Multi-union detection optical biosensor based on singular enhancement effect

Abstract

The invention discloses a singularity enhancement effect-based multi-detection optical biosensor, which comprises a microfluidic structure and a sensing chip, the sensing chip comprises a sensing layer, the sensing layer is modified with a specific antibody, the microfluidic structure introduces a to-be-detected liquid into the sensing layer, and the to-be-detected liquid is combined with the specific antibody at the sensing layer, so that the to-be-detected liquid is detected. The sensing layer is realized based on a micro-ring structure of a non-Hermite singular point, when liquid to be detected is not introduced into the sensing layer, the sensing layer is in a second-order singular point state, and when the liquid to be detected is introduced into the sensing layer and is combined with a specific antibody, the second-order singular point state of the sensing layer is broken, a resonance peak in a spectrum is split, and the specific antibody is detected. The relationship between the splitting degree and the concentration of the target substance in the to-be-detected liquid is established through splitting of the harmonic peak, and quantitative detection of the target substance in the to-be-detected liquid is achieved; the method has the advantages that the method does not depend on a high Q value, can also have high sensitivity and low detection limit, can simultaneously cover ultralow concentration detection requirements of a ng / ml level, a pg / ml level and an fg / ml level, and is wider in application scene.

Description

TECHNICAL FIELD

[0001] The present application relates to an optical biosensor, in particular to a multi-connection detection optical biosensor based on singular enhancement effect. BACKGROUND

[0002] Optical lab-on-a-chip system represents the frontier technology of optical sensors, with advantages of high sensitivity, good selectivity, high stability, anti-electromagnetic interference, high integration and low cost. Optical biosensor has always been the subject of in-depth research in the field of biotechnology, especially in the detection of biological and chemical agents.

[0003] In the field of biological detection, such as early screening of cancer, optical biosensor realizes quantitative detection by specific binding of biological recognition elements (such as enzymes, antibodies) and target substances (such as tumor markers), causing changes in optical signal. Due to the high sensitivity and low detection limit (as low as ng / ml level) of optical biosensor, it can become an effective tool for early screening of cancer.

[0004] The existing optical biosensor usually includes a microfluidic structure and a sensing chip, the sensing chip includes a sensing layer, the sensing layer is modified with specific antibodies, the microfluidic structure is used to guide the to-be-detected liquid into the sensing layer, so that the target substance in the to-be-detected liquid is combined with the specific antibodies at the sensing layer, the refractive index at the sensing layer is changed, the spectrum of the light signal transmitted through the sensing layer is changed, and the concentration of the substance is measured by measuring the offset between the spectrum before the target substance is combined with the specific antibodies and the spectrum after the target substance is combined with the specific antibodies. In the existing optical biosensor, the sensing layer is usually realized by cascading two micro-ring resonators, and the optical biosensor realizes quantitative detection based on the vernier effect.

[0005] However, the existing optical biosensor has low sensitivity, and its detection limit can reach ng / ml level at most, which is only suitable for part of the early screening of cancer. If the application scenario is to be expanded, the sensitivity needs to be further improved and the detection limit needs to be reduced (such as to pg / ml level). However, the improvement of sensitivity and the reduction of detection limit need to rely on the improvement of quality factor Q. But Q value is limited by process precision (such as micro-ring sidewall roughness) and material characteristics (such as transmission loss), which is difficult to break through greatly. Therefore, the existing optical biosensor cannot be applied to ultra-low concentration detection demand scenarios. SUMMARY

[0006] The technical problem to be solved by the present application is to provide a multi-connection detection optical biosensor based on singular enhancement effect, which does not rely on high Q value, has high sensitivity and low detection limit, can cover ultra-low concentration detection demand of ng / ml level, pg / ml level and fg / ml level at the same time, and has more extensive application scenarios.

[0007] The application solves the above technical problems by adopting the technical scheme of a multi-association detection optical biosensor based on singular enhancement effect, comprising a microfluidic structure and a sensing chip, the sensing chip comprising a sensing layer, the sensing layer being modified with specific antibodies, the microfluidic structure being used to guide the to-be-detected liquid into the sensing layer, so that the target substance in the to-be-detected liquid is combined with the specific antibodies at the sensing layer, the sensing layer being realized based on the micro-ring structure of non-Hermite singular point, when the optical biosensor is in a non-detection state, no to-be-detected liquid is guided into the sensing layer, and the sensing layer is in a second-order singular point state, when the optical biosensor is in a detection state, the to-be-detected liquid is guided into the sensing layer, and when the target substance in the to-be-detected liquid is combined with the specific antibodies, the second-order singular point state of the sensing layer is broken, the refractive index at the sensing layer is changed, the spectrum of the optical signal transmitted through the sensing layer is changed, and the resonance peak in the spectrum is split, so that the relationship between the splitting degree and the concentration of the target substance in the to-be-detected liquid is established through the splitting of the resonance peak, and quantitative detection of the target substance in the to-be-detected liquid is realized.

