Analyte detection device and method of detecting an analyte

Abstract

The invention provides an analyte detection apparatus and method, the apparatus comprising: a source of radiation for illuminating a sample; a receiver receiving an optical Raman spectrum of radiation transmitted back from the sample in response to radiation received from the source, wherein the receiver comprises a plurality of different types of analysis device, each analysis device arranged to receive a selected portion of the received spectrum transmitted back from the sample.

Description

[0001] This application is a divisional application of the invention patent application filed on October 24, 2017, with application number 201780085569.4 and entitled "Analyt detection device and method for detecting analytes".

[0002] This invention relates to an analyte detection device and a method for detecting analytes.

[0003] Raman spectroscopy is known for its use in transdermal in vivo measurements of glucose or other analytes present in the skin. In co-pending international application WO-A-2016 / 034448, a confocal detector device with at least one component is described, intended for measuring the concentration of glucose in tissue fluid by detecting and measuring Raman scattered radiation from the sample after irradiating the user's skin with optical radiation. This device operates well and provides a means for non-invasive measurement of blood glucose levels in a user's tissue fluid, which is correlated with blood glucose levels.

[0004] Most known systems that use Raman spectroscopy to measure or determine analyte concentrations are often bulky and static. In the field of blood glucose determination using Raman spectroscopy, miniaturization is desirable because when provided in a suitably miniaturized form, the device becomes convenient and easy to use for diabetic patients who often need to determine their blood glucose levels multiple times a day (directly or otherwise).

[0005] WO2012019102 discloses a portable Raman diagnostic system. This system involves the selection of specific filter combinations that can provide information for multivariate calibration to extract analyte concentrations in biological systems. The system in WO2012019102 utilizes wavelength range selection methods to attempt and minimize the size of the test equipment. Various wavelength selection methods and miniaturized spectroscopic device designs are disclosed, along with the tools required to map from one domain (wavelength selection) to another (design parameters).

[0006] In a paper titled “Non-invasive BloodGlucose Monitoring with Raman Spectroscopy: Prospects for Device Miniaturisation”, published by MSWrobel as part of the 39th International Microelectronics and Packaging (IMAPS) conference in Poland in 2015, several photodetectors are disclosed for detecting optical signals at specified wavelengths within the received Raman spectrum.

[0007] US-A-5701005, US-A-7511255, US-A-5424826, US-A-2006 / 0262303, US-A-2013 / 0289414, and US-A-4997281 disclose optical systems including spectrometers and / or optical filtering devices. Many of these are used within systems that rely on Raman spectroscopy to determine information about a sample.

[0008] Examples of other analytes or metabolites (miniaturized Raman devices would be useful for measuring their concentrations) include any one or more of lactic acid, fatty acids, urea, carbamate, cholesterol, or hemoglobin.

[0009] According to a first aspect of the invention, an analyte detection apparatus is provided, the apparatus comprising: a radiation source for irradiating a sample; and a receiver for receiving a spectrum of radiation transmitted back from the sample in response to radiation received from the source, wherein the receiver comprises a plurality of analytical devices of different types, each analytical device arranged to receive a selected portion of the received spectrum transmitted back from the sample. The spectrum of radiation transmitted back from the sample is typically a Raman spectrum.

[0010] An analyte detection apparatus is provided that includes more than one type of analytical device. This means that different portions of the received spectrum can be fed or coupled accordingly to different types of analytical devices, and in particular to analytical devices that can have different levels of resolution and / or signal-to-noise ratio. Thus, multiple portions of the received spectrum considered important to the analyte in question can be coupled to a first type of analytical device with high resolution and / or high signal-to-noise ratio, while a portion of the spectrum requiring coarser information can be coupled to a second type of analytical device providing lower resolution and lower signal-to-noise ratio.

[0011] This means that a device can be provided overall that can output data with sufficient detail and level of analyte without requiring multiple high-resolution analytical instruments. This implies that the overall device can be smaller and / or more affordable without resulting in output data of unacceptably low quality or resolution. In other words, the same level of high-quality data can be provided about multiple portions of the spectrum considered important, while the device used to provide that data can be simpler, less expensive, and smaller in physical size.

[0012] In other words, this device has the potential to further miniaturize Raman spectroscopy-based blood glucose meters. This would benefit diabetic patients or other patients who may need to measure their blood glucose and would appreciate a portable device.

