Patent Application
20240003741
The present invention relates to an apparatus and method for non-invasive in vivo measurement, by Raman spectroscopy, of glucose or other analyte present in a subject and typically in the skin of a subject. Typically, the apparatus and method is for measurement of glucose or other analyte present in the interstitial fluid in the skin of a subject. The invention also relates to a Raman probe for use in varied fields such as biochemistry, medicine, agriculture, pharmaceuticals, process control/Quality control, forensic applications and technologies, chemical production, material analysis and environmental monitoring.
The use of Raman spectroscopy for the transdermal in vivo measurement of glucose or other analyte present in skin is known. Our previous international applications WO 2018/103943 A1, WO 2016/034448 A1, and WO 2011/083111 A1 describe earlier iterations of such devices and provide details as to how they can function to determine the analyte level in the skin of a subject. Typically, the determination is made with respect to the analyte level in interstitial fluid within the skin.
The devices and methods work well and provide means for non-invasive measurement of, for example, the glucose level within a user's interstitial fluid, which correlates with the user's blood glucose level.
In general, a sample is irradiated by monochromatic light, such as light from a laser. The sample scatters the monochromatic light back to a detector which then analyses its spectrum. Usually monochromatic light that is directed at a sample is elastically scattered. However, in certain circumstances inelastic, Raman, scattering occurs. Raman scattering occurs when the monochromatic light incident on the sample is scattered back at either a higher or lower energy level than the initial energy level of the incident monochromatic light.
An increase in the energy level of scattered monochromatic light occurs when a molecule imparts some of its vibrational energy to the incident monochromatic light that is scattered. Subsequently, a decrease in the energy level of scattered monochromatic light occurs when a molecule absorbs energy from the incident monochromatic light, as vibrational energy. These increases and decreases of the energy level of scattered monochromatic light produce spectra that relate to the vibrations within molecules present in a sample. Analysis of a sample's spectrum, where Raman scattering has occurred, enables the identification of molecules present in a sample, and their concentrations.
Improvements to devices that indicate blood sugar levels of a person are desired. Speed and accuracy in determination of blood sugar levels of diabetics allows for optimal management of their blood sugar levels. Therefore, there is always a need to improve the functionality, accuracy and precision of devices that can be used to determine blood sugar levels.
WO 2006/061565 A1 describes a method and device that uses spatially offset Raman spectroscopy to measure the composition of bone in vivo.
GB 2541110 A describes a device that also uses spatially offset Raman spectroscopy. The disclosed device utilizes a rotatable prism in the optical path.
US-A-2014/171759 discloses an apparatus and method for non-invasive determination of hydration, hydration state, total body water or water concentration by quantitative spectroscopy. The apparatus is able to include non-invasive hydration measurement that can be combined with additional analyte measurement including measurement of glucose. The additional analyte measurement is obtained from the inclusion of additional sensors.
As is mentioned in WO 2018/103943 A1, miniaturisation of the device enables a user to keep the device on their person, which in turn enables them to test their blood sugar levels quickly and easily and whenever necessary. This is particularly important and useful for those with conditions such as diabetes who need regularly to have knowledge of their blood sugar levels.
According to a first aspect of the present invention, there is provided apparatus suitable for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and/or concentration, such as glucose, in the skin of a subject or for Raman spectroscopy of a sample other than human skin such that it has use other than for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and/or concentration, such as glucose, the apparatus comprising; at least one detector; one or more of vertical-cavity surface-emitting lasers spatially distributed around the at least one detector, for irradiating a sample such as the skin of a subject; wherein the at least one detector is configured to receive Raman scattered radiation transmitted from the sample in response to the received radiation from the vertical-cavity surface-emitting lasers.
The applicant has recognised that surprisingly the properties of a VCSEL make them particularly suitable for use in apparatus for non-invasive in vivo measurement, by Raman spectroscopy, of glucose present in interstitial fluid in the skin of a subject. The detector may be a suitable element or component for receiving and/or detecting the Raman scattered radiation emitted in response to incident light from the VCSELs.
In an embodiment, the at least one detector is surrounded by a plurality of VCSELs. In an embodiment, the at least one detector is surrounded by at least one ring of vertical-cavity surface-emitting lasers, i.e. it is arranged within the at least one ring of VCSELs. In another example one or more lines or linear arrays of VCSELs are arranged separated by some distance from the detector.
