Cancer multispecific marker optical fiber sensor system and demodulation method

Abstract

The invention discloses a cancer multispecific marker optical fiber sensor system and a demodulation method, and belongs to the field of optical fiber biosensors, the system comprises a laser, a junction box, a sensing unit, a photoelectric detector group and a demodulation unit which are connected in sequence, the sensing unit comprises a plurality of micro-nano optical fiber sensors, the tail end of the micro-nano fiber is a high-reflection chirped fiber grating. The ultra-low detection limit and high-sensitivity detection of the cancer specific marker are realized through the high refractive index sensitivity of the micro-nano optical fiber sensor structure, so that the detection of the low-concentration specific marker is realized; meanwhile, the same or different cancer specific marker antibodies can be fixed on the surface of each micro-nano optical fiber sensor, and signal transmission is performed in combination with a time division multiplexing mode, so that simultaneous sensing of multiple specific markers or multi-part measurement of the same marker can be realized, misdiagnosis and missed diagnosis caused by single marker detection are further reduced, and the detection accuracy is improved. Meanwhile, the same marker is measured for multiple times, so that the detection reliability is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of fiber optic biosensors, and particularly to a fiber optic sensor system and demodulation method for multiple cancer-specific markers. Background Art

[0002] Among multiple markers for cancer diagnosis, carcinoembryonic antigen (CEA) is a glycoprotein widely used in the detection of tumor markers, especially in the diagnosis and monitoring of various cancers such as colorectal cancer, breast cancer, and lung cancer. Generally speaking, the CEA content in the serum of 97% of healthy adults is lower than 2.5 ng / ml, and a CEA content exceeding this standard threshold may indicate the occurrence of cancer.

[0003] Currently, relevant scholars have proposed an early detection scheme for cancer-specific markers based on fiber optic sensing, achieving rapid and simple detection of cancer-specific markers. However, limited by the low refractive index sensitivity of fiber Bragg gratings (RUI: 1.30 - 1.40) and the high cost and complexity of detection instruments, the detection of low-concentration specific markers and early diagnosis of cancer have not been achieved. For example, in 2024, Wanmei Guo et al. used nanobodies as biological probes to prepare two CEA sensors of graphene oxide (GO) and gold nanoparticles (GNP) on an S-tapered fiber (STF), with detection limits of 0.05 nM and 0.02 nM respectively; in 2023, Ling Chen et al. prepared a CEA biosensor with a detection limit of 36.14 fg / mL on an SMF fiber based on the Fabry-Perot interferometer and vernier effect, and the response time was less than 30 minutes; in 2024, Luxiao Sang et al. proposed a CEA sensor based on the resonant optical tunneling effect (ROTE), with a detection limit of 0.5 ng / ml.

[0004] In addition, many cancer-specific markers do not only appear in specific cancers but may also increase in other benign diseases or physiological states. For example, carcinoembryonic antigen CEA not only increases in various cancers such as colorectal cancer, breast cancer, and lung cancer but may also increase in some benign diseases such as inflammation. Cancer cannot be diagnosed solely based on its increase. Moreover, in the early stage of cancer, the number of tumor cells is small, and the concentration of markers released into biological samples such as blood may be very low. Existing detection technologies are difficult to accurately detect, resulting in negative marker detection results for some early cancer patients and missed diagnoses. Summary of the Invention

[0005] The purpose of the present invention is to overcome the problems of the prior art and provide a fiber optic sensor system and demodulation method for multiple cancer-specific markers.

[0006] The object of the present invention is achieved by the following technical solutions: A fiber optic sensor system for cancer multi-specific markers, the system includes a laser, a splitter box, a sensing unit, a photodetector group and a demodulation unit connected in sequence. The laser outputs lasers of different wavelengths. The sensing unit includes a number of micro-nano fiber optic sensors. The end of the micro-nano fiber in the micro-nano fiber optic sensor is a high-reflection chirped fiber grating. The same or different cancer-specific marker antibodies are fixed on the surface of each micro-nano fiber, which are used to react with the cancer-specific markers in the test reagent. The micro-nano fiber optic sensor transmits different wavelength lasers with the reflected light intensity changed after reaction through the high-reflection chirped fiber grating based on the time division multiplexing method. The photodetector group detects different wavelength lasers with the changed light intensity and converts them into electrical signals. The demodulation unit processes the electrical signals according to the differential demodulation algorithm, demodulates the central wavelength drift of each micro-nano fiber optic sensor, and further obtains the concentration of the cancer-specific markers.

[0007] In one example, the system further includes a control unit, which is connected to the laser and used to regulate the tunable filter of the laser, so as to make the laser output lasers of different wavelengths.

