CN113533294B - Time domain, space domain and spectrum domain single molecule characterization device based on nanometer gap electrode pair - Google Patents
Time domain, space domain and spectrum domain single molecule characterization device based on nanometer gap electrode pair Download PDFInfo
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Abstract
The invention discloses a time domain, space domain and spectrum domain single molecule characterization device based on a nanometer gap electrode pair, which comprises the following components: the illumination system is provided with a laser, a reflecting mirror, a femtosecond laser, a pulse selector, a dichroic mirror, a half-wave plate, a quarter-wave plate, a beam splitter, a scanning galvanometer system and a microscope objective which are sequentially arranged along a light path; the probe and tunneling electricity test system comprises a nanogap probe, a three-dimensional nano precision moving platform and a tunnel signal detection module, wherein the three-dimensional nano precision moving platform controls the movement of the nanogap probe, and the tunnel signal detection module is used for collecting signal light; the ultrafast optical modulation tunneling detection system mainly comprises a laser light source, a light beam polarization modulation module, a focusing scanning module and a femtosecond time synchronization module; and the single-molecule Raman detection system is used for collecting a Raman radiation image emitted by the sample.
Description
Technical Field
The invention relates to the technical field of photoelectricity, in particular to a time domain, space domain and spectrum domain single molecule characterization device based on a nanometer gap electrode pair.
Background
High spatiotemporal resolution characterization at the single molecular scale is key to the development of molecular optoelectronics, addressing biological, chemical, and medical challenges, and is also considered to be one of the keys to the development of precision medicine and addressing major medical challenges.
Currently, they rely mainly on high-energy probes (such as transmission electron microscopes, X-ray diffraction and scanning electron microscopes), scanning probes (such as atomic force microscopes, scanning tunneling microscopes, spectral fingerprint probes, etc.), fluorescent probes, and nanopore technologies. The high-energy probe technology is mature and applied to the characteristics of surface characteristics, generally has good spatial resolution, but has weak analysis capability on material characteristics, particularly needs special conditions such as vacuum conduction and the like, has great limitation in practical application, and particularly cannot realize the characterization analysis on the change process of dynamic organisms and single molecules.
The optical imaging technology is rapidly developed in the year, the spatial resolution of a fluorescence-labeled sample can reach dozens of nanometers, vacuum and ultralow temperature conditions are not needed, the sample observation condition is friendly, but the dynamic tracking and non-fluorescence-labeled in-situ detection of a single molecule with a smaller spatial scale (such as less than 5 nanometers) from nanometer to sub-nanometer scale in real time still have great difficulty.
The nanopore monomolecular detection technology utilizes a nanometer restricted domain channel as a unit component, and an excitation signal (such as constant potential) is applied to the outside to measure the signal change (such as ionic current) of a target object when the target object passes through a nanopore, so that the analysis of the monomolecular is realized, and the nanopore monomolecular detection technology has the performances of high sensitivity, no mark, monomolecular detection and the like, but generally can only provide quasi-stable single information, has time resolution of second level, and greatly limits the knowledge of molecular system kinetic information.
In order to obtain both temporally and spatially resolved information, one possible solution is to introduce the pump-detection method into a spatially resolved characterization technique, which is currently shown to function in combination with electron microscopy or scanning probes. The problem that the application of the time-resolved transmission electron microscope technology combined with the electron microscope is limited by the special environmental requirements still exists in the fields of biological and chemical engineering. And the time-resolved Scanning Tunneling Microscope (STM) technology combined with the scanning probe utilizes ultrafast laser pulses to induce electrons in a sample to be in a nonequilibrium state, and combines high-space-resolved imaging of tunneling electrons to obtain ultrafast dynamic characteristics of electron excited state changes. However, this technique also has significant drawbacks, namely the lack of a stable and reliable electrical probe, the instability of the STM probe caused by optical excitation; and secondly, the proportion of components for exciting the tunneling current to the total tunneling current is very small, and the traditional STM is adopted to always cause signals to be submerged in noise, so that the improvement of the tunneling current change caused by optical excitation is a very key problem in experiments.
