Surface plasmon resonance imaging system for expanding dynamic range through multi-mode light path

Abstract

The invention discloses a surface plasmon resonance imaging system for expanding a dynamic range through a multi-mode optical path, and relates to the technical field of microscopic imaging, a laser outputs a monochromatic and linearly polarized continuous wave beam, a first dynamic beam deflection device performs dynamic angle deflection adjustment on the continuous wave beam, a prism is used for providing a total reflection interface, and a second dynamic beam deflection device is used for performing dynamic angle deflection adjustment on the continuous wave beam. Exciting an evanescent wave; a surface plasma resonance effect is generated through interaction of the SPR detection chip and evanescent waves, and sample characteristics are detected; the flow cell provides a sample flow channel, so that a sample is in full contact with the surface of the SPR detection chip; the second dynamic light beam deflection device cooperatively adjusts the propagation direction of reflected light on the surface of the SPR detection chip, and the imaging detection device captures a high-spatial-resolution SPR image formed by the reflected light and transmits the image to the upper computer in real time for processing and analysis. According to the invention, the change of the resonance angle can be tracked in real time, and high-sensitivity and high-resolution monitoring of the dynamic process of biomolecule interaction is realized.

Description

Technical Field

[0001] The present invention relates to the field of microscopic imaging technology, and more particularly to a surface plasmon resonance imaging system with a multi-modal optical path and extended dynamic range. Background Art

[0002] Surface Plasmon Resonance Microscopy (SPR) microscopy is an advanced optical detection method that combines surface plasmon resonance (SPR) technology with microscopic imaging. With its unique advantages, it has become an important tool in the fields of bioanalysis, materials science, and medical diagnostics. The basic principle of SPR technology is that free electrons on the metal surface undergo collective oscillations under light excitation, forming surface plasmon waves. This resonance is very sensitive to changes in the metal's refractive index, and molecular binding processes can be analyzed by detecting changes in the intensity or phase of the reflected light. Microscopic imaging combines the high sensitivity of SPR with the spatial resolution of a microscope, enabling microscopic dynamic analysis of biological samples (such as cells, proteins, DNA) or nanomaterials through wide-field or hyperspectral imaging techniques.

[0003] Traditional SPR systems primarily employ two detection modes: fixed-angle detection, which monitors changes in reflected light intensity at a preset resonance angle. However, this method is unable to dynamically track resonance angle shifts, resulting in limited sensitivity and susceptibility to environmental noise. Second, resonance angle detection, which measures reflectivity at discrete angle steps and then determines the resonance angle through interpolation or fitting. However, these methods suffer from low temporal resolution, insufficient spatial resolution, and low data processing accuracy. While phase-type SPR and interferometric SPR technologies have made progress in recent years, they remain constrained by fixed-angle detection. For example, phase-type SPR requires a complex interferometric optical path to acquire phase information, which not only increases system complexity but also limits its dynamic scanning capabilities.

[0004] Therefore, how to track the changes in the resonance angle in real time, achieve high-sensitivity and high-resolution monitoring of the dynamic process of biomolecular interactions, and overcome the shortcomings of existing SPR technology in terms of dynamic range, detection speed, multimodal collaboration and system integration are technical problems that technicians in this field urgently need to solve. Summary of the Invention

[0005] In view of this, the present invention provides a surface plasmon resonance imaging system with a multi-modal optical path and extended dynamic range, which solves the problems existing in the background technology.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] A surface plasmon resonance imaging system with a multi-modal optical path and extended dynamic range includes: a laser, a first dynamic beam deflection device, a prism, an SPR detection chip, a flow cell, a second dynamic beam deflection device, an imaging detection device, and a host computer;

[0008] A laser for outputting a monochromatic, linearly polarized continuous wave beam;

[0009] A first dynamic beam deflection device is provided on the output optical path of the laser and is used to dynamically deflect the continuous wave beam to expand the dynamic range of the refractive index detected by SPR;

