Fiber device for detecting an optical signal emitted by a sample, and physicochemical characterization systems provided with such devices

Abstract

According to one aspect, the present description relates to a fiber device (201) for detecting an optical signal emitted by a sample (10). The fiber device comprises a movable head (260) and a first optical fiber (210) configured to carry at least a first pump pulse train (511). The movable head comprises a mount (265) configured to receive a distal part of the first optical fiber; first light deflection means (221), which are integral with the mount and configured to receive the pump pulses at the output of the first optical fiber and to deflect the pump pulses toward a measurement region (230), such that, in operation, the pump pulses propagate substantially in the measurement region along a second axis (Δ2); receiving means configured to receive an optical signal emitted forward substantially along the second axis (Δ2) and resulting from the interaction, in the measurement region, of at least the pump pulses with the sample.

Description

[0001] Fiber optic devices for detecting optical signals emitted by samples and physicochemical characterization systems equipped with such devices

[0002] Technical field of the invention

[0003] This description concerns fiber-optic devices for detecting optical signals emitted by a sample, as well as physicochemical characterization systems equipped with such devices. More specifically, this description relates to fiber-optic devices for detecting optical signals resulting from nonlinear optical processes, including coherent Raman scattering (CRS), such as stimulated Raman scattering (SRS). This description is particularly applicable to the physicochemical characterization of biological tissues.

[0004] State of the art

[0005] Each year, approximately 14 million cancers are diagnosed and 8 million people die from cancer worldwide (13% of all annual deaths). About 80% of cancers develop in the epithelium, or lining of organs. Endoscopy plays a crucial role in the diagnosis, classification, and treatment of epithelial cancers, and for many types of cancer, it is the only viable option for accessing the tumor site. For example, the diagnosis of gastrointestinal (GI) cancers is highly dependent on endoscopic techniques, and they are among the most prevalent cancers in developed countries.

[0006] Endoscopic diagnosis still relies on techniques developed over a century ago: the operator's ability to visualize abnormal patterns in the image created by light scattered by tissues. Because precancerous or early-stage tissues exhibit subtle changes impossible to detect visually, two methods are currently used for histopathology, which limit endoscopic cancer imaging. The first method requires endoscopic sampling of suspicious areas (biopsies), which are then stained with hematoxylin and eosin (H&E) for microscopic examination. However, cancerous areas can be missed, and precancerous or early-stage tissues require further analysis (proteomics and genomics) that cannot be systematically performed with this method.A second method involves the use of external fluorescent markers injected into the patient's blood to aid image-guided surgery; however, their clinical approval is limited. Specifically, agents such as fluorescein, acriflavine, and indocyanine green (ICG) help visualize tissue vascularization and architecture, but their ability to highlight nuclear and cytoplasmic features is limited [Ref. 1]. Providing direct, intraoperative, marker-free endoscopic histopathological diagnosis would represent a major advance, eliminating the need for time-consuming tissue sampling and histology, and overcoming the limitations associated with the use of external fluorescent markers.

[0007] Coherent Raman scattering microscopy (CRS) offers a marker-free, high-resolution approach for visualizing cell nuclei and cytoplasm [Ref. 2]. CRS microscopy includes coherent anti-Stokes Raman scattering microscopy (CARS) and stimulated Raman scattering microscopy (SRS). CRS microscopy can detect CFE chemical bonds (2845 cm⁻¹). 1 ) and CH3 (2930 cm' 1) in the cytoplasm and nuclei of cells, respectively, through their molecular vibrations. SRS microscopy also eliminates the non-resonant noise inherent in CARS microscopy, which can distort CH2 and CH3 images. Thus, SRS microscopy of CH2 and CH3 chemical bonds, combined with collagen visible via second harmonic generation (SHG) and virtually stained, provides a tissue image with a striking similarity to conventional H&E histology images, which are very familiar to histopathologists, surgeons, and oncologists. This major advance introduces stimulated Raman histology (or SRH, short for Stimulated Raman Histology) as a powerful tool enabling the real-time identification and resection of cancerous tissues in an surgical setting.

[0008] As a reminder, in a spontaneous Raman scattering process, a pulsating pump wave co p The incident light on a molecule is scattered inelastically as a Stokes wave with a pulsation of co s and a so-called anti-Stokes wave with a co-pulsation AS The frequency difference between the generated waves and the pump wave depends on the molecular Raman transition (pulsation). R ) such that

[0009]

[0010] As a reminder, the angular frequency co is related to the wavelength X by the equation co = 2KC / A, where C is the speed of light in a vacuum. In a photonic view of the process, Stokes and anti-Stokes waves correspond to absorption from the ground or excited vibrational level, respectively. The process generating the anti-Stokes wave, starting from the excited vibrational level, is much less probable than the process creating the Stokes wave, which is the only one observed in practice in spontaneous Raman spectroscopy. A detailed study of the spectral distribution of Stokes waves provides information on the chemical bond densities present in the sample. This spontaneous inelastic scattering process is very inefficient compared to the

[0011] -30 2

[0012] fluorescence (Raman cross-sections are on the order of 10 cm² / molecule, at

[0013] -16 compare with the 1-photon absorption cross-section of a fluorophore which reaches 10²

[0014] cm / molecule).

[0015] CARS and SRS stimulated Raman techniques are coherent Raman scattering processes that offer a gain of approximately 10 compared to spontaneous Raman scattering processes. 7 In these techniques (see Fig. 1, diagram IA), two laser pulses of co-pulsations p and co s whose difference in angular frequencies is made equal to the angular frequency Q R The vibrational level to be addressed is sent into the medium to be analyzed. These impulses, denoted respectively pump and Stokes, create a frequency beat that allows the vibrational mode with pulse Q to resonate. R .

[0016] In the degenerate CARS process, this resonance is probed by the pump beam, which induces anti-Stokes diffusion at the co-pulsation AS .

[0017] Stimulated Raman scattering (SRS) is a process resulting from the enhancement of the nonlinear response due to the interaction of the nonlinear field induced by the pump and Stokes fields with the excitation (pump) field. Therefore, unlike the CARS process, it is observed at the same frequencies as the pump and Stokes pulses. It results in an energy transfer between the pump and Stokes beams. Thus, as illustrated in Fig. 1, diagram IB, stimulated Raman scattering encompasses two processes: the SRL process (short for "Stimulated Raman Loss") and the SRG process (short for "Stimulated Raman Gain"), which induce, respectively, an intensity loss AISRL on the pump beam and an intensity gain AISRG on the Stokes beam. The SRS process is described, for example, in the review article by N. Bloembergen et al. [Ref.3], It is shown that the intensity depletion AISRL of the pump beam and the intensity gain AISRG of the Stokes beam are proportional to the imaginary part of the nonlinear 3rd order susceptibility (Im( / R). (3) )). Measuring these quantities therefore allows us to rigorously reconstruct the Raman spectrum.

[0018] Recently, vibrational optical techniques have focused more on SRS techniques, which have the advantage over CARS techniques of generating a nonlinear optical signal of linear intensity with the concentration of the chemical species and of not being subject to a non-resonant background.

[0019] SRS microscopy has also benefited from recent advances in femtosecond SRS spectroscopy. However, an SRS microscope based on an amplified laser system delivering femtosecond pulses induces a strong SRS signal but is not suitable for biological imaging. Indeed, the high peak powers involved (on the order of a few hundred nJ or even pJ) damage the samples, and the low repetition rates (1 kHz) are incompatible with high-speed scanning microscopy.

