CN114235708B - Terahertz photoacoustic detection device and method - Google Patents
Terahertz photoacoustic detection device and method Download PDFInfo
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Abstract
The embodiment of the invention discloses a terahertz photoacoustic detection device and a terahertz photoacoustic detection method. The terahertz photoacoustic detection device comprises a light source module, an ultrasonic detection module, a processing module and a temperature control module, wherein the light source module is used for emitting terahertz light beams with tunable wavelengths, the terahertz light beams are incident to a sample to be detected, and photoacoustic signals are formed after the terahertz light beams pass through the sample to be detected; the temperature control module is used for adjusting the temperature of the sample to be measured; the ultrasonic detection module is used for detecting the photoacoustic signal and converting the photoacoustic signal into an electric signal; the processing module is connected with the ultrasonic detection module and is used for acquiring an absorption spectrum in a sample to be detected according to the electric signal so as to realize fusion of a terahertz technology and a photoacoustic technology, acquire terahertz characteristic absorption information of a target detection object in the sample to be detected, expand further application of terahertz radiation in life science, and have the characteristics of simple structure, convenience in operation and low cost.
Description
Technical Field
The embodiment of the invention relates to the technical field of terahertz, in particular to a terahertz photoacoustic detection device and method.
Background
Terahertz (THz) waves refer to electromagnetic waves having frequencies in the range of 0.1THz to 10THz, lying between the microwave and infrared regions. Because terahertz light beams have the advantages of low photon energy, rich absorption spectrum, good penetrability and the like, the terahertz light beams have shown great application prospects in a plurality of important fields such as physics, chemistry, electronic information, life science, material science, communication radar, national security and the like.
The photon energy of terahertz radiation is very low (the magnitude of meV) and does not cause ionization damage, the terahertz spectrum of the substance contains rich physical and chemical information, and the research on the spectrum of the substance in the wave band has important significance for exploring the characteristics of the substance.
However, the existing terahertz biological detection uses terahertz reflection spectrum and attenuated total reflection spectrum technologies, and mostly needs to perform complex pretreatment on a sample or directly detect an extremely thin (200 μm) water-rich sample, so that internal information of the sample is difficult to obtain, and a weak signal emitted by a target biomolecule is often submerged by a strong absorption signal of water, so that further application of terahertz radiation in life science is greatly limited.
Disclosure of Invention
The embodiment of the invention provides a terahertz photoacoustic detection device and a terahertz photoacoustic detection method, which are used for realizing the fusion of a terahertz technology and a photoacoustic technology, acquiring terahertz characteristic absorption information of a target detection object in a sample to be detected, expanding the further application of terahertz radiation in life science, and have the characteristics of simple structure, convenience in operation and low cost.
In a first aspect, an embodiment of the present invention provides a terahertz photoacoustic detection apparatus, including a light source module, an ultrasonic detection module, a processing module, and a temperature control module;
the light source module is used for outputting a terahertz light beam with tunable wavelength, the terahertz light beam is incident to a sample to be tested, and a photoacoustic signal is formed after the terahertz light beam passes through the sample to be tested;
the temperature control module is used for adjusting the temperature of the sample to be measured;
the ultrasonic detection module is used for receiving the photoacoustic signal and converting the photoacoustic signal into an electric signal;
the processing module is connected with the ultrasonic detection module and is used for acquiring an absorption spectrum in the sample to be detected according to the electric signal.
Optionally, the light source module comprises a first pulse laser, a reflector group, a grating, a half wave plate, a converging lens, a first nonlinear crystal and a plurality of filters; the pulse laser output by the first pulse laser sequentially passes through the reflector group, the grating, the half wave plate and the converging lens and then is focused on the first nonlinear crystal so as to excite the terahertz light beam; the filters are used for transmitting terahertz light beams with different wavelengths, so that the light source module outputs the terahertz light beams with tunable wavelengths.
Optionally, the terahertz photoacoustic detection device further includes a parabolic mirror group, where the parabolic mirror group is used for focusing the terahertz light beam output by the light source module to the sample to be detected.
Optionally, the light source module further includes a pump light filter, where the pump light filter is located at an output end of the first nonlinear crystal and is configured to block the pulse laser output by the first pulse laser and transmit the terahertz light beam output by the first nonlinear crystal.
Optionally, the first nonlinear crystal comprises a lithium niobate crystal.
Optionally, the light source module comprises a second pulse laser, a telescope group, an iris diaphragm, a first parallel plane mirror, a second nonlinear crystal, a second parallel plane mirror and a rotary table; the pulsed laser output by the second pulsed laser sequentially passes through the telescope group and the iris diaphragm and is incident into an optical parametric oscillation cavity formed by the first parallel plane mirror, the second nonlinear crystal and the second parallel plane mirror, and the rotary table is used for driving the second nonlinear crystal to rotate so as to output terahertz light beams with tunable wavelengths.
Optionally, the second nonlinear crystal comprises a near stoichiometric lithium niobate crystal.
Optionally, the light source module further includes a third pulse laser, where the third pulse laser is used to emit an ultraviolet pulse laser, and the ultraviolet pulse laser and the terahertz beam are incident to the sample to be measured together.
Optionally, the terahertz photoacoustic detection device further comprises a scanning translation stage, wherein the scanning translation stage is used for driving the sample to be detected to perform point-by-point two-dimensional scanning;
and the processing module is used for acquiring photoacoustic imaging of the sample to be detected according to the point-by-point two-dimensional scanning information of the sample to be detected.
Optionally, the temperature control module is used for adjusting the temperature of the sample to be measured.
In a second aspect, an embodiment of the present invention further provides a terahertz photoacoustic detection method, which is performed by the terahertz photoacoustic detection apparatus described above, including:
the light source module outputs a terahertz light beam with tunable wavelength, the terahertz light beam is incident to a sample to be tested, and a photoacoustic signal is formed after the terahertz light beam passes through the sample to be tested;
the ultrasonic detection module receives the photoacoustic signal and converts the photoacoustic signal into an electrical signal;
the processing module acquires an absorption spectrum in the sample to be detected according to the electric signal;
the temperature control module adjusts the temperature of the sample to be detected, and the light source module tunes the wavelength of the terahertz light beam to realize the absorption spectrum detection of the sample to be detected with different multispectral temperatures.