[0008] In one example, the surface of the micro-nano fiber is modified by two-dimensional materials.

[0009] In one example, the micro-nano fiber is a high-reflection chirped fiber grating in the 2-3μm band.

[0010] In one example, the laser is a 2-3μm continuously tunable narrow bandwidth laser.

[0011] In one example, the system further includes a calibration unit connected to the demodulation unit and the splitter box. The calibration unit includes a calibration optical fiber encapsulated in a constant temperature module, which is used to correct the output error of the laser and / or the cross-sensitivity error caused by environmental temperature and strain.

[0012] In one example, the system further includes a differential signal acquisition unit. The photodetector group is connected to the demodulation unit through the differential signal acquisition unit.

[0013] The present invention also includes a demodulation method, which is implemented based on the cancer multi-specific marker fiber optic sensor system formed by any one of the above examples or a combination of multiple examples. The method includes the following steps:

[0014] According to the interference spectrum model, select three initial spectral feature points, namely the zero point, the peak point and the middle point, and calculate the phase difference and the interference spectrum intensity of the three feature points.

[0015] Calculate the phase difference and the interference spectrum intensity of the three feature points after the spectrum undergoes redshift.

[0016] The demodulation signal is calculated based on the interference spectral intensities of three feature points, and then the central wavelength drift of each micro-nano fiber sensor is obtained based on the demodulation signal;

[0017] Based on the central wavelength drift, combined with the pre-established mathematical model, the concentration of the cancer-specific marker is obtained; the mapping relationship between the central wavelength drift and the known concentration value of the cancer-specific marker is stored in the mathematical model.

[0018] In one example, the calculation expression of the demodulation signal is:

[0019]

[0020] where S represents the demodulation signal; the coefficient B = 2I1I2, I1 represents the fundamental mode optical intensity, I2 represents the high-order mode optical intensity in the micro-nano fiber; k represents a constant; λ represents the wavelength; Δλ represents the spectral red shift.

[0021] It should be further noted that the technical features corresponding to the above examples can be combined with each other or replaced to form a new technical solution.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] 1. In one example, through the high refractive index sensitivity of the micro-nano fiber structure, an ultra-low detection limit and high-sensitivity detection of cancer-specific markers are achieved, and then the detection of low-concentration specific markers is realized to assist in the early diagnosis of cancer; at the same time, the same or different cancer-specific marker antibodies can be immobilized on the surface of each micro-nano fiber, and signal transmission is carried out in combination with the time-division multiplexing method, enabling the simultaneous sensing of multiple specific markers or multiple measurements of the same marker, thereby reducing misdiagnosis and missed diagnosis caused by single marker detection. At the same time, multiple measurements of the same marker are carried out, which can improve the reliability of detection.

[0024] In addition, through the differential demodulation method, the detection of highly integrated cancer-specific markers is realized, solving the problems of insufficient detection limit, low sensitivity, and long response time of traditional optical detection methods, and having the advantages of high integration, low cost, easy operation, and good performance. At the same time, the complexity of the fiber optic sensing system is simplified, and expensive spectrometers and other detection equipment are not required, reducing the system cost.

[0025] 2. In one example, the tunable filter of the 2-3μm continuously tunable narrow-bandwidth laser is controlled by the control unit to realize the output of different wavelength lasers at certain wavelength intervals.

[0026] 3. In one example, by introducing two-dimensional materials on the fiber surface, the binding sites of specific marker antibodies on the fiber surface can be increased, the affinity coefficient and response time of the sensing unit can be improved, and the dissociation coefficient can be reduced.

[0027] 4. In one example, the demodulation method is implemented based on the three-wavelength differential demodulation technique. By selecting three wavelengths of the initial spectrum and performing differential demodulation on the improved spectral model, it can solve the problem that the free spectral range of the interference spectrum between the fundamental mode and the high-order mode of the micro-nano optical fiber increases with the increase of wavelength. Furthermore, it can more accurately calculate the wavelength drift amount, effectively reduce errors, and improve the demodulation accuracy. Description of the Drawings

[0028] The following further elaborates on the specific implementation manners of the present invention in conjunction with the drawings. The drawings described herein are used to provide a further understanding of the present application and constitute a part of the present application. The same reference numerals are used to represent the same or similar parts in these drawings. The schematic embodiments of the present application and their descriptions are used to explain the present application and do not constitute an improper limitation to the present application.

