WO2024038268A1

WO2024038268A1 - Glucose concentration measuring device

Info

Publication number: WO2024038268A1
Application number: PCT/GB2023/052149
Authority: WO
Inventors: Qiandong ZHUANG; Nicholas DAVISON
Original assignee: University Of Lancaster
Priority date: 2022-08-18
Filing date: 2023-08-16
Publication date: 2024-02-22
Also published as: GB202212043D0

Abstract

Aspects of the invention relate to a glucose concentration measuring device and a method of measuring glucose concentration. The device comprises at least one transmitter, at least one receiver, and at least one controller. The at least one transmitter is configured to emit a first electromagnetic radiation signal having a first wavelength and a second electromagnetic radiation signal having a second wavelength to illuminate an in vivo blood sample, and the at least one receiver is configured to receive the first and second electromagnetic radiation signals after the electromagnetic radiation signals have illuminated said blood sample. The at least one controller is configured to generate first spectral data indicative of glucose absorbance based on the first received electromagnetic radiation signal and second spectral data indicative of water absorbance based on the second received electromagnetic radiation signal, and determine a glucose concentration measurement in dependence on the first and second spectral data.

Description

Title - Glucose concentration measuring device

The present invention relates to a glucose concentration measuring device and a method of measuring glucose concentration.

In a healthy human body, the amount of sugar present in the blood is controlled by the insulin hormone, which is produced by the pancreas. When food is digested and enters the bloodstream, insulin moves glucose out of the blood and into cells, where the glucose is broken down to produce usable energy for the body.

Diabetes is a medical condition that causes a human's blood sugar level to become too high, due to the body’s inability to produce enough functioning insulin to break down the glucose. Typically, to ensure their glucose levels remain healthy, a diabetic person will take regular blood tests to monitor the glucose content of their bloodstream.

In turn, the information about their blood glucose levels, and any regular patterns or changes that may be identified, enables them to regulate their blood glucose levels accordingly, for example by planning meals, physical exercise, and insulin supplementation, for example via an injection. The better the patient's blood glucose control, the less likely it is that the diabetes will cause damage in the body and lead to medical complications.

Conventionally, glucose measurements have been taken by pricking the fingertip with a lancet, drawing a small amount of blood that is applied to a test strip to determine the patient’s blood glucose level. The test strip is coated with a thin layer of conductive material, typically gold, and one end of the test strip is coated with a glucose absorbing chemical, which soaks up the glucose from the blood sample. As the glucose is absorbed by the chemical, an electric signal is transferred by the layer of gold, and the strength of the signal is indicative of the amount of glucose present. However, there are clear drawbacks with this method of testing. Most prominently, because this method only provides an instantaneous indication of the blood glucose level, most diabetics will need to test multiple times a day to obtain useful data as to the variations in their blood glucose levels. Indeed, it is believed that each diabetic person may be advised to test up to 10 times a day.

Since each test strip can only be used once, a new test strip is required for each individual test, which quickly becomes very costly. Furthermore, because the diabetic person is testing so often, pricking their own finger, and drawing blood so often, is uncomfortable.

It is therefore desirable to provide a method of monitoring glucose levels that is less invasive, more cost-effective, and less time-consuming.

In this regard, non-invasive methods have been proposed that utilise absorption spectroscopy to determine glucose levels in the blood. In these methods, a transmitter focuses light on the patient’s body, and photons within the light beam are absorbed by glucose within the blood. A detector then receives any photons that are not absorbed by glucose, and by comparing the attenuation of the transmitted or reflected light with the incident light, the amount of glucose can be determined based on the amount of light that has been absorbed in the blood. However, the reliability and accuracy of these proposed methods remain in doubt because of factors such as strong wavelength dependent light penetration through skin, technical availability of light emitters and receivers that operate at ambient temperature at desired wavelengths, light absorption from other bio-molecules, strong light scattering by biological tissues and blood components, and the condition of the user, e.g. their motion, their temperature and any sweating.

There has now been devised an improved glucose concentration measuring device, and an improved method of measuring glucose concentration, which overcomes or substantially mitigate some or all of the aforementioned disadvantages associated with the prior art. According to a first aspect of the invention, there is provided a glucose concentration measuring device comprising at least one transmitter, at least one receiver, and at least one controller; the at least one transmitter being configured to emit a first electromagnetic radiation signal having a first wavelength along a first path to illuminate an in vivo blood sample, and to emit a second electromagnetic radiation signal having a second wavelength along a second path to illuminate the in vivo blood sample; the at least one receiver being configured to receive the first and second electromagnetic radiation signals after the electromagnetic radiation signals have illuminated said blood sample; and the at least one controller being configured to determine a glucose concentration measurement dependent on the received first and second electromagnetic radiation signals, wherein the first and second electromagnetic signals are emitted simultaneously and at least a portion of the first and second paths are the same.

According to a second aspect of the invention, there is provided a method of measuring glucose concentration, the method comprising the steps of: (a) simultaneously emitting a first electromagnetic radiation signal having a first wavelength along a first path to illuminate an in vivo blood sample and a second electromagnetic radiation signal having a second wavelength along a second path to illuminate the in vivo blood sample; (b) receiving the first and second electromagnetic radiation signals after the electromagnetic radiation signals have illuminated said blood sample; (c) determining a glucose concentration measurement dependent on the received electromagnetic radiation signals, wherein at least a portion of the first and second paths are the same and the first and second wavelengths are different wavelengths.