Optionally, the photoacoustic detection device further comprises a scanning translation stage, wherein the scanning translation stage is used for driving the sample to be detected to perform point-by-point two-dimensional scanning;
and the processing module acquires photoacoustic imaging of the sample to be detected according to the point-by-point two-dimensional scanning information of the sample to be detected.
The terahertz photoacoustic detection device provided by the embodiment of the invention comprises a light source module, an ultrasonic detection module, a processing module and a temperature control module, wherein the light source module outputs a terahertz light beam with tunable wavelength, the terahertz light beam is incident to a sample to be detected, a photoacoustic signal is formed after the terahertz light beam passes through the sample to be detected, and the photoacoustic signal is detected by the light signal and converted into the detection of the acoustic signal, so that the cost is reduced; the temperature of the sample to be detected is adjusted through the temperature control module, so that the detection sensitivity can be adjusted; receiving the photoacoustic signal through an ultrasonic detection module and converting the photoacoustic signal into an electrical signal; and acquiring an absorption spectrum in the sample to be detected according to the electric signal by a processing module. The terahertz characteristic absorption information of the target detection object in the sample to be detected is obtained by combining the terahertz technology and the photoacoustic technology, the further application of terahertz radiation in life science is expanded, and the device has the characteristics of simple structure, convenience in operation and low cost.
Drawings
Fig. 1 is a schematic structural diagram of a terahertz photoacoustic detection apparatus provided in an embodiment of the present invention;
fig. 2 is a schematic structural diagram of another terahertz photoacoustic detection apparatus according to an embodiment of the present invention;
fig. 3 is a schematic structural diagram of yet another terahertz photoacoustic detection apparatus provided by an embodiment of the present invention;
fig. 4 is a schematic structural diagram of still another terahertz photoacoustic detection apparatus provided by an embodiment of the present invention;
fig. 5 is a schematic structural diagram of still another terahertz photoacoustic detection apparatus provided by an embodiment of the present invention;
fig. 6 is a schematic structural diagram of still another terahertz photoacoustic detection apparatus provided by an embodiment of the present invention;
fig. 7 is a schematic flow chart of a terahertz photoacoustic detection method provided by an embodiment of the present invention;
fig. 8 is a schematic structural diagram of still another terahertz photoacoustic detection apparatus provided by an embodiment of the present invention;
fig. 9 is a flowchart of another terahertz photoacoustic detection method provided by an embodiment of the present invention.
Detailed Description
The invention is described in further detail below with reference to the drawings and examples. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting thereof. It should be further noted that, for convenience of description, only some, but not all of the structures related to the present invention are shown in the drawings.
At present, the terahertz wave has the following characteristics that the terahertz wave has great advantages in the biomedical field: 1. terahertz radiation photon energy is very low (1 THz is about 4.1 meV), and compared with the current clinical common X-ray (keV), the terahertz radiation photon energy is reduced by several orders of magnitude, and ionization damage is not caused, so that the terahertz radiation photon energy is possibly and safely applied to living body detection; 2. the frequency of radical vibration and conformational changes within many biological macromolecules, as well as interactions between the biomolecules and the surrounding medium, is mostly in the terahertz range; 3. polar molecules, particularly water molecules, have strong absorptivity to terahertz waves, and the characteristic can be utilized to carry out related research on the water content of biological tissues. Because of these advantages, terahertz spectroscopy and imaging have evolved into very potential technical means for detecting biomolecules like proteins, DNA, RNA, sugar, etc. in vitro and in vivo, and can also be used to analyze the structural dynamics of water and ion hydration or to distinguish tumor and healthy tissue based on water content.
Although the high absorptivity of water to terahertz radiation is advantageous in biomedicine, it can distinguish tumor cells from normal cells according to different water contents and is used for researching the structural dynamics of water and biomolecules, the strong absorptivity of water still limits the application of terahertz technology to water-rich samples such as aqueous solutions, biological tissues and the like in view of the fact that many biological samples can only maintain the biological activity in water environment. Conventional terahertz biological analysis uses terahertz reflection spectrum and attenuated total reflection spectrum technologies, and mostly needs to perform complex pretreatment on a sample or directly detect an extremely thin (200 μm) water-rich sample, so that internal information of the sample is difficult to obtain, and a weak signal emitted by a target biomolecule is often submerged by a strong absorption signal of water, so that further application of terahertz radiation in life science is greatly limited. There are also some research teams continually seeking to enhance the desired signal by increasing the intensity of the terahertz radiation or increasing the sensitivity of the terahertz detector. But in the long term these solutions may not be satisfactory because the water background exponentially decays the target signal, the ultra-strong radiation presents health risks, and the price of ultra-sensitive detectors may be prohibitive.
Fig. 1 is a schematic structural diagram of a terahertz photoacoustic detection apparatus according to an embodiment of the present invention. Referring to fig. 1, the terahertz photoacoustic detection apparatus 100 provided in this embodiment includes a light source module 101, an ultrasonic detection module 102, a processing module 103, and a temperature control module 104, where the light source module 101 is configured to output a terahertz light beam with a tunable wavelength, and the terahertz light beam is incident on a sample 105 to be tested, and forms a photoacoustic signal after passing through the sample 105 to be tested; the temperature control module 104 is used for adjusting the temperature of the sample 105 to be measured; the ultrasonic detection module 102 is configured to receive the photoacoustic signal and convert the photoacoustic signal into an electrical signal; the processing module 103 is connected with the ultrasonic detection module 102, and the processing module 103 is used for acquiring an absorption spectrum in the sample 105 to be detected according to the electric signal.