[0020] A SRS microscope based on the use of a high repetition rate (80 MHz) picosecond laser system, compatible with image formation of biological samples, was then proposed (see, for example, the article by CW Freudiger et al. [Ref. 4]). In CARS microscopy, the useful signal, i.e., the anti-Stokes signal, is generated at a different frequency than the excitation beams. This can be detected by extremely sensitive detectors such as avalanche photodiodes or photomultiplier tubes. In SRS microscopy, the detection problem is different because the useful signal is generated at the same frequency as the excitation beams. The challenge then becomes detecting the energy loss of the pump beam (AISRL) OR, alternatively, the energy gain of the Stokes beam (AISRG). In practice, the AISRL / IP energy loss of the pump beam is between 10⁻¹⁰⁰ 5 and 10' 8In the article cited above, it is proposed to modulate the Stokes signal at a given frequency and to extract the pump signal loss at said frequency by synchronous detection to increase detection sensitivity. The detection method described above has been applied to the realization of an endoscope using SRS signal detection (see [Ref. 5]). In this article, an endoscopic imaging system is described in which a Stokes laser beam is amplitude modulated and combined with a pump laser beam by means of a dichroic mirror. The beams are coupled in a polarization-maintaining fiber.

[0021] The distal end of the fiber is moved using a piezoelectric actuator to scan the sample. The light exiting the fiber is focused onto the sample using a graded-index lens. The resulting modulated nonlinear optical signal, generated by the interaction of the pump and Stokes beams within the sample and backscattered by multiple scattering within the tissue, is then detected at the pump beam wavelength. Backscattering (or "epi") detection is performed using a photodetector arranged at the periphery of the distal fiber, coupled to an optical filter that blocks the light at the Stokes beam wavelength. Detection by a large-area photodiode at the fiber periphery optimizes detection efficiency. Demodulation at the Stokes beam modulation frequency yields the SRS image.

[0022] More recently, devices for detecting an SRS signal in a sample with improved modulation schemes have been described (see [Ref. 6], [Ref. 7]). These devices are also applicable to endoscopy.

[0023] In all SRS endoscopic imaging systems described in the state of the art mentioned above, the nonlinear signal(s) resulting from pump beam and Stokes beam interactions in the sample are detected in a backscatter detection mode (or "e / ?z") by exploiting the nonlinear signal backscattered by the tissue.

[0024] This description outlines fiber optic devices adapted for endoscope-type instruments and configured for forward detection. These devices enable the exploitation, within a physicochemical characterization system for a sample, of the optical signal emitted in the direction of propagation of the excitation beams, which is inherently stronger than the backscattered signal. This description applies particularly to CRS (SRS and CARS) processes, as well as other optical processes, including nonlinear optical processes.These optical processes include, for example, three-wave mixing, such as the sum or difference of frequencies, including second harmonic generation (or SHG), four-wave mixing (or FWM), such as the sum or difference of frequencies, including third harmonic generation (or THG), parametric amplification, stimulated emission, and other nonlinear optical processes involving higher nonlinear orders such as 5- or 6-wave mixing.

[0025] Summary of the invention

[0026] In this description, the term "include" means the same as "include" or "contain," and is inclusive or open-ended and does not exclude other elements not described or depicted. Furthermore, in this description, the term "around" or

[0027] "substantially" is synonymous with (means the same as) a lower and / or upper margin of 10%, for example 5%, of the respective value.

[0028] According to a first aspect, the invention relates to a fiber optic device for detecting an optical signal emitted by a sample, comprising

[0029] at least one first optical fiber configured to carry at least one first train of pump pulses at a first pulse;

[0030] a movable head comprising:

[0031] a mount configured to receive a distal portion of the first optical fiber such that in operation, said pump pulses at the output of the first optical fiber propagate substantially along a first axis of said mount;

[0032] of the first means of light deflection, attached to said mount, arranged in a distal part of the head and configured to receive said pump pulses at the output of said first optical fiber and deflect said pump pulses towards a measurement region, such that in operation, said pump pulses propagate substantially in said measurement region along a second axis of said mount;

[0033] receiving means configured to receive an optical signal emitted forward, substantially along said second axis, said optical signal resulting from the interaction, in said measurement region, of at least said pump pulses with the sample, said receiving means being fixed to the mount; the movable head further comprising:

[0034] scanning means attached to said mount, said scanning means being configured to scan at least said pump pulses in the measurement region.

[0035] In this description, the moving head is a head that, during operation, moves or moves very little, unlike a module fixed to a support. This allows, in particular, for approaching a sample that one seeks to analyze. Thus, the fiber optic device according to the first aspect is suitable for in vivo detection and allows for the detection of the forward optical signal. This forward optical signal results from the interaction with the sample; that is, it detects the optical signal emitted in the direction of propagation of the pump pulses, i.e., along the propagation axis and in the direction of propagation of the pump pulses, as opposed to the optical signal resulting from the interaction with the sample and backscattered to the rear.

[0036] This is particularly advantageous for all nonlinear optical processes, especially phase-tuned nonlinear optical processes for which, by nature, the optical signal generated in front is much more intense than the signal backscattered behind by the sample, notably (but not exclusively) CRS processes (SRS and CARS), wave mixing processes (THG, SHG, ...), stimulated emission.

[0037] In the fiber optic device described in the first aspect, the head mount comprises a first axis and a second axis. The first axis of the mount is defined, for example, by one or more optomechanical elements attached to the mount, with, for example, at least one of said elements configured to receive the distal end of the first optical fiber. The second axis is defined, for example, by one or more optomechanical elements attached to the mount, including said first deflection means. In operation, the pump pulses at the output of the first optical fiber propagate substantially along the first axis, and the pump pulses in said measurement region propagate substantially along the second axis.In this description, "approximately" means that the pump impulses propagate in a direction that forms an angle with either the first or second axis of between approximately -15 degrees and +15 degrees, advantageously between approximately -10 degrees and +10 degrees. According to one or more embodiments, the angular distance between the first and second axes is between approximately 45 degrees and approximately 135 degrees, advantageously between approximately 75 degrees and approximately 105 degrees, and advantageously, an angular distance between the first and second axes is approximately 90 degrees. Such a configuration allows for limiting the size of the distal part of the head.

[0038] According to one or more embodiments, the width of the mount, defined as a maximum dimension of the mount measured in a plane perpendicular to the first axis, is less than approximately 50 mm, advantageously less than approximately 20 mm, advantageously less than approximately 10 mm, and advantageously less than approximately 5 mm. The width of the mount is, for example, the maximum dimension of an external surface of the mount, measured in a plane perpendicular to the first axis. In some embodiments, the external surface of the mount is a substantially cylindrical surface, with a generatrix of the cylinder parallel to the first axis, and the width of the mount corresponds to a maximum dimension of a cross-section of said cylindrical surface. This width of the mount is determined according to the application.For example, for a fiber device configured to be inserted into an endoscope-type surgical instrument, the smallest possible width will be chosen.

[0039] According to one or more embodiments, the length of the mount, defined as a maximum dimension of the mount measured along a direction parallel to the first axis, is less than approximately 50 mm, advantageously less than approximately 20 mm, and advantageously less than approximately 10 mm. A shorter mount length is advantageous for reducing overall size. In particular, since the mount is not flexible, the longer the mount, the less maneuverable the head will be in applications such as endoscopy.

[0040] According to one or more exemplary embodiments, the receiving means include secondary light-deflection means, attached to the mount, configured to redirect the optical signal towards a proximal part of the head. These secondary deflection means help to minimize bulk in the distal part of the head, particularly along the second axis.

[0041] According to one or more exemplary embodiments, the first means of deflecting light and / or the second means of deflecting light include at least one optical element chosen from: a reflective optical element, a diffractive element, a waveguide.

[0042] In exemplary embodiments, said reflective optical element includes a mirror, for example a mirror arranged on a mount or placed on a bar, for example a beveled glass bar, or a refractive element with total reflection of light, for example a microprism.

[0043] In some embodiments, the diffractive element comprises a lattice, a metasurface, or a metamaterial—that is, an artificial composite surface and / or material possessing properties not found in natural materials. Metasurfaces or metamaterials are described, for example, in [Ref. 8].

