnyCheck Information Technology Co Ltd
E Techno Information Technologies Co Ltd
Bio Tech Academy China Co Ltd
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Publication of WO2016149980A1 publication Critical patent/WO2016149980A1/zh
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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
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/27—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands using photo-electric detection ; circuits for computing concentration

Definitions

  • the invention relates to the field of biomarker detection, and more particularly to a variable intervention type biomarker concentration detection method and device.
  • Biomarker refers to a biochemical indicator that can label changes or possible changes in the structure, function, organization, cell and subcellular structure or function of a system, and has a very wide range of uses. Biomarkers can be used for disease diagnosis, for judging disease staging, or for assessing the safety and efficacy of new drugs or new therapies in the target population.
  • Surface plasmon resonance technology SPR (Surface) is commonly used when detecting biomarkers Plasmon Reson ⁇ ance), which uses a physical optical phenomenon caused by total reflection connection of metal film/liquid surface interface to analyze biomolecular interactions, and measures the concentration of biomarkers by infrared light combined with SPR technology.
  • SPR Surface plasmon resonance technology
  • Plasmon Reson ⁇ ance uses a physical optical phenomenon caused by total reflection connection of metal film/liquid surface interface to analyze biomolecular interactions, and measures the concentration of biomarkers by infrared light combined with SPR technology.
  • photometry is a more common method, which combines the components of body fluid samples with one or more test reagents in vitro to determine the concentration of analytes multiple times, thereby triggering organisms.
  • a chemical reaction that causes a measurable change in the optical properties of the analyte, which is detected by photometry and utilizes the attenuation of the occurrence of light flow through the optically and/or astigmatic medium, however, this measurement method Affected by the type of the sample itself and the interfering substances it may contain, it is easy to cause systematic errors in the measurement, making the measurement of the concentration of the biomarker inaccurate, and the adjustment of the direction of the optical flow during measurement is difficult to control. It often causes great trouble to the measurer.
  • the optical detecting unit 700 which will be employed in the present invention
  • a spectrum with a dark region is formed thereon, which simultaneously outputs an electrical signal.
  • the position of the spectrum will vary with the presence of the biomarker in the substance, and the position information is very difficult to measure and determine.
  • the present invention provides a method and apparatus for detecting a variable intervention biomarker concentration for quickly and accurately obtaining a biomarker concentration in a test object.
  • a variable intervention biomarker concentration detecting method comprising the following steps, the light receiving module receives a polarized light beam, forms a spectrum, and outputs an electrical signal Qn to set an output electrical signal thereof.
  • the zero value Q0; the intervention variable An is introduced, the position of the spectrum formed on the light receiving module is adjusted by the intervention variable, and the electrical signal output value of the light receiving module is adjusted, and each intervention variable value An corresponds to the electrical signal output of one light receiving module.
  • the intervention variable An A+n ⁇ a, wherein A is a fixed value, and a is a single adjustment range of the intervention variable, n is a natural number.
  • variable intervention biomarker concentration detection method in the present invention as a possible occurrence in the actual measurement, there is a slight change in the biomarker concentration in the measured analyte, the light receiving module output
  • the zero value Q0 of the electrical signal, the adjusted intervention variable value Am, and the obtained biomarker concentration value Bm are all interval values.
  • the intervention variable An is a variable controllable, recordable current or voltage.
  • a variable intervention type biomarker concentration detecting device comprises a light receiving module, a transmission mechanism, an adjusting device and a control system, wherein the light receiving module and the adjusting device are respectively connected with the transmission mechanism, and the control system Receiving electrical signal information output by the light receiving module and correspondingly controlling the movement of the adjusting device.
  • the transmission mechanism includes rack and pinion meshing with each other, the adjustment The device comprises a coil, a magnet and a base, the rack is fixed on the light receiving module, the gear is rotatably fixed on the base, and the coil is fixed on the transmission mechanism
  • the magnet is adjacent to the coil, so that after the coil is energized, it can move the light receiving module by the transmission mechanism under the action of the magnet.
  • variable intervening biomarker concentration detecting device of the present invention as a further arrangement of an embodiment of the above transmission mechanism, further comprising a shaft, the gear sleeve being sleeved on the shaft, the The shaft is fixed to the base.
  • the transmission mechanism includes a meshing worm wheel and a worm
  • the adjusting device The utility model comprises a coil, a magnet and a base, wherein the worm is fixed on the light receiving module, the worm wheel is rotatably fixed on the base, and the coil is fixed on the transmission mechanism.
  • the magnet is adjacent to the coil, so that after the coil is energized, it can move the light receiving module by the transmission mechanism under the action of the magnet.
  • variable intervention type biomarker concentration detecting device of the present invention as a further arrangement, it further includes a spring, and the light receiving module is supported by the spring.
  • a balance device is further disposed on the transmission mechanism, and the balance device and the coil are distributed in the transmission On both sides of the body.
  • the magnet is a neodymium magnet and has a strip shape or a circular arc shape.
  • the technical effect brought by the invention is that the invention uses the variable intervention biomarker concentration detection method to adopt the light receiving module to receive specific spectral information, form a spectrum, and set a zero point position, and adjust the object to be tested in the light receiving module through the intervention variable.
