GB2489717A - Detection of blood analytes using portable Raman spectroscopy device - Google Patents

Detection of blood analytes using portable Raman spectroscopy device Download PDF

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Publication number
GB2489717A
GB2489717A GB201105771A GB201105771A GB2489717A GB 2489717 A GB2489717 A GB 2489717A GB 201105771 A GB201105771 A GB 201105771A GB 201105771 A GB201105771 A GB 201105771A GB 2489717 A GB2489717 A GB 2489717A
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Prior art keywords
light
device
raman
filter
scattered
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GB201105771A
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GB2489717B (en )
GB201105771D0 (en )
Inventor
Sara Murray
Gajendra Pratap Singh
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ELECTRONIC MEDICAL SOLUTIONS Ltd
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ELECTRONIC MEDICAL SOLUTIONS Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/0059Detecting, measuring or recording for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0075Detecting, measuring or recording for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14546Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/145Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/68Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6802Sensor mounted on worn items
    • A61B5/681Wristwatch-type devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/72Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7203Signal processing specially adapted for physiological signals or for diagnostic purposes for noise prevention, reduction or removal
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01JMEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRA-RED, VISIBLE OR ULTRA-VIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02Details
    • G01J3/0205Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
    • G01J3/0208Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using focussing or collimating elements, e.g. lenses or mirrors; performing aberration correction
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01JMEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRA-RED, VISIBLE OR ULTRA-VIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02Details
    • G01J3/0205Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
    • G01J3/0227Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using notch filters
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01JMEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRA-RED, VISIBLE OR ULTRA-VIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02Details
    • G01J3/0256Compact construction
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01JMEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRA-RED, VISIBLE OR ULTRA-VIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02Details
    • G01J3/0262Constructional arrangements for removing stray light
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01JMEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRA-RED, VISIBLE OR ULTRA-VIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02Details
    • G01J3/027Control of working procedures of a spectrometer; Failure detection; Bandwidth calculation
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01JMEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRA-RED, VISIBLE OR ULTRA-VIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02Details
    • G01J3/0291Housings; Spectrometer accessories; Spatial arrangement of elements, e.g. folded path arrangements
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01JMEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRA-RED, VISIBLE OR ULTRA-VIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02Details
    • G01J3/10Arrangements of light sources specially adapted for spectrometry or colorimetry
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01JMEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRA-RED, VISIBLE OR ULTRA-VIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/12Generating the spectrum; Monochromators
    • G01J3/26Generating the spectrum; Monochromators using multiple reflection, e.g. Fabry-Perot interferometer, variable interference filters
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01JMEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRA-RED, VISIBLE OR ULTRA-VIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/28Investigating the spectrum
    • G01J3/44Raman spectrometry; Scattering spectrometry ; Fluorescence spectrometry
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/62Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65Raman scattering

Abstract

A portable device for detecting a change in concentration of a blood analyte e.g. glucose in a subject comprises a light source 302 such as a laser adapted to irradiate a portion of the skin of the subject with incident light such that said light undergoes Raman scattering by a blood analyte present in a dermal tissue layer and a detection system 308 adapted to detect Raman scattered light emitted from said dermal tissue layer. The detection system 308 comprises a first (e.g. notch) filter 309 adapted to reject reflected incident light and a second (e.g. bandpass) filter 310 adapted to filter the Raman scattered light such that a selected portion of the Raman scattered light is transmitted to the detector 311. A processor is operably coupled to the detector 311, and is adapted to determine the change in intensity of the Raman scattered light and determine the change in concentration of the analyte therefrom. The device may be adapted to be worn about the wrist of the subject.

Description

DEVICE AND METHOD FOR THE

DETECTION OF BLOOD ANALYTES

Field of the Invention

The present invention relates to the detection of blood analytes. In particular, the invention relates to a device and method for detecting changes in concentration of blood analytes by Raman spectroscopy.

Background to the Invention

It is predicted that, by 2020, one in two adults in the US will be diabetic or pre-diabetic.

