A creatinine sensor based on an asymmetric Mach-Zehnder structure

Abstract

The present invention provides a creatinine sensor based on an asymmetric Mach-Zehnder structure, which belongs to the field of bio-optical sensing technology. The sensor includes a PDMS lower cladding, a PMMA core layer and a PDMS upper cladding, the PMMA core layer includes an input waveguide, a beam splitter, a modulation arm waveguide, a beam combiner and an output waveguide, and the modulation arm waveguide includes a sensing arm and a reference arm of unequal width. The sensing arm adopts a suspended design and is windowed, and a creatinase mixed solution is fixed on the surface to increase the response to the creatinine concentration. By optimizing the design of the reference arm width, its sensitivity is reduced, so that the phase change of the interference signal is mainly caused by the sensing arm, thereby improving the sensing sensitivity. The sensor can detect creatinine concentrations within the range of 0-110 μmoL / L, covering the physiological concentration range of creatinine in human blood, has the characteristics of high sensitivity and compact structure, and is suitable for wearable health detection applications.

Description

Technical Field

[0001] The invention belongs to the technical field of bio-optical sensing, and in particular relates to a creatinine sensor based on an asymmetric Mach-Zehnder structure. Background Art

[0002] Creatinine is one of the main waste products of human metabolism and is produced by the metabolic decomposition of creatine and creatine phosphate in muscles. In clinical medicine, the concentration of creatinine in serum or urine is widely used as a biomarker for renal function testing. Therefore, the rapid and accurate detection of creatinine has important medical value. At present, the detection methods of creatinine mainly use traditional technologies such as electrochemical sensing and fluorescence detection. Although these methods can meet the needs to a certain extent, they still have many shortcomings, such as complex equipment operation, large size, long detection time, and low sensitivity of some methods.

[0003] Optical sensors have become a technology that has attracted much attention in biosensing in recent years due to their non-invasive, real-time detection and high sensitivity. Polymer optical waveguide sensors can detect target substances by utilizing the interaction between specific substances and optical waveguide structures, making them have strong advantages in sensing sensitivity, low cost, easy processing, integration and miniaturization.

[0004] At present, sensors for creatinine detection are still relatively scarce. Existing sensing technologies have problems such as low sensitivity, complex operation, and low accuracy, which greatly limit the widespread application of creatinine detection in clinical and daily health testing. Moreover, as an important biomarker, the detection results of creatinine are of great significance in the early diagnosis and health management of kidney disease. Therefore, the development of a new, small-sized, highly sensitive optical sensor that can quickly and accurately detect creatinine concentration has become a technical demand that needs to be urgently addressed. Summary of the invention

[0005] In view of this, the present invention aims to propose a creatinine sensor based on an asymmetric Mach-Zehnder structure, which improves the sensitivity and detection accuracy of the sensor through optimized design, and provides a new solution for the rapid detection of creatinine.

[0006] To achieve the above object, the technical solution of the present invention is:

[0007] A creatinine sensor based on an asymmetric Mach-Zehnder structure comprises a PDMS lower cladding, a PMMA core layer and a PDMS upper cladding which are arranged in sequence from bottom to top; wherein the PMMA core layer is a main optical sensing layer, responsible for the transmission and interference of optical signals; the PMMA core layer comprises an input waveguide, a beam splitter, a modulation arm waveguide, a beam combiner and an output waveguide; the modulation arm waveguide comprises a sensing arm and a reference arm, the reference arm comprises a straight waveguide and a tapered waveguide connected at both ends of the straight waveguide, the length of the sensing arm is equal to the sum of the straight waveguide length of the reference arm and the length of two tapered waveguides, the width of the reference arm is greater than the width of the sensing arm, thereby forming an asymmetric structure, a suspended groove is provided below the sensing arm to form a suspended waveguide, a window is formed by opening a window at the corresponding PDMS upper cladding above the sensing arm, so as to be in direct contact with a creatinine solution, and the width of the suspended groove and the width of the window are both greater than the width of the sensing arm; a creatinase mixed solution is fixed on the surface of the sensing arm, and the sensing arm is in direct contact with a substance to be measured at the window.

[0008] Furthermore, the width of the reference arm is 4.8-6.4 μm, and the normalized maximum output optical power is greater than 0.7 au, which is small in size while achieving sensing; the width of the sensor arm is not less than 1 μm, and the length of the sensor arm is 5548-9038 μm.

