Measuring head and measuring device for performing surface enhanced Raman spectroscopy measurements

Abstract

The invention relates to a measuring head and a measuring device for performing surface enhanced Raman spectroscopy measurements. A measuring head and a measuring apparatus including a measuring head for performing surface enhanced Raman spectroscopy measurements. The measurement head includes a housing, an optical device including a window closing an opening of the housing and a prism extending into an interior of the housing, and a SERS substrate disposed outside of the measurement head. The SERS substrate includes a nanostructured layer and a chemically inert transparent passivation layer. The optical device is evanescently coupled to the SERS substrate and is configured to receive excitation light emitted through the housing to the optical device, emit the excitation light toward the SERS substrate such that an evanescent field extends from the SERS substrate into a medium adjacent an outer side surface of the passivation layer, and receive Raman scattered light emitted from the medium through the SERS substrate and direct the Raman scattered light through the housing.

Description

Technical Field

[0001] The present disclosure relates to surface enhanced Raman spectroscopy, and more particularly to a measuring head and a measuring device for performing surface enhanced Raman spectroscopy measurements on at least one measured quantity of a medium. Background Art

[0002] Conventional Raman spectrometers typically include a monochromatic light source that emits monochromatic excitation light onto a medium sample, and a spectral determination unit that is used to determine and provide a measurement spectrum of Raman scattered light emitted from the irradiated sample. The measurement spectrum is provided, for example, to an evaluation unit that is used to determine and provide the measured quantity of the medium, such as the concentration of a target analyte contained in the medium, based on a previously determined model that is used to determine the measured quantity based on the spectral intensity of the measurement spectrum.

[0003] One of the disadvantages of conventional Raman spectroscopy is that the intensity of Raman scattered light emitted from the irradiated sample is relatively low. This limits the measurement range achievable with conventional Raman spectroscopy. As an example, the concentration measurement of a target analyte included in a medium is typically limited to concentrations above a certain minimum concentration value, for example, a minimum concentration value of 50 ppm.

[0004] Therefore, conventional Raman spectroscopy is not suitable for applications where measurements of relatively low concentrations are required and / or desired. These applications include, for example, applications in the life science industry, bioprocessing, and pharmaceutical industry where the concentration of the target analyte may be significantly lower than the minimum concentration required by conventional Raman spectroscopy.

[0005] In this regard, surface enhanced Raman spectroscopy (SERS) constitutes a promising alternative to conventional Raman spectroscopy. In SERS, enhancement of Raman scattered light emitted by molecules of a target analyte can be achieved by exposing the molecules to an evanescent field emitted by a SERS substrate that receives excitation light. SERS substrates that have been studied in the past include thin films exhibiting nanostructured surfaces, such as nanostructured noble metal surfaces. However, one disadvantage of SERS is that most SERS substrates are made of fragile objects that should be protected from environmental influences, for example, to prevent damage and / or contamination of the SERS substrate.

[0006] Due to the short range of the evanescent field emitted from the irradiated SERS substrate, SERS measurements are typically performed under the following measurement conditions: molecules dispersed in a colloidal material are contained in a small cavity adjacent to the SERS substrate, and the molecules adsorbed on the SERS substrate experience the evanescent field.

[0007] A cavity for containing a colloidal material provides the advantage of protecting the SERS substrate and achieving static measurement conditions that promote adsorption. Depending on the design of the measurement instrument employed, the cavity may also need to be able to emit excitation light along an emission path passing through the cavity to the SERS substrate and / or be able to receive Raman scattered light along a reception path passing through the cavity.

[0008] However, the adsorption of molecules (especially macromolecules) on the SERS substrate may disrupt the structure and / or damage the molecules. This may prevent the further use of the colloidal material. In addition, adsorption is an exothermic process, which may also prevent the further use of the colloidal material. Another problem associated with adsorption is that an exchange process should be performed between successive SERS measurements to update the SERS substrate and / or remove previously adsorbed molecules from the SERS substrate. As a result, SERS measurements of adsorbed molecules are less suitable for performing online measurements, for example, measurements of the medium contained in, processed, and / or produced in a vessel (such as a bioreactor).

[0009] Another problem is that the cavities required to contain the colloidal material in SERS measurements are generally incompatible with online measurements, and they may be difficult to clean and / or sterilize. This makes measurement instruments that include or require cavities unsuitable for applications that require sterile or aseptic conditions. In this regard, the cavities are incompatible with cleaning in place (CIP) and / or steaming in place (SIP) protocols that may be required in these applications.

[0010] US 2008 / 0174774A1 discloses a Raman spectroscopy measurement device for spectroscopic analysis of analyte molecules deposited near a metal film, the metal film being composed of, for example, gold and having a film thickness of 20 nm to 40 nm. The metal film includes lithographically patterned features designed to enhance surface plasmon resonance along the metal film to promote the emission of Raman radiation from the analyte molecules. Within the device, the metal film is positioned between a liquid or gas medium and a prism positioned in evanescent communication with the metal film. The device also includes an excitation light source that emits monochromatic excitation light to the prism and a radiation detector that detects Raman radiation from the analyte molecules. Regarding evanescent communication, US2008 / 0174774A1 discloses two embodiments.

[0011] In the first embodiment, evanescent communication is achieved through a Kretschmann configuration. In this case, the metal film is deposited on the prism, the analyte molecules are deposited near the upper side of the metal film facing away from the prism, and the radiation detector is positioned at a certain distance above the upper side of the metal film facing away from the prism. Correspondingly, the radiation detector receives Raman radiation emitted along an optical path extending through the liquid or gas medium.