  • the spectral position of the upper part, the concentration value information of the biomarker in the test object is calculated correspondingly by the intervention variable, and the concentration of the biomarker in the test object can be detected conveniently, quickly and accurately; the variable in the present invention
  • the intervention biomarker concentration detecting device controls the transmission mechanism to drive the adjustment of the light receiving module through the recordable intervention variable, thereby adjusting the position of the spectrum on the light receiving module, and acquiring the spectral position change information, when the electrical signal output thereof
  • the concentration of the biomarker in the test can be obtained correspondingly, the structure is simple, the production cost is low, and the use is very convenient, and the concentration of the biomarker in the test can be accurately and quickly obtained.
  • FIG. 1 is a working principle diagram of a surface plasmon resonance technique according to the present invention.
  • FIG. 2 is a working flow chart of a method for detecting a variable intervention biomarker concentration in the invention
  • 3 is a mapping table between the intervention variable An of the variable intervention biomarker concentration detection method, the electrical signal output value Qn of the light receiving module, and the biomarker concentration Bn in the present invention
  • Fig. 4 is a schematic view showing the overall structure of a variable intervention type biomarker concentration detecting device in the present invention.
  • FIG. 1 is a working principle diagram of a surface plasmon resonance technique according to the present invention, which is a prior art, as shown in the figure, a process of detecting a concentration of a biomarker by using a surface plasmon resonance technique, first, setting a flow channel 300 and transmitting
  • the sensing chip 400 is provided with a gold film on the sensing chip 400, and a side portion of the sensing chip 400 with the gold film is located in the flow channel 300, so that the object to be detected flowing into the flow channel 300 can be contacted with
  • the gold film sensor chip 400 when measuring, passes the object to be detected with the biomarker into the flow channel 300, so that the object to be detected is in contact with the sensor chip, and a layer of antibody molecules is modified in advance at the reaction interface.
  • the refractive index of the surface of the gold film changes, and the SPR resonance angle changes with the change of the refractive index.
  • the change of the refractive index is proportional to the change of the mass of the biomacromolecules bound to the metal surface.
  • the magnitude of the peak shift will reflect changes in the biological molecular weight immobilized on the metal surface to enable immunoassay.
  • a light beam is emitted from a light source 600, which is irradiated onto the sensor chip 400, and is reflected by the optical detecting unit 700 (which will replace the optical detecting unit 700 with the light receiving module in the present invention) through the optical detecting unit 700.
  • the change of the received beam information is sensed, and the corresponding relationship between the change information and the biomarker concentration of the object to be detected is obtained, and finally the biomarker concentration value in the object to be detected is obtained from the change information.
  • a monochromatic light source such as an infrared beam source can be used, which is effective.
  • the flow chart of the method for detecting variable intervention biomarker concentration in the present invention is as shown in FIG. 2, which includes the following processing steps: S1.
  • the light receiving module receives the polarized light beam and outputs an electrical signal, and sets the zero value of the output electrical signal.
  • Q2; S2 the intervention variable An is introduced, so that each intervention variable value An corresponds to the electrical signal output value Qn of one light receiving module;
  • the above specific process is: receiving a polarized light beam by using a light receiving module, forming a spectrum thereon, and outputting an electrical signal Qn, and setting a zero value Q0 of the output electrical signal, the zero value is a biological object to be detected that does not contain a biological substance.
  • the light receiving module receives the polarized light beam and outputs the electrical signal value, and then sets the intervention variable An.
  • the intervention variable is used to adjust the position of the spectrum formed on the light receiving module, and adjust the electrical signal output value of the light receiving module.
  • the intervention variable herein may be a change amount of a driving current or a voltage or the like that changes an incident angle of a light beam that is irradiated onto the light receiving module, or may be a change amount of a current or a voltage of the device that adjusts the position of the light receiving module,
  • Each intervention variable value An corresponds to an electrical signal output value Qn of a light receiving module; a correspondence relationship between the intervention variable An and the biomarker concentration Bn in the detection is set, since the intervention variable An is a spectrum formed on the light receiving module
  • the position is adjusted by adjusting the position of the spectrum of the polarized light beam emitted from the sensor chip on the light receiving module
  • the position of the spectrum containing the biomarker to be detected overlaps on the light receiving module, and the specific condition of the adjustment is determined by the value of the electrical signal outputted on the light receiving module.
  • the concentration of the biomarker in the test substance can be obtained by querying the biomarker concentration Bm corresponding to the intervention variable Am.
  • n and m are natural numbers, and n>m.
  • the accuracy requirements of the system are determined. When the measurement system requires high measurement accuracy, a should be as small as possible and achievable to meet the measurement accuracy requirements of the measurement system.
  • n is a natural number.
  • the intervention variable An of the variable intervention biomarker concentration detection method is the specific numerical record after multiple adjustments.
  • the electric signal value Qn output by the light receiving module is the specific value obtained by the change of the intervention variable An, and the biomarker Bn corresponding to the above two.
  • the value can also be pre-arranged.
  • the An can be adjusted multiple times.
