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Coherent Raman scattering microscopy utilizing bioorthogonal tagging approaches like isotope or alkyne labeling allows for a targeted monitoring of spatial distribution and dynamics of small molecules of interest in cells, tissues, and other complex biological matrices. To fully exploit this approach in terms of real-time monitoring of several Raman tags, e.g., to study drug uptake dynamics, extremely fast tunable lasers are needed. Here, we present a laser concept without moving parts and fully electronically controlled for the quasi-simultaneous acquisition of coherent anti-Stokes Raman scattering images at multiple Raman resonances. The laser concept is based on the combination of a low noise and spectrally narrow Fourier domain mode-locked laser seeding a compact four wave mixing-based high-power fiber-based optical parametric amplifier.
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In this work we measure the frequency dependent transfer function of the amplitude noise for both the seed and pump power in an Yb3+-doped fiber amplifier chain. In particular, the relative intensity noise transfer function of this amplifier chain in the frequency range of 10 Hz - 100 kHz has been investigated. It is shown that the pump power noise of the pre-amplifier stages is transformed into seed power noise for the next amplification stage. Crucially, the seed power noise in the frequency range of interest is strongly damped by the main-amplifier. This, however, does not happen for the pump power noise. Thus, the noise of the pump of the last amplifier stage is the factor with the strongest impact on the overall noise level of the system. Finally, useful guidelines to minimize the output amplitude noise of an Yb3+-doped fiber amplifier chain are given.
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This work explores the frequency conversion and generation of short pulses with an optical parametric oscillator based on micro-structured fibers. Depending on the operation regime, the optical cavity can either behave as a normal-dispersion cavity delivering linearly chirped pulses, which were externally compressed down to only 26 fs, or as a dispersion-managed oscillator, which directly delivered compressed pulses with a pulse duration of only 39 fs.
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We present an ultrafast fiber laser system delivering 4.6 W average power at 258 nm based on two-stage fourth-harmonic generation in beta barium borate (BBO). The beam quality is close to being diffraction limited with an M2 value of 1.3×1.6. The pulse duration is 150 fs, which, potentially, is compressible down to 40 fs. A plain BBO and a sapphire-BBO compound are compared with respect to the achievable beam quality in the conversion process. This laser is applicable in scientific and industrial fields. Further scaling to higher average power is discussed.
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We have developed a dual-focus coherent anti-Stokes Raman scattering (CARS) microscope based on a dual output, compact fiber laser source. The underlying concepts of time-multiplexed, two-beam scanning and demultiplexed detection that we already employed for second-harmonic generation are here naturally extended for CARS microscopy. The layout of a robust, all-fiber laser source was reconfigured to provide two outputs, each containing the two colors necessary for the CARS process. The utilization of the design for simultaneously imaging two laterally or axially separated fields of view and, thus, inherently speeding up the image acquisition process, is demonstrated on human artery tissue samples.
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Arterias/fisiología , Espectrometría Raman/métodos , Humanos , Rayos LáserRESUMEN
Few-cycle lasers are essential for many research areas such as attosecond physics that promise to address fundamental questions in science and technology. Therefore, further advancements are connected to significant progress in the underlying laser technology. Here, two-stage nonlinear compression of a 660 W femtosecond fiber laser system is utilized to achieve unprecedented average power levels of energetic ultrashort or even few-cycle laser pulses. In a first compression step, 408 W, 320 µJ, 30 fs pulses are achieved, which can be further compressed to 216 W, 170 µJ, 6.3 fs pulses in a second compression stage. To the best of our knowledge, this is the highest average power few-cycle laser system presented so far. It is expected to significantly advance the fields of high harmonic generation and attosecond science.
