CN203606280U - Biological chip based on grating guided mode resonance technique - Google Patents
Biological chip based on grating guided mode resonance technique Download PDFInfo
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- CN203606280U CN203606280U CN201320469201.7U CN201320469201U CN203606280U CN 203606280 U CN203606280 U CN 203606280U CN 201320469201 U CN201320469201 U CN 201320469201U CN 203606280 U CN203606280 U CN 203606280U
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Abstract
The utility model discloses a biological chip based on a grating guided mode resonance technique. The biological chip comprises a substrate layer (1), wherein a titanium film layer (2) is arranged on the upper surface of the substrate layer (1); a grating wave guide layer is arranged on the upper surface of the titanium film layer (2). By adopting the biologic chip, the problems in the prior art that the biologic chip is large in size, high in cost, complex in structure, unbeneficial for commercial popularization or although the biologic chip is small in size and low in price, temperature compensation defects exist and the like, are solved.
Description
Technical field
The utility model belongs to biochip technology, relates in particular to a kind of biochip based on grating guide mode resonance technology.
Background technology
Scientific research is at present found, the different phase of disease, or even without any the disease commitment of symptom, in people's body fluid just there is variation in the level of protein, and then affect organ, tissue and organic function, show as the generation of clinical disease, the level of human body liquid internal protein fast and effectively, has great meaning for prevention, diagnosis and the treatment of disease.In addition, the level of traditional biochemical analysis technology for detection protein needs numerous and diverse operation, consuming timely can not accomplish again Non-Destructive Testing, brings great misery also to patient's body and mind simultaneously, and has increased the weight of patient's financial burden.
According to current understanding, in human body, exist 100,000 kinds of above protein. there is separately different structures and physiological function.Compare with DNA molecular, the space structure complexity of protein molecule, its biologically active and space structure are closely related, protein can not be increased simply or original position synthetic, be difficult to utilize the mode of " copy " to improve the sensitivity of detection. secondly, the interaction that albumen is interrogated can follow without sequence. but be similar to the interactional specific bond of antigen one antibody, in addition. in operating process, protein is easy to sex change.Therefore, development protein-chip is very difficult, becomes the challenge in biochip field.
Since nineteen ninety Herry etc. propose the concept of biological immune chip, because it is in the superiority of the aspect such as medical diagnosis, examination, biological immune chip has been obtained very large development, and its coverage is from gene, protein to many biological samples such as cells.The principle of work of biological immune chip and traditional immunological method are similar, are fixed on the surface of holder by antigen or antibody, detect antigen or antibody in testing sample.
At present, on market, the commercial product of biochip mainly contains the Biacoret3000 series of products of Biacore AB company of Sweden, the Iasys system series of products of Affinity Sensors company of the U.S., the SpR-670 of Nippon Laser Electronics company of Japan, German Biotul AG series of products; At home, the SPR-2000 of Zhong Ke research institute electron institute exploitation, and the protein-chip biochip of the commercial ellipsometry imaging technology of standard of the effort of Chinese Academy of Sciences's more than ten years that mechanics is gone through exploitation, the major defect of these biochips is that volume is large, cost is high, complex structure, does not utilize commercialization universal; Although a series of module biochip of the Sprecta volume of U.S. Texas Instrument exploitation is little, low price, has the shortcomings such as temperature compensation; So, develop a kind of fast, parallel, integrated, and cheap biochip and relevant supporting product are one of focal issues now and in significant period of time clinical practice research from now on.
Summary of the invention
The technical problems to be solved in the utility model: a kind of biochip based on grating guide mode resonance technology is provided, to solve, the volume that the biochip of prior art exists is large, cost is high, complex structure, though do not utilize, commercialization is universal or volume is little, low price, but has the problems such as temperature compensation shortcoming.
Technical solutions of the utility model:
Based on a biochip for grating guide mode resonance technology, it comprises basalis, and the upper surface of basalis is ti thin film layer, and the upper surface of ti thin film layer is grating waveguide layer.
Basalis is quartz or glass.
Grating waveguide layer comprises titania medium and low-refraction organism medium, and low-refraction organism Filled Dielectrics is between titania medium.
