A device for non-invasive analyte measurement

Abstract

An apparatus 2 for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and / or concentration, such as glucose, in the skin of a subject is provided. The apparatus comprises a pla

Description

The present invention relates to apparatus and a method for non-invasive measurement of the presence or concentration of an analyte in a user’s skin or body. In our copending International application WO2022 / 084539 there is described an apparatus and probe for the non-invasive in vivo measurement of an analyte present in a user’s blood or interstitial fluid. The device works well. It includes an integrated planar probe having an opening such as a slit e.g. longitudinal slit, or other shaped opening, for receiving light for analysis. An optical source is provided as part of the device and is arranged to irradiate the skin of a user under test. A Raman scattering response is generated in the user’s skin or body and a scattered light signal is then received by the probe from the patient. The received Raman signal is provided to a spectrometer for analysis. One of the methodologies used and described in WO2022 / 084539 is spatially Offset Raman Spectroscopy (SORS). In such an arrangement, it is typical that an optical source is provided surrounded by multiple rings of Raman detectors. Alternatively multiple optical sources can be provided around a common detector. In both cases, the Raman detector(s) and optical source(s) 10 are spatially offset. A problem related to the VCSEL-based SORS probe approach with direct-to-slit spectrometer coupling is overfilling of the spectrometer. “Direct-to-slit” as used herein refers to a situation in which Raman radiation from a sample is collected directly using a spectrometer slit without any additional optical elements. In such cases, it can be difficult for the spectrometer to control incoming light outside the numerical aperture of the spectrometer resulting in straylight. Given the inherent weakness of Raman signals any straylight can negatively affect the quality of the spectrometer signal. Other examples of devices for measuring the concentration of an analyte using laser sources are disclosed in US2014 / 171759, WO2020191347, US10684226, US2015233836, US2002041166 and US2006146322. The article by Signe Lundsgaard-Nielsen et al entitled “Critical Depth Raman Spectroscopy Enables Home use Non- Invasive Glucose Monitoring” also discloses a system for non-invasive determination of analyte concentration in a body or sample. According to a first aspect of the present invention, there is provided apparatus for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and / or concentration, such as glucose, in the skin of a subject, the apparatus comprising; a planar probe having one or more optical sources for irradiating a sample such as the skin of a subject; a spectrometer configured to receive Raman scattered radiation transmitted from the sample in response to the received radiation from the one or more optical sources; a numerical aperture controller to determine the numerical aperture of the apparatus, and thereby control the input light received by, the spectrometer. Preferably, the numerical aperture controller is provided as part of the spectrometer. Preferably, the spectrometer comprises an optical opening through which light to be analysed passes and in which the numerical aperture controller comprises an aperture stop within the spectrometer. Preferably, the aperture stop is shaped to correspond to the shape of the optical opening of the spectrometer. Preferably, the aperture stop and the optical opening are both circular holes. Preferably, the distance between the aperture stop and the optical opening of the spectrometer is variable. According to one embodiment, the numerical aperture controller is provided as part of the probe. Preferably, the probe comprises a PCB layer having an opening for receiving a sample-generated Raman signal, the configuration of the opening defining the numerical aperture of the apparatus. Preferably, the PCB layer has a light absorbing region around the opening. Preferably, the light absorbing region is a hollow region with a light absorbing coating. Preferably, the shape of the hollow region is formed to correspond to that of the opening for receiving the sample-generated Raman signal. Preferably, the PCB layer comprises upper and lower metal layers with an intermediate PCB core, the light absorbing region being formed within the PCB core. Preferably, the PCB layer comprises upper and lower light blocking layers with an intermediate PCB core, the upper and lower light blocking layers having openings of sizes selected to limit the numerical aperture of the apparatus. Preferably, the apparatus comprises a light absorbing layer between upper and lower light blocking layers. Preferably, the apparatus comprises a protective transmission layer on the upper and / or the lower light blocking layer. Preferably, each protective transmission layer is formed from a material selected from the group consisting of glass, polymer, plastic and crystal. According to one embodiment, the