[0044] In some embodiments, the waveguide is formed by an optical fiber or a planar waveguide. According to one or more embodiments, the head further includes focusing means, attached to the mount, configured to focus at least the pump pulses into a focusing volume of the measurement region. Focusing the pump pulses makes it possible to obtain high energy densities in the sample, in particular energy densities sufficient to generate nonlinear optical effects. In some embodiments, the focusing volume includes a cross-section in a direction perpendicular to the second axis with a maximum dimension less than approximately 1 micron.

[0045] According to one or more exemplary embodiments, the focusing means comprise a focusing optic including an optical axis substantially coinciding with said first axis. In exemplary embodiments, the focusing optic includes one or more lenses, for example, an assembly of achromatic doublets.

[0046] In some embodiments, the first deflection means are configured to further converge at least the pump pulses towards a focusing volume in the measurement region, and the focusing means include the first focusing means. For example, when the first deflection means include a reflective optical element with a reflective surface, whether a mirror or a refractive element, the reflective surface can be curved to generate the convergence of the pump pulses. Convergence of the pump pulses can also be achieved with metasurfaces and / or metamaterials functionalized to introduce a convergence effect. In some embodiments, a focusing optic ensures the convergence of the pump pulses in cooperation with the first deflection means.

[0047] In some embodiment examples, the convergence of pump pulses is made possible by a spatial shaping of the pump pulses carried out upstream of the fiber device, so that a focusing optics and / or first means of deflection configured to make the pump pulses converge are not necessary to ensure said convergence.

[0048] According to one or more embodiments, the optical signal reception means further include focusing means configured to converge said optical signal towards an input face of a second optical collection fiber or a detection surface of a detector. These focusing means include, for example, a focusing optic comprising, for example, one or more lenses, such as an assembly of achromatic doublets. In other embodiments, the second deflection means are configured to further converge said optical signal towards an input face of a second optical collection fiber or a detection surface of a detector, and the reception means include said second deflection means.For example, when the second means of deflection include a reflective optical element with a reflective surface, whether a mirror or a refractive element, said reflective surface can be curved to generate said pump pulse convergence. Pump pulse convergence can also be achieved with metasurfaces and / or metamaterials functionalized to introduce a convergence effect. In some embodiments, a focusing optic ensures the convergence of the optical signal in cooperation with said second means of deflection.

[0049] According to one or more embodiment examples, the measurement region is formed by a cavity in a distal part of the mount.

[0050] According to one or more exemplary embodiments, the head of the fiber optic device further comprises transparent windows arranged on either side of the cavity such as to allow passage, respectively, at least the pump pulses deflected by the first deflection means and the optical signal emitted in the direction of propagation of the pump pulses in the measurement region. In the case where the first and / or second deflection means are microprisms, these can be configured to form the transparent windows on either side of the cavity.

[0051] A measurement region formed by a cavity in the distal part of the mount is advantageous because the optical components of the head, in particular the first deflection means and possibly the second deflection means, can be kept without contacting the sample, thus facilitating cleaning of the fiber optic device head. In other embodiments, the measurement region can be formed outside the mount, for example, by the space between the first and second deflection means, with said first and second deflection means arranged outside the mount.

[0052] According to one or more embodiments, the measurement region has a width measured along the second axis, said width being substantially between approximately 10 µm and approximately 10 mm, advantageously between approximately 100 µm and approximately 1 mm. Such a width of the measurement region is a good compromise for defining a space sufficient to insert a minimum amount of sample into the measurement region while also limiting the sample thickness along the second axis so that the optical signal generated at the focal point is not scattered by the rest of the sample.

[0053] According to one or more embodiment examples, the fiber device further includes a suction tube configured for suction of the sample in the measurement region.

[0054] Suction makes it easier to insert the sample into the measurement area.

[0055] According to this description, the head of the fiber optic device further comprises scanning means, fixed to the mount, and configured to scan at least the pump pulses in the measurement region. The scanning means may include means for moving a distal end of the first optical fiber, including, for example, a piezoelectric element. Such a piezoelectric element, fixed to the mount, may be attached to define the first axis. In other embodiments, the scanning means may include micromirrors configured to deflect the pulses, for example, microelectromechanical systems (MEMS). The scanning means allow the pump pulses to be moved within the measurement region in order to form an image of the sample.The sweep of said pump pulses is limited, typically less than + / - 10 degrees, so that the pump pulses always propagate substantially along the first axis and the second axis, even when there is a sweep.

[0056] According to one or more embodiment examples, said first fiber is a hollow core fiber.

[0057] A hollow core fiber, as defined herein, generally comprises a core containing a gas, for example, air or a vacuum, and a microstructured portion surrounding it, for example, a mixture of air and glass, such as capillaries. This microstructured portion guides, for example, at least the pump pulses within the hollow core for transmission to the distal end of the fiber optic device. The hollow core is, for example, single-mode or weakly multimode, meaning it can propagate one or a few modes, up to a maximum of about 10 modes. The hollow core is configured for guiding light within a first wavelength range. For example, for endoscopic applications, the first wavelength range is between approximately 700 nm and approximately 1800 nm. A hollow core optical fiber is described, for example, in [Ref. 9].

[0058] According to one or more embodiments, the first optical fiber is configured to also carry a second train of probe pulses at a second frequency. Depending on the application, the difference between the first and second frequencies can be equal to a molecular vibrational resonance frequency of the sample; these are then referred to as Stokes pulses. The optical signal emitted in the direction of these pump pulses then results from the interaction, in the measurement region, of these pump pulses and probe pulses with the sample. The first optical fiber can be, as before, a hollow-core fiber, for example, with a single-mode or weakly multimode core.

[0059] In some embodiment examples, the second pulse is identical to the first pulse, for example for the implementation of SHG or THG processes.

[0060] In exemplary embodiments, where the head includes a focusing optic and / or scanning means, said focusing optic and / or said scanning means may be configured to converge the pump pulses and the probe pulses into a common focusing volume of the measurement region and / or to scan the pump pulses and the probe pulses into a common focusing volume of the measurement region.

[0061] According to one or more embodiments, the receiving means further include an optical filter configured for optical filtering of the optical signal emitted by the sample. Such an optical filter allows only the useful signal to be retained. For example, in an SRS process, the optical filter can be configured to allow only the optical signal to pass at the first pulse (pump) or the second pulse (Stokes), depending on whether SRL or SRG is detected. In a CARS, SHG, or THG process, the optical filter can be configured to allow only the useful optical signal to pass at the pulse of the process under consideration. Such an optical filter integrated into the head of the fiber optic device is advantageous, but in some embodiments, when the detector is outside the head of the fiber optic device, the optical filter can also be located outside the head.

[0062] According to one or more exemplary embodiments, the fiber optic device described in the first aspect further comprises a second optical fiber configured to carry the optical signal received by the receiving means outside the head. In these embodiments, the optical detection of the optical signal is performed outside the fiber optic device.

[0063] According to one or more implementation examples, said second optical fiber is a large core and / or large digital aperture multimode optical fiber.

[0064] A large-core and / or high-numerical-aperture multimode optical fiber, as defined herein, is a light guide, for example, made of glass or other transparent material at the wavelength of the optical signal, configured to guide light at the wavelength of the nonlinear optical signal, having a core diameter greater than approximately 50 pm, advantageously greater than approximately 200 pm, and / or a numerical aperture greater than approximately 0.1, advantageously greater than approximately 0.5, so as to maximize light-gathering efficiency. The numerical aperture of the optical fiber is defined by the difference in refractive index between the material constituting the core of the optical fiber and that constituting the cladding.Advantageously, the large-core, high-digital-aperture multimode optical fiber is highly multimode, meaning it is capable of propagating from several hundred to several hundred thousand modes, for example, between approximately 100 modes and approximately 1,000,000 modes. According to one or more embodiments, the receiving means include an optical detector configured for the optical detection of said optical signal. Optical detection may be performed after reflection by secondary deflection means or directly in the direction of propagation of the pump pulses (second axis). In these embodiments, the optical detection of said optical signal is performed within the head of the fiber optic device, and the fiber optic device may include an electrical cable or other wired electrical connection for carrying the electrical signal generated by the optical detector for processing.