[0013] In one embodiment, the apparatus includes one or more filtering devices arranged to filter the received spectrum and direct designated components to a specific analytical device among the plurality of different types of analytical devices.

[0014] Using a filtering device allows the received spectrum to be easily and efficiently separated into desired components or wavelength regions. This also enables each spectral sub-region to be directed to an accurate and specified analytical device. Therefore, the received spectrum is subdivided into multiple regions by a filtering device, and then each subdivided region is routed to a specific analytical device.

[0015] In one embodiment, the filtering device includes at least one tunable filtering device. Providing a tunable filtering device enables selective configuration of the device, thus allowing it to be tuned to analyze desired analytes. Each analyte that may be studied will have its own Raman spectrum, and therefore the region of interest may differ across the entire received spectrum.

[0016] In one embodiment, the tunable filter device includes a filter element that is tunable by changing the angle of incidence (AOI) on the filter device. In another embodiment, the tunable filter device includes a filter element that is tunable by filter displacement (linear variable filter). In this type of filter, the transmission window is displaced relative to the lateral position of the filter. In another embodiment, an acousto-optic (electro-optic) tunable filter is used. In some embodiments, any combination of different types of filter elements may be used.

[0017] Another example is a filter element that periodically modulates the refractive index of a crystal by passing high-frequency acoustic waves generated by a piezoelectric transducer. In this type of device, the frequency of the wave generated by the piezoelectric transducer determines the refractive index modulation period, which in turn determines the wavelength of the diffracted light.

[0018] In one implementation, the different analytical devices include at least one CCD-based spectrometer.

[0019] In one implementation, the different analytical devices include at least one CMOS-based spectrometer.

[0020] According to a second aspect of the invention, a method for detecting an analyte is provided, the method comprising: irradiating a sample with optical radiation; receiving a spectrum of radiation emitted back from the sample in response to radiation received from the source; and selectively coupling different portions of the received spectrum to different analytical devices. The spectrum of radiation emitted back from the sample is typically a Raman spectrum.

[0021] In one embodiment, the method includes: filtering the received spectrum into two or more components; and coupling a first component of the two or more components to a first analytical device and coupling a second component of the two or more components to a second analytical device.

[0022] In one embodiment, the first analytical device includes a CCD-based spectrometer.

[0023] In one embodiment, the second analytical device includes a CMOS-based spectrometer.

[0024] Embodiments of the present invention will now be described in detail with reference to the accompanying drawings, in which:

[0025] Figure 1 This is a schematic diagram of the Raman shift spectrum of an irradiated skin sample.

[0026] Figure 2 This is a schematic diagram of a device used for analyte detection;

[0027] Figure 3 For use in Figure 2 A schematic diagram of the filter structure in the device.

[0028] As is known, the basis for spectral setup is the light source used to illuminate the sample, such as a laser. The light from the light source interacts with the sample and often causes changes in the light transmitted through the sample, emitted by the sample, reflected by the sample, and / or scattered by the sample. By collecting the changed light and analyzing its spectral distribution, information related to the interaction between the incident light and the sample can be obtained. Therefore, information related to the molecular composition within the sample can be obtained.

[0029] One mode of interaction between incident light and molecular composition is Raman scattering, in which energy is exchanged between molecules and photons of the incident light. The frequency (i.e., spectral distribution) of the Raman-scattered light will differ from the frequency of the incident light and uniquely reflect molecules at specific oscillation levels; therefore, it is a fingerprint. This can be used to identify the molecular composition of the substance being probed and / or the concentration of specific molecules within the substance.

[0030] The spectrum sent back from the sample can be called the received spectrum because it can be processed or analyzed after being received by the receiver to obtain information about the sample.

[0031] The co-pending application WO-A-2016 / 034448 describes an optical configuration and apparatus that enables results to be obtained by specifying a depth within a sample, among other factors, from which radiation detected is to be analyzed. Indeed, as illustrated, WO-A-2016 / 034448 teaches that ensuring the Raman scattered light collected for measurement originates from or near a specific depth within the skin can provide some advantages.

[0032] The entire contents of WO-A-2016 / 034448 are incorporated herein by reference, including but not limited to specific aspects of depth within a sample retrieved from data, and the optical and physical configuration of the interface or lens between the sample and the device.

[0033] A spectrophotometer is typically used to measure the spectral distribution of a received spectrum. A spectrophotometer is an optical device that works by separating a beam of light directed into the optical device into different frequency components and then measuring the intensity of these components using an analytical device such as a CCD detector or CCD array.

