CN112798535A - Terahertz microstructure circular dichroism sensing system for living cell detection - Google Patents
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Abstract
The invention discloses a THz microstructure circular dichroism sensing system for living cells in a liquid environment. The reflective structure can effectively weaken the absorption loss of water to THz waves, and the purpose of improving the signal-to-noise ratio of the system is achieved; adding a THz wave plate at an incident end to enable incident waves to be changed into circularly polarized light near the frequency of 0.8THz, and performing chiral sensing detection by generating a THz chiral spectrum with a high Q value; a THz polaroid is added behind the reflection system, and complete polarization state information of the emergent wave is obtained through detection of the rotating polaroid to obtain a circular dichroism spectrum; in addition, the silicon dielectric grating is used as a sensor, the interaction between the THz wave and the sample can be enhanced by the strong local resonance generated by the silicon dielectric grating, the contact area between the dielectric grating microstructure and the measured object is increased, a microfluidic channel is formed, the optical response of the sample is enhanced, and the sensing sensitivity is improved. The experimental results show that: the sensitivity of the sensor to the change of resonance strength and the frequency shift can reach 3.4dB·mL/106cells and 5.2 GHz. mL/106On the order of cells.
Description
Technical Field
The invention belongs to the technical field of terahertz science, and particularly relates to a terahertz microstructure circular dichroism sensing system for living cell detection in a liquid environment and a using method thereof.
Background
Terahertz (THz) waves generally refer to waves having a frequency of 0.1-10 THz (1 THz-10)12Hz), between microwave and infrared, have received wide attention due to their excellent properties of small photon energy, non-invasive and non-ionizing. In recent years with THzThe development of sources, detectors and various modulation devices, the continuous maturation of the THz technology, has been widely used in the field of biomedical sensing, and researchers have now conducted sensing studies on biological substances such as enzymes, proteins, microorganisms, cells, tissues, etc. The method has important significance in timely and accurately sensing and detecting the cells, and at present, physical instruments such as a fluorescence confocal microscope, a flow cytometer, a mass spectrometer and the like are widely applied to cell detection. In contrast, THz sensing has the advantages of real-time, broadband, no-mark, nondestructive detection and the like, but also has the problems of low sensitivity, strong water absorption and the like.
THz sensing is mainly based on Time Domain Spectroscopy (TDS) systems, i.e. sensing characterization by the THz transmission or absorption spectrum of the sample. However, this method has strict requirements on the state of the sample, and cannot detect liquid (especially aqueous) samples, so that the THz detection of cells usually needs to be performed by water absorption or drying treatment to ensure the drying of the sample environment to reduce the absorption of water to signals [ Biosensors and Bioelectronics, 22, 1075 (2007); applied Physics Letters, 108, 241105, (2016); biomedical Optics Express, 11, 2416 (2020). However, most cell cultures need to be performed in a water-rich or liquid environment, and water shortage is unfavorable for cell growth and even affects the activity of cells, so that detection of living cells cannot be realized. In order to measure cells in a liquid environment, a reflective time domain spectroscopy system is needed, and THz waves are not needed to penetrate through a liquid material, so that the purposes of enhancing detection signals and improving the signal-to-noise ratio of the system are achieved.
In addition, in addition to the detection of a sample by transmission or absorption spectroscopy, the polarization state of the emergent wave may also change with the sample. Conventional THz sensing ignores the detected phase and polarization information and therefore the sample characteristic information that can be detected is very limited. If the polarization state change of the emergent signal can be detected, the circular dichroism spectrum of the sample can be obtained, besides reflecting the type and size of the detected sample, the circular dichroism spectrum can also provide the structural, kinetic and thermodynamic information of cells, and is a powerful tool for researching cells with different types and sizes in the fields of biology, medicine, chemistry, physics and the like [ Science Advances 3: e1602735 (2017), which has very important significance in sensing.