[0008] Compared with the prior art, the application has the advantages that the sensing layer is realized based on the micro-ring structure of non-Hermite singular point, when the optical biosensor is in a non-detection state, no to-be-detected liquid is guided into the sensing layer, and the sensing layer is in a second-order singular point state, when the optical biosensor is in a detection state, the to-be-detected liquid is guided into the sensing layer, and when the target substance in the to-be-detected liquid is combined with the specific antibodies, the second-order singular point state of the sensing layer is broken, the refractive index of the sensing layer at the second-order singular point state is changed relative to the refractive index of the sensing layer at the second-order singular point, the spectrum of the optical signal is changed, the resonance peak in the spectrum is split, and the relationship between the splitting degree and the concentration of the target substance in the to-be-detected liquid can be established through the splitting of the resonance peak, so that the concentration of the target substance in the to-be-detected liquid is detected; since the second-order singular point state of the sensing layer is broken when the optical biosensor is in the detection state, the response ΔE of the optical biosensor is ep in a quadratic relationship with the perturbation ε, that is, the response ΔE ep is in a linear relationship with the square root of the perturbation ε , and the sensing layer itself has an amplification effect on the perturbation ε, so that the optical biosensor has high sensitivity even when the concentration of the target substance in the to-be-detected liquid is low, and can realize detection of the target substance with low concentration; thus, the application does not depend on high Q value, and can also have high sensitivity and low detection limit, can simultaneously cover the detection requirements of ng / ml level, pg / ml level and fg / ml level of ultra-low concentration, and has a more extensive application scenario.

[0009] Further, the sensing chip further comprises an upper cladding layer and a lower cladding layer, and the upper cladding layer and the lower cladding layer cover the sensing layer.

[0010] Further, the sensing layer comprises a first strip waveguide, a first grating coupler, a second grating coupler and n sensing units, n is an integer greater than or equal to 1; the first strip waveguide extends along the left-right direction, the left end of the first strip waveguide is connected with the first grating coupler, and the right end of the first strip waveguide is connected with the second grating coupler; n sensing units are arranged on the back side of the first strip waveguide and are spaced apart from left to right, and there is a gap between each sensing unit and the first strip waveguide; each sensing unit comprises two micro-ring resonators, a second strip waveguide and a third grating coupler, the two micro-ring resonators are two ring waveguides with the same size and spaced apart from front to back; the two ring waveguides are a first ring waveguide and a second ring waveguide, the first ring waveguide is located on the front side of the second ring waveguide; the second ring waveguide is modified with specific antibodies; the second strip waveguide is located on the back side of the second ring waveguide and has a gap with the second ring waveguide; the left end of the second strip waveguide is an open end, and the right end of the second strip waveguide is connected with the third grating coupler; n windows are formed in the upper cladding layer, the n windows are spaced apart from left to right, and the second ring waveguide of the n sensing units is exposed one by one at the n windows; the microfluidic structure and the n windows are in communication; in any two sensing units, the inner diameter and the outer diameter of the ring waveguide are not the same.

[0011] Further, in each sensing unit, the first ring waveguide and the adjacent part of the first strip waveguide form a first directional coupler, the first directional coupler is used for coupling the light transmitted in the first strip waveguide to the first ring waveguide, and coupling the light transmitted in the first ring waveguide to the first strip waveguide; the first ring waveguide and the adjacent part of the second ring waveguide form a second directional coupler, the second directional coupler is used for coupling the light transmitted in the second ring waveguide to the first ring waveguide, and coupling the light transmitted in the first ring waveguide to the second ring waveguide; the second ring waveguide and the adjacent part of the second strip waveguide form a third directional coupler, the third directional coupler is used for coupling the light transmitted in the second ring waveguide to the second strip waveguide, and coupling the light transmitted in the second strip waveguide to the second ring waveguide.

[0012] Further, the upper cladding layer and the lower cladding layer are both cuboid structures, and the length of each of them is along the left-right direction, the width is along the front-back direction, and the thickness is along the up-down direction; the upper cladding layer is above the lower cladding layer; the upper cladding layer and the lower cladding layer are aligned in the front, back, left, and right directions; the lower end surface of the upper cladding layer is attached to the upper end surface of the lower cladding layer; and the sensing layer is embedded in the upper cladding layer.

[0013] Further, the first bar-shaped waveguide is a cuboid structure, and the length is along the left-right direction, the width is along the front-back direction, and the thickness is along the up-down direction; the front end surface of the first bar-shaped waveguide is located on the rear side of the plane on which the front end surface of the lower cladding layer is located, and there is a distance between the two; the lower end surface of the first bar-shaped waveguide is in an attached state with the upper end surface of the lower cladding layer; the first grating coupler is located on the right side of the plane on which the left end surface of the lower cladding layer is located, and there is a distance; the second grating coupler is located on the left side of the plane on which the right end surface of the lower cladding layer is located, and there is a distance; the plane that makes the lower cladding layer symmetrical left and right is called the first symmetry plane; the overall structure composed of the first grating coupler, the first bar-shaped waveguide, and the second grating coupler is symmetrical left and right about the first symmetry plane; each of the n windows extends downward from the upper surface of the upper cladding layer.

