INCLUDING A QUANTUM-CASCADE-LASER-BASED LIGHT AMPLIFICATION

TECHNICAL FIELD

The invention relates to a method of measuring a spectral response of a sample and a spectroscopic measuring apparatus being configured for measuring a spectral response of a sample. In particular, the invention relates to a method of measuring the spectral re sponse by irradiating the sample with broadband mid-infrared probe light and sensing changes of the probe light spectral content and/or temporal structure, resulting from an interaction of the probe light with the sample. In addition, the invention relates, in partic ular, to a spectroscopic measuring apparatus including a broadband mid-infrared light source for irradiating the sample with probe light and a detector device for detecting changes of the probe light resulting from an interaction of the probe light with the sample in spectral and/or time domains. Applications of the invention are available in spectros copy, in particular high dynamic range field-resolved infrared spectroscopy, of a sample, e.g. a biological sample or another sample having an IR response, in particular for analys ing a (molecular) composition of a sample and/or changes thereof.

BACKGROUND ART

For illustrating background art relating to the invention, reference is made to the follow ing prior art documents:

[1] Lasch, P. & Kneipp, J. Biomedical Vibrational Spectroscopy (Wiley, 2010);

[2] Pupeza, loachim, et al. "Field-resolved infrared spectroscopy of biological sys tems"

Nature 577, 7788, 52-59 (2020); [3] Zhang, Jinwei, et al. "Intra-pulse difference-frequency generation of mid-infrared (2.7-20 pm) by random quasi-phase-matching" Optics Letters 44, 12, 2986-2989 (2019);

[4] Wang, Qing, et al. "Broadband mid-infrared coverage (2-17 pm) with few-cycle pulses via cascaded parametric processes" Optics Letters 44, 10 (2019): 2566- 2569;

[5] Novak, Ondfej, et al. "Femtosecond 8.5 pm source based on intrapulse differ ence-frequency generation of 2.1 pm pulses" Optics Letters 43, 6, 1335-1338 (2018);

[6] Williams, B. "Terahertz quantum-cascade lasers" Nature Photonics 1, 517-525 (2007);

[7] Rauter, Patrick, et al. "Multi - wavelength quantum cascade laser arrays" Laser & Photonics Reviews 9.5, 452-477(2015);

[8] Zhu, Huan, et al. "Terahertz master-oscillator power-amplifier quantum cascade laser with a grating coupler of extremely low reflectivity" Optics Express 26,2, 1942-1953 (2018);

[9] Zhou, Wenjia, et al. "Single-mode, high-power, mid-infrared, quantum cascade laser phased arrays" Scientific Reports 8, 1, 1-6 (2018);

[10] Andriukaitis, Giedrius, et al. "90 GW peak power few-cycle mid-infrared pulses from an optical parametric amplifier" Optics Letters 36, 15, 2755-2757 (2011);

[11] Seidel, Marcus, et al. "Multi-watt, multi-octave, mid-infrared femtosecond source" Science advances 4, 4, eaaql526 (2018);

[12] Jukam, Nathan, et al. "Terahertz amplifier based on gain switching in a quantum cascade laser" Nature Photonics 3, 12 (2009): 715-719;

[13] Bachmann, Dominic, et al. "Broadband terahertz amplification in a heterogene ous quantum cascade laser" Optics Express 23, 3 (2015): 3117-3125;

[14] Oustinov, Dimitri, et al. "Phase seeding of a terahertz quantum cascade laser" Nature communications 1.1 (2010): 1-6; and

[15] Schubert, Olaf, et al. "Rapid-scan acousto-optical delay line with 34 kHz scan rate and 15 as precision" Optics Letters 38, 15 (2013): 2907-2910. It is generally known that broadband infrared spectroscopy can distinguish changes in molecular composition of a complex sample by detecting the variation of absorptions in the spectral range from 400 cm ¹ to 3300 cm ¹ or 3 pm to 25 pm (so-called molecular fin gerprint absorptions), making it an ideal metrology for biomedical sensing [1]

It has recently been shown that field-resolved spectroscopy (FRS) based on femtosecond mid-infrared (MIR) laser pulses can achieve higher dynamic range, sensitivity and specific ity for molecular detection when compared to current state-of-the-art Fourier transform infrared (FTIR) spectroscopy [2]. In FRS, a few-optical-cycle, broadband MIR pulse excites the sample, and the full electric field including the molecular response in the wake of the pulse is directly captured in a time-domain electro-optic sampling (EOS) measurement. Despite its success and the prospect to reach multi-octave spectral coverage in future,

FRS still faces in particular the following limitations: i. The intensity of the MIR driving pulses and the corresponding strength of the mo lecular response are limited by the low efficiency of the nonlinear MIR generation processes. For example, for intra-pulse difference frequency generation (IPDFG) that provides particularly phase-stable pulse, the efficiency is only 0.1 % to 3 % [3- 5]; ii. The current achievable optical signal/noise ratios start to reach the dynamic range limitations of detection electronics [2]; and iii. MIR generation generally relies on phase matching in nonlinear crystals, which produces spectra with non-uniform spectral density across the targeted wave length range.

There is a need to overcome the limitations to better employ the potential of the FRS or other high-dynamic-range/high-sensitivity techniques.

DESCRIPTION OF THE INVENTION The objective of the invention is to provide an improved apparatus and method for meas uring a spectral response of a sample, e. g., for measuring the molecular composition and/or changes in the molecular composition of the sample, which avoids disadvantages of conventional techniques. In particular, the objective of the invention is to provide a method and a measuring apparatus for measuring a spectral response of a sample with an increased sensitivity, improved signal-to-noise-ratio (SNR), enhanced selectivity, im proved uniformity of the spectral density across a targeted wavelength range and/or im proved capability of covering an extended spectral range, e.g., in the mid-infrared spec tral range (MIR).

