CN210665507U - High-flux optical waveguide biological sensing chip - Google Patents
High-flux optical waveguide biological sensing chip Download PDFInfo
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- CN210665507U CN210665507U CN201921706354.2U CN201921706354U CN210665507U CN 210665507 U CN210665507 U CN 210665507U CN 201921706354 U CN201921706354 U CN 201921706354U CN 210665507 U CN210665507 U CN 210665507U
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Abstract
The utility model discloses a high flux optical waveguide biological sensing chip, including optical waveguide array and biological detection point array, the optical waveguide array is a plurality of optical waveguides that are arranged in parallel and fixed on the basement, the biological detection point array is a plurality of biological detection points that are used for taking place specific biochemical reaction along optical waveguide axis direction interval distribution; the biological detection point array is solidified on the optical waveguide array or the isolating layer on the optical waveguide array; the end surfaces of two ends of the optical waveguide are used as the input end and the output end of the optical signal; waveguide grating can be engraved in the optical waveguide, which can improve signal-to-noise ratio. The utility model discloses be in the same place high flux biochemical reaction and optical waveguide array integration, simple structure, parallelly acquire information, can realize high flux biosensing.
Description
Technical Field
The utility model relates to an optical waveguide and biosensing chip technical field.
Background
Biosensing is widely used in the fields of biochemistry, medical treatment, environmental monitoring, food hygiene and the like. The biosensor is a sensor device which mainly uses biological active substances with optical or electrophysiological properties or molecular specificity, such as enzymes, proteins, microorganisms, DNA and the like, as biological probes (sensitive elements) and acquires biological information from biochemical reaction substances or photoelectric physiological signals and the like. The optical biosensor has the characteristics of high sensitivity and strong adaptability, and is generally regarded by people. The optical biosensor mainly uses photo-physiological characteristics, or uses specific molecules to combine with tested biological molecules and cause the optical parameters (such as refractive index) of the specific molecules to change, and uses the photoelectric information technology to obtain the optical parameter change and further obtain biological information. Biomolecules have the characteristic of huge information content, and a biosensor is required to simultaneously acquire information of a large number of biomolecules, i.e., high-throughput sensing. The high-throughput biosensors that are widely used at present are mainly biochips based on microarray imprinting technology. The method comprises the steps of densely arranging biomolecule probes on a substrate to form a biochip, labeling sensed biomolecules with fluorescent molecules, interacting the sensed biomolecules with the probes, acquiring a fluorescent image of a probe array by a cleaning and detecting instrument (such as a laser confocal scanner and a high-sensitivity CCD image scanner), and analyzing the fluorescent image to obtain interaction information of the biomolecules. The biochip needs fluorescent labeling and laser irradiation to excite fluorescence, which affects the structure and properties of biomolecules, and also has a photobleaching phenomenon, which seriously interferes with the interaction process of biomolecules. In addition, higher throughput biomolecule sensing is also possible using biomolecule probe arrays and Surface Plasmon Resonance (SPR) imaging techniques. The method has the characteristics of high sensitivity and no need of labeling, but the sensing probe density (flux) is lower than that of a biochip.
An optical waveguide is a dielectric that binds and transmits light waves, and is classified into a substrate-based optical waveguide (e.g., a planar optical waveguide, a rectangular or ridge optical waveguide, etc.) and an optical fiber (e.g., a cylindrical or D-shaped optical fiber) according to its structure. All optical waveguides are provided with waveguide cores with higher refractive indexes and cladding media (containing air) with lower refractive indexes, have higher sensing sensitivity and extremely weak photobleaching effect, and can acquire biological information in situ.
In summary, the existing high-throughput biosensor is mainly a biochip, and the high-throughput biosensor based on the optical waveguide is lacked. The fluorescence labeling and fluorescence excitation in the biochip will affect the structure and properties of the biomolecules, and there are disadvantages of photobleaching, large detection error, difficulty in obtaining information of the biomolecule action process, etc.