[0010] The prism is attached to the bottom of the SPR detection chip to provide a total reflection interface and stimulate the evanescent wave;

[0011] The SPR detection chip is placed on the evanescent wave propagation path and is used to interact with the evanescent wave to generate a surface plasmon resonance effect to detect sample characteristics;

[0012] The flow cell is fixed above the SPR detection chip and is used to provide a sample flow channel so that the sample can fully contact the surface of the SPR detection chip;

[0013] The second dynamic beam deflection device is arranged on the reflected light path of the SPR detection chip, and is used to coordinately adjust the propagation direction of the reflected light on the surface of the SPR detection chip to achieve angle-wavelength multimodal data fusion;

[0014] An imaging detection device is arranged on the propagation path of the reflected light after the orientation, and is used to capture the high spatial resolution SPR image formed by the reflected light and transmit it to the host computer in real time for processing and analysis;

[0015] The host computer is used to receive the SPR image data from the imaging detection device, analyze the resonance angle offset in real time through a machine learning algorithm, and feed back the collaborative working parameters of the first dynamic beam deflection device and the second dynamic beam deflection device to form a closed-loop dynamic scan.

[0016] Optionally, the laser is a tunable laser with a wavelength adjustable range of 600-800 nm, an output power stability within ±0.5%, and an output beam divergence angle less than 1 mrad.

[0017] Optionally, it further includes a fiber coupler, a total internal reflection collimator, a polarizer, and an aperture disposed between the laser and the first dynamic beam deflection device;

[0018] A fiber coupler is provided at the output port of the laser and is used to couple the light beam output by the laser into the optical fiber for transmission;

[0019] A total internal reflection collimator is provided at the optical fiber output end of the optical fiber coupler and is used to collimate the divergent light beam output by the optical fiber into a parallel light beam;

[0020] A polarizer is placed on the outgoing light path of the collimator to filter out light beams with a specific polarization direction;

[0021] The aperture is set on the output light path of the polarizer to limit the diameter and shape of the light beam and remove stray light and noise.

[0022] Optionally, the first dynamic beam deflection device and the second dynamic beam deflection device both use a galvanometer galvanometer mirror, which is composed of a reflective mirror driven by a motor;

[0023] A first galvanometer galvanometer mirror is provided on the outgoing light path of the attenuator and is used to adjust the dynamic angle deflection of the light beam by controlling the rotation angle of the reflector through a motor;

[0024] The second galvanometer galvanometer is arranged on the reflected light path of the SPR detection chip and is used to control the rotation angle of the reflector through a motor to orient the reflected light.

[0025] Optionally, it further includes a half wave plate and a first focusing lens group disposed between the first galvanometer galvanometer and the SPR detection chip, and a second focusing lens group disposed between the second galvanometer galvanometer and the imaging detection device;

[0026] A half-wave plate, used to compensate for the polarization rotation caused by the reflection of the first galvanometer galvanometer mirror;

[0027] a first focusing lens group, optimized based on the polarization angle and optical path length of the first galvanometer galvanometer mirror, for focusing the deflected light beam onto the prism;

[0028] The second focusing lens group is used to focus the directed reflected light onto the imaging detection device.

[0029] Optionally, the first dynamic light beam deflection device and the second dynamic light beam deflection device both use an electro-optical modulator, which is composed of an electro-optical crystal, an electrode, and a driving circuit;

[0030] A first electro-optical modulator is provided on the outgoing optical path of the attenuator and is used to change the propagation direction of the light beam by applying a voltage through a driving circuit;

[0031] The second electro-optic modulator is arranged on the reflected light path of the SPR detection chip and is used to adjust the angle of the reflected light by controlling the change of the refractive index of the electro-optic crystal through the driving circuit.

[0032] Optionally, it further includes a first polarization controller disposed before the first electro-optical modulator and a second polarization controller disposed before the second electro-optical modulator;

[0033] a first polarization controller, configured to control the polarization state of the continuous wave light beam by combining a half-wave plate and a quarter-wave plate to meet the working requirements of the first electro-optical modulator;

[0034] The second polarization controller is used to control the polarization state of the reflected light through a combination of a half wave plate and a quarter wave plate to meet the working requirements of the second electro-optical modulator.