[0034] Figure 1 The Raman spectrum received from the measurement subject is shown. The data originates from a Raman spectral study of the thenar eminence of the subject. Light was shone onto the thenar eminence of the subject, and... Figure 1 The detected spectrum 1 is shown in the figure. Figure 1 It also includes Raman glucose spectroscopy², so the concentration of glucose in the test region can be determined using the Raman spectrum obtained from the measurement subject. The fish-side Raman spectrum includes contributions from any molecules present in the test region, and therefore needs to be used to determine the true concentration of glucose.

[0035] Note that the glucose spectrum includes four main regions of increased intensity, labeled A through D and enclosed by boxes 3 through 6. Therefore, these regions in the thenar spectrum 1 will contain a relatively higher level of information about the glucose concentration in the sampled area compared to the rest of the spectrum 1.

[0036] It has been recognized that if the output from the spectrometer is arranged to resolve the portion of the spectrum that requires a higher level of high sensitivity / low noise, then a high-quality signal can be obtained while minimizing the necessary use of an expensive CCD detector.

[0037] Spectral patterns A through D were identified, where most significant variations were due to glucose levels. The entire spectrum was then analyzed at different levels of detail, with a particular focus on high detail to investigate regions where the contribution from the analyte content was most significant. This implies that other regions of the spectrum (if applicable) can be analyzed using simpler and less expensive analytical mechanisms.

[0038] High-resolution and sensitive methods can be assigned to the parts of the spectrum with higher levels of information, while lower-resolution and sensitive methods can be assigned to the parts of the spectrum with less information, thereby significantly reducing the complexity of the measurement setup.

[0039] Figure 2 A schematic diagram of an apparatus for measuring glucose concentration subcutaneously and in vivo using Raman spectroscopy is shown. Although the detection and measurement of glucose levels are described herein with reference to other methods and apparatus, they can be used to measure the concentrations of other analytes of interest.

[0040] Device 7 includes a light source 8, a probe 9, and a detector 10. See below for further details. Figure 3 Detector 10 is described in more detail.

[0041] The subject 11 is tested by engaging the tip of probe 9 with the surface of the skin. The mechanism for coupling light from source 8 to the skin 11 of the subject can be described in detail in WO-A-2016 / 034448, as described above. In fact, there are numerous known mechanisms for obtaining Raman spectra from a subject in vivo, and any suitable system disclosed in the art can be used for this purpose.

[0042] Figure 2 The diagram schematically illustrates how light from source 8 is coupled to body 11 via probe 9 and then received by probe 9 for transmission to analysis device 10. Analysis system 10 includes multiple devices for light detection, having possible dispersive elements as described below. Each light detection device is selected from multiple different types of light detection devices, thereby enabling the detection of the received signal with a desired level of resolution and signal-to-noise ratio. At least two different types of light detection devices are present within system 10, thereby providing detection utilizing at least two levels of resolution and / or signal-to-noise ratio.

[0043] For example, in Figure 1 In regions A, B, C, and D of the fish-like spectrum 1, the high-sensitivity and low-noise portions of the spectrum can be resolved using a CCD-based spectrometer, while the portions requiring high resolution but tolerating a lower signal-to-noise ratio can be resolved using a CMOS-based spectrometer.

[0044] When using an 830 nm laser as the excitation source (i.e., as...) Figure 2 When using a light source (8), measurements are taken from 850 nm to 985 nm or from 283 cm⁻¹. -1 Up to 1900cm -1 Raman spectra.

[0045] Reference Figure 3 The diagram shows a schematic of the analysis system 10.

[0046] Light 12 is received as input to the analysis system 10. Multiple filtering devices 141-144 are provided. Each filtering device 141-144 is arranged to transmit a portion of the light and reflect another portion. Therefore, the portion of light 161-164 transmitted by each element 141-144 represents a selected portion of the spectrum according to its frequency. Multiple analysis devices 181-184 are provided, each arranged to receive the corresponding transmitted or reflected component from the filtering elements 141-144 as input. Therefore, the device has built-in flexibility because each analysis device or detection unit 181-184 can be selected to provide a desired level of resolution and / or signal-to-noise ratio for the corresponding portion of the spectrum it is arranged to receive.

[0047] In one example, filter elements 141-144 are all dichroic filters. In another example, they can be gratings or virtually any other wavelength-dependent filtering device. In one example, at least two different types of filtering devices are used, such as a dichroic mirror and a grating, to select different portions of the spectrum.