[0009] The overall size of the sensor is no larger than 1.1cm×0.01cm.

[0010] Furthermore, the depth of the suspended groove is 1-2 μm.

[0011] Furthermore, the beam splitter and the beam combiner are both composed of an MMI coupler and a branch waveguide.

[0012] The beam splitter is composed of a 1×2 MMI coupler and a branch waveguide, and the beam combiner is composed of a 2×1 MMI coupler and a branch waveguide.

[0013] Furthermore, the reference arm is transitionally connected to the branch waveguides of the beam splitter and the beam combiner through a tapered waveguide.

[0014] Furthermore, the creatinine enzyme mixed solution is fixed to the surface of the sensor arm from four directions through a multi-layer cross-linking method; the multi-layer cross-linking method first uses glutaraldehyde solution for preliminary fixation, and on the basis of the preliminary fixation, chitosan or PEG is used to secondarily fix the enzyme molecules to the surface of the sensor arm.

[0015] Furthermore, the creatinase mixed solution comprises creatinase, creatinase and sarcosine oxidase mixed in a volume ratio of 1:1:2, wherein the concentrations of creatinase, creatinase and sarcosine oxidase are 5.3-7.3U / μL, 2.3-2.7U / μL and 1.3-1.7U / μL, respectively, and the three are mixed at a pH of 7.0-8.5.

[0016] Furthermore, the refractive index of the creatinase mixed solution varies in the range of 1.34438-1.34496, corresponding to a creatinine detection concentration range of 0-110 μmoL / L, a detection sensitivity of not less than 950 mW / RIU, and a loss of not more than 2 dB.

[0017] Furthermore, the creatinine sensor is prepared by the following method:

[0018] S1, prepare the PDMS lower cladding layer, PMMA core layer and PDMS upper cladding layer respectively;

[0019] S2, using reactive ion etching process to open windows on the PDMS upper cladding;

[0020] S3, preparing a suspended groove below the sensor arm by using a reactive ion etching process;

[0021] S4. Use a multi-layer cross-linking method to fix the creatinine enzyme mixed solution to the surface of the sensor arm from four directions.

[0022] Further, in S2, the reactive ion etching process uses 200W RF power, SF6:O2=15:30sccm, and an etching rate of 510nm / min;

[0023] In S3, the reactive ion etching process uses 200 W of RF power, SF4:O2=10:15 sccm, and a speed of 140 nm / min;

[0024] In S4, before multi-layer cross-linking, the PDMS upper layer was treated with O2 plasma, and then the device surface was functionalized using a glutaraldehyde solution with a volume concentration of 0.5-1%.

[0025] Compared with the prior art, the creatinine sensor based on the asymmetric Mach-Zehnder structure of the present invention has the following advantages:

[0026] 1. The present invention adopts an asymmetric Mach-Zehnder structure design and an optimized configuration of a suspended sensor arm and a widened reference arm to significantly improve the optical sensitivity of the sensor, and can detect a wide range of creatinine concentrations of 0-110 μmoL / L, covering and exceeding the physiological creatinine concentration range of the human body. It is suitable for creatinine concentration detection under different physiological states and various special needs, and expands the application field.

[0027] 2. The present invention adopts multi-layer cross-linking technology to fix creatinase, creatinase and sarcosine oxidase on the surface of the sensor arm. The enzyme activity is effectively maintained through the primary fixation with glutaraldehyde solution and the secondary fixation with chitosan or PEG derivatives, thereby improving the long-term stability and reusability of the sensor. At the same time, through the optimization design of the sensor arm length and the overall structure, a compact design is achieved, which is suitable for portable and integrated applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The accompanying drawings constituting a part of the present invention are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the accompanying drawings:

[0029] Figure 1 3D schematic diagram of the creatinine sensor based on the asymmetric Mach-Zehnder structure according to the present invention;

[0030] Figure 2 It is a three-dimensional exploded view of the creatinine sensor based on the asymmetric Mach-Zehnder structure of the present invention and a schematic diagram of the enlarged structure of part A;

[0031] Figure 3 is a flow chart of the preparation of the creatinine sensor based on the asymmetric Mach-Zehnder structure of the present invention;

[0032] Figure 4 is a curve diagram showing the relationship between the output optical power and the refractive index change of the creatinine sensor based on the asymmetric Mach-Zehnder structure of the present invention;