[0035] Optionally, the SPR detection chip includes a glass substrate, a transition layer, a metal film layer and a chemically modified surface arranged in sequence; wherein, the transition layer is deposited on the glass substrate by atomic deposition technology, the metal film layer is deposited on the transition layer by electron beam evaporation, and the chemically modified surface is modified on the outer surface of the metal film layer to achieve the fixation of the target ligand molecules; the circulation pool is sealed and fixed to the SPR detection chip by curing glue to form a closed detection chamber to accommodate the sample solution and prevent it from leaking.

[0036] Optionally, the imaging detection device uses an sCMOS camera or a CCD camera, and the photosensitive surface of the sCMOS camera or CCD camera is perpendicular to the propagation direction of the reflected light after being directed by the second dynamic beam deflection device. It is used to convert the reflected light signal received by the photosensitive surface into an electrical signal through the equipped data acquisition and processing module and perform preliminary amplification, filtering and digital processing.

[0037] Optionally, the laser, the first dynamic beam deflection device, the SPR detection chip, the second dynamic beam deflection device, and the imaging detection device are all installed on a seismic isolation platform, and the optical components are connected through standardized interfaces.

[0038] As can be seen from the above technical solutions, compared with the prior art, the present invention provides a surface plasmon resonance imaging system with a multi-modal optical path and extended dynamic range, which has the following beneficial effects:

[0039] (1) The present invention uses a first dynamic beam deflection device to dynamically adjust the angle of the continuous wave beam output by the laser, and uses a second dynamic beam deflection device to direct the reflected light on the surface of the SPR detection chip, thereby realizing a multimodal optical path, expanding the dynamic range of the surface plasmon resonance imaging system, and improving the system's ability to detect different sample characteristics;

[0040] (2) The dynamic beam deflection device of the present invention can adopt a galvanometer galvanometer or an electro-optical modulator. The galvanometer galvanometer controls the rotation angle of the reflector through a motor to realize the dynamic angle deflection adjustment of the light beam and the orientation of the reflected light, and has high flexibility and response speed; the electro-optical modulator changes the propagation direction of the light beam or controls the refractive index change of the electro-optical crystal by applying voltage through the driving circuit to adjust the angle of the reflected light, and has the characteristics of high precision and fast response. The appropriate deflection device can be selected according to actual needs to meet different detection requirements; the change of the resonance angle is tracked in real time to realize high-sensitivity and high-resolution monitoring of the dynamic process of biomolecular interaction;

[0041] (3) The present invention uses an sCMOS camera or a CCD camera to capture the high spatial resolution SPR image formed by the reflected light and uploads it to the host computer for processing and analysis in real time, so as to facilitate timely acquisition of the detection results; all optical components are installed on the seismic isolation platform, and the optical components are connected through standardized interfaces, which can reduce the interference of external vibrations on the system, ensure the stability and reliability of the system, and facilitate assembly, debugging and maintenance. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are merely embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying any creative work.

[0043] Figure 1 This is a structural diagram of the surface plasmon resonance imaging system with multi-modal optical path and extended dynamic range provided by the present invention. DETAILED DESCRIPTION

[0044] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. 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 making creative efforts are within the scope of protection of the present invention.

[0045] At present, existing SPR systems generally adopt fixed-angle or static scanning methods, which have the following shortcomings: the dynamic response speed is not fast enough, making it difficult to capture rapid biomolecular interactions; the spatial resolution is not high enough to meet the analysis needs at the single cell or subcellular level; the sensitivity is insufficient, especially when detecting low-concentration samples; the system structure is complex and the cost is high, which is not conducive to promotion and application.