These objectives are solved by the subject matter of the independent claims. Preferred embodiments and applications of the invention are defined in the dependent claims.

According to a first general aspect of the invention, a spectroscopic measuring apparatus is provided. The spectroscopic measuring apparatus is configured for measuring a spectral response of a sample, e.g., a biological sample or another sample with an IR response. To this end, the spectroscopic measuring apparatus comprises a femtosecond (fs) laser source device (e.g., including a Ho-YAG laser, an Yb:YAG thin-disk laser, a Ti:Sa laser, an Erfiber laser or a Cr:ZnS laser) being arranged for an irradiation of the sample with a se quence of probe light pulses having a primary spectrum. Preferably, the primary spectrum - i.e., the spectral composition of the probe light pulses - is a continuous or quasi-contin- uous spectrum in the mid-infrared range. For example, the primary spectrum may cover the wavelength range from 5 pm to 15 pm. Further, the spectroscopic measuring appa ratus comprises a detector device (e.g., an FTIR-spectrometer; preferably field-resolved detection with EOS) being arranged for a spectrally and/or temporally resolved detection of response light pulses having an altered spectrum and/or temporal structure and result ing from an interaction of the probe light pulses with the sample. Each of the response light pulses results from one of the probe light pulses interacting with the sample. In other words, the detector device may be arranged to measure the spectral composition and/or temporal profile of the modified probe light pulses (i. e., the response light pulses), whose spectra and/or temporal structures may differ from that of the initial probe light pulses due to light-matter interactions (e.g., excitation of vibrational and/or rotational molecular states of the sample) and may be used, for example, for analysing the molecular composition of the sample.

In addition, according to the invention, the claimed spectroscopic measuring apparatus further includes a pulse modification device comprising at least one quantum cascade la ser (QCL). This type of laser is basically known in the prior art and refers to a (inter-sub- band) semiconductor laser emitting around a centre wavelength ranging in the mid-infra- red (e.g., from 3 pm to above 24 pm) with, e. g., up to several Watts of output power. Ad vantageously, the emission properties of QCLs can be designed by creating specific quan tum well structures with semiconductor-multilayer sequences, providing a plethora of powerful and customizable on-chip lasers [6, 7]

According to the invention, the pulse modification device is configured to modify the probe light pulses and/or the response light pulses by amplifying one or more spectral components of the probe light pulses and/or the response light pulses with the at least one quantum cascade laser. In other words, the pulse modification device may be config ured to modify the probe light pulses before reaching, in particular interacting with, the sample, and/or to modify the response light pulses before entering the detector device. As described in detail below, the use of the QCL technology within the claimed spectro scopic measuring apparatus advantageously allows for boosting the power of the probe light pulses from the usual tens-of-milli-Watt regime (see, e.g., [2]) to a multi-Watt level, increasing the molecular response and leading to a higher detected signal/noise and hence higher sensitivity. A further advantage of the claimed pulse modification device is that it may allow for shaping the primary spectrum (e.g., by selectively enhancing specific spectral regions, for example with typical absorption bands), such that each probe light pulse optimally excites the sample. Alternatively, or in addition, the pulse modification device may also be used for time-gated amplification of the probe light pulses and/or the response light pulses, in particular to selectively enhance the molecular response in the wake (tail) of the main (excitation) pulse, thus strongly reducing the demands on the dy namic range of the detector. The inventors have found, that a QCL, compared with other available amplification tech niques, provides in particular the following further advantages, which can be employed in the spectroscopic measurement. The energy conversion in QCLs is very efficient since it allows the re-use of each electron to generate multiple photons. The direct conversion of electric energy into photons and their small size give QCLs also advantages in reaching lower amplification noise compared to, e. g., optical parametric amplifiers (OPAs). In addi tion, the energy conversion efficiency in the MIR OPA is limited by its low quantum effi ciency, defined by the photon energy ratio between MIR output and NIR pump laser. It thus requires high power pump lasers in order to achieve similar output as QCLs. Besides, the OPA requires multiple optical elements and usually takes up much more space than a QCL that implements amplification on a chip.

In the present context, the term "probe light pulse" may generally refer to a light pulse in the optical path between the fs laser source device and the sample, though it may even tually be a "modified probe light pulse" when interacting with the sample. Similarly, the term "response light pulse" may generally refer to a light pulse in the optical path be tween the sample and the detector device, though it may eventually be a "modified re sponse light pulse" when entering the detector device.

For creating the sequence of probe laser pulses, the fs laser source device preferably is a pulsed fs laser source device which may be configured to generate periodic pulse trains, preferably with a repetition rate in a range from e. g. 100 kHz to 10 MHz or more, e. g., to several hundreds of MHz. Furthermore, it is clear to those skilled in the art that, though the invention is primarily described in the context of sequences of probe/response light pulses, its teaching can also be applied in the context of employing a few or a single probe light pulse(s).

The basic advantage of the invention results from employing one or more quantum cas cade lasers for selectively amplifying spectral components of the probe light before reaching the sample and/or for selectively amplifying spectral components of the re sponse light, resulting from the interaction of the probe light with the sample, before reaching the detector. By this, for example, the power of the probe light can be boosted from the usual tens-of-milli-Watt regime (see e.g. [2]) to a multi-Watt level, increasing the molecular response and leading to a higher detected signal/noise and hence higher sensi tivity. Additionally, or alternatively, the quantum cascade laser(s) can also be used for modifying the response light, e.g. by selectively enhancing only the molecular response after the main pulse, which results in signal levels of the molecular response similar to the excitation pulse, thus strongly reducing the demands on the dynamic range of the detec tor.