The device and method according to the first and second aspects of the invention may be advantageous in that the simultaneous emission of electromagnetic signals having different wavelengths along the same path enables a reliable glucose concentration measurement to be determined using referenced absorption regardless of the previously-described factors that would ordinarily affect the measurement. In particular, the inventors have found that by emitting the electromagnetic signals at the same time, and along the same path, this problem is negated.

The at least one transmitter may be configured to emit a third electromagnetic radiation signal having a third wavelength. The third electromagnetic radiation signal may be emitted along a third path to illuminate the in vivo blood sample. The at least one receiver may be configured to receive the third electromagnetic radiation signal. The at least one controller may be configured to determine the glucose concentration measurement dependent on the received third electromagnetic radiation signal. The first, second and third electromagnetic radiation signals may be emitted simultaneously. At least a portion of the first, second and third paths may be the same. The entirety of the first, second and third paths may be the same.

The at least one transmitter may comprise a laser. The at least one transmitter may comprise a single transmitter having at least two laser elements capable of simultaneously emitting at least two electromagnetic signals having two different wavelengths. Where the at least one transmitter is configured to emit a third electromagnetic radiation signal, the at least one transmitter may comprise a single transmitter having at least three laser elements capable of simultaneously emitting at least three electromagnetic signals having three different wavelengths. Alternatively, the at least one transmitter may comprise a plurality of discrete lasers. The lasers or laser elements may be vertical-cavity surface-emitting lasers or laser elements. Although lasers are described as the preferred transmitter sources, other illumination means, including non-coherent, discrete wavelength light sources, may be employed.

The at least one receiver may be integral with the at least one transmitter. The at least one receiver may comprise a single receiver capable of simultaneously receiving at least two electromagnetic signals having two different wavelengths. Where the at least one receiver is configured to receive a third electromagnetic radiation signal, the at least one receiver may comprise a single receiver capable of simultaneously receiving at least three electromagnetic signals having three different wavelengths. Alternatively, the at least one receiver may comprise a plurality of receiving elements. The plurality of receiving elements may be housed within the same receiver, or may be a plurality of discrete receivers.

The at least one controller may be configured to generate first spectral data based on the first received electromagnetic radiation signal and second spectral data based on the second received electromagnetic radiation signal. The at least one controller may also be configured to determine a glucose concentration measurement dependent on the first and second spectral data. The first spectral data may relate to glucose absorbance data. The second spectral data may relate to water absorbance data. The at least one controller may be configured to generate third spectral data based on the third received electromagnetic radiation signal. The at least one controller may also be configured to determine a glucose concentration measurement dependent on the third spectral data. The third spectral data may relate to light scattering data. The third spectral data may be indicative of the amount of light lost from the emitted third radioactive signal as a result of scattering.

The method of measuring glucose concentration may further comprise some or all of the following steps: generating first spectral data based on the first received electromagnetic radiation signal; generating second spectral data based on the second received electromagnetic radiation signal; generating third spectral data based on the third received electromagnetic radiation signal; determining a glucose concentration measurement dependent on the first and second spectral data; determining a glucose concentration measurement dependent on the first, second and third spectral data. The first spectral data may relate to glucose absorbance data and the second spectral data may relate to water absorbance data.

The first electromagnetic radiation signal may have a transmitter intensity when transmitted by the at least one transmitter. The first electromagnetic radiation signal may have a receiver intensity when received by the at least one receiver. The receiver intensity may be different to the transmitter intensity. The receiver intensity may be less than the transmitter intensity, for example due to attenuation of the electromagnetic radiation signal as a result of the absorption of light by glucose molecules in the blood sample.

The difference between the receiver intensity and the transmitter intensity may be an indication of the amount of light absorbed by glucose molecules in the blood sample. The difference between the receiver intensity and the transmitter intensity may therefore be an indication of the amount of glucose molecules in the blood sample, i.e. the glucose concentration of the blood sample.

The first wavelength may be a wavelength at which glucose absorbance data is reliably obtained. The first wavelength may be a wavelength at which glucose exhibits strong absorption characteristics. The first wavelength may be a wavelength at which glucose absorbs a significant amount of the first electromagnetic radiation signal. That is, the first wavelength may be a wavelength at which the intensity of the first electromagnetic radiation signal is significantly reduced due to the absorption of electromagnetic radiation by glucose molecules.

The first wavelength may be a wavelength at which water and/or proteins and/or lipids exhibit weak absorption characteristics. The first wavelength may be a wavelength at which water and/or proteins and/or lipids absorb a minimal amount of the first electromagnetic radiation signal. That is, the first wavelength may be a wavelength at which the intensity of the first electromagnetic radiation signal is not significantly reduced due to the absorption of electromagnetic radiation by water and/or protein and/or lipid molecules.

The first wavelength may be between 1550 nm and 1650nm. For example, the first wavelength may be approximately 1550nm, or approximately 1650nm, where approximately means within 5nm, 10nm, 25nm, 50nm or 100nm of 1650nm.

The second electromagnetic radiation signal may have a transmitter intensity when transmitted by the at least one transmitter. The second electromagnetic radiation signal may have a receiver intensity when received by the at least one receiver. The receiver intensity may be different to the transmitter intensity. The receiver intensity may be less than the transmitter intensity, for example due to attenuation of the electromagnetic radiation signal as a result of the absorption of electromagnetic by water molecules in the blood sample.