Current efforts in the area of glucose monitoring are focused on finding a way to measure blood glucose levels in patients who are already diabetic.

Non-invasive glucose monitoring is a technical "Holy Grail". The most promising attempts at non-invasive glucose monitoring have been based on optical spectroscopy, using infrared (IR) or near infrared (NIR) wavelengths to obtain optical signatures that indicate serum levels of glucose. Raman spectroscopy is particularly suited to the detection of glucose and other blood analytes as it can be employed across a wide spectrum and used in conjunction with non-ideal samples such as moving fluids.

However, a problem associated with detecting absolute serum levels of glucose is that IR and NIR radiation have limited penetration depth in vivo. Consequently, Raman spectroscopy cannot be used to provide a reading of absolute serum levels of glucose that is sufficiently accurate to be relied upon by a diabetic patient. In order to address this problem, the detection of glucose levels at locations in the body where serum glucose is nearer the surface (e.g. the eye or tongue) has been proposed. However, issues with laser safety preclude these areas of the body as viable zones. There exists a need for a portable device for monitoring changes in concentration of glucose and other blood analytes, especially in pre-diabetic patients. In particular, there exists a need for a device for monitoring changes in concentration of blood analytes that can be comfortably worn on the body.

Summary of the Invention

According to a first aspect of the present invention, there is provided a portable device for detecting a change in concentration of a blood analyte in a subject, the device comprising: (a) a light source adapted to irradiate a portion of the skin of the subject with incident light such that said light undergoes Raman scattering by a blood analyte present in a dermal tissue layer; (b) a detection system adapted to detect Raman scattered light emitted from said dermal tissue layer, the detection system comprising a first filter, a second filter and a detector, wherein the first filter is adapted to reject reflected incident light and the second filter is adapted to filter the Raman scattered light such that a selected portion of the Raman scattered light is transmitted to the detector, wherein the selected portion of light includes Raman scattered light of a wavelength at which the analyte exhibits a detectable Raman signal and wherein the detector is adapted to detect the intensity of Raman scattered light of said wavelength; and (c) a processor operably coupled to the detector, wherein the processor is adapted to determine the change in intensity of the Raman scattered light at said wavelength and determine the change in concentration of the analyte therefrom.

According to a second aspect of the present invention, there is provided a method of detecting a change in concentration of a blood analyte in a dermal tissue layer of a subject using a device of the present invention. A further aspect of the present invention is directed to the use of a device of the present invention for detecting a change in concentration of a blood analyte in a dermal tissue layer of a subject.

A device of the present invention may be used to monitor changes in concentration of a blood analyte over time in a subject. Where the analyte is glucose, the device may be used to detect changes in glucose levels in pre-diabetic patients, encouraging them to change their lifestyle (e.g. their movement and/or eating habits) in order to reduce the risk of diabetes. Detection may take place in a non-invasive manner and the device may allow accurate readings to be taken over time without the need for frequent re-calibration.

Brief Descri�tion of the Drawings Figure 1 shows a Raman spectrum of glucose in aqueous solution.

Figure 2 shows Raman spectra obtained from aqueous solutions of glucose (lower line), creatinine (middle line) and urea (upper line).

Figure 3 is a schematic diagram depicting a light source system and detection system forming part of a device according to one embodiment of the present invention.

Figure 4 is a schematic diagram depicting a light source suitable for use in a device of the present invention.

Figure 5 is a schematic diagram depicting a detection system suitable for use in a device of the present invention.

Figure 6 is a schematic diagram of a detection system suitable for use in a device of the present invention.

Figure 7 depicts a side view (a) and a bottom view (b) of a device according to one embodiment of the present invention, wherein the device is suitable for placement about the wrist.

Figure 8 is a schematic diagram depicting a light source system and a detection system of a device according to another embodiment of the present invention.

Figure 9 is a flowchart depicting the steps which may be performed during operation of a device of the present invention.