probe has a light guide interface for receiving Raman signal from a sample, and in which the numerical aperture of the optical fibre interface is selected to provide a specified value of numerical aperture. The light guide interface could be, in one example, an optical fibre interface. Preferably, the optical fibre comprises a single fibre core. In an alternative example, the optical fibre comprises multiple fibre cores. Preferably, each of the optical fibre cores is rectangular in cross section. Preferably, the optical fibre couples the probe to the spectrometer. According to one embodiment, the probe has a buried light guide for receiving and / or transmitting the Raman signal from a sample, and in which the numerical aperture of the buried light guide is selected to provide a specified value of numerical aperture. Preferably, the apparatus comprises a mirror for receiving a sample generated Raman signal and directing the signal into the light guide. Preferably, the mirror is a dichroic mirror. According to one embodiment, the probe comprises a pinhole array and a corresponding micro lens array, in which each of the pinholes is arranged in required alignment with the micro lenses of the micro lens array, and in which the combination of the micro lenses and the pinholes are selected to determine the numerical aperture of the apparatus. Preferably, the micro lens array comprises plural micro lenses and the pinhole array comprises plural pinholes. In one example, a single micro lens and single pinhole are used. According to one embodiment, the probe comprises an angle tuned mirror to determine the numerical aperture of the apparatus. Embodiments of the present invention will now be described in detail with reference to the accompanying drawings, in which: Figures 1A and 1B are schematic representations of apparatus for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and / or concentration in the skin of a subject; Figure 1C shows a schematic exploded view of an integrated probe suitable for use in the systems of Figures 1A and 1B; Figures 2A to 2C show schematic representations of a slit in a spectrometer for use in the apparatus of Figures 1A or 1B; Figures 3A and 3B show schematic representations of a single hole probe for use in the apparatus of Figures 1A or 1B; Figures 4A and 4B show schematic representations of a multi-hole probe for use in the apparatus of Figures 1A or 1B; Figures 5A to 5C show schematic representations of examples of a probe comprising a light guide for use in the apparatus of Figures 1A or 1B; Figures 6A and 6B show schematic representations of an example of apparatus for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and / or concentration in the skin of a subject using a buried waveguide; Figures 7A and 7B show schematic representations of a multi-hole probe for use in the apparatus of Figures 1A or 1B; Figure 8 shows a schematic representation of a probe employing an “angle-tuned” mirror for use in the apparatus of Figures 1A or 1B; Figures 9 and 10 show examples of light guides for numerical aperture control for use in the apparatus of Figures 1A or 1B; Figure 11 shows an example of an optical device for numerical aperture control for use in the apparatus of Figures 1A or 1B; and Figure 12 shows an example of an optical device for numerical aperture control for use in the apparatus of Figures 1A or 1B; and The present system provides apparatus for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and / or concentration in the skin of a subject. The system includes one or more means for the control of the numerical aperture of a spectrometer or probe. This ensures and / or maximises the possibility of accurate determinations being made of analyte concentrations based on received Raman spectra. The system is particularly applicable in the area of planar probes in which the physical space available for control of the numerical aperture is limited. The skilled person will understand that the spectrometer can be a separate component, connected to the probe, or it can be integrated with the probe. Figures 1A and 1B are schematic representations of apparatus for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and / or concentration in the skin of a subject. The examples of Figures 1A and 1B, which will be described separately, share a number of common components which are numbered with the same reference numerals. Referring to Figure 1 A, a spectrometer the system 2 comprises a spectrometer 4 coupled to a processing system 6. The spectrometer 4 is arranged to receive a Raman signal from a probe 8. In the example shown, the probe 8 is remote from the spectrometer 4, detected by some light coupling means 10. The probe 8 in this example is generally planar, as will be discussed in greater detail below. In the example of Figure 1B, the probe 8 and the spectrometer 4 are, in effect, provided as an integrated system. As explained above, the spectrometer 4 can be a separate component, connected to the probe, or it can be integrated with the probe. The difference between the arrangements of Figures 1A and 1B lead to a number of options in the