JP2024508203A - High energy efficiency coherent Raman spectroscopy system and method using dual comb laser - Google Patents

Abstract

Systems and methods for operating dual comb lasers. In this method, pulsed laser light is generated by a first laser light source and a second laser light source of a dual comb laser, and at least one of the first laser light source and the second laser light source is a diode-pumped solid-state laser whose output intensity can be changed. and matching the phase repetition frequency of the pulsed laser light by selectively changing the output intensity of the diode-pumped solid-state laser.

Description

(Cross reference to related applications)
This application claims priority to U.S. Provisional Patent Application No. 63/071,388 filed on August 28, 2020 and Japanese Patent Application No. 2020-153374 filed on September 11, 2020. , the disclosure of which is incorporated herein by reference.

TECHNICAL FIELD This application relates to spectrometry systems. More specifically, the present application relates to a high energy efficient coherent Raman spectroscopy system and method using a dual comb laser.

In recent years, the advent of high-speed vibrational spectroscopy and imaging techniques has spurred discoveries in biomedical science and materials science. These techniques are based on coherent Raman scattering processes (e.g. stimulated Raman scattering (SRS) and coherent anti-Stokes Raman scattering (CARS)) and are used in a wide variety of applications (e.g. cancer detection, metabolic analysis). , drug discovery, flow cytometry, and polymerization analysis). These techniques are also extremely effective in studying fast dynamic events that are difficult or impossible to reproduce using conventional pump-probe techniques. Among various fast vibrational spectroscopy methods, nonlinear dual-comb spectroscopy, more specifically, dual-comb CARS (DC-CARS) spectroscopy, rapidly generates high-resolution Raman spectra in the fingerprint region with a single-pixel photodetector. It is attracting particular attention because of its unique ability to acquire. For example, state-of-the-art laser technology exhibits high performance in the spectral range of 200 to 1400 cm ⁻¹ , the spectral resolution of 3 cm ⁻¹ , and the spectral acquisition rate of 10,000 spectra/second. These outstanding features of DC-CARS spectroscopy are realized based on a principle known as asynchronous optical sampling. Asynchronous optical sampling uses a pair of optical frequency combs with slightly different fixed pulse repetition frequencies. In this method, due to the frequency difference between the two combs, the group delay between the ultrashort pump pulse and the ultrashort probe pulse is automatically swept quickly without the need for any mechanical movement, while The pump pulse excites molecular vibrations in the sample, and the probe pulse allows the time evolution of the molecular vibrations to be observed as a time domain interferogram. The Raman spectrum of the sample is then obtained by taking the Fourier transform of the time-domain interferogram measured by the single-pixel photodetector.

However, DC-CARS spectroscopy is very inefficient as more than 99% of the laser energy is not used in the CARS process and is simply wasted. This is because the duty cycle of spectral acquisition is only less than 1% due to the mismatch between the laser pulse spacing (>1 nm) and the coherence lifetime of molecular vibrations (~3 ps). As a result, a decrease in spectrum acquisition rate and a decrease in signal-to-noise ratio (SNR) are caused. The simplest approach to improving the duty cycle is to increase the laser repetition frequency by shortening the cavity length of each frequency comb laser. Model-locked lasers with high repetition frequencies exceeding 1 GHz have been developed and are commercially available, but because there is a trade-off between pulse repetition frequency and pulse energy, mode-locked lasers sacrifice pulse energy, and the basic This is undesirable for nonlinear optical interactions that require high pulse peak intensities. Another approach to fast CARS spectroscopy is Fourier transform CARS (FT-CARS) spectroscopy, which uses a mechanically operated scanner to rapidly sweep the group delay between the pump and probe pulses. It is. However, the inertia of mechanically operated scanners limits the spectral acquisition rate.

This application relates to systems and methods for operating dual comb lasers. The system generates pulsed laser light using a first laser light source and a second laser light source of a dual comb laser, and at least one of the first laser light source and the second laser light source is a diode-pumped solid-state laser whose output intensity can be changed. and by selectively changing the output intensity of the diode-pumped solid-state laser (e.g., by transitioning the diode-pumped solid-state laser from a first output intensity value to a different second output intensity value), the phase of the pulsed laser light is changed. including matching repetition frequencies.

In one scenario, the first laser source comprises a diode-pumped solid-state laser with a fixed output intensity and the second laser source comprises a diode-pumped solid-state laser with variable output intensity. The output intensity of the diode-pumped solid-state laser can be selectively modified based on group delay values determined using dichroic interference and/or by varying the current supplied to the diode-pumped solid-state laser. The current can be changed depending on the group delay value. By selectively changing the output intensity of the diode-pumped solid-state laser, the refractive index of the crystal is changed to match the pulse repetition frequency.

In those or other scenarios, the method includes generating a feedback signal using one of the pulsed laser lights, and using the feedback signal to generate a first laser light source or a second laser light source driven by a piezoelectric transducer. The method further includes controlling the position of a mirror of a laser resonator of the laser light source and/or rapidly modulating the difference in phase repetition frequency of the first laser light source and the second laser light source.

The present application further relates to systems and methods for operating laser light sources. This method generates pulsed laser light using a crystal excited by excitation laser light output from a diode-pumped solid-state laser, and changes the refractive index of the crystal by selectively changing the intensity of the excitation laser light. Including. Adjust the current supplied to the diode-pumped solid-state laser based on the group delay value determined using dichroic interference and/or (e.g., based on the group delay value determined using dichroic interference) By doing so, the intensity of the excitation laser beam can be selectively changed.