The difference between the receiver intensity and the transmitter intensity may be an indication of the amount of light absorbed by water molecules in the blood sample. The difference between the receiver intensity and the transmitter intensity may therefore be an indication of the amount of water molecules in the blood sample, i.e. , the water concentration of the blood sample.

The second wavelength may be a wavelength at which water absorbance data is reliably obtained. The second wavelength may be a wavelength at which water exhibits strong absorption characteristics. The second wavelength may be a wavelength at which water absorbs a significant amount of the second electromagnetic radiation signal. That is, the second wavelength may be a wavelength at which the intensity of the second electromagnetic radiation signal is significantly reduced due to absorption of light by water molecules.

The second wavelength may be a wavelength at which proteins and/or lipids exhibit weak absorption characteristics. The second wavelength may be a wavelength at which proteins and/or lipids absorb a minimal amount of the second electromagnetic radiation signal. That is, the second wavelength may be a wavelength at which the intensity of the second electromagnetic radiation signal is not significantly reduced due to the absorption of electromagnetic radiation by protein and/or lipid molecules.

Most preferably, the second wavelength is approximately 1425nm, where approximately means within 5nm, 10nm, 25nm, 50nm or 100nm of 1425nm.

The third electromagnetic radiation signal may have a transmitter intensity when transmitted by the at least one transmitter. The third electromagnetic radiation signal may have a receiver intensity when received by the at least one receiver. The receiver intensity may be different to the transmitter intensity. The receiver intensity may be less than the transmitter intensity, for example due to loss of the electromagnetic radiation signal as a result of the scattering of light within the blood sample.

The difference between the receiver intensity and the transmitter intensity may be an indication of the amount of light scattering that occurs on the skin and within the blood sample. The difference between the receiver intensity and the transmitter intensity may therefore be an indication of the amount of light that is lost from the first and/or the second electromagnetic radiation signals as a result of device wearing position and light scattering that occurs on the skin and within the blood sample. The third electromagnetic radiation signal may therefore be referred to as a calibration signal.

The third wavelength may be a wavelength at which light scattering data is readily obtained. The third wavelength may be a wavelength at which glucose exhibits weak absorption characteristics. The third wavelength may be a wavelength at which glucose absorbs a minimal amount of the third electromagnetic radiation signal.

The third wavelength may be a wavelength at which water and/or proteins and/or lipids exhibit weak absorption characteristics. The third wavelength may be a wavelength at which water and/or proteins and/or lipids absorb a minimal amount of the third electromagnetic radiation signal. That is, the third wavelength may be a wavelength at which the intensity of the third electromagnetic radiation signal is not significantly reduced due to the absorption of electromagnetic radiation by water and/or protein and/or lipid molecules.

Most preferably, the third wavelength is approximately 900nm, or approximately 110Onm, where approximately means within 5nm, 10nm, 25nm, 50nm or 10Onm of those values. Where the transmitter intensity of all three electromagnetic radiation signals is the same, the receiver intensity of the received third electromagnetic radiation signal may be greater than the receiver intensity of the received first electromagnetic radiation signal and/or the receiver intensity of the received second electromagnetic radiation signal. This may be due to the negligible attenuation from the absorptions of water and glucoses molecules at the third wavelength.

Where the transmitter intensity of all three electromagnetic radiation signals is the same, the receiver intensity of the received second electromagnetic radiation signal may be less than the receiver intensity of the received first electromagnetic radiation signal. This may be due to stronger attenuation of the electromagnetic radiation by water molecules at the second wavelength than by glucose molecules at the first wavelength.

By using electromagnetic radiation signals that have the abovementioned wavelength characteristics, it is ensured that the first and second electromagnetic radiation signals penetrate deeper through the skin of a patient in use. This in turn means that the glucose concentration measurement is determined based on absorption data that is taken from the blood of the patient, rather than being obscured by some of the electromagnetic radiation being absorbed by protein and/or lipid cells between the surface of the skin and the blood. In addition, it is ensured that the third electromagnetic radiation signal accounts for light lost as a result of wearing position and scattering on the skin and within the blood, not by absorption by water and/or glucose molecules. This enables the glucose concentration determination to be calibrated to account for light lost as a result of scattering.

Hence, according to a third aspect of the invention, there is provided a glucose concentration measuring device comprising at least one transmitter, at least one receiver, and at least one controller; the at least one transmitter being configured to emit a first electromagnetic radiation signal having a first wavelength and a second electromagnetic radiation signal having a second wavelength to illuminate an in vivo blood sample; the at least one receiver being configured to receive the first and second electromagnetic radiation signals after the electromagnetic radiation signals have illuminated said blood sample; and the at least one controller being configured to generate first spectral data indicative of glucose absorbance based on the first received electromagnetic radiation signal and second spectral data indicative of water absorbance based on the second received electromagnetic radiation signal, the at least one controller also being configured to determine a glucose concentration measurement in dependence on the first and second spectral data.