manner in which the numerical aperture of the system as a whole and the spectrometer 4 in particular can be controlled. In practice, in both cases the Raman signal received by the spectrometer 4 is detected and then provided to the processing means or system 6. The spectrometer 4 can be provided as an integrated part of the processing means or system 6 or alternatively can be provided separately from it. As is known, the numerical aperture of an optical system is a dimensionless number that characterizes which angular range of incidence light rays can be accepted by the system.. In a system without control of the numerical aperture of the spectrometer or the system as a whole, it can be difficult to control which light is incident on the spectrometer sensor, and this can make it difficult to distinguish between desired signal light from a Raman scattering event, straylight, or simply undesired extraneous light from an ambient source. The present system provides a simple and robust mechanism for control of the numerical aperture of the system as a whole which can avoid optical overfilling of the spectrometer. Although there are some similarities between the two embodiments shown in Figures 1A and 1B, there are also some significant differences. The mechanism for control of the numerical aperture can be provided either inside or on the spectrometer 4 itself or alternatively or in addition, in the probe 8. Examples of both will be described below. This distinction can be made irrespective of whether or not the spectrometer 4 is a separate component, connected to the probe, or integrated with the probe 8. As mentioned above, the probe 8 is preferably planar. This means that the overall arrangement of the probe is substantially planar such that the width of the probe, shown schematically as “X” in Figure 1A, in its entirety is between 0.5 and 10mm, and preferably between 1 and 5mm or more preferably between 1 and 3mm. Examples of planar configurations for probes are described in detail in our copending application WO2022 / 084539, referenced above. The present system is suitable for use on systems such as those described in WO2022 / 084539. Typically, the probe for provision of Raman derived radiation to a spectrometer, is an integrated probe for coupling to a spectrometer, wherein the probe is of generally planar configuration. For example, the probe typically comprises a PCB having one or more VCSELs or other light sources formed thereon and controlled to emit radiation to a sample. The PCB preferably has a slit, which in use may be arranged in alignment with a spectrometer entrance slit. If the probe and the spectrometer are not integrated together (as in Figure 1B) some form of optical connection between the probe and the spectrometer is required. The VCSELs or optical sources might typically be arranged adjacent to the longitudinal sides of the slit. The VCSELs or other optical sources are preferably controlled or controllable to operate in accordance with a SORS methodology. All of the relevant details are as disclosed in WO2022 / 084539, referenced above. Figure 1C shows an exploded side view of an integrated probe 8 that could be used as the probe in the configurations of either Figures 1A or 1B. In other words it can be provided integrated with a spectrometer (1B) or separate from it (1 A). In the example, the slit plate or PCB 146 is provided with the illumination sources 151, typically VCSELs, provided thereon. Illumination source optics 160 is provided. Typically, this could be in the form of (micro-)lenses, an optical window and optical filters for laser clean-up, such as a shortpass or bandpass filters. In addition, slit optics are provided such as a lens which, in one embodiment, could be combined with the illumination source optics 160. The overall arrangement of the probe is substantially planar such that the width of the probe in its entirety (represented schematically by the dimension “X”) is between 0.5 and 10mm, and preferably between 1 and 5mm or 1 and 3mm. An optical filter 164 is provided in the form of a Rayleigh filter. In this example, the Rayleigh filter 164 is provided behind the slit plate 146, but it will be appreciated that it can be provided on the other of the slit plate 146 as well. It will be appreciated that the probe assembly 148 is effectively planar which means that it can be provided in position on the side of the spectrometer, e.g., the spectrometer 4 in Figure 1A or 1B. The overall footprint of the system including the probe 148 and the spectrometer 4 is, in effect, substantially the same as that of the spectrometer 4 alone. Optionally, a metal slit plate 166 is provided. The metal slit plate 166 is provided to provide a control over the dimensions of the slit in the PCB or slit plate 146. For example, in situations where the slit specifications or tolerances cannot be met by PCB tooling, a metal slit plate can be attached to the system. The metal slit plate can be placed both on the top side or the back side of the PCB. In the example shown, it is provided on the back side of the PCB. Referring to Figures 2A and 2B, which could include a probe