The photoacoustic technique is a technique for irradiating biological tissue with a photoacoustic effect, i.e., a short pulse laser as an excitation source, and if the duration of the laser pulse is far less than the thermal conduction time of the optical absorption region inside the tissue, the optical absorption region inside the tissue adiabatically expands and radiates ultrasonic waves, and detecting the generated ultrasonic waves. Photoacoustic imaging, which is a new method of imaging biological tissue, combines the advantages of both optical imaging and ultrasound imaging. Because different biological tissues have very different optical absorption coefficients for laser with specific wavelengths, the photoacoustic imaging can achieve higher imaging contrast; photoacoustic imaging can achieve higher imaging resolution and deeper imaging depth with ultrasound as the carrier of information, which is not possible with pure optical or acoustic imaging. Experiments have shown that pulsed terahertz radiation can generate ultrasonic waves through thermal expansion of a terahertz absorption material, wherein the change of an ultrasonic signal reflects the change of the terahertz signal, and terahertz wave detection is realized, in this embodiment, the terahertz beam is absorbed and converted into an ultrasonic signal (i.e. a photoacoustic signal) through a sample 105 to be detected, and specifically, the main action mechanism of the photoacoustic effect is that the medium is irradiated by the pulsed beam, the temperature changes after the energy is absorbed by an irradiated area, the light energy is converted into heat energy, the heat energy is converted into mechanical energy of mechanical vibration through thermal expansion after the temperature changes, then the ultrasonic waves are generated through mechanical vibration, and the absorption spectrum of the sample 105 to be detected is further inverted through collecting the ultrasonic signal.
It can be understood that, when the light source module 101 outputs the terahertz light beams with tunable wavelengths, and the temperature control module 104 controls the temperature of the sample 105 to be measured to be the same after the terahertz light beams with different wavelengths are incident on the sample 105 to be measured, the terahertz photoacoustic detection apparatus 100 can obtain the absorption spectra of the sample 105 to be measured with multiple wavelengths under the terahertz light beams with different wavelengths.
In addition, when the wavelength of the terahertz light beam output by the light source module 101 is kept unchanged, the temperature control module 104 controls the temperature of the sample 105 to be measured to change, and the temperature adjustment range of the temperature control module 104 can be adjusted to 0-40 ℃, so that the sensitivity adjustment of terahertz photoacoustic detection is realized, and the terahertz photoacoustic detection device 100 can acquire the absorption spectra of the sample 105 to be measured at different temperatures under the terahertz light beam with the same wavelength. Wherein the sample 105 to be tested may be a rich water sample.
Therefore, the terahertz photoacoustic detection device 100 can acquire the absorption spectrum of the sample 105 to be detected under terahertz light beams with different temperatures or different wavelengths, and the terahertz photoacoustic detection device 100 has the advantages of simple structure and low cost.
The detected terahertz photoacoustic signals are all based on an initial sound pressure formula:
In the formula Γ is defined as the green parameter (dimensionless), representing the non-harmony of the absorbing material, depending only on the material properties; beta is related to the thermal coefficient of volumetric expansion of the material; vs is the speed of sound; cp is the specific heat capacity of the material; mu (mu) a The light absorption coefficient is determined by the characteristics of the material and the wavelength of electromagnetic waves; η (eta) th The percentage of the absorbed energy converted to heat is related to the characteristics of the terahertz band material, and is generally considered to be 1, f being the light source power. For absorbing unknown substances, detecting to obtain terahertz photoacoustic signals P 0 Can obtain absorption spectrum mu a (lambda); for substances whose terahertz absorption spectrum is already known, the terahertz photoacoustic signal P is detected by 0 And the concentration of the substance can be calculated by inverse solution according to the lambert-beer law.
For example, when detectingThe terahertz photoacoustic signal to an unknown substance (such as a mixed solution of several solutions) is P 0 In this case, the absorption spectrum μ of the unknown substance can be obtained based on the initial sound pressure formula a (lambda), however, the individual absorption spectra of each of the several solutions are known in advance, and the unknown composition of the several solutions and their relative contents can be solved back according to lambert-beer's law.
According to the technical scheme, the light source module outputs the terahertz light beam with tunable wavelength, the terahertz light beam is incident to the sample to be detected, the photoacoustic signal is formed after the terahertz light beam passes through the sample to be detected, and the photoacoustic signal is detected and converted into the acoustic signal detection, so that the cost is reduced; the temperature of the sample to be detected is adjusted through the temperature control module, so that the detection sensitivity can be adjusted; receiving the photoacoustic signal through an ultrasonic detection module and converting the photoacoustic signal into an electrical signal; and acquiring an absorption spectrum in the sample to be detected according to the electric signal by a processing module. The terahertz characteristic absorption information of the target detection object in the sample to be detected is obtained by combining the terahertz technology and the photoacoustic technology, the further application of terahertz radiation in life science is expanded, and the device has the characteristics of simple structure, convenience in operation and low cost.
Fig. 2 is a schematic structural diagram of another terahertz photoacoustic detection apparatus according to an embodiment of the present invention. Referring to fig. 2, the light source module 101 includes a first pulse laser 106, a mirror group 200, a grating 110, a half wave plate 111, a converging lens 112, a first nonlinear crystal 113, and a plurality of filters 124 (only one filter is shown in fig. 2 by way of example); the pulse laser output by the first pulse laser 106 sequentially passes through the reflector group 200, the grating 110, the half wave plate 111 and the converging lens 112 and then is focused on the first nonlinear crystal 113 so as to excite the terahertz light beam; the plurality of filters 124 are used to transmit terahertz light beams of different wavelengths so that the light source module 101 outputs a terahertz light beam whose wavelength is tunable.
The first pulse laser 106 may be a Legend Elite series titanium gemstone femtosecond pulse regeneration amplification stage laser, which uses a power Evolution-HE laser as a standard pumping light source, uses a Vitara oscillator as a seed light source, and performs two-stage amplification on the seed light, wherein the single pulse energy output can reach 8mJ at most, the pulse width is 40fs, the repetition frequency is 1kHz, the center wavelength is 800nm, and the spectrum width is 30nm. For example, in this embodiment, the mirror group 200 includes the first mirror 107, the second mirror 108, and the third mirror 109, and in other embodiments, the number of mirrors in the mirror group 200 may be increased or decreased according to actual requirements, and only the laser beam emitted by the first pulse laser 106 needs to be reflected to the grating 110.