Description of Various Embodiments

The present invention provides a portable device for detecting a change in concentration of a blood analyte in a dermal tissue layer of a subject. The term "dermal tissue layer" as used herein refers to any layer of the skin in which the blood analyte may be contained. The dermal tissue layer may be a tissue layer present in the dermis or at the interface between the dermis and the epidermis. Preferably, the dermal tissue layer is a tissue layer present at the interface between the epidermis and the dermis. The device may be used to monitor changes in concentration of the analyte in the dermal tissue layer in a non-invasive manner.

The device comprises a light source, a detection system and a processor. The light source is adapted to irradiate a portion of the skin of the subject with incident light such that the incident light penetrates through the skin to the dermal tissue layer, where it undergoes Raman scattering by analyte present within said tissue layer. The detection system is adapted to detect Raman scattered light emitted from the dermal tissue layer, and comprises a first filter, a second filter and a detector. The first filter is adapted to reject incident light reflected by the skin, whilst the second filter is adapted to filter the Raman scattered light such that a selected portion of the Raman scattered light is transmitted to the detector. The selected portion of light includes Raman scattered light of a wavelength at which the analyte exhibits a detectable Raman signal, and the detector is adapted to detect the intensity of the Raman scattered light at that wavelength. The device further comprises a processor that is operably linked to the detector. The processor is adapted to determine the change in intensity of the Raman scattered light at said wavelength and determine the change in concentration of the analyte therefrom.

Since the detection system transmits and detects only a portion of the spectrum of Raman scattered light, the device may be sufficiently miniaturised such that it can be carried or even worn about the body of the user. Thus, in one embodiment, the device is in the form of a wearable article that can be worn about the body of the subject. In a particular embodiment, the device is adapted to be worn about the wrist. Thus, for instance, the device may be in the form of a wristband or bracelet which can be worn on the wrist. Preferably, the device is adapted to detect a change in concentration of the analyte in a dermal tissue layer that is present on the inside of the wrist. The relatively thin nature of the epidermis on the inside of the wrist means that blood analytes may be advantageously detected there. Thus, the light source and detection system may be arranged such that the analyte present in a dermal tissue layer on the inside of the wrist is detected.

The device comprises a light source adapted to irradiate a portion of the skin of the subject with incident light. The excitation wavelength of the incident light may be selected to ensure optimum penetration of the skin. The degree of penetration is related to the wavelength of the light, and therefore light of longer wavelengths will generally penetrate deeper into skin. However, it may be desirable to optimise the power of the light source against the required reduction in fluorescence in order to maximise the signal to noise ratio. In particular, the choice of an excitation wavelength in the NIR range may reduce the background signal obtained. A desirable signal to noise ratio may also be achieved when the light source and the detector are arranged in a substantially orthogonal relationship.

In an embodiment, the light source emits light having a wavelength of from about 600 nm to about 1050 nm, e.g. from about 750 nm to about 1050 nm, e.g. from about 800 to about 1000 nm. The use of light of such wavelengths may be particularly preferable when a silicon detector is used in the device, as the quantum efficiency of silicon detectors may fall drastically at higher wavelengths. Particularly where the analyte is glucose, it may be preferable to use a light source that emits light of a wavelength of from about 800 nm to about 950 nm, e.g. about 830 nm or about 915 nm.

The light source is preferably a source of monochromatic light and is more preferably a laser. In an embodiment, the light source comprises a semiconductor laser, e.g. a laser diode or a vertical-cavity surface-emitting laser. The device may comprise a plurality of light sources, e.g. a plurality of semiconductor lasers, in which case each light source may provide light of a different wavelength. In one embodiment, the device comprises at least two lasers and a beam combiner which merges the beams of light emitted from each light source into a single coincident beam, which is then used to irradiate a portion of the skin of the subject. The difference in wavelength between the lasers may be selected to excite a Raman mode in the selected analyte which increases the signal level through stimulated emission. The device may further comprise one or more other optical components, e.g. one or more bandpass filters and/or one or more convex lenses, through which the incident light passes prior to the light contacting the skin.