[0033] Figure 5 It is a graph showing the relationship between creatinine concentration and refractive index change;

[0034] Figure 6 It is a light field diagram of each part of the creatinine sensor based on the asymmetric Mach-Zehnder structure of the present invention;

[0035] Figure 7 The sensitivity comparison diagram of the creatinine sensor based on the asymmetric Mach-Zehnder structure of the present invention under three different sensor arm structures: (a) is only the upper surface of the exposed sensor arm, (b) is the upper surface and side surface of the exposed sensor arm, and (c) is the four surfaces of the exposed sensor arm from top to bottom and left to right;

[0036] Figure 8 1 is a sensitivity comparison diagram of the creatinine sensor based on the asymmetric Mach-Zehnder structure of the present invention before and after the reference arm is widened; (a) is the sensitivity before widening, and (b) is the sensitivity after widening;

[0037] Fig. 9 1 is a schematic diagram comparing the output optical powers of the reference arm of the creatinine sensor based on the asymmetric Mach-Zehnder structure of the present invention at different widths;

[0038] Fig.10 It is a schematic diagram comparing the output optical powers of the sensing arms of the creatinine sensor based on the asymmetric Mach-Zehnder structure described in the present invention at different lengths.

[0039] Reference numerals:

[0040] 1. PMMA core layer, 2. PDMS lower cladding layer, 3. PDMS upper cladding layer, 4. Input waveguide, 5. 1×2 MMI coupler, 6. Branch waveguide, 7. Reference arm, 8. Sensing arm, 9. Suspended slot, 10. Window, 11. 2×1 MMI coupler, 12. Output waveguide, 13. Creatinase mixed solution. DETAILED DESCRIPTION

[0041] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments may be combined with each other.

[0042] In the description of the present invention, it should be understood that the terms "center", "longitudinal", "lateral", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside" and the like indicate positions or positional relationships based on the positions or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as limiting the present invention. In addition, the terms "first", "second", and the like are only used for descriptive purposes, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, features defined as "first", "second", and the like may explicitly or implicitly include one or more of the features. In the description of the present invention, unless otherwise specified, "multiple" means two or more.

[0043] In the description of the present invention, it should be noted that, unless otherwise clearly specified and limited, the terms "installed", "connected", and "connected" should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection, or it can be indirectly connected through an intermediate medium, or it can be the internal communication of two components. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood by specific circumstances.

[0044] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0045] Explanation of terms: PDMS: polydimethylsiloxane; PMMA: polymethyl methacrylate; MMI: multimode interference; PBS: phosphate; PEG: polyethylene glycol.

[0046] Example 1 Creatinine Sensor

[0047] The three-dimensional structure of the creatinine sensor based on the asymmetric Mach-Zehnder structure is shown in Figure 2. Figure 1-2 As shown, it includes a PDMS lower cladding 2, a PMMA core layer 1 and a PDMS upper cladding 3 arranged in sequence from bottom to top; wherein the PMMA core layer 1 is the main optical sensing layer, responsible for the transmission and interference of optical signals; the PMMA core layer 1 includes an input waveguide 4, a beam splitter, a modulation arm waveguide, a combiner and an output waveguide 12; the beam splitter is composed of a 1×2 MMI coupler 5 and a branch waveguide 6, and the combiner is composed of a 2×1 MMI coupler 11 and a branch waveguide 6; the modulation arm waveguide includes a sensing arm 8 and a reference arm 7, and the reference arm 7 is composed of a straight waveguide and The sensor arm 8 is composed of tapered waveguides connected at both ends of the straight waveguide. The length of the sensor arm 8 is equal to the sum of the straight waveguide length of the reference arm 7 and the length of the two tapered waveguides. In order to optimize the phase change of the interference signal, the width of the reference arm 7 is widened relative to the sensor arm 8 to form an asymmetric structure. The straight waveguide width of the reference arm 7 is 5.6 μm, and the width of the tapered waveguide gradually narrows. The maximum width of the tapered waveguide is 5.6 μm, the minimum width of the tapered waveguide is 1.6 μm, the width of the sensor arm 8 is 1.6 μm, and the length of the sensor arm 8 is 8748 μm. By widening the reference arm 7, reducing its optical sensitivity, so that the phase change of the interference signal is mainly caused by the change of the optical characteristics of the sensor arm 8, thereby improving the sensitivity of the sensor; in order to reduce the optical loss at the connection caused by the widening design of the reference arm 7, the present invention adopts a tapered waveguide structure at the connection between the reference arm 7 and the branch waveguide 6, and through the tapered waveguide transition, the connection between waveguides of different widths is effectively smoothed, the optical loss is reduced, and the transmission of the optical signal is ensured; the PDMS lower cladding 2 corresponding to the lower part of the sensor arm 8 is etched to obtain a suspended groove 9 to form a suspended waveguide The depth of the suspended groove 9 is 1 μm, thereby ensuring that more evanescent fields are in contact with the creatinine solution; the PDMS upper cladding 3 corresponding to the sensing arm 8 is opened to form a window 10 so as to be in direct contact with the creatinine solution, and the width of the suspended groove 9 and the width of the window 10 are both greater than the width of the sensing arm 8, so that the creatinine solution is in all-round contact with the sensing arm 8 in four directions of up, down, left and right, thereby enhancing the sensitivity to the change of the refractive index of creatinine; a creatinine enzyme mixed solution 13 is fixed on the surface of the sensing arm 8, and the sensing arm 8 is in direct contact with the substance to be tested at the window 10.