In addition, the THz wave emitted by the THz source of the conventional TDS system is linearly polarized, i.e., the THz wave incident on the sample is linearly polarized in a wide band. For some biological samples, under the condition of chiral light incidence, namely circularly polarized light incidence, complex chiral polarization response can be generated, so that the sensing sensitivity can be improved, and more sample information can be reflected. Therefore, the proper wave plate is added at the THz incident end, the polarization sensing is carried out by generating the chiral polarized light, the circular dichroism spectrum of the sample is obtained through calculation for characterization, and the performance of the sensing system can be effectively improved. The method is rarely reported in the existing THz sensing field.
Furthermore, by using an artificially fabricated microstructure device as a sensor, a local field is formed between the structure and the sample under the condition of oblique incidence of an incident wave with a complex polarization state, and strong resonance and polarization responses are generated in the field, so that the interaction between the electromagnetic wave and the sample can be enhanced, and the Optical response of the sample can be enhanced [ Advanced Optical Materials, 1900721 (2019) ]; applied Physics Letter, 108, 241105 (2016). In addition, the microstructure can increase the contact area between the sensor and a sample to be detected, the sensing effect can be further improved, and the sensing capability of the system is enhanced.
In summary, on one hand, the rapid development of the THz technology and the urgent needs in the fields of biology, chemistry and the like put forward higher performance requirements on the THz sensing detection system; on the other hand, the existing traditional THz sensing system has the defects of low sensitivity, limited detection information, poor applicability and the like. Therefore, a THz biosensing method with high sensitivity, no label and polarization detection capability facing to liquid samples is urgently needed.
Disclosure of Invention
The invention aims to provide a THz microstructure circular dichroism sensing system facing living cells in a liquid environment, and a specific detection method thereof is explained. The system can carry out high-sensitivity sensing detection on living cells in a liquid environment, obtain the circular dichroism spectrum of the sample for sensing characterization, and provide more sensing information of the cell sample while improving the sensing sensitivity.
In order to achieve the purpose, the system structure and key components comprise a front THz polaroid (1), a THz wave plate (2), a front THz lens (3), a metal reflecting prism (4), a silicon dielectric grating sensor (5), a sample cell (6), a rear THz lens (7) and a rear THz polaroid (8), wherein the silicon dielectric grating sensor (5) is used as the bottom of the sample cell (6), and the sample cell (6) is positioned above the metal reflecting prism (4). The THz wave plate (2) is a birefringent element for generating pi/2 phase delay, the working wavelength is within the range of 300-400 mu m, and the included angle between the optical axis orientation of the wave plate and the polarization direction of incident electromagnetic waves is +/-45 degrees during working; the microstructure sensor adopts a silicon medium grating (5) which is formed by periodically etching rectangular grooves on the surface of a high-resistance silicon wafer, wherein the grating period of the silicon medium grating is 100-150 mu m, the groove etching depth is 100-150 mu m, and the etching width is 50-75 mu m.
The basic principle of the invention is as follows: the linear polarization THz plane wave of the electric field vibrating along the vertical direction is transmitted along the horizontal direction, the polarization degree is improved through the preposed polarization plate (1), the polarization state is changed through the THz wave plate (2), the THz wave is focused through the preposed THz lens (3), and the THz wave is reflected to the silicon medium grating sensor (5) by the metal reflection prism (4) at a certain angle; THz waves are reflected on the contact surface of the silicon medium grating sensor (5) and the living cell liquid sample, are recovered into plane waves which are transmitted in parallel through a rear THz lens (7), and are emitted through a rear polaroid (8); the reflection system can be placed in the THz parallel optical path of a traditional time domain spectroscopy system, and a sample cell (6) is prepared for containing cell sample solution.