[0046] In order to track the changes in resonance angle in real time and achieve high-sensitivity and high-resolution monitoring of the dynamic process of biomolecular interactions, the embodiment of the present invention discloses a surface plasmon resonance imaging system with a multi-modal optical path and an extended dynamic range, such as Figure 1 As shown, it includes: a laser, a first dynamic beam deflection device, a prism, an SPR detection chip, a flow cell, a second dynamic beam deflection device, an imaging detection device and a host computer;

[0047] A laser for outputting a monochromatic, linearly polarized continuous wave beam;

[0048] A first dynamic beam deflection device is provided on the output optical path of the laser and is used to dynamically deflect the continuous wave beam to expand the dynamic range of the refractive index detected by SPR;

[0049] The prism is attached to the bottom of the SPR detection chip to provide a total reflection interface and stimulate evanescent waves. As a high-refractive-index medium, the prism is tightly attached to the metal film of the SPR detection chip. When polarized light is incident on the prism-metal interface at a specific angle, total reflection occurs, and an evanescent wave (an attenuated electromagnetic wave whose energy penetrates the metal) is generated on the metal surface. This evanescent wave is a necessary condition for exciting free electrons on the metal surface to form plasma oscillations. SPR detection relies on the resonance angle, and the prism can fix the incident light path through a precise structure, making the incident angle adjustable. When the incident angle matches the plasma resonance angle, the evanescent wave energy couples with the electron oscillations on the metal surface, triggering a resonance signal. In addition, the wavelength of the prism material needs to be compatible with the light source and the metal film. BK7 or SF10 materials can be used, and the refractive index is selected to be 1.72 or 1.52.

[0050] The SPR detection chip is placed on the evanescent wave propagation path and is used to interact with the evanescent wave to generate a surface plasmon resonance effect to detect sample characteristics;

[0051] The flow cell is fixed above the SPR detection chip and is used to provide a sample flow channel to ensure full contact between the sample and the surface of the SPR detection chip for effective detection. Specifically, the flow cell is a flow channel structure with an inlet and an outlet, which can achieve stable flow and uniform coverage of the sample solution in the detection area. The flow cell and the SPR detection chip are tightly bonded by curing glue, and the flow channel height is 50-200μm, ensuring full contact between the liquid and the sensor surface, reducing dead volume and bubble interference, and helping to improve imaging quality and detection sensitivity. The flow cell structure is suitable for a variety of automated injection systems and has good sealing, reusability, and easy cleaning and maintenance.

[0052] The second dynamic beam deflection device is arranged on the reflected light path of the SPR detection chip, and is used to coordinately adjust the propagation direction of the reflected light on the surface of the SPR detection chip to achieve angle-wavelength multimodal data fusion;

[0053] An imaging detection device is arranged on the propagation path of the reflected light after the orientation, and is used to capture the high spatial resolution SPR image formed by the reflected light and transmit it to the host computer in real time for processing and analysis;

[0054] The host computer is used to receive the SPR image data from the imaging detection device, analyze the resonance angle offset in real time through a machine learning algorithm, and feed back the collaborative working parameters of the first dynamic beam deflection device and the second dynamic beam deflection device to form a closed-loop dynamic scan.

[0055] Furthermore, the laser is a tunable laser with a wavelength adjustable range of 600-800nm, an output power stability within ±0.5%, and an output beam divergence angle of less than 1mrad to meet the requirements of surface plasmon resonance excitation.

[0056] In this embodiment, the laser emits a monochromatic, linearly polarized continuous wave beam. SPR is sensitive to wavelength, and monochromatic light can ensure the stability of the resonance conditions. The wavelength range of 600-800nm ​​can cover the visible light to near-infrared band, adapting to the SPR excitation requirements of different metal films; SPR is sensitive to polarization state, and linearly polarized light can avoid signal fluctuations caused by random changes in polarization state; continuous wave output can avoid the interference of pulsed light on the dynamic scanning signal, ensuring the continuity of the reflected light intensity detection. The divergence angle is less than 1mrad, which can ensure that the light beam can still be effectively focused on the surface of the SPR detection chip after dynamic deflection, avoiding energy loss and increasing the light intensity on the surface of the SPR detection chip; the power stability is within ±0.5%, which can reduce the impact of light source fluctuations on the reflectivity measurement accuracy and reduce the detection error caused by power fluctuations.