[0014] Further, in each sensing unit, the lower end surface of each of the two ring-shaped waveguides is in an attached state with the upper end surface of the lower cladding layer, the upper end surface of each of the two ring-shaped waveguides is located on the same plane as the upper end surface of the first bar-shaped waveguide, the central axis of each of the two ring-shaped waveguides is located on the same plane, and the plane is parallel to the first symmetry plane; the difference between the outer diameter and the inner diameter of each ring-shaped waveguide is equal to the width of the first bar-shaped waveguide; the second bar-shaped waveguide is implemented by a cuboid structure waveguide with the length along the left-right direction, the width along the front-back direction, and the thickness along the up-down direction, or by a curved waveguide structure formed by bending a cuboid structure waveguide with the length along the left-right direction, the width along the front-back direction, and the thickness along the up-down direction to the rear; the lower end surface of the second bar-shaped waveguide is in an attached state with the upper end surface of the lower cladding layer, and the upper end surface is located on the same plane as the upper end surface of the first bar-shaped waveguide; there is a gap between the second bar-shaped waveguide and the plane on which the rear end surface of the lower cladding layer is located.

[0015] Further, the microfluidic structure comprises a substrate, a liquid inlet, a liquid outlet, a serpentine microfluidic channel, n detection zones, n-1 transmission flow channels and a liquid discharge channel; the substrate is a cuboid structure, the length of which is along the left-right direction, the width of which is along the front-back direction, and the thickness of which is along the up-down direction; the substrate is aligned with the upper cladding layer in the front, back, left and right directions; the lower end surface of the substrate is in a state of adhesion with the upper end surface of the upper cladding layer; the serpentine microfluidic channel is realized by opening a serpentine groove upwardly recessed on the lower surface of the substrate; each detection zone is realized by opening a groove upwardly recessed on the lower surface of the substrate; the n detection zones are distributed from left to right on the right side of the serpentine microfluidic channel, and the n detection zones and the n windows are one-to-one correspondingly connected and communicated in the up-down direction; each transmission flow channel is realized by opening a groove upwardly recessed on the lower surface of the substrate; any two adjacent detection zones are connected by one transmission flow channel; the liquid discharge channel is located on the right side of the rightmost detection zone and is realized by opening a groove upwardly recessed on the lower surface of the substrate; the serpentine microfluidic channel is connected with the leftmost detection zone, and the liquid discharge channel is connected with the rightmost detection zone; the liquid inlet and the liquid outlet are respectively holes penetrating through the substrate in the up-down direction, the liquid inlet is connected with the serpentine microfluidic channel, and the liquid outlet is connected with the liquid discharge channel.

[0016] The materials of the lower cladding layer and the upper cladding layer are both SiO2, the material inside each window is air, and the materials of the first strip waveguide, the first grating coupler, the second grating coupler, and the two ring waveguides, the second strip waveguide and the third grating coupler in each sensing unit are all SiN. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 Perspective view of the multi-association detection optical biosensor based on the singular enhancement effect of the application when n = 1; Figure 2 Top view of the upper cladding layer of the multi-association detection optical biosensor based on the singular enhancement effect of the application when n = 1; Figure 3 Perspective view of the microfluidic structure of the multi-association detection optical biosensor based on the singular enhancement effect of the application when n = 1; Figure 4 Perspective view of the lower cladding layer and the sensing layer of the multi-association detection optical biosensor based on the singular enhancement effect of the application when n = 1; Figure 5 Perspective view of the multi-association detection optical biosensor based on the singular enhancement effect of the application when n = 3; Figure 6 Response comparison chart of the multi-association detection optical biosensor based on the singular enhancement effect of the application and the existing optical biosensor based on the vernier effect. Figure 7 The transmission spectrum of the multi-detection optical biosensor based on the singular enhancement effect of the present invention is shown. Figure 8 This is a spectrum of the splitting of the eigenvalues ​​of the Hamiltonian matrix as a function of perturbation when the multi-detection optical biosensor based on the singular enhancement effect of the present invention detects a target substance. Detailed Implementation

[0018] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0019] Example 1: A multi-detection optical biosensor based on singularity enhancement effect includes a microfluidic structure 1 and a sensing chip. The sensing chip includes a sensing layer modified with specific antibodies. The microfluidic structure 1 is used to introduce the test liquid into the sensing layer, allowing the target substance in the test liquid to bind with the specific antibody in the sensing layer. The sensing layer is based on a micro-ring structure of non-Hermitian singularity. When the optical biosensor is in a non-detection state, no test liquid is introduced into the sensing layer, which is in a second-order singularity state. When the optical biosensor is in a detection state, the test liquid is introduced into the sensing layer. When the target substance in the test liquid binds with the specific antibody, the second-order singularity state of the sensing layer is broken, changing the refractive index at the sensing layer. This changes the spectrum of the light signal transmitted through the sensing layer, causing the resonance peaks in the spectrum to split. The relationship between the degree of splitting and the concentration of the target substance in the test liquid is established through the splitting of the resonance peaks, thereby achieving quantitative detection of the target substance in the test liquid.

[0020] In this embodiment, because the second-order singularity state of the sensing layer is broken when the optical biosensor is in the detection state, the response ΔE of the optical biosensor is... ep The response is related to the first power of the perturbation ε, i.e. Response △E ep square root of perturbation ε The relationship is linear, and the sensing layer itself amplifies micro-perturbations ε, exhibiting high sensitivity and a low detection limit regardless of the Q value. Therefore, even when the concentration of the target substance in the analyte is low, the optical biosensor maintains high sensitivity and can detect target substances at low concentrations.