System sensitivity may be increased through the use of a pulsed laser and time-delayed acquisition of Raman spectra. The use of such techniques minimises the uncertainty in background signal variations by reducing the possibility of photobleaching and, moreover, may enhance the signal to noise ratio. System sensitivity may also be increased through the use of a dual laser system wherein the difference in wavelength between the lasers is selected to obtain shifted excitation spectra. The difference in the shifted excitation spectra can be used to eliminate the fluorescence background and retrieve a useful Raman signal. As mentioned above, system sensitivity may also be increased through the use of a dual laser system wherein the difference in wavelength between the lasers is selected to excite a Raman mode in the analyte to increase signal level through stimulated emission. Alternatively or additionally, system sensitivity may be increased through the use of a dual laser system wherein turbidity correction scheme is implemented to account for tissue heterogeneity.

Irradiation of the dermal tissue layer with incident light causes excitation of analyte present in the dermal tissue layer, resulting in Raman scattering of incident light. The device comprises a detection system adapted to receive and detect Raman scattered light emitted from said dermal tissue layer. The detection system comprises a first filter, a second filter and a detector, The device may comprise one or more additional components, such as one or more convex tenses and/or one or more mirrors, which may assist in directing the Raman scattered light towards the first and second filters and the detector.

The first filter is used to reject incident light reflected by the skin. The first filter will typically be a notch (interference) filter and may have a band blocking width of e.g. from about 25 nm to about 45 nm, centered at the corresponding wavelength of the incident light. Preferably, the first filter has a blocking band optical density (OD) of greater than 6. Typically, the first and second filters will be arranged such that Raman scattered light emitted from the dermal tissue layer will pass through the first filter and then the second filter, before reaching the detector. The order of the first and second filters may however be reversed.

The second filter is adapted to filter the Raman scattered light such that a selected portion of the Raman scattered light is transmitted to the detector. Thus, the second filter may transmit a portion of the Raman scattered light and reject some or all of the remaining Raman scattered light. The second filter may be a bandpass filter, a longpass filter or a transmission grating. Preferably, the second filter is a bandpass filter. In an embodiment, the second filter has a bandwidth of from about 5 nm to about 150 nm, from about 857 nm to about 866 nm, or from about 905 nm to about 920 nm.

Particularly where the analyte is glucose, it may be preferable to employ a second filter which transmits Raman scattered light having a wavelength in the range of from about 850 nm to about 1100 nm, e.g. from about 850 nm to about 960 nm or from about 950 nm to about 1070 nm.

In an embodiment, the device comprises a plurality of second filters. In an embodiment, the device comprises a second filter comprising an articulated filter tray, wherein the tray comprises a plurality of bandpass filters and a motorised gear mechanism to articulate the filter tray to select for a particular filter and thereby facilitate wavelength selection.

The light source and the detector may be arranged in a back scattering geometry, in which case a longpass filter may be advantageously employed as the second filter.

In order to account for variables such as movement of the device, external lighting conditions and temperature, it may be preferable for the device to include a reference in order to normalise the Raman signal. In this regard, the detection system may be adapted to detect the fluorescence of the scattered light to be detected, and a relatively bright point on the fluorescence curve selected as a reference for normalising the Raman signal. For instance, the detection system may comprise a beam splitter arranged such that the Raman scattered light is split into two or more beams, wherein each beam of light is passed through a separate second filter, e.g. through separate bandpass filters, to a separate detector. In this way, the device may be used to simultaneously detect light of different wavelengths. This arrangement may therefore allow a fluorescent peak and a Raman active peak to be simultaneously measured.