According to a fourth aspect of the invention, there is provided a method of measuring glucose concentration, the method comprising the steps of: (a) emitting a first electromagnetic radiation signal having a first wavelength to illuminate an in vivo blood sample; (b) emitting a second electromagnetic radiation signal having a second wavelength to illuminate the in vivo blood sample; (c) receiving the first and second electromagnetic radiation signals after the electromagnetic radiation signals have illuminated said blood sample; (d) generating first spectral data indicative of glucose absorbance based on the first received electromagnetic radiation signal and generating second spectral data indicative of water absorbance based on the second received electromagnetic radiation signal; and (e) determining a glucose concentration measurement dependent on the first and second spectral data.

The first wavelength may be a wavelength at which glucose exhibits strong absorption characteristics. The first wavelength may be a wavelength at which glucose absorbs a significant amount of the first electromagnetic radiation signal. That is, the first wavelength may be a wavelength at which the intensity of the first electromagnetic radiation signal is significantly reduced due to the absorption of electromagnetic radiation by glucose molecules. The first wavelength may be a wavelength at which water and/or proteins and/or lipids exhibit weak absorption characteristics. The first wavelength may be a wavelength at which water and/or proteins and/or lipids absorb a minimal amount of the first electromagnetic radiation signal. That is, the first wavelength may be a wavelength at which the intensity of the first electromagnetic radiation signal is not significantly reduced due to the absorption of electromagnetic radiation by water and/or protein and/or lipid molecules. The first wavelength may be between 1550 nm and 1650nm. For example, the first wavelength may be approximately 1550nm, or approximately 1650nm, where approximately means within 5nm, 10nm, 25nm, 50nm or 100nm of 1650nm.

The second wavelength may be a wavelength at which water absorbance data is reliably obtained. The second wavelength may be a wavelength at which water exhibits strong absorption characteristics. The second wavelength may be a wavelength at which water absorbs a significant amount of the second electromagnetic radiation signal. That is, the second wavelength may be a wavelength at which the intensity of the second electromagnetic radiation signal is significantly reduced due to absorption of light by water molecules. The second wavelength may be a wavelength at which proteins and/or lipids exhibit weak absorption characteristics. The second wavelength may be a wavelength at which proteins and/or lipids absorb a minimal amount of the second electromagnetic radiation signal. That is, the second wavelength may be a wavelength at which the intensity of the second electromagnetic radiation signal is not significantly reduced due to the absorption of electromagnetic radiation by protein and/or lipid molecules. Most preferably, the second wavelength is approximately 1425nm, where approximately means within 5nm, 10nm, 25nm, 50nm or 100nm of 1425nm.

The at least one transmitter may be configured to emit a third electromagnetic radiation signal having a third wavelength. The at least one receiver may be configured to receive the third electromagnetic radiation signal. The at least one controller may be configured to generate third spectral data indicative of light scattering data based on the third received electromagnetic radiation signal. The at least one controller may also be configured to determine the glucose concentration measurement dependent on the third spectral data.

The third wavelength may be a wavelength at which glucose and/or water and/or proteins and/or lipids exhibit weak absorption characteristics. The third wavelength may be a wavelength at which glucose and/or water and/or proteins and/or lipids absorb a minimal amount of the third electromagnetic radiation signal. That is, the third wavelength may be a wavelength at which the intensity of the third electromagnetic radiation signal is not significantly reduced due to the absorption of electromagnetic radiation by water and/or protein and/or lipid molecules. Most preferably, the third wavelength is approximately 900nm, or approximately

110Onm, where approximately means within 5nm, 10nm, 25nm, 50nm or 10Onm of those values.

The first spectral data may be spectral data that is indicative of glucose absorbance data. The first spectral data may be spectral data that is indicative of amount of the first electromagnetic radiation signal absorbed by glucose molecules in the blood sample. The first spectral data may be spectral data that is indicative of the attenuation of the first electromagnetic radiation signal as a result of the absorption of electromagnetic radiation by glucose molecules in the blood sample. The first spectral data may be spectral data that is indicative of the amount of glucose molecules in the blood sample, i.e., the glucose concentration of the blood sample. The first spectral data may be indicative of a first loss of intensity Ah of the first electromagnetic radiation signal between the transmitter and the receiver at the first wavelength. That is, the first spectral data may be indicative of an amount of the first electromagnetic radiation signal at the first wavelength attenuated by the in vivo blood sample.

The second spectral data may be spectral data that is indicative of water absorbance data. The second spectral data may be spectral data that is indicative of amount of the second electromagnetic radiation signal absorbed by water molecules in the blood sample. The second spectral data may be spectral data that is indicative of the attenuation of the second electromagnetic radiation signal as a result of the absorption of electromagnetic radiation by glucose molecules in the blood sample. The second spectral data may be spectral data that is indicative of the amount of water molecules in the blood sample, i.e., the water concentration of the blood sample. The second spectral data may be indicative of a second loss of intensity A of the second electromagnetic radiation signal between the transmitter and the receiver at the second wavelength. That is, the second spectral data may be indicative of an amount of the second electromagnetic radiation signal at the second wavelength attenuated by the in vivo blood sample.

The third spectral data may be spectral data that is indicative of light scattering data. The third spectral data may be indicative of the amount of light lost from the emitted third radioactive signal as a result of scattering. The third spectral data may be spectral data that is indicative of the attenuation of the third electromagnetic radiation signal as a result of the scattering of electromagnetic radiation by skin and blood components, e.g. glucose molecules, in the blood sample. The third spectral data may be indicative of a third loss of intensity AH of the third electromagnetic radiation signal between the transmitter and the receiver at the third wavelength. That is, the third spectral data may be indicative of an amount of the third electromagnetic radiation signal at the third wavelength attenuated by the in vivo blood sample and skin.