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Unraveling and controlling chemical dynamics requires techniques to image structural changes of molecules with femtosecond temporal and picometer spatial resolution. Ultrashort-pulse x-ray free-electron lasers have significantly advanced the field by enabling advanced pump-probe schemes. There is an increasing interest in using table-top photon sources enabled by high-harmonic generation of ultrashort-pulse lasers for such studies. We present a novel high-harmonic source driven by a 100 kHz fiber laser system, which delivers 1011 photons/s in a single 1.3 eV bandwidth harmonic at 68.6 eV. The combination of record-high photon flux and high repetition rate paves the way for time-resolved studies of the dissociation dynamics of inner-shell ionized molecules in a coincidence detection scheme. First coincidence measurements on CH3I are shown and it is outlined how the anticipated advancement of fiber laser technology and improved sample delivery will, in the next step, allow pump-probe studies of ultrafast molecular dynamics with table-top XUV-photon sources. These table-top sources can provide significantly higher repetition rates than the currently operating free-electron lasers and they offer very high temporal resolution due to the intrinsically small timing jitter between pump and probe pulses.
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An ultrafast fiber chirped-pulse amplifier comprising eight coherently combined amplifier channels is presented. The laser delivers 1 kW average power at 1 mJ pulse energy and 260 fs pulse duration. Excellent beam quality and low-noise performance are confirmed. The laser has proven suitable for demanding scientific applications. Further power scaling is possible right away using even more amplifier channels.
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Periodic dumping of ultrashort laser pulses from a passive multi-MHz repetition-rate enhancement cavity is a promising route towards multi-kHz repetition-rate pulses with Joule-level energies at an unparalleled average power. Here, we demonstrate this so-called stack-and-dump scheme with a 30-m-long cavity. Using an acousto-optic modulator, we extract pulses of 0.16 mJ at 30-kHz repetition rate, corresponding to 65 stacked input pulses, representing an improvement in three orders of magnitude over previously extracted pulse energies. The ten times longer cavity affords three essential benefits over former approaches. First, the time between subsequent pulses is increased to 100 ns, relaxing the requirements on the switch. Second, it allows for the stacking of strongly stretched pulses (here from 800 fs to 1.5 ns), thus mitigating nonlinear effects in the cavity optics. Third, the choice of a long cavity offers increased design flexibility with regard to thermal robustness, which will be crucial for future power scaling. The herein presented results constitute a necessary step towards stack-and-dump systems providing access to unprecedented laser parameter regimes.
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A novel concept for an optical parametric oscillator based on four-wave mixing (FOPO) in an optical fiber is presented. This setup has the ability of generating highly chirped signal and idler pulses with compressed pulse durations below 600 fs and pulse energies of up to 250 nJ. At a fixed pump wavelength of 1040 nm, the emerging signal and idler wavelengths can be easily tuned between 867 to 918 nm and 1200 to 1300 nm, respectively, only by altering the cavity length. With compressed peak powers >100 kW and a repetition rate of only 785 kHz, this source provides tunable intense ultra-short pulses at moderate average powers. This setup constitutes a stable, simple and in many ways superior alternative to bulk state-of-the-art OPO light converters for demanding biomedical applications and non-linear microspectroscopy.
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In this Letter, we report on a femtosecond fiber chirped-pulse-amplification system based on the coherent combination of the output of four ytterbium-doped large-pitch fibers. Each single channel delivers a peak power of about 6.2 GW after compression. The combined system emits 200 fs long pulses with a pulse energy of 5.7 mJ at 230 W of average power together with an excellent beam quality. The resulting peak power is 22 GW, which to the best of our knowledge is the highest value directly emitted from any fiber-based laser system.
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Imaging based on coherent anti-Stokes Raman scattering (CARS) relies on the interaction of high peak-power, synchronized picosecond pulses with narrow bandwidths and a well-defined frequency difference. Recently a new type of fiber-based CARS laser source based on four-wave-mixing (FWM) has been developed. In order to enhance its spectral resolution and efficiency, a FWM based fiber optical parametric oscillator (FOPO) is proposed in this work. The source delivers 180 mW with 5.6 kW peak power for the CARS pump and 130 mW with 2.9 kW peak power for the Stokes signal. CARS resonances around 2850 and 2930 cm(-1) can be resolved with a resolution of 1 cm(-1) enabling high-contrast, spectrally resolved CARS imaging of biological tissue.