[0029] Figure 1 System block diagram provided for an example of the present invention;

[0030] Figure 2 System block diagram provided for another example of the present invention;

[0031] Figure 3 Flowchart of the surface modification treatment of the micro-nano optical fiber provided for an example of the present invention;

[0032] Figure 4 Schematic diagram of the structure of the micro-nano optical fiber provided for an example of the present invention;

[0033] Figure 5 Spectrum diagram of the micro-nano optical fiber provided for an example of the present invention in air;

[0034] Figure 6 Schematic diagram of the spectral drift of the micro-nano optical fiber in different refractive index solutions provided for an example of the present invention;

[0035] Figure 7 Schematic diagram of the linear fitting of the refractive index sensitivity of the micro-nano optical fiber provided for an example of the present invention;

[0036] Figure 8 Schematic diagram of the change of the characteristic wavelength of the micro-nano optical fiber sensor provided for an example of the present invention under different CEA concentrations;

[0037] Figure 9 Schematic diagram of the wavelength drift amount detected by the sensor provided for an example of the present invention;

[0038] Figure 10 Langmuir fitting curve graph provided for an example of the present invention;

[0039] Figure 11Graph showing the logarithmic relationship between the solution concentration and the wavelength drift amount provided for an example of the present invention;

[0040] Figure 12 Graph showing the specific detection results of the sensor provided for an example of the present invention;

[0041] Figure 13 Schematic diagram showing the refractive index demodulation result provided for an example of the present invention. Detailed implementation manners

[0042] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are some but not all of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts shall fall within the protection scope of the present invention.

[0043] In the description of the present invention, it should be noted that the directions or positional relationships indicated by terms such as "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc. are based on the directions or positional relationships shown in the drawings. This is 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 thus cannot be construed as a limitation of the present invention. In addition, the use of ordinal numbers (for example, "first and second", "first to fourth", etc.) is to distinguish objects and is not limited to this order, and cannot be construed as indicating or implying relative importance.

[0044] In the description of the present invention, it should be noted that unless otherwise clearly specified and limited, the terms "installation", "connection", and "connection" 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 directly connected or indirectly connected through an intermediate medium, and it can be the communication inside two elements. For those of ordinary skill in the art, the specific meanings of the above terms in the present invention can be understood according to specific situations.

[0045] In addition, the technical features involved in different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0046] In one example, as Figure 1As shown in the figure, a cancer multi-specific marker fiber optic sensor system includes a laser, a splitter box, a sensing unit, a photodetector group, and a demodulation unit connected in sequence. Among them, the laser is used to output lasers with different wavelengths (multi-wavelength lasers), such as dual-wavelength lasers. In this example, it is preferably a laser that outputs lasers with three central wavelengths λ1, λ2, and λ3 at a certain interval, and the input powers of the three-wavelength lasers are P1, P2, and P3 respectively. Preferably, the laser is a 2-3μm continuously tunable narrow-bandwidth laser. The splitter box is used to perform equal-proportion beam splitting on the laser. The specific beam splitting ratio can be adaptively adjusted according to the actual application scenario, and the split laser is transmitted to the sensing unit. The sensing unit includes several micro-nano fiber optic sensors. The micro-nano fiber optic sensor includes a micro-nano fiber, and the end of the micro-nano fiber is a high-reflection chirped fiber grating. Preferably, a 2-3μm band high-reflection chirped fiber grating is added to the end of the micro-nano fiber. Specifically, a chirped fiber grating corresponding to the 2-3μm band can be inscribed at the end of the micro-nano fiber optic sensor through the ultraviolet femtosecond pulse laser + phase mask technology. The reflectivity of the chirped fiber grating is preferably greater than 99%, and then the transmission spectrum is changed to a reflection spectrum for demodulation to meet the requirements of clinical medical applications and wearable detection technologies. The micro-nano fiber is a fiber whose middle section is thinned to the micro-nano level and the middle section does not include a coating layer. Its free spectral range (FSR) decreases as the fiber diameter decreases. In the present invention, the diameter of the micro-nano fiber is preferably about 6μm. Optionally, in this example, the sensing unit includes 6 micro-nano fiber optic sensors as an example for illustration. The sensing unit includes a TPA (Tissue Polypeptide Antigen) sensor, an SCCA (Squamous Cell Carcinoma Antigen) sensor, a Ca125 (Cancer Antigen 125) sensor, a CYF (cytokeratin fragment) sensor, an NSE (Neuron-Specific Enolase) sensor, and a CEA sensor. The specific number of sensors can be adaptively adjusted according to the actual application scenario. The same or different cancer-specific marker antibodies are fixed on the surfaces of the 6 micro-nano fibers. In this example, different cancer-specific marker antibodies are fixed on the surfaces of the 6 micro-nano fibers, such as TPA antibody, SCCA antibody, Ca125 antibody, CYF antibody, NSE antibody, CEA antibody, etc. When the cancer-specific marker antibodies responding on the surfaces of the sensors react with the corresponding specific markers in the test reagent, the refractive index on the fiber surface changes, and the interference phase between the fundamental mode beam and the high-order mode beam inside the micro-nano fiber optic sensor changes, causing the interference spectrum to drift. As a result, the photodetector group detects lasers with wavelengths of λ1, λ2, and λ3 respectively. At this time, the powers of the three-wavelength lasers change to P1’, P2’, and P3’ respectively.It should be noted that there is a transmission time delay between adjacent micro-nano optical fibers, which can be achieved by sequentially increasing the length of single-mode / multimode transmission optical fibers. As a result, the time for the laser to reach the photodetector group is different, that is, multi-specific markers are simultaneously sensed or multiple measurements of the same marker are realized through the time-division multiplexing (TDM) method. Then, the photodetector group converts the laser power of different wavelengths into electrical signals, and the demodulation unit processes the electrical signals according to the differential demodulation algorithm, such as processing the electrical signals according to the three-wavelength differential demodulation algorithm, demodulating the central wavelength drift of each micro-nano optical fiber sensor, and then obtaining the concentration of the cancer-specific marker, realizing the detection of the cancer-specific marker. At the same time, through the detection results of multiple specific markers of the present invention, the misdiagnosis probability can be reduced.