[0012] Although not explicitly stated in US 2008 / 0174774A1, it is reasonable to assume that positioning a metal film between a liquid or gas medium and a prism and detecting Raman radiation emitted by molecules in a direction away from the metal film requires the device according to the first embodiment to include a cavity adjacent to the metal film that houses the liquid or gas medium and protects the metal film.

[0013] As mentioned above, cavities are generally incompatible with in-line measurements and are not easily cleaned and / or sterilized. In addition, the device, particularly the cavity and the metal film, may be incompatible with clean-in-place (CIP) and / or steam-in-place (SIP) protocols required in many applications that must meet high hygiene standards.

[0014] In a second embodiment, evanescent wave communication is achieved by an Otto configuration in which the metal film is separated from the prism by a small gap, such as a gap of 10 nm to 20 nm. Here, the analyte molecules are positioned between the prism and the metal film, on the underside of the metal film facing the prism, and Raman radiation that is typically emitted downward away from the metal film is detected. In the second embodiment, the gap constitutes a very small cavity that exhibits the above-mentioned disadvantages.

[0015] According to US 2008 / 0174774A1, the metal film is preferably derivatized or functionalized by attaching receptors or ligands that promote the binding of specific analyte molecules near its surface. However, the field of use of the device in this regard is limited to measurements related to that specific analyte.

[0016] In addition, in applications where in-line measurements are required or desired, the binding of analyte molecules is undesirable. Like adsorption, binding may modify and / or damage the medium including the analyte in a way that may prevent further use of the medium, and an exchange process may have to be performed between successive measurements to update the metal film and / or remove molecules from the metal film.

[0017] Therefore, there is still a need for further contributions in this technical field. Summary of the Invention

[0018] The present disclosure includes a measurement head for performing surface-enhanced Raman spectroscopy measurements on at least one measurand of a medium, the measurement head comprising:

[0019] a housing that surrounds the interior of the measurement head;

[0020] an optical device that includes a window closing an opening of the housing and a prism extending into the interior of the housing; and

[0021] A SERS substrate, which is disposed on the outer side of the medium adjacent to the measurement head during the measurement operation; the SERS substrate includes a nanostructure layer and a chemically inert transparent passivation layer;

[0022] Wherein, the optical device is evanescently coupled to the SERS substrate and is configured to:

[0023] Receive the excitation light emitted into the optical device along the excitation light path passing through the interior of the housing;

[0024] Refract the received excitation light towards the SERS substrate such that during the measurement operation, an evanescent field extends from the evanescently coupled SERS substrate into the medium adjacent to the outer surface of the passivation layer; and

[0025] Receive the Raman scattered light emitted by the medium during exposure to the evanescent field through the evanescently coupled SERS substrate and guide the Raman scattered light along the measurement light path extending through the interior of the housing.

[0026] The measurement head provides the advantage that it can perform on-line measurement of the quantity to be measured.

[0027] In this regard, the chemical inertness of the passivation layer of the SERS substrate provides the following advantages: it effectively prevents any adsorption of molecules dispersed in the medium, which otherwise might damage or even destroy the molecules and / or might alter or impair the medium in other ways that prevent further use of the medium. It also provides the following advantage: molecules can freely pass through the decaying field extending in front of the passivation layer without binding to the SERS substrate and without contaminating the SERS substrate. This enables the measurement head to operate continuously without performing an exchange process between successive measurements.

[0028] The present disclosure recognizes that the optical transparency of the passivation layer enables the evanescent coupling between the optical device and the SERS substrate to be used as a bidirectional coupling to generate an evanescent field and emit Raman scattered light. Contrary to the common belief that Raman scattered light emitted from the medium in a direction away from the SERS substrate should be detected, this aspect enables the Raman scattered light to be received through the SERS substrate.

[0029] In this regard, the optical device receiving the excitation light through the interior of the measurement head housing and guiding the Raman scattered light received through the evanescently coupled SERS substrate provides the following advantages: the measurement head neither includes nor requires any cavity of finite size to accommodate the medium - accommodating the medium is not in line with the hygiene requirements of the measurement location. Additionally, the robustness of the passivation layer provides the following advantages: for example, the measurement head can be cleaned and / or disinfected in-situ by performing in-situ cleaning (CIP) and / or in-situ sterilization (SIP) procedures at the measurement location where the measurement head is installed.

[0030] In some embodiments, the measurement head is an in-line probe.

[0031] In a further embodiment, the window and the prism are made of a transparent material or a transparent glass and / or the optical device is a monolithic element including the window and the prism.

[0032] In certain embodiments, the optical device is sealed, brazed, compression bonded or press fit into the aperture of the housing.

[0033] According to an embodiment, the SERS substrate is provided or deposited on the outer surface of the transparent window, away from the prism; the passivation layer is provided or deposited on the nanostructured layer; the passivation layer covers the outer surface of the SERS substrate adjacent to the medium during the measurement operation; the nanostructured layer includes a nanostructured noble metal layer or a nanostructured gold layer; the passivation layer is a graphene layer; and / or the passivation layer is a thin layer or a thin graphene layer having a thickness of 0.1 nm to 5 nm.

[0034] In certain embodiments, the prism includes:

[0035] A receiving surface that receives the excitation light emitted into the optical device along the excitation light path and refracts the incident excitation light through the window towards the SERS substrate; and

[0036] A transmission surface that receives the measurement light including the Raman scattered light received by the SERS substrate through attenuated coupling by the optical device and refracts the incident measurement light onto the measurement light path.