Optionally, the first nonlinear crystal 113 comprises a lithium niobate crystal. In this example, the terahertz radiation has a repetition frequency of 1kHz, a subpicosecond pulse width, and a pulse energy of 0.23mJ/cm 2 The spectral range is 0.2-1.5THz. The terahertz light beam is formed by excitation of the lithium niobate crystal, the terahertz light beam excited by the lithium niobate crystal is emitted perpendicular to the surface of the crystal at a smaller emission angle, and the terahertz light beam is approximately regarded as a point source with a smaller divergence angle.
The plurality of filters 124 may be a plurality of filters, and the terahertz light beam having the wavelength that cannot pass through the filter 124 is filtered by passing through a different filter 124 after the first nonlinear crystal 113 is excited to form the terahertz light beam, and passes through the terahertz light beam having the same wavelength as the filter 124. The selection among the plurality of filters 124 may be made as desired to achieve wavelength tunability of the terahertz beam.
The processing module 103 may include a data acquisition card, which may be an acquisition device such as an oscilloscope, where the processing module 103 is connected to the ultrasonic detection module 102 and is used for acquiring an electrical signal, and illustratively, fig. 2 also shows that the processing module 103 is connected to the first pulse laser 106 and may be used for signal synchronization and other functions.
Optionally, with continued reference to fig. 2, the terahertz photoacoustic detection apparatus 100 further includes a parabolic mirror set 300, where the parabolic mirror set 300 is used to focus the terahertz light beam output by the light source module 101 to the sample 105 to be measured.
The parabolic mirror set 300 may include a first parabolic mirror 114 and a second parabolic mirror 115, where a plurality of filters 124 are located between the first parabolic mirror 114 and the second parabolic mirror 115, and the terahertz light beam excited by the first nonlinear crystal 113 is collimated by the first parabolic mirror 114 and then is incident on the filters 124, and is incident on the second parabolic mirror 115 after being collimated by the filters 124, and is incident on the sample 105 to be measured through the second parabolic mirror 115.
In this embodiment, the first parabolic mirror pm1=101.6 mm, the second parabolic mirror pm2=50.8 mm, and the two parabolic mirrors are disposed in a confocal manner, which has the advantage of no aberration and no filtering, and the terahertz beam is compressed to half of the output of the surface of the first nonlinear crystal 113 at the back focal point of the second parabolic mirror 115, which is about 1.5mm. In other embodiments, focusing of the terahertz beam may be achieved using other numbers of parabolic mirrors, or using other focusing mirror groups, which are not limited by the embodiments of the present invention.
Fig. 3 is a schematic structural diagram of still another terahertz photoacoustic detection apparatus according to an embodiment of the present invention. Referring to fig. 3, the light source module 101 further includes a pump filter 400, where the pump filter 400 is located at the output end of the first nonlinear crystal 113 and is used to block the pulse laser light output by the first pulse laser 106 and transmit the terahertz light beam output by the first nonlinear crystal 113. The pump filter 400 may be a silicon wafer. By adding the silicon wafer, the terahertz light beam output by the first nonlinear crystal 113 does not include the pump laser output by the first pulse laser 106, the terahertz light beam has fewer impurity light beams, and the final spectrum acquisition accuracy is higher.
Fig. 4 is a schematic structural diagram of still another terahertz photoacoustic detection apparatus according to an embodiment of the present invention. Referring to fig. 4, the light source module 101 further includes a third pulse laser 116, where the third pulse laser 116 is configured to emit an ultraviolet pulse laser, and the ultraviolet pulse laser and the terahertz beam are incident on the sample 105 to be measured together.
In this embodiment, the third pulse laser 116 outputs a center wavelength of 266nm, a frequency of 1Hz-1kHz, an average power of 93.4mW/1kHz, and a pulse width of 4.6ns/1kHz.
The sample 105 to be measured has a special absorption spectrum in a terahertz wave band; exciting the sample 105 to be measured by using the terahertz pulse beam; the temperature of the sample 105 to be measured rises; then exciting the sample 105 to be measured by using ultraviolet pulse laser within the thermal diffusion constraint time (100-500 ns) (the delay between pulses can be realized by controlling the ultraviolet laser to be triggered externally by a delay device); collecting photoacoustic signals generated by ultraviolet pulses; thus, the sample absorption characteristic of the terahertz wave band is utilized, and the photoacoustic signal is enhanced; meanwhile, the resolution (about 266 nm) of the focused ultraviolet pulse laser is utilized, so that the high-resolution photoacoustic imaging which cannot be achieved by the pure terahertz pulse laser can be realized. Further, after the third pulse laser 116 is added, the accuracy of the finally obtained absorption spectrum of the sample 105 to be measured is higher.
Fig. 5 is a schematic structural diagram of still another terahertz photoacoustic detection apparatus according to an embodiment of the present invention. Referring to fig. 5, the light source module 101 includes a second pulse laser 106', a telescope group 117, an iris 118, a first parallel flat mirror 119, a second nonlinear crystal 120, a second parallel flat mirror 121, and a rotary table (not shown in fig. 5); the pulse laser output by the second pulse laser 106' sequentially passes through the telescope group 117 and the iris 118 and is incident into an optical parametric oscillation cavity formed by the first parallel plane mirror 119, the second nonlinear crystal 120 and the second parallel plane mirror 121, and the rotary table is used for driving the second nonlinear crystal 120 to rotate so as to output a terahertz light beam with tunable wavelength.