[0047] In one example, as Figure 2 shown, the system further includes a control unit connected to the laser. In this example, the control unit may include a microprocessor and a drive circuit. The microprocessor controls the drive circuit according to the preset parameter values, adjusts the tunable filter of the laser, thereby regulating the parameters of the laser, and further enabling the laser to output three-wavelength laser.

[0048] In one example, the surface of the micro-nano optical fiber is modified with a two-dimensional material. The two-dimensional material can be molybdenum disulfide (MoS2), etc. The MoS2 thin film can be grown on the surface of the micro-nano optical fiber by methods such as chemical vapor deposition (CVD) to modify the surface of the micro-nano optical fiber, increase the binding sites of specific marker antibodies on the fiber surface, improve the affinity coefficient and response time of the sensing unit, and reduce the dissociation coefficient.

[0049] Specifically, as Figure 3 shown, taking the CEA micro-nano optical fiber sensor as an example, the surface modification of the CEA micro-nano optical fiber sensor includes the following steps:

[0050] 1. Prepare reagents and materials:

[0051] Pure water (RO water), 5% nitric acid (HNO3), 1 mol / L sodium hydroxide (NaOH), phosphate buffer solution (PBS), (3-mercaptopropyl) trimethoxysilane (MPTES), thin-layer molybdenum disulfide solution (MoS2), carcinoembryonic antibody (Antigen CEA), etc.

[0052] 2. Pretreatment of the fiber surface:

[0053] Soak the waist area of the micro-nano optical fiber in a 5% HNO3 solution at room temperature for 1 hour. The waist area is the middle thinned part after the micro-nano optical fiber is tapered, and then rinse it 5 times with RO water to remove other impurities on the fiber surface.

[0054] 3. Hydroxylation (-OH) of the fiber surface:

[0055] Soak the waist area with 1 mol / L NaOH solution at room temperature for 1 hour, and then rinse it 5 times with RO water to generate free hydroxyl groups on the fiber surface.

[0056] 4. Silanization:

[0057] Soak the waist area with 5% MPTMS solution for 20 minutes, and then rinse it 5 times with absolute ethanol to form free silyl groups on the fiber surface.

[0058] 5. Coating MoS2:

[0059] Soak the waist area with 0.5 mol / ml MoS2 solution for 5 minutes, and then dry it for 5 min. Repeat 6 - 8 times to ensure that MoS2 is uniformly coated on the fiber surface.

[0060] 6. Modifying antibody:

[0061] Take 50 μL of CEA antibody solution, dilute it 100 times with PBS solution, soak the waist area for 1 hour, and gently shake the CEA antibody solution every 20 minutes to make the solution concentration uniform. Optionally, the corresponding labeled antibody can be replaced to prepare the corresponding marker fiber optic sensor and achieve the corresponding concentration detection.

[0062] 7. Blocking with skim milk powder:

[0063] Soak the waist area with 5% skim milk powder blocking solution for 1 hour to block the sites on MoS2 that are not bound to the CEA antibody and prevent non-specific binding.