[0037] According to a further embodiment, the measurement head further includes a filter or a notch filter inserted in the measurement light path. In this embodiment, the optical device is configured to emit the measurement light including the Raman scattered light received by the SERS substrate through attenuated coupling by the optical device along a first section of the measurement light path to the filter; and the filter is configured to attenuate the light included in the measurement light having a wavelength within a limited wavelength range including the excitation wavelength of the excitation light and allow the Raman scattered light to be emitted along a second section of the measurement light path.

[0038] In certain embodiments, the excitation light path or the first section of the excitation light extends parallel to the longitudinal axis of the housing, and the measurement light path or the second section of the measurement light path extends parallel to the longitudinal axis of the housing.

[0039] A further embodiment includes that the measurement head further includes at least one of the following:

[0040] A process connector for mounting the measurement head to a corresponding docking connector around an opening at the measurement site;

[0041] An input port for connecting the measurement head to an external excitation light source; and

[0042] An input port for connecting the measurement head to an external spectroscopic device.

[0043] According to the first embodiment, the SERS substrate is disposed or deposited on the front surface of the measurement head and / or on the outer surface of the transparent window remote from the prism, and the transparent window closes an opening through the front wall of the housing.

[0044] According to an improvement of the first embodiment, the measurement head is configured to be flush-mounted at the measurement location and / or includes a process connector configured to be mounted to a corresponding docking connector around an opening at the measurement site such that the front side of the measurement head extending through the docking connector is flush with the mounting surface around the opening.

[0045] According to the second embodiment, the SERS substrate is disposed or deposited on the side surface of the measurement head and / or on the outer surface of the transparent window remote from the prism, and the transparent window closes an opening through the side wall of the housing.

[0046] According to an improvement of the second embodiment, the measurement head further comprises:

[0047] A first reflector inserted into the excitation light path and configured to reflect the excitation light received by the first reflector along a first section of the excitation light path along a second section of the excitation light path towards the optical device; and

[0048] A second reflector inserted into the measurement light path and configured to reflect the measurement light received by the second reflector along a first section of the measurement light path along a second section of the measurement light path.

[0049] According to a further improvement of the second embodiment, the first section of the excitation light path extends parallel to the longitudinal axis of the housing; the second section of the excitation light path extends perpendicular to the longitudinal axis of the housing; the first section of the measurement light path extends perpendicular to the longitudinal axis of the housing; the second section of the measurement light path extends parallel to the longitudinal axis of the housing.

[0050] In a further embodiment:

[0051] The measurement head is an elongated insertion probe; and / or

[0052] The measurement head includes a process connector configured to be mounted to a corresponding docking connector around an opening at the measurement location such that the elongated section of the measurement head protrudes in front of the mounting surface around the opening; and / or

[0053] The SERS substrate is disposed or deposited on the front surface or the side surface of the measurement head; or is disposed or deposited on the side surface of the measurement head configured to be placed at the measurement location such that the orientation of the SERS substrate can be adjusted by rotating the measurement head along its longitudinal axis.

[0054] In certain embodiments, the measurement head further comprises at least one of the following:

[0055] at least one other optical element;

[0056] an input optical device that receives the excitation light provided to the measurement head and guides the received excitation light to the optical device;

[0057] a collimating lens that collimates the excitation light provided to the measurement head via the input port of the measurement head toward the receiving surface of the prism, and the prism refracts the incident excitation light toward the SERS substrate; and

[0058] an output optical device or a collimating lens that receives the Raman scattered light from the optical device and guides the incident Raman scattered light to the output port of the measurement head.

[0059] The present disclosure includes a measurement device for performing surface-enhanced Raman spectroscopy measurement on at least one measured object of a medium, the measurement device including:

[0060] the measurement head disclosed herein;

[0061] an excitation light source for generating and providing monochromatic excitation light to the measurement head;

[0062] a spectroscopic determination unit that receives the Raman scattered light from the measurement head and determines and provides a measurement spectrum of the medium based on the received Raman scattered light; and

[0063] a processing unit that is connected to and / or communicates with the spectroscopic determination unit and is configured to determine and provide a measurement result of each measured object of the medium based on the measurement spectrum from the spectroscopic determination unit and a previously determined model for determining the measurement result of each measured object based on the spectral intensity value of the measurement spectrum.

[0064] In some embodiments, the measurement device further includes at least one of the following:

[0065] an optical fiber that connects or releasably connects the measurement head to the excitation light source;

[0066] an optical fiber that connects or releasably connects the measurement head to the spectroscopic determination unit; and

[0067] a filter or a notch filter that receives the measurement light including the Raman scattered light from the measurement head, attenuates the light having a wavelength within a limited wavelength range including the excitation wavelength of the excitation light included in the incident measurement light, and transmits the Raman scattered light to the spectroscopic determination unit. Description of the Drawings

[0068] By referring to the following description of various embodiments of the present disclosure in conjunction with the accompanying drawings, the described embodiments and other features, advantages, and disclosures herein and the manner of achieving them will become apparent, and the present disclosure will be better understood, wherein:

[0069] Figure 1 shows a Raman spectroscopy measuring device including a measuring head according to the present invention;

[0070] Figure 2 shows a further embodiment of the measuring head according to the present disclosure;

[0071] Figure 3 shows a filter and a spectrometric unit; and

[0072] Figure 4 shows two measuring heads according to the present invention arranged on a container.