The present application further relates to dual comb lasers. Each dual comb laser includes a first laser light source and a second laser light source that generate pulsed laser light. At least one of the first laser light source and the second laser light source includes a diode-pumped solid-state laser whose output intensity can be changed. The dual comb laser further includes a circuit that selectively changes the output intensity of the diode-pumped solid-state laser in order to match the phase repetition frequency of the pulsed laser light.

In one scenario, the first laser source comprises a diode-pumped solid-state laser with a fixed output intensity and the second laser source comprises a diode-pumped solid-state laser with variable output intensity. and/or by transitioning the diode-pumped solid-state laser from a first output intensity value to a different second output intensity value based on the group delay value determined using dichroic interference. By varying the current flowing through the diode-pumped solid-state laser, the output intensity of the diode-pumped solid-state laser can be selectively changed. The current may vary depending on the group delay value determined using dichroic interference.

The dual comb laser further includes a crystal having a refractive index that changes when the output intensity of the diode-pumped solid-state laser is changed, and the change in refractive index matches the pulse repetition frequency. The circuit further includes (i) generating a feedback signal using one of the pulsed laser lights, and (ii) using the feedback signal to generate a first laser light source or a second laser light source driven by the piezoelectric transducer. Control the position of the mirror of the laser cavity of the light source.

The present application further relates to laser light sources. A laser light source consists of a diode-pumped solid-state laser, a crystal that generates a pulsed laser beam when excited by the excitation laser beam output from the diode-pumped solid-state laser, and a crystal that generates a pulsed laser beam by selectively changing the intensity of the excitation laser beam. and a circuit for changing the refractive index of the refractive index. The intensity of the pump laser light can be selectively varied based on group delay values determined using dichroic interference and/or by adjusting the current supplied to the diode pumped solid state laser. The current is adjusted based on the group delay value determined using dichroic interference.

The present disclosure will be made with reference to the following drawings, throughout which like reference numerals represent like features.

FIGS. 1 and 2 are graphs useful for understanding the conceptual differences between conventional DC-CARS spectroscopy and Quasi-DC-CARS spectroscopy.

FIG. 3 is an explanatory diagram of the Quasi-DC-CARS spectrometer.

FIG. 4 is a block diagram of an illustrative laser light source circuit.

5(a) to 5(e) (collectively referred to as “FIG. 5”) are graphs useful for understanding the process of calculating group delay from a two-color interferogram (TCI).

FIGS. 6(a) to 6(d) (collectively referred to as "FIG. 6") are graphs showing the results of a demonstration experiment of Quasi-DC-CARS spectroscopy.

FIGS. 7(a) to 7(c) (collectively referred to as "FIG. 7") are graphs showing SNR analysis results in Quasi-DC-CARS spectroscopy.

FIG. 8 is a flow diagram of an illustrative method of Quasi-DC-CARS spectroscopy.

FIG. 9 is a flow diagram of an illustrative method for determining group delay measurements.

FIG. 10 is an explanatory diagram of a computing device.

FIG. 11 is a graph useful in understanding the modulation of pulse repetition frequency by controlling the intensity of the pump laser on the crystal.

It will be readily understood that the solution described in this application and illustrated in the accompanying drawings may include a wide variety of different configurations. Accordingly, the illustrated and more detailed description below does not limit the scope of the disclosure, but is merely representative of particular implementations in different scenarios. Although various aspects are illustrated, the drawings are not necessarily drawn to scale, unless explicitly indicated.

Throughout this specification, references to features, advantages, or similar language do not imply that all of the features and advantages that may be achieved are to be present in any single embodiment of the invention. Rather, language referring to features and advantages is understood to mean that the particular feature, advantage, or property described in connection with the embodiment is included in at least one embodiment of the invention. Thus, discussions of features and advantages and similar language throughout this specification may, but do not necessarily, refer to the same embodiment.

The term "spectroscopy" refers to the analysis of the interaction of electromagnetic radiation with matter as a function of the wavelength or frequency of the radiation. During this analysis, it is possible to measure the spectrum produced when the substance interacts with or emits electromagnetic radiation.

The term "Raman spectroscopy" refers to a spectroscopic technique used to determine the vibrational modes of molecules. These vibrational modes provide structural fingerprints that allow molecules to be identified. Raman spectroscopy relies on inelastic scattering of photons, known as Raman scattering. When laser light interacts with molecular vibrations, the energy of the laser photons increases or decreases. The shift in energy provides information that can be used to determine the vibrational modes of the molecule.

The term "dual-comb spectroscopy" refers to a spectroscopic technique that utilizes two coherent laser sources with different repetition frequencies to excite and probe a molecular sample.

The term "Dual-Comb Coherent Anti-stokes Raman Spectroscopy" or "DC-CARS" refers to the use of two coherent laser sources with different repetition frequencies to determine the vibrational modes of molecules. It refers to a spectroscopic method that uses DC-CARS allows non-invasive measurements for chemical analysis of objects. The DC-CARS system automatically sweeps the group delay between the pump and probe pulses by generating ultrashort laser pulses and superimposing a pair of laser pulses with slightly different pulse repetition frequencies. As the laser pulse passes through the sample, it excites molecular vibrations in the sample. A time domain interferogram is measured. By Fourier transforming the time-domain interferogram, a Raman spectrum of the sample can be obtained.

DC-CARS is a powerful technique for rapidly probing molecular vibrational signatures in fingerprint regions. However, due to the mismatch between the laser pulse spacing (>1 nm) and the coherence lifetime of molecular vibrations (~3 ps), the duty cycle of spectral acquisition is only less than 1%, resulting in 99% of the incident laser energy. More than % was wasted without being used. In this application, we describe a 100% energy efficient DC-CRS using a "quasi" dual comb laser. The DC-CRS of the present application has higher sensitivity than conventional slow DC-CRS and can provide relatively high spectral acquisition rates of 100,000 spectra/second.