According to a preferred embodiment of the invention, the at least one quantum cascade laser may comprise an array of multiple (i. e., at least two, e.g., five or up to ten or even more) quantum cascade lasers with different centre wavelengths. In this context, the term "centre wavelength" may be considered as the respective wavelength correspond ing to the centre of mass of the spectrum in frequency domain of the QCL. Preferably, the centre wavelengths of the QCLs of the array are evenly distributed in the mid-infrared re gime. Since the spectral bandwidth of a single QCL is usually limited to around 5 % of the centre wavelength the inventive use of multiple quantum cascade lasers advantageously allows to possibly cover the full spectrum of an ultra-broadband (e.g., a super-octave) mid-infrared pulse.

As a result, the pulse modification device may be used for a section-wise spectral amplifi cation, which advantageously allows for a controlled tailoring of the pulse spectrum (e.g. flattening the spectrum, enhancing the spectral wings, and/or to increase the power spectral density at frequencies of expected molecular resonances).

According to another preferred embodiment of the invention, the multiple quantum cas cade lasers of the array may be arranged in a parallel configuration. Like in the context of parallel electrical circuits, the term "parallel" refers to a configuration, where the QCLs are arranged in different optical branches extending between two common nodes in the optical path. Advantageously, this enables simultaneously amplifying different spectral regimes, thus providing a fast and low-loss solution for modifying mid-infrared light pulses.

In addition, or alternatively, the pulse modification device may comprise a splitter device configured to spatially separate a laser beam input into several sub-beams with different spectral intervals. Furthermore, the pulse modification device may comprise a relaying device configured to direct each of the sub-beams to one of the multiple quantum cas cade lasers respectively. In other words, the relaying device - which may also be referred to as a guiding or deflecting device in this context - may be configured to guide each of the sub-beams generated by the splitter device to a respective QCL. Preferably, the as signment of the sub-beams to the respective QCLs is based on the spectral interval of the sub-beams, i.e., the middle of each spectral interval may correspond to a centre wave length of a QLC. Furthermore, the pulse modification device may comprise a combiner device configured to collimate an amplified output of each of the multiple quantum cas cade lasers into a single laser beam output. By this, advantageously, a simultaneous am plification of different spectral regimes is enabled, wherein the usually compact chip de sign of QCLs facilitates a very space-saving implementation of the pulse modification de vice.

According to an alternative or additional aspect of the invention, the multiple quantum cascade lasers may be arranged in a sequential configuration (or: serial configuration).

Like in the context of serial electrical circuits, also here the term "sequential" may refer to a configuration, where the multiple QCLs are connected "in a line" within a single optical path. Alternatively, or in addition, the pulse modification device may also comprise a re laying device configured to direct a laser beam input in a consecutive order to each of the multiple quantum cascade lasers. Advantageously, this allows for a successive amplifica tion or modification of different spectral regimes.

The parallel and sequential configurations can be combined. Thus, according to another aspect of the invention, the pulse modification device may comprise a first QCL-subset and a second QCL-subset, wherein the first QCL-subset of the multiple quantum cascade lasers is arranged in a parallel configuration and the second QCL-subset of the multiple quantum cascade lasers is arranged in a sequential configuration. In other words, some QCLs of the pulse modification device may be arranged in parallel, e.g., for amplifying the respective spectral regimes simultaneously, while some QCLs of the pulse modification device may be arranged sequentially, e.g., for amplifying the respective spectral regimes consecutively. Each of the first and second subset may include different QCLs, or the first and second subset may share at least one QCL. Thereby, the pulse modification device may also comprise the respective devices (splitter device, relaying device, combiner de vice) mentioned before in the context of the exclusively parallel or sequential configura tions.

According to another aspect of the invention, at least one quantum cascade laser has an output power of at least 1 Watt and/or a centre wavelength in the range between 3 pm and 24 pm. If the pulse modification device comprises an array of multiple QCLs, prefera bly, all QCLs have an output power of at least 1 Watt and/or a centre wavelength in the range between 3 pm and 24 pm, respectively. Advantageously, this allows for boosting the power of the light pulses from the usual tens-of-milli-Watt regime (see e.g. [2]) to a multi-Watt level. The increased power may result in a correspondingly stronger molecular response, leading to a higher detected signal/noise and hence higher sensitivity in the measurement.

In order to advantageously enhance specific regions of a light pulse in the time domain, according to another aspect of the invention, the pulse modification device may be con figured to shape a temporal profile of the probe light pulses and/or the response light pulses by time-gated amplifying one or more spectral components of the probe light pulses and/or the response light pulses. In this context, the term "time-gated" refers to a temporal enhancement of the probe and/or response light pulse based on a controlled on/off-switching of the QCL(s) for a predetermined time interval. For this, e.g., a time gate provided by a radio frequency (RF) setup may be used. In an exemplary embodi ment, RF pulses may be generated by illuminating a fast photodiode with a fraction of a d riving pulse of the fs laser source device used to generate the (mid-infrared) probe light pulses. The power of the - optionally delayed - RF pulse may then be increased by an am plifier so that the QCL(s) can operate above threshold, driven by the RF pulse, wherein the on-switching of the QCL(s) will be synchronized with the probe light pulse.