[0073] For visualizing elements of different sizes, the drawings use a non - scaled representation. Detailed Description

[0074] The present disclosure includes a measuring head 10 for performing surface - enhanced Raman spectroscopy measurement (SERS measurement) on at least one measurand of a medium M, and includes a measuring device 100 including the measuring head 10.

[0075] The medium M is, for example, a liquid or gas medium, a colloidal medium including molecules of at least one target analyte, and / or a process medium, such as a process medium contained, transported, provided, processed, and / or generated at a measurement site in a given application, such as an application in the life science industry, the bioprocessing industry, or the pharmaceutical industry.

[0076] Depending on the application using the measuring head 10 and / or the measuring device 100, the at least one measurand includes, for example, the concentration of at least one target analyte included in the medium M, the pH value of the medium, and / or at least one other measurand determinable based on Raman spectroscopy.

[0077] Figure 1 shows an example of a measuring device 100 including the measuring head 10.

[0078] The measuring head 10 disclosed by the present invention includes a housing 1 surrounding the interior of the measuring head 10, an optical device 3, and a SERS substrate 5.

[0079] In certain embodiments, the housing 1 is, for example, an elongated and / or tubular housing. Additionally or alternatively, in certain embodiments, the housing 1 is, for example, a metal housing, such as a stainless - steel housing.

[0080] The optical device 3 includes a transparent window 7 closing an opening of the housing 1 and a prism 9 extending into the interior of the housing 1.

[0081] As Figure 1 shown, in certain embodiments, the transparent window 7 closes an opening through the front wall WF of the housing 1. Figure 2Shows an alternative embodiment of the measuring head 10', in which the transparent window 7 closes an opening through the side wall WS of the housing 1 of the measuring head 10'.

[0082] Regardless of the position of the opening, in some embodiments, the optical device 3 is, for example, a monolithic element including the window 7 and the prism 9. In such an embodiment, the monolithic element is, for example, a single component made of a transparent material (e.g., glass or sapphire).

[0083] As an alternative, the window 7 and the prism 9 are, for example, configured as separate components made of a transparent material (e.g., glass or sapphire). In such an embodiment, the prism 9 and the window 7 are preferably made of the same transparent material, and the prism 9 is, for example, disposed inside the housing 1 such that the outer side surface of the prism 9 is adjacent to the inner surface of the window 7 facing the inside of the housing 1.

[0084] In any such embodiment, the optical device 3 is fixed inside the housing 1 such that the transparent window 7 closes the opening in the housing 1. This can be achieved in various ways.

[0085] As an example, in some embodiments, the optical device 3 is, for example, inserted into a hole in the opening from the outside. When the housing 1 is an elongated or tubular housing with an axial length exceeding a certain value, it is particularly advantageous to insert the optical device 3 from the outside rather than through the inside of the housing 1.

[0086] As Figure 1 and Figure 2 shown, the hole includes, for example, an inner surface 11, for example, a tapered inner surface, surrounding and / or adjacent to the outer side surface of the optical device 3. The optical device 3 is, for example, sealed in the hole. The seal between the optical device 3 and the housing 1 is, for example, achieved by brazing, compression bonding, or press-fitting the optical device 3 into the hole. As an alternative, the measuring heads 10, 10' may include other means for fixing the optical device 3 inside the housing 1 and / or for providing a seal between the optical device 3 and the housing 1.

[0087] Regardless of how the optical device 3 is fixed inside the housing 1, during the measurement operation, the SERS substrate 5 is disposed on the outer side of the measuring heads 10, 10' adjacent to the medium M. Figure 1 and Figure 2 Shows an embodiment in which the SERS substrate 5 is disposed (e.g., deposited) on the outer side surface 13 of the transparent window 7 away from the prism 9. Correspondingly, in Figure 1 , the SERS substrate 5 is disposed on the front surface of the measuring head 10, and in Figure 2 , the SERS substrate 5 is disposed on the side surface of the measuring head 10'.

[0088] The SERS substrate 5 includes a nanostructured layer 15 and a chemically inert, optically transparent passivation layer 17. AsFigure 1 and Figure 2 As shown in Figure 2 , the passivation layer 17 is, for example, disposed (e.g., deposited) on the nanostructured layer 15 and covers the outer surface of the adjacent medium M of the SERS substrate 5 during the measurement operation.

[0089] For the SERS substrate 5, the SERS substrate disclosed in the article titled "Graphene-Veiled Gold Substrate for Surface-Enhanced Raman Spectroscopy" published by Weigao Xu, Jiaqi Xiao, Yanfeng Chen, and Yabin Chen in the 25th column of the journal "Advanced Materials" on February 13, 2013, and the SERS substrate disclosed in the article titled "Graphene: A platform for surface-enhanced Raman spectroscopy" by Weigao Xu, Nannan Mao, and Jin Zhang in the 9th column of the journal "Small" in 2013 can be used.

[0090] Correspondingly, in some embodiments, the nanostructured layer 15 is, for example, a nanostructured noble metal layer, such as a nanostructured gold layer. Additionally or alternatively, in some embodiments, the passivation layer 17 is, for example, a graphene layer. The graphene layer provides the advantages of being optically transparent, chemically inert, and having high mechanical strength.

[0091] In some embodiments, the passivation layer 17 is, for example, a thin layer, such as a thin graphene layer and / or a thin layer having a thickness of 0.1 nm to 5 nm.