[0048] The creatinase mixed solution 13 is fixed to the surface of the sensor arm 8 from four directions by a multi-layer cross-linking method; the multi-layer cross-linking method first uses a glutaraldehyde solution for preliminary fixation, and then uses chitosan or PEG to fix the enzyme molecules to the surface of the sensor arm 8 for a secondary fixation, effectively maintaining the activity of the enzyme. The creatinase mixed solution 13 contains creatinase, creatinase, and sarcosine oxidase mixed in a volume ratio of 1:1:2, wherein the concentrations of creatinase, creatinase, and sarcosine oxidase are 6U / μL, 2.5U / μL, and 1.6U / μL, respectively, and the three are mixed under a pH of 7.5.

[0049] When light is transmitted on the sensor arm 8, the effective refractive index of the evanescent field changes on the sensor arm 8 due to the fixed creatinase mixed solution 13, and the optical power at the port of the output waveguide 12 changes. By detecting the change of optical power in the linear region, the creatinine content in the solution can be calculated.

[0050] The thickness of the PDMS lower cladding 2 and the PDMS upper cladding 3 are both 10 μm, and the refractive index is 1.41. The refractive index of the PMMA core layer 1 is 1.488. The initial refractive index of the creatinase mixed solution 13 is 1.34575, which is smaller than the refractive index of the PMMA core layer 1, satisfying the total reflection condition.

[0051] Figure 3 This is a preparation flow chart of a creatinine sensor based on an asymmetric Mach-Zehnder structure. The overall preparation process of the device mainly includes spin coating, etching, vacuum evaporation, PDMS surface modification, PDMS upper cladding 3 window opening, dry etching of suspended grooves 9, and suspended modification. The PMMA core layer pattern is masked by a stepper UV lithography machine, and its minimum line width is 1µm, which meets the design requirements.

[0052] The preparation method specifically comprises the following steps:

[0053] (1) Prepare the substrate:

[0054] Based on the characteristics of polymer materials, 2-inch indium tin oxide was selected as the substrate, and then ultrasonic cleaning was performed using polytetrafluoroethylene, ethanol, acetone and deionized water in sequence.

[0055] (2) Preparation of PDMS lower cladding:

[0056] The PDMS lower cladding prepolymer and curing agent were mixed evenly in a volume ratio of 6:1, and a 10 μm thick PDMS lower cladding layer 2 was formed by spin coating at a low speed of 500 r / min for 5 seconds and then at a high speed of 4700 r / min for 100 seconds using a glue spreader; then it was placed on a heating table, first heated at 80 ° C for 5 minutes, and then heated at 110 ° C for 25 minutes to complete the curing. Subsequently, the PDMS lower cladding layer 2 film was treated with O2 plasma at a power of 500 W for 5 minutes using a plasma cleaner. Finally, it was immersed in a silanization agent γ-(2,3-epoxypropoxy)propyltrimethoxysilane with a volume fraction of 2% for 1 hour.