  • the zero value Q0 of the output signal of the light receiving module, the adjusted intervention variable value Am, and the obtained concentration value Bm of the biomarker may each be an interval value because the content of each component in the sample is
  • the test object in the test object may float to a certain extent during the flow.
  • the test object has a certain floating property due to the combination of the antibody and the antigen during the detection process.
  • the zero value of the electrical signal output by the light receiving module may have a small range of floating (for example, the range of the mathematical value of Q0 may be 0.0015-0.0016), therefore,
  • the relevant intervention variable value Am and the corresponding biomarker concentration value Bm will have interval values similar to Q0, but relatively speaking, when there are subtle changes in the interval value and the fixed point value, the two The effect is the same.
  • the trace amount can be adjusted and recordable, for example, the change of the recordable trace current, the trace voltage, etc. is used to realize the spectrum on the light receiving module. Adjustment of position.
  • a device for adjusting the light receiving module using current is provided below, but it should be noted that the embodiments listed below are only based on the above principle of the present invention, and other alternatives are more, and the present invention will not be used. An enumeration.
  • the overall structure of the variable intervention biomarker concentration detecting device is shown in FIG. 4, and includes a light receiving module 3, a spring 4, a gear 7, a coil 9, a magnet 10, and a control system (not shown), and the strip 2
  • a light receiving module 3 One end is fixed in an articulated manner, the other end is fixedly connected to the rack 6 , and a gear 7 is disposed beside the rack 6 .
  • the gear 7 is engaged with the rack 6
  • the gear 7 is rotatably fixed on the shaft 8 .
  • the shaft 8 is fixed on the bracket 11.
  • the light receiving module 3 can be disposed on one strip 2 (but the strip 2 can also be omitted), and then in the strip 2
  • a rack 6 is provided on the upper side.
  • the coil 9 is fixed on the gear 7, and the magnet 10 is located beside the coil 9.
  • the control system applies a current to the coil 9, the magnetic field generated by the magnet 10 causes the coil 9 to rotate, thereby driving the gear 7 to move, and adjusting the light receiving module 3 Position, changing the position of the spectrum above it.
  • the rack 6 and the gear 7 are in meshing state.
  • the gear 7 is rotated by the external force, the rack 6 rotates with the rotation of the gear 7, thereby causing the light receiving module 3 to move.
  • a closed coil 9 is attached to the gear 7, which extends 9 out of the body of the gear 7 and extends outwardly a distance, with a fixed magnet 10 placed next to the coil 9.
  • a part of the coil 9 overlaps with the magnet 10, so that when a current is applied to the coil 9, the coil 9 in the closed state forms a closed loop, and when there is current in the closed loop, it is itself charged.
  • the magnetic field generates a magnetic field, and the magnetic field generated by the coil 9 and the magnetic field of the magnet 10 interact with each other.
  • the control system changes the magnitude/direction of the current flowing into the coil 9 to change the magnetic field strength and magnetic field generated by the coil 9.
  • a spring 4 is connected to the light receiving module 3, and the other end of the spring 4 is fixed, and an initial position is set, so that the spring 4 is In the initial position, the entire device is at a zero point.
  • the horizontal angle of the light receiving module 3 needs to be adjusted, the light receiving module 3 can be more easily restored to the initial position by the elastic force of the spring 4.
  • the module 3 rises/falls under the rotation of the gear 7, and also starts to stretch/compress the spring 4.
  • the control system changes the access coil accordingly.
  • the spring 4 can provide a contraction force or a tensile force correspondingly, so that the light receiving module 3 can be more sensitive and fast with the assistance of the force of the spring 4. Revert to the initial location or desired location.
  • Fig. 4 when the strip 2 is provided, one end of the strip 2 is hingedly fixed, and various hinge devices including hinges, hinged balls, and the like can be used here, and the hinge fixing method is adopted, that is, only need to ensure The strip 2 can be rotated around the support point 1 with a low frictional force.
  • the shape of the magnet 10 is exemplified in the figure, so that the N pole and its S pole are reasonably distributed, so that the coil 9 can move between the N pole and the S pole of the magnet 10 within the range of the magnetic field of the magnet 10, for the magnet 10 It is set to an arc shape as shown in the drawing so as to correspond to the rotation direction of the coil 9, which can exert a relatively wide influence on the coil 9.
  • the shape of the magnet 10 is not limited thereto, and the use of a strip magnet U-shaped magnet or other existing-shaped magnets can also satisfy the above-mentioned use requirements, and will not be described one by one.
  • a balancing device 5 is attached to the gear 7, and the balancing device 5 is mounted on the gear 7 at a position corresponding to the coil 9. That is, the balancing device 5 and the coil 9 are respectively located on both sides of the gear, and the two are at the same level, which play a certain balance between each other.
  • the balancing device 5 can be arranged in a coil shape, which can make The part extends out of the gear 7, so that the weight of the balancing device 5 can be reduced.
  • the balancing device 5 can also balance the position of the coil 9 under the action of the lever by its own gravity, that is, when the coil 9 When the magnetic field force of the magnet 10 is up/down (only the orientation in the figure, the actual direction is not limited to this), under the action of the balancing device 5, the coil 9 can be moved out of the stationary state with only a small force. Similarly, when the coil 9 needs to be adjusted to the initial position, it is only necessary to overcome the small resistance, that is, the position of the coil 9 can be realized without greatly changing the current flowing into the coil 9. Whole.