The refractive index of low-refraction organism medium is 1.40-1.60, described low-refraction organism medium is polymetylmethacrylate film, polydimethylsiloxane film, polyacrylate film, or the mixture film of polymetylmethacrylate film, polydimethylsiloxane film, polyacrylate film and silane coupling agent composition.
Silane coupling agent is γ-glycidoxypropyltrime,hoxysilane or γ-methacryloxypropyl trimethoxy silane.
The beneficial effects of the utility model:
The biochip of dielectric grating guide mode resonance technology is take diffraction grating as the raw guided mode of basic excitation wave artificial delivery, and refractive index, thickness and density, the molecular weight etc. of the generation of guided mode and transmission and detected protein rete have close relationship, by the measurement to receiving optical signals and then draw the information of protein molecule rete refractive index, thickness and density, molecular weight, realize a kind of quick, the harmless senser element of the mensuration to protein molecule to be measured.Compared with other electrochemical method, utilizing optical bio to pass technology for detection protein level has many advantages, mainly comprises: detection speed is fast, precision is high, do not destroy performance and the structure of protein, has advantages of Non-Destructive Testing.In addition, be also easy to realize device microminiaturization, sample consumption and reach the magnitude of microlitre, this for reduce patient misery, reduce medical treatment cost aspect and have important meaning.
The core technology of the protein biosensor of grating guide mode resonance technology is the preparation of sensing substrate, and it has determined the performance of biology sensor.
Biochip based on grating guide mode resonance technology that the utility model proposes and preparation method thereof specifically has following feature: 1, sensor mechanism is to be sensing unit for leading membrane resonance grating, be easy to processing in batches, with existing Ic process compatible, also be easy to be integrated into microminiaturized integrated device with other optical device, reduce the volume of whole system, can reduce widely the consumption figure of testing sample, reduce patient blood extracted amount simultaneously, 2, the structure of this integrated light guide is also easy to realize the microcell point sample of testing sample, utilizes spraying technology accurately testing sample to be added to detection zone, has further reduced the consumption figure of sample device, and integrating and can controlling sample preparation device consumption figure is microlitre, what 3, the utility model adopted is the technology based on grating layer mould Resonance Mechanism, in fact to interact between light and testing sample, this can realize, Non-Destructive Testing real-time to sample, and can duplicate measurements and do not destroy testing sample, this also traditional electrochemical method, PCR method, electrophoresis etc. to detect advantage obvious, traditional electrochemical process has bad broken effect to protein example, 4, the utility model adopts the technology that hyperchannel detects simultaneously, can realize parallel fast detecting, does not also need additional cooling system because the thermal value of core detection zone light is small, 5, the utility model method for making common segment and traditional Ic process compatible, comprise TiO 2 coating film, and the method for organism plated film is applied traditional chemical plating method and can be easy to realize as immersion plating, solution coating method etc., and cost is low, 6, grating waveguide is made district and is adopted anodizing to form the periodic structure of periodic titania-air at the periodic oxygen of titanium dioxide surface, wherein no matter from processing or the accurate job operation of array, atomic force microscope is that a kind of fabulous anodic oxidation machining tool is current, the price of domestic atomic force microscope is far below Ic technique Anodic Oxidation process equipment, and precision is high without atomic force microscope, in addition, adopt organism low refractive index dielectric to form the organic periodic structure of titania-low-refraction, make grating transmission lead film very responsive to the variations in refractive index of protein molecule rete, and comparing the protein molecule rete directly forming on grating wants evenly, thereby improve accuracy of detection, 7, be processed to form the standardization of titania-air circle optical grating construction in the oxidation of titanium Surface Oxygen sun, be easy to batch production, namely base seat is placed under atomic force microscopy ytterbium on large sample scan table, select " nanoprocessing pattern " input optical grating construction array bitmap, setting voltage 8.2V, voltage pulsewidth 87ms, sweep frequency 0.2HZ, and be filled with the dry air that flow velocity is 0.1ml/s simultaneously, start processing, formation array
periodicity grating with air.The utility model has solved that the volume that the biochip of prior art exists is large, cost is high, complex structure, though do not utilize, commercialization is universal or volume is little, low price, but has the problems such as temperature compensation shortcoming.