The solution of the present application involves 100% energy efficient DC-CARS spectroscopy using a pseudo-dual comb laser. Although the concept of the present solution originates from THz time-domain spectroscopy with electrically controlled optical sampling, it does not apply directly to fast vibrational spectroscopy methods (eg DC-CARS spectroscopy). This is because the operation is relatively slow (~1 kHz) due to the slow response of the piezoelectric transducer that modulates the laser cavity length, and the accuracy of group delay measurements is far from that required by fast vibrational spectroscopy methods. . To overcome this limitation, the cavity length of one frequency comb is rapidly modulated through modulation of the Kerr lens effect in the laser gain medium (this is called a pseudo-comb state). Accurately measure the group delay between the pump and probe pulses by dichroic interference to calibrate the phase of each Raman active mode in the sample. Specifically, by sweeping the group delay from 0.0 ps to 0.7 ps at a sweep rate of up to 100,000 times/s at a nearly 100% duty cycle, a relatively high spectral acquisition rate of 100,000 spectra/s was achieved. DC-CARS spectroscopy will be realized. Thanks to the high duty cycle, the detection sensitivity of the present solution is also enhanced by more than 100 times over conventional DC-CARS spectroscopy with a fixed comb frequency difference. In other words, the solution (referred to as Quasi-DC-CARS spectroscopy) has a product of spectral acquisition rate and spectral power density that is more than 100 times higher than conventional DC-CARS spectroscopy. Quasi-DC-CARS spectroscopy can be used in a wide range of applications, and vibrational spectroscopy is required to be fast and sensitive. Such applications include, but are not limited to, particle analysis, flow cytometry, high throughput screening, real-time large tissue imaging, and/or polymerization analysis.

Theory of Quasi-DC-CARS spectroscopy

Referring to FIGS. 1 and 2, the conceptual difference between conventional DC-CARS spectroscopy and Quasi-DC-CARS spectroscopy can be understood. As shown in FIG. 1, conventional DC-CARS spectroscopy uses a pair of frequency combs with slightly different fixed repetition frequencies. If the pulse repetition frequencies of frequency comb 1 and frequency comb 2 are f ₁ and f ₂ , respectively, and f ₁ < f ₂ , then the group delay between the pump pulse and the probe pulse is Δt=f ₁ ^-1 - f ₂ ⁻¹ , the group delay is swept from zero to 1/f ₁ . Based on the highest pulse repetition frequency of commercially available lasers, f ₁ ≒ f ₂ ≒ 1 GHz, the group delay exceeds the coherence lifetime of molecular vibrations (~3 ps) for over 99% of the spectrum acquisition time. Therefore, the duty cycle becomes a very small value of more than 1%. Furthermore, the spectral acquisition rate of conventional DC-CARS spectroscopy is limited by the Nyquist frequency. In order to cover the entire fingerprint area (200 to 1600 cm ⁻¹ ) with a 1 GHz dual comb laser, the repetition frequency difference Δf=|f ₂ −f ₁ | must be less than 10.4 kHz.

Referring to FIG. 2, one can understand the solution's strategy to achieve nearly 100% duty cycle. By rapidly modulating the repetition frequency of one frequency comb with the modulation frequency f _mod (i.e., by rapidly modulating the difference between the repetition frequencies of the two frequency combs), the group delay can be reduced from zero to approximately 3 picoseconds ( (close to the coherence lifetime of molecular vibrations), and almost all pump and probe pulses contribute to CARS signal generation. Therefore, the spectrum acquisition rate of Quasi-DC-CARS spectroscopy is determined to be twice the modulation frequency of the frequency difference. Due to its high energy efficiency, Quasi-DC-CARS spectroscopy can not only achieve much higher spectral acquisition times but also much higher sensitivity than traditional DC-CARS spectroscopy.

Example of Quasi-DC-CARS spectrometer

Referring to FIG. 3, a diagram of a Quasi-DC-CARS spectrometer 300 is shown. A pair of laser light sources 302 and 304 are used as a dual comb laser light source 306. The laser light sources 302, 304 include lasers based on titanium-doped sapphire crystals (Ti:sapphire crystals) in vibrational electronic states. These lasers are called Ti:sapphire lasers. Ti:sapphire lasers include, but are not limited to, the taccor power laser available from Cambridge Technology, Inc. of Bedford, Massachusetts. Ti:Sapphire lasers operate at a repetition frequency of approximately 1 GHz, are mode-locked, and have ultrashort laser beam widths ranging from a few picoseconds (ps) to tens of attoseconds (as) (e.g., tens of femtoseconds (fs)). Can output pulses. Each Ti:sapphire laser emits laser light generated by exciting a Ti:sapphire crystal at a shorter wavelength using excitation laser light. The excitation laser light is generated by a diode pumped solid state (DPSS) laser. By adjusting the intensity of the current applied to the DPSS laser, the intensity of the DPSS laser can be controlled quickly. As a result, the refractive index of the Ti:sapphire crystal changes depending on the excitation power due to the nonlinear optical Kerr effect, so the optical path length of the Ti:sapphire crystal can be modulated. The pulse repetition frequency of the laser light source 302 can be modulated up to f _mod =50kHz.

The two laser beams output from the dual comb laser light source 306 are combined by a polarizing beam splitter (PBS) 308 and caused to travel along two paths 310 and 312. Path 310 is used for CARS signal measurements, while path 312 is used for group delay measurements with dichroic interference.