In addition, the nano-sensor device has also received full attention in recent years, including single molecule detection technologies based on nano-pores, tunneling sensing, field effect transistors, and the like, and has gained wide attention and development. The measuring mode of tunneling sensing is applied to the research of mechanisms of DNA sequencing, single-molecule detection and single-molecule chemical reaction by taking a sub-5 nanometer gap electrode device as an analysis element and measuring the change of tunneling current brought by applying a constant potential measuring target object, and is one of the important leading fields of the current world development. However, the tunneling sensing measurement method in the constant potential mode also has unavoidable technical limitations, and the method has single signal, poor sensitivity and low selectivity, and cannot provide analyte dynamics information, so that the application of quantum tunneling sensing is greatly limited.
Disclosure of Invention
The invention provides a method and a device for single molecule characterization of time domain, space domain and spectral domain based on nanometer gap electrode pair, which utilizes a multifunctional integrated nanometer tunnel probe of nanometer gap to replace the metal needle tip of the traditional STM, introduces a femtosecond-excited single molecule tunneling technology, and simultaneously utilizes a unique probe structure to realize the combination of a plasmon polariton local enhanced Raman probe and a fluorescent probe, thereby realizing the precise multifunctional nanometer scale time-space comprehensive characterization of single molecules.
The invention discloses a time domain, space domain and spectral domain single molecule characterization device system based on a nanometer gap electrode pair, which mainly comprises three detection subsystems, namely a probe and tunneling electricity test system (subsystem uniform), an ultrafast optical modulation tunneling detection system (subsystem two) and a single molecule Raman detection system (subsystem three), wherein corresponding control processors are arranged among the three detection subsystems, and all the control processors and a computer jointly form a system control system (subsystem four).
1) Probe and tunneling electricity test system: the system consists of a nanometer gap probe, a three-dimensional nanometer precision mobile platform and a tunnel signal detection module.
Preferably, the nanogap probe can analyze single molecules with smaller nanoscale, and the tunneling current change of the single molecules in the process of passing through the probe electrode gap is observed by applying constant potential, so that the nanogap probe has the capability of realizing the mechanism research of DNA sequencing, single molecule detection and single molecule chemical reaction, and can further realize the improvement of time resolution by combining with ultrafast light modulation; the three-dimensional nano precise moving platform can precisely move the nano probe to a required position to perform nano scanning and high-precision sub-nano positioning of a detection sample; the high-precision tunneling signal detection module can realize the time delay and the precise synchronization of the pulse laser of the femtosecond laser which is related to a control system.
2) Ultrafast light modulation tunneling detection system: the device mainly comprises a laser source, a light beam polarization modulation module, a confocal scanning module and a femtosecond laser pumping-detecting module.
The subsystem can combine the tunneling electrical detection platform with the femtosecond laser pumping-detection system, can provide multi-parameter signal output (such as tunneling current, fluorescence spectrum, fluorescence imaging and the like) for the measurement process, and realizes single molecule analysis with higher time and space resolution.
Preferably, the light source regulating and controlling module comprises a titanium gem laser femtosecond pulse high repetition frequency adjustable laser, a collimating and beam expanding unit, a wavefront regulating and controlling unit, a two-dimensional high-precision scanning unit and a confocal focusing unit. After the femtosecond laser beam is subjected to beam expanding collimation, the pulse number is selected by using a pulse selector, and the spatial light modulator or the polarizer is used for regulating and controlling the beam so as to generate different pumping photon states and form stronger excitation signal codes. Meanwhile, the pulse laser passes through the confocal scanning module and is focused on the needle point of the sample through the high-numerical-aperture objective lens, so that the local fluorescence effect and the tunnel junction barrier change can be induced. The change of each pulse is indicative of the ability of the system to detect carrier excitations and transitions, and the frequency of the pulses reflects the continuous change of the state. Outputting femtosecond laser pulse synchronous signals to control the single-molecule photoelectric integrated detection system of tunneling sensing, and realizing the nano probe-tunneling detection and the time gating adopting femtosecond pulse waves.
3) Single molecule raman detection module: the invention utilizes the metal nano structure of the tunnel junction to construct special needle tip surface plasmon polariton local field enhancement characteristics, and can combine fluorescence and Raman spectrum detection technologies to obtain the fingerprint spectrum information of molecules in the tunnel junction.