such as that shown in Figure 1C, an example is shown in which the control of the numerical aperture is provided on the spectrometer itself. In the example shown, a numerical aperture defining feature 14 is provided inside the spectrometer 4 to limit the available angle of incidence for light impinging upon the optical interface of spectrometer. Referring to Figures 2A and 2B, spectrometer 4 has a slit or opening 12 through which, in normal use, light passes for detection of its spectroscopic properties downstream at the optical interface of the spectrometer. The body of the spectrometer itself is not shown. An aperture stop 14 is provided, downstream of the entrance slit 12, which determines or limits the numerical aperture of the spectrometer 4. As can be seen, in Figure 2B, an impinging light ray 16 at one angle of incidence is within the numerical aperture as defined by the aperture stop 14, whereas an impinging light ray 18 which has a greater angle of incidence, falls outside the numerical aperture as defined by the aperture stop 14. Accordingly, the simple use of an aperture stop 14 is able to control or determine the numerical aperture of the spectrometer and thereby simply facilitate the solution to the defined technical problem. Variation of the separation Y of the NA defining feature 14 and the plane of the spectrometer entrance slit 12 can be used to determine a desired numerical aperture. Similarly, the relative dimensions of the openings of the aperture stop 14 and the spectrometer entrance slit 12 can be used to determine the value of the numerical aperture. Figures 2A and 2B show sections through the spectrometer entrance plane and the NA defining feature. The openings 12 and 14 when viewed from above could be in the form of a longitudinal slit or in the form of square or circular (or indeed any desired shape) openings consistent with the arrangement and set-up of the spectrometer. Referring to Figure 2C, an example is shown in which a numerical aperture limiting slit is provided in the probe 8 itself. The probe is generally planar and is formed of a PCB core 23 arranged between copper layers 19 and 21. Circuitry and light generating components (not shown) such as VCSELs will typically be provided arranged on the probe 8 and controlled to emit a probe laser signal. The laser signal is arranged to impinge upon a user’s skin. A Raman scattered response will be generated for detection. Light impinges on the probe from a sample under test and enters the probe through the opening 15. In this example, similar to the examples of 2A and 2B, an acceptance angle 13 is defined by the presence of openings 15 and 17 in the upper and lower layers of the probe. The upper and lower layers 19 and 21 are typically provided by metal layers. A PCB core 23 is provided between the upper 19 and lower 21 copper layers. A light absorbing region is provided by a space 25 arranged around the openings 15 and 17. One or more (or all) of the inner surfaces of the region 25 and preferably coated internally with a light absorbing material. This functions, not only to control the numerical aperture of light that can progress onto the spectrometer, but further to absorb any such light that does not fall within the numerical aperture thereby minimising the chance of straylight or light pollution from the extraneous light. The shape of the region 25 will in use be determined by and arranged to correspond with the shape of the opening 15. For example, if the opening is a longitudinal slit, the shape of the region 25 will be arranged to correspond to the shape of the slit and might, for example be shaped like a running track, when viewed from above. If the opening is circular, the shape 25 can be toroidal. Any suitable shapes, including curved slits, can be used as will be understood by a skilled person. Figures 3A and 3B show a further example of a similar arrangement to that of Figure 2C. Again, the numerical aperture limiting feature is provided in the probe. The probe can be integrated with the spectrometer as in Figure 1B, or separate from it, as in Figure 1A. In this example, an opening 20 is provided for receiving incoming light for analysis. Optical sources, such as VCSELs 22, are provided. These are arranged to emit light onto a sample under investigation. As in the example above, the light emitted from the VCSELs will then interact with the sample and generate a Raman signal which is received through the opening 20. Referring to Figure 3A, showing a sectional view along line AA’, a numerical aperture limiting feature 24 is provided, similar to the opening 14 shown in Figures 2A and 2B. In this example, the openings 20 and 24 are provided in sheets of light blocking material, such as metals which serve to absorb any light that is not transmitted through the opening 24 and onto the spectrometer. A light absorbing layer 26 is provided. The light absorbing layer 26 is arranged to absorb light that is incident upon it, i.e., light that falls outside the numerical aperture defined by the layers 12 and 14. In the example shown, a light transmission layer 32 can be provided on either side of the light