Optionally, the second nonlinear crystal 120 comprises a near stoichiometric lithium niobate crystal. The light source module 101 is used to generate a terahertz strong field system (terahertz radiation repetition frequency is 10Hz, continuous tuning output range is 1.16THz-4.64 THz). In addition, the light source module 101 may also adopt a terahertz strong field system based on other generation mechanisms, for example, organic crystal light rectification, infrared laser difference frequency, laser driving solid plasma, etc., and may be selected according to practical situations in practical implementation.
The first parallel plane mirror 119 and the second parallel plane mirror 121 are stokes light cavity mirrors, the first parallel plane mirror 119 and the second parallel plane mirror 121 are formed by using high-transmittance and high-reflection plane mirrors with coating films, the first parallel plane mirror 119 and the second parallel plane mirror 121 are parallel to the side surfaces of the nonlinear crystal 120, the base angle of the nonlinear crystal 120 is 65 degrees, and the nonlinear crystal is an isosceles trapezoid and is formed by a near-stoichiometric lithium niobate crystal. The first parallel plane mirror 119, the second parallel plane mirror 121 and the nonlinear crystal 120 form an optical parametric oscillation cavity, and the pulsed laser light output by the second pulsed laser 106' generates stokes light and terahertz light based on the scattering effect of the excited electromagnetic coupler. The terahertz light generated by the mode has good stability.
Fig. 6 is a schematic structural diagram of still another terahertz photoacoustic detection apparatus according to an embodiment of the present invention. Referring to fig. 6, the light source module 101 further includes a third pulse laser 116, where the third pulse laser 116 is configured to emit an ultraviolet pulse laser, and the ultraviolet pulse laser and the terahertz beam are incident on the sample 105 to be measured together. Among other things, this embodiment is advantageous for improving the final spectral accuracy.
It will be appreciated that, in the light source module 101 shown in fig. 5 and 6, a pump filter 400 (not shown in fig. 5 and 6) may be added to the output end of the second nonlinear crystal 120, so as to filter the laser beam emitted by the second pulse laser 106'.
Fig. 7 is a schematic flow chart of a terahertz photoacoustic detection method provided by an embodiment of the invention. Referring to fig. 7, the detection method may be performed by any of the terahertz photoacoustic detection apparatuses provided in the above embodiments, including:
s101, a light source module outputs a terahertz light beam with tunable wavelength, the terahertz light beam is incident to a sample to be tested, and a photoacoustic signal is formed after the terahertz light beam passes through the sample to be tested;
s102, an ultrasonic detection module receives a photoacoustic signal and converts the photoacoustic signal into an electrical signal;
s103, the processing module acquires an absorption spectrum in the sample to be detected according to the electric signal;
the temperature control module adjusts the temperature of the sample to be detected, and the light source module tunes the wavelength of the terahertz light beam to realize the absorption spectrum detection of the sample to be detected with different multispectral temperatures.
Specifically, the sample to be detected may be a water-rich sample, the water-rich sample is a water-rich biological sample, and the water-rich biological sample contains biological molecular information, wherein the biological molecular information may be at least one of biological molecular information such as protein molecules, DNA molecules, sugar molecules, and the like.
Based on an initial sound pressure formula, for unknown substances, changing terahertz irradiation wavelength, and firstly measuring light source power P at different wavelengths a (λ 1 )、P a (λ 2 )、…、P a (λ n ) The method comprises the steps of carrying out a first treatment on the surface of the Placing a sample to be detected, detecting photoacoustic signals of the sample to be detected, and obtaining terahertz-based photoacoustic signals respectively based on P when different wavelengths are detected 0 (λ 1 )、P 0 (λ 2 )、…、P 0 (λ n ). Then uses the result to normalize, P 0 (λ n )/P a (λ n ) The ratio of the two components can obtain the wavelength distribution of the absorption coefficient of the sample to be measured, namely the absorption spectrum mu of the sample to be measured a (λ)。
The preparation process of the sample to be tested is as follows: the terahertz photoacoustic detection device comprises a microfluidic chip, a peristaltic pump, a silica gel hose and a sample frame, wherein the microfluidic chip is connected with the peristaltic pump through the silica gel hose, the peristaltic pump conveys a sample to be detected to the microfluidic chip through the silica gel hose, the microfluidic chip is fixed at the center of a small hole of the sample frame, and the small hole of the sample frame is used for emitting a light beam through a light source module.
Firstly, a first sample solution to be detected is injected into a customized micro-fluidic chip through a needle tube, and bubbles are avoided in the process. And then tightly combining the temperature control module and the micro-fluidic chip. And finally, connecting the peristaltic pump with the microfluidic chip through a silica gel hose.
The device adjusting process comprises the following steps: placing a sample frame with small holes, wherein the sizes of the small holes are slightly smaller than the sizes of terahertz light spots, adjusting the relative positions of the small holes and the ultrasonic detection module, and adjusting the detection light path signals to an optimal state. Then, the micro-fluidic chip for sealing the liquid is fixed at the center of the small hole, and after the metal adhesive is adhered to the detection surface of the chip, an ultrasonic couplant is smeared to connect an ultrasonic detection module (an ultrasonic probe) and a processing module (an amplifier and an oscilloscope). And after the completion, opening the oscilloscope, adjusting the relative position of the ultrasonic detection module and the sample to be detected, and fixing the ultrasonic detection module after the oscillograph displays the optimal and stable waveform.
The measuring process comprises the following steps: observing oscillograph waveforms, and storing terahertz photoacoustic signals of a sample to be tested under a first group of filter sheets at normal temperature; then changing the temperature of the sample to be measured, and storing the terahertz photoacoustic spectrum of the sample to be measured under the terahertz photoacoustic of the wave band at different temperatures; then, by rotating to change to the second set of filters, the above process is repeated, and the photoacoustic signals … … recorded at different temperatures in this band repeat the measurement process until the last set of filters. The next sample to be measured is replaced by a peristaltic pump, and the measurement process is repeated. And further obtaining terahertz photoacoustic signals of the sample to be tested at different temperatures in different wave bands, and obtaining terahertz photoacoustic spectra of the sample to be tested at different temperatures in different wave bands through normalization processing.