This time-gated setup advantageously enables for example to amplify a temporal section of the response light pulse (preferably the part following the main excitation), in which the sample response is encoded. In the context of the "temporal section amplification", it should be noted that the response light pulse in a typical FRS measurement usually con tains a main pulse, which mainly corresponds to the probe light pulse, and the molecular response in the wake (tail) of the main pulse. Therefore, the onset of the RF pulse is ad vantageously timed such that amplification starts after the main pulse. By fast switching on and off the RF pulse, the molecular response at the pulse tail may be selectively ampli fied. Since the time-gated amplification acts on each pulse waveform individually, this im plementation is also suited both for multi-shot acquisition, and for a detection scheme that measures the full EOS trace with a single laser shot.

Alternatively, the time-gated setup also advantageously enables a delay-dependent am plification, wherein the time-gated QCL(s) amplification acts on the full pulse waveform, either before or after sample interaction. Thereby, the on/off switching of amplification may be synchronized with the delay in a multi-pulse scanning experiment, like conven tional EOS detection. In this context, the spectroscopic measuring apparatus may com prise a delay device (e.g., a mechanical delay stage) configured to delay the driving pulse temporally driving the time gate relative to the probe light pulse.

According to another embodiment of the invention, the spectroscopic measuring appa ratus may further comprise a control device. The control device may be configured to control the pulse modification device to generate a predefined, i.e., a previously deter mined, spectral and/or temporal profile of the at least one of the probe light pulses and the response light pulses. In other words, the control device may be configured to cause the pulse modification device to modify the spectral and/or temporal shape of the probe light pulse and/or the response light pulse in a defined way. Advantageously, this facili tates for example to shape the probe light pulse spectrally and/or temporally such that it optimally excites the sample, e.g. by increasing the power spectral density at frequencies of expected molecular resonances.

According to another advantageous aspect of the invention the fs laser source device may be adapted for generating the probe light pulses with at least one of the following fea tures: The probe light pulses may comprise ultra-broadband mid-infrared pulses. The probe light pulses may have a pulse duration below 100 fs, in particular below 50 fs. The probe light pulses may have an average power above 10 mW, in particular above 100 mW. The primary spectrum of the probe light pulse may cover at least one frequency oc tave, in particular at least two frequency octaves. The primary spectrum of the probe light pulse may cover a wavelength range from 5 pm to 15 pm, in particular from 3 pm to 30 pm. The primary spectrum of the probe light pulse may be a continuous or quasi-continu- ous spectrum.

According to a second general aspect of the invention, a method of measuring a spectral response of a sample (e.g., a biological sample) is provided. To this end, the method com prises the step of irradiating the sample with a sequence of probe light pulses generated by a fs laser source device (e.g., including an Yb-YAG laser), wherein the probe light pulses have a primary spectrum. Preferably, the primary spectrum is a continuous or quasi-con- tinuous spectrum in the mid-infrared regime, e.g., covering the wavelength range from 5 pm to 15 pm. Further, the method comprises the step of spectrally resolved detecting a response light pulse by a detector device (e.g., a detector device configured for electro optic sampling), wherein the response light pulse has an altered spectrum resulting from an interaction of the probe light pulses with the sample. In addition, the method includes the step of modifying the probe light pulses and/or the response light pulses with a pulse modification device. Thereby, the pulse modification device comprises at least one quan tum cascade laser, wherein one or more spectral components of the probe light pulses and/or the response light pulses are amplified with the at least one quantum cascade la ser. By this, advantageously, the power of the probe light may be boosted from the usual tens-of-milli-Watt regime (see, e.g., [2]) to a multi-Watt level, increasing the molecular re sponse and leading to a higher detected signal/noise and hence higher sensitivity.

Preferably, the method of the second general aspect of the invention or embodiments thereof is executed by the spectroscopic measuring apparatus of the first general aspect of the invention or embodiments thereof.

According to a preferred embodiment of the invention, the probe light pulses are modi fied before reaching the sample. Alternatively, or in addition the response light pulses are modified before reaching and/or entering the detector device. Advantageously, this al lows for a controlled shaping of the probe light pulses, as well as the response light pulses in dependence of the particular requirements in the different parts of the measurement.

According to another aspect of the invention the at least one quantum cascade laser may comprise an array of multiple quantum cascade lasers with different centre wavelengths. For example, the array of multiple QCLs may comprise 2 to 10 or more QCLs. Preferably, the centre wavelengths of the respective QCLs (i.e., the wavelength of each QCL's band width that might be considered its "middle") are evenly distributed in the mid-infrared re gime. Advantageously, the pulse modification device enables such a section-wise spectral amplification, which allows for a controlled tailoring of the pulse spectrum (e.g., flatten ing the spectrum, enhancing the spectral wings, and/or increasing the power spectral density at frequencies of expected molecular resonances).

According to another aspect of the invention the multiple quantum cascade lasers may be arranged in a parallel configuration. Advantageously, this enables simultaneous amplifica tion of different spectral regimes, thus providing a fast and low-loss solution for modify ing a mid-infrared light pulse. Alternatively, or in addition, the step of modifying may in clude the following steps: splitting the probe light pulses and/or the response light pulses by a splitter device into several sub-beams with different spectral intervals; directing each of the sub-beams to one of the several quantum cascade lasers respectively by a relaying device; and collimating an amplified output of each of the multiple quantum cascade la sers into a single laser beam output by a combiner device.