of the light blocking layers 28 and 30. The transmission layers 32 provide physical protection to the device and can typically be formed of a light transmitting material such as glass, polymer or crystal. Figures 4A and 4B show a probe of similar arrangement to that of Figures 3A and 3B. Figure 4B shows a plan view and Figure 4A a cross sectional view along the line BB’. In this case, a multi-hole device is shown including multiple openings 20. Each opening 20 defines a numerical aperture limiting feature of the type described above with reference to Figures 3A and 3B. Figures 5A to 5C show an example generally consistent with the schematic example shown in Figure 1A above. In this example, referring to Figure 5C, a spectrometer 4 is provided coupled to a probe 8 by a connector such as an optical fibre 36. In the example shown, the probe 8 is generally planar with thickness X and comprises a transmissive optical window 38. An input interface 40 of the optical fibre 36 is arranged upon the window 38. The probe 8 comprises a support surface 40 which might typically be in the form of a PCB having arranged thereon optical sources 42. The optical sources 42 are arranged and configured to generate a stimulating optical output. The optical sources might typically be one or more VCSELs controlled to generate a laser output. The optical fibre 36 is arranged to couple to the spectrometer 4 and provide light to the spectrometer for spectral analysis in known ways. Referring to Figures 5A and 5B, examples of the optical fibre 36 can be seen. In each case, an end face of the optical fibre 40 is shown as would typically be arranged adjacent to the optical window 38 described with reference to Figure 5C. In the example of Figure 5A, the optical fibre includes a single fibre core 44 surrounded by a cladding 46. In the example of Figure 5B, the optical fibre includes multiple fibre cores 48 surrounded by the cladding 46. The numerical aperture of an optical fibre is a known parameter of the fibre. Accordingly, in the present examples, fibres are selected with numerical apertures that correspond to a desired numerical aperture of the spectrometer 4. Accordingly, by selection of an appropriate optical fibre, the numerical aperture of the system as a whole can be determined. In the example shown in Figure 5A, the optical fibre preferably has a rectangular cross section but, it will be appreciated, that any type of optical fibre can be used for this purpose, the only determining feature being the required numerical aperture. Referring to Figure 5B, in this example, an array of individual fibres provided within the body of the cladding 40. Each of the individual fibre components 48 is selected so as to be consistent with the desired numerical aperture of the spectrometer. The optical fibre 36 thus functions as a light guide which by its own intrinsic properties defines the numerical aperture of the system as a whole. Figures 6A and 6B show, respectively, a plan view and a cross sectional side , view (along line CC’) of another example of apparatus for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and / or concentration in the skin of the subject. In the example of Figures 6A and 6B, a spectrometer 50 is provided optically coupled to an input mirror 52 via a light guide 54. The light guide 54 is “buried” meaning it is arranged between two layers, e.g., PCB layers, or windows 56 and 58, of optical material. The windows 56 and 58 allow incoming light signal to pass to the mirror 52 which directs the incoming signal along the light guide 54. The mirror 52 is selected so as to be a focusing or a flat mirror and is arranged to direct received light into an end face 60 of the light guide 54. The light guide might typically be integrated into the window of the probe 8 shown in Figures 1A and 1B. The light guide and its dimensions intrinsically define a numerical aperture for the spectrometer 50. In other words, light that falls outside the numerical aperture of the spectrometer will be lost from the light guide such that the light that actually makes it to the output end 62 of the light guide will have the desired numerical aperture for impingement upon the spectrometer 50. Figures 7A and 7B show an example in which a micro lens array 68 is used to control the rays of incoming light that are able to pass through a numerical aperture limiting pin hole and thus impinge upon a spectrometer below. In the example shown, a pin hole array 64 is provided. The array 64 comprises a plurality of pin holes 66, each defining, in combination with a corresponding micro lens of the micro lens array 68, a numerical aperture limiting opening for the passage of incoming light. In the example shown, a plurality of openings or pinholes 66 is shown. The arrangement of a pinhole with a first and second micro lens in the manner shown in Figure 7A provides a simple and easily configurable numerical aperture limiting system. The skilled person will understand that the optical arrangement shown as an array including multiple micro lenses and pin holes 66 can in fact function 71 with only a single row of holes and corresponding