In an embodiment, the at least one detector is surrounded by a plurality of concentric rings of radiation sources. In this preferred embodiment, a plurality of rings of optical sources, such as VCSELs are provided. In an apparatus for in vivo measurement of analyte concentration this is particularly advantageous as it provides for the easy and repeatable selection of analysis depth, without requiring moving parts in a probe or apparatus itself. In other words, different rings or groups of optical sources e.g. VCSELs, can be arranged such that when activated they irradiate a region some determined distance from the sources or the probe if contained within a probe. For example, if the sources are arranged at an end surface or near a surface that in use will engage with a user's skin, by activating different subgroups of the sources in the apparatus the resultant point of interrogation, i.e. the point to which the optical radiation is directed can be controllably varied.
As used herein “ring” clearly is not limited to (although it does include) a geometrical circle. The rings can be square, elliptical, triangular or any other shape that generally surround the detector.
In an embodiment, the at least one detector is surrounded by a plurality of rings of vertical-cavity surface-emitting lasers.
In an embodiment, the apparatus comprises a plurality of detectors surrounded by a common ring of vertical-cavity surface-emitting lasers.
In an embodiment, the apparatus comprises a plurality of detectors surrounded by shared rings of vertical-cavity surface-emitting lasers.
In an embodiment, the vertical-cavity surface-emitting lasers are configured to provide at least two different wavelengths of radiation to irradiate a sample.
In one example, the detector(s) and source(s) are arranged such that they are placed in use on the same side of a user's skin under investigation. In another example, the detector(s) and source(s) are arranged such that they are placed in use on the opposite side of a user's skin under investigation.
In an embodiment, the apparatus includes a temperature sensor to control or monitor the VCSEL temperature. Knowledge of the VCSEL temperature is enables the recorded spectra to be adjusted in accordance with the excitation wavelength (due to the relationship between VCSEL temperature and VCSEL wavelength).
In an embodiment, the apparatus further includes means for temperature stabilization of the VCSELs such as, say, a thermoelectric cooler, so as to avoid excitation wavelength drift.
In one example, with or without use of temperature stabilization, the excitation wavelength is tracked by use of a spectrometer. If drift is detected the recorded spectra can be adjusted in dependence on the excitation wavelength. The excitation wavelength can be stabilized by control of VCSEL temperature and/or the applied driving current or signal.
According to a second 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 a sample such as the skin of a subject, or for Raman spectroscopy of a sample other than human skin such that it has use other than for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and/or concentration, such as glucose, the apparatus comprising; at least one radiation source, for irradiating a sample such as a the skin of a subject; and a plurality of detectors spatially distributed around the radiation source, wherein the plurality of detectors are configured to receive Raman scattered radiation from the sample in response to the received radiation from the at least one radiation source.
In an embodiment, the at least one radiation source is a vertical-cavity surface-emitting laser.
In an embodiment, the at least one radiation source is surrounded by at least one ring of detectors. In another example one or more lines or linear arrays of detectors are arranged separated by some distance from the radiation source.
In an embodiment, the at least one radiation source is surrounded by a plurality of rings of detectors.
In an embodiment, the apparatus comprises a plurality of radiation sources surrounded by at least one ring of detectors.
In an embodiment, the apparatus comprises a plurality of radiation sources surrounded by a shared plurality of rings of detectors.
In an embodiment, the radiation sources are configured to provide at least two different wavelengths of radiation to irradiate a sample.
In an embodiment, the apparatus further comprises an analysis unit configured to analyse the detected Raman spectrum and infer glucose levels within a sample.
In an embodiment, the analysis unit is further configured to eliminate background radiation and highlight the Raman spectrum of a sample.
In an embodiment, the apparatus comprises a focusing device for focusing the spectrum of Raman scattered radiation transmitted back from the sample for detection.
In an embodiment, the focusing device comprises of at least one optical lens.
In an embodiment, the at least one optical lens is a convex lens.
In an embodiment, the focusing device comprises a plurality of optical lenses.
In an embodiment, the plurality of optical lenses comprises a plurality of convex and/or concave lenses.
In an embodiment, a fibre or fibre bundle is used to receive the Raman scattered radiation transmitted back from the sample.
In an embodiment, the focusing device comprises at least one mirror.