According to another aspect of the invention the multiple quantum cascade lasers may be arranged in a sequential configuration. Alternatively, or in addition, the step of modifying may include the step of directing the probe light pulses and/or the response light pulses in a consecutive order to each of the several quantum cascade lasers by a relaying device. Advantageously, this allows for a successive amplification or modification of different spectral regimes.

According to another aspect of the invention the pulse modification device may comprise a first QCL-subset and a second QCL-subset, wherein the first QCL-subset of the multiple QCLs is arranged in a parallel configuration and the second QCL-subset of the multiple QCLs is arranged in a sequential configuration. In other words, some QCLs of the pulse modification device may be arranged in parallel, e.g. for amplifying the respective spectral regimes simultaneously, while other QCLs of the pulse modification device may be ar ranged sequential, e.g. for amplifying the respective spectral regimes consecutively. Thereby, the pulse modification device may also comprise the respective devices (splitter device, relaying device, combiner device) mentioned before in the context of the only parallel or sequential configurations.

According to another aspect of the invention the at least one quantum cascade laser may have an output power of at least 1 Watt and/or a centre wavelength in the range be tween 3 pm and 24 pm. If the pulse modification device comprises an array of multiple QCLs, preferably, all QCLs have an output power of at least 1 Watt and/or a centre wave length in the range between 3 pm and 24 pm respectively.

According to another aspect of the invention the method may further comprise the step of determining at least one spectral region of interest (e.g., a frequency of an expected molecular resonance of the sample). Preferably, the spectral region of interest may cover a spectral range, in which a characteristic vibrational and/or rotational transition in the sample may be excited. Further, the step of modifying may include increasing a power spectral density in the spectral region of interest. Advantageously, this allows selectively probing molecular fingerprints of expected constituents of the sample.

According to another aspect of the invention the step of modifying may include time gated amplification of one or more spectral components of the response light pulses for shaping the temporal profile of the response light pulses. As discussed in detail before, this technique advantageously enables to temporally enhance specific regions of the probe light pulses and/or the response light pulses in the time domain by a controlled on/off-switching of the QCL(s). To this end, a time gate provided by a radio frequency (RF) setup may be used, wherein RF pulses (generated by illuminating a fast photodiode with a fraction of a driving pulse of the fs laser source device) are used to trigger the temporal operation of the QCL(s). By this, advantageously a section of each of the temporally ex tended response light pulse, preferably the molecular response after the main (excitation) pulse, can be selectively enhanced, resulting in signal levels of the molecular response similar to the excitation pulse, thus strongly reducing the demands on the dynamic range of the detector.

According to another aspect of the invention the method may comprise the step of defin ing a target spectral profile and/or a target temporal profile of the probe light pulses and/or the response light pulses. For example, the target spectral profile may be a spec tral profile of a light pulse, where specific spectral regions (e.g., absorption bands, ex pected molecular resonances, etc.) are enhanced. Further, a target temporal profile may be, for example, a temporal profile of a light pulse, where a specific region of a light pulse in the time domain (e.g. the tail of a pulse) is enhanced. Thereby, the term "target" should be understood such that the respective profile is a profile intended to achieve. In addition, the method may comprise the step of controlling the pulse modification device by a control device based on the defined target spectral and/or temporal profile. In other words, the pulse modification device may be controlled such that it modifies the spectral and/or temporal shape of the probe and/or the response light pulse in order to corre- spond with the target spectral and/or temporal profile as best as possible. Advanta geously, this allows for a controlled shaping of the spectral and/or temporal profile of the light pulses depending on the particular measurement requirements.

According to another aspect of the inventive apparatus or method, the sample may be a biological sample (e.g., a sample from a human or animal organism, a medical sample). In particular, the sample may be, for example, at least one biological cell or part thereof, a cell group or cell culture, or tissue of an organism, a liquid, like, e.g., blood or other body liquids, optionally diluted, an aerosol, like e.g. breath including traces of liquid droplets, a gas and a vapour, e.g., emanating from a biological organism. Preferably, the sample may be a biological sample for diagnostic purposes. In this context, it should, however, be em phasized that the invention is not restricted to the investigation of biological samples, but rather can be implemented with other samples, like, e.g., substance samples from tech nical processes or environmental samples, that have a light-matter interaction with the probe light pulses.

Further, all features disclosed in this document in connection with the spectroscopic measurement apparatus are also intended to be disclosed and claimable in connection with the method, and vice versa.

BRIEF DESCRIPTION OF THE DRAWINGS

Further advantages and details of the invention are described in the following with refer ence to the attached drawings, which schematically show in:

Figure 1: features of a first embodiment of a spectroscopic measurement apparatus ac cording to the invention;

Figure 2: features of a second embodiment of a spectroscopic measurement apparatus according to the invention; Figure 3: an illustration of the amplification of spectral components of a mid-infrared light pulse by multiple quantum cascade lasers;

Figure 4: an illustration of a pulse modification device with an array of multiple quantum cascade lasers arranged in a parallel configuration;

Figure 5: an illustration of a pulse modification device with an array of multiple quantum cascade lasers arranged in a sequential configuration;

Figure 6: a flow diagram of a method of measuring a spectral response of a sample ac cording to an embodiment of the invention; and

Figures 7 and 8: features of time-gated amplification with a QCL.

MODES FOR CARRYING OUT THE INVENTION

Features of preferred embodiments of the invention are described in the following with particular reference to the provision of at least one QCL in a spectroscopic measuring setup. Details of QCLs, in particular the configuration and operation thereof, are not de scribed as far as they are known per se from available QCL techniques.

Details of a spectroscopic measuring setup, which are known per se from prior art, like details of FRS, are not described. In the drawings, identical or functionally equivalent ele ments are labelled with the same reference signs.