[0057] (3) Preparation of PMMA core layer:

[0058] The coating was firstly spin-coated at a low speed of 500 r / min for 5 seconds using a coating machine, and then spin-coated at a high speed of 3000 r / min for 60 seconds to form a core layer with a thickness of 1 μm. Subsequently, the coating was allowed to stand at room temperature for 1 hour, and then heat cured on a heating platform at 65°C for 10 minutes.

[0059] (4) Etching of PMMA core layer:

[0060] The core layer pattern was prepared by reactive ion etching process, and the etching parameters were set as 200W RF power, SF4:O2=10:15sccm, and 140nm / min rate during the operation. Finally, the surface modification of the chip was completed by using a plasma cleaner with 500W power for 30s.

[0061] (5) Preparation of PDMS upper layer:

[0062] The PDMS upper cladding layer 3 is made of the same material as the PDMS lower cladding layer 2, and the preparation process parameters are consistent with those of the PDMS lower cladding layer 2, and the spin coating thickness is 10 μm. Subsequently, the PDMS upper cladding layer 3 film is treated with O2 plasma for 60 seconds using a plasma cleaning machine with a power of 500 W to complete the modification operation.

[0063] (6) Window processing:

[0064] The PDMS upper cladding layer 3 was windowed by reactive ion etching process. During the operation, the RF power was set to 200 W, SF6:O2=15:30 sccm, and the etching rate was 510 nm / min. The etching depth was 10 µm.

[0065] (7) Etching suspended grooves:

[0066] The suspended groove 9 below the sensor arm 8 is prepared by reactive ion etching process, and alignment is achieved with the help of reserved positioning marks. Then, a dry etching process is used, with 200W RF power, SF4:O2=10:15sccm, and a speed of 140nm / min, to etch a depth of 1μm below the sensor arm 8.

[0067] The depth of the suspended groove may be 1-2 μm. In this embodiment, an etching depth of 1 μm is selected. The reasons for selecting this depth range are as follows:

[0068] First, this range can not only meet the process requirements, reduce manufacturing process defects, and ensure the basic performance and quality of the device, but also avoid problems such as reduced coupling efficiency, increased background noise, and easy arm breakage caused by excessive suspension height; second, it is conducive to the detection solution to diffuse smoothly to the enzyme active site, thereby ensuring that creatinine and the creatinine enzyme mixed solution 13 react fully.

[0069] (8) Dangling modifier:

[0070] First, a plasma cleaning machine is used to perform O2 plasma treatment on the PDMS upper cladding layer 3 to clean the surface and improve its hydrophilicity; then, a glutaraldehyde solution with a concentration of 0.5-1% is used to functionalize the device surface. Specifically, in this embodiment, the glutaraldehyde solution is prepared by mixing 0.1 mL 50% glutaraldehyde and 4.9 µL PBS.

[0071] Next, in a weakly alkaline environment with a pH of 7.5 and a temperature of 25°C, a multilayer cross-linking method is used to initially fix the enzyme with a glutaraldehyde solution, using the dialdehyde group of glutaraldehyde to form a covalent bond with the amino group of the enzyme molecule to achieve initial fixation. The enzyme is allowed to stand for 40 minutes. After the glutaraldehyde on the surface of the sensor arm 8 is completely dry, chitosan or PEG is used for secondary fixation to enhance the activity of the enzyme, improve the binding strength between the enzyme and the surface of the sensor arm 8, ensure that the enzyme activity is more stable, and thereby make the sensor more reliable in detection.

[0072] Under this condition, the prepared creatinine enzyme mixed solution 13 is fixed to the surface of the sensor arm 8 from four directions to complete the fixation operation of the creatinine enzyme on the sensor arm at the window opening to ensure the activity and fixation effect of the enzyme.

[0073] The creatinine sensor prepared in this example was used to detect creatinine solutions of different concentrations, and the results were Figure 4 and Figure 5 .

[0074] Figure 4 is a graph showing the output optical power of a creatinine sensor based on an asymmetric Mach-Zehnder structure versus the refractive index; Figure 5This is a curve chart showing the relationship between creatinine concentration and refractive index change. In the refractive index change range of 1.34438-1.34496, the corresponding creatinine concentration detection range is 0-110μmoL / L, and the creatinine concentration and refractive index change are linear. As can be seen from the figure, within the target refractive index range (1.34438-1.34496), as the refractive index increases, the output optical power increases from 0.033 to 0.846, and the linearity is good. Figure 4 and Figure 5 This shows that the variation of the output light power and the refractive index can also reflect the variation of the output light power and the creatinine concentration, and they are also linearly related, indicating that the creatinine sensor with an asymmetric Mach-Zehnder structure can detect creatinine of different concentrations.