The portion of Raman scattered light that is transmitted by the second filter includes light of a wavelength at which the analyte exhibits a Raman signal, and the detector is adapted to detect the change in intensity of the Raman scattered light at that wavelength. The device may be used to detect changes in concentration of a variety of blood analytes. Preferably, the analyte exhibits a Raman signal at said wavelength which is characteristic to the analyte, thereby allowing the analyte to be distinguished from one or more other analytes that may be present in the dermal tissue layer. The Raman spectra of blood analytes are well documented (see e.g. Applied Optics, Vol. 38, Issue 13, pp. 291 6-2926, 1999) and may also be determined by spectroscopic analysis of the analyte in a relatively pure form, e.g. in water. Examples of analytes which may be detected using a device of the present invention include glucose, an alcohol (e.g. ethanol), urea, a protein, triglycerides, drug substances (e.g. benzoylmethylecgonine, diacetylmorphine, lysergic acid diethylamide, amphetamines, methamphetamines, cannabis, codeine, methcathinone or methylphenidate), acetylsalicylic acid, acetaminophen, theophylline, valproic acid, bilirubin, creatinine, albumin and haemoglobin.

In a particular embodiment, the analyte is glucose. In this case, it may be preferable to detect the intensity of Raman scattered light of a wavelength corresponding to a wavenun-iber in the range of from about 380 cm1 to about 500 cm1, from about 820 cm1 to about 950 cm1, from about 1000 cm1 to about 1180 cm1, or from about 1200 cm1 to about 1500 cm1. In a particular embodiment, the detector is adapted to detect the intensity of Raman scattered light of a wavelength corresponding to a wavenumber in the range of from about 1000 cm1 to about 1180 cm1, e.g. at about 1126 cml The detector may comprise a charge coupled device (CCD) array or a single channel detector. Preferably, the detector comprises a silicon detector, more preferably a black silicon detector. Black silicon detectors are particularly preferred as they generally do not require cooling and have desirable quantum efficiency for NIR measurements than ordinary silicon detectors. The device may comprise a plurality of detectors, wherein each detector is adapted to detect Raman scattered light of a different wavelength.

The detector produces an output value representative of the intensity of the Raman scattered light at the wavelength of interest. The device further comprises a processor adapted to receive and process the output value produced by the detector in order to determine the change in intensity of the Raman signal at said wavelength compared with a predetermined value. The processor then calculates the change in concentration of the analyte based on the change in intensity. Preferably, the predetermined value is one obtained by the device at an earlier point in time. Thus, the device may comprise computer memory operably coupled to the processor, in which one or more predetermined output values produced by the detector can be stored and retrieved by the processor. In this way, the device may be used to record and monitor changes in concentration of the analyte over time. The device may be used to determine changes in analyte concentration at regular intervals, e.g. ranging from once per hour to once per minute. In an embodiment, the device determines the change in analyte concentration between 100 and 350,000 times per day, e.g. between 30,000 and 350,000 times per day.

The device may comprise a visual display, e.g. an LCD or LED display, which is operably coupled to the processor and which indicates a change in concentration of the analyte. The device may also comprise means for transmitting data produced by the processor to a remote receiver, where the data can be further processed and/or analysed. Data may be delivered to an internet protocol (IF) address, where various data, e.g. norms, ranges of standard deviation, charts and exception reports, can be viewed and/or recorded. Data may be transmitted by any means known in the art, e.g. in the form of radio frequency radiation.

The device may comprise a housing within which the light source, the detection system and the processor are contained. The housing may comprise a first transparent window located in the optical path of the incident light and a second transparent window located in the optical path of the Raman scattered light emitted from said dermal tissue layer.

Other components, such as e.g. associated electronic components and/or a battery to power the device, may also be contained within the housing. The housing may be formed of a metal or plastics material. Preferably, the housing is constructed such that it is substantially resistant to the ingress of water. The device may further comprise one or more other components, such as a temperature sensor.