The glucose concentration measurement may be indicative of the amount of glucose molecules in the blood sample, i.e., the glucose concentration of the blood sample. The glucose concentration measurement may be determined in dependence on a ratio of the first loss of intensity AI1 to the second loss of intensity AI2. For example, the glucose concentration measurement may be determined according to:

A/i . Bir₂ ^/ao wherein B is a constant and wherein a_g is a glucose absorption coefficient.

The glucose concentration measuring device may comprise a display. The controller may be configured to display the glucose concentration measurement on the display. The glucose concentration measuring device may be arranged to be attached to the human body, either permanently or in use. For example, the glucose concentration measuring device may comprise a strap. Most preferably, the glucose concentration measuring device is a watch. The glucose concentration measurement may be compared with one or more threshold value. For example, the controller may be arranged to compare the glucose concentration measurement with a minimum threshold value and/or a maximum threshold value. Where the controller determines that the glucose concentration measurement is outside of the one or more threshold value, e.g. below the minimum threshold value or above the maximum threshold value, the controller may be configured to provide an alarm or warning signal. The alarm or warning signal may be a light or sound signal.

A water concentration measurement may be determined in dependence on the second spectral data and the third spectral data. The water concentration measurement may be determined dependence on a ratio of the second loss of intensity Ahto the third loss of intensity AH. For example, the water concentration measurement may be determined according to:

Where C is a pre-calibrated parameter.

The method of measuring glucose concentration may further comprise a step of comparing the water concentration measurement with one or more threshold value. For example, the method may comprise the step of comparing the water concentration measurement with a minimum threshold value and/or a maximum threshold value. The threshold value may be indicative of whether the device is being used appropriately, e.g. being properly worn and/or ensuring no sweat is obscuring the emitting and receiving of electromagnetic radiation signals between the device and the skin. Where it is determined that the water concentration measurement is outside of the one or more threshold value, e.g. below the minimum threshold value or above the maximum threshold value, the method may comprise the step of providing an alarm or warning signal. The alarm or warning signal may be a light or sound signal. The glucose measuring device may comprise means for conveying an alarm or warning signal to a wearer. For example, the glucose measuring device may comprise a speaker or a light source that is actuated in response to the provision of an alarm or warning signal. Alternatively, where the glucose measuring device comprises a display, a message may be displayed on the display in response to the provision of an alarm or warning signal.

The first electromagnetic radiation signal may be emitted along a first path. The second electromagnetic radiation signal may be emitted along a second path. The third electromagnetic radiation signal may be emitted along a third path. At least a portion of the first, second and third paths may be the same. Preferably, at least the portion of the first path at which the first electromagnetic radiation signal is incident on the human body, the portion of the second path at which the second electromagnetic radiation signal is incident on the human body, and the portion of the third path at which the third electromagnetic radiation signal is incident on the human body are the same.

According to aspects of the invention there is provided one or more processors comprising machine readable instructions for performing or controlling any, any combination of, or all of, the method steps described in relation to previous aspects of the invention. According to further aspects of the invention there is provided a data carrier or data storage medium comprising machine readable instructions for controlling one or more processor to perform said method step(s).

Practicable embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, of which:

Figure 1 is a graph plotting the near-infrared absorption spectra for molecules found in the blood;

Figure 2 is a graph plotting the near-infrared reflectance spectra for different blood glucose concentrations; Figure 3 is a graph plotting the relationship between reflected light and glucose concentration for a number of discrete wavelengths;

Figure 4 is a graph plotting the experimental measurement of predicted glucose solution using a technique according to the present invention that shows a resolution of 3.29 mmol/L;

Figure 5 is a schematic diagram of a glucose concentration measuring device according to an embodiment of the invention; and

Figure 6 is a flow diagram illustrating a method of measuring glucose concentration according to an embodiment of the invention.

Figure 1 illustrates the near-infrared absorption spectra for three molecules commonly found in the bloodstream of a human - water, glucose and lipids. Of particular note from these absorption spectra is that the strongest absorption of water is at 1425nm, the strongest absorption of glucose is 1650nm, and that there are some wavelengths at which none of the molecules have strong absorption characteristics, such as at 900nm or at 1100nm.

Figure 2 illustrates the near-infrared reflectance spectra for different blood glucose concentrations. It can be seen that at 900nm and 1100nm, because none of the aforementioned molecules have strong absorption spectra at these wavelengths, the reflected light is approximately the same for each of the three blood glucose concentrations.

At 1425nm, it can be seen that there is a greater variance in the reflectance of light between each of the three glucose concentrations, believed to be caused by the strong absorption characteristics of water molecules at this wavelength.

Similarly, at 1650nm, it can be seen that there is a greater variance in the reflectance of light between each of the three glucose concentrations, believed to be caused by the strong absorption characteristics of glucose molecules at this wavelength.

Figure 3 illustrates the relationship between reflected light and glucose concentration for a number of discrete wavelengths. It can be seen from Figure 3 that for any emitted wavelength, the greater the glucose concentration of the blood sample, the lower the amount of reflected light, i.e. because the presence of more glucose molecules leads to a greater absorption of emitted light, thus meaning less light is reflected.