[0021] Embodiment two: this embodiment is basically the same as embodiment one, the difference is that in this embodiment, the sensing chip further comprises an upper cladding layer 2 and a lower cladding layer 3, and the sensing layer is covered by the upper cladding layer 2 and the lower cladding layer 3. The sensing layer comprises a first strip waveguide 4, a first grating coupler 5, a second grating coupler 6 and n sensing units, n is an integer greater than or equal to 1; the first strip waveguide 4 extends along the left-right direction, the left end is connected with the first grating coupler 5, and the right end is connected with the second grating coupler 6; the n sensing units are arranged on the back side of the first strip waveguide 4 and are spaced apart from left to right, and there is a gap between each sensing unit and the first strip waveguide 4; each sensing unit comprises two micro-ring resonators, a second strip waveguide 7 and a third grating coupler 8, the two micro-ring resonators are two ring waveguides with the same size and spaced apart front and back; the two ring waveguides are a first ring waveguide 9 and a second ring waveguide 10, the first ring waveguide 9 is located in front of the second ring waveguide 10; the second ring waveguide 10 is modified with specific antibodies; the second strip waveguide 7 is located behind the second ring waveguide 10 and has a gap between the second strip waveguide 7 and the second ring waveguide 10; the left end of the second strip waveguide 7 is an open end, and the right end is connected with the third grating coupler 8; n windows 11 are opened on the upper cladding layer 2, the n windows 11 are spaced apart from left to right, and the second ring waveguide 10 of the n sensing units is exposed one by one at the n windows 11; the microfluidic structure 1 is in communication with the n windows 11; in any two sensing units, the inner diameter and the outer diameter of the ring waveguide are not the same.

[0022] In this embodiment, in each sensing unit, the region where the first ring waveguide 9 and the adjacent part of the first strip waveguide 4 are located forms a first directional coupler, the first directional coupler is used for coupling the light transmitted in the first strip waveguide 4 to the first ring waveguide 9, and coupling the light transmitted in the first ring waveguide 9 to the first strip waveguide 4; the region where the first ring waveguide 9 and the second ring waveguide 10 are adjacent forms a second directional coupler, the second directional coupler is used for coupling the light transmitted in the second ring waveguide 10 to the first ring waveguide 9, and coupling the light transmitted in the first ring waveguide 9 to the second ring waveguide 10; the region where the second ring waveguide 10 and the second strip waveguide 7 are adjacent forms a third directional coupler, the third directional coupler is used for coupling the light transmitted in the second ring waveguide 10 to the second strip waveguide 7, and coupling the light transmitted in the second strip waveguide 7 to the second ring waveguide 10.

[0023] In this embodiment, the upper cladding layer 2 and the lower cladding layer 3 are both cuboid structures, and their lengths are along the left-right direction, their widths are along the front-back direction, and their thicknesses are along the up-down direction; the upper cladding layer 2 is located above the lower cladding layer 3; the upper cladding layer 2 and the lower cladding layer 3 are aligned in the front, back, left and right directions; the lower end surface of the upper cladding layer 2 is attached to the upper end surface of the lower cladding layer 3; the sensing layer is embedded in the upper cladding layer 2.

[0024] In the embodiment, the first strip waveguide 4 has a cuboid structure, and its length is along the left-right direction, its width is along the front-back direction, and its thickness is along the up-down direction. The front end surface of the first strip waveguide 4 is located at the rear side of the plane where the front end surface of the lower cladding layer 3 is located, and there is a distance between the two. The lower end surface of the first strip waveguide 4 is in a state of adhesion with the upper end surface of the lower cladding layer 3. The first grating coupler 5 is located at the right side of the plane where the left end surface of the lower cladding layer 3 is located, and there is a distance. The second grating coupler 6 is located at the left side of the plane where the right end surface of the lower cladding layer 3 is located, and there is a distance. The plane that makes the lower cladding layer 3 symmetrical left and right is called the first symmetry plane. The overall structure composed of the first grating coupler 5, the first strip waveguide 4 and the second grating coupler 6 is symmetrical left and right about the first symmetry plane. The n windows 11 all extend downward from the upper surface of the upper cladding layer 2.

[0025] In the embodiment, in each sensing unit, the lower end surfaces of the two ring waveguides are in a state of adhesion with the upper end surface of the lower cladding layer 3, and the upper end surfaces of the two ring waveguides are located in the same plane as the upper end surface of the first strip waveguide 4. The central axes of the two ring waveguides are located in the same plane, and the plane is parallel to the first symmetry plane. The difference between the outer diameter and the inner diameter of each ring waveguide is equal to the width of the first strip waveguide 4. The second strip waveguide 7 is implemented by a cuboid structure waveguide with a length along the left-right direction, a width along the front-back direction, and a thickness along the up-down direction, or by a curved waveguide structure formed by bending a cuboid structure waveguide with a length along the left-right direction, a width along the front-back direction, and a thickness along the up-down direction to the rear. The lower end surface of the second strip waveguide 7 is in a state of adhesion with the upper end surface of the lower cladding layer 3, and the upper end surface is located in the same plane as the upper end surface of the first strip waveguide 4. There is a gap between the second strip waveguide 7 and the plane where the rear end surface of the lower cladding layer 3 is located.