[0048] In a preferred embodiment, one or more of the analytical devices 181-184 include a dispersive element. This is particularly useful for regions where it is desirable to include data related to the analyte under study, because dispersing the receiving portion of the spectrum will allow it to be analyzed in more detail.

[0049] exist Figure 1 In this configuration, chambers 3 to 6 indicate spectral regions containing high-level glucose information. Filter elements 141-144 decompose energy into different detectors with varying resolutions and background noise based on frequency or wavelength. As an example, the spectral regions containing important Raman vibrations related to glucose, represented by chambers A to D, are preferably detected by a CCD-based spectrometer with a resolution of 9 cm.

[0050] It is possible to achieve this simply by having sufficient resolution (e.g., 25cm). -1 A CMOS-based spectrometer detects the spectral region outside the area represented by chambers A to D to evaluate the signal slope over frequency intervals, or alternatively, simply uses photodiodes, provided that only the average intensity needs to be evaluated. In fact, it could be the case that no detector is provided at all for the region outside the chambers where there is almost no information about glucose.

[0051] Therefore, a system capable of selective analysis of different portions of a spectrum is provided. This system allows more data to be derived from the most important parts of the spectrum for analysis in question, without inefficiently investing the same amount of resources in less important parts of the spectrum. The required level of thoroughness of analysis and research can be achieved on the important parts of the spectrum without wasting time, effort, resources, or cost on less important parts. In the given example, the glucose spectrum is shown as an overlay on a finger-derived spectrum. This enables the identification of regions of interest in the thenar eminence spectrum, where the window of interest can be well located elsewhere in the spectrum if another metabolite or analyte is being studied.

[0052] In one example, a spectrometer is used as at least one of the detection devices. For example, in a non-limiting embodiment, Stationary-Wave Integrated Fourier-Transform Spectrometry (SWIFTS) is used. This SWIFT technique is described in detail in the paper entitled "Wavelength-Scale Stationary-Wave Integrated Fourier-Transform spectrometry" published by Le Coarer et al. in Nature Photonics (Vol. 1, August 2007), the entire contents of which are incorporated herein by reference. More general Fourier transform spectroscopy may also be used.

[0053] If the filter elements are selectively and reconfigurably tunable, the system can be modified to focus on different portions of the spectrum depending on the metabolite or analyte being studied. Therefore, during fabrication, the filter elements are tuned to the desired frequencies so that the system as a whole is configured to analyze a specific, selected analyte.

[0054] Tunable filters or filtration devices can be of a variety of different types. Examples include filters that are tunable by changing the angle of incidence (AOI) on the filtration device. In such devices, the transmission window shifts with respect to the AOI relative to the filter normal. Examples include those manufactured by Semrock (part of IDEX Health and Science LLC) and viewable, for example, at the website https: / / www.semrock.com / versachrome-edge-tunabIe-fiIters.aspx.

[0055] Other examples include those tuned by filter shifting (linear variable filters). In these filters, the transmission window is shifted relative to the lateral position of the filter. Examples include those manufactured by Delta Optical Thin Film A / S and viewable, for example, at http: / / www.deltaopticalthinfilm.com / products / linear-variable-filters / .

[0056] Another example would be an acousto-optic (electro-optic) tunable filter, in which the refractive index of a crystal is modulated periodically by high-frequency acoustic waves generated by a piezoelectric transducer. In such devices, the frequency of the wave generated by the piezoelectric transducer determines the refractive index modulation period, which in turn determines the wavelength of the diffracted light. Examples are included, for instance, those available at http: / / www.olvmpusmicro.com / primer / techniques / confocal / aotfintro.html.

[0057] Refer again Figure 1 The example uses a dichroic mirror to filter out the values ​​from 0cm. -1 Up to 280cm -1 The light, with a spectral range of 283 cm⁻¹ -1 Up to 1900cm -1 The light passes through. This light then strikes another set of filters / dichroic mirrors, which directs the spectral portion to a suitable spectrometer and / or detector. Thus, the filter array is arranged to separate the light into well-defined spectral portions, allowing different analytical methods to be applied to different parts.