The apparatus may comprise means for reducing detector noise. For instance, stimulated or pulsed Raman techniques may be used to boost signal strength or reduce fluorescence respectively. Application of multivariate analysis methods, including principal component analysis, may also be used to extract useful Raman signal information from a higher fluorescence background signal. The device may also be used to determine absolute concentrations of the analyte, in which case it may be preferable to apply correlation functions.

Preferred embodiments of the present invention will now be described with reference to the accompanying drawings.

Figure 1 shows a Raman spectrum of D-glucose in aqueous solution. It can be seen that the spectrum exhibits significant peaks in the following ranges of wavenumbers: from about 380 cm1 to about 500 cm1, from about 820 cm1 to about 950 cm1, from about 1000 cm1 to about 1180 cm1 and from about 1200 cm1 to about 1500 cm1. The band at from about 1000 cm1 to about 1180 cm1 is particularly useful for detecting changes in glucose concentration, as it contains a significant peak at approximately 1126 cm1.

Figure 2 shows Raman spectra of glucose, creatinine and urea in aqueous solution. It can be seen that neither creatinine nor urea exhibits a significant Raman peak in the range of from about 1000 cm1 to about 1180 cm1. Consequently, this band is particularly useful for detecting changes in glucose concentrations in the presence of either of these analytes.

Figure 3 illustrates a light source system and a detection system for use in a device of the present invention. Light source system 301 comprises laser 302, band pass filter 303 and lens 304. The light source provides a monochromatic beam 305 of incident light which is used to irradiate a portion of the skin of the subject. The incident light penetrates the epidermis E of the skin, causing excitation of analyte contained in blood capillaries present at the dermis D and/or at the interface between dermis and epidermis. Excitation of the analyte by the incident light causes Raman scattering of light. The resulting Raman scattered light 306 is guided by lens 307 and received and collected by detection system 308. The detection system comprises first (e.g. notch) filter 309 for rejecting incident light and a second (e.g. bandpass) filter 310 for filtering the Raman scattered light such that a band of Raman scattered light is selectively transmitted to detector 311. The size of the lens 307 may be varied in order to optimise the transfer of scattered Raman photons to the detector, thereby enhancing sensitivity.

Figure 4 illustrates a light source system suitable for use in a device of the present invention. Light source system 401 comprises lasers 402 and 403, respective band pass filters 404 and 405, and beam splitter 406. The beam splitter merges the two beams 407 and 408 emitted from lasers into a single coincident beam 409 which is passed through lens 410, which is used to focus the light on the skin. The difference in wavelength between the lasers may be selected to excite a Raman mode in the analyte to increase signal level through stimulated emission.

Figure 5 illustrates a detection system suitable for use in a device of the present invention. The detection system 501 comprises first (e.g. notch) filter 502, second filter 503 and detector 504. The second filter comprises an articulated filter tray, comprising a plurality of bandpass filters 505, 506, 507 (top view shown below) and a motorised gear mechanism 508 to articulate the filter tray to select for a particular filter and thereby facilitate wavelength selection.

An alternative detection system is shown in Figure 6. Detection system 601 comprises first (e.g. notch) filter 602, beam splitter 603, second (e.g. bandpass) filters 604 and 605, and detectors 606 and 607. The use of a separate bandpass filter for each detector allows the detection system to simultaneously detect light of different wavelengths. This arrangement therefore allows for the simultaneous measurement of light of two different wavelengths, such as a fluorescent peak and a Raman active peak.

Figure 7 shows side (a) and bottom (b) views of a device 701 that is wearable about the wrist of the subject, in which the light source system 702 and detection system 703 are shown. In the illustrated embodiment, the optical path and acquisition volume is completely sealed by the device, thereby protecting the eye from exposure to laser light.