SUMMERY OF THE UTILITY MODEL
The utility model provides a high flux optical waveguide biological sensing chip breaks through the restriction that relies on fluorescence mark and arouse among the prior art to the not enough of above-mentioned technique. The utility model discloses utilize optical waveguide and biological probe array high flux ground sensing biomolecule, its light wave does not directly act on the biomolecule, need not fluorescence labeling, can obtain information and on-line sensing biomolecule's effect process in parallel.
The utility model discloses a high flux optical waveguide biosensing chip, including optical waveguide array and biological detection point array, the optical waveguide array is a plurality of optical waveguides of arranging and fixing on the basement in parallel, each row in the biological detection point array is along optical waveguide biography light direction interval distribution, can take place a plurality of biological detection points of specificity biochemical reaction with the biomolecule that is sensed; the biological detection point array is solidified on the optical waveguide array or the isolation layer on the optical waveguide array, and the end faces at two ends of each optical waveguide are used as the input end and the output end of the optical signal.
Further, the optimized distance between two adjacent optical waveguides in the optical waveguide array is larger than 5 μm.
Specifically, the optical waveguide is a rectangular optical waveguide or a D-shaped optical fiber, the rectangular optical waveguide is embedded or embedded in the substrate, and the D-shaped optical fiber is fixed on the substrate.
Further, the refractive index of the rectangular optical waveguide is greater than that of the substrate.
Furthermore, when the rectangular optical waveguide is embedded in the substrate, the end surfaces of the rectangular optical waveguide for inputting and outputting optical signals are exposed outside the substrate; when the rectangular optical waveguide is embedded on the substrate, the upper surface of the rectangular optical waveguide and the end surface of the input and output optical signal are exposed outside the substrate.
Further, when the D-shaped optical fiber is fixed to the substrate, the planar portion of the D-shaped optical fiber, the end face from which the output optical signal is input, is bare.
Specifically, a waveguide grating is inscribed inside the optical waveguide, and the waveguide grating is a waveguide grating capable of coupling light in the same direction or in the opposite direction.
Further, the optimized structure of the waveguide grating comprises a uniform grating, a chirped grating, a superstructure grating and a phase-shift grating.
Specifically, the biological detection point is a biological molecule or a biological sensitive membrane with a biological specificity recognition function, and has specificity recognition capability on the sensed biological molecule.
Specifically, the biological detection point is directly solidified on the surface of the optical waveguide array or on the surface of the isolation layer above the optical waveguide array, or is solidified on the optical waveguide array or the isolation layer above the optical waveguide array through a groove or a blind hole; when the optical waveguide is embedded in the substrate, the substrate is used as an isolation layer.
Further, the grooves or the blind holes are arranged on the optical waveguide or the substrate at intervals in parallel along the light transmission direction.
Further, the optimized distance between adjacent grooves or blind holes on the same optical waveguide or substrate is larger than 1 μm.
Specifically, the reflected light of the optical waveguide is used as the output signal light, and the optimized distance between the biological detection point and the core of the optical waveguide is less than 2 times of the wavelength of the sensing light.
Further, on the optical waveguide array which is engraved with the reverse coupling waveguide grating, the optimized distance between the solidified biological detection point and the core of the optical waveguide is less than 2 times of the wavelength of the sensing light.
Specifically, the optical waveguide transmits light as output signal light, and the optimized distance between the biological detection point and the core of the optical waveguide is smaller than 100 times of the wavelength of the sensing light.
Further, on the optical waveguide array which is inscribed with the homodromous coupling waveguide grating, the optimized distance between the solidified biological detection point and the core of the optical waveguide is less than 100 times of the wavelength of the sensing light.
Compared with the prior art, the utility model has the advantages of include:
1. different from the separation of biochemical reaction and signal detection in the existing biochip, the method comprises the following steps: the utility model discloses on integrated to the optical waveguide chip with biochemical reactions's biological detection point array, the structure is simpler relatively, can be on-line parallel acquire information, and biochemical reactions and signal detection can go on simultaneously, have improved detection efficiency.
2. The optical signal is transmitted in the optical waveguide and does not directly act on the bio-detection point.
3. Each optical waveguide can be distributed with a plurality of biological detection points, and each biological detection point can solidify different specific recognition molecules, thereby realizing the simultaneous detection of a plurality of or a plurality of biological molecules and meeting the requirement of high-throughput detection.