[0092] The optical device 3 is evanescently coupled to the SERS substrate 5.

[0093] As Figure 1 and Figure 2 shown, the optical device 3 is configured to receive the excitation light L0 emitted along the excitation light path extending through the interior of the housing 1 into the optical device 3 and refract the incident excitation light L0 to the SERS substrate 5 such that during the measurement operation, the evanescent field F extends from the evanescently coupled SERS substrate 5 into the medium M adjacent to the outer surface of the passivation layer 17.

[0094] In Figure 1 and Figure 2 the embodiment shown, the excitation light L0 is guided to the SERS substrate 5 via the receiving surface 19 of the prism 9. The prism 9 receives the excitation light L0 emitted along the excitation light path into the optical device 3 and refracts the incident excitation light L0 asFigure 1 and Figure 2 is refracted through window 7 as indicated by arrow L1 in Figure 2 to the SERS substrate 5.

[0095] The optical device 3 is further configured to receive Raman scattered light LR emitted from the medium M during exposure of the SERS substrate 5 to the evanescent field F by evanescent coupling of the medium M, and guide the received Raman scattered light LR along a measurement light path extending through the interior of the housing 1.

[0096] In Figure 1 and Figure 2 In the illustrated embodiment, this is achieved by a prism 9 which includes a transmission surface 21 that receives the measurement light LM (including the Raman scattered light LR) received by the optical device 3 via the evanescent-coupled SERS substrate 5 and refracts the incident measurement light LM onto a measurement light path extending through the interior of the housing 1.

[0097] Depending on the design of the optical device 3, in particular the orientation of the receiving surface 19 of the prism 9 relative to the excitation light path and the outer surface 13 of the window 7, the measurement light LM includes, for example, the excitation light L0 reflected onto the transmission surface 21. Additionally, the measurement light LM may include Rayleigh scattered light emitted from the medium M and received by the optical device 3 via the evanescent-coupled SERS substrate 5.

[0098] In some embodiments, the measurement heads 10, 10' are configured, for example, to provide Raman scattered light LR by providing measurement light LM that includes the Raman scattered light LR.

[0099] As an alternative, in some embodiments, the measurement heads 10, 10' include, for example, a filter 23, such as a notch-filter. As Figure 1 shown, in such an embodiment, the optional filter 23 is inserted, for example, into the measurement light path extending through the housing 1 and is configured to receive the measurement light LM emitted along a first section of the measurement light path onto the filter 23 to attenuate light having wavelengths within a finite wavelength range including the excitation wavelength of the excitation light L0 in the incident measurement light LM, and allow the Raman shifted Raman scattered light LR along a second section of the measurement light path.

[0100] Regardless of whether the measurement heads 10, 10' include the filter 23, in some embodiments, the measurement heads 10, 10' are configured such that the excitation light path and the measurement light path are anti-parallel paths. This is achieved, for example, by selecting the transparent material of the optical device 3 and correspondingly designing the shape of the prism 9, in particular the orientation of the receiving surface 19 and the transmission surface 21.

[0101] In Figure 1In the illustrated embodiment, the excitation light path and the measurement light path are anti-parallel straight paths extending parallel to the longitudinal axis of the housing 1.

[0102] In Figure 2 the illustrated embodiment, the excitation light path and the measurement light path are L-shaped anti-parallel light paths. This is achieved, for example, by a measurement head 10' including a first reflector R0 (e.g., a first mirror) and a second reflector RM (e.g., a second mirror) disposed inside the housing 1.

[0103] The first reflector R0 is inserted into the excitation light path and is configured to reflect the excitation light L0 received by the first reflector R0 along a first section of the excitation light path extending parallel to the longitudinal axis of the housing 1 towards the optical device 3 along a second section of the excitation light path extending perpendicular to the longitudinal axis of the housing 1.

[0104] The second reflector RM is inserted into the measurement light path and is configured to reflect the measurement light LM received by the second reflector RM along a first section of the measurement light path extending perpendicular to the longitudinal axis of the housing 1 to a second section of the measurement light path extending parallel to the longitudinal axis of the housing 1.

[0105] The embodiment in which at least one section of the excitation light path and at least one section of the measurement light path extend parallel to the longitudinal axis of the housing 1 provides the advantage of high flexibility with respect to the axial length of the housing 1 and correspondingly the height of the measurement heads 10, 10'.

[0106] In certain embodiments, the housing 1 and the corresponding measurement heads 10, 10' have an axial length of, for example, 1 cm to 80 cm or more.

[0107] As described above, the present invention also includes a measuring device 100, which includes the measurement heads disclosed herein, such as Figure 1 the illustrated measurement head 10 or Figure 2 the illustrated measurement head 10'.

[0108] As Figure 1 shown, the measuring device 100 further includes: an excitation light source 20, which generates excitation light L0 and supplies it to the measurement head 10; a spectroscopic determination unit 30, which receives Raman scattered light LR from the measurement head 10; and a processing unit 40, for example, a computer with a memory, a microprocessor, or other types of signal and / or data processing units, connected and / or communicating with the spectroscopic determination unit 30.

[0109] The excitation light source 20 is preferably a monochromatic light source, such as a laser, for generating monochromatic excitation light L0 with a predetermined excitation wavelength to the measurement heads 10, 10'. In certain embodiments, the excitation wavelength is a wavelength in the visible or near-infrared wavelength range, for example, a wavelength between 400 nm and 1200 nm.