  • the fixed end of the strip 2, the fixed end of the spring 4, and the fixed portion of the bracket 11 are all platforms for supporting, for example: A bench-top work platform or a support platform placed on the rack, etc.
  • a rack or casing may be added to secure the entire unit to the frame or casing.
  • the rotatably fixed manner of the gear 7 on the shaft 8 can be solved by the prior art.
  • the gear 7 can be placed on the outer ring of the bearing so that it can rotate around the bearing and then the inner ring of the bearing.
  • Fixed on the shaft 8, the shaft 8 is fixed on the bracket 11; in addition, the gear 7 can also directly use the bearing gear to directly fix it on the shaft 8; other existing methods of rotating connection, such as hinge, socket, It is within the scope of the present invention that the gear 7 can be rotatably fixed.
  • variable intervention biomarker concentration detecting device in the present invention is not limited to the above embodiment, for example, the gear 7 in which the movement of the light receiving module 3 is realized and the rack 6 meshed therewith can be It can be replaced by the intermeshing turbine, worm or socket-mounted nut and screw, and the required changed parts can be modified as needed.
  • the worm or nut can be fixed on the light receiving module 3.
  • the worm wheel or the nut can be fixed on the base, and the above-mentioned changes can be easily made by those skilled in the art and other fields who have common knowledge in the field of the prior art, and are not exemplified herein;
  • the position of the spring 4 is also not limited to the position shown in the drawing, and it can also be moved to the vicinity of the support point 1, so that the effect of the spring 4 may be better.

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Abstract

一种变量干预式生物标志物浓度检测方法和装置，光接收模块（3）接收偏振光束形成光谱，并输出电信号Qn，设定其零值Q0；引入干预变量An，调整光接收模块（3）上形成的光谱的位置，同时调整光接收模块（3）的电信号输出值，一个干预变量值An对应一个光接收模块（3）的电信号输出值Qn；设定干预变量An与检测物中生物标志物浓度Bn的对应关系，调整干预变量An至Am，使得Qn＝Q0，查询干预变量Am对应的生物标志物浓度Bm，获得检测物中生物标志物的浓度；n、m为自然数，n＞m。该方法和装置能够方便、快捷的获取检测物中生物标志物的有效信息。

Description

变量干预式生物标志物浓度检测方法及装置
技术领域
本发明涉及生物标志物检测领域，更具体的说涉及变量干预式生物标志物浓度检测方法及装置。
背景技术