4. Waveguide grating can be inscribed in the optical waveguide, so that the signal-to-noise ratio is improved; the biological detection point can be solidified on the optical waveguide core through the groove and the blind hole, and the sensitivity is improved.
Drawings
FIG. 1 is a schematic structural diagram of a high-throughput optical waveguide biosensor chip according to embodiment 1.
FIG. 2 is a top view of the structure of the high throughput optical waveguide biosensor chip according to embodiment 1.
FIG. 3 is a front view of a high throughput optical waveguide biosensor chip with the optical waveguide fully embedded in the substrate.
FIG. 4 is a schematic structural diagram of a high-throughput optical waveguide biosensor chip according to embodiment 2.
FIG. 5 is a schematic structural diagram of a high-throughput optical waveguide biosensor chip according to embodiment 3.
FIG. 6 is a schematic structural diagram of a high-throughput optical waveguide biosensor chip according to embodiment 4.
Fig. 7 is a front view of an optical waveguide array structure with portions of the optical waveguides embedded in a substrate.
Fig. 8 is a front view of the optical waveguide array structure with the optical waveguides at the substrate surface.
FIG. 9 is a schematic structural diagram of a high-throughput optical waveguide biosensor chip according to embodiment 5.
FIG. 10 is a front view of a high throughput optical waveguide biosensor chip with optical waveguides embedded in the substrate.
FIG. 11 is a schematic structural diagram of a high-throughput optical waveguide biosensor chip according to embodiment 6.
FIG. 12 is a schematic diagram of a D-shaped fiber configuration when the side plane of the D-shaped fiber intersects the core of the fiber.
FIG. 13 is a schematic diagram of a D-shaped optical fiber configuration with the side plane of the D-shaped fiber separated from the fiber core.
Fig. 14 is a schematic structural view of a single D-shaped optical fiber in embodiment 7.
Fig. 15 is a schematic cross-sectional view of a single D-shaped fiber with a waveguide grating written therein.
Detailed Description
In order to make the present invention easier to understand, the related principles and sensing methods of the present invention are described as follows: the biological detection point array becomes a component of the optical waveguide after being solidified on the optical waveguide array, and the interaction between the biological molecules and the biological detection point array causes the refractive index change at the biological detection point, so as to change the effective refractive index distribution of the optical waveguide and modulate the amplitude and phase quantity of the output optical signal; the change of the effective refractive index distribution in the optical waveguide is reconstructed by the amplitude and phase quantity of the output optical signal, and the size and the position of the interaction between the biomolecule and the biological detection point (probe) can be determined. In each of the following embodiments, the center wavelength of the sensing signal light inputted into the output optical waveguide is 1.55 μm.
Detailed description of the preferred embodiment 1
Referring to fig. 1, 2 and 3, a high-throughput optical waveguide biosensor chip comprises an optical waveguide 1 array with a biological detection point array on the top: a plurality of (for example 10) optical waveguides 1 are arranged in parallel to form an optical waveguide array and are completely embedded in a substrate 3, the upper surface of each optical waveguide 1 is exposed outside the substrate, and the refractive index of each optical waveguide 1 is larger than that of the substrate 3; the optical waveguide 1 here is a waveguide core, and the substrate 3 and the air on the upper surface have the role of a cladding; end faces 102 or 103 at both ends of each optical waveguide 1 are used as an input end and an output end of an optical signal; the biological detection point array is solidified on each optical waveguide core and comprises a plurality of biological detection points 101 which are distributed at intervals along the optical waveguide light transmission direction and can generate specific biochemical reaction; the biological detection point is a biomolecule or sensitive membrane with specific recognition capability; the biological detection points are solidified on the optical waveguide, and the distance between every two adjacent biological detection points is greater than 1 mu m; the specific recognition molecules at each biological detection site may or may not be the same as the specific recognition molecules at other biological detection sites.