According to a third aspect of the present invention, there is provided a method for non-invasive in vivo measurement, by Raman spectroscopy, of analyte presence and/or concentration, such as glucose, in the skin of a subject or for Raman spectroscopy of a sample other than human skin such that it has use other than for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and/or concentration, such as glucose, the method comprising; using the apparatus of any of the previous claims to detect and measure the spectrum of Raman scattered radiation from a sample such as the skin of a subject; and analysing the spectrum of the detected Raman scattered radiation to determine the presence and/or concentration of analyte in the sample such as the skin of a subject.
In an embodiment, the method comprises controlling the vertical-cavity surface-emitting lasers to vary collection depth of the Raman scattered radiation.
In an embodiment, the method comprises executing an algorithm to determine the Raman spectrum in dependence on the respective positions of the at least one radiation source and at least one detector relative to the position of the sample.
In an embodiment, the method comprises executing the algorithm to eliminate background fluorescence.
In an embodiment, the algorithm utilizes Shift-Excitation Raman Difference Spectroscopy (SERDS).
In an embodiment, the method comprises: eliminating non-Raman background fluorescence by comparing the shifts in spectral peaks of observed scattered radiation from a sample, irradiated by at least two different wavelengths; removing spectral features, such as spectral peaks, that do not shift between the spectra created by the at least two difference wavelengths of radiation; and analysing remaining spectral peaks, for the presence of analyte within the sample.
According to a fourth 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; at least one detector a radiation source for irradiating the skin of a subject, spatially distributed around the at least one detector; wherein the at least one detector is configured to receive a spectrum of Raman scattered radiation transmitted back from the sample in response to the received radiation from the radiation source. The apparatus is also suitable for Raman spectroscopy of a sample other than human skin such that it has use other than for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and/or concentration, such as glucose.
According to a further aspect of the present invention, there is provided apparatus for non-invasive in vivo measurement, by Raman spectroscopy, of glucose present in interstitial fluid in the skin of a subject, the apparatus comprising; a plurality of radiation sources, for irradiating a sample in the skin of a subject; and at least one detector; wherein the plurality of radiation sources are spatially distributed around the at least one detector; and wherein the at least one detector is configured to receive a spectrum of Raman scattered radiation transmitted back from the sample in response to the received radiation from the at least one radiation source. The apparatus is also for Raman spectroscopy of a sample other than human skin such that it has use other than for non-invasive in vivo measurement by Raman spectroscopy of analyte presence and/or concentration, such as glucose.
In an embodiment, the plurality of radiation sources are vertical-cavity surface-emitting lasers. As is known, a VCSEL is a laser that generates beam emission perpendicular to a top surface, contrary to conventional edge-emitting semiconductor lasers which emit from surfaces formed by cleaving an individual chip out of a semiconductor wafer. The applicant has recognised that surprisingly the properties of a VCSEL make them particularly suitable for use in apparatus for non-invasive in vivo measurement, by Raman spectroscopy, of glucose present in interstitial fluid in the skin of a subject.
In an embodiment, the at least one detector is surrounded by at least one concentric ring of radiation sources. The dimensions and vertical emission surface of a VCSEL makes them particularly suitable for use in an arrangement such as a ring of optical sources to provide incident light in an apparatus for non-invasive in vivo measurement, by Raman spectroscopy, of glucose or other present in the skin of a subject.
Again, as used herein “ring” clearly is not limited to (although it does include) a geometrical circle. The rings can be square, elliptical, triangular or any other shape that generally surround the detector. As mentioned above, in another example one or more lines or linear arrays of radiation sources such as VCSELs can be used separated from the detector.
In an embodiment, there are a plurality of detectors that are surrounded by at least one concentric ring of radiation sources.
In an embodiment, there are a plurality of detectors that are surrounded by a plurality of concentric rings of radiation sources.
In an embodiment, the radiation sources are configured to provide at least two different wavelengths of radiation to irradiate a sample.
According to a further aspect of the present invention, there is provided apparatus for non-invasive in vivo measurement, by Raman spectroscopy, of glucose present in interstitial fluid in the skin of a subject (or for other uses as in the aspects mentioned above), the apparatus comprising; at least one radiation source, for irradiating a sample in the skin of a subject; and a plurality of detectors; wherein the plurality of detectors are spatially distributed around the at least one detector; and wherein the plurality of detectors are configured to receive a spectrum of Raman scattered radiation transmitted back from the sample in response to the received radiation from the at least one radiation source.