Figure 1 schematically illustrates a first embodiment of the spectroscopic measuring ap paratus 100 being configured for measuring a spectral response of a sample 1 according to the invention. The spectroscopic measuring apparatus 100, thereby, comprises a fs la ser source device 10 being arranged for an irradiation of the sample 1 with a sequence of probe light pulses 2 having a primary spectrum. Preferably, the probe light pulses 2 are ultra-broadband mid-infrared pulse with a quasi-continuous spectrum. For generating the probe light pulses 2, the fs laser source device 10 may include a driving source 11, like, e.g., an Yb-YAG-disk laser resonator combined with a broadening stage and a chirped mir ror compressor, and a difference frequency generation (DFG) unit 12. For example, the driving source 11 may create driving pulses (not shown) with a centre wavelength of 1030 nm, a pulse duration of 250 fs and a repetition rate of 28 MHz, which then enter the DFG unit 12. The DFG unit 12 may be configured to employ intra-pulse difference frequency generation of the input driving pulses by an optically non-linear crystal, like, e.g., a LiGaS2- based crystal, resulting - based on the previous exemplary numbers - in probe light pulses 2 having a primary spectrum ranging from 3 pm to 30 pm (mid-infrared).

Furthermore, the spectroscopic measuring apparatus 100 comprises a detector device 20 being arranged for a spectrally resolved detection of a response light pulse 2' having an altered spectrum resulting from an interaction of the probe light pulse 2 with the sample 1. For this purpose, the detector device 20 may be a (standard) FTIR-spectrometer. How ever, preferably more sophisticated detector setups are used. As exemplarily shown in Figure 1, the detector device 20, therefore, may be configured for electro-optic sampling the electric field of the response light pulse 2' in time domain by exploiting the linear electro-optic effect (also called Pockels effect). To this end, the spectroscopic measuring apparatus 100 may comprise a beam splitter element 51, which directs part of the pulses emitted from the laser source device 10 via a delay beam path 50 to the detector device

20.

For example, as illustrated in Figure 1, the beam splitter element 51 may be a dichroic beam splitting mirror, which is arranged in the beam path between the DFG unit 12 and the sample 1 and exhibits different transmittance/reflectance characteristics in the near- infrared and mid-infrared for separating the initial driving pulses and the generated probe light pulses after the DFG unit 12. Alternatively, the beam splitter element 51 could also be realized as a semi-transparent beam splitting mirror arranged in the beam path be tween the driving source 11 and the DFG unit 12.

For electro-optically sampling the waveform of the response light pulse 2' in the detector device 20, the response light pulse 2' and a driving pulse - which will be referred to in the following as a sampling pulse - may be spatially recombined and directed into an electro optic crystal 21 of the detector device 20. The electro-optic crystal 21 can be an optically non-linear crystal, e.g., GaSe, having a c ² non-linearity. Thereby, the polarization state of the sampling pulse passing the electro-optic crystal 21 is changed by the electric field of the response light pulses 2'. The sampling pulse with the modified polarization state may pass a half- or quarter-wave plate 22 and a Wollaston prism 23 separating sub-pulses and with two orthogonally polarized polarization components of the sampling pulse. These two sub-pulses and carrying the different polarization components are sensed with detec tor elements 24 and 24', comprising, e.g., photodiodes. Preferably, the detector elements 24 and 24' are balanced, i.e. calibrated such that a difference between the detector sig nals of the detector elements 24 and 24' is proportional to the electric field of the re sponse light pulse 2'. By iterative measurements, wherein the delay between the two pulses is varied via a delay drive unit (not shown) such that the (short) sampling pulse co incides with different parts of the (longer) response light pulse 2', the full temporal shape of the response light pulse 2' can be recovered. Fourier transforming the temporal shape, i.e. Fourier transforming the detector signal difference, lastly yields the spectral response of the sample 1.

In addition to the above-mentioned components known per se in field of FRS, the claimed spectroscopic measuring apparatus 100 further includes a pulse modification device 30 comprising at least one quantum cascade laser. In the illustrated embodiment, the pulse modification device 30 is configured to modify the probe light pulses 2 before reaching the sample 1 by amplifying one or more spectral components of each of the probe light pulses 2 with the at least one quantum cascade laser. To this end, the modification device 30 is arranged in the beam path between the fs laser source device 10 and the sample 1. Preferably, the modification device 30, thereby, comprises an array, i.e. an arrangement, of multiple (e.g., ten) quantum cascade lasers 3I...3N with different centre wavelengths li. .l _N , as described in more in the context of Figure 3.

In addition to increasing the power of the probe light pulses 2, which may advantageously result in a stronger molecular response, a higher detected signal/noise ratio, and thus a higher sensitivity, the pre-sample amplification also allows for shaping the (primary) spec trum (e.g. by selectively enhancing of specific spectral regions) such that the probe light pulses 2 optimally excite the sample 1.

In this context, the spectroscopic measuring apparatus 100 may also comprise a control device 40 being configured to control the pulse modification device 30 to generate a pre defined spectral and/or temporal profile of the probe light pulse 2. For example, the con trol device 40 may be configured to activate a particular QCL subset of the array of multi ple quantum cascade lasers 3I...3N each for a predetermined time.