In the present embodiment, the width of the substrate 3 along the optical waveguide arrangement direction is 12mm, and the length along the light transmission direction is 16 mm; the optical waveguide 1 and the substrate 3 are respectively made of quartz materials with different doping, the refractive index of the optical waveguide 1 is 1.468, the refractive index of the substrate 3 is 1.454, each optical waveguide 1 adopts a rectangular optical waveguide, and the distance between two adjacent rectangular optical waveguides arranged in parallel is 300 mu m; the height of the rectangular optical waveguide is 20 μm, the width along the arrangement direction of the optical waveguide is 30 μm, and the length along the light transmission direction is the length of the substrate; an array of grooves or blind holes is engraved on each rectangular optical waveguide core along the light transmission direction, the depth of the grooves or blind holes is 6 μm, the length along the light transmission direction and the width along the optical waveguide arrangement direction are 60 μm and 30 μm, respectively, and the pitch between adjacent grooves or blind holes along the light transmission direction is 100 μm. Solidifying the array of the biological detection points 101 into a groove or blind hole array with the depth of 6 mu m; the biological detection point is in the optical waveguide core at a distance of-6 μm from the optical waveguide core, and the negative distance is always smaller than the wavelength of the sensing signal light. This constitutes a high-flux optical waveguide biosensor chip.
Detailed description of the preferred embodiment 2
Referring to fig. 4, in this embodiment, a waveguide grating is added to embodiment 1: in order to modulate or filter the optical signal to improve the signal-to-noise ratio, a waveguide grating 2 is written in each rectangular optical waveguide 1 or at the interface of the optical waveguide 1 and the substrate 3 in the light transmission direction. The waveguide grating is a superstructure grating, and the length and the width of the waveguide grating are respectively equal to the length and the width of the optical waveguide 1Same, its height is 5 μm; 24 small sections of gratings are arranged in the superstructure grating, the length of each small section of grating is 40 mu m, the period of each small section of grating is 0.528 mu m, and the amplitude of the grating perturbation is 1.2 multiplied by 10-4The distance between adjacent small segments of the grating in the light transmission direction is 160 μm. The inscribed waveguide grating can also be a grating with other structures, and the optimized grating structure is a uniform grating, a chirped grating, a superstructure grating and a phase-shift grating.
Detailed description of preferred embodiments 3
Referring to fig. 5, the present embodiment is different from embodiment 1 in that a bio-sensitive film or bio-molecules (probes) are directly cured on the exposed surface of each optical waveguide 1 (i.e., the upper surface of the rectangular waveguide core), thereby realizing array sensing of bio-molecules. The specific scheme is as follows: the multiple rectangular optical waveguides 1 which are arranged in parallel are completely embedded into the upper part of the substrate 3, the upper surface and two end faces of each rectangular optical waveguide are exposed outside the substrate 3, a biological detection point 101 is directly solidified on the exposed optical waveguide surface, the biological detection point 101 is a biomolecule or a sensitive membrane which has specific identification capability with a sensed biomolecule, and the distance between the biological detection point and the rectangular waveguide core is 0. The structure only needs to directly solidify the biological detection point on the surface of the rectangular waveguide core, and the manufacture and the use are relatively simple and convenient.
Detailed description of preferred embodiments 4
Referring to fig. 6, 7 and 8, the present embodiment differs from embodiment 3 in that the optical waveguide 1 is a ridge optical waveguide, that is, a portion of a rectangular optical waveguide is embedded in the substrate 3 or the entire rectangular optical waveguide is on the surface of the substrate 3. The specific scheme is as follows: each rectangular optical waveguide is embedded on the substrate 3, the height of the rectangular optical waveguide is 28 μm, wherein the lower part of the rectangular optical waveguide with the height of 18 μm is embedded in the substrate, and the upper part of the rectangular optical waveguide with the height of 10 μm is exposed outside the substrate 3, as shown in fig. 6 and 7, the biological detection point 101 is located in the groove of the rectangular optical waveguide; or each rectangular optical waveguide having a height of 28 μm is fabricated on the surface of the substrate 3, and the biodetection spot 101 is located in a groove of the rectangular waveguide as shown in fig. 8.