For CARS signal measurement on path 310, the laser light is focused onto sample 320 via achromatic lens 318 after chirp compensation by chirp mirror pair 314. The CARS signal generated from the sample is extracted from the incident light by an optical long-pass filter 316 provided in front of the sample 320 and an optical short-pass filter 324 provided behind the sample 320. The CARS signal is detected by photodetector 326. Photodetector 326 may include, but is not limited to, a high sensitivity avalanche photodetector with part number APD210 available from Menlo Systems GmbH of Germany.

For dichroic interferometry in path 312, the laser light is spatially dispersed by a diffraction grating 328 into two laser lights 330, 332 of approximately equal intensity and different frequencies (eg, red and blue). Laser light 330, 332 passes through one or more achromatic lenses 334. Achromatic lens 334 focuses the laser light toward photodetectors 336 and 338. The light intensity of laser light 330 is detected and measured by photodetector 336. The light intensity of laser light 332 is detected and measured by photodetector 338. The measured light intensity is then provided from the photodetectors 336, 338 to the computing device 340 for storage and/or processing.

Computing device 340 uses the measured light intensity to determine group delay value 360. Group delay values and techniques for determining group delay values based on intensity measurements are well known. Group delay value 360 is passed from computing device 340 to dual comb laser source 306 for use in selectively controlling the output intensity of the DPSS laser of one or both of laser sources 302, 304. The output intensity is selectively changeable between high and low intensity values. For example, when the group delay has a value of zero picoseconds, the DPSS laser is controlled to have a high intensity value, and when the group delay has a value between 1/2 picosecond and a few picoseconds, the DPSS laser is controlled to have a low intensity value. It is controlled to have an intensity value. The solution of the present application is not limited to the details of this example.

By selectively changing the output intensity of the DPSS laser, the refractive index of the Ti:sapphire crystal can be changed relatively quickly to create a laser cavity via a piezoelectric transducer (i.e., piezoelectric transducer 406 in FIG. 4). The pulse repetition frequency of the pulsed laser beam can be changed at least several orders of magnitude faster than when adjusting the mirror (ie, the mirror 408 in FIG. 4). In one or both of the laser sources 302, 304, the output intensity of the DPSS laser is selectively varied. In addition to selectively changing the output intensity of the DPSS laser, the position of the laser cavity mirror in one or both of the laser sources 302, 304 may be optionally selectively changed.

In this setting, using a diffraction grating 328 with a groove density of 12,000 grooves per 1 mm, an achromatic lens 334 with a focal length of 200 mm, and photodetectors 336 and 338 with an effective area of 0.126 mm ² , the measurement The maximum possible group delay is estimated to be 18.7 ps. The measured CARS signal and dichroic interference signal were electrically filtered by low-pass filters (not shown) with cutoff frequencies of 530 MHz and 600 MHz, respectively, and digitized by a high-speed oscilloscope (not shown) at 5 Giga samples/s. be done. High speed oscilloscopes include, but are not limited to, digital oscilloscopes available from Rohde & Schwarz USA, Inc. of Columbia, MD, part number RTOl 004.

Referring to FIG. 4, a detailed block diagram of laser light source 400 is shown. Laser light sources 302, 304 in FIG. 3 may be the same as or similar to laser light source 400. Therefore, the discussion of laser light source 400 is sufficient to understand laser light sources 302, 304 of FIG. Laser light source 400 includes various electronic circuit elements 402 - 430 that control the pulse repetition frequency of output pulsed laser light 450 . The operations of these elements will first be explained with respect to the laser light source 302 in FIG. 3, and then with respect to the laser light source 304 in FIG.

The pulse repetition frequency of the laser light source 302 of FIG. 1 is stabilized at a constant frequency f1 by the servo controller 402 using feedback information. Servo controller 402 receives feedback signals 432 output from feedback branches 422 - 426 and uses the content of the feedback signals to control the position of laser resonator mirror 408 driven by piezoelectric transducer 406 . A piezoelectric transducer 406 is provided to modulate the length of a laser cavity consisting of a set of mirrors 408, 410, 412, 414. Laser resonators 408 - 414 (i) cause the generated light to follow a closed path, and (ii) control the frequency at which light pulses are generated by laser light source 400 . This optical pulse frequency is referred to as a pulse repetition frequency in this application. Mirror 414 also functions as an output coupler that transmits a portion of the incident light, thereby providing a repeating train or sequence of pulses as pulsed light 440.

Pulsed laser light 440 propagates to beam splitter 420. Beam splitter 420 includes an optical device that separates pulsed laser light 440 into two pulsed laser lights 450 and 452. Pulsed laser light 450 is output from laser light source 400. Meanwhile, pulsed laser light 452 is provided to feedback branches 422-426.

Feedback branches 422-426 include a photodiode 422, a mixer 424, and a low pass filter 426. Photodiode 422 includes a semiconductor diode that converts pulsed laser light 452 into current 454. Current 454 flows to mixer 424 and mixes with waveform 434 from signal generator 428. Signal generator 428 may include, but is not limited to, a signal generator having part number SMA 100A available from Rohde & Schwarz USA, Inc. of Columbia, Maryland. This signal mixing is minimized by Proportional-Integral (PI) control. A feedback signal 432 is generated by filtering the signal 456 output from the mixer 424 by the low-pass filter 426. By using the feedback signal 432 in the servo controller 402, the pulse repetition frequency of the laser light source is stabilized at a constant frequency f1.