[0057] To optimize the quality and characteristics of the light beam and ensure efficient and stable operation of the system, the surface plasmon resonance imaging system of this embodiment further includes a fiber coupler, a total internal reflection collimator, a polarizer, and an aperture disposed between the laser and the first dynamic beam deflection device;

[0058] The fiber coupler is installed at the output port of the laser to couple the laser output beam into the optical fiber for transmission. It uses the good flexibility and low loss characteristics of the optical fiber to achieve long-distance and stable transmission of the light beam.

[0059] A total internal reflection collimator, disposed at the optical fiber output end of the optical fiber coupler, is used to collimate the divergent optical beam output by the optical fiber into a parallel beam. The collimator is composed of one or more lenses, preferably aspheric lenses, to improve collimation accuracy and beam quality. The collimator optimizes the optical path through a total internal reflection structure, guiding the light beam into the first dynamic beam deflection device in a parallel state, thereby improving the propagation efficiency and subsequent focusing performance of the light beam.

[0060] A polarizer is provided on the outgoing light path of the collimator to filter out a light beam with a specific polarization direction. The polarizer is made of a polarizing film material to ensure that the light beam entering the first dynamic beam deflection device has an accurate polarization state, meeting the surface plasmon resonance imaging system's requirements for polarized light and improving the system's detection sensitivity and stability.

[0061] The aperture is set on the output light path of the polarizer to limit the diameter and shape of the light beam, remove stray light and noise, and improve the quality and purity of the light beam. The aperture is a metal plate with an adjustable aperture. By adjusting the aperture size, the energy of the light beam entering the first dynamic beam deflection device can be controlled to prevent excessive energy from damaging subsequent optical components, while reducing the impact of background noise on the detection results.

[0062] Furthermore, the first dynamic beam deflection device and the second dynamic beam deflection device both use a galvanometer galvanometer mirror, which is composed of a reflective mirror driven by a motor;

[0063] The first galvanometer galvanometer is arranged on the output light path of the attenuator and is used to dynamically adjust the angle of the light beam by controlling the rotation angle of the reflector through a motor. The attenuator uses a neutral density filter or a variable attenuator to adjust the power of the light beam to an appropriate range as required to ensure the normal operation of the system and the accuracy of the detection.

[0064] The second galvanometer galvanometer is arranged on the reflected light path of the SPR detection chip and is used to control the rotation angle of the reflector through a motor to orient the reflected light.

[0065] Furthermore, to cooperate with the galvanometer galvanometer and ensure the performance and stability of the system, the surface plasmon resonance imaging system of this embodiment further includes a half-wave plate and a first focusing lens group disposed between the first galvanometer galvanometer and the SPR detection chip, and a second focusing lens group disposed between the second galvanometer and the imaging detection device.

[0066] A half-wave plate is used to compensate for the polarization rotation caused by the reflection of the first galvanometer galvanometer mirror, so that the polarization state of the light beam is restored to a state that meets the system requirements;

[0067] The first focusing lens group is optimized based on the polarization angle and optical path length of the first galvanometer galvanometer mirror and is used to focus the deflected light beam onto the prism to improve the focusing effect and imaging quality of the light beam;

[0068] The second focusing lens group is used to focus the directed reflected light onto the imaging detection device.

[0069] Furthermore, a specialized control circuit and feedback system can be designed to precisely control the galvanometer galvanometer. The control circuit precisely controls the motor drive signal based on the system's detection requirements, rotating the mirror to a preset angle. The feedback system provides real-time feedback to the control circuit, monitoring the actual rotation angle, allowing for timely adjustments to ensure accurate angle control.