[0075] Figure 6 TABLE 1 creatinine sensor based on asymmetric Mach-Zehnder structure has an overall size of 9830.7 μm × 69.7 μm, and its parameters are shown in Table 1.

[0076] Table 1 Parameters of MZI creatinine sensor

[0077]

[0078] Example 2 Influence of sensor arm structure

[0079] In order to study the sensitivity of different sensor arm structures, three experimental comparisons were conducted, such as Figure 7 shown. Figure 7 In (a), the upper surface of the sensor arm, where only the creatinase mixed solution is immobilized, is in contact with the creatinine solution. Figure 7 (b) The upper surface and two side surfaces of the sensor arm on which the creatinase mixed solution is fixed are in contact with the creatinine solution. Figure 7 (c) The sensor arm fixed with the creatinase mixed solution is in full contact with the creatinine solution in four directions, namely, Figure 7 (a) and Figure 7 (b) No suspended groove is set, and it is directly in contact with the PDMS lower cladding. Figure 7 (c) A suspended groove is provided.

[0080] The extinction ratio describes the intensity difference between different polarization states (such as horizontal and vertical polarization) in the output light wave after the input light wave passes through the MZI. For the MZI, the extinction ratio should be as large as possible so that it can respond significantly to different creatinine solution concentrations.

[0081] The formula for extinction ratio is:

[0082] ;

[0083] In the formula Emax is the maximum output optical power, E min is the minimum output optical power.

[0084] exist Figure 7 In (a), within the target refractive index range (1.34438-1.34496), the normalized output optical power changes from 0.429 to 0.574, and its extinction ratio is The extinction ratio is low, which indicates that the sensing arm 8 in contact with the upper surface can only interact with the creatinine solution to a limited extent, resulting in reduced sensitivity and the extinction ratio failing to reach an ideal value.

[0085] exist Figure 7 In (b), within the target refractive index range (1.34438-1.34496), the normalized output optical power changes from 0.126 to 0.645, and its extinction ratio is .and Figure 7 Compared with (a), this contact mode increases the contact area between the sensor arm 8 and the creatinine solution, thereby improving the sensitivity. Figure 7 (a) is somewhat expanded and shows a certain sensitivity improvement, proving the role of side contact.

[0086] exist Figure 7 (c) further shows the situation where the creatinine solution is in contact with the upper and lower sides and both sides of the sensor arm 8. At this time, the sensor arm 8 is suspended, and the creatinine solution fully wraps the sensor arm 8. The normalized output optical power changes from 0.105 to 0.689 within the target refractive index range (1.34438-1.34496), and its extinction ratio is , the sensitivity is improved, and the extinction ratio reaches the maximum value, indicating that under this contact mode, the contact between the creatinine solution and the sensor arm 8 is the most complete, providing the strongest interaction, which greatly enhances the detection performance of the sensor.

[0087] Example 3 Effect of reference arm width

[0088] In order to study the influence of the reference arm width on the sensitivity of the sensing arm, a comparison was made before and after the reference arm was widened. At the same time, straight waveguides with reference arms of different widths were set up for comparison, namely 4.8μm, 5.2μm, 5.6μm and 6.4μm.

[0089] 1. Comparison of reference arm before and after widening

[0090] For MZI optical waveguide sensors, their sensitivity is usually divided into device sensitivity ( S d ) and waveguide sensitivity ( S w). The device sensitivity is mainly related to the overall performance of the sensor, while the waveguide sensitivity is closely related to the design of the waveguide structure.

[0091] Device sensitivity S d The sensor output optical power change The change in effective refractive index corresponding to the concentration of the substance to be measured Ratio of:

[0092] ;

[0093] Waveguide sensitivity S w The definition is as follows:

[0094] ;

[0095] in, It indicates the change of effective refractive index corresponding to the concentration of the substance to be measured. Indicates the change in the refractive index of the cladding. Waveguide sensitivity directly affects the optical response capability of the sensor. The sensing arm 8 should have a higher waveguide sensitivity, while the reference arm 7 needs to have a lower waveguide sensitivity. Ideally, the waveguide sensitivity of the reference arm 7 should be close to zero to avoid interfering with the measurement signal of the sensing arm 8.