[0064] Furthermore, the high-sensitivity and high-specificity micro-nano fiber optic sensor of the present invention adopts the phase modulation principle. During preparation, the SMF-28 single-mode fiber is placed on the electric displacement platform and fixed by vacuum adsorption. The oxyhydrogen flame generated by the hydrogen generator is used to heat the SMF-28 single-mode fiber with the coating layer peeled off at high temperature to make it melt. At the same time, the electric displacement stage is controlled to stretch uniformly to both sides for taper processing to draw it thin to the micro-nano level. The waist area of the micro-nano fiber in this example is 6 μm. After stretching to the appropriate length, a micro-nano fiber with a free spectral range (FSR) of about 21 nm can be obtained, and its structure is as Figure 4 shown.

[0065] Furthermore, the sensing principle of the micro-nano fiber optic sensor is as follows:

[0066] The phase modulation type micro-nano fiber optic sensor senses by detecting the interference generated by the phase change between the LP 01 mode and other higher-order modes mainly composed of LP 11 mode in the micro-nano fiber when the external refractive index changes. Then there is:

[0067]

[0068] where I1 and I2 are the intensities of two interfering light beams; is the phase difference between two mode lights; Δn eff is the effective refractive index difference between two modes; λ is the transmission wavelength; L is the optical path.

[0069] Furthermore, the spectrum of the micro-nano fiber in air is as shown in Figure 5 where the abscissa Wavelength represents the wavelength and the ordinate Trasmission represents the transmission loss in the figure; the spectral drift of the micro-nano fiber in different refractive index solutions is as shown in Figure 6 where when the refractive index of the external solution (1.3333 - 1.3516) increases, the interference valleys (peaks) of the fabricated micro-nano fiber exhibit red shift. As shown in Figure 7 through linear fitting, it can be seen that its refractive index Refractive lndex sensitivity reaches 1915.955 nm / RIU and the linearity R 2 = 0.99.

[0070] Specifically, within the detection range of 1 pg / mL to 50 ng / mL CEA antigen concentration, the relationship between the central wavelength drift of the micro-nano fiber sensor and the logarithmic concentration of the CEA antigen solution was measured. Among them, the change in the transmission loss when the laser passes through the micro-nano fiber is as shown in Figure 8 where the wavelength drift amount detected by the sensor is as shown in Figure 9 and the wavelength drift amount is related to the CEA antigen concentration. Among them, the Langmuir model is expressed as:

[0071]

[0072] In the formula, C is the concentration of the CEA antigen solution; Δλ is the resonant wavelength drift amount corresponding to the concentration; Δλ MAX is the maximum resonant wavelength drift amount during the detection process; K D is the dissociation constant of the antibody-antigen in the micro-nano fiber.

[0073] As shown in Figure 10 at this time, the Langmuir curve obtained is:

[0074]

[0075] Among them, Y represents the variable related to the wavelength drift amount Δλ, usually By experimentally measuring the wavelength drift amounts at different concentrations, calculate and perform non-linear fitting with the concentration C to obtain the parameters of the Langmuir model.

[0076] According to the fitting results of the sensor, the dissociation coefficient and affinity coefficient of the sensor can be calculated. Among them, the dissociation coefficient K D = 2.09×10 -10 , representing the equilibrium constant of antigen-antibody dissociation during the specific binding reaction; the affinity coefficient K A = 4.78×10 9 M -1 , representing the equilibrium constant of antigen-antibody binding. Generally speaking, the smaller the dissociation coefficient K D , and the larger the affinity coefficient K A , the closer the specific binding of antigen and antibody is. Therefore, through the calculation of the dissociation coefficient and affinity coefficient, it can be known that the micro-nano fiber sensor has excellent molecular affinity.

[0077] The detection limit (LOD) of the micro-nano fiber sensor (biosensor) is calculated using the recommendations of the International Union of Pure and Applied Chemistry (IUPAC):

[0078]

[0079] In the formula, f -1 is the inverse function of the Langmuir curve function relationship fitted from the experimental results; is the average value of the blank measurement, and σ MAX is the standard deviation of the blank measurement.

[0080] The detection limit of the biosensor calculated from the above two formulas is 15.86 fg / ml, indicating the minimum value of the CEA concentration that the sensor can detect. Comparing the performance of the sensor of the present invention with that of the existing sensors, a performance comparison table of CEA sensors is obtained:

[0081] Table 1 Performance Comparison Table of CEA Sensors

[0082]

[0083]

[0084] It can be clearly seen from Table 1 by comparing the same type of CEA biosensors that the performance of this sensor in terms of detection limit is significantly better than that of other types of sensors. The detection limit of the sensor prepared by the present invention is extremely low, and it can detect lower concentrations of CEA antigen molecules, which is attributed to the extremely high refractive index sensitivity of the micro-nano fiber and the large number of binding sites provided by the MoS2 sandwich structure for CEA antibodies. This sensor is expected to provide a high-precision, high-sensitivity, and fast-response analysis tool for the analysis of the early stage of cancer development in the medical field.