In an embodiment, the at least one radiation source is a vertical-cavity surface-emitting laser. The applicant has recognised that surprisingly the properties of a VCSEL make them particularly suitable for use in apparatus for non-invasive in vivo measurement, by Raman spectroscopy, of glucose present in interstitial fluid in the skin of a subject.
In an embodiment, the at least one radiation source is surrounded by at least one concentric ring of detectors. Each of the detectors may be simply an optical interface arranged to receive radiation and couple it onwards for analysis, and/or they could be a photosensitive component such as a photodiode or a component of a CCD to determine the intensity and wavelength of incident light. In the case of an optical interface, they can include one or more filters as required or desired.
In an embodiment, the at least one radiation source is surrounded by a plurality of concentric rings of detectors. As above, “ring” clearly is not limited to (although it does include) a geometrical circle. The rings can be square, elliptical, triangular or any other shape that generally surround the optical source.
In an embodiment, there are a plurality of radiation sources that are surrounded by at least one concentric ring of detectors.
In an embodiment, there are a plurality of radiation sources that are surrounded by a plurality of concentric rings of detectors.
In an embodiment, the radiation sources are configured to provide at least two different wavelengths of radiation to irradiate a sample.
In an embodiment, the apparatus further comprises an analysis unit configured to analyse the detected Raman spectrum and infer glucose levels within a sample.
In an embodiment, the analysis unit is further configured to eliminate background radiation and highlight the Raman spectrum of a sample. A filter such as a Rayleigh filter is preferably used for this purpose.
In an embodiment, there is a focusing device for focusing the spectrum of Raman scattered radiation transmitted back from the sample for detection. In an embodiment, the focusing device comprises of at least one optical fibre.
In an embodiment, the focusing device is comprised of at least one optical lens.
In an embodiment, the at least one optical lens is a convex lens.
In an embodiment, the focusing device is comprised of a plurality of optical lenses.
In an embodiment, the plurality of optical lenses is a plurality of convex and/or concave lenses.
In an embodiment, the focusing device is comprised of at least one mirror.
In an embodiment, the at least one mirror is a concave mirror.
In an embodiment, the focusing device is comprised of a plurality of mirrors.
According to a further aspect of the present invention, there is provided a method for non-invasive in vivo measurement, by Raman spectroscopy, of glucose present in interstitial fluid in the skin of a subject (or for other uses as in the aspects mentioned above), the method comprising; using the apparatus of any of the previous claims to detect and measure the spectrum of Raman scattered radiation from a sample in the skin of a subject; and analysing the spectrum of the detected Raman scattered radiation to determine the concentration of glucose present in the interstitial fluid in the skin of a subject.
In an embodiment, an algorithm is used to improve the accuracy and precision of the analysis of the spectrum of the detected Raman scattered radiation based on the respective positions of the at least one radiation source and at least one detector relative to the position of the sample.
In an embodiment, the algorithm also applies a technique for fluorescence background elimination.
In an embodiment, the technique for fluorescence background elimination eliminates non-Raman background fluorescence by comparing the shifts in spectral peaks of observed scattered radiation from a sample, irradiated by at least two different wavelengths of radiation, and removing any spectral peaks that do not shift between the spectra created by the at least two difference wavelengths of radiation, and to analyse the remaining spectral peaks, that shifted, for the presence of glucose within a sample.
In WO 2006/061565 A1 there is no discussion of spatially distributing radiation sources around the detector, or spatially distributing detectors around the radiation source.
GB 2541110 A does not discuss spatially distributing radiation sources around the detector, or spatially distributing detectors around the radiation source.
Accordingly, the present system and method provides the benefits of spatially offset Raman spectroscopy, but in a compact device that is more convenient to a user as it allows them to check their blood sugar levels when necessary, throughout the day, wherever they may be.
According to a further 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 (or for other uses as in the aspects mentioned above), the apparatus comprising; at least one detector; a controllable VCSEL radiation source spaced from the at least one detector, for irradiating the skin of a subject with light, and being configured to selectively change the wavelength of the light in accordance with a SWEPT Source Raman methodology; a bandpass filter to receive Raman scattered radiation transmitted back from the sample; a processor to generate a Raman spectrum from the received Raman scattered radiation.