[0070] Furthermore, the first dynamic light beam deflection device and the second dynamic light beam deflection device both use an electro-optical modulator, which is composed of an electro-optical crystal, electrodes and a driving circuit;

[0071] A first electro-optic modulator is disposed in the output optical path of the attenuator and is configured to change the propagation direction of the light beam by applying a voltage via a driving circuit. When the driving circuit applies a voltage, the refractive index of the electro-optic crystal changes, thereby changing the propagation direction of the light beam to meet the detection requirements of surface plasmon resonance imaging for different incident angles.

[0072] The second electro-optic modulator is arranged in the reflected light path of the SPR detection chip, and is used to adjust the angle of the reflected light by controlling the change of the refractive index of the electro-optic crystal through the driving circuit to ensure that the reflected light is focused within the effective detection area of ​​the imaging detection device.

[0073] Furthermore, to ensure system performance, the surface plasmon resonance imaging system of this embodiment further includes a first polarization controller disposed before the first electro-optic modulator and a second polarization controller disposed before the second electro-optic modulator;

[0074] a first polarization controller, configured to control the polarization state of the continuous wave light beam by combining a half-wave plate and a quarter-wave plate to meet the working requirements of the first electro-optical modulator;

[0075] The second polarization controller is used to control the polarization state of the reflected light through a combination of a half wave plate and a quarter wave plate to meet the working requirements of the second electro-optical modulator.

[0076] Furthermore, to ensure the angular adjustment accuracy of the electro-optical modulator, a calibration optical path and feedback system can be designed. The calibration optical path uses a reference beam to monitor the actual deflection angle in real time. The feedback system feeds this deviation information back to the driver circuit, adjusting the output voltage in real time. This achieves closed-loop control and improves the accuracy of beam angle adjustment.

[0077] Furthermore, the SPR detection chip includes a glass substrate, a transition layer, a metal film layer, and a chemically modified surface, which are arranged in sequence; wherein the transition layer is deposited on the glass substrate by atomic deposition (ALD) technology, the metal film layer is deposited on the transition layer by electron beam evaporation, and the chemically modified surface is modified on the outer surface of the metal film layer to achieve the fixation of the target ligand molecule; the flow cell is sealed and fixed to the SPR detection chip by curing glue to form a closed detection chamber to accommodate the sample solution and prevent it from leaking. When the light beam irradiates the metal film layer, the free electrons in the metal film layer will couple with photons to generate surface plasmon waves, forming a surface plasmon resonance phenomenon; because the ligand molecules fixed on the chip surface specifically bind to the target molecules in the sample, the refractive index near the detection surface changes, which in turn causes a change in the surface plasmon resonance angle or the intensity of the reflected light. Afterwards, the imaging detection device obtains the change information by capturing the reflected light and transmits it to the host computer for processing and analysis, thereby achieving qualitative and quantitative detection of the target molecules in the sample.

[0078] Specifically, the glass substrate is made of a material with high transparency, low fluorescence background and excellent chemical stability to ensure the accuracy of signal acquisition and system stability; the transition layer is made of nanomaterials with excellent optical and electrical properties such as wide band gap, high transparency and low resistivity, and has good optical ductility; the metal film layer preferably uses gold, silver or their alloy materials, which have excellent plasma response performance and surface stability; the chemically modified surface can use different functional groups according to the different detection objects, such as photocrosslinking, amino, carboxyl, etc.; the flow cell is preferably made of materials with good mechanical strength and chemical stability such as polyetheretherketone (PEEK), and is connected to the detection chip through a curing glue, which can effectively protect the internal structure of the chip and prevent sample leakage, ensuring the reliability and repeatability of the detection process.

[0079] In addition, the circulation pool is designed with a straight channel to quickly transport samples and reagents; a serpentine channel is designed to increase the flow path and residence time of the fluid, which is conducive to the full mixing of samples and reagents; and multiple inlets are designed to inject different samples and reagents respectively.

[0080] Furthermore, the imaging detection device uses an sCMOS camera or a CCD camera, and the photosensitive surface of the sCMOS camera or CCD camera is perpendicular to the propagation direction of the reflected light after being directed by the second dynamic beam deflection device. It is used to convert the reflected light signal received by the photosensitive surface into an electrical signal through the equipped data acquisition and processing module and perform preliminary amplification, filtering and digital processing.