[0085] After logarithmic processing of the CEA antigen solution concentration, the linear relationship between the solution concentration and the wavelength drift amount is as Figure 11As shown, the fitting straight-line equation is:

[0086] y = 4.727x + 27.703

[0087] Wherein, x represents the logarithmic concentration of the CEA antigen solution; y represents the corresponding wavelength drift amount; according to this fitting straight-line equation, the sensitivity of this biosensor can be obtained as 4.727 nm / log(mg / ml).

[0088] Furthermore, use L-cysteine (L-Cys), L-glutamic acid (L-Glu), methylene blue (MB), bovine serum albumin (BSA), bovine serum γ-globulin (BGG), human serum albumin (HSA), and CEA antigen solution, and prepare them into solutions with a concentration of 50 ng / ml respectively. React them with the prepared micro-nano optical fiber sensor in turn for 15 minutes, and wash 5 times with PBS solution after each reaction, and record the spectral data. It should be noted that the CEA antigen solution is detected last. The detection results are as follows Figure 12 As shown, it can be seen that there are slight redshifts in the wavelengths in the 6 specific detection reagents. The minimum redshift amount is 0.0999 nm, and the maximum redshift amount is 0.9042 nm, but they are all much lower than the redshift amount of 23.0360 nm of the CEA antigen concentration at the same concentration. The main reason for the wavelength redshift in other solutions is that the refractive index of the solution is slightly higher than that of the blank PSB solution. It can be seen that the micro-nano optical fiber sensor of the present invention has good specific functions in biomolecular recognition detection and has great application value in the field of biomedicine.

[0089] In one example, as Figure 2 shown, the system further includes a calibration unit connected to the demodulation unit and the distribution box. In this example, the calibration unit includes two calibration optical fibers RC1 and RC2, which can be micro-nano optical fibers. RC1 and RC2 are not subjected to any surface modification and are only encapsulated in a thermostatic module controlled by a TEC. The distribution box distributes the optical signal output by the DFB laser to the sensing unit and the calibration unit. The calibration optical fibers RC1 and RC2 receive the optical signal distributed by the distribution box and transmit it to the demodulation unit. The demodulation unit uses the reference signals provided by the calibration optical fibers RC1 and RC2, calculates the difference by comparing the output signals of the calibration optical fiber and the sensing unit, and further corrects the output error of the DFB laser and the cross-sensitivity error caused by environmental factors.

[0090] In one example, the system further includes a differential signal acquisition unit, and the photodetector group is connected to the demodulation unit through the differential signal acquisition unit. The differential signal acquisition unit can include a signal amplification circuit, a noise suppression circuit, etc. The signal amplification circuit is used to amplify the signal and enhance the signal amplitude for subsequent demodulation processing; the noise suppression circuit is used to suppress noise and improve the signal-to-noise ratio of the signal.

[0091] Combining the above examples gives a preferred example of the system of the present invention. At this time, the system includes a control unit, a 2-3μm continuously tunable narrow-bandwidth laser, a splitter box, a sensing unit, a photodetector group, a differential signal acquisition unit, and a demodulation unit connected in sequence. It also includes a calibration unit connected to the splitter box and the demodulation unit. The sensing unit includes a TPA sensor S1, an SCCA sensor S2, a Ca125 sensor S3, a CYF sensor S4, an NSE sensor S5, and a CEA sensor S6. The calibration unit includes calibration optical fibers RC1 and RC2. Taking the output of three-wavelength laser by the laser as an example, the working principle of the system is as follows:

[0092] The 2-3μm continuously tunable narrow-bandwidth laser controls the parameters of the tunable filter through a drive circuit to achieve the output of three wavelengths λ1, λ2, and λ3 with a certain interval between the output wavelengths. It is split by the splitter box into 6 sensor connectors S1-S6 and calibration optical fibers RC1 and RC2. Another 6 micro-nano optical fibers are fixed through surface treatment for detecting cancer-specific markers. The ends of the micro-nano optical fibers are inscribed with chirped fiber gratings (CFBG) corresponding to the 2-3μm band by using an ultraviolet femtosecond pulse laser + phase mask technology. The output delay between every two sensing heads is achieved by increasing the length of the transmission optical fiber, so that the arrival times of the reflected pulses are different (time-division multiplexing). Once all the reflected pulses arrive, another measurement sequence starts. The shape of the reflection spectrum is used to determine the state of the sensor, that is, whether the sensor is affected by the external environment, whether there is damage or performance degradation. This is done by calculating the difference pulse of the reflected power at the start and end of the reflection, and then dividing by the normalized sum.