In the current applicant's International application number WO2011/83111 (granted in many jurisdictions) there is described a method and apparatus for non-invasive in vivo measurement by Raman spectroscopy of glucose present in interstitial fluid in skin. Amongst other aspects there is described apparatus for non-invasive in vivo measurement by Raman spectroscopy of glucose present in interstitial fluid in the skin of a subject, comprising a light source, optical components defining a light path from said light source to a measurement location, a light detection unit, optical components defining a return path for Raman scattered light from said measurement location to said light detection unit, and a skin engaging member having a distal surface for defining the position of said optical components defining the return path with respect to a surface of said skin in use, and wherein said optical components defining a return path for Raman scattered light selectively transmit to said light detection unit light scattered from near said measurement location such that at least 50% of Raman scattered light received at the light detection unit originates at depths from 60 to 400 μm beyond said distal surface of the skin engaging member.
There is a desire to further miniaturise the spectrometer probe used in such devices.
According to a further aspect of the present invention, there is provided apparatus for in vivo measurement, such as 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 spectrometer having a slit for receiving a Raman spectrum from a sample; an integrated probe for coupling to the spectrometer, wherein the probe is of generally planar configuration.
In an example, the integrated probe comprises a PCB having arranged thereon plural optical sources and arranged around the slit of the spectrometer.
In an example, the plural optical sources are VCSELs.
In an example, the PCB comprises a window and the optical sources are arranged around the window.
In an example, plural rows of VCSELs are provided on either side of the window.
In an example, the apparatus comprises directing optics to control the distance of the focal point of the optical sources from the plane of the planar integrated probe.
In an example, the apparatus comprises source optics arranged for controlling the transmission of light from the optical sources.
According to a further aspect of the present invention, there is provided an integrated probe for coupling to a spectrometer, for in vivo measurement, such as non-invasive in vivo measurement, by Raman spectroscopy of analyte presence and/or concentration, such as glucose, in the skin of a subject, wherein the probe is of generally planar configuration.
There is also a desire to have a Raman probe that is compact and easy to use in varied technical fields.
According to a further aspect of the present invention, there is provided apparatus for Raman spectroscopy, the apparatus comprising; a spectrometer having a slit for receiving a Raman spectrum from a sample; an integrated probe for coupling to the spectrometer, wherein the probe is of generally planar configuration.
According to a further aspect of the present invention, there is provided a Raman probe for provision of Raman derived radiation to a spectrometer, the probe being an integrated probe for coupling to a spectrometer, wherein the probe is of generally planar configuration. Preferably the probe comprises a PCB having one or more VCSELs or other light sources formed thereon and controlled to radiation to a sample. The PCB preferably has a slit, which in use may be arranged in alignment with a spectrometer entrance slit. The VCSELs or optical sources are preferably 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 the SORS methodologies described herein.
Embodiments of the present invention will now be described in detail with reference to the accompanying drawings, in which:
The arrangement shown will typically be provided as part of a system, described in general below with reference to schematic view of
The arrangement 14 will typically be provided as part of a probe, as shown in
The laser source 10 of the SORS arrangement 14 is most preferably a vertical-cavity surface-emitting laser (VCSEL) which enables miniaturisation of the device without any loss of functionality.
The detectors 12 of the SORS arrangement 14 are a means for communicating the detected Raman signal to one or more spectrometers or in combination work as spectrometers. A spectrometer is an optical apparatus that works by separating the light beam directed into the optical apparatus into different frequency components and subsequently measuring the intensity of these components by using analysis devices such as CCD detectors, CCD arrays or any other suitable light capturing device.
The detectors 12 are shown in the example of
In another example, one or more detector strips may be provided, e.g. two parallel detector strips on either side of the optical source 10 are provided. The, or each of the, detector strips may be provided as straight line linear detector strips or curved detector strips, each provided some separation from the optical source 10. One could be curved and another straight. It will be appreciated that the detectors 12 can function simply as receivers arranged to receive and couple the Raman signal onwards for analysis. The detectors 12 could include circuits or componentry to enable the detectors themselves to determine the spectrum from the received radiation.
The arrangement 24 will typically be provided as part of a probe, as shown in
The detector 20 could be the end face of an optical fibre or an optical fibre bundle comprising multiple fibres. Preferably some optical arrangement such as a lensing arrangement is provided on the end of the fibre or fibre bundle to communicate the received light into the fibre bundle for onward coupling to a processor or spectrometer, as described above with reference to
The Raman detector 20 of the inverse SORS arrangement 24 is preferably a spectrometer or is coupled to one to enable a determination of the Raman spectrum to be made.