[0110] The spectroscopic unit 30 is configured to determine and provide a measurement spectrum I of the medium M based on the received Raman scattered light LR m .

[0111] Figure 3 An exemplary embodiment of the spectroscopic unit 30 is shown. As shown, the spectroscopic unit 30 includes, for example, a disperser 25 (such as a diffraction grating or a holographic grating) that disperses the incident Raman shifted Raman scattered light LR, a detector 27 that receives the dispersed light, and a signal processor 29 (such as a microprocessor). The signal processor 29 is connected to the detector 27 and is configured to determine and provide the measurement spectrum I m . In this regard, the detector 27 is, for example, configured to determine the intensity and generate a detector signal corresponding to the spectral intensity of the incident dispersed light. In certain embodiments, the detector 27 includes, for example, an array of detection elements, such as a charge-coupled device (CCD) array or a photodiode array. Each detection element receives a portion of the dispersed light and determines and generates a detector signal corresponding to the intensity of the received portion - such as the number of photons received over a given duration of time period - and gives it to the signal processor 29, which determines and provides the measurement spectrum I m of the spectral intensity values.

[0112] In an embodiment where the measurement head 10 includes the above-described optional filter 23, the Raman scattered light LR is transmitted through the filter 23 to the spectroscopic unit 30.

[0113] In an embodiment where the measurement head 10' does not include the optional filter 23, the Raman scattered light LR is provided to the spectroscopic unit 30, for example, by the spectroscopic unit 30 receiving the measurement light LM from the optical device 3 of the measurement head 10'. As an alternative, as Figure 3 shown, the measuring device 100 includes, for example, a filter 23' located outside the measurement head 10', such as a notch filter, which is configured to receive the measurement light LM from the measurement head 10' and transmit the Raman scattered light LR to the spectroscopic unit 30.

[0114] The processing unit 40 is configured to determine and provide at least one measured measurement result MR of the medium M based on the measurement spectrum I provided by the spectroscopic unit 30 m and a previously determined model MOD (for example, stored in a memory) for determining the measurement result MR of each spectroscopic unit I m of the measurement result MR.

[0115] Depending on the application in which the measuring device 100 is employed, each measured measurement result MR is, for example, employed to monitor, regulate, and / or control the process being performed in the application and / or to monitor and / or control the quality of the product being processed and / or produced in each application.

[0116] The present invention provides the above advantages. Individual components of the measuring heads 10, 10' and / or the measuring device 100 can be implemented in different ways without departing from the scope of the present invention. Several alternative embodiments are described in more detail below.

[0117] As Figure 1 and Figure 2 shown, the measuring heads 10, 10' are designed as in-line probes, which are configured to perform in-line measurements.

[0118] In certain embodiments, the measuring heads 10, 10' include, for example, a process connector 31, such as a fastener, flange, or other type of connector, for mounting the measuring heads 10, 10' to a corresponding docking connector 33 at the measurement location.

[0119] Figure 4 An example of an application is shown, in which two exemplary embodiments of the above-described measuring heads 10, 10' are arranged on a container 35 that houses and / or transports a medium M, where the container 35 is, for example, a bioreactor, tank, container, or other type of open or closed container.

[0120] In Figure 4 correspondence with Figure 1 shown, the first measuring head 10 corresponding to the measuring head 10 shown in

[0121] is, for example, configured to be flush-mounted at the measurement location. In this case, the axial length of the housing 1 and the corresponding axial length of the measuring head 10 are also correspondingly short. As an example, the housing 1 of the first measuring head 10 and the corresponding first measuring head 10 can have an axial length of one centimeter or a few centimeters. Figure 4 Correspondingly, the process connector 31 of the first measuring head 10 is, for example, configured to be mounted to a corresponding docking connector 33 around an opening at the measurement location such that the front side of the measuring head 10 extending through the docking connector 33 is flush with the mounting surface S1 of the opening around the measurement location. As

[0122] shown, where the first measuring head 10 is arranged on a port provided on the side wall of the container 35 including the docking connector 33, in this embodiment, only the flush-mounted front side of the measuring head 10 is adjacent to the medium M contained in the container 35.

[0123] In Figure 4In it, the process connector 31 of the second measuring head 10' surrounds the rear end portion of the second measuring head 10'. As shown in the figure, the second measuring head 10' is mounted on the corresponding docking connector 33 surrounding the opening such that the elongated section of the second measuring head 10' protrudes in front of the mounting surface S2 surrounding the opening.

[0124] As Figure 4 shown, based on the second measuring head 10' corresponding to the measuring head 10' shown in Figure 2 it, in an embodiment where the measuring head 10' is an elongated insertion probe, the SERS substrate 5 is, for example, arranged on the side surface of the measuring head 10'. This provides the advantage that by rotating the measuring head 10' about the longitudinal axis of the housing 1, the orientation of the SERS substrate 5 at the measurement location (e.g., inside the container 35) can be adjusted. As an example, the measuring head 10' can be arranged such that the SERS substrate 5 is arranged on the outer surface of the measuring head 10' away from the area inside the container 35 where disturbances and / or turbulences may occur during filling and / or emptying of the container 35 or when stirring the medium M.

[0125] As an alternative, the SERS substrate 5 can be arranged on the front surface of the elongated insertion probe, for example, as Figure 1 shown.

[0126] In some embodiments, the measuring device 100 is configured, for example, as a modular device. In such an embodiment, the measuring heads 10, 10' form one of the modules of the measuring device 100, which are connected to or configured to be connected to or releasably connected to the excitation light source 20 and the spectrometric unit 30. This configuration can be achieved in various ways.