In a reflective sensing system, THz waves do not need to pass through a sample, and the absorption loss of water to the THz waves can be effectively weakened, so that the aims of enhancing detection signals and improving the signal-to-noise ratio of the system are fulfilled. A THz quarter wave plate is added at an incident end, so that incident waves are changed into a narrow-band circular polarization state near the frequency of 0.8 THz; a THz polaroid is added behind a reflection system, a group of orthogonal signals of emergent waves can be obtained by detecting through rotating the direction of the polaroid, complete polarization state information is restored, a reflection type time domain polarization spectrum (RTDPS) system is formed, detection sensitivity is improved, complete polarization state detection of a sample in a broadband range is achieved, and a circular dichroism spectrum is obtained through further analyzing the difference between levorotatory light and dextrorotatory light. The narrow-band circularly polarized light generated by the wave plate added at the incident end is represented as a resonance peak (valley) with a high Q value on the circular dichroism spectrum. In addition, a silicon dielectric grating structure is adopted as a sensor, and the microstructure has strong resonance and polarization response under the condition of oblique incidence of electromagnetic waves, so that the sensing sensitivity of the system can be remarkably enhanced. The method can not only detect the difference of the same cell under different concentrations, but also distinguish the difference of different cells under the same concentration.
The invention has the advantages that:
1. by adopting the reflective THz sensing system, THz waves do not need to pass through the whole sample solution, so that huge THz wave absorption loss caused by the solution is avoided, the intensity of detected signals can be obviously increased, and the signal-to-noise ratio is improved.
2. The THz wave plate is added at the incident end, so that incident waves are changed into circularly polarized light near the frequency of 0.8THz, and the chiral sensing detection is carried out by generating a THz chiral spectrum with a high Q value, so that the sensitivity of sensing can be effectively improved, and more sample information can be reflected.
3. The THz polaroid is added behind the reflection system, a group of orthogonal signals of the emergent wave can be obtained by detecting through rotating the direction of the polaroid, and complete information of any polarization state is restored, so that the effective information amount of a system detection sample is increased, and the detection sensitivity is further improved.
4. The silicon dielectric grating structure is used as a sensor, the interaction between the THz wave and a sample can be enhanced by the strong local resonance generated by the sensor, the contact area between the dielectric grating structure and a measured object is increased, a micro-fluid channel is formed, the optical response of the sample is enhanced, and the sensing sensitivity is improved.
5. The circular dichroism spectrum is utilized to characterize the sample, not only the quantity detection can be carried out on the same cell, but also different cell types can be distinguished under the condition of the same quantity.
Description of the drawings:
FIG. 1 is a schematic diagram of a high-sensitivity reflective microstructure circular dichroism sensing system facing living cells in a liquid environment;
FIG. 2 is a schematic diagram of (a) the operation of the THz wave plate; (b) schematic diagram of the structure and size of the silicon medium grating used in the example;
FIG. 3 shows the performance parameters of the THz wave plate: (a) -45 ° and +45 ° polarization components of the THz-TDS signal of the wave plate; (b) -the phase of the 45 ° and +45 ° polarization components and their phase difference; (c) simulated (sim) and experimental (exp) CD spectra of THz plate;
FIG. 4 is a CD profile of HepG2 cells and cell culture fluid under different amounts of aspirin treatment, inset graph showing the relationship between the amount of aspirin drug added and the number of cells;
FIG. 5 is a polarization ellipse of an output THz wave at three characteristic frequencies (a)0.53THz, (b)0.78THz and (c)1.05 THz;
FIG. 6 is a graph showing the relationship between (a) the CD spectrum peak and the amount of aspirin added in the vicinity of 0.53, 0.80 and 1.05 THz. (b) The relationship between the frequency shift of CD spectrum near 0.53THz and the amount of aspirin added; the points in the graph are the experiments, and the dotted line is the fitting result;
FIG. 7 is (a) CD profiles of three hepatoma cells HepG2, Huh7 and H7402; (b) polarization ellipse of output wave of three kinds of liver cancer cells at 0.53 THz.