ｆ_１の周りでパルス繰り返し周波数を変調するために、レーザ光源３０２に関して上述したものと同じ方法でミラー４０８の位置を制御する。高速変調ｇ（ｔ）は、（ｉ）モードロックレーザを励起するＤＰＳＳレーザ４１８の強度を制御することによって、又は（ｉｉ）ポンプダイオードのドライバで電流を特異的に変化させることによって発生する。あるシナリオでは、矩形関数発生器４１６を用いて、１００％に近いスペクトル掃引のデューティサイクルを与えるように調整された振幅を有する信号を発生する。 The pulse repetition frequency of the laser light source 304 in FIG. 3 is rapidly modulated as f ₂ =f ₁ +g(t). Here, g(t) is a symmetric modulation function that satisfies the following equation.

To modulate the pulse repetition frequency around f ₁ , the position of mirror 408 is controlled in the same manner as described above with respect to laser source 302 . The fast modulation g(t) is generated by (i) controlling the intensity of the DPSS laser 418 that excites the mode-locked laser, or (ii) by specifically varying the current in the pump diode driver. In one scenario, a rectangular function generator 416 is used to generate a signal with an amplitude adjusted to provide a spectral sweep duty cycle close to 100%.

Since the modulation g(t) does not necessarily follow the input drive function due to the time variation of the pump intensity, the role of the dichroic interferometer is to accurately measure the group delay in conjunction with the CARS signal measurement. is used to calibrate the phase of each Raman active mode in the sample 320. Specifically, the group delay can be calculated from the TCI at wavelengths w ₁ and w ₂ according to the known process shown in FIG. FIG. 5(a) shows an example of measured TCI. As shown by arrow 502, the measured TCI is Fourier transformed to give a spectrum with three peaks as shown in FIG. 5(b). Next, as shown by arrow 504, by applying a mask function, necessary frequency components of the spectrum around 21 kHz are extracted and unnecessary frequency components are removed. The masked spectrum is then subjected to inverse Fourier transform to reconstruct the complex TCI as shown in FIG. 5(c). As shown in FIG. 5(d), the phase delay at w ₁ and w ₂ can be calculated from the complex TCI as its argument. The group delay τ between two pulses is obtained as τ=(φ ₁ −φ ₂ )/(w ₁ −w ₂ ). Here, φ ₁ and φ ₂ are the phase delays at w ₁ and w ₂ , respectively (see FIG. 5(e)). When the accuracy of TCI-based group delay measurement was evaluated under the condition that the pulse repetition frequencies of the two laser light sources 302 and 304 were fixed at 1000.200 MHz and 1000.190 MHz, respectively, the error was 17.5 fs. It was found that this corresponds to an error of 0.146 cm ⁻¹ in the Raman spectral region.

Demonstration experiment of Quasi-DC-CARS spectroscopy

The principle of Quasi-DC-CARS spectroscopy was demonstrated using liquid toluene as a sample at a modulation frequency of 50 kHz. Figure 6(a) shows the TCI obtained at 767 nm and 816 nm, from which the group delay was calculated according to the process described above in connection with Figure 5, as shown in Figure 6(b). . The CARS signal recorded simultaneously with the TCI was accurately calibrated using the calculated group delay, as shown in Figure 5(c). By Fourier transforming the calibrated CARS signal, a series of CARS spectra as shown in FIG. 5(d) were obtained. The obtained CARS spectrum shows Raman peaks at 532 cm ⁻¹ , 786 cm ⁻¹ , 1004 cm ⁻¹ , and 1210 cm ⁻¹ . The spectral acquisition rate of the Quasi-DC-CARS spectrometer is 100,000 spectra/second, which is 10 times higher than the highest value reported for conventional DC-CARS spectroscopy, which is faster than FT-CARS spectroscopy with delayed sweep with mechanical motion. This is twice as high as the highest value reported under the Act. At 100,000 spectra/sec, the group delay sweep range is calculated to be 0.71 ps, which corresponds to a spectral resolution of 23.4 cm ⁻¹ . The spectral resolution is determined by the group delay sweep range, which is inversely proportional to the modulation frequency, and thus degrades, but thanks to the highly energy-efficient Quasi-DC-CARS scheme, it includes Raman peaks at 532 cm ^-1 and 1210 cm ^-1 . Spectral characteristics that were previously hidden in noise can now be recognized. Recently proposed methods can improve spectral resolution without sacrificing spectral acquisition rate. This method improves the spectral resolution of Raman spectra obtained from time-domain interferograms measured in a limited time domain by assuming that the time-domain interferograms consist of multiple exponentially decaying sinusoidal functions. can be improved.

Further quantitative analysis of SNR as a function of modulation frequency and sample concentration is described below. The SNR of the measured CARS spectrum of toluene with a peak at about 1004 cm ⁻¹ and an intensity standard deviation of about 1780 cm ⁻¹ was evaluated at various spectral acquisition rates. As shown in Figure 7(a), by fitting, the SNR in conventional DC-CARS spectroscopy is proportional to (spectral acquisition rate) ^-0.489 , and when the noise floor is occupied by photon shot noise, Close to what was predicted theoretically. On the other hand, the SNR in Quasi-DC-CARS spectroscopy is proportional to (spectral acquisition rate) ^-0.104 . It is presumed that the reason why the slope becomes smaller in this way is that the origin of noise is different from that in the conventional DC-CARS method, such as temporal fluctuations in laser intensity where the repetition frequency is rapidly modulated. Specifically, through fitting, at a spectrum acquisition rate of 100,000 spectra/sec, Quasi-DC-CARS spectroscopy has an SNR approximately 20 times higher than conventional DC-CARS spectroscopy (however, at a spectral acquisition rate of 100,000 spectra/second, /second is possible). In other words, thanks to the high energy efficiency, Quasi-DC-CARS spectroscopy at 100,000 spectra/sec achieves the same SNR as conventional DC-CARS spectroscopy at 200 spectra/sec. Furthermore, as shown in FIG. 7(b), the sample concentration dependence of SNR was analyzed using a toluene solution in ethanol. The SNR shows a quadratic dependence on the concentration of the sample, which takes into account the interference between the CARS electric field and the local oscillator and the CARS signal originating from the square of the absolute value of the CARS electric field. This can be explained by: The relationship between sample concentration and SNR indicates that Quasi-DC-CARS spectroscopy is effective for quantitative chemical analysis. Moreover, as shown in FIG. 7(c), at a spectrum acquisition rate of 100,000 spectra/second, a sufficient SNR is provided even at a low sample concentration of 0.4 mol/L.