[0127] As Figure 1 shown, in some embodiments, the measuring device 100 includes, for example, an optical fiber 37 that connects or releasably connects the measuring heads 10, 10' to the excitation light source 20 and an optical fiber 39 that connects or releasably connects the measuring head 10 to the spectrometric unit 30.

[0128] Correspondingly, in some embodiments, the measuring heads 10, 10' include, for example, an input port 41 for connecting the measuring heads 10, 10' to an external excitation light source 20 and an output port 43 for connecting the measuring heads 10, 10' to an external spectrometric unit 30.

[0129] The modular device 100 provides the advantage that only the measuring heads 10, 10' are exposed to the process conditions at the measurement location, while other components, such as the excitation light source 20, the spectrometric unit 30, and / or the processing unit 40, can be located at a remote location.

[0130] As an alternative, the measuring device 100 can be designed as a compact measuring device. In such an embodiment, the excitation light source 20 and the spectrometric unit 30 are, for example, accommodated in a device housing that is mounted at the rear end of the measuring head 10, for example as Figure 1 shown by the dashed line 45 in

[0131] Regardless of whether the measuring heads 10, 10' are configured as modules or components of a compact measuring device, in some embodiments, the measuring heads 10, 10' can include at least one other optical element. The other optical element(s) can, for example, include an input optical device 47 that receives the excitation light L0 from the excitation light source 20 and guides the received excitation light L0 to the optical device 3. As Figure 1 and 2 shown, the input optical device 47 can, for example, include a collimating lens - for example, a collimating lens adapted to collimate the excitation light L0 received via the input port 41 towards the receiving surface 19 of the prism 9.

[0132] Additionally or as an alternative, the other optical element(s) can, for example, include an output optical device 49 that is adapted to receive the measurement light LM from the optical device 3 or the Raman scattered light LR from the filter 23 and guide the incident light to the output port 43. As Figure 1 and Figure 2 shown, the output optical device 49 can, for example, include a condenser lens that guides the measurement light LM or the Raman scattered light LR to the output port 43.

Claims

1. A measuring head (10, 10') for performing surface enhanced Raman spectroscopy (SERS) measurement on at least one measured object of a medium (M), the measuring head (10, 10') comprising: a housing (1), the housing (1) enclosing the interior of the measuring head (10, 10'), An optical device (3), comprising a window (7) closing an opening of the housing (1) and a prism (9) extending into the interior of the housing (1); and A SERS substrate (5) is arranged on the outside of the measuring head (10, 10'), the outside being adjacent to the medium (M) during the measuring operation, the SERS substrate (5) comprising a nanostructure layer (15) and a chemically inert transparent passivation layer (17), The optical device (3) is evanescently coupled to the SERS substrate (5) and is configured as follows: receiving excitation light (L0) emitted to the optical device (3) along an excitation light path extending through the interior of the housing (1); refracting the received excitation light (L0) toward the SERS substrate (5) so that during the measurement operation, the evanescent field (F) extends from the evanescently coupled SERS substrate (5) into the medium (M) adjacent to the outer surface (13) of the passivation layer (17); and Raman scattered light (LR) emitted from the medium (M) during exposure to the evanescent field (F) is received by an evanescently coupled SERS substrate (5), and the Raman scattered light (LR) is guided along a measurement light path extending through the interior of the housing (1).

2. The measuring head (10, 10') according to claim 1, wherein The measuring head (10, 10') is adapted as an online probe; The window (7) and the prism (9) are made of transparent material or transparent glass; The optical device (3) is a monolithic element comprising the window (7) and the prism (9); and / or The optical device (3) is sealed, brazed, compression bonded or press-fitted into the aperture of the housing (1) within the opening.

3. The measuring head (10, 10') according to claim 1, wherein: At least one of the following: The SERS substrate (5) is arranged or deposited on an outer surface (13) of the window (7) away from the prism (9); The passivation layer (17) is arranged or deposited on the nanostructure layer (15); The passivation layer (17) covers an outer surface (13) of the SERS substrate (5), wherein the outer surface (13) is adjacent to the medium (M) during the measurement operation; The nanostructured layer (15) comprises a nanostructured noble metal layer or a nanostructured gold layer; The passivation layer (17) is a graphene layer; and The passivation layer (17) is a thin layer or a thin graphene layer having a thickness of 0.1 nm to 5 nm.

4. The measuring head (10) according to claim 1, wherein: The prism (9) comprises: a receiving surface (19), the receiving surface (19) being configured to receive the excitation light (L0) emitted to the optical device (3) along the excitation light path, and to refract the incident excitation light (L0) toward the SERS substrate (5) through the window (7); and A transmission surface (21) is configured to receive measurement light (LM) including the Raman scattered light (LR) received by the optical device (3) through the evanescently coupled SERS substrate (5), and refract the incident measurement light (LM) onto the measurement light path.

5. The measuring head (10) according to claim 1, further comprising a filter (23) or a notch filter inserted in the measuring light path, wherein: The optical device (3) is configured to transmit measurement light (LM) including Raman scattered light (LR) received by the optical device (3) through the evanescently coupled SERS substrate (5) to the filter (23) along a first section of the measurement light path; and The filter (23) is configured to attenuate light included in the measurement light (LM) and having a wavelength within a limited wavelength range, the limited wavelength range including the excitation wavelength of the excitation light, and the filter (23) is configured to allow the Raman scattered light (LR) to travel along a second section of the measurement light path.