The specific implementation mode is as follows:
the invention relates to a terahertz microstructure circular dichroism sensing system for living cell detection. The system structure schematic diagram is shown in FIG. 1: the sensing system can obtain the circular dichroism spectrum of a sample, and performs high-sensitivity polarization sensing detection on living cells in a liquid environment. In order to realize the sensing detection of the liquid sample and avoid the absorption loss of the liquid sample to THz, a reflection type system is adopted, so that the signal-to-noise ratio of the system can be obviously improved; the THz wave plate is a birefringent element for generating pi/2 phase delay, THz linearly polarized waves of an electric field along the y direction vertically enter the wave plate, and emergent light becomes a narrow-band circular polarization state; THz polaroids are respectively arranged in front of and behind the reflection system, a group of orthogonal signals of emergent waves can be obtained by detecting through rotating the directions of the polaroids, complete polarization state information is restored, an RTDPS system is formed, and polarization state detection of a sample in a broadband range is realized while the detection sensitivity is improved; in addition, the silicon medium grating is used as a sensor, the microstructure has strong resonance and polarization response under the condition of oblique incidence of electromagnetic waves, and has the functions of increasing the contact area with a measured object and forming a microfluidic channel, so that the sensing sensitivity of the system can be obviously enhanced.
In order to obtain the complete polarization state of the emergent wave, the rear polarization plate is respectively rotated by +45 degrees and-45 degrees to obtain time domain spectrum information of two orthogonal components of the emergent THz wave, and the amplitude and the phase are respectively obtained through Fourier transform calculation: a. the±45°(ω) and δ±45°(ω) reflectance spectra R for left-handed Light (LCP) and right-handed light (RCP)LCPAnd RRCPCan be calculated by the following formula:
we define the circular dichroism spectrum (CD spectrum) as RLCPAnd RRCPThe difference in dB between, and thus CD, can be calculated by the following equation:
the sensing CD spectrum reflects the influence of the sample on the THz polarization state, can reflect the type and size of the detected sample, can provide structural, kinetic and thermodynamic information of cells, is a powerful tool for researching cells of different types and sizes in the fields of biology, medicine, chemistry, physics and the like, and has very important significance in sensing.
In addition, the formula for calculating the Q value of the spectrum is:
the invention is further illustrated by the following specific embodiment; it is to be understood that the specific embodiments described herein are for purposes of illustration only and are not to be construed as limitations of the invention. All other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without any creative work belong to the protection scope of the present invention. The THz wave plate (2) is a birefringent element generating pi/2 phase delay, the working wavelength is 375 mu m, the included angle between the optical axis orientation of the wave plate and the polarization direction of the incident electromagnetic wave is +/-45 degrees when the THz linearly polarized wave vertical incidence wave plate is in work, the emergent light becomes a narrow-band circular polarization state, and the emergent light deviating from the working wavelength is an elliptical polarization state, as shown in figure 2 (a). The silicon dielectric grating is formed by periodically etching grooves on a silicon wafer, and has an overall thickness h of 500 μm, a period a of 105 μm, a groove width b of 60 μm, and a depth d of 120 μm, as shown in fig. 2 (b). In the experiment, a culture solution of HepG2 liver cancer cells is used as a sample for sensing, and different amounts of aspirin medicines (1mM, 2mM and 4mM) are added into 1mL of cell culture solution to inhibit proliferation of the cells, so as to obtain cell solutions with different concentrations.
FIG. 3 shows some of the performance parameters of the THz plate: fig. 3(a) shows ± 45 ° components of the time-domain spectral signal passing through the THz plate when the y-direction linearly polarized light is incident. It can be seen that the two mutually perpendicular signals differ by about 0.32 ps. After fourier transform, the phases in two directions are obtained, as shown in fig. 3 (b). It can be seen that in the range of 0.1 to 1.5THz, the phase difference between + -45 deg. components decreases with increasing frequency. At 0.8THz, the phase difference is pi/2 (as shown in the inset in fig. 3 (b)), i.e., at this frequency position, the device functions as a λ/4 plate at this frequency, so for linearly polarized light incident in the y-axis direction, the emergent wave becomes circularly polarized light at 0.8THz, CD reaches an extremum, and experiments can reach 50dB or more, and the Q value reaches 21 or more. While at other frequencies the output wave is elliptical or linearly polarized, as shown in fig. 3 (c). The figure shows that the experimental result is well matched with the simulation result.