[0065] The optical detector includes, for example, a photodiode. Advantageously, such embodiments are used in the case of an implementation of a nonlinear SRS-type process for which the optical signal emitted by the sample is sufficiently intense to be detected by a small optical detector, such as a photodiode.

[0066] According to a second aspect, the invention relates to a fiber-reinforced instrument, for example a surgical instrument, comprising at least one working channel and a fiber-reinforced device according to the first aspect, arranged in said at least one working channel. Such a surgical instrument is, for example, an endoscope or a trocar for the physicochemical characterization of biological tissue.

[0067] According to a third aspect, the invention relates to a system for the physicochemical characterization of a sample comprising:

[0068] an emission source configured to emit at least one first train of pump pulses at a first pulse;

[0069] a fibre device according to the first aspect or a fibre instrument according to the second aspect, said first optical fibre of the fibre device being configured to carry at least said pump pulses;

[0070] a processing module configured to extract from at least one first optical signal resulting from the interaction of at least said first pump pulses with the sample, at least one first signal characteristic of a physicochemical property of the sample.

[0071] According to one or more exemplary embodiments, the emission source is configured to emit pump pulses of durations between approximately Ips and approximately 10 ps, ​​for example between approximately Ips and approximately 3 ps. Such pulses are spectrally narrow with a spectral width between approximately 15 cm⁻¹ 1 and about 5 cm' 1 The first pulse depends on the nonlinear mechanisms being investigated and the sample being imaged. For example, for the physicochemical characterization of biological tissues, the first pulse may correspond to a wavelength between approximately 650 nm and approximately 1500 nm.

[0072] According to one or more embodiment examples, the pulses are emitted at rates of a few tens of MHz, for example between about 10 MHz and about 100 MHz, for example around 80 MHz.

[0073] In some embodiment examples, only pump pulses are emitted by the emission source, for example for the implementation of non-linear processes of type SHG, THG.

[0074] According to one or more exemplary embodiments, said emission source is configured to further emit a second probe pulse train at a second pulse rate, the first pulse train and the second pulse train being time-synchronized, said at least a first optical signal resulting from the interaction, in said measurement region, of said pump pulses and said probe pulses with the sample. According to one or more exemplary embodiments, the second probe pulse train is a Stokes pulse train, the second pulse rate being such that a difference between the first pulse rate and the second pulse rate is equal to a molecular vibrational resonance pulse rate of the sample, said at least a first signal extracted by the processing module being characteristic of a molecular vibrational resonance of the sample.

[0075] Such an emission source is suitable for implementing CARS and SRS processes. According to one or more exemplary embodiments, the pulses of the first and / or second pulse train have durations between approximately 1 ps and approximately 10 ps, ​​for example, between approximately 1 ps and approximately 3 ps. Such pulses are spectrally narrow, centered respectively on the first and second pulses, with spectral widths between approximately 15 cm⁻¹ 1 and about 5 cm' 1For example, the emission source comprises a picosecond laser source including a master laser emitting pump pulse trains with the first pulse and an optical parametric oscillator (OPO) configured to produce, from the pump pulses emitted by the master laser, Stokes pulse trains with the second pulse. This arrangement has the advantage that the pump and Stokes pulse trains are automatically synchronized. Furthermore, it is possible to modify the pulse rate of the Stokes pulses, as the OPO is tunable.

[0076] In another example, the emission source comprises a master laser and two OPOs, the two OPOs being configured to generate pump and Stokes pulse trains from pulses emitted by the master laser. The pulse trains are again automatically synchronized, and it is possible to modify the pulsation of the pump and Stokes pulses, as the OPOs are tunable.

[0077] In another example, the emission source comprises two synchronized lasers generating pump and Stokes pulse trains, for example, an Ytterbium laser and an Erbium laser. In this case, the pulse difference between the pump and Stokes pulse trains is fixed.

[0078] According to one or more embodiment examples, the pulses of the first and / or second pulse train are frequency-drifted ("chirped") pulses of pulsations centered respectively on the first and second pulsations.

[0079] For example, the emission source includes a femtosecond laser source comprising a master laser emitting pump pulse trains with the first pulse, an optical parametric oscillator (OPO) configured to produce, from the pump pulses emitted by the master laser, Stokes pulse trains with the second pulse, and a time stretcher configured to temporally extend the pump and / or Stokes pulses. According to one or more embodiments, the time stretcher includes a prism dispersive line, a grating dispersive line, or a simple glass bar configured to disperse the femtosecond pulses.

[0080] As before, the emission source may also include a master laser and two OPOs or two synchronized lasers.

[0081] According to one or more embodiment examples, in the case of frequency drift pulses, the device may further include a delay line enabling the generation of a time offset between the pulses of the first and second pulse trains, the variation of the time offset enabling the probing of different molecular vibrational resonance pulsations of the sample.

[0082] According to one or more embodiment examples, the physicochemical characterization system further includes:

[0083] at least one first amplitude modulator configured to amplitude modulate at a first modulation frequency one of the first pump pulse trains or second Stokes pulse trains; and wherein:

[0084] the processing module includes an electronic filter at said first modulation frequency configured to extract from said at least a first optical signal resulting from the interaction of said first pump pulses and said second Stokes pulses in the sample, at least a first SRS signal characteristic of the molecular vibrational resonance of the sample.

[0085] The electronic filter may include means for synchronous detection at said first modulation frequency or a radio frequency filtering device at said first modulation frequency.

[0086] Note that in the case of a CARS type nonlinear optical signal, a nonlinear optical signal is detected at a wavelength different from that of the pump and probe pulses, namely the wavelength of the anti-Stokes wave, so that amplitude modulation is not necessary.

[0087] Based on one or more examples of implementation:

[0088] said fiber device includes a second optical fiber configured to carry said first optical signal returned by the second deflection means; and the processing module includes an optical detector configured for detecting said first optical signal at the output of a proximal end of the second optical fiber.

[0089] In these embodiment examples, the optical detector is arranged outside the fiber optic device, which provides greater flexibility in the choice of optical detector and detection mode. The detector can include, for example, a photodiode or a photomultiplier tube, such as a silicon photomultiplier tube (SiPM).

[0090] In these embodiment examples, the processing module may further include a focusing optic and / or an optical filter upstream of the optical detector to focus and / or filter the optical signal from the second optical fiber and sent to the optical detector.

[0091] Based on one or more examples of implementation:

[0092] the processing module is configured to generate an image of the sample from said at least a first signal characteristic of a physicochemical property of the sample.

[0093] In these examples, the physico-chemical characterization system is an imaging system.

[0094] In embodiments where the nonlinear process is of the SRS type, the detection module may include two optical detectors and synchronous detection means for implementing a process as described in [Ref. 7]. According to one or more embodiments, the physicochemical characterization system according to the third aspect further includes means for spatially shaping the pump pulses configured to generate a focal point and / or a sweep of said pump pulses in the measurement region. Such processes, known as "lensless," are described, for example, in [Ref. 10]. They eliminate the need for focusing optics and / or sweeping means in the head of the fiber optic device. In this case, the first optical fiber is advantageously a multi-core optical fiber.