Preferably, the invention adopts a direct current laser, and laser emitted by the direct current laser is expanded and collimated, then passes through a high numerical aperture objective lens, is converged and irradiated on the sample and the electrode probe, generates a local plasma laser element wave, and induces and generates Raman radiation of the sample. The Raman radiation is collected and then forms a spectrum image through a Raman monochromatic system, and an area array EMCCD camera is used for detecting spectrum signals, so that real-time high-resolution imaging and spectrum analysis utilization are realized.
Based on the plasmon enhancement effect, the characteristics of electromagnetic field intensity distribution and Raman enhancement exponential attenuation of the plasmon enhancement effect have the near field enhancement effect, the Raman molecular signals can be greatly improved, and the interference of background light noise is reduced. When the molecule passes through the tunnel junction, the molecular probe with Raman activity can position and track the molecule to be detected in real time. By means of surface Raman or fluorescence increasing and other methods, interaction between the perforated molecules and the tunnel junction can be reflected through changes of Raman fingerprint information, light intensity, wavelength, service life and the like of the molecules, the purpose that the molecules pass through the tunnel junction through spectrum monitoring is achieved, and the method is complementary to a direct current tunneling sensing analysis technology.
4) A system control system: the device mainly comprises a light source controller, a light spot modulation controller, a scanning controller and a signal detection controller which are all connected with a computer.
Preferably, the high precision synchronization and time delay in time of the control system, the sub-nanometer motion and alignment of the control movement and scanning system, the detection of the optical spectrum, the detection of the image, the detection of the tunneling current signal.
The invention discloses a method for comprehensively representing single molecules based on light-electricity under a nanometer gap electrode pair, which utilizes a nanometer probe to detect tunneling current to realize high-precision detection of the single molecules, utilizes an ultrafast light modulation tunneling detection system to combine a tunneling electricity detection platform with a femtosecond laser pumping-detection system, can provide multi-parameter signal output (such as tunneling current, fluorescence spectrum, fluorescence imaging and the like) for a measurement process, and realizes single molecule analysis with higher time and light resolution; the fingerprint spectrum information of molecules in the tunnel junction can be obtained by utilizing the enhancement characteristic of the probe tip surface plasma wave local field and combining the fluorescence and Raman spectrum detection technology, thereby realizing the characterization of single molecules in time domain, space domain and spectrum domain.
Drawings
FIG. 1 is a system diagram of the apparatus of the present invention;
FIG. 2 is a schematic view showing the structure of a single-molecule detecting device of a pair of nanogap electrodes;
FIG. 3 is a graph of conductance versus time for a tunneling electrode in the presence of single stranded DNA molecules.
Detailed Description
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced in other ways than those specifically described herein, and thus the present invention is not limited to the specific embodiments disclosed below.
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the accompanying drawings are illustrative and intended to explain the present invention and should not be construed as limiting the present invention.
As shown in fig. 1, the multifunctional single molecule characterization device system device based on sub-5 nm gap electrode pair of this embodiment includes: the laser device comprises a 632nm wavelength laser 1, a single-mode polarization-maintaining optical fiber 2a and a single-mode polarization-maintaining optical fiber 2b, a collimation beam expander 3a and a collimation beam expander 3b, a reflector 4a, a reflector 4b and a reflector 4c, a femtosecond laser 5, a pulse selector 6, a dichroic mirror 7a and a dichroic mirror 7b, a half wave plate 8, a quarter wave plate 9, a beam splitter 10, a scanning galvanometer system 11, a lens 12a, a lens 12b and a lens 12c, a Field lens 13, a microscope objective 14, a sample stage 15, a 20-60 times collection objective 16, a CCD17, a nanogap electrode tunneling probe 18, a filter 19, a multimode optical fiber 20a and a multimode optical fiber 20b, an avalanche detector photodiode APD21, a Raman spectrometer 22, a three-dimensional nanometer precision moving stage 23, a tunnel junction monomolecular analyzer 24, a synchronous control FPGA (Field Programmable Gate Array) board 25, a signal collection FPGA board 26 and a computer 27.