[0058] In the described example, the apparatus is arranged to determine the glucose level in a sample using a Raman spectrometer. As described above, this apparatus and method can be used regardless of the analyte being measured. Other examples include any one or more of lactic acid, fatty acids, urea, carbamide, cholesterol, or hemoglobin. Raman spectra are shown. Figure 1 Other molecules are indicated on it, which are considered as Raman peaks with specific wavelengths or shifts. Therefore, if it is necessary to primarily analyze other terms among these, the analytical apparatus arranged to receive one or more important parts of the spectrum will be selected with high resolution and high SNR.

[0059] Embodiments of the invention have been described with particular reference to the illustrated examples. However, it will be understood that changes and modifications can be made to the described examples within the scope of the invention.

Claims

1. An analyte detection device, the device comprising: A radiation source, used to irradiate the sample; A receiver receives a Raman spectrum of radiation transmitted back from the sample in response to radiation received from the source, the Raman spectrum including portions significant to the analyte to be detected and portions insignificant to the analyte to be detected. The receiver includes multiple analytical devices of different types, each arranged to receive selected portions of the received Raman spectrum transmitted back from the sample. The different types of analytical devices include a first type for detecting portions of the Raman spectrum important to the analyte to be detected, and a second type for detecting portions of the Raman spectrum that are not important to the analyte to be detected. The different types of analytical devices have different levels of signal-to-noise ratio, wherein a first type of analytical device for detecting an important portion of the Raman spectrum of the analyte to be detected has a higher signal-to-noise ratio than a second different type of analytical device for detecting an unimportant portion of the Raman spectrum of the analyte to be detected, wherein the different analytical devices include at least one CCD-based spectrometer, and wherein the different analytical devices include at least one CMOS-based spectrometer.

2. The apparatus of claim 1, further comprising one or more filtering devices arranged to filter the received Raman spectrum and direct a specified component to a particular analytical device among the plurality of different types of analytical devices.

3. The apparatus according to claim 1 or 2, wherein, The different types of analytical devices have different levels of resolution, wherein the first type of analytical device, used to detect the important Raman spectral portion of the analyte to be detected, has a higher level of resolution than the second different type of analytical device, used to detect the unimportant Raman spectral portion of the analyte to be detected.

4. The apparatus according to claim 2, wherein, The filtration device includes at least one tunable filtration device, which can be selectively configured to be tuned to a desired frequency according to the analyte.

5. The apparatus according to claim 4, wherein, The tunable filtration device includes one or more of mechanically tunable filtration devices, electrically tunable filtration devices, and acoustically and optically tunable filtration devices.

6. The apparatus according to claim 1, wherein, One or more of Fourier wave spectroscopy and standing wave integrated Fourier transform spectroscopy can be used.

7. The apparatus according to claim 1, wherein, One or more of the selected portions of the received Raman spectrum are coupled to the dispersive element.

8. The apparatus according to claim 1, wherein, The apparatus is arranged to determine the concentration of the analyte.

9. The apparatus according to claim 8, wherein, The analytes are selected from the group including glucose, lactic acid, fatty acids, urea, carbamide, cholesterol, alcohol and hemoglobin.

10. The apparatus according to claim 9, wherein, The apparatus is arranged such that, depending on the analyte to be primarily analyzed, the analytical device receiving one or more important portions of the spectrum is selected as an analytical device with high resolution and high signal-to-noise ratio.

11. A method for detecting an analyte, comprising using an analyte detection apparatus according to any one of claims 1 to 10, the method comprising: The sample is illuminated using optical radiation; Receive the Raman spectrum of radiation transmitted back from the sample in response to radiation received from the source; Different portions of the received Raman spectrum are selectively coupled to different analytical devices.

12. The method according to claim 11, wherein, The method includes: filtering the received Raman spectrum into two or more components; and coupling a first component of the two or more components to a first analytical device and coupling a second component of the two or more components to a second analytical device.

13. The method of claim 11, further comprising detecting the one or more components at different levels of resolution.

14. The method of claim 11, further comprising detecting the one or more components at different levels of signal-to-noise ratio.

15. The method according to claim 13, wherein, One or more of Fourier wave spectroscopy and standing wave integrated Fourier transform spectroscopy can be used.

16. The method according to claim 13, wherein, One or more of the selected portions of the received Raman spectrum are coupled to the dispersive element.

17. The method of claim 13, further comprising determining the concentration of the analyte.

18. The method according to claim 17, wherein, The analytes are selected from the group including glucose, lactic acid, fatty acids, urea, carbamide, cholesterol, alcohol and hemoglobin.

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