Fig. 8 is a schematic structural diagram of still another terahertz photoacoustic detection apparatus provided by an embodiment of the present invention. Referring to fig. 8, the terahertz photoacoustic detection apparatus 100 provided in this embodiment further includes a scanning translation stage 122, where the scanning translation stage 122 is configured to drive the sample 105 to be detected to perform a point-by-point two-dimensional scanning; the processing module 103 is configured to obtain photoacoustic imaging of the sample 105 to be measured according to the point-by-point two-dimensional scanning information of the sample 105 to be measured.
It can be understood that the strong absorption of water severely limits the application of the terahertz technology to the information extraction of other target biomolecules in water-rich samples such as aqueous solution, biological tissues and the like, and the high-sensitivity detection of other target molecules in the aqueous solution can be realized by inhibiting the terahertz photoacoustic signals of the water, so that the effective absorption information of target substances is extracted; the photoacoustic spectrum of the biological tissue is detected, and the energy generated by the radiant energy absorption and non-radiative back excitation of the biological tissue is detected, namely the absorption is directly detected, so that the spectral characteristics of the biological tissue can be reflected.
In addition, on the basis of the previous embodiment, that is, after the terahertz photoacoustic spectrum of the sample to be measured is obtained, it can be determined at which frequency band and at which temperature the biomolecules in the sample to be measured are obviously absorbed, and further, the sample to be measured can be irradiated with the terahertz light of the frequency band, and the temperature of the sample to be measured is adjusted at the temperature, so that clear photoacoustic imaging of the solute in the sample to be measured can be obtained, wherein the terahertz light beam is used as a light source to excite the sample to generate a photoacoustic signal, and imaging resolution of about 100 μm can be realized.
Fig. 9 is a flowchart of another terahertz photoacoustic detection method provided by an embodiment of the present invention. Referring to fig. 9, the method is applied to the terahertz photoacoustic detection apparatus shown in fig. 8, and the detection method includes:
S201, a scanning translation stage drives a sample to be detected to carry out point-by-point two-dimensional scanning;
s202, the processing module acquires photoacoustic imaging of the sample to be detected according to the point-by-point two-dimensional scanning information of the sample to be detected.
The working principle of the photoacoustic imaging embodiment is described in detail below.
Referring to fig. 8, the apparatus 100 further includes a frame 123 for fixing a sample to be measured, the frame 123 is fixed on the scanning translation stage 122, a through hole is formed at the bottom of the frame 123, an optical filter (may be a silicon wafer) is placed on the bottom of the frame 123, the sample to be measured 105 is placed above the optical filter, and two sets of adjustable compression springs are further disposed on the frame 123 and are used for fixing the sample to be measured 105; the scanning translation stage 122 drives the sample 105 to be detected to move, so that the light beam emitted by the light source module 101 scans the sample 105 to be detected point by point in two dimensions; the temperature control module 104 is located on the sample 105 to be measured.
In this embodiment, the terahertz photoacoustic detection apparatus 100 adopts a transmission structure, that is, the light beam emitted from the light source module 101 is emitted into the sample 105 to be detected from bottom to top, and the ultrasonic detection module 102 receives the ultrasonic signal of the sample 105 to be detected above the sample 105 to be detected. The frame 123 carries the thin and thick slice-shaped sample 105 to be measured, is easy to fix and take out, can ensure the loading of coupling agents such as water and the like, does not permeate the sample 105 to be measured, so as to avoid interference to light intensity, and the whole frame can perform temperature rise and reduction control and keep low vibration. In this example, the frame 123 is made of light and cool-conducting aluminum material, and the aluminum material is provided with holes and is provided with optical filters with corresponding wave bands, so that the sample 105 to be measured can be directly placed while light is transmitted. Two sets of adjustable compression springs are arranged in the frame 123 so as to fix different samples with different tightness degrees, and the sample 105 to be measured is taken out after the measurement is finished conveniently, so that a layer of ultrasonic transparent preservative film can be wrapped on the upper surface of the sample 105 to be measured and filled with liquid in order to prevent the couplant from penetrating between the sample 105 to be measured and light, and the coupling of the ultrasonic detection module 102 and the sample 105 to be measured is ensured.
The scanning translation stage 122 drives the frame 123 to perform point-by-point scanning in a raster scan manner. The two-dimensional scanning translation stage adopts an L509 linear translation stage of PI company, and the acquisition card adopts GaGeRazor14 (sampling frequency 200MHz, 14-bit conversion precision). The program control of the imaging scan was written using Labview. The system scan mode can be divided into a slow scan mode and a fast scan mode. In the slow scan mode, the scan translation stage 122 is moved in fixed steps (e.g., 50 μm), and the post-processing module 103 is activated each time a step is performed, and the average is repeated after n a lines are acquired, and then the step is performed to the next point until the whole scan range is acquired. The signal obtained by the slow scanning is stable and has high signal to noise ratio. In the fast scan mode, the two-axis translation stage respectively works in a fast axis mode and a slow axis mode, the fast axis translation stage continuously moves (e.g. from 0mm to 10 mm), in the process of moving the fast axis, the processing module 103 acquires photoacoustic signals at equal time intervals under the external trigger of the laser, and simultaneously Labview accesses the position information of the translation stage in real time. When the fast axis movement is finished, the slow axis is moved stepwise (for example, 50 μm), and the fast axis is continuously moved. The process is repeated continuously, the purpose of quick scanning is achieved, and the quick scanning mode is high in scanning speed.
Specifically, the slow scan mode procedure is as follows:
step1: the scanning translation stage is moved to (x, y);
step2: the light source module activates the light to emit light, and the circuit triggers the processing module. The terahertz light beam irradiates a sample to be detected, generates a photoacoustic signal, is received by an ultrasonic detection module, is collected by a processing module and is converted into a digital signal, and is recorded as a series of (x, y) Alines;
step3: adding a time window to the series of Aline photoacoustic signals, and calculating a peak value Vpp in the window as intensity I (x, y);
step4: the scanning translation stage moves to the next site (x, y) at a Step interval of 50 μm, returns to Step2 until a complete rectangular area is scanned, and enters Step5;
step5: i (x, y) is formed into an n x n image, where n x n represents the number of scan sites.