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Incorporation of coherent combination into a state-of-the-art fiber-chirped pulse amplification system obtains 1.1 mJ, 340 fs pulses with up to 280 W of average power at 250 kHz repetition rate. Propagation of this laser pulse inside a krypton-filled hollow-core fiber results in significant spectral broadening. Chirped mirrors are used to compress the pulses to 26 fs, 540 µJ (135 W) leading to a peak power of more than 11 GW. This unprecedented combination of high peak and average power ultrashort pulses opens up new possibilities in multidimensional surface science and coherent soft x-ray generation.
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We report on a femtosecond fiber laser system comprising four coherently combined large-pitch fibers as the main amplifier. With this system, a pulse energy of 1.3 mJ and a peak power of 1.8 GW are achieved at 400 kHz repetition rate. The corresponding average output power is as high as 530 W. Additionally, an excellent beam quality and efficiency of the combination have been obtained. To the best of our knowledge, such a parameter combination, i.e., gigawatt pulses with half a kilowatt average power, has not been demonstrated so far with any other laser architecture.
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Over the past years fast label-free nonlinear imaging modalities providing molecular contrast of endogenous disease markers with subcellular spatial resolution have been emerged. However, applications of these imaging modalities in clinical settings are still at the very beginning. This is because single nonlinear imaging modalities such as second-harmonic generation (SHG) and two-photon excited fluorescence (TPEF) have only limited value for diagnosing diseases due to the small number of endogenous markers. Coherent anti-Stokes Raman scattering (CARS) microscopy on the other hand can potentially be added to SHG and TPEF to visualize a much broader range of marker molecules. However, CARS requires a second synchronized laser source and the detection of a certain wavenumber range of the vibrational spectrum to differentiate multiple molecules, which results in increased experimental complexity and often inefficient excitation of SHG and TPEF signals. Here we report the application of a novel near-infrared (NIR) fiber laser of 1 MHz repetition rate, 65 ps pulse duration, and 1 cm(-1) spectral resolution to realize an efficient but experimentally simple SGH/TPEF/multiplex CARS multimodal imaging approach for a label-free characterization of composition of complex tissue samples. This is demonstrated for arterial tissue specimens demonstrating differentiation of elastic fibers, triglycerides, collagen, myelin, cellular cytoplasm, and lipid droplets by analyzing the CARS spectra within the C-H stretching region only. A novel image analysis approach for multispectral CARS data based on colocalization allows correlating spectrally distinct pixels to morphologic structures. Transfer of this highly precise but compact and simple to use imaging approach into clinical settings is expected in the near future.
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Pruebas Diagnósticas de Rutina/métodos , Imagen Multimodal/métodos , Espectrometría Raman/métodos , Arterias/química , Arterias/patología , Humanos , Microscopía/métodosRESUMEN
The past years have seen increasing interest in nonlinear optical microscopic imaging approaches for the investigation of diseases due to the method's unique capabilities of deep tissue penetration, 3D sectioning and molecular contrast. Its application in clinical routine diagnostics, however, is hampered by large and costly equipment requiring trained staff and regular maintenance, hence it has not yet matured to a reliable tool for application in clinics. In this contribution implementing a novel compact fiber laser system into a tailored designed laser scanning microscope results in a small footprint easy to use multimodal imaging platform enabling simultaneously highly efficient generation and acquisition of second harmonic generation (SHG), two-photon excited fluorescence (TPEF) as well as coherent anti-Stokes Raman scattering (CARS) signals with optimized CARS contrast for lipid imaging for label-free investigation of tissue samples. The instrument combining a laser source and a microscope features a unique combination of the highest NIR transmission and a fourfold enlarged field of view suited for investigating large tissue specimens. Despite its small size and turnkey operation rendering daily alignment dispensable the system provides the highest flexibility, an imaging speed of 1 megapixel per second and diffraction limited spatial resolution. This is illustrated by imaging samples of squamous cell carcinoma of the head and neck (HNSCC) and an animal model of atherosclerosis allowing for a complete characterization of the tissue composition and morphology, i.e. the tissue's morphochemistry. Highly valuable information for clinical diagnostics, e.g. monitoring the disease progression at the cellular level with molecular specificity, can be retrieved. Future combination with microscopic probes for in vivo imaging or even implementation in endoscopes will allow for in vivo grading of HNSCC and characterization of plaque deposits towards the detection of high risk plaques.