It can also be seen that the relationship between glucose concentration and reflected light is different for different wavelengths of emitted light, due to the varying effect of light scattering and absorption of light by different molecules at different wavelengths.

The amount of reflected light is most strongly dependent on glucose concentration at 1650nm, where the emitted light is reduced due to absorption by glucose molecules and light scattering. The amount of reflected light is less strongly dependent on glucose concentration at 1425nm, where the emitted light is reduced due to absorption by glucose molecules and by water molecules. The amount of reflected light is least strongly dependent on glucose concentration at 900nm, where the emitted light is reduced only due to light scattering.

The present invention provides a non-invasive technique for accurately measuring glucose concentration by harnessing the properties of light at a combination of wavelengths, as will be described. Figure 4 shows a graph indicating data captured using the present invention, in particular captured using the device 10 described with reference to Figure 5 and the method described with reference to Figure 6. The graph illustrates the relationship between predicted concentration of glucose solution in mmol/L (y-axis) as determined using the present invention, and a known concentration of the glucose solution (x-axis). It can be seen from Figure 4 that a resolution of 3.29 mmol/L for the predicted concentration can be obtained from this technology. Figure 5 illustrates an exploded view of a glucose concentration measuring device 10 used to obtain the data shown in Figure 4. The device 10 comprises a first light emitter 20, a second light emitter 30, a third light emitter 35, a reflector 40, a detector 60, and a controller 70.

The first light emitter 20, the second light emitter 30 and the third light emitter 35 are provided in the form of a multi-wavelength vertical-cavity surface-emitting laser. The first light emitter 20 is arranged to emit light having a wavelength of around 1650nm, the second light emitter 30 is arranged to emit light having a wavelength of around 1425nm, and the third light emitter 35 is arranged to emit light having a wavelength of around 900nm or around 1100nm.

Beneficially, in order to provide a cost effective wearable sensor, the device 10 according to the present invention utilises wavelengths in the telecommunication region of 900-1650nm. Operation in this range enables the use of readily available, cost-effective light emitters 30, 35 and detectors 60 with good performance at room temperature. This wavelength range has also been found to provide a reasonable penetration depth, and facilitates the selection of three wavelengths having suitable glucose absorption characteristics, as will be explained.

The reflector 40 is arranged to focus the light emitted by the emitters 20, 30, 35 in use on to the body of a user 50, such that the light emitted by each of the emitters 20, 30, 35 follows the same path on to the surface of the body of the user 50.

The detector 60 is arranged to receive light reflected by the body of the user 50 in use, and to convey a signal(s) to the controller 70 indicative of the amount of light detected for each wavelength. The controller 70 is configured to receive said signal from the detector 60, and to calculate a glucose concentration measurement of the user 50 based on that signal. The spacing and orientation of the components of the device 10 illustrated in Figure 1 are not to scale. It is foreseen that at least the first light emitter 20, the second light emitter 30, the third light emitter 35, the reflector 40 and the detector 60 may be positioned within a single housing which can be worn upon the body of the user 50, for example as a watch upon the wrist of the user 50. The controller 70 may also be contained within the housing, or may be positioned remotely of the housing and the other components of the device 10.

Figure 6 illustrates a method 100 of measuring glucose concentration, which may be implemented using glucose concentration measuring device 10, once placed worn by a user, for example on their wrist as part of a watch. At step 110, a first light signal having a wavelength of approximately 1650nm is emitted by the first light emitter 20 towards a user’s body. At step 120, a second light signal having a wavelength of approximately 1425nm is emitted by the second light emitter 30 towards the user’s body. At step 125, a third light signal having a wavelength of approximately 900nm or approximately 1100nm is emitted by the third light emitter 35 towards the user’s body. Preferably, steps 110, 120 and 125 occur simultaneously, although in some embodiments they may instead occur sequentially.

At step 130, detector 60 collects a first light signal having a wavelength of approximately 1625nm. At step 140, detector 60 collects a second light signal having a wavelength of approximately 1425nm. At step 145, detector 60 collects a third light signal having a wavelength of approximately 900nm or approximately 110nm, dependent on the wavelength that was emitted in step 125. Steps 130, 140 and 145 may occur simultaneously or sequentially.

The first light signal collected by detector 60 at step 130 is indicative of the attenuation of the first light signal emitted by the first light emitter 20, i.e. the amount of light that has been lost from the first signal as a result of impinging on the user’s body. The second light signal collected by detector 60 at step 140 is indicative of the attenuation of the second light signal emitted by the second light emitter 30, i.e. the amount of light that has been lost from the second signal as a result of impinging on the user’s body. The third light signal collected by detector 60 at step 145 is indicative of the attenuation of the third light signal emitted by the third light emitter 35, i.e. the amount of light that has been lost from the third signal as a result of impinging on the user’s body.

The three wavelengths have been specifically selected to enable delineation of glucose absorbance, water absorbance, scattering and other use conditions. By enabling this delineation, the method enables accurate estimation of glucose concentration levels as shown in the data of Figure 4.

A wavelength of approximately 1650nm has been chosen for the first light signal emitted by the first light emitter 20 because good glucose absorbance data is reliably obtained at this wavelength, i.e. because glucose molecules will absorb a significant amount of light at this wavelength. At the 1650nm wavelength, the main attenuation of the first light signal is caused by glucose absorbance. Thus, at this first wavelength the main loss is from glucose, however the attenuation of the first light signal will also include secondary losses from water, other bio-molecules and scattering.