Figure 8 illustrates various features of a device according to another embodiment of the present invention. Device 801 comprises a semiconductor laser 802, bandpass filter 803, Iongpass filter 804 and lens 805, which provides a monochromatic beam 806 of incident light which is used to irradiate a portion of the skin (not shown). The resulting Raman scattered light 807 passes through lens 805 towards longpass filter 804. In the embodiment shown, the longpass filter is arranged at an angle of approximately 45° relative to the incident light, such that the Raman scattered light is directed towards mirror 808. The mirror reflects the Raman scattered light towards first (e.g. notch) filter 809 and second (e.g. bandpass) filter 810. The second filter filters the Raman scattered light such that a portion of the Raman scattered light is selectively transmitted via lens 811 to detector 812.

Figure 9 depicts a flowchart sequence for the firmware operation of the instrument indicating the interlock safety sequence followed by the signal acquisition process based on an apparatus incorporating a single laser and a scanning filter slide detector of the type illustrated in Figure 5.

A device of the present invention may be used to monitor changes in concentration of one or more blood analytes in a subject. The device is primarily intended for use by human subjects, but the device may find application in the detection of blood analytes in animals. The device may be used to monitor blood glucose trends in diabetic or pre-diabetic patients. Among several applications of this non-invasive point-of-care measurement device, one is the diagnosis of gestational diabetes, which requires close monitoring of blood glucose levels after a specific glucose challenge. The device may also be useful in the clinical implementation of treatment modalities such as artificial pancreas systems. The device may also be used to monitor cholesterol trends in cardiac patients, levels of advanced glycation end products in diabetic patients, and alcohol or drug usage in treatment programs or offender monitoring. The device may be used in a wide variety of clinical settings including operating theatres and the physician's office in connection with outpatient visits.

It will be understood that the present invention has been described above purely by way of example, and modification of detail can be made within the scope of the invention.

Each feature disclosed in the description, and where appropriate the claims and drawings may be provided independently or in any appropriate combination. -14-

Claims (31)