single row of micro lens on either side of the pinholes 66 in the row 71. Similarly this applies to a single pinhole and single micro lens. Referring to Figure 7A, a micro lens array 68 is provided including a plurality of micro lenses 70, one arranged in alignment with each of the openings 66 in the pin hole array 64. As can be seen, due to the functioning of the lens 70 in the array 68, the incident angles of light that impinges upon the array can be selected so that light within a certain limit will be transmitted through the opening 66 whereas light that is received at an incident angle greater than some specified acceptance angle is directed into a light absorbing material. Thus, the pinhole size and micro lens properties are selected to control which rays can pass and which rays cannot. In the example shown in Figure 7A, a second micro lens array 72 is also provided. This is optional and the device can be provided without the second micro lens array 72. Where it is provided, the second micro lens array can function as a collimating element to provide a further degree of collimation for light that has been accepted by the first micro lens array 68 and the corresponding openings 66. Figure 8 shows a further example of a planar probe, of width X, having numerical aperture limiting functionality. In the example shown, the probe 74 comprises a PCB 76 upon which is arranged a plurality of optical sources 78 preferably in the form of VCSELs. An optical window 80 is provided arranged to allow transmission of outgoing light from the VCSELs 78 which can then impinge upon the skin of a user which, typically, in use would be pressed against the window 80. An angle-tuned mirror 82 is provided. The angle-tuned mirror is arranged to reflect light that is received at an angle of incidence greater than some threshold angle as indicated by the acceptance angle 84 shown in the Figure. Any light that is received by the angle-tuned mirror 82 at an angle of incidents within the acceptance cone 84 will be transmitted onwards through the spectrometer entrance slit 86 for onward processing. Light 88 that has an angle of incidence greater than the acceptance angle 84 will be reflected and will not pass to the spectrometer entrance slit 86. Thus, the use of the angle-tuned mirror 82 ensures that the numerical aperture of the spectrometer entrance slit is controlled in the manner desired and described herein. Figures 9 and 10 show examples of light guides for numerical aperture control for use in the apparatus of Figures 1A or 1B; In both cases a light guide 88 and 90 is provided. In the case of Figure 9, the light guide is a parallel sided light guide which could have square, circular, triangular or any other suitably shaped cross-section. Due to total internal reflection, and loss of light incident at angles greater than the critical angle at the longitudinal boundaries of the light guide, the numerical aperture of the light output is controlled. Light 92 at NA greater than some specified or desired value is intentionally lost. As can be seen in the example of Figure 10, the light guide 90 serves to convert light at area A1 with numerical aperture NA1 to light at area A2 with numerical aperture NA2. Figure 11 shows another example of an optical device for numerical aperture control for use in the apparatus of Figures 1A or 1B; In this example, a reversed optical concentrator is used. It serves to convert light at area A1 and numerical aperture NA1 to light at area A2 with numerical aperture NA2. The material from which the reversed optical concentrator is made can be selected as long as it has the requisite optical properties to enable reflection at its boundary as shown. In one example a void is used such that the reverse concentrator is defined by the shape of a void in a surrounding material such as any bulk material with a reflective surface. The reverse concentrator will be arranged such that the focus of the parabolic shape will be at the source of the Raman signal to be detected. Figure 12 shows an example of an optical device 94 for numerical aperture control for use in the apparatus of Figures 1A or 1B. The device 94 is a fibre optical faceplate which, through total internal reflection defines the acceptable or transmissible ray angles. Typically, the face plate consists of a thin slab of material made up of plural light guides 96. Between, or surrounding, each of the light guides 96 is an optically absorbent material 98. This has the effect of controlling the NA at the output since rays 99 that are not within the defined or specified NA are absorbed as they leave the fibres. The faceplate is preferably thin, e.g. between 0.1 and 10 mm in thickness. Preferably it is less than 3mm thick. The area or shape of the face plate can be selected to correspond to an input interface of the downstream optical device, e.g. the spectrometer itself. Embodiments of the present invention have been described with particular reference to the examples illustrated. However, it will be appreciated that variations and modifications may be made to the examples described within the scope of the present invention.