生物标志物（Biomarker）是指可以标记系统、器官、组织、细胞及亚细胞结构或功能的改变或可能发生的改变的生化指标，具有非常广泛的用途。生物标志物可用于疾病诊断、判断疾病分期或者用来评价新药或新疗法在目标人群中的安全性及有效性。在检测生物标志物时，常用到表面等离子共振技术SPR（Surface Plasmon Reson×ance），即利用金属膜/液面界面光的全反射连接引起的一种物理光学现象来分析生物分子相互作用，并通过红外光结合SPR技术测量生物标志物浓度，具体可参照论文“表面等离子共振技术在生物医学中的应用”，以及论文“表面等离子体共振免疫传感器在蛋白质检测中的应用及其研究进展”—《分析化学》2010年第七期1052-1059。
在生物标志物检测领域，光度测量法是较为常用的方法，其通过在体外将人体的体液标本的分量与一种或多种检验试剂混合，多次确定被分析物的浓度，由此引发生物化学反应，这使得被测物的光学特性发生可测的变化，光度测量法检测并利用光流穿过吸光性的和/或散光性的媒介时的发生的减弱，然而，这种测量方法由于受样本本身的类型和其可能包含的干扰性物质的影响，导致在测量时易发生系统错误，使得对生物标志物的浓度的测量结果不够准确，而且，在测量时光流方向的调节很难掌控，往往给测量者带来极大的困扰。如图1中所示，在使用光学检测单元700（本发明中将采用光接收模块）接收传感芯片处射出的光束时，其上面会形成带有暗区的光谱，其同时会输出电信号，当通入流动通道中的物质不同时，光谱的位置会随着物质中生物标志物的存在而不同，此位置信息是十分难以测量确定的。
发明内容
为了解决上述技术问题，本发明提供一种快速、准确获取待测物中生物标志物浓度的变量干预式生物标志物浓度检测方法、装置。
本发明为解决上述技术问题所采用的技术方案为：变量干预式生物标志物浓度检测方法，包括以下步骤，光接收模块接收偏振光束，形成光谱，并输出电信号Qn，设定其输出电信号的零值Q0；引入干预变量An，通过干预变量调整光接收模块上形成的光谱的位置，同时调整光接收模块的电信号输出值，每一个干预变量值An对应一个光接收模块的电信号输出值Qn；设定干预变量An与检测物中生物标志物浓度Bn的对应关系，调整干预变量An至Am，使得Qn=Q0，查询干预变量Am对应的生物标志物浓度Bm，获得检测物中生物标志物的浓度；上述，n、m为自然数，且n>m。
对于本发明中的变量干预式生物标志物浓度检测方法，作为进一步的设置，所述的干预变量An=A+n×a，其中，A为定值，a为干预变量的单次调整幅度，n为自然数。
对于本发明中的变量干预式生物标志物浓度检测方法，作为实际测量中的一种可能出现的情况，在所测量的待测物中生物标志物浓度存在细微的变化，所述光接收模块输出电信号的零值Q0、调整后的干预变量值Am以及所得的生物标志物的浓度值Bm均为区间值。
对于本发明中的变量干预式生物标志物浓度检测方法，所述的干预变量An为变化的可控制、可记录的电流或电压。
一种变量干预式生物标志物浓度检测用装置，包括光接收模块、传动机构、调节装置以及控制系统，所述的光接收模块、调节装置分别与所述的传动机构连接，所述的控制系统接收光接收模块输出的电信号信息并相应的控制调节装置运动。
对于本发明中的变量干预式生物标志物浓度检测用装置，作为针对传动机构和调节装置的一种可选的实施例，所述的传动机构包括相互啮合的齿条和齿轮，所述的调节装置包括线圈、磁铁和底座，所述的齿条固定在所述的光接收模块上，所述的齿轮可转动的固定在所述的底座上，所述的线圈固定在所述的传动机构上，所述的磁铁靠近所述线圈，使得向所述线圈中通电后其能够在所述磁铁的作用下通过所述的传动机构带动所述的光接收模块运动。
对于本发明中的变量干预式生物标志物浓度检测用装置，作为上述传动机构的一种实施例的进一步的设置，其还包括轴，所述的齿轮套在所述的轴上，所述的轴固定在底座上。
对于本发明中的变量干预式生物标志物浓度检测用装置，作为针对传动机构和调节装置的一种可选的实施例，所述的传动机构包括相互啮合的蜗轮和蜗杆，所述的调节装置包括线圈、磁铁和底座，所述的蜗杆固定在所述的光接收模块上，所述的蜗轮可转动的固定在所述的底座上，所述的线圈固定在所述的传动机构上，所述的磁铁靠近所述线圈，使得向所述线圈中通电后其能够在所述磁铁的作用下通过所述的传动机构带动所述的光接收模块运动。
对于本发明中上述的变量干预式生物标志物浓度检测用装置，作为进一步的设置，其还包括弹簧，所述的光接收模块由所述弹簧支撑。
对于本发明中上述的变量干预式生物标志物浓度检测用装置，作为进一步的设置，在所述的传动机构上还设有平衡装置，所述的平衡装置与所述的线圈分布在所述传动机构的两侧。
对于本发明中上述的变量干预式生物标志物浓度检测用装置，作为针对磁铁的最优选择，所述的磁铁为钕磁铁，其形状为条形或圆弧形。
本发明带来的技术效果为：本发明使用变量干预式生物标志物浓度检测方法采用光接收模块接收特定光谱信息，形成光谱，并设定零点位置，通过干预变量调整待测物在光接收模块上的光谱位置，通过该干预变量对应计算出待测物中的生物标志物的浓度值信息，能够方便、快速、准确的检测出待测物中的生物标志物的浓度；本发明中的变量干预式生物标志物浓度检测装置，通过可记录的干预变量控制传动机构带动光接收模块的调整，从而调节光接收模块上的光谱的位置，并获取光谱位置变化信息，当其所输出的电信号为初始至时即可相应的得出检测物中生物标志物的浓度，其结构简单，制作成本低廉，且使用起来非常方便，能够精准快速的获得检测物中生物标志物的浓度。