A wavelength of approximately 1400nm or 1425nm has been chosen for the second light signal emitted by the second light emitter 30 because good water absorbance data is reliably obtained at this wavelength, i.e. because water molecules will absorb a significant amount of light at this wavelength. At the 1400nm or 1425nm wavelength, the attenuation of the second light signal is caused by the sum of losses from water absorbance and scattering.

A wavelength of approximately 900nm or approximately 1100nm has been chosen for the third light signal emitted by the third light emitter 35 because good light scattering data is reliably obtained at this wavelength, i.e. because no significant absorption occurs from the major bio-molecules in a typical blood sample. Thus, at the 900nm or 110Onm wavelength, the attenuation of the third light signal is caused by scattering and/or other use conditions. Thus, as will be described fully with reference to steps 150 and 160, the combination of the received first to third light signals can be used to calculate glucose concentration, calibrated to account for any scattering or other use conditions of the device 10.

At step 150, second light signal collected by detector 60 at step 140 is compared with the third light signal collected by detector 60 at step 145 to determine the water concentration in the blood. The determined water concentration is then compared with a predetermined range of values to determine whether the device is being worn correctly, i.e. to check whether steps 110-145 have been performed correctly. If the determined water concentration is within the predetermined range, then the method proceeds to step 160. If the determined water concentration is not within the predetermined range, then an error message is indicated to the user, asking the user to reposition the device and start the method again.

In alternative embodiments, it is envisaged that the signals may be emitted and collected in a different order, e.g. to test whether the device is correctly worn before emitting the signal having a wavelength of 1650nm, since it is not necessary to make this determination.

At step 160, the three received light signals are analysed to determine the glucose concentration of the blood. The glucose absorbance data alone is not sufficient to determine the glucose concentration of the blood, because the absorbance data will be affected by other factors, e.g. the absorption of the electromagnetic radiation by other molecules in the blood, such as water, protein and lipids, as well as the scattering of light within the blood and external use factors, such as temperature. However, by obtaining water absorbance data and light scattering data at the same time, it is possible to determine a glucose concentration that takes these factors into account.

In particular, the glucose concentration measurement may be obtained using the following derivation. By defining the emitted intensity for each wavelength as Io, and the collected intensity of each wavelength after reflection or transmission as , then the loss of intensity (i.e. the loss of light due to scattering and/or absorption) for each wavelength can be defined as:

It is known from the absorption spectra in Figure 1 that the absorption of light by water, glucose or lipid molecules at 900nm or 1100nm is negligible, and thus it can be assumed that the loss of light intensity at the third wavelength, A/3, is due to scattering rather than absorption, and can thus be defined as: I3 ⁼ g g where S_g is a glucose scattering coefficient, and L_g is the glucose concentration of the blood sample.

Hence, the loss of light emitted at the second wavelength may be defined as:

where A is a constant that represents a pre-calibrated factor associated with water absorption; and law is the absorption of light by water molecules.

Similarly, the loss of light emitted at the first wavelength may be defined as:

where B is a constant that represents a pre-calibrated factor associated with glucose absorption, and l_ag is the absorption of light by glucose molecules.

In view of the definition of A/2 above, this can be reformulated as: A/i - BI_ag + A/₂ which in turn can be reformulated as:

A/i ^x = Ba y_aL y_a + A/₂- where a_g represents the glucose absorption coefficient for light having a wavelength of 1650 nm.

Hence, the relative concentration of glucose molecules in the blood can be determined from its percentage with respect to the presence of water, and expressed as:

where B is a constant that represents the pre-calibrated dependence of the ratio of glucose to water on the absolute concentration of glucose molecules in the blood.

In addition, the ratio of loss of light at the second wavelength compared to the third wavelength indicates the water concentration in the blood sample, which can be tightly controlled and therefore used to check if the device is being worn correctly, i.e. as a calibration check:

Where Lw is the water concentration in the blood sample, and C is a pre-calibrated parameter that gives water concentration in a healthy environment.

Claims

1. A glucose concentration measuring device comprising at least one transmitter, at least one receiver, and at least one controller; the at least one transmitter being configured to emit a first electromagnetic radiation signal having a first wavelength and a second electromagnetic radiation signal having a second wavelength to illuminate an in vivo blood sample; the at least one receiver being configured to receive the first and second electromagnetic radiation signals after the electromagnetic radiation signals have illuminated said blood sample; and the at least one controller being configured to: generate first spectral data indicative of glucose absorbance based on the first received electromagnetic radiation signal and second spectral data indicative of water absorbance based on the second received electromagnetic radiation signal, and determine a glucose concentration measurement in dependence on the first and second spectral data.

2. The glucose concentration measuring device according to claim 1 , wherein each of the first wavelength and the second wavelength is a wavelength at which proteins and/or lipids exhibit weak absorption characteristics.

3. The glucose concentration measuring device according to any preceding claim, wherein the first wavelength is a wavelength at which glucose exhibits strong absorption characteristics.

4. The glucose concentration measuring device according to any preceding claim, wherein the first wavelength is approximately 1650nm.