Claims

1. Apparatus for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and / or concentration, such as glucose, in the skin of a subject, the apparatus comprising;a planar probe having one or more optical sources for irradiating a sample such as the skin of a subject;a spectrometer configured to receive Raman scattered radiation collected from the sample in response to the received radiation from the one or more optical sources;a numerical aperture controller to determine the numerical aperture of the apparatus, and thereby control the input light received by the spectrometer.

2. Apparatus according to claim 1, in which the numerical aperture controller is provided as part of the spectrometer.

3. Apparatus according to claim 1 or 2, in which the spectrometer comprises an optical opening through which light to be analysed passes and in which the numerical aperture controller comprises an aperture stop within the spectrometer.

4. Apparatus according to claim 3, in which the aperture stop is shaped to correspond to the shape of the optical opening of the spectrometer.

5. Apparatus according to claim 4, in which the aperture stop and the optical opening are both holes, such as circular holes.

6. Apparatus according to any of claims 3 to 5, in which the distance between the aperture stop and the optical opening of the spectrometer is variable.

7. Apparatus according to claim 1, in which the numerical aperture controller is provided as part of the probe.

8. Apparatus according to claim 7, in which the probe comprises a PCB layer having an opening for receiving a sample-generated Raman signal, the configuration of the opening defining the numerical aperture of the apparatus.

9. Apparatus according to claim 8, in PCB layer has a light absorbing region around the opening.

10. Apparatus according to claim 9, in which the light absorbing region is a hollow region with a light absorbing coating.

11. Apparatus according to claim 10, in which the shape of the hollow region is formed to correspond to that of the opening for receiving the sample-generated Raman signal.

12. Apparatus according to claims 9 to 11, in which the PCB layer comprises upper and lower metal layers with an intermediate PCB core, the light absorbing region being formed within the PCB core.

13. Apparatus according to claims 7 or 8, in which the PCB layer comprises upper and lower light blocking layers with an intermediate PCB core, the upper and lower light blocking layers having openings of sizes selected to limit the numerical aperture of the apparatus.

14. Apparatus according to claim 13, comprising a light absorbing layer between upper and lower light blocking layers.

15. Apparatus according to any of claims 7 to 14, comprising a protective transmission layer on the upper and / or the lower light blocking layer.

16. Apparatus according to claim 15, in which each protective transmission layer is formed from a material selected from the group consisting of glass, polymer, plastic and crystal.

17. Apparatus according to claim 7, in which probe has an optical light guide interface for receiving Raman signal from a sample, and in which the numerical aperture of the optical fibre interface is selected to provide a specified value of numerical aperture.

18. Apparatus according to claim 17, in which the optical light guide comprises an optical fibre.

19. Apparatus according to claim 18, in which the optical fibre comprises a single fibre core.

20. Apparatus according to claim 18, in which the optical fibre comprises multiple fibre cores.

21. Apparatus according to claim 19 or 20, in which the or each of the optical fibre cores is rectangular in cross section.

22. Apparatus according to any of claims 17 to 21, in which the optical fibre couples the probe to the spectrometer.

23. Apparatus according to claim 7, in which probe has a buried light guide for receiving Raman signal from a sample, and in which the numerical aperture of the buried light guide is selected to provide a specified value of numerical aperture.

24. Apparatus according to claim 23, comprising a mirror for receiving a sample generated Raman signal and directing the signal into the light guide.

25. Apparatus according to claim 24, in which the mirror is a dichroic mirror.

26. Apparatus according to claim 7, in which the probe comprises a pinhole arrayand a corresponding micro lens array, in which each of the pinholes is arranged in required alignment with one or more of the micro lenses of the micro lens array, and in which the combination of the micro lens and the pinhole are selected to determine the numerical aperture of the apparatus.

27. Apparatus according to claim 26, in which the micro lens array comprises plural micro lenses and the pinhole array comprises plural pinholes.

28. Apparatus according to claim 26, in which the micro lens array comprises a single micro lens and the pinhole array comprises a single pinhole.

29. Apparatus according to claim 7, in which the probe comprises an angle tuned5 mirror to determine the numerical aperture of the apparatus.

30. Apparatus according to claim 17, in which the light guide forms part of an optical faceplate.io 31. Apparatus according to claim 30, in which the optical faceplate has a thickness between 0.1 and 10 mm..21

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