附图说明
图1为本发明涉及到的表面等离子共振技术的工作原理图；
图2为发明中的变量干预式生物标志物浓度检测方法的工作流程图；
图3为本发明中的变量干预式生物标志物浓度检测方法的干预变量An、光接收模块的电信号输出值Qn以及生物标志物浓度Bn之间的对应关系映射表；
图4为本发明中的变量干预式生物标志物浓度检测装置的整体结构示意图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
图1为本发明涉及到的表面等离子共振技术的工作原理图，其为现有技术，如图所示，利用表面等离子共振技术检测生物标志物浓度的过程，首先，设置一个流动通道300和传感芯片400，在传感芯片400上设置一层金膜，并使传感芯片400设有金膜的一面部分位于流动通道300中，使得流入流动通道300内的待检测物能够接触到带有金膜的传感芯片400，测量时，将带有生物标志物的待检测物通入流动通道300，使得待检测物与传感芯片接触，预先在反应界面上修饰一层抗体分子，当目标抗原与抗体识别后，金膜表面介质的折射率发生改变，SPR共振角会随着折射率的改变而改变，折射率的变化又与结合在金属表面的生物大分子质量的变化成正比，共振峰位移的大小将反映固定在金属表面生物分子量的变化，进而实现免疫分析。在图1中，由光源600发出光束，照射到传感芯片400上，经其反射后由光学检测单元700（本发明中将用光接收模块替代光学检测单元700）接收，通过光学检测单元700感应其所接收到的光束信息的变化，得出该变化信息与待检测物生物标志物浓度的对应关系，最终从该变化信息中得出待检测物中生物标志物浓度值。对于光源600，可采用单色光源，例如红外线束光源，效果较好。
本发明中的变量干预式生物标志物浓度检测方法的流程图如图2所示，其包括以下处理步骤：S1、光接收模块接收偏振光束并输出电信号，设定其输出电信号的零值Q0；S2、引入干预变量An，使每一个干预变量值An对应一个光接收模块的电信号输出值Qn；S3、设定干预变量An与检测物中生物标志物浓度Bn的对应关系，并调整干预变量An至Am，使得Qn=Q0；S4、查询干预变量Am对应的生物标志物的浓度Bm，即获得检测物中生物标志物的浓度。上述具体过程为：采用光接收模块接收偏振光束，其上面会形成光谱，并输出电信号Qn，设定其输出电信号的零值Q0，该零值为通入的待检测物中不含有生物标志物时的光接收模块接收偏振光束后所输出的电信号值，之后设定干预变量An，干预变量用来调整光接收模块上形成的光谱的位置，同时调整光接收模块的电信号输出值，此处的干预变量，可以是改变照射到光接收模块上的光束的入射角度的驱动电流或电压等的变化量，也可以是调整光接收模块位置的装置的电流或电压等的变化量，每一个干预变量值An对应一个光接收模块的电信号输出值Qn；设定干预变量An与检测物中生物标志物浓度Bn的对应关系，由于干预变量An是将光接收模块上形成的光谱的位置进行调整，通过调整使得检测物的从传感芯片处射出的偏振光束在光接收模块上的光谱的位置与不含有所要检测的生物标志物的检测物在光接收模块上的光谱的位置重叠，并通过光接收模块上输出的电信号值确定调整的具体情况，当调整干预变量An至Am，使得Qn=Q0，此时只需查询干预变量Am对应的生物标志物浓度Bm，即可获得检测物中生物标志物的浓度，上述的n、m为自然数，且n>m。
本发明进一步的，为了便于调节干预变量An，可将所述的干预变量An进行具体的细化设置，例如使得An=A+n×a，其中，A为定值，可为零也可为设定的电流值或电压值等，a为干预变量的单次调整幅度（当为电流时，可为0.01mA；当为电压时，可为0.01mV等，诸如此类），a的取值根据检测系统的精度要求来确定，当检测系统测量精度要求较高时，a应取尽可能小且能够实现的值，以满足测量系统的测量精度要求，n为自然数。
图3为本发明中的变量干预式生物标志物浓度检测方法的干预变量An、光接收模块的电信号输出值Qn以及生物标志物浓度Bn之间的对应关系映射表，如图所示，干预变量An的列表内为多次调节后的具体数值记录，光接收模块输出的电信号值Qn为干预变量An变化后随其变化相应得出的具体数值，与上述二者对应的生物标志物Bn的数值也可预先列好，进行测量时，可多次调节An，等到光接收模块Qn输出的电信号值Qm=Q0时，记录对应的干预变量Am，即可从上述表中查出（或计算出）对应的生物标志物的浓度Bm。
本发明中，光接收模块输出电信号的零值Q0、调整后的干预变量值Am以及所得的生物标志物的浓度值Bm均可为区间值，因为，对于检测物中的各种成分的含量，当检测精度达到一定程度后，检测物中的待测物在流动过程中会出现一定程度的浮动，在本发明中，待测物在检测过程中，由于抗体与抗原结合存在一定的浮动性，这使得其偏振光束也会出现微量的变化，故光接收模块输出的电信号的零值可能会有小范围的浮动（例如Q0的数学值的区间可为0.0015-0.0016），因此，与此相关的干预变量值Am以及对应的生物标志物的浓度值Bm均会出现与Q0相类似的区间值，但是，相对来说，存在细微变化的区间值与固定点值对应起来时，二者的效果是相同的。