Best mode for carrying out the invention
Referring to fig. 9 and 10, the present embodiment is different from embodiment 1 in that an array of optical waveguides 1 is embedded in a substrate 3, and the distance from a bio-detection spot to an optical waveguide core when reflected light is used as output signal light is less than 2 times the wavelength of the sensing signal light, and the distance from a bio-detection spot to an optical waveguide core when transmitted light is used as output signal light is less than 100 times the wavelength of the sensing signal light. The specific scheme is as follows: each rectangular optical waveguide 1 is embedded in a position 0.5 mu m below the upper surface of the substrate 3, namely the distance from the upper surface of the substrate 3 to each rectangular optical waveguide is 0.5 mu m, and the end face of each rectangular optical waveguide for inputting and outputting light is exposed outside the substrate 3; an array of biological detection points arranged at intervals is solidified on the upper surface of the substrate corresponding to the positions of the rectangular optical waveguides along the light transmission direction, each biological detection point is a biological sensitive film, and the size of each biological sensitive film on the upper surface of the substrate is 100 multiplied by 100 mu m2The distance between two adjacent sensitive films along the light transmission direction is 60 μm, and the reflected light or transmitted light of the light waveguide can be used as the output signal light. Or, each rectangular optical waveguide 1 is embedded in a position 100 μm below the upper surface of the substrate 3, that is, the distance from the upper surface of the substrate 3 to each rectangular optical waveguide is 100 μm, and the end face of each rectangular optical waveguide for inputting and outputting light is exposed outside the substrate 3; grooves or blind holes which are arranged at intervals are engraved on the upper surface of the substrate corresponding to the positions of the rectangular optical waveguides along the light transmission direction, biomolecules or sensitive films which have specific recognition capability on sensed biomolecules are cured to the bottoms of the grooves or blind holes to form biological detection points, the depth range of the grooves or blind holes is 99-105 mu m, and reflected light or transmitted light of the optical waveguides is used as output signal light; the depth value range can ensure that the distance from the biological detection point in the groove or the blind hole to the optical waveguide core is less than 2 times of the wavelength of the sensing light, wherein the depth of 105 mu m can ensure that the biological detection point is in each optical waveguide core, and the depth of 99 mu m can ensure that the distance from the biological detection point to the optical waveguide core is less than 1.55 mu m of the central wavelength of the signal light. When the reflected light of the optical waveguide is used as the output signal light, only one end face of each rectangular optical waveguide needs to be exposed; when the transmitted light of the optical waveguide is used as output signal light, the two end faces of each rectangular optical waveguide need to be exposed. The grooves or blind holes can effectively separate differentThe detection point increases the detection sensitivity and can also improve the use flexibility.
Detailed description of preferred embodiments 6
Referring to fig. 11, 12, and 13, the present embodiment differs from embodiment 1 in that: the optical waveguide 1 is a D-shaped optical fiber, a plurality of (e.g., 30) D-shaped optical fibers are arranged in parallel and fixed to the substrate 3 with their arc surfaces, and the interval between adjacent D-shaped optical fibers ranges from 0 to 50 μm; the structural parameters of the D-shaped optical fiber are as follows: the refractive index of the optical fiber core 104 is 1.4681, the diameter of the optical fiber core is 50 μm, the refractive index of the optical fiber cladding 105 is 1.4628, the diameter of the optical fiber cladding is 250 μm, and the sensing length of the D-shaped optical fiber is the same as the length of the substrate 3; the side planes of the D-shaped optical fibers are intersected (as shown in FIG. 12) or separated (as shown in FIG. 13) with the optical fiber core 104, grooves are engraved at intervals on the side planes of the D-shaped optical fibers along the axial direction of the optical fibers, the bottom surfaces of the grooves are in contact with the optical fiber core 104 or the distance between the bottom surfaces of the grooves and the optical fiber core 104 is less than 2 times of the wavelength of the sensing signal light, the width of the grooves is 10 μm, the distance between adjacent grooves is 100 μm, and the maximum length of the grooves is the cladding diameter of the D-shaped optical fibers; the biodetection spot 101 is solidified in or at the bottom of the groove, and the reflected or transmitted light in the fiber core is used as the output signal light.