The pulse selector 6 is used for obtaining femtosecond laser pulses with different delay times, and continuous time delay within the range from femtosecond to microsecond can be obtained, so that dynamic information of a sample excited state can be obtained, and time resolution is improved to femtosecond.
Wherein, the microscope objective 14 is a high numerical aperture objective, and the numerical aperture NA is 1.4; the collection objective 16 and the CCD17 are used to obtain wide field imaging information of the sample.
Where a nanogap generally refers to an aperture, channel or via formed or otherwise provided in a material and then connected to an electrode to access a sensing region and can be used to measure a change in tunneling current caused by a single molecule (see figure 2). Meanwhile, the nano metal gap probe can generate local plasma element excimer oscillation to induce and generate enhanced Raman radiation; the three-dimensional nanometer precision moving platform 23 is used for precisely moving the nanometer probe to a required position to perform nanometer scanning and high-precision sub-nanometer positioning of a detection sample.
The Raman spectrometer is used for receiving Raman radiation signals enhanced by probe local plasmon polariton waves and realizing Raman spectrum detection.
The synchronous control of the laser 1, the femtosecond laser 5, the pulse selector 6, the scanning galvanometer system 11, the three-dimensional nanometer precise mobile platform 23 and the signal acquisition FPGA board 26 is realized by controlling the FPGA board 25 synchronously by the computer, the signal acquisition FPGA board 26 can synchronously acquire wide-field signals of the CCD17, electric signals of the tunnel junction single-molecule analyzer 24, fluorescence signals detected by confocal excitation of the detector avalanche photodiode APD21 and spectrum signals of the Raman spectrometer 22, and relevant information is transmitted to the computer 27 to be transmitted to a user.
The process of obtaining single-molecule characterization time domain information by using the device shown in FIG. 1 is as follows:
the device comprises a tunneling current detection module, a traditional direct current constant potential mode can be adopted to record tunneling current, and by adopting an ion current detection technology, tunneling single molecules can provide molecular intrinsic physical property information including molecular substructure and energy level structure information. The tunneling detection module is simplified and expressed in fig. 1 and is composed of a nano probe 18 and a tunnel junction single molecule analyzer 24, and the single molecule detection embodiment expressed in fig. 2 shows the process of acquiring single molecule meter time domain information and detecting tunneling current in the device of the present invention in detail.
FIG. 2 is a schematic diagram showing the structure of a single-molecule detection device with a pair of nanogap electrodes, in which a probe is composed of a pair of sub-nanogap electrodes 28a to 28B and dielectrics 29a to 29B, the end A is a near-sample end, and the end B is a current detection end. The single molecule analyzer is composed of a measurement power supply 30, electrophoresis electrode pairs 31 a-31 b, an electrophoresis power supply 32, a current amplification module 35, an ammeter 36 and a control unit 33. The control unit 33 can control the measurement power supply 30, the electrophoresis power supply 32 and the current amplification module 35, and is responsible for controlling the bias voltage of the tunnel probe and the amplification and detection of the current signal, realizing the detection of tunneling electrical information, and transmitting the amplified current to the signal acquisition FPGA board 26.
In the embodiment of DNA single strand detection, the A-terminal is shown in FIG. 2 (b), and the voltage of the appropriate electrophoresis electrode pair 31 a-31 b is set by the electrophoresis power supply 32, thereby controlling the movement of single molecules through the tunnel junction. The measurement power supply 30 may apply a voltage to the electrodes of the nanogap electrode pairs 28 a-28B, and when the single molecule 34 passes through the tunnel junction, the nanogap electrode pairs 28 a-28B generate a tunneling current, which is conducted from the a terminal to the B terminal in the nanogap electrode pairs 28 a-28B, thereby facilitating the measurement of the current at the B terminal. The terminal B is connected to a current amplification module 35, and an ammeter 36 measures the amplified tunneling current and sends the current to the signal acquisition FPGA board 26. When an analyte passes through a tunneling junction (a nano electrode gap) under the action of a driving force, the tunneling current changes instantaneously, so that the conductance changes, the size and the duration of the conductance reflect the information of the analyte, and the analyte can be detected through the statistical analysis of a large amount of pulse currents. FIG. 3 is a graph of conductance-time generated when a single-stranded DNA molecule continuously passes through a tunneling electrode with a gap of about 1.1 nm, when the DNA molecule is located in the middle of the electrode gap, a sharp impulse signal (tunneling current) can be detected, and thus the change of the current (conductance) reflects the corresponding information of each single-stranded DNA molecule passing through the electrode pair.