对于本发明中变量干预式生物标志物浓度检测方法的上述的干预变量，只要能达到微量可调节可记录即可，例如采用可记录的微量电流、微量电压等的改变实现光接收模块上的光谱位置的调节。
下面提供一种使用电流对光接收模块进行调节的装置，但需要说明的是，以下列举的实施例只是基于本发明上述原理的一种，其它可替换的方案较多，本发明将不再一一列举。
变量干预式生物标志物浓度检测装置的整体结构示意图如图4所示，包括光接收模块3、弹簧4、齿轮7、线圈9、磁铁10和控制系统（图中未示出），条板2的一端以铰接的方式固定，另一端与齿条6固定连接，在齿条6的旁边设置有一个齿轮7，齿轮7与齿条6处于啮合状态，齿轮7可转动的固定在轴8上，轴8固定在支架11上，为了方便在光接收模块3上固定齿条6，可将光接收模块3设置在一个条板2上（但条板2也可以省去），然后在条板2上设置齿条6。线圈9固定在齿轮7上，磁铁10位于线圈9旁边，当控制系统给线圈9中通入电流时，磁铁10产生的磁场会使得线圈9转动，从而带动齿轮7运动，调整光接收模块3的位置，使其上面的光谱的位置发生改变。
如图4所示，齿条6与齿轮7处于啮合状态，当齿轮7在外力的作用下转动时，齿条6随着齿轮7的转动而转动，从而带动光接收模块3发生运动。为了控制/调节齿轮7的转动，在齿轮7上固定一个闭合的线圈9，该线圈9要延伸出齿轮7的本体，并向外延伸一段距离，在与线圈9旁边设置一个固定着的磁铁10，线圈9的一部分与磁铁10重叠，这样以来，当向线圈9上通入电流时，处于闭合状态的线圈9形成一个闭合的回路，当这个闭合的回路中有电流通过时，其自身在电磁感应作用下产生磁场，线圈9产生的磁场与磁铁10的磁场相互之间发生作用力，此时，控制系统改变通入线圈9中的电流大小/方向可以改变线圈9所产生的磁场强度以及磁场方向，由于磁铁10所产生的磁场的大小和方向是固定的，因此，当改变线圈9中的电流大小和/或方向时，在磁铁10的磁场的作用下，线圈9发生转动，由于线圈9是固定在齿轮7上的，因此，在线圈9开始转动时，齿轮7随着线圈9转动而转动，齿轮7与光接收模块3上的齿条结构或齿条6啮合，因此光接收模块3随着齿轮7的转动而运动（图中为竖直方向运动）。
如图4所示，为了进一步提高光接收模块3的水平夹角的调节灵敏度，在光接收模块3上连接一个弹簧4，弹簧4的另一端固定，设定一个初始位置，使得弹簧4在该初始位置时整个装置处于一个零点，当需要调整光接收模块3的水平夹角时，可借助弹簧4的弹力，使得光接收模块3更加容易回复至初始位置。上述具体过程表现为：当向线圈9中通入电流，线圈中产生磁场，在磁铁10的作用下，线圈9在磁场交互的作用力下绕轴8转动，同时齿轮7也开始转动，光接收模块3在齿轮7的转动下上升/下降，同时也开始拉伸/压缩弹簧4，当需使光接收模块3回复至初始位置或所需设定的位置时，控制系统相应的改变通入线圈9中的电流大小或方向，光接收模块3在相应的运动时，弹簧4能够相应的提供收缩力或拉伸力，使得光接收模块3能够在弹簧4的作用力的协助下更加灵敏、快速的回复至初始位置或所需位置。
在图4中，当设置条板2时，条板2的一端是铰接固定着的，此处可采用包括合页、铰接球等在内的多种铰接装置及铰接固定方式，即只需确保条板2能够绕支撑点1以较低的摩擦力旋转即可。
磁铁10的形状以图中为例，使其N极和其S极合理分布，使得线圈9能够在磁铁10磁场的作用范围内，在磁铁10的N极和S极之间运动，对于磁铁10，将其设置成如图中所示的弧形，使其与线圈9的旋转方向相应，能够对线圈9产生较为宽广的影响。但磁铁10的形状并不局限于此，选用条形磁铁U形磁铁或者其它现有形状的磁铁也可满足上述使用要求，在此不再一一描述。为了使其能够产生足够强的磁场，最好使用钕磁铁，可以获得较强的磁场，使其能够强力的促使通电后的线圈9的运动。
为了提高线圈9在齿轮7上的稳定性，并进一步提高线圈9的调节灵敏性，在齿轮7上固定一个平衡装置5，该平衡装置5安装在齿轮7上，其位置要与线圈9对应，即使得平衡装置5和线圈9分别位于齿轮的两侧，并使其二者位于同一水平高度，彼此之间起到一定的平衡作用，在此，可以将平衡装置5设置成线圈状，可以使其部分延伸出齿轮7，这样一来可以减轻平衡装置5的重量，同时，平衡装置5还可以借助自身重力，在杠杆作用下对线圈9的位置高度起到很好的平衡作用，即当线圈9受磁铁10的磁场力向上/下（仅指图中方位，实际方向不限于此）运动时，在平衡装置5的作用下，线圈9只需克服很小的力便可摆脱静止状态进行运动，同样的，当需将线圈9调整至初始位置时，只需克服较小的阻力即可实现，即无需大幅度变动通入线圈9中的电流即可实现对线圈9的位置调整。
对于图3中的轴8，可将其通过支架11进行固定，本发明中，条板2的固定端部、弹簧4的固定端以及支架11的固定处均为具有支撑作用的平台，例如：台式的工作平台或者设置在机架上的支撑平台等，然而，也可以增设一个机架或者外壳，将整套装置固定在机架或外壳上。
对于齿轮7在轴8上的可转动的固定方式，可采用现有技术进行解决，例如，可采用将齿轮7套在轴承的外圈上，使其可围绕轴承转动，然后将轴承的内圈固定在轴8上，将轴8固定在支架11上；另外，齿轮7也可直接使用轴承齿轮，将其直接固定在轴8上；其它现有的转动连接的方式，如铰接、套接，等等能够实现齿轮7可转动固定的均在本发明的可实施范围之内。