Best mode for carrying out the invention
Referring to fig. 12, 13, 14 and 15, the present embodiment differs from embodiment 6 in that the biosensing point 101 is consolidated on the side plane of the D-shaped optical fiber. The specific scheme is as follows: the side plane of the D-shaped fiber intersects the fiber core 104 or is at a distance of 0.2 μm from the fiber core 104, see fig. 12 and 13; the waveguide grating 2 is engraved on the D-shaped optical fiber core 104 along the axial direction of the optical fiber, the waveguide grating is a superstructure fiber grating, 20 small sections of gratings are arranged in the superstructure fiber grating, the length of each small section of grating is 50 mu m, the distance between two adjacent small sections of gratings is 150 mu m, the period of each small section of grating is 0.528 mu m, the refractive index perturbation amplitude of the grating is 1.2 multiplied by 10-4(ii) a On the side plane of each D-shaped optical fiber, biomolecules or sensitive films which are arranged at intervals and can specifically identify sensed biomolecules are solidified along the axis of the optical fiber, and refer to fig. 14 and 15. This structure eliminates the need to etch the optical waveguideThe manufacturing process is relatively simple when the groove or the blind hole is manufactured.
Best mode for carrying out the invention
The present embodiment differs from embodiment 7 in that the waveguide grating 2 inscribed in the D-shaped optical fiber core 104 is a long-period grating capable of co-directionally coupling light; the length of the long period grating is the same as that of the substrate 3, the grating period is 292 mu m, and the refractive index perturbation amplitude of the grating is 2 multiplied by 10-3(ii) a The bottom surface of the groove is in contact with the optical fiber core or the distance between the bottom surface of the groove and the optical fiber core is less than 100 times of the wavelength of the sensing signal light, and the transmission light of the optical fiber core or the optical fiber cladding serves as the sensing signal light.
The above-described embodiments are merely preferred embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalent replacements, and improvements made within the spirit and principles of the present invention should be included within the scope of the present invention.
Claims (8)
1. A high-flux optical waveguide biosensor chip, comprising: the biosensor comprises an optical waveguide array and a biological detection point array, wherein the optical waveguide array is a plurality of optical waveguides which are arranged in parallel and fixed on a substrate, and each row of the biological detection point array is a plurality of biological detection points which are distributed at intervals along the light transmission direction of the optical waveguides and can generate specific biochemical reaction with sensed biomolecules; the biological detection point array is solidified on the optical waveguide array or the isolation layer on the optical waveguide array, and the end faces at two ends of each optical waveguide are used as the input end and the output end of the optical signal.
2. The high throughput optical waveguide biosensor chip of claim 1, wherein: the optical waveguide is a rectangular optical waveguide buried or embedded in a substrate, or a D-shaped optical fiber fixed to a substrate.
3. The high throughput optical waveguide biosensor chip of claim 2, wherein: the rectangular optical waveguide has a refractive index greater than that of the substrate.
4. The high throughput optical waveguide biosensor chip of claim 1, wherein: waveguide gratings capable of coupling light in the same direction or in the opposite direction are engraved in the optical waveguide, and the optimized structures of the waveguide gratings are uniform gratings, chirped gratings, superstructure gratings and phase shift gratings.
5. The high throughput optical waveguide biosensor chip of claim 1, wherein: the biological detection point is a biomolecule or sensitive membrane with specific recognition capability to the sensed biomolecule.
6. The high throughput optical waveguide biosensor chip of claim 1, wherein: the biological detection point is directly solidified on the surface of the optical waveguide array or the surface of the isolation layer above the optical waveguide array, or is solidified on the optical waveguide array or the isolation layer above the optical waveguide array through a groove or a blind hole; when the optical waveguide is embedded in the substrate, the substrate is used as an isolation layer.
7. The high throughput optical waveguide biosensor chip of claim 1, wherein: the reflected light of the optical waveguide is used as output signal light, and the optimized distance between the biological detection point and the core of the optical waveguide is less than 2 times of the wavelength of the sensing light.
8. The high throughput optical waveguide biosensor chip of claim 1, wherein: the transmitted light of the optical waveguide is used as output signal light, and the optimized distance between the biological detection point and the core of the optical waveguide is less than 100 times of the wavelength of the sensing light.
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