FIG. 4 shows the CD spectrum sensing results of HepG2 cells and cell culture fluid under different amounts of aspirin treatment using silicon medium grating as sensor under the condition that wave plate changes the polarization state of incident light; from the results, it can be seen that: there are three characteristic peak (valley) positions of the CD spectrum, located at 0.53THz, 0.80THz and 1.05THz, respectively. Analysis shows that the characteristic valley near the 0.53THz position has good intensity change of peak frequency shift along with the increase of the dosage of aspirin; whereas at 0.80 and 1.05THz, the characteristic peaks (valleys) respond to changes in aspirin dosage primarily by a change in the intensity of the CD value, with the CD values at both locations decreasing with increasing dosage. The inset in fig. 4 is the relationship between the amount of aspirin drug added and the number of cells, and it can be seen that the number of cells decreases with increasing aspirin drug. The number of cells in the absence of added drug, i.e., when cells normally proliferate, is 4.3X 106cells/mL, cell number decreased to 1.1X 10 when 4mM aspirin drug was added6cells/mL。
Fig. 5 is a polarization ellipse of the output THz wave at the three characteristic frequencies described above. The terminal trajectory equation for the electric vector E, also called the polarization ellipse, is as follows:
it can be seen that at 0.53THz, the output wave is in the right-handed polarization state at different aspirin doses, and as aspirin is reduced, the output wave is more likely to be in the circular polarization state (the degree of polarization is reduced). At 0.80THz, the output wave is in a left-handed polarization state under different dosages, the output wave is more in a linear polarization state (the polarization degree is increased) along with the decrease of the dosages, and at 1.05THz, the output wave is in a right-handed polarization state under different dosages, and the output wave has a trend of changing to a circular polarization state (the polarization degree is reduced) along with the decrease of the dosages.
We further analyzed the CD spectra around the characteristic location as a function of the specific value of aspirin dose. As shown in fig. 6: FIG. 6(a) is a graph showing the relationship between the peak of the CD spectrum and the amount of aspirin added at around 0.53, 0.80 and 1.05 THz; (b) the relationship between the frequency shift of the CD spectrum around 0.53THz and the amount of aspirin is added; the points in the graph are the experimental results and the dashed line is the fitting result. It can be seen from the graph that at the three characteristic frequencies, the CD value linearly decreases with increasing aspirin dose, while in the vicinity of 0.5THz, the resonance frequency linearly shifts toward the high frequency with increasing aspirin concentration.
We define the formula of the detection sensitivity as:
wherein S isdBAnd SΔfThe sensitivity to the change in the characteristic peak intensity and the change in the characteristic frequency, respectively, and Δ CD and Δ f are the corresponding change in the characteristic peak intensity and the change in the characteristic frequency, respectively, when the cell concentration is Δ n. As can be seen from FIG. 4, when the aspirin amount was increased from 0mM to 4mM, Δ n was 3.2X 106cell/mL. From the results in fig. 6(a) and (b), it can be obtained that the intensity sensitivities of the three characteristic positions are S, respectivelydB-0.53＝2.0dB×mL/106cells、SdB-0.80＝3.4dB×mL/106cells、 SdB-1.05＝1.9dB×mL/106cells, frequency shift sensitivity at 0.53THz position is SΔf-0.53＝5.2GHz×mL/106cells。
In addition, sensing detection is carried out on three different types of liver cancer cells, namely HepG2, Huh7 and H7402 under the condition of not adding aspirin. FIG. 7(a) shows the CD spectrum difference of three hepatoma cells, and FIG. 7(b) shows the polarization ellipse of the output wave of the three hepatoma cells at 0.53 THz. It can be seen that the CD spectra of the three hepatoma cells have a significant difference around 0.53THz, and the difference is also reflected in the polarization state of the emergent wave.