The rings of laser sources 22 of the inverse SORS device 24 can include any suitable form of laser emitting device. However, to improve the miniaturisation of the device the laser sources 22 are preferably VCSELs. Typically, the dimension of the probe and or arrangement is such that it is easily and ergonomically usable by an individual. In practice, the diameter of the outer rings shown in each of
The optical arrangement described herein provides a number of advantages. The use of VCSELs facilitates the collection of Raman signal from a larger volume which means that the system as a whole is less sensitive to skin variation, such as skin thickness variation. In the example in which a plurality of VCSELs are provided, preferably in rings of some shape, it is possible to vary collection depths without actually having to move anything within the probe. Simply activating a different selection of the VCSELs will stimulate Raman signal within a user at different locations or depths. Finally, the use of VCSELs enables the reduction in the probe of other optical elements such as focusing hardware and the like.
The lens 30 is arranged to receive Raman scattered radiation generated by the incident radiation from the VCSELs 32 and focus it for onward transmission to a detector or a spectrometer for further analysis.
The focusing device 30 is preferably but not limited to being a collection optic which refracts the received Raman scattered light for onward transmission. The focusing device 30 may also include or consist of one or more of a mirror, a group of interconnected mirrors, an array of collection optics, or a combination of mirrors and collection optics, and filters.
In order to infer the concentration of glucose in the sample of a subject the openings of any of the previous arrangements 14, 24, or 34 in combination with the features of
The Raman detectors 12 or Raman detector unit 20 then communicates the received Raman signal onwards for analysis of the spectra received for the presence of glucose in the sample, and provides an indication of, say, the blood glucose level in the sample to the subject.
Referring to
Preferably the processing unit 46 includes a display 48 which functions as a GUI to indicate a reading or result to a user when a test is done using the system. In one example the processing unit is entirely electrical without optical functionality. The optical componentry and processing is all integrated and incorporated within the probe 40. This is achievable due to the use of VCSELs enabling miniaturisation of the optics. Thus, the cabling 44 is electrical, communicating control signals and data between the probe 40 and the processing unit 46.
In another example, the probe 40 includes VCSELs but the spectrometer or CCD devices that might be used are housed within the processing unit, such that the cabling 44 includes one or more optical fibres as well as electrical cabling for power and/or signalling.
In the example shown, a temperature sensor (or sensors) 47 is provided as part of the probe 40. The temperature sensor 47 is coupled to the processing unit 46 via conductor 49. The temperature sensor is arranged and configured to measure the temperature of the VCSELs provided within the probe, and preferably arranged to couple the measured temperature to the controller 46. If required, the VCSEL temperature is mapped/converted to an excitation wavelength and if necessary, the recorded spectra are adjusted in accordance with the excitation wavelength.
Furthermore, in an example, temperature stabilization of the VCSELs is enabled by use of, say, a thermoelectric cooler, so as to avoid excitation wavelength drift.
In one example, with or without use of temperature stabilization, the excitation wavelength is tracked by use of a spectrometer. If drift is detected the recorded spectra can be adjusted in dependence on the excitation wavelength. The excitation wavelength can be stabilized by control of VCSEL temperature and/or the applied driving current or signal.
In an embodiment an algorithm is used to analyse the received Raman spectrum to determine the concentration of glucose or some other analyte. If the signal comes from the skin it is likely that it will indicate the concentration of glucose within the interstitial fluid rather than directly in the blood, but this corresponds closely to the level of glucose in the blood albeit with a small time shift. The algorithm, known as dual wavelength shift-excitation Raman Difference Spectroscopy is used. The difference between the two wavelengths is typically less than 5 nm and preferably about 1 nm. The method enables use of a VCSEL probe as described herein arranged to provide background fluorescence elimination. In a general sense this is done with the use of two incident wavelengths. VCSELs are provided having two different transmission wavelengths and due to their small size it is possible to arrange them all within the system as described above with reference to any of
As follows from Kasha's rule, the shift-excitation wavelength for fluorescence background elimination is unaltered for small changes in excitation photon energy, while the generated Raman spectrum does shift according to the excitation photon energy change. Thus, by subtraction of two spectra from each other, acquired with slightly different excitation wavelengths, provides for the elimination of the background florescence while a Raman difference spectrum remains.