accompanying drawing explanation:
Fig. 1 is the utility model structural representation;
Fig. 2 is the utility model grating sensitizing range guide mode resonance structural representation;
Fig. 3 is the utility model array bio-chip schematic diagram;
Fig. 4 is the complex refractive index of the utility model grating waveguide and the index of refraction relationship schematic diagram of tested protein molecule rete.
embodiment:
A kind of biochip (seeing accompanying drawing 1) based on grating guide mode resonance technology, it comprises basalis 1, and the upper surface of basalis 1 is ti thin film layer 2, and the upper surface of ti thin film layer 2 is grating waveguide layers.
Basalis 1 is quartz or glass.
Grating waveguide layer comprises titania medium 3 and low-refraction organism medium 4, and low-refraction organism medium 4 is filled between titania medium 3.
The refractive index of low-refraction organism medium 4 is 1.40-1.60, described low-refraction organism medium 4 is polymetylmethacrylate film, polydimethylsiloxane film, polyacrylate film, or the mixture film of polymetylmethacrylate film, polydimethylsiloxane film, polyacrylate film and silane coupling agent composition.
Silane coupling agent is γ-glycidoxypropyltrime,hoxysilane or γ-methacryloxypropyl trimethoxy silane.
Basalis 1 is for optical signal transmission waveguide and biochip sensitive zones; Ti thin film layer 2 produces TiO for anode process oxidation
2with air circle grating, the transport layer of waveguide antenna mould; Grating waveguide layer, the guided mode layer and the biochip sensitizing range that produce diffraction and transmission waveguide for grating; Antigen is also antibody layer, is antigen for fixing monoclonal antibody to be detected.
The principle of work of grating waveguide layer is as follows:
As shown in Figure 2, waveguide is grating region to grating waveguide layer structure, grating region waveguide by
the periodicity grating of medium 3 and low-refraction organism medium composition, the refractive index of its grating region can be described with complex refractive index
Wherein,
for
the refractive index of medium,
for the refractive index of low-refraction organism medium of filling,
for fill factor, curve factor, relevant with the cycle of grating.Substrate is metal
, refractive index is
, thickness is 2 μ m, the refractive index of the testing protein rete above grating sensitizing range is
.
When a certain wavelength plane light wave incides grating surface at a certain angle from testing protein molecule rete top, there is diffraction, form the inferior diffraction light wave of multiple levels, vowing when certain first-order diffraction light wave the propagation constant of supporting with waveguide at horizontal wave vector component equates, excite guide mode resonance, incident light energy major part is coupled in waveguide, propagates in waveguide with guided mode form.Certain first-order diffraction light wave is vowed at horizontal wave vector component
Wherein
for airborne wave vector,
for the refractive index of air,
for airborne incident angle,
for the cycle of grating,
for the level time of diffraction light.If a certain senior diffraction light wave excites guided mode to produce guide mode resonance, meet wave vector matching condition
represent
the propagation constant of rank guided mode, according to the definition of effective refractive index
（4）
Relation can obtain producing guide mode resonance in conjunction with (1), (2), (3) formula time between incident angle and effective refractive index
（5）
Given waveguide and adjacent media refractive index, given
,
,
value, corresponding to a certain wavelength, limited pattern supported in waveguide, effectively several independently values are got in refraction.
In grating waveguide layer, guided mode existence condition is
（
） (6)
In formula
for in waveguide along vertical
the wave vector of direction,
for the thickness of waveguide,
,
for the phase shift of light when the waveguide upper and lower interface generation total reflection, wherein
Consider
the effective refractive index of rank guided mode changes, and in (6) formula, gets
, (7), (8), (9) formula substitution (6) formula are turned to
（10）
For
,
,
,
,
,
by (1) formula
, the pattern that above formula is supported
it is a determined value.The refractive index sensitivity of system is the function effectively reflecting, known by calculating,
time,
in scope, when
time, refractive index sensitivity has maximal value,
.Therefore, in above formula in testing medium refractive index
time, the guided wave mode of getting support is
, solve satisfied by (10) formula
the duct thickness that rank guided mode exists
.