The sensing system has the advantages that the polarization state of the incident THz wave is changed through the wave plate, the quantity detection and the cell type identification of the living cells in the liquid environment are realized by utilizing the RTDPS system and the silicon medium grating sensor, and the resonance intensity is changedThe sensing sensitivity of the chemosynthesis and the frequency shift can reach 3.4 dB.mL/10 respectively6cells and 5.2 GHz. mL/106On the order of cells. The novel THz sensing system and the sensing method are expected to become a non-labeling, non-damaging and real-time detection sensing method, and can be used for quantitative and qualitative detection of living cells in a liquid environment.
Claims (6)
1. A terahertz microstructure circular dichroism sensing system for living cell detection is characterized by comprising a front terahertz polarizing film (1), a terahertz wave plate (2), a front terahertz lens (3), a metal reflecting prism (4), a silicon medium grating sensor (5), a sample cell (6), a rear terahertz lens (7) and a rear terahertz polarizing film (8), wherein the silicon medium grating sensor (5) is used as the bottom of the sample cell (6), and the sample cell (6) is positioned above the metal reflecting prism (4); the terahertz wave plate (2) can generate narrow-band circularly polarized incident light, and is used for sensing and detecting living cells by detecting a circular dichroism spectrum with strong artificial resonance after being enhanced by the silicon medium grating sensor (5).
2. The terahertz microstructure circular dichroism sensing system oriented to living cell detection, which adopts a reflection system to avoid absorption loss of a solvent to terahertz waves, is characterized in that: the linear polarization terahertz plane wave with the electric field vibrating along the vertical direction is transmitted along the horizontal direction, the polarization degree is improved through the front polarization plate (1), the polarization state is changed through the terahertz wave plate (2), the terahertz wave is focused through the front terahertz lens (3), and the terahertz wave is reflected to the silicon dielectric grating sensor (5) through the metal reflecting prism (4) at a certain angle; the terahertz waves are reflected on the contact surface of the silicon medium grating sensor (5) and the living cell liquid sample, are recovered into plane waves which are transmitted in parallel through a rear terahertz lens (7), and are emitted through a rear polaroid (8); the reflection system can be arranged in a terahertz parallel light path of a traditional time-domain spectroscopy system, and a preparation sample cell (6) is used for containing cell sample solution.
3. The terahertz microstructure circular dichroism sensing system oriented to living cell detection as claimed in claim 1, wherein the terahertz wave plate (2) is a birefringent element generating pi/2 phase retardation, the operating wavelength is within a range of 300-400 μm, an included angle between an optical axis of the wave plate and a polarization direction of an incident electromagnetic wave is ± 45 ° during operation, a terahertz linearly polarized wave with an electric field along a y direction is vertically incident on the wave plate, emergent light becomes a narrow-band circular polarization state, and emergent light deviating from the operating wavelength is an elliptical polarization state.
4. The terahertz microstructure circular dichroism sensing system oriented to living cell detection as claimed in claim 1, wherein the silicon medium grating sensor (5) is formed by etching periodic rectangular grooves on the surface of a silicon wafer, the grating period of the silicon medium grating is 100-150 μm, the groove etching depth is 100-150 μm, and the etching width is 50-75 μm.
5. The terahertz microstructure circular dichroism sensing system oriented to living cell detection is characterized in that: in the detection process, a pair of orthogonal linear polarization components can be detected by rotating the rear polarizer (8) at the detection end to +/-45 degrees, and the complete polarization state of the emergent signal can be restored by calculation to obtain the circular dichroism spectrum.
6. The terahertz microstructure circular dichroism sensing system oriented to living cell detection is characterized in that: the grating direction of the silicon medium grating sensor (5) is along the z-axis, and strong resonance and polarization response can be realized under the condition that incident waves with complex polarization states are obliquely incident, so that the sensing capability of the system can be remarkably enhanced; the microstructure sensor can detect the number of living cells by circular dichroism spectrum, and the sensitivity of the sensor to the change of resonance intensity and the frequency shift can reach 3.4 dB.mL/106cells and 5.2 GHz. mL/106On the order of cells.
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