Figure 2 schematically illustrates a second embodiment of the spectroscopic measuring apparatus 100 being configured for measuring a spectral response of a sample 1 accord ing to the invention. Different to the embodiment of Figure 1, which is particularly adapted for modifying the probe light pulse 2 before reaching the sample 1, the spectro scopic measuring apparatus 100 according to Figure 2 is adapted for modifying the re sponse light pulse 2' before reaching the detector device 20. Accordingly, the pulse modi fication device 30 comprising at least one quantum cascade laser is arranged in the beam path between the sample 1 and the detector device 20.

Advantageously, the embodiments of Figures 1 and 2 enable to perform a time-gated am plification measurement, where at least one section of the temporally extended response light pulse 2', preferably the molecular response after the main (excitation) pulse, is selec tively enhanced. This approach, thereby, benefits from the picosecond relaxation dynam ics in QCLs that provide an ultrafast switching of the amplification process. In order to control the respective switching of the pulse modification device 30, the spectroscopic measuring apparatus 100 may comprise a control device 40 being configured to control the pulse modification device 30 to generate a predefined temporal profile of the probe light pulse 2 and/or the response light pulse 2'. In particular, the post-sample amplifica tion advantageously allows to raise the molecular signal to similar levels as the excitation pulse, thereby strongly reducing the demands on the dynamic range of the detector. De tails of the time-gated amplification are described below with reference to Figures 7 and

8.

Figure 3 schematically illustrates the amplification of spectral components of a mid-infra- red light pulse, e.g., the afore-mentioned probe light pulse 2 or response light pulse 2', by an array of multiple quantum cascade lasers 3I...3N. The quantum cascade lasers 3I...3N thereby exhibit narrow wavelength emission around different centre wavelengths li. .l _N in the mid-infrared. In this context, the expression "centre wavelength" may be consid ered as the centre of mass in frequency domain. Preferably, the centre wavelengths li. .l _N of the quantum cascade lasers 3I...3N are evenly distributed in the mid-infrared re gime. By varying the output power of each QCLs 3I...3N individually, the corresponding spectral regions can be differently enhanced, thus advantageously allowing for a con trolled modification of the spectral profile of the original mid-infrared light pulse.

Alternatively or in addition to the afore-mentioned modification in the frequency (wave length) domain, the respective mid-infrared light pulse can be also varied in the time do main. For this, the output power of the QCLs 3I...3N is individually varied over time, e.g. turned on/off for a predetermined period of time respectively.

While Figure 3 illustrates the basic principle of the pulse modification, in the following, two specific QCL array arrangements, namely a parallel configuration and a sequential configuration, will be discussed.

Figure 4 schematically illustrates a pulse modification device 30 with an array of multiple quantum cascade lasers 3I...3N arranged in the parallel configuration. For this embodi ment, the pulse modification device 30 preferably comprises a splitter device 31 config ured to spatially separate a laser beam input into several sub-beams with different spec tral intervals. Thereby, the number of spectral intervals may preferably correspond to the number of quantum cascade lasers 3I...3N and/or the middle of each spectral interval may correspond to a centre wavelength li. .l _N of one of the quantum cascade lasers 3I...3N. Furthermore, the pulse modification device 30 may comprise a relaying device 32 (details not shown) configured to direct each of the sub-beams to one of the multiple quantum cascade lasers 3I...3N respectively. In addition, the pulse modification device 30 may com prise a combiner device 33 configured to collimate an amplified output of each of the multiple quantum cascade lasers 3I...3N into a single laser beam output.

In total, the parallel configuration with the different optical sub-paths advantageously en ables to simultaneously amplify different spectral regimes, thus providing a fast and low- loss solution for modifying a mid-infrared light pulse.

Figure 5 schematically illustrates a pulse modification device 30 with an array of multiple quantum cascade lasers 3I...3N arranged in a sequential configuration. For this, the pulse modification device 30 may comprise a relaying device 32' configured to direct a laser beam input in a consecutive order to each of the multiple quantum cascade lasers 3I...3N. In other words, the multiple cascade lasers 3I...3N are connected "in a line" within a single optical path. As discusses before, the quantum cascade lasers 3I...3N preferably have dif ferent centre wavelengths li. .l _N , i.e. the QCLs are configured to amplify different spectral regimes. By this, the different spectral regimes of the laser beam input can be enhanced one after the other in a sequential order.

Figure 6 schematically illustrates a flow chart of a method of measuring a spectral re sponse of a sample 1 according to an embodiment of the invention. The method com prises the following steps: step SI includes irradiating the sample 1 with a probe light pulse 2 generated by a fs laser source device 10. Step S2 then includes modifying the probe light pulse 2 before reaching the sample 1 and/or modifying a response light pulse 2' (resulting from an interaction of the probe light pulse 2 with the sample 1) with a pulse modification device 30 comprising at least one quantum cascade laser 3i. Preferably the pulse modification device 30 comprises an array of multiple quantum cascade lasers 3I...3N with different centre wavelengths li. .l _N , as described before in the context of Fig ures 3 to 5. Thereby, the step of modifying may involve amplifying one or more spectral components of the probe light pulse 2 and/or amplifying one or more spectral compo nents of the response light pulse 2' with the at least one quantum cascade laser 3i. For example, specific spectral regions of the probe light pulse 2 may be selectively enhanced such that the probe light pulse 2 optimally excites the sample 1. In addition or alterna tively, the response light pulse 2' may be temporally enhanced in the time domain such that the molecular response, which is encoded in the wake of the main (excitation) pulse, is selectively amplified. Step S3 includes spectrally resolved detection of the response light pulse 2' by a detector device 20 in time or frequency domains (e.g., a FTIR-spectrom- eter, but preferably field-resolved detection with EOS).