[0095] Brief description of the figures

[0096] Other advantages and features of the invention will become apparent from the description, illustrated by the following figures: [Fig. 1], already described, represents (diagram IA) a simplified diagram illustrating the principle of coherent Raman scattering (CRS) and (diagram IB) a simplified diagram illustrating the SRL and SRG processes;

[0097] [Fig. 2A], represents a first example of a fiber device according to the present description, in a first embodiment;

[0098] [Fig. 2B] represents a second example of a fiber device according to the present description, in the first embodiment;

[0099] [Fig. 2C] represents a third example of a fiber device according to the present description, in the first embodiment;

[0100] [Fig. 2D] represents a fourth example of a fiber device according to the present description, in the first embodiment;

[0101] [Fig. 3] schematically illustrates a cross-sectional view of an example of a first optical fiber suitable for a fiber-optic device according to the present description;

[0102] [Fig. 4A] schematically illustrates a view of the distal part of an example of an endoscope configured to receive a fiber device as described herein;

[0103] [Fig. 4B] schematically illustrates a cross-sectional view of an example of an endoscope as illustrated in Fig. 4A;

[0104] [Fig. 5A] shows a diagram of a first example of a physico-chemical characterization system configured to work with a fiber-optic device according to the first embodiment, as illustrated for example in Fig. 2A, Fig. 2B, Fig. 2C, or Fig. 2D; [Fig. 5B] shows a diagram of a second example of a physico-chemical characterization system configured to work with a fiber-optic device according to the first embodiment, as illustrated for example in Fig. 2A, Fig. 2B, Fig. 2C, or Fig. 2D; [Fig. 6] shows an example of a fiber-optic device according to the present description, in a second embodiment;

[0105] [Fig. 7] represents a diagram of an example of a physicochemical characterization system configured to work with a fiber-optic device according to the second embodiment, as illustrated for example in Fig. 6.

[0106] Detailed description of the invention

[0107] In the figures, the elements are not represented to scale for better visibility.

[0108] Figures 2A, 2B, 2C, and 2D illustrate examples of fiber-optic devices 201, 202, 203, and 204 for detecting an optical signal emitted by a sample 10, in a first embodiment as described herein, in which the optical detection of the signal emitted by the sample 10 is located outside the device head. These embodiments include various variations that can be combined.

[0109] In each of the examples, the fiber device includes a first optical fiber 210 configured to carry at least one first train of pump pulses at a first pulse o p, and a head 260 comprising a mount 265 configured to receive a distal portion of the first optical fiber such that in operation, said pump pulses at the output of the first optical fiber propagate substantially along a first axis Ai of said mount.

[0110] The first axis of the mount is defined, for example, by one or more optomechanical elements fixed to the mount, with, for example, at least one of said elements configured to receive the distal end of the first optical fiber. In some embodiments, the first axis is defined by an axis of a piezoelectric actuator 215 forming the scanning means.

[0111] Optical fiber 210 may include a 212 fiber end configured to reduce the bundle size, for example a piece of fiber or a glass bead.

[0112] The first optical fiber 210 is, for example, a hollow core fiber as will be described with reference to Fig. 3.

[0113] The head 260 of the fiber device includes first light deflection means 221, attached to the mount 260, arranged in a distal part 261 of the head and configured to receive the pump pulses at the output of said first optical fiber and deflect the pump pulses towards a measurement region 230, such that in operation the pump pulses propagate in the measurement region substantially along a second axis A2 of the mount.

[0114] The second axis is defined for example by one or more optomechanical elements attached to the frame, including the first means of deviation 221.

[0115] For example, the angular separation between the first and second axes is between approximately 45 degrees and approximately 135 degrees, advantageously between approximately 75 degrees and approximately 105 degrees, and advantageously an angular separation between the first and second axes is approximately 90 degrees, as illustrated in the figures. Such a configuration makes it possible to limit the size of the distal part of the head. The head 260 of the fiber optic device further includes receiving means configured to receive an optical signal emitted substantially along said second axis A2, in the direction of the pump pulses, said optical signal resulting from the interaction, in said measurement region, of at least said pump pulses with the sample, said receiving means being fixed to the mount.

[0116] In the examples in Fig. 2A to Fig. 2D, the receiving means include in particular second light deflection means 222 configured to return the optical signal to a proximal part 262 of the head.

[0117] In these examples, the fiber optic device further includes a second optical fiber 240 configured to carry the optical signal received by the receiving means. In these examples, the second optical fiber 240 is configured to carry the optical signal returned by the second deflection means 222. In other examples, the second optical fiber 240 may be configured to carry the optical signal directly transmitted along the second axis A2, and the receiving means may then include one or more elements configured to send the optical signal to a distal end of the second optical fiber.

[0118] In these examples, the optical detection of the optical signal is located outside the fiber optic device.

[0119] The fiber optic device may also include a 245 optical block with one or more optical lens(es) and / or an optical filter.

[0120] The 265 mount can be made up of several joined elements (referenced 266, 267, 268 in the examples) or can be made in one piece.

[0121] In the examples illustrated with reference to Fig. 2A to Fig. 2D, the mount 265 comprises a first tubular element 266 configured to receive the distal end of the first optical fiber and in which are arranged, in particular, the first deflection means 221; a second tubular element 267 configured in these examples to receive the distal end of the second optical fiber and in which are arranged, in particular, the receiving means, for example, the second deflection means 222; and a mechanical element 268, for example, a spacer, which mechanically connects the tubular elements 266 and 267 and which, in some examples, may be drilled to receive the suction tube. The mount 265 may also be made in a single piece drilled to receive the various elements. The mount has, for example, a substantially cylindrical external surface with a generatrix parallel to the first axis Ai.

[0122] In the fiber device 201 illustrated in Fig. 2A, the first means for deflecting light 221 and the second means for deflecting light 222 comprise a reflective optical element, here a mirror with a substantially flat reflecting surface, deposited on a beveled glass rod.

[0123] The measuring region 230 is formed in this example by a cavity arranged in a distal part of the head mount 260. The measuring region has a width d measured along the second axis A2, for example between approximately 10 pm and approximately 10 mm, advantageously between 200 pm and approximately 1 mm.

[0124] The head 260 of the fiber device 201 further includes in this example transparent windows 232, 234 arranged on either side of the cavity so as to allow passage respectively at least the pump pulses deflected by the first deflection means 221 and the optical signal emitted towards the second deflection means 222.

[0125] The first deflection means and the second deflection means are thus kept without contact with the sample, which facilitates the cleaning of the head of the fiber device.

[0126] The head 260 of the fiber device 201 also includes in this example a focusing optic 218, fixed to the mount, configured to focus at least the pump pulses in the measurement region, and scanning means 215, arranged in the distal part of the head, and configured to scan at least the pump pulses in the measurement region 230. The scanning means include, for example, a piezoelectric actuator configured to move the distal end of the fiber.

[0127] In this example, the fiber optic device also includes an optional suction tube 250, configured for aspirating the sample 10 into the measurement region 230. As illustrated in Fig. 2A, the suction tube 250 is housed, for example, in an opening in the spacer 268, which is part of the frame. In this example, the suction tube 250 is separated from the measurement region 230 by means of a protective filter 255, which prevents any sample from entering the tube 250. However, the tube 250 could also remain open if the sample is sufficiently viscous, for example.

[0128] In the fiber device 202 illustrated in Fig. 2B, the first means of deflecting light 221 and the second means of deflecting light 222 include a reflective optical element, here mirrors with curved surfaces, for example mirrors glued onto supports (not shown).

[0129] Mirror 221 is configured to deflect by reflection of light the pump pulses in the measurement region and to focus the pulses into a focusing volume of the measurement region, so that focusing optics are not required, but can be provided as an addition.

[0130] Mirror 222 is configured to deflect by reflection of light the optical signal emitted by the sample and to focus the optical signal into a distal end of the second optical fiber 240. In this example, the optical block 245 may consist of only an optical filter.

[0131] In this example as well, the measurement region 230 is formed by a cavity in a distal portion of the head's mount 260. The head 260 of the fiber optic device 201 further includes transparent windows 232, 234 arranged on either side of the cavity such as to allow passage, respectively, at least the pump pulses deflected by the first deflection means 221 and the optical signal emitted towards the second deflection means 222. The head 260 of the fiber optic device 201 also includes, in this example, scanning means 215, arranged in the distal portion of the head, and configured to scan at least the pump pulses in the measurement region 230.