When after the antigen (antibody) of grating waveguide, change
size, the thickness that its change amount and rete increase can be described with Feijter formula, forms the mass density of molecule rete, generally gets for the calculated value of most of protein adsorption
.
In formula
,
for refractive index, the thickness of molecule rete,
for the refractive index of environment solution,
for refractive index is to detecting solution concentration rate of growth,
The relation that the complex refractive index in simulation grating waveguide district and protein molecule rete form between refractive index is shown in accompanying drawing 3.
The detection sensitivity of grating guide mode resonance biochip:
Effective refractive index is to detecting the Thickness sensitivity of protein molecule mould layer
The incident angle of incident light wave is to detecting the Thickness sensitivity of protein molecule mould layer
Getting above-mentioned parameter calculating calculates by above-mentioned parameter: incident angle exists
there is guide mode resonance, the sensitivity of angle to thickness in place
, detectable minimum thickness changes
, wherein,
,
the energy gradient of leading for coupling afferent echo.
The preparation method of the biochip based on grating guide mode resonance technology: it comprises the steps:
Step 1, basalis plated film, be that the basalis 1 that 3mm is thick plates one deck ti thin film layer 2 by the specification cutting, and adopts the mode of evaporation, and the thickness of ti thin film layer 2 is 1-3um.Then be cut into the fritter that is cut into 20mm*10mm*3mm specification;
Step 3, grating processing, the base seat that step 2 is cleaned up is processed into the titania of array and the periodicity grating of air; Base seat is placed under atomic force microscope on full-page proof device scan table, selects " nanoprocessing pattern " input optical grating construction array bitmap, setting voltage 8.2V, voltage pulsewidth 87ms, sweep frequency 0.2HZ, and be filled with the dry air that flow velocity is 0.1ml/s simultaneously, start processing, formation array
periodicity grating with air.
Step 4, the base seat that step 3 is processed to grating clean up;
Step 5, the chemical method such as base seat aqua-solution method or immersion plating etc. that step 4 is processed to grating plate low-refraction organism medium, low-refraction organism medium is selected polymethylmethacrylate (PMMA) film, its thickness is identical with the thickness of grating, puts into dry constant temperature oven set aside for use; Choosing of low refraction organic media should be followed the periodically complex refractive index formula of the light waveguide-layer of grating formation
Illustrate: in scheme, choose fill factor, curve factor
between, and
for
refractive index, the organic refractive index of low-refraction is got
between (because form complex refractive index in this interval to protein molecule rete sensitivity, the another formula (11) referring in text that calculates also can illustrate, the low-refraction organism medium here can be selected polymethylmethacrylate (PMMA) film, dimethyl silicone polymer (PDMS), polyacrylate, and they and silane coupling agent (γ-glycidoxypropyltrime,hoxysilane, also claim Kh-560, γ-methacryloxypropyl trimethoxy silane, also claims Kh-570) composition potpourri.
Claims (1)
1. the biochip based on grating guide mode resonance technology, it comprises basalis (1), the upper surface of basalis (1) is ti thin film layer (2), the upper surface of ti thin film layer (2) is grating waveguide layer, basalis (1) is quartz or glass, it is characterized in that: grating waveguide layer comprises titania medium (3) and low-refraction organism medium (4), low-refraction organism medium (4) is filled between titania medium (3), and the refractive index of low-refraction organism medium (4) is 1.40-1.60.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108107036A (en) * | 2017-12-13 | 2018-06-01 | 杭州埃锐晶生物医学技术有限公司 | The preparation method and solid-phase matrix of arrays of immobilized protein detection solid-phase matrix |
| US10753868B2 (en) | 2016-06-17 | 2020-08-25 | University Of York | Sensor and associated methods |
-
2013
- 2013-08-02 CN CN201320469201.7U patent/CN203606280U/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10753868B2 (en) | 2016-06-17 | 2020-08-25 | University Of York | Sensor and associated methods |
| CN108107036A (en) * | 2017-12-13 | 2018-06-01 | 杭州埃锐晶生物医学技术有限公司 | The preparation method and solid-phase matrix of arrays of immobilized protein detection solid-phase matrix |
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|---|---|---|---|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140521 Termination date: 20160802 |