[0026] In this embodiment, the microfluidic structure 1 includes a substrate 12, an inlet 13, an outlet 14, a serpentine microchannel 15, n detection zones 16, n-1 transport channels 17, and an outlet channel 18. The substrate 12 is a cuboid structure with its length along the left-right direction, its width along the front-back direction, and its thickness along the top-bottom direction. The substrate 12 and the upper cladding 2 are vertically aligned in the front-back, left-right, and top-bottom directions. The lower end face of the substrate 12 is in contact with the upper end face of the upper cladding 2. The serpentine microchannel 15 is formed by creating upwardly recessed serpentine grooves on the lower surface of the substrate 12. Each detection zone 16 is formed by creating upwardly recessed grooves on the lower surface of the substrate 12, and the n detection zones 16 are distributed from left to right in the serpentine microchannel 15. On the right side, n detection areas 16 and n windows 11 are connected vertically and vertically in a one-to-one correspondence; each transmission channel 17 is realized by opening an upwardly recessed groove on the lower surface of the substrate 12; any two adjacent detection areas 16 are connected by a transmission channel 17; the drain channel 18 is located to the right of the rightmost detection area 16 and is realized by opening an upwardly recessed groove on the lower surface of the substrate 12; the serpentine microchannel 15 is connected to the leftmost detection area 16 and the drain channel 18 is connected to the rightmost detection area 16; the inlet 13 and the outlet 14 are holes that penetrate the substrate 12 vertically and vertically, respectively, the inlet 13 is connected to the serpentine microchannel 15 and the outlet 14 is connected to the drain channel 18.

[0027] In this embodiment, the materials of the lower cladding layer 3 and the upper cladding layer 2 are both SiO2, the material inside each window 11 is air, and the materials of the first strip waveguide 4, the first grating coupler 5, the second grating coupler 6, and the two ring waveguides, the second strip waveguide 7 and the third grating coupler 8 in each sensing unit are all SiN.

[0028] In this embodiment, the serpentine microchannel 15 of the microfluidic structure 1 can achieve fluid stabilization (reducing droplet error), and the detection area 16 is precisely aligned with the window area of ​​the sensing unit (ensuring that the analyte is in full contact with the second annular waveguide 10). At the same time, the two annular waveguides, the second strip waveguide 7, and the third grating coupler 8 in each sensing unit have low temperature coefficients. Combined with the heat insulation effect of the lower cladding 3 and the upper cladding 2, the influence of temperature drift on the detection results can be reduced, and the detection stability can be improved.

[0029] In this embodiment, as Figures 1 to 4 As shown, n=1. The width of the first strip waveguide 4 and the thickness of the second strip waveguide 7 are both 1 micrometer and 0.5 micrometers, respectively. The inner diameter of the first ring waveguide 9 and the outer diameter of the second ring waveguide 10 are both 79 micrometers and 81 micrometers, respectively.

[0030] The multi-detection optical biosensor based on the singular enhancement effect in this embodiment can be described by a non-Hermi Hamiltonian: wherein, is the resonance frequency of the first ring waveguide 9, is the resonance frequency of the second ring waveguide 10, is the loss coefficient of the first ring waveguide 9, is the loss coefficient of the second ring waveguide 10, k is the coupling strength between the first ring waveguide 9 and the second ring waveguide 10, H is the Hamiltonian matrix of the multi-coupled detection optical biosensor based on singular enhancement effect of the present embodiment, i is the imaginary unit.

[0031] By solving formula (1), two eigenvalues of the Hamiltonian matrix H of the multi-coupled detection optical biosensor based on singular enhancement effect of the present embodiment can be obtained as follows: and , respectively,

[0032] The difference between the two eigenvalues and is: wherein, | | is the absolute value symbol, and are obtained by using formula (5) and (6), respectively: When the sensing layer of the multi-coupled detection optical biosensor based on singular enhancement effect of the present embodiment is at the second-order singular point, the conditions shown in formula (7) and (8) need to be met:

[0033] By solving formula (7) and (8), the condition that the eigenvalue and the eigenvector of the Hamiltonian matrix H of the multi-coupled detection optical biosensor based on singular enhancement effect of the present embodiment are simultaneously degenerate is obtained as follows:

[0034] Formula (9) and (10) are also the conditions that need to be met when the sensing layer of the multi-coupled detection optical biosensor based on singular enhancement effect of the present embodiment is at the second-order singular point.

[0035] Now introduce a small parameter perturbation ε to make the sensing layer of the multi-coupled detection optical biosensor based on singular enhancement effect of the present embodiment deviate from the second-order singular point. Let , keep , then we can get: ​

[0036] For small parameter perturbation ε, ignore high order term ε 2 According to formula (11), the following can be obtained:

[0037] Bringing formula (12) into formula (4), the following can be obtained:

[0038] Thus, the following can be obtained:

[0039] Since Corresponding to response △E ep That is, the response .