[0132] As in the previous example, the fiber device includes a 250 suction tube (optional), configured for aspiration of sample 10 in the measurement region 230.

[0133] In the fiber device 203 illustrated in Fig. 2C, the first means for deflecting light 221 include a waveguide and the second means for deflecting light 222 include a reflective optical element, in this example a reflective element with a flat surface.

[0134] The 221 waveguide is further configured to focus at least the pump pulses in the measurement region, so that focusing optics are not required, but can be provided as an addition.

[0135] Mirror 222 is configured to reflect the optical signal emitted by the sample back to a distal end of the second optical fiber 240. In this example, the optical block 245 may include a focusing optic and / or an optical filter.

[0136] In this example as well, the measurement region 230 is formed by a cavity in a distal portion of the head's mount 260. The head 260 of the fiber optic device 201 further includes transparent windows 232, 234 arranged on either side of the cavity such as to allow passage, respectively, at least the pump pulses deflected by the first deflection means 221 and the optical signal emitted towards the second deflection means 222. The head 260 of the fiber optic device 201 also includes, in this example, scanning means 215, arranged in the distal portion of the head, and configured to scan at least the pump pulses in the measurement region 230.

[0137] As in the previous example, the fiber device includes a 250 suction tube (optional), configured for aspiration of sample 10 in the measurement region 230.

[0138] Of course, the examples illustrated in Figs. 2A, 2B, and 2C exhibit characteristics that can be combined in various ways. For example, the light-deflection means 221 and the light-deflection means 222 may be identical or different and may include any of the following: a reflective optical element, for example, a mirror, with a flat or curved reflective surface; a refractive element with total internal reflection, for example, a microprism; a diffractive element, for example, a grating, a metasurface, or a metamaterial; or a waveguide. Furthermore, in some embodiments, the receiving means may not include any deflection means.

[0139] In the case of using micro-prisms for example, one face of the micro-prism can interface with the measurement region, so a transparent window is not necessary.

[0140] In the fiber device 204 illustrated in Fig. 2D, unlike the previous examples, the measurement region 230 is formed outside the mount, for example by the space between the first deflection means 221 and the second deflection means 222 which are arranged in a fixed manner with the mount, outside the mount.

[0141] In this example, the first deflection means 221 and the second deflection means 222 are micro-primes fixed on a transparent slide 270 arranged in the distal part of the mount 265. The use of micro-prisms is advantageous because cleaning the faces in contact with the sample is easier, but other deflection means can be used.

[0142] The head 260 of the fiber optic device 204 further includes, in this example, a focusing optic 218. Such a focusing optic may be omitted if the first deflection means 221 are configured to converge the pulses in the measurement region. The head 260 of the fiber optic device 204 also includes scanning means 215, arranged in the distal part of the head, and configured to scan at least the pump pulses in the measurement region 230.

[0143] In this example, the fiber optic device is shown without the suction tube 250, but it can be included, as in the previous examples. The mechanical part 268, in this example a plate-shaped spacer, serves to hold parts 267 and 267 together; the three parts together form the frame. Note that the frame can be manufactured in a known manner as a single piece, drilled to accommodate the various optomechanical components.

[0144] Fig. 3 schematically illustrates a cross-sectional view of an example of a first optical fiber 210 adapted for a fiber device according to the present description.

[0145] A hollow core fiber generally comprises a hollow core 310, at the periphery of which is a microstructured portion, for example, made of air and glass, formed by capillaries 311, as illustrated in Fig. 3. The microstructured portion, for example, guides the light within the hollow core for the transmission of pulses to the sample. The hollow core fiber also includes a cladding 320 whose function is to support the capillaries surrounding the hollow core.

[0146] Fig. 4A schematically illustrates a view of the distal part of an example of a 400 endoscope configured to receive a fiber device as described herein, and Fig. 4B schematically illustrates a cross-sectional view of an example of an endoscope as illustrated in Fig. 4A.

[0147] An endoscope is known to comprise a set of working channels, references 401, 402, 403, 404, 405, 406 in this example, configured to receive different instruments, for example 411 represents a resection forceps for removing small pieces of tissue as part of a biopsy and 412 is a lasso which allows polyps in the intestine to be sectioned.

[0148] Of course, a fiber-reinforced device as described herein can be inserted into other types of instruments. These can include surgical instruments for the analysis of biological tissue, comprising at least one working channel into which the fiber-reinforced device is inserted, for example, an endoscope as illustrated in Fig. 4A and Fig. 4B, or a trocar, used for example in laparoscopies and comprising a single working channel. They can also include instruments configured to examine other types of samples besides biological samples.

[0149] Fig. 5A represents a diagram of a first example of a physico-chemical characterization system 501 configured to work with a fiber device according to the first embodiment, as illustrated for example in Fig. 2A, Fig. 2B, Fig. 2C or Fig. 2D. In this first embodiment, the optical detection is located outside the fiber device.

[0150] More specifically, Fig. 5 A illustrates a sample analysis system, for example an imaging system, configured for the detection of a resonant nonlinear optical signal of the Stimulated Raman Scattering (SRS) type induced in a sample 10. The sample 10 is for example a biological tissue.

[0151] The 501 system includes an emission source 510 configured for the emission of a first beam, or "pump beam", consisting of a first train of pump pulses at a first pulse o p and configured for the emission of a second beam, or "Stokes beam" consisting of a second train of Stokes pulses at a second pulse rate s such as a difference o p - o sThe interval between the first and second pulses is equal to a molecular vibrational resonance pulse QR of the sample 10 that we seek to observe. The first and second pulse trains are time-synchronized to allow the interaction of pump and Stokes pulses in the sample, for example by means of a delay line.

[0152] The pulses are, for example, picosecond pulses, with durations between approximately Ips and approximately 10 ps, ​​for example between approximately Ips and approximately 3ps, with spectral resolutions between approximately 15 cm' 1 and about 5 cm' 1 , or they may be frequency-drifted pulses for spectral scanning. Typically, the pulses are emitted at rates of a few tens of MHz, for example between about 10 MHz and about 100 MHz, for example around 80 MHz, for a duration on the order of a microsecond.

[0153] The 510 emission source can comprise synchronized independent lasers. In other embodiments, the 510 source can comprise a laser system with a master laser emitting pump pulse trains and an OPO (or Optical Parametric Oscillator) laser receiving pump pulses from the master laser and configured to emit Stokes pulses. The 510 source can also comprise a laser system with a master laser and two OPOs configured to generate pump and Stokes pulse trains from pulses emitted by the master laser. In both cases, the pulse trains are automatically synchronized. Furthermore, it is possible to modify the Stokes pulse rate, and optionally the pump pulse rate in the case of two OPOs, the OPOs being wavelength-tunable.For example, in a laser system consisting of a master laser and an OPO, the master laser can emit pump pulses with a pump pulsation corresponding to a wavelength between approximately 1000 nm and approximately 1100 nm, for example, between approximately 1030 nm and approximately 1065 nm. This wavelength range covers the emission wavelengths of an ytterbium laser and a YAG laser. The OPO can emit Stokes pulses with a Stokes pulsation corresponding to a wavelength between approximately 600 nm and approximately 1000 nm, for example, between approximately 640 nm and approximately 960 nm.In the case of a laser system comprising a master laser and two OPOs, the master laser can emit pulses with a pulsation corresponding to a wavelength between approximately 1000 nm and approximately 1100 nm, for example between approximately 1030 nm and approximately 1065 nm, and the OPOs can each emit pump and Stokes pulses with pulsations corresponding to wavelengths between approximately 600 nm and approximately 1000 nm, for example between approximately 640 nm and approximately 960 nm.