In order to improve the time resolution and the space resolution of the tunnel current detection, the device can also realize the optical coupling tunneling current detection through femtosecond laser pumping-detection. The device adopts the confocal system to arouse, realizes spatial resolution's promotion. The femtosecond laser 5 outputs femtosecond laser through the single-mode polarization-maintaining fiber 2b, and the femtosecond laser enters the pulse selector 6 after passing through the collimation beam expander 3b, and the pulse selector can control the pulse delay of the femtosecond laser through different delay settings. After being modulated by the pulse selector, the excitation light is reflected by the dichroic mirror 7a and the dichroic mirror 7b, enters the scanning galvanometer system 11 to scan the excitation light on the sample surface, and is modulated into circularly polarized light (or other required polarized light) by the half-wave plate 8 and the quarter-wave plate 9. After passing through a 4f system composed of a lens 12a and a field lens 13, the femtosecond excitation light is focused by a microscope objective 14 onto the tip of a nanoprobe 18. The excitation stimulation of the femtosecond laser generates the potential barrier change of the tunneling junction to form rapid change, and then the rapid and accurate electric signal detection of the tunneling electrode is carried out under the control of the tunnel junction single molecule analyzer 24, so that the time resolution of tunnel current detection is remarkably improved.
The method for acquiring single molecule representation spatial domain information by adopting the device shown in FIG. 1 comprises the following steps:
the invention can obtain the fluorescence information of single molecule representation based on the confocal system of the device, after the exciting light passes through the confocal system, the exciting light can be focused on the sample fixed on the sample stage 15 by the microscope objective 14, the fluorescence generated by the sample can be firstly collected by the collecting objective 16, then received by the CCD17 and collected into the signal collecting FPGA plate 26, and simultaneously can be collected by the microscope objective 14, and then passes through the field lens 13 and the 4f system of the lens 12a again, and then is descanned by the scanning galvanometer system. Then, the fluorescent signal penetrates through the dichroic mirror 7b, is filtered by the optical filter 19 to remove stray light, is collected by the multimode fiber 20a and is sent to the detector APD21, and finally is collected by the signal collection FPGA board to obtain fluorescent information, so that the resolution of a spatial domain is improved under the excitation detection of a confocal system.
Besides, the invention can also obtain the spatial information of single molecules by utilizing the plasma excitation of the nanoprobe. Under the excitation of proper voltage control or femtosecond excitation light, the nano probe 18 and a sample realize local plasma excitation in a near field, excited optical signals are collected through a microscope objective 14, then are collected through a field lens 13, a reflector 4b, a lens 12a, a scanning galvanometer system 11, a dichroic mirror 7b and an optical filter 19, are collected through a multimode optical fiber 20a and a detector APD21 after being converged through the lens 12b, and the three-dimensional nano precise moving platform 23 is controlled through a synchronous control FPGA board to realize high-precision movement of the probe, so that the sample is scanned, and ultrahigh-resolution spatial information of the sample is obtained.
The method for obtaining single-molecule characterization spectral domain information by using the device shown in FIG. 1 is as follows:
the laser 1 with the wavelength of 632nm outputs exciting light through the single-mode polarization-maintaining optical fiber 2a, and after being collimated and expanded by the collimating and expanding lens 3a and reflected by the reflecting lens 4a, the exciting light passes through the dichroic mirror 7a to be combined with a femtosecond exciting light path and enters the confocal system. After passing through the optical path, the Raman radiation signal is collected by the microscope objective 14, passes through the field lens 13, the reflecting mirror 4b, the lens 12a and the scanning galvanometer system 11, enters the Raman spectrum detection optical path after being reflected by the beam splitter 10, is reflected by the reflecting mirror 4c, is focused by the lens 12c into the multimode optical fiber 20b and is transmitted to the Raman spectrometer 22 for collection and analysis, and finally, the spectrum information is collected by the signal collection FPGA board 26.