Specifically, the fast scan mode procedure is as follows:
step1: the scanning translation stage moves to a starting point (x) 0 ，y 0 )；
Step2: setting the speed and the movement end point (X) of an X-scanning translation stage (fast scanning axis) 1 ，y 0 ) Opening the laser, emitting light, starting the scanning translation stage to move, and starting the processing module; wherein the processing module comprises an acquisition card (shown at 126 in fig. 8) and an amplifier (shown at 125 in fig. 8);
step3: and the processing module acquires 1K Aline and specific coordinates (xi, yi) corresponding to the Aline for 1s at the pulse repetition frequency of 1KHZ of the laser in the process that the X-scanning translation stage moves to the end point until the X-scanning translation stage stops moving.
Step4: the Y-scan translation stage is moved 50 μm and returns to Step2. (the end point set at this time corresponds to the X-scan translation stage moving back). Until the Y scanning translation stage moves to a set target site, entering Step5;
step5: calculating peak-to-peak value Vpp of the collected Aline, and corresponding to the position coordinates to obtain a data set (x) i ，y i Vpp) (note that, unlike slow sweeps, the various points of the fast sweep (x i ，y i ) Not equally spaced), and interpolation is performed to obtain the final interpolated image.
And finally, acquiring an image of the biomolecules in the water-rich biological sample by adopting a linear interpolation and maximum amplitude projection algorithm, wherein the computing functions are an edge diffusion function and a line diffusion function. Because the obtained signal contains high-frequency noise, a butterworth filter is generally adopted to carry out band-pass filtering on the signal, and the frequency characteristic of the ultrasonic detection module 102 is used as a parameter of the filter to filter the high-frequency noise. And constructing a reconstruction grid, and obtaining a maximum amplitude projection graph by utilizing linear interpolation of the peak-to-peak value (Vpp) and the corresponding position (x, y) of the electric signal. Because the 4 ℃ silencing control is used, the obtained imaging image is the terahertz-based photoacoustic imaging image which is irrelevant to water.
According to one embodiment of the present invention, the temperature control module 104 is used to adjust the temperature of the sample 105 to be measured, for example, the temperature of water may be controlled to 4 ℃.
Because the elastic coefficient of water is 0 at 4 ℃, the water is in a silencing phenomenon, namely no sound signal appears after the water absorbs the pulse laser energy. Therefore, the temperature control module 104 is added into the frame 123 and kept at 4 ℃, which is beneficial to 'silencing' water in the sample 105 to be tested, so that the signal-to-noise ratio of the photoacoustic signals of other important biomolecules is increased, and the problem of terahertz measurement of non-water molecules is solved. Referring to fig. 8, the temperature control module 104 includes a temperature sensor 1041, a temperature control plate 1042 and a temperature controller 1043, the temperature control plate 1042 adopts a TEC12706, the temperature sensor 1041 adopts a thin film probe, the control algorithm adopts a PID adjustment algorithm, and the control accuracy reaches 0.1 ℃. In order to ensure the refrigeration effect of the temperature control sheet and the cooling vibration during imaging to be as small as possible, the temperature control sheet adopts a circulating water cooling mode for refrigeration, and the heat end of the temperature control sheet takes away the heat in a mode of approaching to 0 vibration.
The temperature control module can be used for adjusting the temperature of a sample to be detected, for example, the temperature of the sample to be detected is controlled at 4 ℃, the photoacoustic signal of water can be restrained, and the ultraviolet pulse laser can further eliminate the photoacoustic signal of water, so that the final photoacoustic image and photoacoustic spectrum of the target detection molecule which is almost irrelevant to water molecules are obtained, the problem that the weak signal sent by the target biological molecule is often submerged by the strong absorption signal of water is solved, and the further application of terahertz radiation in life science is expanded.
In the terahertz photoacoustic detection apparatus provided by the embodiment of the invention, the ultrasonic detection module 102 is a focused ultrasonic detector.
In summary, according to the terahertz photoacoustic detection method provided by the embodiment of the invention, the device comprises the light source module, the ultrasonic detection module, the processing module and the temperature control module, wherein the light source module is used for outputting the terahertz light beam with tunable wavelength, the terahertz light beam is incident to the sample to be detected, the photoacoustic signal is formed after passing through the sample to be detected, and the photoacoustic signal is detected by the optical signal and converted into the detection of the acoustic signal, so that the cost is reduced; the temperature control module is used for adjusting the temperature of the sample to be detected, so that the detection sensitivity can be adjusted; the ultrasonic detection module is used for receiving the photoacoustic signal and converting the photoacoustic signal into an electric signal; the processing module is connected with the ultrasonic detection module and is used for acquiring an absorption spectrum in the sample to be detected according to the electric signal. The terahertz characteristic absorption information and the projection image of the target detection object in the water-rich sample are acquired by combining the terahertz technology and the photoacoustic technology, so that the further application of terahertz radiation in life science is expanded.
Note that the above is only a preferred embodiment of the present invention and the technical principle applied. It will be understood by those skilled in the art that the present invention is not limited to the particular embodiments described herein, but is capable of various obvious changes, rearrangements and substitutions as will now become apparent to those skilled in the art without departing from the scope of the invention. Therefore, while the invention has been described in connection with the above embodiments, the invention is not limited to the embodiments, but may be embodied in many other equivalent forms without departing from the spirit or scope of the invention, which is set forth in the following claims.