[0040] In this embodiment, when there is only one sensing unit in the sensing layer, light is input from the first grating coupler 5, transmitted to the first strip waveguide 4 through the first grating coupler 5, and starts to transmit from left to right in the first strip waveguide 4. When the light passes through the first directional coupler, part of the light is coupled to the first ring waveguide 9 through the first directional coupler, and the other part continues to transmit along the first strip waveguide 4. At this time, the light coupled to the first ring waveguide 9 transmits along the clockwise direction in the first ring waveguide 9. When the light transmits to the second directional coupler, part of the light is coupled to the second ring waveguide 10, and the other part of the light continues to transmit in the first ring waveguide 9. The light that continues to transmit in the first ring waveguide 9 is coupled to the first strip waveguide 4 when it passes through the first directional coupler, and continues to transmit through the first strip waveguide 4. When the light transmits to the second grating coupler 6, the second grating coupler 6 outputs the light. The light coupled to the second ring waveguide 10 transmits along the counterclockwise direction in the second ring waveguide 10. When the light in the second ring waveguide 10 transmits to the third directional coupler, part of the light is coupled to the second strip waveguide 7, and the other part of the light continues to transmit in the second ring waveguide 10. At this time, the light coupled to the second strip waveguide 7 continues to transmit through the second strip waveguide 7. When the light transmits to the third grating coupler 8, the third grating coupler 8 outputs the light. The light that continues to transmit in the second ring waveguide 10 is coupled to the first ring waveguide 9 when it transmits to the second directional coupler, and continues to transmit along the clockwise direction in the first ring waveguide 9. When the light transmits to the first directional coupler, it is coupled to the first strip waveguide 4 and continues to transmit along the first strip waveguide 4. When the light transmits to the second grating coupler 6, it is output through the second grating coupler 6.

[0041] After the solution to be measured is input from the liquid inlet 13, the solution to be measured flows into the detection area 16 through the serpentine micro flow channel 15 and directly contacts the second ring waveguide 10 at the window 11. At this time, the target substance in the solution to be measured is combined with the specific antibody at the second ring waveguide 10, i.e. the perturbation acts on the sensing unit, changes the refractive index of the sensing layer, and after the detection is completed, the waste liquid is discharged through the liquid outlet 14.

[0042] Therefore, by obtaining the light output by the second grating coupler 6 before the microfluidic structure 1 introduces the liquid to be measured into the sensing layer and the light output by the second grating coupler 6 after the microfluidic structure 1 introduces the liquid to be measured into the sensing layer, the corresponding spectrum can be obtained, and the relationship between the splitting degree and the concentration of the target substance in the liquid to be measured can be established by the splitting of the resonance peak in the spectrum. Because there is only a single sensing unit, only one resonance peak is split in the spectrum, and the concentration of the measured substance can be obtained by observing the splitting degree.

[0043] Embodiment Three: This embodiment is basically the same as Embodiment Two, except that in this embodiment, as shown in FIG. 3, n = 3. Figure 4

[0044] ​In this embodiment, there are multiple sensing units in the sensing layer, and different specific antibodies are modified at the second ring waveguide 10 of each sensing unit. Light is input from the first grating coupler 5, transmitted to the first strip waveguide 4 through the first grating coupler 5, and transmitted from left to right in the first strip waveguide 4, sequentially passing through the first directional couplers at multiple sensing units. When the light passes through the first directional coupler at a certain sensing unit, the light is transmitted at the sensing unit in the following manner: part of the light is coupled to the first ring waveguide 9, and the other part continues to transmit along the first strip waveguide 4. At this time, the light coupled to the first ring waveguide 9 is transmitted in the first ring waveguide 9 in a clockwise direction. When passing through the second directional coupler, part of the light is coupled to the second ring waveguide 10, and the other part of the light continues to transmit in the first ring waveguide 9. When the light that continues to transmit in the first ring waveguide 9 passes through the first directional coupler, it is coupled to the first strip waveguide 4. Due to the different sizes of the ring waveguides in different sensing units, specific frequency light will be filtered out. At this time, the light will not pass through the subsequent sensing units and will be directly output from the second grating coupler 6. The light coupled to the second ring waveguide 10 is transmitted in the second ring waveguide 10 in a counterclockwise direction. When passing through the third directional coupler, part of the light is coupled to the second strip waveguide 7, and the other part of the light continues to transmit in the second ring waveguide 10. At this time, the light coupled to the second strip waveguide 7 continues to transmit through the second strip waveguide 7 and is output from the third grating coupler 8 when it transmits to the third grating coupler 8. The light that continues to transmit in the second ring waveguide 10 is coupled to the first ring waveguide 9 when it passes through the second directional coupler and continues to transmit in the first ring waveguide 9 in a clockwise direction. When it passes through the first directional coupler, it is coupled to the first strip waveguide 4. Due to the different sizes of the ring waveguides in different sensing units, specific frequency light will be filtered out. At this time, the light will not pass through the subsequent sensing units and will be directly output from the second grating coupler 6.

[0045] Thus, by obtaining the light output from the second grating coupler 6 before the microfluidic structure 1 introduces the liquid to be tested into the sensing layer and the light output from the second grating coupler 6 after the microfluidic structure 1 introduces the liquid to be tested into the sensing layer, the corresponding spectra can be obtained. The relationship between the splitting degree and the concentration of the target substance in the liquid to be tested can be established by the splitting of the resonance peaks in the spectrum. Because there are multiple sensing units, the frequencies of the light in each sensing unit are inconsistent due to the inconsistent sizes of the ring waveguides in any two sensing units. The splitting degree of the resonance peak at the frequency corresponding to each sensing unit can be observed from the spectrum obtained from the second grating coupler 6, so as to determine the content of the target substance in the liquid to be tested detected by each sensing unit.