The above description is only exemplary of the preferred embodiments of the present invention, and is not intended to limit the present invention, and any modifications, equivalents, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (6)
1. A time domain, space domain and spectrum domain single molecule characterization device based on a nanometer gap electrode pair is characterized by comprising:
the probe and tunneling electricity test system comprises a nanometer gap probe, a three-dimensional nanometer precise mobile platform and a tunnel junction single molecule analyzer; controlling the movement of the nanometer gap probe by a three-dimensional nanometer precise moving platform; under the excitation of proper voltage control or femtosecond excitation light, the local plasma excitation of the nano-gap probe and the sample is realized in a near field, an excited optical signal is collected by a microscope objective and then collected by a detector through a field lens, a reflector, a lens, a scanning galvanometer system, a dichroscope and an optical filter, the high-precision movement of the nano-gap probe is realized by controlling a three-dimensional nano precision moving platform, the sample is scanned, and the ultrahigh-resolution spatial information of the sample is obtained;
the ultrafast optical modulation tunneling detection system realizes optical coupling tunneling current detection through femtosecond laser pumping-detection, a femtosecond laser output by a femtosecond laser enters a pulse selector after passing through a collimation beam expander, and the pulse selector controls pulse delay of the femtosecond laser through different delay settings; after being modulated by the pulse selector, the exciting light enters the scanning galvanometer system to realize the scanning of the exciting light on the sample surface, is modulated into circularly polarized light by the half wave plate and the quarter wave plate, and is focused on the needle tip of the nano probe by the microscope objective; the excitation stimulation of the femtosecond laser generates the potential barrier change of the tunneling junction to form rapid change, and then the rapid and accurate electric signal detection of the tunneling electrode is carried out under the control of the tunnel junction single-molecule analyzer, so that the time resolution of tunnel current detection is remarkably improved;
the single-molecule Raman detection system is used for collecting a Raman radiation image emitted by the sample; the laser is collimated and expanded by the collimating and expanding lens, penetrates through the dichroic mirror, is combined with the femtosecond excitation light path and enters the confocal system; the Raman radiation signal is collected by the microscope objective again, passes through a field lens, a reflector, a lens and a scanning galvanometer system, enters a Raman spectrum detection light path after being reflected by a beam splitter, and is transmitted to a Raman spectrometer for collection and analysis.
2. The time, space and spectral domain single molecule characterization device based on nanogap electrode pair down according to claim 1, wherein after the femtosecond laser beam is expanded and collimated, the pulse number is selected by using a pulse selector, and a spatial light modulator or a polarizer is used for beam regulation and control so as to generate different pump photon states and form stronger excitation signal codes.
3. The time domain, space domain and spectral domain single molecule characterization device based on the nanometer gap electrode pair down according to claim 2, characterized in that the pulse laser is focused on the needle tip of the nanometer gap probe through the confocal system and the high numerical aperture objective lens to induce the local fluorescence effect and the tunnel junction barrier change;
the change of each pulse is indicative of the ability of the system to detect carrier excitations and transitions, and the frequency of the pulses reflects the continuous change of the state.
4. The time domain, space domain and spectral domain monomolecular characterization device based on the nanogap electrode pair as claimed in claim 1, wherein in the monomolecular Raman detection system, a direct current laser is adopted, after beam expanding and collimation, laser passes through a high-numerical-aperture objective lens to be converged and irradiated on a sample and an electrode probe, a local plasma laser element wave is generated, and Raman radiation of the sample is induced; the Raman radiation is collected and then forms a spectrum image through a Raman monochromatic system, and an area array EMCCD camera is used for detecting spectrum signals.
5. The single-molecule characterization device based on the time domain, the space domain and the spectral domain under the nanogap electrode pair according to claim 1, further comprising a control system, wherein the control system specifically comprises a light source controller, a light spot modulation controller, a scanning controller and a signal detection controller, and the light source controller, the light spot modulation controller, the scanning controller and the signal detection controller are all connected with a computer.
6. The apparatus according to claim 5, wherein the control system controls the detection of the spectrum, the image detection, and the tunneling current signal with high precision synchronization and time delay.
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