Claims (10)
1. The terahertz photoacoustic detection device is characterized by comprising a light source module, an ultrasonic detection module, a processing module and a temperature control module;
the light source module is used for outputting a terahertz light beam with tunable wavelength, the terahertz light beam is incident to a sample to be tested, and after passing through the sample to be tested, a photoacoustic signal is formed, so that 100 mu m imaging resolution can be realized; the light source module further includes: a third pulse laser for emitting ultraviolet pulse laser light;
the temperature control module is used for adjusting the temperature of the sample to be detected, controlling the temperature of the sample to be detected to be 4 ℃ so as to inhibit the photoacoustic signal of water; the third pulse laser is used for inhibiting a photoacoustic signal of water and is also used for exciting the sample to be detected by utilizing the ultraviolet pulse laser within the thermal diffusion constraint time of the sample to be detected after the terahertz light beam excites the sample to be detected; collecting photoacoustic signals generated by the ultraviolet pulse laser; the resolution of the focused ultraviolet pulse laser is utilized, so that high-resolution photoacoustic imaging which cannot be achieved by the pure terahertz pulse laser can be realized;
the ultrasonic detection module is used for receiving the photoacoustic signal and converting the photoacoustic signal into an electric signal;
The processing module is connected with the ultrasonic detection module and is used for acquiring an absorption spectrum and an image in the sample to be detected according to the electric signal; the processing module acquires an image of biomolecules in the water-rich biological sample by adopting a linear interpolation and maximum amplitude projection algorithm;
wherein the absorption spectrum is determined by an initial sound pressure formula, the initial sound pressure formula is that
Wherein Γ is the Green parameter, β is the material volume expansion coefficient, vs is the sound velocity, cp is the material specific heat capacity, μ a Is the light absorption coefficient eta th F is the power of the light source for absorbing unknown substances and detecting to obtain terahertz photoacoustic signals P 0 Can obtain absorption spectrum mu a (λ)。
2. The terahertz photoacoustic detection apparatus of claim 1, wherein the light source module comprises a first pulse laser, a mirror group, a grating, a half-wave plate, a converging lens, a first nonlinear crystal, and a plurality of filters;
the pulse laser output by the first pulse laser sequentially passes through the reflector group, the grating, the half wave plate and the converging lens and then is focused on the first nonlinear crystal so as to excite the terahertz light beam;
The filters are used for transmitting terahertz light beams with different wavelengths, so that the light source module outputs the terahertz light beams with tunable wavelengths.
3. The terahertz photoacoustic detection apparatus according to claim 2, further comprising a parabolic mirror group for focusing the terahertz light beam output from the light source module to the sample to be measured.
4. The terahertz photoacoustic detection apparatus of claim 2, wherein the light source module further comprises a pump light filter located at an output end of the first nonlinear crystal for shielding the pulsed laser light output by the first pulse laser and transmitting the terahertz light beam output by the first nonlinear crystal.
5. The terahertz photoacoustic detection apparatus of claim 2, wherein the first nonlinear crystal comprises a lithium niobate crystal.
6. The terahertz photoacoustic detection apparatus of claim 1, wherein the light source module comprises a second pulse laser, a telescope set, an iris, a first parallel plane mirror, a second nonlinear crystal, a second parallel plane mirror, and a rotation stage;
The pulsed laser output by the second pulsed laser sequentially passes through the telescope group and the iris diaphragm and is incident into an optical parametric oscillation cavity formed by the first parallel plane mirror, the second nonlinear crystal and the second parallel plane mirror, and the rotary table is used for driving the second nonlinear crystal to rotate so as to output terahertz light beams with tunable wavelengths.
7. The terahertz photoacoustic detection apparatus of claim 6, wherein the second nonlinear crystal comprises a near stoichiometric lithium niobate crystal.
8. The terahertz photoacoustic detection apparatus of claim 7, further comprising a scanning translation stage for driving the sample to be measured to perform a point-by-point two-dimensional scan;
and the processing module is used for acquiring photoacoustic imaging of the sample to be detected according to the point-by-point two-dimensional scanning information of the sample to be detected.
9. A terahertz photoacoustic detection method, characterized by being performed by the terahertz photoacoustic detection apparatus of any one of claims 1 to 7, comprising:
the light source module outputs a terahertz light beam with tunable wavelength, the terahertz light beam is incident to a sample to be detected, and a photoacoustic signal is formed after the terahertz light beam passes through the sample to be detected, so that 100 mu m imaging resolution can be realized; the light source module also emits ultraviolet pulse laser;
The ultrasonic detection module receives the photoacoustic signal and converts the photoacoustic signal into an electrical signal;
the processing module acquires an absorption spectrum and an image in the sample to be detected according to the electric signal; the processing module acquires an image of biomolecules in the water-rich biological sample by adopting a linear interpolation and maximum amplitude projection algorithm;
the temperature control module adjusts the temperature of the sample to be detected, controls the temperature of the sample to be detected to be 4 ℃ so as to inhibit the photoacoustic signal of water, and the third pulse laser inhibits the photoacoustic signal of water, and after the terahertz light beam excites the sample to be detected, the ultraviolet pulse laser excites the sample to be detected within the thermal diffusion constraint time of the sample to be detected; collecting photoacoustic signals generated by the ultraviolet pulse laser; the resolution of the focused ultraviolet pulse laser is utilized, so that high-resolution photoacoustic imaging which cannot be achieved by the pure terahertz pulse laser can be realized;
the light source module tunes the wavelength of the terahertz light beam to realize the detection of absorption spectra of samples to be detected with different multispectral temperatures;
wherein the absorption spectrum is determined by an initial sound pressure formula, the initial sound pressure formula is that
Wherein Γ is the Green parameter, β is the material volume expansion thermal coefficientVs is the sound velocity, cp is the specific heat capacity of the material, μ a Is the light absorption coefficient eta th F is the power of the light source for absorbing unknown substances and detecting to obtain terahertz photoacoustic signals P 0 Can obtain absorption spectrum mu a (λ)。
10. The terahertz photoacoustic detection method of claim 9, wherein the photoacoustic detection apparatus further comprises a scanning translation stage for driving the sample to be detected to perform point-by-point two-dimensional scanning;
and the processing module acquires photoacoustic imaging of the sample to be detected according to the point-by-point two-dimensional scanning information of the sample to be detected.
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