[0096] Figure 8 (a) shows the sensitivity when the reference arm is not widened. At this time, the widths of the reference arm 7 and the sensing arm 8 are equal, both 1.6 μm. In the target refractive index range (1.34438-1.34496), the normalized maximum and minimum output optical powers are 0.747 au and 0.187 au, respectively. Normalized output optical power and the actual output optical power E Satisfaction between , The input optical power used in the simulation is 1mW. Since the input optical power = the reference optical power, it can be known that the reference optical power is 1mW. Then the maximum actual output optical power and the minimum actual output optical power can be obtained as 0.747mW and 0.187mW respectively. The sensitivity is , where RIU is the abbreviation of Refractive Index Unit. Since the waveguide widths of the reference arm 7 and the sensing arm 8 are the same, the waveguide sensitivities of the two are relatively close, so the overall optical power response of the sensor is relatively sensitive, but there is still some interference in the sensitivity of the reference arm.

[0097] Figure 8(b) shows the sensitivity after widening the reference arm waveguide. In the target refractive index range (1.34438-1.34496), the sensitivity is increased to 1106.90mW / RIU. By widening the waveguide of the reference arm, the waveguide sensitivity of the reference arm is effectively reduced, and the sensitivity of the sensing arm is relatively improved, which optimizes the performance of the sensor. By adjusting the structural difference between the reference arm and the sensing arm, the sensitivity of the sensing arm is enhanced, and the interference of the reference arm on the sensing signal is reduced, thereby further improving the accuracy and stability of the sensor.

[0098] 2. Different reference arm widths

[0099] Fig. 9 This is a comparison of the output optical power response of the creatinine sensor based on the asymmetric Mach-Zehnder structure at different reference arm widths. The figure shows the changes in the output optical power of the sensor at different refractive indices when the width of the reference arm straight waveguide is 4.8μm, 5.2μm, 5.6μm and 6.4μm respectively. The results show that within the width range of the reference arm 7, as the width of the reference arm straight waveguide increases, the maximum normalized output optical power of the sensor first increases and then decreases. When the width of the reference arm 7 is 5.6μm, the normalized output optical power reaches the maximum, and the maximum normalized output optical power is close to 0.85au.

[0100] Example 4 Effect of sensor arm length

[0101] In order to study the influence of the sensor arm length on the sensitivity of the sensor arm, sensor arms of different lengths were set up for comparison, namely 5548μm, 7418μm, 8748μm, and 9038μm. The lengths of the straight waveguides of the corresponding reference arms were 5510μm, 7380μm, 8710μm, and 9000μm, respectively.

[0102] Fig.10 It is a comparison chart of the output optical power of the sensing arm of the creatinine sensor based on the asymmetric Mach-Zehnder structure at different lengths. Table 2 shows the minimum and maximum normalized output optical power and sensitivity at different arm lengths.

[0103] The results show that the refractive index of creatinine solution varies within the range of 1.34438-1.34496, the normalized maximum output optical power is greater than 0.7 au, and the linearity increases linearly with the increase of arm length. When the arm length is in the range of 5548-9038 μm, in the target refractive index range (1.34438-1.34496), the refractive index change and the optical power change are both linearly related, which can meet the sensing requirements. When the length of the sensor arm 8 is 8748 μm, the output optical power not only shows a monotonic change, but also has the best linearity of the normalized output optical power and excellent sensitivity. Therefore, the length of the sensor arm 8 is selected to be 8748 μm.

[0104] Table 2 Comparison results of different sensor arm lengths

[0105]

[0106] The creatinine sensor described in the present invention has a wide creatinine concentration detection range, can work effectively in the concentration range of 0-110μmoL / L, covers and exceeds the physiological creatinine concentration of the human body, and is suitable for creatinine concentration detection needs of different physiological states and various special needs. Through the optimization of structural design and enzyme immobilization method, the sensitivity of the sensor within this detection range is not less than 950mW / RIU, and it can detect slight concentration changes, meeting the full range detection requirements of creatinine concentration from low to high. In order to meet the requirements of portable and integrated applications, the present invention strictly controls the size of the sensor arm and the overall structure. The length of the sensor arm does not exceed 9100μm, and the overall size of the sensor is controlled within 1.1cm×0.01cm. It has the advantage of compact structure and is suitable for applications in biomedicine and special needs creatinine concentration detection.