[0081] Furthermore, the laser, the first dynamic beam deflection device, the SPR detection chip, the second dynamic beam deflection device, and the imaging detection device are all installed on a seismic isolation platform to avoid vibration interference with the optical path and detection results; the optical components are connected through standardized interfaces to facilitate the reconstruction of the optical path and the maintenance and upgrade of the system.

[0082] In addition, the host computer uses a machine learning algorithm to provide real-time feedback control over the dynamic beam deflection device, forming a closed-loop dynamic scan. The data sources for the model include: SPR images captured by an sCMOS camera or CCD camera, real-time angle / wavelength scanning parameters of the dynamic beam deflection device, and environmental parameters such as the flow rate, temperature, and pressure of the circulation pool. The machine learning model can choose a hybrid architecture of a lightweight convolutional neural network (CNN) + a time series recurrent network (LSTM), where: the CNN branch can process sCMOS images and extract spatial features, such as the shape of the resonance spot and intensity distribution; the LSTM branch can analyze time series data, such as the angle scanning array and the refractive index change trend; and the fusion layer can combine spatiotemporal features with dynamic parameters to output control instructions. This solution deeply embeds machine learning into the SPR system control closed loop, which can significantly improve the system's dynamic range, sensitivity, and robustness, and reduce manual dependence and resource consumption.

[0083] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

[0084] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A surface plasmon resonance imaging system with multimodal optical path and extended dynamic range, characterized in that: include: Laser, first dynamic beam deflection device, prism, SPR detection chip, flow cell, second dynamic beam deflection device, imaging detection device and host computer; A laser for outputting a monochromatic, linearly polarized continuous wave beam; A first dynamic beam deflection device is provided on the output optical path of the laser and is used to dynamically deflect the continuous wave beam to expand the dynamic range of the refractive index detected by SPR; The prism is attached to the bottom of the SPR detection chip to provide a total reflection interface and stimulate the evanescent wave; The SPR detection chip is placed on the evanescent wave propagation path and is used to interact with the evanescent wave to generate a surface plasmon resonance effect to detect sample characteristics; The flow cell is fixed above the SPR detection chip and is used to provide a sample flow channel so that the sample can fully contact the surface of the SPR detection chip; The second dynamic beam deflection device is arranged on the reflected light path of the SPR detection chip, and is used to coordinately adjust the propagation direction of the reflected light on the surface of the SPR detection chip to achieve angle-wavelength multimodal data fusion; An imaging detection device is arranged on the propagation path of the reflected light after the orientation, and is used to capture the high spatial resolution SPR image formed by the reflected light and transmit it to the host computer in real time for processing and analysis; The host computer is used to receive the SPR image data from the imaging detection device, analyze the resonance angle offset in real time through a machine learning algorithm, and feed back the collaborative working parameters of the first dynamic beam deflection device and the second dynamic beam deflection device to form a closed-loop dynamic scan.

2. The surface plasmon resonance imaging system with multimodal optical path and extended dynamic range according to claim 1, characterized in that: The laser is a tunable laser with an adjustable wavelength range of 600-800nm, an output power stability within ±0.5%, and an output beam divergence angle of less than 1mrad.

3. The surface plasmon resonance imaging system with multimodal optical path and extended dynamic range according to claim 1, characterized in that: It also includes a fiber coupler, a total internal reflection collimator, a polarizer, and an aperture disposed between the laser and the first dynamic beam deflection device; A fiber coupler is provided at the output port of the laser and is used to couple the light beam output by the laser into the optical fiber for transmission; A total internal reflection collimator is provided at the optical fiber output end of the optical fiber coupler and is used to collimate the divergent light beam output by the optical fiber into a parallel light beam; A polarizer is placed on the outgoing light path of the collimator to filter out light beams with a specific polarization direction; The aperture is set on the output light path of the polarizer to limit the diameter and shape of the light beam and remove stray light and noise.