6. The measuring head (10, 10') according to claim 1, wherein: The excitation light path or the first section of the excitation light path extends parallel to the longitudinal axis of the housing (1); and The measuring light path or the second section of the measuring light path extends parallel to the longitudinal axis of the housing (1).

7. The measuring head (10, 10') according to claim 1, further comprising at least one of the following: a process connector (31) configured to enable mounting of the measuring head (10, 10') to a corresponding docking connector (33) surrounding an opening at a measuring location; an input port (41), the input port (41) being configured to be able to connect the measurement head (10, 10') to an external excitation light (20) source; as well as An output port (43) is configured to enable the measurement head (10, 10') to be connected to an external spectrometric unit (30).

8. The measurement head (10) according to any one of claims 1 to 7, wherein the SERS substrate (5) is arranged or deposited: on the front surface of the measuring head (10); and / or On an outer side surface (13) of the window (7) remote from the prism (9), the window (7) closes the opening extending through the front wall (WF) of the housing (1).

9. The measuring head (10) according to claim 8, wherein: The measuring head (10): is configured to be flush mounted at the measurement site; and / or A process connector (31) is included, the process connector (31) being configured to be mounted on a corresponding docking connector (33) surrounding an opening at the measurement location, so that a front side of the measurement head (10) extending through the docking connector (33) is flush with a mounting surface (S1) surrounding the opening.

10. The measuring head (10') according to any one of claims 1 to 7, wherein: The SERS substrate (5) is configured or deposited as: on a side surface of the measuring head (10'); and / or On an outer side surface (13) of the window (7) remote from the prism (9), the window (7) closes the opening extending through the side wall (WS) of the housing (1).

11. The measuring head (10') according to claim 10, further comprising: a first reflector (R0) disposed in the excitation light path and configured to reflect the excitation light (L0) incident on the first reflector (R0) along a first section of the excitation light path toward the optical device (3) along a second section of the excitation light path; as well as A second reflector (RM) is disposed in the measuring light path and is configured to reflect the measuring light (LM) incident on the second reflector (RM) along a first section of the measuring light path along a second section of the measuring light path.

12. The measuring head (10) according to claim 11, wherein: The first section of the excitation light path extends parallel to the longitudinal axis of the housing (1); The second section of the excitation light path extends perpendicularly to the longitudinal axis of the housing (1); The first section of the measuring light path extends perpendicularly to the longitudinal axis of the housing (1); as well as The second section of the measuring light path extends parallel to the longitudinal axis of the housing (1).

13. The measuring head (10') according to any one of claims 1 to 7, wherein: At least one of the following: The measuring head (10') is a slender insertion probe; The measuring head (10') comprises a process connector (31) configured to be mounted to a corresponding docking connector (33) surrounding an opening at a measuring location such that an elongated section of the measuring head (10) protrudes in front of a mounting surface (S2) surrounding the opening; and The SERS substrate (5) is provided or deposited: on the front surface or side surface of the measuring head; or on a side surface of the measurement head (10'), wherein the measurement head (10') is configured to be placed at the measurement site so that the orientation of the SERS substrate (5) can be adjusted by rotating the measurement head (10') along its longitudinal axis.

14. The measuring head (10, 10') according to any one of claims 1 to 7, further comprising at least one of the following: at least one other optical element; an input optical device (47), the input optical device (47) being adapted to receive the excitation light (L0) provided to the measuring head (10, 10') and to guide the received excitation light (L0) to the optical device (3); a collimating lens adapted to collimate the excitation light (L0) provided to the measuring head (10) via an input port (41) of the measuring head (10, 10') toward a receiving surface (19) of the prism (9), the prism (9) being adapted to refract the incident excitation light (L0) toward the SERS substrate (5); and Output optics (49) or a collimating lens, the output optics (49) or a collimating lens being adapted to receive the Raman scattered light (LR) from the optical device (3) and direct the incident Raman scattered light (LR) to an output port (43) of the measuring head (10, 10').

15. A measuring device (100) for performing surface enhanced Raman spectroscopy measurement (SERS measurement) on at least one measured object of a medium (M), the measuring device (100) comprising: The measuring head (10, 10') according to any one of claims 1 to 14; an excitation light source (20), the excitation light source (20) being configured to generate monochromatic excitation light, the monochromatic excitation light being emitted to the measuring head (10, 10'); A spectrometry unit (30) configured to receive Raman scattered light (LR) from the measuring head (10, 10') and determine and provide a measurement spectrum (I ) of the medium (M) based on the received Raman scattered light (LR). m );as well as a processing unit (40) connected to the spectrometry unit (30) and / or in communication with the spectrometry unit (30) and configured to process a measured spectrum (I m ) and for the measurement spectrum based on the (I m ) to determine and provide a measurement result (MR) for each measurand of the medium (M).

16. The measuring device (100) according to claim 15, further comprising at least one of the following: Connecting or releasably connecting the measuring head (10, 10') to an optical fiber (37) of the excitation light source (20); An optical fiber (39) connecting or releasably connecting the measuring head (10, 10') to the spectrometric unit (30); and A filter or notch filter is adapted to receive the measurement light (LM) including the Raman scattered light (LR) from the measurement head (10, 10'), to attenuate light included in the incident measurement light (LM) and having a wavelength within a limited wavelength range including the excitation wavelength of the excitation light (L0), and to transmit the Raman scattered light (LR) to the spectrometry unit (30).

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