Referring to FIG. 8, a flow diagram of an illustrative method 800 for Quasi-DC-CARS spectroscopy using a pseudo-dual comb laser as a light source is shown. The present solution method 800 provides an unprecedentedly high CARS spectral acquisition rate of 100,000 spectra/second and is even more sensitive than traditional slow DC-CARS spectroscopy. Due to the significantly improved spectral acquisition rate and sensitivity, Quasi-DC-CARS spectroscopy can be used in a wide range of applications, including biomedical and materials science applications.

First, video-rate imaging of living cells with vibrational fingerprints by laser-swept Quasi-DC-CARS spectroscopy not only provides an approach for intraoperative tissue diagnosis, but also provides an approach to detect high-speed mechanisms such as signal transduction and mass transport. It can also be an approach to visualizing intracellular dynamics. Compared to SRS imaging in the high-frequency region (2700 cm ^-1 to 3000 cm ^-1 ) that covers CH/OH expansion and contraction, the fingerprint region provides more molecular information (about 10 times more biological information than the high-frequency region). Raman imaging will help gain deeper insights into the mechanisms of biological function.

Second, large-scale single-cell analysis based on coherent Raman spectroscopy is a novel way to characterize cellular diversity and discover rare cell subpopulations without the need for fluorescent labels that can interfere with functions such as metabolism. It is a means. Although its scope of application has been limited to microorganisms (e.g., microalgae) due to its low sensitivity, Quasi-DC-CARS spectroscopy can be used for high-precision Ramanization of mammalian cells, which requires precision several orders of magnitude higher than that for microorganisms. Paving the way to flow cytometry.

Third, Quasi-DC-CARS spectroscopy may be useful for observing fast and nonrepetitive events such as phase transitions, polymerization, non-photochemical reactions, and blinking of surface-enhanced Raman scattering. Despite their importance in basic science and industry, the underlying mechanisms of these phenomena remain unclear due to the lack of methods that allow them to be observed in real-time. Quasi-DC-CARS spectroscopy will help elucidate the mechanism.

As shown in FIG. 8, the method 800 begins at 802, followed by 804, where a current (e.g., current 448 in FIG. 4) is transferred from a function generator (e.g., function generator 416 in FIG. 4) to a dual comb. At least one of the laser light sources (e.g., dual comb laser source 306 of FIG. 3) is provided to a DPSS laser (e.g., DPSS laser 418 of FIG. 4). Ru. At 806, the output intensity of the DPSS laser of the first laser source (eg, laser source 302 of FIG. 3) is fixed. Meanwhile, at 808, the output of the DPSS laser of the second laser source (e.g., laser source 304 of FIG. 3) is adjusted by adjusting the strength of the current provided from the function generator (e.g., current 448 of FIG. 4). Intensity controlled. The output intensity of the DPSS laser is controlled to have a high or low intensity value based on a predetermined initial output intensity or a previously determined group delay value. Group delay values are well known, and techniques for determining group delay values are also well known.

At 810, the Ti:sapphire crystal (eg, crystal 470 of FIG. 4) of each laser source (eg, laser sources 302, 304 of FIG. 3) is excited with excitation laser light output from the respective DPSS laser. At 812, each laser source uses a laser resonator (eg, laser resonator 472 in FIG. 4) to control the frequency at which light pulses are generated by the Ti:sapphire crystal. The frequency at which the light pulses are generated is also referred to in this application as the pulse repetition frequency or pulse frequency. At 814, pulsed laser light (eg, laser light 440 in FIG. 4) is generated using the first mirror of the laser resonator of each laser light source (eg, mirror 414 in FIG. 4). The first mirror transmits a portion of the incident light along the output path of the dual comb laser source. The pulsed laser light generated by the first laser light source (e.g., laser light source 302 in FIG. 3) is referred to as the first pulsed laser light in this application, and the pulsed laser light generated by the second laser light source (e.g., laser light source 304 in FIG. 4) is referred to as the first pulsed laser light in this application. The pulsed laser beam is referred to as a second pulsed laser beam in this application. The first pulsed laser beam and the second pulsed laser beam have different pulse repetition frequencies or pulse frequencies.

Each of the first pulsed laser beam and the second pulsed laser beam is separated into an output pulsed laser beam (for example, the pulsed laser beam 450 in FIG. 4) and a feedback pulsed laser beam (for example, the feedback pulsed laser beam 452 in FIG. 4). be done. At 818, output pulsed laser light is emitted from the dual comb laser light source.

At 820, each feedback pulsed laser light is converted to a feedback signal (eg, feedback signal 432 of FIG. 4). At 822, the feedback signal is used to control the position of a second mirror (e.g., mirror 408 of FIG. 4) of a laser resonator driven by a piezoelectric transducer (e.g., piezoelectric transducer 406 of FIG. 4) to generate an output pulse. Promotes stabilization of the pulse repetition frequency of laser light.