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Aterosclerosis/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Neoplasias de Cabeza y Cuello/diagnóstico , Microscopía Confocal , Espectrometría Raman/métodos , Animales , Aterosclerosis/etiología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Procesamiento de Imagen Asistido por Computador , Lípidos/análisis , Masculino , Fotones , ConejosRESUMEN
We report on a laser system producing a burst comprising femtosecond pulses with a total energy of 58 mJ. Every single pulse within this burst has an energy between 27 and 31 µJ. The pump is able to rebuild the inversion fast enough between the pulses, resulting in an almost constant gain for every pulse during the burst. This causes a very homogenous energy distribution during the burst. The output burst has a repetition frequency of 20 Hz, is 200 µs long and, therefore, contains 2000 pulses at a pulse repetition rate of 10 MHz.
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An environmentally-stable low-repetition rate fiber oscillator is developed to produce narrow-bandwidth pulses with several tens of picoseconds duration. Based on this oscillator an alignment-free all-fiber laser for multi-photon microscopy is realized using in-fiber frequency conversion based on four-wave-mixing. Both pump and Stokes pulses for coherent anti-Stokes Raman scattering (CARS) microscopy are readily available from one fiber end, intrinsically overlapped in space and time, which drastically simplifies the experimental handling for the user. The complete laser setup is mounted on a home-built laser scanning microscope with small footprint. High-quality multimodal microscope images of biological tissue are presented probing the CH-stretching resonance of lipids at an anti-Stokes Raman-shift of 2845 cm(-1) and second-harmonic generation of collagen. Due to its simplicity, compactness, maintenance-free operation, and ease-of-use the presented low-cost laser is an ideal source for bio-medical applications outside laser laboratories and in particular inside clinics.
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Rayos Láser , Microscopía/métodos , Espectrometría Raman/métodos , Arterias/patología , Aterosclerosis/patología , Cristalización , Humanos , Lípidos/análisis , FotonesRESUMEN
We present a fiber-based laser source for multiplex coherent anti-Stokes Raman scattering (CARS) microscopy. This source is very compact and potentially alignment-free. The corresponding pump and Stokes pulses for the CARS process are generated by degenerate four-wave mixing (FWM) in photonic-crystal fibers. In addition, an ytterbium-doped fiber laser emitting spectrally narrow 100 ps pulses at 1035 nm wavelength serves as pump for the FWM frequency conversion. The FWM process delivers narrow-band pulses at 648 nm and drives a continuum-like spectrum ranging from 700 to 820 nm. With the presented source vibrational resonances with energies between 1200 cm-1 and 3200 cm-1 can be accessed with a resolution of 10 cm-1. Additionally, the temporal characteristics of the FWM output have been investigated by a cross-correlation setup, revealing the suitability of the emitted pulses for CARS microscopy. This work marks a significant step towards a simple and powerful all-fiber, maintenance-free multiplex-CARS source for real-world applications outside a laboratory environment.
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Tecnología de Fibra Óptica/instrumentación , Aumento de la Imagen/instrumentación , Rayos Láser , Microscopía/instrumentación , Espectrometría Raman/instrumentación , Diseño de Equipo , Análisis de Falla de EquipoRESUMEN
We present a high-average-power femtosecond laser system at 520 nm central wavelength. The laser system delivers sub-500 fs pulses with 135 W average power at a pulse repetition rate of 5.25 MHz. Excellent beam quality is provided by high power fiber amplifiers and maintained during frequency doubling, resulting in a beam quality factor of M2<1.2. To our knowledge, the system presented here is the highest average power green laser source generating femtosecond pulses with diffraction-limited beam quality.