[0046] This embodiment can simultaneously detect multiple tumor markers in the same solution to be tested, reduce the risk of false positives and missed diagnosis in single marker detection, and adapt to the precise needs of early cancer screening.

[0047] To verify the performance of the multi-sensor optical biosensor based on the singular enhancement effect of this invention, simulations were performed on the multi-sensor optical biosensor based on the singular enhancement effect of this invention and an existing optical biosensor (an optical biosensor whose sensing layer is implemented by cascading two microring resonators and achieves quantitative detection based on the vernier effect). The response comparison graph between the multi-sensor optical biosensor based on the singular enhancement effect of this invention and the existing optical biosensor based on the vernier effect is shown below. Figure 6 As shown; the transmission spectrum of the multi-detection optical biosensor based on the singular enhancement effect of the present invention, as shown. Figure 7 As shown; when the multi-detection optical biosensor based on the singular enhancement effect of the present invention detects target substances, the eigenvalues ​​of its Hamiltonian matrix H change with the perturbation, and the resulting spectral lines are as follows. Figure 8 As shown. Observation Figure 6 It can be seen that, under the same perturbation, the response of the multi-detection optical biosensor based on the singular enhancement effect of the present invention to low perturbation (response) The performance of this invention's multi-sensor optical biosensor based on the singular enhancement effect is significantly higher than that of optical biosensors based on the vernier effect, demonstrating its advantage in detecting ultra-low concentrations of substances. Therefore, for extremely small perturbations, the performance of this invention's multi-sensor optical biosensor based on the singular enhancement effect is far superior to that of optical biosensors based on the vernier effect. (Observation) Figure 7 It can be seen that when the sensing layer is in a second-order singularity state, the eigenvalues ​​and eigenvectors of the Hamiltonian matrix H of the multi-sensor optical biosensor based on the singular enhancement effect are in a degenerate state. Observation Figure 8 It is understood that in the multi-detection optical biosensor based on the singular enhancement effect of the present invention, the change generated in the detection area 16 at the second ring waveguide 10 is introduced by the perturbation ε, that is, ε represents the change generated in the detection area 16 at the second ring waveguide 10.

[0048] In summary, the response ΔE of the multi-detection optical biosensor based on the singular enhancement effect of the present invention is... ep The response is related to the first power of the perturbation ε, i.e. Response △E ep square root of perturbation ε The relationship is linear, and the sensing layer itself amplifies the perturbation ε. Even when the concentration of the target substance in the liquid to be tested is low, the optical biosensor has high sensitivity and can detect target substances with low concentrations. Therefore, this invention does not rely on a high Q value and can also have high sensitivity and low detection limit. It can simultaneously cover the ultra-low concentration detection needs at the ng / ml, pg / ml and fg / ml levels, and has a wider range of application scenarios.

Claims

1. A multi-detection optical biosensor based on a singular enhancement effect, comprising a microfluidic structure and a sensing chip, wherein the sensing chip includes a sensing layer, the sensing layer being modified with a specific antibody, and the microfluidic structure is used to introduce a test liquid into the sensing layer, so that the target substance in the test liquid binds to the specific antibody at the sensing layer, characterized in that: The sensing layer is based on a micro-ring structure with a non-Hermitian singularity. When the optical biosensor is in a non-detection state, no test liquid is introduced into the sensing layer, which is in a second-order singularity state. When the optical biosensor is in a detection state, the test liquid is introduced into the sensing layer. When the target substance in the test liquid binds to the specific antibody, the second-order singularity state of the sensing layer is broken, changing the refractive index at the sensing layer. This alters the spectrum of the light signal transmitted through the sensing layer, causing the resonance peaks in the spectrum to split. By establishing the relationship between the degree of splitting of the resonance peaks and the concentration of the target substance in the test liquid, quantitative detection of the target substance in the test liquid can be achieved.

2. The multi-detection optical biosensor based on the singular enhancement effect according to claim 1, characterized in that: The sensing chip further includes an upper cladding layer and a lower cladding layer, which cover the sensing layer.

3. The multi-detection optical biosensor based on the singular enhancement effect according to claim 2, characterized in that: The sensing layer includes a first strip waveguide, a first grating coupler, a second grating coupler, and n sensing units, where n is an integer greater than or equal to 1. The first strip waveguide extends in a left-right direction, with its left end connected to the first grating coupler and its right end connected to the second grating coupler. The n sensing units are disposed behind the first strip waveguide and are spaced apart from left to right, each with a gap between it and the first strip waveguide. Each sensing unit includes two micro-ring resonators, a second strip waveguide, and a third grating coupler. The two micro-ring resonators are two ring waveguides of the same size, spaced apart. The two ring waveguides are respectively the first... The system comprises a ring waveguide and a second ring waveguide, with the first ring waveguide located in front of the second ring waveguide. The second ring waveguide is modified with a specific antibody. A second strip waveguide is located behind the second ring waveguide and has a gap with it. The left end of the second strip waveguide is an open circuit, and its right end is connected to the third grating coupler. The upper cladding has n windows spaced from left to right, and the second ring waveguides of the n sensing units are exposed at each of the n windows. The microfluidic structure is connected to each of the n windows. In any two sensing units, the inner and outer diameters of the ring waveguides are different.