  1. CLAIMS1. A portable device for detecting a change in concentration of a blood analyte in a subject, the device comprising: (a) a light source adapted to irradiate a portion of the skin of the subject with incident light such that said light undergoes Raman scattering by a blood analyte present in a dermal tissue layer; (b) a detection system adapted to detect Raman scattered light emitted from said dermal tissue layer, the detection system comprising a first filter, a second filter and a detector, wherein the first filter is adapted to reject reflected incident light and the second filter is adapted to filter the Raman scattered light such that a selected portion of the Raman scattered light is transmitted to the detector, wherein the selected portion of light includes Raman scattered light of a wavelength at which the analyte exhibits a detectable Raman signal and wherein the detector is adapted to detect the intensity of Raman scattered light of said wavelength; and (c) a processor operably coupled to the detector, wherein the processor is adapted to determine the change in intensity of the Raman scattered light at said wavelength and determine the change in concentration of the analyte therefrom.
  2. 2. A device according to claim 1, wherein the device is adapted to be worn about the body of the subject.
  3. 3. A device according to claim 2, wherein the device is adapted to be worn about the wrist.
  4. 4. A device according to claim 3, wherein the device is adapted to detect a change in concentration of the analyte in a dermal tissue layer present on the inside of the wrist.
  5. 5. A device according to any preceding claim, wherein the dermal tissue layer is present in the dermis or at the interface between the dermis and the epidermis.
  6. 6. A device according to any preceding claim, wherein the light source is a source of monochromatic incident light.
  7. 7. A device according to any preceding claim, wherein the light source is a semiconductor laser, e.g. a laser diode.
  8. 8. A device according to any preceding claim, wherein the incident light has a wavelength in the range of from about 600 nm to about 1050 nm, e.g. from about 750 nm to about 1050 nm.
  9. 9. A device according to any preceding claim, wherein the first filter is a notch filter.
  10. 10. A device according to any preceding claim, wherein the second filter is a bandpass filter.
  11. 11. A device according to any preceding claim, wherein the detector comprises a silicon detector, e.g. a black silicon detector.
  12. 12. A device according to any preceding claim, wherein the processor is adapted to determine the change in intensity of Raman scattered light of said wavelength compared with a predetermined value stored on the device.
  13. 13. A device according to claim 12, wherein the predetermined value was obtained using the device.
  14. 14. A device according to any preceding claim, wherein the device further comprises a visual display operably coupled to the processor, wherein the visual display indicates the change in concentration of the analyte as determined by the processor.
  15. 15. A device according to any preceding claim, wherein the device further comprises a transmitter operably coupled to the processor, wherein the transmitter is adapted to transmit data produced by the processor to a remote receiver.
  16. 16. A device according to any preceding claim, wherein the device comprises a housing within which the light source, detection system and the processor are contained.
  17. 17. A device according to any preceding claim, wherein the analyte is glucose, alcohol, urea, a protein, a triglyceride, a drug substance, acetylsalicylic acid, acetaminophen, theophylline, valproic acid, bilirubin, creatinine, albumin or haemoglobin.
  18. 18. A device according to claim 17, wherein the analyte is glucose.
  19. 19. A device according to claim 18, wherein the incident light has a wavelength of from about 800 nm to about 950 nm, e.g. about 830 nm or about 915 nm.
  20. 20. A device according to claim 18 or claim 19, wherein the second filter transmits Raman scattered light having a wavelength in the range of from about 850 nm to about 1100 nm, e.g. from about 850 nm to about 960 nm or from about 950 nm to about 1070 nm.
  21. 21. A device according to any of claims 18 to 20, wherein the detector is adapted to detect the intensity of Raman scattered light of a wavelength corresponding to a wavenumber of from about 1000 cm1 to about 1180 cm1, e.g. about 1126 cm1.
  22. 22. A method of detecting a change in concentration of a blood analyte in a subject using a portable device of claim 1, the method comprising: (a) irradiating a portion of the skin of the subject with incident light from the light source, wherein the light undergoes Raman scattering by a blood analyte present within a dermal tissue layer; (b) detecting Raman scattered light emitted from said dermal tissue layer using the detection system, wherein reflected incident light is rejected by the first filter and the Raman scattered light is filtered by the second filter such that a selected portion of the Raman scattered light is transmitted to the detector, wherein the selected portion of light includes Raman scattered light of a wavelength at which the analyte exhibits a detectable Raman signal and wherein the intensity of Raman scattered light of said wavelength is detected by the detector; (c) operating the processor to determine the change in intensity of the Raman scattered light at said wavelength and determine the change in concentration of the analyte therefrom.
  23. 23. A method according to claim 22, wherein the device is as defined in any of claims 2 to 16.
  24. 24. A method according to claim 22 or claim 23, wherein the analyte is glucose, an alcohol, urea, a protein, a triglyceride, a drug substance, acetylsalicylic acid, acetaminophen, theophylline, valproic acid, bilirubin, creatinine, albumin or haemoglobin.
  25. 25. A method according to claim 24, wherein the analyte is glucose.
  26. 26. A method according to claim 25, wherein the incident light has a wavelength of from about 800 nm to about 950 nm, e.g. about 830 nm or about 915 nm.
  27. 27. A method according to claim 25 or claim 26, wherein the second filter transmits Raman scattered light having a wavelength in the range of from about 850 nm to about 1100 nm, e.g. from about 850 nm to about 960 nm or from about 950 nm to about 1070 nm.
  28. 28. A method according to any of claims 25 to 27, wherein the detector is adapted to detect the intensity of Raman scattered light of a wavelength corresponding to a wavenumber of from about 1000 cm1 to about 1180 cm1, e.g. about 1126 cm1.
  29. 29. Use of a device of any of claims I to 21, for the detection of a change in concentration of a blood analyte in a dermal tissue layer of a subject.
  30. 30. A portable device substantially as described herein with reference to the accompanying drawings.
  31. 31. A method substantially as described herein with reference to the accompanying drawings.
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