[0107] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A creatinine sensor based on an asymmetric Mach-Zehnder structure, characterized in that: It includes a PDMS lower cladding, a PMMA core layer and a PDMS upper cladding which are arranged in sequence from bottom to top; wherein the PMMA core layer includes an input waveguide, a beam splitter, a modulation arm waveguide, a beam combiner and an output waveguide; the modulation arm waveguide includes a sensing arm and a reference arm, the reference arm consists of a straight waveguide and a tapered waveguide connected at both ends of the straight waveguide, the length of the sensing arm is equal to the sum of the length of the straight waveguide of the reference arm and the length of two tapered waveguides, the width of the reference arm is greater than the width of the sensing arm to form an asymmetric structure, a suspended groove is provided below the sensing arm to form a suspended waveguide, a window is formed by opening a window at the corresponding PDMS upper cladding above the sensing arm to facilitate direct contact with a creatinine solution, and the width of the suspended groove and the width of the window are both greater than the width of the sensing arm; a creatinase mixed solution is fixed on the surface of the sensing arm in the window area to directly contact with the substance to be tested.

2. The creatinine sensor based on the asymmetric Mach-Zehnder structure according to claim 1, characterized in that: The width of the reference arm is 4.8-6.4 μm, the width of the sensing arm is not less than 1.0 μm, and the length of the sensing arm is 5548-9038 μm.

3. The creatinine sensor based on the asymmetric Mach-Zehnder structure according to claim 1, characterized in that: The depth of the suspended groove is 1-2 μm.

4. The creatinine sensor based on the asymmetric Mach-Zehnder structure according to claim 1, characterized in that: Both the beam splitter and the beam combiner are composed of MMI couplers and branch waveguides.

5. The creatinine sensor based on the asymmetric Mach-Zehnder structure according to claim 4, characterized in that: The reference arm is transitionally connected to the branch waveguides of the beam splitter and the beam combiner through a tapered waveguide.

6. The creatinine sensor based on the asymmetric Mach-Zehnder structure according to claim 1, characterized in that: The creatinine enzyme mixed solution was fixed to the surface of the sensor arm from four directions by a multi-layer cross-linking method; The multi-layer cross-linking method first uses glutaraldehyde solution for preliminary fixation. Based on the preliminary fixation, chitosan or PEG is used to secondarily fix the enzyme molecules to the surface of the sensor arm.

7. The creatinine sensor based on the asymmetric Mach-Zehnder structure according to claim 1, characterized in that: The creatinase mixed solution contains creatinase, creatinase and sarcosine oxidase mixed in a volume ratio of 1:1:2, wherein the concentrations of creatinase, creatinase and sarcosine oxidase are 5.3-7.3U / μL, 2.3-2.7U / μL and 1.3-1.7U / μL, respectively, and the three are mixed at a pH of 7.0-8.

5.

8. The creatinine sensor based on the asymmetric Mach-Zehnder structure according to claim 1, characterized in that: The refractive index of the creatinine enzyme mixed solution varies in the range of 1.34438-1.34496, corresponding to a creatinine detection concentration range of 0-110 μmoL / L, a detection sensitivity of not less than 950 mW / RIU, and a loss of not more than 2 dB.

9. The creatinine sensor based on the asymmetric Mach-Zehnder structure according to claim 1, characterized in that: The creatinine sensor is prepared by the following method: S1, prepare the PDMS lower cladding layer, PMMA core layer and PDMS upper cladding layer respectively; S2, using reactive ion etching process to open windows on the PDMS upper cladding; S3, preparing a suspended groove below the sensor arm by using a reactive ion etching process; S4. Use a multi-layer cross-linking method to fix the creatinine enzyme mixed solution to the surface of the sensor arm from four directions.

10. The creatinine sensor based on the asymmetric Mach-Zehnder structure according to claim 9, characterized in that: In S2, the reactive ion etching process uses 200 W of RF power, SF6:O2=15:30 sccm, and an etching rate of 510 nm / min; In S3, the reactive ion etching process uses 200 W of RF power, SF4:O2=10:15 sccm, and a speed of 140 nm / min; In S4, before multi-layer cross-linking, the PDMS upper layer was treated with O2 plasma, and then the device surface was functionalized using a glutaraldehyde solution with a volume concentration of 0.5-1%.

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