[0154] The 501 system further includes in this example at least one first amplitude modulator 531 configured to amplitude modulate the first pump pulse train at a first modulation frequency f m As illustrated in Fig. 5A, this results in a modulated pump pulse train and an unmodulated Stokes pulse train, represented respectively by the intensity I pfrom the pump pulse train to the pump pulse o p , amplitude modulated at frequency f m (curve 511) and the intensity Is of the Stokes pulse train at the pump pulse rate, unmodulated (curve 512). In other embodiments, it is possible to modulate the Stokes beam in amplitude at the modulation frequency f m , or even the pump beam at a first modulation frequency and the Stokes beam at a second modulation frequency (see [Ref. 7]).

[0155] The amplitude modulator 531 is, for example, an acousto- or electro-optical modulator receiving modulation signals from a radio frequency (RF) generator 530. The modulation frequency f mis, for example, between 1 MHz and 40 MHz. In the example of Fig. 5A, the system 501 further includes optomechanical means configured to send the pump and Stokes pulses into the first optical fiber 210 of a fiber-optic device represented by the moving head 260, according to the present description. The optomechanical means include, for example, reflective elements 561, 562, 563, including, for example, a dichroic mirror 562, as well as a lens 551 configured to focus the pump and Stokes pulses into the first optical fiber 210.

[0156] System 501 also includes a processing module 570 configured to extract, from at least one first optical signal resulting from the interaction of pump and Stokes pulses with the sample, at least one first signal characteristic of a physicochemical property of the sample; in this example, an SRG signal detected at the wavelength of the Stokes pulses. Diagram 513 shows the intensity Is of the Stokes pulse train at the pump pulse os output of System 501. Note that in the case of amplitude modulation of the second Stokes pulse train, the processing module 570 would be configured to extract an SRL signal detected at the wavelength of the pump pulses. More precisely, in this example, the processing module 570 includes an optical detector 575 configured for detecting the first optical signal at the output of a proximal end of the second optical fiber (not shown) of the fiber optic device.The optical detector is, for example, a photodiode configured for detection at the wavelength of Stokes pulses in the case of SRG detection, and configured for detection at the wavelength of pump pulses in the case of SRL detection. The processing module further includes an electronic filter 577 at said first modulation frequency f. m configured to extract from the first optical signal resulting from the interaction of said first pump pulses and said second Stokes pulses in the sample, an SRS signal characteristic of the molecular vibrational resonance of the sample, in this example an SRG signal. The electronic filter includes, for example, means for synchronous detection at the modulation frequency f m or a radio frequency filtering device at the modulation frequency f m .

[0157] As illustrated in Fig. 5 A, the processing module may further include one or more optical conjugation elements 572 and optical filtering means (not shown), for example an interference optical filter, allowing the selection of radiation at the pulsation of interest. As illustrated in Fig. 5 A, the processing module may further include a calculation and / or display unit 578 for the electrical signal.

[0158] More specifically, in embodiment examples, when the head 260 of the fiber device includes scanning means configured to scan pump pulses and Stokes pulses in the measurement region, the computing and / or display unit 578 will be able to produce a user-visible image of the sample from the SRS signal determined at several points in the sample.

[0159] Although SRS processes are particularly advantageous, the physico-chemical characterization system described herein can implement other optical interaction processes with the sample to determine physico-chemical properties.

[0160] Fig. 5B thus represents a diagram of a second example of a physico-chemical characterization system 502 configured to work with a fiber device according to the first embodiment, as illustrated for example in Fig. 2A, Fig. 2B, Fig. 2C or Fig. 2D. Here again, the optical detection is located outside the fiber device.

[0161] For example, the 502 physico-chemical characterization system is configured for the detection of a CARS optical signal.

[0162] The 502 system includes a 510 emission source configured for the emission of a first beam, or "pump beam", consisting of a first train of pump pulses at a first pulse o p , and as in the previous example, for the additional emission of a second beam, or "Stokes beam" formed from a second train of Stokes pulses at a second pulsation o s such as a difference o p - o sThe interval between the first and second pulses is equal to a molecular vibrational resonance pulse QR of the sample 10 that we seek to observe. The emission source can be similar to that described in relation to the example in Fig. 5A. The first and second pulse trains are time-synchronized to allow the interaction of pump and Stokes pulses in the sample, for example, by means of a delay line. However, the pulse trains do not need to be modulated for the implementation of a CARS process.

[0163] The system 502 also includes a processing module 570, comprising an optical detector 575 and a processing and / or display unit 578. For the detection of a CARS optical signal, the detector is advantageously a photomultiplier tube. As in the previous example, the processing module may further include one or more optical conjugation elements 572 and optical filtering means (not shown), for example, an interference optical filter, allowing the selection of radiation at the CARS pulsation.

[0164] In other examples, the 502 physico-chemical characterization system is configured for the detection of a nonlinear optical signal of the SHG or THG type.

[0165] The 510 emission source is configured to emit a single beam, the "pump beam", formed from a train of pump pulses at the pulsation o p .

[0166] The 502 system includes, as before, a processing module 570, comprising an optical detector 575 and a computing and / or display unit 578. For the detection of an SHG or THS optical signal, the detector is advantageously a photomultiplier.

[0167] In all cases, an image of the sample can be obtained from the optical signal detected at several points of the sample.

[0168] Fig. 6 shows an example of a fiber optic device 601 according to this description, in a second embodiment. In this second embodiment, the receiving means of the fiber optic device include an optical detector 640, for example a photodiode, so that, unlike the examples of the first embodiment illustrated by Fig. 2A, Fig. 2B, Fig. 2C, and Fig. 2D, the optical detection of the optical signal emitted by the sample is performed within the head 260 of the optical device. The fiber optic device 601 further includes a wired electrical connection 645, for example an electrical cable, for carrying the electrical signal from the optical detector 645 to a processing module external to the fiber optic device 601.

[0169] The other characteristics may be similar to those of the previous examples.

[0170] Thus, the fiber device 601 includes a first optical fiber 210 configured to carry at least one first train of pump pulses at a first pulse o pFor example, a hollow-core fiber. The fiber device 601 further includes a head 260 with a mount 265 configured to receive a distal portion of the first optical fiber. The optical fiber 210 may include a fiber end 212 configured to reduce the beam size, for example, a piece of fiber or a glass bead. The mount 265 has, for example, a substantially cylindrical external surface. The head 260 of the fiber device includes first light-deflection means 221, integral with the mount 260, arranged in a distal portion 261 of the head and configured to receive the pump pulses at the output of said first optical fiber and deflect the pump pulses toward a measurement region 230, such that in operation, the pump pulses propagate in the measurement region substantially along a second axis A2.The head 260 of the fiber optic device further includes means for receiving an optical signal emitted substantially along the second axis A2, the optical signal resulting from the interaction, in the measurement region 230, of at least some of said pump pulses with the sample 10. The receiving means include, for example, as illustrated in Fig. 6, second light-deflection means 222. The second light-deflection means 222 are configured to reflect the optical signal back to a proximal part 262 of the head. The first deflection means 221 and the second deflection means 222 can be identical to those described in connection with the preceding examples.

[0171] In some embodiments, the receiving means do not include second means for deflecting the light, and the optical detector 640 is configured to receive the signal directly emitted along the second axis A2. The receiving means may nevertheless include an optical focusing element to send the optical signal to the optical detector.

[0172] The measurement region 230 can be formed by a cavity in a distal portion of the head mount 260, as illustrated in Fig. 6, or outside the mount, as illustrated in Fig. 2D. As in the previous examples, the head 260 of the fiber device 201 can also include a focusing optic 218, configured to focus at least the pump pulses into the measurement region; scanning means 215, arranged in the distal portion of the head and configured to scan at least the pump pulses into the measurement region 230; and an optical block 245 comprising a focusing optic and / or an optical filter. The fiber device can also include an aspiration tube 250 (optional), configured for aspirating the sample 10 into the measurement region 230.