[0093] It should be noted that there is a "dark zone time" between the laser trigger and the first reflected wave. This time is generally about 100ns at present. The average signal value during this period is used as the "zero power" level. Subtracting the zero level is to obtain the power of each precise pulse. The default duration of each pulse is 60ns, the interval between each echo pulse is 10ns, the power of the pulse is usually about 20mW, and the delay between the trigger pulse and the first transmitted wave pulse is 100ns. The pulse duration is defaulted to 60ns, the pulse period is defaulted to 80ns, and the number of measurement sequence averages is defaulted to 2 17 。

[0094] The present invention also includes a demodulation method for demodulating the laser signals detected by the photodetector group in the cancer multi-specific marker optical fiber sensor system formed by combining any one of the above examples or multiple examples. The method includes the following steps:

[0095] Step 1: According to the interference spectrum model, select three characteristic points, namely the zero point, the peak point, and the middle point, and calculate the phase differences and interference spectrum intensities of the three characteristic points.

[0096] Among them, the interference spectrum intensity in the interference spectrum model is:

[0097] I(λ) = A + Bcos(φ(λ));

[0098] Among them, I(λ) is the interference spectrum intensity, representing the light intensity at wavelength λ; the coefficient A = I1 + I2; the coefficient B = 2√(I1I2); where I1 is the fundamental mode light intensity and I2 is the high-order mode light intensity in the micro-nano fiber; φ(λ) represents the phase difference, representing the phase change at wavelength λ, and the calculation expression is:

[0099]

[0100] Among them, k is a constant that satisfies the chirp condition FSR(λ) = kλ; λ0 represents the reference wavelength.

[0101] Furthermore, the phase difference φ(λ z ) and the interference spectrum intensity I(λ z ) at the zero wavelength are:

[0102]

[0103] The phase difference φ(λ p ) and the interference spectrum intensity I(λ p ) at the peak wavelength are:

[0104]

[0105] The phase difference φ(λ m ) and the interference spectrum intensity I(λ m ) at the middle wavelength are:

[0106]

[0107] Step 2: Calculate the phase differences and interference spectrum intensities of the three characteristic points after the spectrum undergoes redshift.

[0108] Among them, when the spectrum undergoes a redshift of Δλ, the interference intensity becomes:

[0109]

[0110] The change in the phase difference after redshift is:

[0111]

[0112] When (Δλ << λ), the change in the phase difference is:

[0113]

[0114] It can be seen that the change in phase difference φ′(λ) is proportional to the wavelength drift Δλ, and the change in phase difference reflects the wavelength drift. Step 3: Calculate the demodulation signal S based on the interference spectral intensities of three characteristic points, and its calculation expression is:

[0115] S = [I′(λ m ) - I′(λ z )] - [I′(λ p ) - I′(λ m )];

[0116] When Δλ << λ, using Taylor expansion, the demodulation signal is obtained as:

[0117]

[0118] It can be seen that the demodulation signal S is inversely proportional to the wavelength drift Δλ, and then the central wavelength drift of each micro-nano fiber sensor is obtained according to the demodulation signal. Optionally, when using the CEA micro-nano fiber sensor described in the above example for detection, since the cancer-specific marker binds to the antibody on the sensor surface, the refractive index on the surface of the micro-nano fiber sensor changes, thereby causing a change in the demodulation signal S (or wavelength drift). At this time, the refractive index demodulation result is as Figure 13 shown.

[0119] Step 4: According to the central wavelength drift, combined with the pre-established mathematical model, obtain the concentration content of the cancer-specific marker; the mathematical model stores the mapping relationship between the central wavelength drift and the known concentration value of the cancer-specific marker.

[0120] In this example, the three-wavelength difference demodulation algorithm is used for demodulation. Of course, the dual-wavelength difference demodulation algorithm (DWDD) can also be used for demodulation. It should be noted that the dual-wavelength difference demodulation algorithm (DWDD) is based on a Gaussian-type spectrum for demodulation calculation, while the spectrum of the micro-nano fiber sensor is not a standard Gaussian type, and its free spectral range increases with the increase of wavelength. Therefore, when using the DWDD demodulation algorithm, when the wavelength drifts, its demodulation result is no longer a linear result, resulting in an increase in demodulation error. The present invention uses three-wavelength difference demodulation. When modeling, considering the change of the free spectral range, the chirp coefficient k is introduced to optimize the phase difference:

[0121]

[0122] Furthermore, to improve the accuracy of the demodulation result, and different from DWDD demodulation, the three-wavelength differential demodulation used in the present invention selects the peak point, zero point and middle point when selecting the initial demodulation point, maximizing the demodulation sensitivity. Therefore, the demodulation result can be made more accurate with less error.