4. The multi-detection optical biosensor based on the singular enhancement effect according to claim 3, characterized in that: In each sensing unit, a first directional coupler is formed between the first annular waveguide and the adjacent region of the first strip waveguide. The first directional coupler is used to couple light transmitted in the first strip waveguide to the first annular waveguide and light transmitted in the first annular waveguide to the first strip waveguide. A second directional coupler is formed between the first annular waveguide and the adjacent region of the second annular waveguide. The second directional coupler is used to couple light transmitted in the second annular waveguide to the first annular waveguide and light transmitted in the first annular waveguide to the second annular waveguide. A third directional coupler is formed between the second annular waveguide and the adjacent region of the second strip waveguide. The third directional coupler is used to couple light transmitted in the second annular waveguide to the second strip waveguide and light transmitted in the second strip waveguide to the second annular waveguide.

5. The multi-detection optical biosensor based on the singular enhancement effect according to claim 3, characterized in that: Both the upper and lower cladding layers are cuboid structures, with their lengths along the left-right direction, their widths along the front-back direction, and their thicknesses along the top-bottom direction. The upper cladding layer is located above the lower cladding layer. The upper and lower cladding layers are aligned vertically in the front, back, left, and right directions. The lower end face of the upper cladding layer is attached to the upper end face of the lower cladding layer. The sensing layer is embedded within the upper cladding layer.

6. The multi-detection optical biosensor based on the singular enhancement effect according to claim 5, characterized in that; The first strip waveguide is a cuboid structure with its length along the left-right direction, its width along the front-back direction, and its thickness along the top-bottom direction. The front end face of the first strip waveguide is located behind the plane containing the front end face of the lower cladding, and there is a distance between them. The lower end face of the first strip waveguide is in contact with the upper end face of the lower cladding. The first grating coupler is located to the right of the plane containing the left end face of the lower cladding, and there is a distance between them. The second grating coupler is located to the left of the plane containing the right end face of the lower cladding, and there is a distance between them. The plane that makes the lower cladding symmetrical is called the first symmetry plane. The overall structure formed by the first grating coupler, the first strip waveguide, and the second grating coupler is symmetrical about the first symmetry plane. All n windows extend downward from the upper surface of the upper cladding.

7. The multi-detection optical biosensor based on the singular enhancement effect according to claim 6, characterized in that; In each sensing unit, the lower end faces of the two annular waveguides are in contact with the upper end face of the lower cladding, and the upper end faces of the two annular waveguides are on the same plane as the upper end face of the first strip waveguide. The central axes of the two annular waveguides are on the same plane, and this plane is parallel to the first plane of symmetry. The difference between the outer diameter and the inner diameter of each annular waveguide is equal to the width of the first strip waveguide. The second strip waveguide is implemented as a cuboid waveguide with a length along the left-right direction, a width along the front-back direction, and a thickness along the top-bottom direction, or as a curved waveguide structure formed by bending a cuboid waveguide with a length along the left-right direction, a width along the front-back direction, and a thickness along the top-bottom direction. The lower end face of the second strip waveguide is in contact with the upper end face of the lower cladding, and the upper end face is on the same plane as the upper end face of the first strip waveguide. There is a gap between the plane containing the rear end face of the second strip waveguide and the lower cladding.

8. The multi-detection optical biosensor based on the singular enhancement effect according to claim 7, characterized in that: The microfluidic structure includes a substrate, an inlet, an outlet, a serpentine microchannel, n detection zones, n-1 transport channels, and an outlet channel. The substrate is a cuboid structure with its length along the left-right direction, its width along the front-back direction, and its thickness along the top-bottom direction. The substrate and the upper cladding are vertically aligned in the front-back, left-right, and top-bottom directions. The lower end face of the substrate is in contact with the upper end face of the upper cladding. The serpentine microchannel is formed by creating upwardly recessed serpentine grooves on the lower surface of the substrate. Each detection zone is formed by creating upwardly recessed grooves on the lower surface of the substrate, and the n detection zones are distributed from left to right on the right side of the serpentine microchannel. The n detection zones and n windows are connected vertically and vertically in a one-to-one correspondence; each transmission channel is realized by forming an upwardly recessed groove on the lower surface of the substrate; any two adjacent detection zones are connected by one of the transmission channels; the drain channel is located to the right of the rightmost detection zone and is realized by forming an upwardly recessed groove on the lower surface of the substrate; the serpentine microchannel is connected to the leftmost detection zone, and the drain channel is connected to the rightmost detection zone; the inlet and the outlet are holes that penetrate the substrate vertically, the inlet is connected to the serpentine microchannel, and the outlet is connected to the drain channel.

9. The multi-detection optical biosensor based on the singular enhancement effect according to claim 3, characterized in that: The lower cladding and the upper cladding are both made of SiO2, and the interior of each window is made of air. The first strip waveguide, the first grating coupler, the second grating coupler, and the two ring waveguides, the second strip waveguide, and the third grating coupler in each sensing unit are all made of SiN.

Images