In other words, the algorithm for fluorescence background elimination, eliminates non-Raman background fluorescence by comparing the shifts in spectral peaks of observed scattered radiation from a sample, irradiated by at least two different wavelengths of radiation by the laser sources. This enables isolation of the shifted signal, for analysis of the presence of glucose or some other analyte with the sampled volume. In an example this is achieved by providing the optical sources, such as VCSELs, in a distributed way around the detector. Different groups of the individual optical sources are activated such that the target is sequentially irradiated by radiation of the two different wavelengths. In an example where the optical sources are arranged in one or more rings, any one of the one or more rings may be made up of optical sources in which every other optical source has the same transmission wavelength. If three different wavelengths are used, every third optical source will have the same transmission wavelength.
If the optical sources are not arranged in rings, but, say, in a two dimensional array of rows, every other row, may be arranged to have the same transmission wavelength, with intervening rows having some other transmission wavelength. Alternatively, in one example, an even greater degree of variation is achieved in that every other optical source in both X and Y directions is arranged to have the same wavelength and every other optical source to have some common but different, wavelength.
Where, say, plural rings of sources are used, the different rings may be arranged each to have their own different transmission wavelength. Alternatively, in another example, every other ring is arranged to have the same first transmission wavelength, with the intervening rings having some same but different transmission wavelength from the first transmission wavelength.
In a further example, a SWEPT Raman probe is provided using VCSELs as the optical source. An array of VCSELs having a wavelength range of some desired value is provided. The exact number of wavelengths can be varied as per application, but typically a spectral range of, say, 750 to 960 nm, 750 to 860 nm or 850 to 960 nm is provided. A wavelength step is selected and a bandpass filter provided at some value from the original excitation wavelength. The Raman spectrum can then be reconstructed using known SWEPT Raman methodologies
In general, the use of VCSELs facilitates the creation of a SWEPT Raman probe for use in determining in vivo concentrations of analyte in a user's skin.
Looking now at
A detection cone 84 is shown schematically. Again, as above, Raman signals generated within the detector acceptance cone and that is directed towards the detector can be detected and used to produce the Raman spectrum for the sample.
Each of the VCSELs in the first and second pluralities 80 and 82 are preferably arranged and controlled to provide collimated beams or part-collimated beams and are arranged to be controlled independently. By turning on and off different VCSELs within the first and second pluralities, the Raman signal generated in different volumes within the skin or subject can be collected.
In this example, a number of detectors D1 are provided each having an acceptance cone. The acceptance cones 94 are arranged to intersect the illumination region of a divergent VCSEL source 96. Thus, the use of plural detectors ensures that the signal collected from different areas within the illumination cone 98 of the VCSEL source 96 can be distinguished. Furthermore, understanding can be gained regarding the depth or general location of the optical source due to the use of multiple detectors 97.
In this example, plural detectors 1001, 1002 and 1003 are provided. An optical connection is provided between each of the detectors and a spectrometer entrance slit 102. The arrangement of the inputs from each of the optical fibres 101 within the spectrometer entrance slit is controlled and fixed such that the spectrum produced by each of the signals from the respective fibres 1011 to 1013 can be easily identified.
With the use of a divergent VCSEL source 104 the arrangement can be used to obtain accurate depth information relating to the location origin of a particular spectrum. For example, if the spectrum of D3 is subtracted from the spectrum derived from detector D2 then information regarding the sample within the depth region 106 can be determined. Similarly, other determinations can be made by subtraction of particular pairs of combinations of spectra.
As explained above, the use of VCSELs or other such similar optical sources enables the miniaturisation of the probe and the use of such methodologies as SORS or inverse SORS. One further particular advantage of the use of optical sources such as VCSELs in an optical probe for the in vivo measurement of analyte concentration is the integration of the VCSELs into or around a spectrometer entrance slit as will now be described in detail.
The present embodiment provides an integrated probe in which a spectrometer entrance slit is provided and the probe as shown in
Preferably, the illumination sources are provided in the form of VCSELs although other possible illumination sources could also be provided. The illumination can consist of a single source or multiple sources. In a preferred example, the illumination sources comprise paired sources in order to generate an excitation source with specific optical specifications.