At 824, the output intensity of the DPSS laser of at least the second laser light source (eg, laser light source 304 of FIG. 3) is optionally adjusted. This adjustment may include transitioning the output intensity of the DPSS laser from a high intensity value to a low intensity value, or vice versa. By performing this intensity adjustment, it is possible to promote high-speed modulation of the difference in pulse repetition frequency between the first laser light source and the second laser light source (eg, laser light sources 302 and 304 in FIG. 3). The graph shown in FIG. 11 is useful in understanding that modulation of the pulse repetition frequency can be achieved by controlling the intensity of the DPSS laser of at least the second laser light source.

As shown at 826, the dual comb laser light source continues to emit two output pulsed laser lights. At 828, the two output pulsed laser beams are combined with each other to generate a combined laser beam. At 830, the combined laser beam is routed between a first path (e.g., the path defined by branch 310 in FIG. 3) where CARS signal measurements are performed and a second path (e.g., where group delay measurements are performed by dichroic interference). 3) along the path defined by branch 312 in FIG. CARS signal measurements and group delay measurements are well known, as are techniques for determining them. At 832, group delay measurements are optionally used to match the phase repetition frequencies of the first pulsed laser light and the second pulsed laser light, and/or to match the phase repetition frequency of the first pulsed laser light and the second pulsed laser light, and/or Calibrate the phase of each Raman active mode. Then, at 834, method 800 ends, at least a portion of method 800 is repeated, or other operations are performed.

Referring to FIG. 9, a flow diagram of an example method 900 for determining group delay measurements or values based on TCI is shown. Method 900 may be performed at block 830 of FIG. 8 to perform group delay measurements.

The method 900 begins at 902, followed by 904, where a diffraction grating (e.g., diffraction grating 328 of FIG. 3) is used to combine laser light into two laser lights of approximately equal intensity and different frequencies (e.g., The laser beams 330, 332 in FIG. 3) are spatially dispersed. As shown at 906, these laser beams are caused to travel along different optical paths. At 908, a photodetector (eg, photodetector 336 or 338 in FIG. 3) is used to detect and measure the light intensity of each laser beam over a period of time. At 906, a Fourier transform is used to transform each photodetector measurement from the time domain to the frequency domain to generate a spectrum with multiple peaks. At 908, a mask function is used to generate masked spectra and remove unnecessary frequency components from each spectrum. As shown at 910, the complex dichroic interference signal is reconstructed by inverse Fourier transforming each of the masked spectra. At 912, the phase delay between the two laser beams is calculated based on the reconstructed complex dichroic interference signal. Such phase delay calculations are well known. A group delay measurement between the two pulses is determined based on the phase delay. Such group delay measurement decisions are well known. Then, at 916, method 900 ends, at least a portion of method 900 is repeated, or other operations are performed.

Referring to FIG. 10, hardware blocks comprising an example computer system 1000 that can be used to implement all or a portion of component 340 of FIG. 3 and/or components 402, 416, 428 of FIG. A diagram is shown. The machine may have a set of instructions used to cause a circuit/computer system to perform any one or more of the methods discussed in this application. Although only a single machine is shown in FIG. 10, in other scenarios, as described in this application, the system may include multiple machines executing one or more sets of instructions individually or together. It is to be understood that any collection of may be included.

Computer system 1000 includes a processor 1002 (e.g., central processing unit (CPU)), main memory 1004, static memory 1006, a drive 1008 for mass data storage having a machine-readable medium 1020, and an input. / an output device 1010, a display 1012 (eg, a liquid crystal display (LCD)) or a solid state display, and one or more interface devices 1014. Communication between these various components may be facilitated by data bus 1018. One or more sets of instructions 1024 may be stored in whole or in part in one or more of main memory 1004, static memory 1006, and drive 1008. The instructions may also reside within processor 1002 during execution of the instructions by the computer system. Input/output device 1010 can include a keyboard, a multi-touch surface (eg, a touch screen), and the like. Interface device 1014 may include hardware components and software or firmware to facilitate interfacing with external circuitry. For example, in some scenarios, interface device 1014 may include one or more analog-to-digital (A/D) converters, digital-to-analog (D/A) converters, input voltage buffers, output voltage buffers, voltage drivers, and/or comparators. can have. The connection of these components to communication lines allows the computer system to interpret signal inputs received from external circuitry and generate control signals necessary for certain operations described in this application.

Drive 1008 includes a machine-readable medium 1020 that stores one or more sets of instructions 1024 (eg, software) that are used to facilitate one or more of the methods and functions described herein. It will be understood that the term "machine-readable medium" includes any tangible medium capable of storing instructions or data structures to facilitate any one or more methods of this disclosure. Examples of machine-readable media include solid state memory, Electrically Erasable Programmable Read-Only Memory (EEPROM), and flash memory devices. A tangible medium described in this application is a non-transitory medium insofar as it does not contain a propagating signal.

It should be appreciated that computer system 1000 is one possible example of a computer system that can be employed in connection with various implementations disclosed in this application. However, the systems and methods disclosed in this application are not limited in this regard; other suitable computer system architectures may also be employed without limitation. Specialized hardware implementations, including, but not limited to, application-specific integrated circuits, programmable logic arrays, and other hardware devices can also be configured to implement the methods described in this application. There is a wide variety of applications in which the devices and systems can be implemented, including a wide variety of electronic and computer systems. Thus, the example system is applicable to software, firmware, and hardware implementations.

It should also be appreciated that the embodiments can take the form of a computer program product on a tangible computer-usable storage medium (eg, a hard disk or CD-ROM). A computer-usable storage medium can have computer-usable program code embodied within the medium. The term computer program product as used in this application refers to a device consisting of all the features capable of implementing the methods described in this application. Computer program, software application, computer software routine, and/or other variations of these terms, in the present context, refer to, in any language, code, or notation, directly to an information-processing capable system; or any representation of a set of instructions intended to perform a specified function after either or both of the following: a) translation into another language, code, or notation; b) Reproduction in different material forms.