5. The glucose concentration measuring device according to any preceding claim, wherein the second wavelength is a wavelength at which water exhibits strong absorption characteristics.

6. The glucose concentration measuring device according to any preceding claim, wherein the second wavelength is approximately 1425nm.

7. The glucose concentration measuring device of any preceding claim, wherein the first spectral data is indicative of a first loss of intensity Ah of the first electromagnetic radiation signal between the transmitter and the receiver at the first wavelength, and wherein the second spectral data is indicative of a second loss of intensity A of the second electromagnetic radiation signal between the transmitter and the receiver at the second wavelength.

8. The glucose concentration measuring device of claim 7, wherein the at least one controller is configured to determine the glucose concentration measurement in dependence on a ratio of the first loss of intensity AI1 to the second loss of intensity AI2.

9. The glucose concentration measuring device of claim 8, wherein the at least one controller is configured to determine the glucose concentration measurement according to: /i . B ir₂ ^/ao wherein B is a constant and wherein a_g is a glucose absorption coefficient.

10. The glucose concentration measuring device of any preceding claim, wherein: the at least one transmitter is configured to emit a third electromagnetic radiation signal having a third wavelength, the at least one receiver is configured to receive the third electromagnetic radiation signal; and the at least one controller may be configured to generate third spectral data indicative of light scattering data based on the third received electromagnetic radiation signal and determine the glucose concentration measurement further in dependence on the third spectral data.

11 . The glucose concentration measuring device according to claim 10, wherein the third wavelength is a wavelength at which proteins, lipids, water and glucose exhibit weak absorption characteristics.

12. The glucose concentration measuring device according to claim 10 or 11 , wherein the third wavelength is approximately 900nm or 1100nm.

13. The glucose concentration measuring device of any of claims 10 to 12, wherein the third spectral data is indicative of a third loss of intensity AH of the third electromagnetic radiation signal between the transmitter and the receiver at the third wavelength.

14. The glucose concentration measuring device of claim 13 when dependent through claim 7, wherein the at least one controller is configured to determine a water concentration measurement in dependence on a ratio of the second loss of intensity Ahto the third loss of intensity AI3.

15. The glucose concentration measuring device according to any preceding claim, wherein the glucose concentration measuring device comprises a display, and wherein the controller is configured to display the glucose concentration measurement on the display.

16. The glucose concentration measuring device according to any preceding claim, wherein the glucose concentration measuring device comprises a strap arranged to attach the device to the human body.

17. The glucose concentration measuring device according to any preceding claim, wherein the at least one transmitter is configured to emit the first electromagnetic radiation signal along a first path and the second electromagnetic radiation signal along a second path, wherein the first and second electromagnetic radiation signals are emitted simultaneously and at least a portion of the first and second paths are the same.

18. A method of measuring glucose concentration, the method comprising the steps of:

(a) emitting a first electromagnetic radiation signal having a first wavelength to illuminate an in vivo blood sample;

(b) emitting a second electromagnetic radiation signal having a second wavelength to illuminate the in vivo blood sample;

(c) receiving the first and second electromagnetic radiation signals after the electromagnetic radiation signals have illuminated said blood sample;

(d) generating first spectral data indicative of glucose absorbance based on the first received electromagnetic radiation signal and generating second spectral data indicative of water absorbance based on the second received electromagnetic radiation signal; and

(e) determining a glucose concentration measurement in dependence on the first and second spectral data.

19. The method of measuring glucose concentration of claim 18, wherein the first wavelength is approximately 1650nm and the second wavelength is approximately 1425nm.

20. The method of measuring glucose concentration of claim 18 or 19, wherein the first spectral data is indicative of a first loss of intensity Ah of the first electromagnetic radiation signal between the transmitter and the receiver at the first wavelength, wherein the second spectral data is indicative of a second loss of intensity Ah of the second electromagnetic radiation signal between the transmitter and the receiver at the second wavelength, and wherein step (e) comprises determining the glucose concentration measurement in dependence on a ratio of the first loss of intensity AI1 to the second loss of intensity AI2.

21 . The method of measuring glucose concentration of any of claims 18 to 20, wherein: step (a) further comprises emitting a third electromagnetic radiation signal having a third wavelength along a third path to illuminate the in vivo blood sample, step (c) further comprises receiving the third electromagnetic radiation signal after the third electromagnetic radiation signal has illuminated said blood sample, step (d) further comprises generating third spectral data indicative of light scattering data based on the third received electromagnetic radiation signal; and step (e) comprises determining the glucose concentration measurement dependent on the three received electromagnetic radiation signals.

22. The method of measuring glucose concentration according to claim 21 , wherein the third wavelength is approximately 900nm or 1100nm.

23. The method of measuring glucose concentration according to claim 21 or 22 when dependent through claim 20, wherein the third spectral data is indicative of a third loss of intensity AH of the third electromagnetic radiation signal between the transmitter and the receiver at the third wavelength, and further comprising a step of determining a water concentration measurement in dependence on a ratio of the second loss of intensity A to the third loss of intensity AI3.

24. The method of measuring glucose concentration of cany of claims 18 to 23, further comprising a step of comparing the glucose concentration measurement with one or more threshold value.

25. The method of measuring glucose concentration according to claim 24, wherein where it is determined that the glucose concentration measurement is outside of the one or more threshold value, the method comprises a step of providing an alarm or warning signal.