需要特别说明的是，本发明中的变量干预式生物标志物浓度检测装置实施并不局限于上述的实施方式，例如，其中实现光接收模块3运动的齿轮7以及与其啮合的齿条6，可以由相互啮合的涡轮、蜗杆或者可套接安装的螺母、螺杆进行整体替换，并相应的按需要将所需更改的部位进行修改即可，例如，可将蜗杆或螺母固定在光接收模块3上，将蜗轮或螺母固定在底座上即可，对于本领域技术人员以及结合现有的机械领域公知常识的其它领域人员均可十分容易的做出上述变动，这里不再一一举例；而且，本发明中，弹簧4的位置也并不局限于图中所示的位置，还可将其移动至支撑点1附近，这样弹簧4的作用效果可能会更好。
上面结合附图对本发明的具体实施方式作了详细说明，但是本发明并不限于上述实施方式，在本领域技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。

Claims (15)

  1. 变量干预式生物标志物浓度检测方法，其特征在于：光接收模块接收偏振光束，形成光谱，并输出电信号Qn，设定其输出电信号的零值Q0；引入干预变量An，通过干预变量调整光接收模块上形成的光谱的位置，同时调整光接收模块的电信号输出值，每一个干预变量值An对应一个光接收模块的电信号输出值Qn；设定干预变量An与检测物中生物标志物浓度Bn的对应关系，调整干预变量An至Am，使得Qn=Q0，查询干预变量Am对应的生物标志物浓度Bm，获得检测物中生物标志物的浓度；
    上述，n、m为自然数，且n>m。
  2. 根据权利要求1所述的变量干预式生物标志物浓度检测方法，其特征在于：所述的干预变量An=A+n×a，其中，A为定值，a为干预变量的单次调整幅度，n为自然数。
  3. 根据权利要求1所述的变量干预式生物标志物浓度检测方法，其特征在于：所述光接收模块输出电信号的零值Q0、调整后的干预变量值Am以及所得的生物标志物的浓度值Bm均为区间值。
  4. 根据权利要求1所述的变量干预式生物标志物浓度检测方法，其特征在于：所述的干预变量An为变化的可控制、可记录的电流或电压。
  5. 根据权利要求2所述的变量干预式生物标志物浓度检测方法，其特征在于：所述的干预变量An为变化的可控制、可记录的电流或电压。
  6. 根据权利要求3所述的变量干预式生物标志物浓度检测方法，其特征在于：所述的干预变量An为变化的可控制、可记录的电流或电压。
  7. 一种变量干预式生物标志物浓度检测用装置，其特征在于：包括光接收模块、传动机构、调节装置以及控制系统，所述的光接收模块、调节装置分别与所述的传动机构连接，所述的控制系统接收光接收模块输出的电信号信息并相应的控制调节装置运动。
  8. 根据权利要求7所述的变量干预式生物标志物浓度检测用装置，其特征在于：所述的传动机构包括相互啮合的齿条（6）和齿轮（7），所述的调节装置包括线圈（9）、磁铁（10）和底座（11），所述的齿条（6）固定在所述的光接收模块（3）上，所述的齿轮（7）可转动的固定在所述的底座（11）上，所述的线圈（9）固定在所述的传动机构上，所述的磁铁（10）靠近所述线圈（9），使得向所述线圈（9）中通电后其能够在所述磁铁（10）的作用下通过所述的传动机构带动所述的光接收模块（3）运动。
  9. 根据权利要求8所述的变量干预式生物标志物浓度检测用装置，其特征在于：所述的传动机构还包括轴（8），所述的齿轮（7）套在所述的轴（8）上，所述的轴（8）固定在底座（11）上。
  10. 根据权利要求8所述的变量干预式生物标志物浓度检测用装置，其特征在于：所述的传动机构包括相互啮合的蜗轮和蜗杆，所述的调节装置包括线圈（9）、磁铁（10）和底座（11），所述的蜗杆固定在所述的光接收模块（3）上，所述的蜗轮可转动的固定在所述的底座（11）上，所述的线圈（9）固定在所述的传动机构上，所述的磁铁（10）靠近所述线圈（9），使得向所述线圈（9）中通电后其能够在所述磁铁（10）的作用下通过所述的传动机构带动所述的光接收模块（3）运动。
  11. 根据权利要求7所述的变量干预式生物标志物浓度检测用装置，其特征在于：所述的变量干预式生物标志物浓度检测用装置还包括弹簧（4），所述的光接收模块（3）由所述弹簧（4）支撑。
  12. 根据权利要求8所述的变量干预式生物标志物浓度检测用装置，其特征在于：所述的变量干预式生物标志物浓度检测用装置还包括弹簧（4），所述的光接收模块（3）由所述弹簧（4）支撑。
  13. 根据权利要求9所述的变量干预式生物标志物浓度检测用装置，其特征在于：所述的变量干预式生物标志物浓度检测用装置还包括弹簧（4），所述的光接收模块（3）由所述弹簧（4）支撑。
  14. 根据权利要求11所述的变量干预式生物标志物浓度检测用装置，其特征在于：在所述的传动机构上还设有平衡装置（5），所述的平衡装置（5）与所述的线圈（9）分布在所述传动机构的两侧。
  15. 根据权利要求14所述的变量干预式生物标志物浓度检测用装置，其特征在于：所述的磁铁（10）为钕磁铁，其形状为条形或圆弧形。
PCT/CN2015/077441 2015-03-25 2015-04-24 变量干预式生物标志物浓度检测方法及装置 Ceased WO2016149980A1 (zh)

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