The features, advantages and properties disclosed and described in this application may be combined in any suitable manner. Those skilled in the art will recognize, in light of the description of this application, that the disclosed systems and/or methods can be practiced without one or more of the specific features. In other examples, additional features and advantages may be realized in particular scenarios that are not presented in all examples.

As used in this application, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art. The term "comprising" as used in this application means "including, but not limited to".

Although the systems and methods have been illustrated and described with respect to one or more implementations, equivalent modifications and alterations will occur to others skilled in the art upon reading and understanding this specification and the accompanying drawings. Furthermore, although a particular feature may be disclosed with respect to only one of several implementations, such feature may be disclosed with respect to any or other implementations as desirable and advantageous for a particular application. may be combined with one or more other features. Therefore, the breadth and scope of the present disclosure should not be limited by any of the above descriptions. Rather, the scope of the invention should be defined in accordance with the following claims and their equivalents.

Claims (25)

A method of operating a dual comb laser, the method comprising:
A first laser light source and a second laser light source of the dual comb laser generate pulsed laser light, and at least one of the first laser light source and the second laser light source includes a diode-pumped solid-state laser whose output intensity can be changed. Prepare,
Matching the phase repetition frequency of the pulsed laser light by selectively changing the output intensity of the diode-pumped solid-state laser;
including methods. the first laser light source comprises a diode-pumped solid-state laser with a fixed output intensity;
2. The method of claim 1, wherein the second laser light source comprises the diode-pumped solid state laser whose output intensity is variable. 2. The method of claim 1, wherein the output intensity of the diode-pumped solid-state laser is selectively modified based on group delay values determined using dichroic interference. 2. The method of claim 1, wherein the output intensity of the diode-pumped solid-state laser is selectively changed by transitioning the diode-pumped solid-state laser from a first output intensity value to a different second output intensity value. 2. The method of claim 1, wherein the output intensity of the diode-pumped solid-state laser is selectively varied by varying the current supplied to the diode-pumped solid-state laser. 6. The method of claim 5, wherein the current varies depending on a group delay value determined using dichroic interference. 2. The method of claim 1, wherein the selective modification of the output intensity of the diode pumped solid state laser matches the pulse repetition frequency by changing the refractive index of the crystal. generating a feedback signal using one of the pulsed laser lights;
using the feedback signal to control the position of a mirror of a laser resonator of the first laser light source or the second laser light source driven by a piezoelectric transducer;
2. The method of claim 1, further comprising: 2. The method of claim 1, further comprising rapidly modulating the difference in phase repetition frequencies of the first laser source and the second laser source. A method of operating a laser light source, the method comprising:
A pulsed laser beam is generated using a crystal excited by the excitation laser beam output from a diode-pumped solid-state laser,
changing the refractive index of the crystal by selectively changing the intensity of the excitation laser beam;
including methods. 11. The method of claim 10, wherein the intensity of the excitation laser light is selectively varied based on group delay values determined using dichroic interference. 11. The method of claim 10, wherein the intensity of the pump laser light is selectively varied by adjusting the current supplied to the diode pumped solid state laser. 13. The method of claim 12, wherein the current is adjusted based on group delay values determined using dichroic interference. A first laser light source and a second laser light source that generate pulsed laser light, wherein at least one of the first laser light source and the second laser light source includes a diode-pumped solid-state laser whose output intensity can be changed. 1 laser light source and the second laser light source,
a circuit that selectively changes the output intensity of the diode-pumped solid-state laser in order to match the phase repetition frequency of the pulsed laser light;
Dual comb laser with the first laser light source comprises a diode-pumped solid-state laser with a fixed output intensity;
15. The dual comb laser according to claim 14, wherein the second laser light source includes the diode-pumped solid-state laser whose output intensity is changeable. 15. The dual comb laser of claim 14, wherein the output intensity of the diode-pumped solid-state laser is selectively modified based on a group delay value determined using dichroic interference. 15. The dual comb laser of claim 14, wherein the output intensity of the diode-pumped solid-state laser is selectively changed by transitioning the diode-pumped solid-state laser from a first output intensity value to a different second output intensity value. . 15. The dual comb laser of claim 14, wherein the output intensity of the diode-pumped solid-state laser is selectively varied by varying the current supplied to the diode-pumped solid-state laser. 19. The dual comb laser of claim 18, wherein the current changes depending on a group delay value determined using dichroic interference. 15. The dual comb laser of claim 14, further comprising a crystal having a refractive index that changes when the output intensity of the diode pumped solid state laser is changed, the change in refractive index matching the pulse repetition frequency. The circuit further includes:
(i) generating a feedback signal using one of the pulsed laser lights;
(ii) the dual comb laser of claim 14, wherein the feedback signal is used to control the position of a mirror of a laser resonator of the first laser light source or the second laser light source driven by a piezoelectric transducer. . diode-pumped solid-state laser,
a crystal that generates a pulsed laser beam when excited by the excitation laser beam output from the diode-pumped solid-state laser;
a circuit that changes the refractive index of the crystal by selectively changing the intensity of the excitation laser beam;
A laser light source. 23. The laser light source of claim 22, wherein the intensity of the excitation laser light is selectively changed based on a group delay value determined using dichroic interference. 23. The laser light source of claim 22, wherein the intensity of the pump laser light is selectively varied by adjusting the current supplied to the diode pumped solid state laser. 25. The laser light source of claim 24, wherein the current is adjusted based on a group delay value determined using dichroic interference.

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