[0123] The present invention proposes a simple method for fiber optic sensing detection of cancer-specific markers, and innovatively uses the micro-nano fiber optic sensor structure and two-dimensional materials to improve performance parameters such as the detection limit, sensitivity and response time of the fiber optic sensor, which has great potential in future applications such as cancer medical detection and early diagnosis.

[0124] A fiber optic sensor system and demodulation method for cancer multi-specific markers of the present invention innovatively use the micro-nano fiber optic sensor structure and two-dimensional materials to improve performance parameters such as the detection limit, sensitivity and response time of the fiber optic sensor, and have great potential in future applications such as cancer medical detection and early diagnosis.

[0125] The above specific embodiments are detailed descriptions of the present invention. It cannot be determined that the specific embodiments of the present invention are only limited to these descriptions. For those of ordinary skill in the technical field to which the present invention belongs, without departing from the concept of the present invention, several simple deductions and substitutions can still be made, which should all be regarded as belonging to the protection scope of the present invention.

Claims

1. A fiber optic sensor system for cancer multi-specific markers, characterized in that, It includes a laser, a splitter box, a sensing unit, a photodetector group, and a demodulation unit connected in sequence. The laser outputs lasers with different wavelengths. The sensing unit includes several micro-nano fiber sensors. The tail end of the micro-nano fiber in the micro-nano fiber sensor is a high-reflection chirped fiber grating. The surfaces of the micro-nano fibers are fixed with the same or different cancer-specific marker antibodies, which are used to react with the cancer-specific markers in the test reagent. The micro-nano fiber sensors transmit different-wavelength lasers with the reflected light intensity changed after reaction through the high-reflection chirped fiber grating based on the time-division multiplexing method. The photodetector group detects different-wavelength lasers with the changed light intensity and converts them into electrical signals. The demodulation unit processes the electrical signals according to the differential demodulation algorithm, demodulates the central wavelength drift of each micro-nano fiber sensor, and further obtains the concentration of the cancer-specific marker.

2. The fiber optic sensor system for a multi-specific cancer biomarker according to claim 1, wherein The system further includes a control unit, which is connected to the laser and used to regulate the tunable filter of the laser, so as to make the laser output lasers with different wavelengths.

3. The fiber optic sensor system for multiple cancer specific markers according to claim 1, wherein The surface of the micro-nano fiber is modified by two-dimensional materials.

4. The fiber optic sensor system for cancer multi-specific markers according to claim 1, characterized in that, The laser is a 2-3μm continuously tunable narrow-bandwidth laser.

5. The fiber optic sensor system for multiple cancer specific markers according to claim 1, wherein The system further includes a calibration unit connected to the demodulation unit and the splitter box. The calibration unit includes a calibration fiber encapsulated in a constant-temperature module, which is used to correct the output error of the laser and / or the cross-sensitivity error caused by environmental temperature and strain.

6. The fiber optic sensor system for multiple cancer specific markers according to claim 1, wherein The system further includes a differential signal acquisition unit. The photodetector group is connected to the demodulation unit through the differential signal acquisition unit.

7. A demodulation method, which is implemented based on the cancer multi-specific biomarker optical fiber sensor system according to any one of claims 1-6, characterized in that, The method includes the following steps: According to the interference spectrum model, select three characteristic points of the initial spectrum, namely the zero point, the peak point, and the middle point, and calculate the phase difference and the interference spectrum intensity of the three characteristic points. Calculate the phase difference and the interference spectrum intensity of the three characteristic points after the spectrum undergoes redshift. Calculate the demodulation signal according to the interference spectrum intensity of the three characteristic points, and further obtain the central wavelength drift of each micro-nano fiber sensor according to the demodulation signal. According to the central wavelength drift, combined with the pre-established mathematical model, obtain the concentration of the cancer-specific marker; the mapping relationship between the central wavelength drift and the known concentration value of the cancer-specific marker is stored in the mathematical model.

8. The demodulation method according to claim 7, characterized in that, The calculation expression of the demodulation signal is: Where S represents the demodulation signal; the coefficient B = 2I1I2, I1 represents the fundamental mode light intensity, and I2 represents the higher-order mode light intensity in the micro-nano fiber. k represents a constant; λ represents the wavelength; Δλ represents the spectral redshift amount.

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