As will be described below, optical elements like lenses, optical flats and the like can be placed in front of the illumination sources and/or the spectrometer entrance slit. Such an arrangement including the appropriately sized and configured miniaturised optical components in combination with the optical sources such as the VCSELs still provides for what may be described as an integrated probe. The contrast can be noted markedly in, say, a comparison of
The illumination sources can consist of two or more individual groups, or single sources, which can be individually controlled. Each group can have specific individual specifications in order to support Raman spectroscopic techniques such as stimulated Raman scattering (SRS), coherent anti-stokes Raman scattering (CARS), shift excitation Raman difference spectroscopy (SERDS) and swept source Raman (SSR) spectroscopy. As discussed herein, the expression “integrated probe” will be used since the probe shown in, say
The illumination sources are preferably arranged in configurations by taking advantage of the spatial offset between the illumination and collection optic based on the SORS principle described above, thereby allowing depth-sensitive probing. Indeed, the operation and control of the integrated probe including the VCSELs or other optical sources can be as shown in and described above with reference to any of
Looking at
A Raman signal is generated in response to activation of a laser 120 which is directed via optics 122 such as a beam splitter to impinge upon a sample 124. A contact surface 126 may be provided in the form of a transmissive window through which the laser beam travels. The laser beam impinges on the sample 124 and interacts with it generating a Raman spectrum which is transmitted via other optics including a filter 128 and one or more lenses 130 to the spectrometer entrance slit 118. Within the spectrometer, optics 132 are provided which may typically include one or more lenses and/or mirrors and a grating so as to direct the received spectrum onto a detector 134 such as a CCD detector.
The system now to be described integrates the functionality of the probe system 114 into the spectrometer and on or around its slit thereby facilitating miniaturisation and simplification of the apparatus.
Referring to
Referring to
The integrated probe system comprises a slit plate 146 provided with a slit 148 and a plurality of illumination sources 151 provided thereon. Preferably, the illumination sources 151 are VCSELs although other integrated illumination sources can be used. Typically, the slit size will be dictated by any or all of requirements for spectral resolution, throughput and spectrometer complexity. Typically though, slit dimensions might be between 10 and 200 micrometres wide and between 800 and 1600 micrometres long. Thus, the size and scale of the slit in comparison to the probe system 114 shown in
The control system includes a controller 152 which is typically a microprocessor or an ASIC. The controller 152 is coupled to a laser driver/controller 154 which itself is coupled to the VCSELs 156. A power supply 158 is provided to provide operating power to the laser driver/controller. Typically, the components illustrated schematically in
The components of the control system, as shown schematically in
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 150 in
Referring again to
Reformatting optics 170 can be provided. The reformatting optics is in the form a lens and is used to maximise the throughput and magnify the scattered distribution onto the existing slit 172. Typically, this boosts throughput by at least 10%. Precision alignment will be required between the assembly and the existing slit of the spectrometer.
The VCSEL wafer 168 including the transparent window 174 is shown as a merely exemplary configuration for the integrated probe.
It is possible that the VCSEL wafer 168 is provided in two sections, one on either longitudinal side of the transparent window 174 and they are then machined or connected together with the transparent window 174 in a known manner.
The spectrometer slit is typically dimensioned such as to have a width of 100 micrometres and a length of 1300 micrometres and a numerical aperture of 0.22.
The optical flux of each emitter in this example is typically 1.5 mW representing a total optical flux of 306 mW. Preferably the wavelength is between 760 and 850 nanometres although VCSELs of any desired wavelength can be chosen for use in the system. The indication of wavelength ranges given above applies equally here.
The VCSEL packages 184 are arranged on either side of the slit. In this example, the slit is typically 1500 micrometres long and 100 micrometres wide.
As can be seen, the PCB is arranged on a backing plate 186 and aligned with an opening 190 therein.
The generally flat upper surface is coated with a long pass filter and represents the spectrometer entrance slit. A VCSEL block or die 198 is provided on each side of the slit. Each VCSEL die 198 includes a VCSEL array with possible micro optics 210 arranged on top of them. Transmitted light from the VCSEL array passes through inlet surface 200 on an underside of an overhang within the optical element 195. Angled surfaces 202 totally internally reflect the light for onward transmission to the sample 192. Semiconductor pads 204 and 206 are arranged on the support surface 208. The VCSELS will be operated by control circuitry (not shown) which will be connected to the pads. The arrangement of
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.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2016873.8 | Oct 2020 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/079414 | 10/22/2021 | WO |