[0173] Fig. 7 represents a diagram of an example of a physicochemical characterization system 503 configured to work with a fiber device according to the second embodiment, as illustrated for example in Fig. 6.

[0174] The 503 physico-chemical characterization system is a sample analysis system, for example an imaging system, configured for the detection of a resonant nonlinear optical signal of the Stimulated Raman Scattering (SRS) type induced in the sample 10.

[0175] The physico-chemical characterization system 503 is similar to the physico-chemical characterization system 501 described with reference to Fig. 5 A, except that the optical detection is performed within the fiber optic device. Thus, in this example, the processing module 570 does not include an optical detector but only the electronic filter 577 and the processing and / or display unit 578.

[0176] Such a physico-chemical characterization system 503 is particularly well-suited to SRS processes, which allow the use of photodiodes small enough to be housed within the fiber optic device. This is not the case for other nonlinear processes, which require highly sensitive optical detectors, such as photomultiplier tubes, which are generally larger.

[0177] Although described through a number of embodiments, the devices described herein include various variants, modifications, and improvements that will be obvious to those skilled in the art, it being understood that these various variants, modifications, and improvements form part of the scope of the invention as defined by the following claims. REFERENCES

[0178] [Réf. 1] N. Sanai et al. "Intraoperative Confocal Microscopy for Brain Tumors: A Feasibility Analysis in Humans," Oper. Neurosurg. 68, ons282 (2011).

[0179] [Réf. 2] J.-X. Cheng and X. S. Xie, "Vibrational spectroscopic imaging of living systems: An emerging platform for biology and medicine," Science 350, aaa8870 (2015).

[0180] [Réf. 3] N. Bloembergen elal.« The stimulated raman effect », American Journal of Physics, 35:989-1023, 1967

[0181] [Réf. 4]: C.W. Freudiger et al. « Label-free biomedical imaging with high sensitivity by stimulated Raman scattering microscopy" , Science, 322(5909): 1857-1861, 2008 [Réf. 5] B. G. Saar et al. "Coherent Raman scanning fiber endoscopy," Opt. Lett. 36, 2396-2398, 2011

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[0184] [Réf. 8] Peng Lin et al. « Coherent Raman scattering imaging with a near-infrared achromatic metalens » APL Photonics 1 September 2021 ; 6 (9): 096107.

[0185] [Réf. 9] A. Kudlinski et al., "Double clad tubular anti-resonant hollow core fiber for nonlinear microendoscopy," Opt. Express 28, 15062-15070 (2020)

[0186] [Réf. 10] loannis N. Papadopoulos et al. “Focusing and scanning light through a multimode optical fiber using digital phase conjugation" , OPTICS EXPRESS Vol. 20, No.

[0187] 10 (2012)

Claims

33 DEMANDS 1. Fiber-linked device (201, 601) for detecting an optical signal emitted by a sample (10), comprising at least one first optical fiber (210) configured to carry at least one first train of pump pulses (511) at a first pulse (o p ); a movable head (260) comprising: a mount (265) configured to receive a distal portion of the first optical fiber such that in operation, said pump pulses at the output of the first optical fiber propagate substantially along a first axis (Ai) of said mount; of the first means for deflecting light (221), attached to said mount, arranged in a distal part (261) of the head and configured to receive said pump pulses at the output of said first optical fiber and deflect said pump pulses towards a measurement region (230), such that in operation, said pump pulses propagate substantially in said measurement region along a second axis (A2) of said mount; receiving means configured to receive an optical signal emitted forward, substantially along said second axis (A2), said optical signal resulting from the interaction, in said measurement region, of at least said pump pulses with the sample, said receiving means being fixed to the mount; the movable head further comprising: scanning means (215), attached to said mount and configured to scan at least said pump pulses in the measurement region.

2. A fiber-optic device according to claim 1, wherein: the receiving means include second light deflection means (222), attached to said mount, configured to return said optical signal to a proximal part (262) of the head.

3. A fiber-reinforced device according to any one of the preceding claims, wherein the head further comprises focusing means (218), integral with the mount, configured to focus at least said pump pulses into a 34 volume of focus of the measurement region.

4. Fiber device according to any one of the preceding claims, wherein said first fiber is a hollow core fiber.

5. Fiber device according to any one of the preceding claims, further comprising a second optical fiber (240) configured to carry said optical signal received by said receiving means outside the head.

6. Fiber device according to claim 5, wherein said second fiber is a large core and / or large digital aperture multimode fiber.

7. Fibre device according to any one of claims 1 to 4, wherein said receiving means comprise an optical detector (640) configured for optical detection of said optical signal.

8. Fiber-retained device according to any of the preceding, in which the measurement region is formed by a cavity in a distal part of the mount.

9. Fibre-connected device according to any one of the preceding, wherein the measurement region has a width (d) measured along said second axis (A2) of substantially between about 10 pm and about 10 mm, advantageously between 200 pm and about 1 mm.

10. Fibre device according to any one of the preceding claims, wherein a maximum dimension of the mount, measured in a plane perpendicular to said first axis (Ai), is less than about 10 mm.

11. Fiber device according to any one of the preceding claims, further comprising a suction tube (250), configured for suction of the sample (10) in the measurement region (230).

12. A fiber optic device according to any one of the preceding claims, wherein: said first optical fiber (210) is configured to further carry a second probe pulse train (512) at a second pulse (o s ), and in which said optical signal emitted in the direction of said pump pulses results from the interaction, in said measurement region, of said pump pulses and said probe pulses with the sample.

13. Fibre instrument, for example surgical instrument, comprising at least one working channel and a fibre device according to any one of the preceding claims arranged in said at least one working channel.

14. Physico-chemical characterization system (501, 503) for a sample (10) comprising: an emission source (510) configured to emit at least one first train of pump pulses (511) at a first pulse (o p ) ; a fiber device according to any one of claims 1 to 12 or a fiber instrument according to claim 13, said first optical fiber of the fiber device being configured to carry at least said pump pulses; a processing module (570) configured to extract from at least one first optical signal resulting from the interaction of at least said first pump pulses with the sample, at least one first signal characteristic of a physicochemical property of the sample.

15. A physico-chemical characterization system according to claim 14, wherein: said emission source is configured to emit in addition a second probe pulse train (512) at a second pulse (o s ), the first train of pump pulses and the second train of probe pulses being time-synchronized, said at least a first optical signal resulting from the interaction, in said measurement region, of said pump pulses and said probe pulses with the sample.

16. A physico-chemical characterization system according to claim 15, wherein: the second probe pulse train is a Stokes pulse train, the second pulse (o s ) being such that a difference (o p - ® s ) between the first pulse and the second pulse is equal to a molecular vibrational resonance (QR) pulse of the sample, said at least a first signal extracted by the processing module being characteristic of a molecular vibrational resonance of the sample.

17. A physico-chemical characterization system according to claim 16, further comprising: at least one first amplitude modulator (531) configured to amplitude modulate at a first modulation frequency (f m ) one of the first pump pulse trains or second Stokes pulse trains; and in which: the processing module includes an electronic filter (577) at said first modulation frequency (f m) configured to extract from said at least a first optical signal resulting from the interaction of said first pump pulses and said second Stokes pulses in the sample, at least a first SRS (513) signal characteristic of the molecular vibrational resonance of the sample.

18. A physico-chemical characterization system according to any one of claims 14 to 17, wherein: said fiber optic device includes a second optical fiber (240) configured to carry said first optical signal returned by the second deflection means; and the processing module includes an optical detector (575) configured for the detection of said first optical signal at the output of a proximal end of the second optical fiber.

19. A physico-chemical characterization system according to any one of claims 14 to 18, wherein: the processing module is configured to generate an image of the sample from said at least a first signal characteristic of a physicochemical property of the sample.

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