4. The surface plasmon resonance imaging system with multimodal optical path and extended dynamic range according to claim 1, characterized in that: The first dynamic beam deflection device and the second dynamic beam deflection device both use a galvanometer galvanometer mirror, which is composed of a reflective mirror driven by a motor; A first galvanometer galvanometer mirror is provided on the outgoing light path of the attenuator and is used to adjust the dynamic angle deflection of the light beam by controlling the rotation angle of the reflector through a motor; The second galvanometer galvanometer is arranged on the reflected light path of the SPR detection chip and is used to control the rotation angle of the reflector through a motor to orient the reflected light.

5. The surface plasmon resonance imaging system with multi-modal optical path and extended dynamic range according to claim 4, characterized in that: It also includes a half wave plate and a first focusing lens group arranged between the first galvanometer galvanometer and the SPR detection chip, and a second focusing lens group arranged between the second galvanometer galvanometer and the imaging detection device; A half-wave plate, used to compensate for the polarization rotation caused by the reflection of the first galvanometer galvanometer mirror; a first focusing lens group, optimized based on the polarization angle and optical path length of the first galvanometer galvanometer mirror, for focusing the deflected light beam onto the prism; The second focusing lens group is used to focus the directed reflected light onto the imaging detection device.

6. The surface plasmon resonance imaging system with multimodal optical path and extended dynamic range according to claim 1, characterized in that: The first dynamic light beam deflection device and the second dynamic light beam deflection device both use an electro-optical modulator, which is composed of an electro-optical crystal, electrodes and a driving circuit; A first electro-optical modulator is provided on the outgoing optical path of the attenuator and is used to change the propagation direction of the light beam by applying a voltage through a driving circuit; The second electro-optic modulator is arranged on the reflected light path of the SPR detection chip and is used to adjust the angle of the reflected light by controlling the change of the refractive index of the electro-optic crystal through the driving circuit.

7. The surface plasmon resonance imaging system with multi-modal optical path and extended dynamic range according to claim 6, characterized in that: It also includes a first polarization controller disposed before the first electro-optical modulator and a second polarization controller disposed before the second electro-optical modulator; a first polarization controller, configured to control the polarization state of the continuous wave light beam by combining a half-wave plate and a quarter-wave plate to meet the working requirements of the first electro-optical modulator; The second polarization controller is used to control the polarization state of the reflected light through a combination of a half wave plate and a quarter wave plate to meet the working requirements of the second electro-optical modulator.

8. The surface plasmon resonance imaging system with multi-modal optical path and extended dynamic range according to claim 1, characterized in that: The SPR detection chip includes a glass substrate, a transition layer, a metal film layer and a chemically modified surface arranged in sequence; wherein, the transition layer is deposited on the glass substrate by atomic deposition technology, the metal film layer is deposited on the transition layer by electron beam evaporation, and the chemically modified surface is modified on the outer surface of the metal film layer to achieve the fixation of the target ligand molecule; the flow cell is sealed and fixed to the SPR detection chip by curing glue to form a closed detection chamber to accommodate the sample solution and prevent leakage.

9. The surface plasmon resonance imaging system with multi-modal optical path and extended dynamic range according to claim 1, characterized in that: The imaging detection device uses an sCMOS camera or a CCD camera. The photosensitive surface of the sCMOS camera or CCD camera is perpendicular to the propagation direction of the reflected light after being directed by the second dynamic beam deflection device. It is used to convert the reflected light signal received by the photosensitive surface into an electrical signal through the equipped data acquisition and processing module and perform preliminary amplification, filtering and digital processing.

10. The surface plasmon resonance imaging system with multi-modal optical path and extended dynamic range according to claim 1, characterized in that: The laser, the first dynamic beam deflection device, the SPR detection chip, the second dynamic beam deflection device, and the imaging detection device are all installed on a vibration isolation platform, and the optical components are connected through standardized interfaces.

Images