The time-gated amplification provided with the embodiments of Figure 1 or 2 comprises an amplification achieved in a time gate (time interval). The time gate is provided by an RF pulse as outlined in the following with reference to Figures 7 and 8. For this process, the QCLs comprise gain switched QCLs, see for example [12]. Figures 7 and 8 refer in an exemplary manner to one of the QCLs of multiple QCLs only. With preferred embodi ments of the invention, two applications of time-gated amplification for enhancing the contrast in a MIR measurement can be distinguished: (i) amplification of a section of the MIR waveform, preferably the temporal sample response following MIR excitation in a spectroscopic measurement; and (ii) delay-dependent MIR amplification.

The amplification of a section of the MIR waveform is illustrated in Figure 7, which shows in Figure 7A a schematic illustration of the time-gated amplification and in Figure 7B a temporal shape of an RF pulse used for gating the amplification, an MIR driving pulse (dashed line) and the response light pulse 2' (solid line) coming out of the sample.

With more details, the time-gated amplification may be implemented with the control de vice 40 (see e. g. Figure 2), including a radio frequency (RF) setup for generating RF pulses as the time-gating to switch on/off the gain of the QCL 3i. The RF pulses are generated by illuminating a photodiode 41 with a fraction of the driving pulse of the mid-infrared (MIR) generation. Therefore, the switching on of the QCL 3i will be synchronized with the MIR probe and response pulses. The power of the RF pulse is then increased by an amplifier 42 so that the QCL 3i can operate above threshold, driven by the RF pulse.

The amplification dynamics for this preferred embodiment of amplifying a response light pulse is shown in an exemplary manner in Figure 7B. The electric field E of the MIR wave form to be amplified contains the main pulse, which corresponds to the probe light pulse irradiating the sample, and the molecular response of the sample in the wake of the main pulse. The onset of the RF pulse is timed such that amplification starts after the main pulse. By fast switching on and off the RF pulse, the molecular response at the pulse tail is selectively amplified. Typical rise times of the RF pulses are currently in the 1- to 100-pi- cosecond range. Gain switched QCL devices with 46 ps [12] and 100 ps [13] rise times of the RF pulses have been reported. These time scales are much smaller than the nanosec onds response of e. g. a gas-phase sample so that this implementation makes time-gated amplification ideal for gas-phase detection. EOS measurement in a liquid sample, which has a shorter relaxation time, are also conceivable with faster photodiodes and electronic amplifiers. As the time-gated amplification acts here in serial manner on each MIR wave form individually, this implementation is suited both for multi-shot acquisition, and for a detection scheme that measures the full EOS trace with a single laser shot.

The delay-dependent MIR amplification in a multi-pulse scanning experiment is illustrated in Figure 8, which shows in Figure 8A an EOS measurement controlled by the delay line 50 (see Figures 1, 2). Black circles represent different measurements with different time de lay between sample and MIR probe light pulses. The bars on top show the temporal range where QCL 3i is switched on/off. Figure 8B shows an RF pulse and an EOS trace in the la boratory time , Figure 8C shows a schematic setup for QCL amplification in front of the sample 1, and Figure 8D shows a schematic setup for QCL amplification after the sample 1 (see Figures 1 and 2, resp.).

With more details, the delay-dependent MIR amplification acts on the full MIR waveform either of the probe light pulses before sample interaction or the response light pulses af ter sample interaction, with the on/off switching of amplification synchronized with the delay in a multi-pulse scanning experiment, like conventional EOS detection. In the case of EOS the measurement is performed by scanning the delay between the MIR waveform of the probe light pulse and the gate pulse and acquiring the EOS signal at each delay, generating the EOS waveform, that represents with constant amplification the MIR wave form, convolved with the instrumental response.

As shown in Figure 8A, the measured EOS waveform consists of data points that corre spond to at least one laser shot each. Depending on the detection bandwidth and scan speed, each data point may also be the time-averaged result of multiple laser shots. The time span between each data acquisition is thus at least equal or larger than the pulse-to- pulse temporal separation given by the repetition rate of the driving input laser. It is thus typically longer than multiple nanoseconds, so that time-gated amplification can be switched on and off from one data acquisition point to the next.

By switching on QCL amplification only at delays after the main pulse, it selectively en hances the signal measured for the molecular response in the wake of the pulse. In this multi-pulse application, the QCLs amplify the full MIR waveform (Figure 8B), but the de- lay-dependence of the amplification leads to an increased sample response signal in the EOS waveform measured by the detector device 20 (Figure 8B). This application of time gating is not limited by the time scale of the sample response, and applicable also to pico second or shorter MIR waveforms.

Figures 8C and 8D show two preferred embodiments, wherein in the first embodiment (Figure 8C) the QCL 3i amplifies the MIR probe light pulse received for the DFG unit 12 be fore the sample 1 and is switched on/off depending on the delay of the sample pulse (gate pulse). Amplification can still be additionally triggered by RF pulses synchronized with the MIR waveforms to increase amplification efficiency [14]. The delay scan corre sponds to a change of the optical delay of the gate pulse with respect to the MIR probe light pulse, for example with a mechanical change of the optical path length (mechanical stage) or with acousto-optic modulation in the delay line 50 [15]. ln the other embodiment (Figure 8C), QCL amplification takes place after the sample 1, thus amplifying both the residual excitation probe laser pulse and the sample response laser pulse, with the same delay-control of the amplification as in the embodiment of Fig ure 8C.

The features of the invention disclosed in the above description, the drawing and the claims can be of significance both individually as well as in combination or sub-combina tion for the realisation of the invention in its various embodiments.