GB2606691A

GB2606691A - Non-invasive blood analysis

Info

Publication number: GB2606691A
Application number: GB2104910.1A
Authority: GB
Inventors: Elliott Christopher; Jones Mark-Eric
Original assignee: LEMAN MICRO DEVICES SA
Current assignee: LEMAN MICRO DEVICES SA
Priority date: 2021-04-07
Filing date: 2021-04-07
Publication date: 2022-11-23
Also published as: GB202104910D0

Abstract

A personal hand-held monitor for determining the concentration of an analyte in a user’s blood includes a signal acquisition device having a blood photosensor with photo-emitters and detectors, and two or more optical cells through which light is transmitted or scattered before detection, wherein one of the optical cells contains an analyte or mimics the absorption spectrum of the analyte. The difference in intensity of light passing through each cell is calculated to determine the analyte concentration in the user’s blood. The monitor includes one or more beam splitters 401, 407 to ensure a single optical path between each emitter and detector. In a first embodiment, the light source is an LED. In a second embodiment, the optical cell mimicking the analyte absorption spectrum is a manufactured optical filter. In a third embodiment, optical signals are provided at multiple wavelengths to estimate the blood volume in the photosensor field of view. In a fourth embodiment, there is a ridge on the surface of the signal acquisition device between the photo-emitters and detectors.

Description

NON-INVASIVE BLOOD ANALYSIS

Field of the invention

The present invention relates to a personal hand-held monitor (PHHM) adapted to measure the concentration of an analyte in blood.

Background to the invention

There are many circumstances in which it is desirable to measure the concentration of an analyte in blood. One of the most important is the measurement of blood glucose concentration, of cmcial importance to the management of diabetes. It is estimated by Danaei et al. ("National, regional, and global trends in lasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants", Lancet, 2011, 378(9785):31-40) that 370 million people in the world suffer from diabetes and the WHO predicts that diabetes will be the seventh leading cause of death by 2030 ("Global status report on non-communicable diseases 2010", WHO 2011). At present, the only accurate and inexpensive way for diabetics to measure their blood glucose concentration is by taking a blood sample, usually by pricking a finger, and placing a drop of blood on a test strip. A measurement of the change of colour of the strip or a measurement of a redox reaction on the strip after application of the blood sample provides an indication of the blood glucose concentration.

Inexpensive automated equipment exists to estimate the change in colour or the redox reaction but there is no consumer equipment capable of making die measurement without taking a blood sample and many diabetics have to do this several times per day.

Other analytes, such as alcohol, haemoglobin, creatinine, cholesterol, stimulants or other drugs, including illegal or otherwise forbidden substances, are also important and again there is no accurate, reliable and inexpensive way of estimating their concentration non-invasively.

In principle, absorption spectroscopy would be a good method for estimating the concentration of an analyte but this is difficult in vivo if the contribution to the absorption from the analyte is small compared to the absorption by other materials in the blood and tissue, especially if the analyte has few or no narrow absorption bands in the useable near infra-red (NIR) and/or if those bands are overlapping with those of water, which is the predominant component of blood and tissue. For example, Klonoff ("Non-invasive blood glucose monitoring", Diabetes Care, 20, 3, 435-437 1997) states: "Glucose is responsible.lor <0.1% of NIR absorbed by the body Water, .tat, skin, muscle and bone account1bl' the vast majority of NIR absorption. Perturbations in the amounts of these substances can alter NIR absorption and thus invalidate the calibration _formula for correlating light absorption with blood glucose concentrations...".

Even if the problem of low absorption could be overcome, the measurement of the specific absorption would require a precise spectrometer that is not easily made inexpensively and reliably.

WO 2013/001265 discloses significant improvements on the prior art. Claim 25 of WO 2013/001265 discloses a personal hand-held monitor (PHFIN) comprising a signal acquisition device for acquiring signals which can be used to derive a measurement of a parameter related to the health of the user, the signal acquisition device being integrated with a personal hand-held computing device (PHHCD), wherein the signal acquisition device comprises a blood photosensor having a photo-emitter for transmitting light to a body part of a user, a photo-detector for detecting light transmitted through or scattered by the body part and an optical cell, containing an analyTte to be detected, through which light transmitted through or scattered by the body part passes before it reaches the photo-detector, wherein the processor of the PHI-1M is adapted to process signals obtained from the photo-detector in the presence of the body part and in the absence of the body part to provide a measurement of the concentration of the analyte in the user's blood. WO 2013/001265 also discloses using the principle of two beams, one of which passes through a cell containing the analyte or mimicking the analyte, and comparing the power in each beam.

The invention disclosed in WO 2013/001265 goes some way towards the goal of a monitor that is non-invasive, inexpensive, accurate mid reliable. However, it is not specific to the analyte contained in blood because the signal is also affected by analyte in the surrounding tissue. Further improvements are also desirable to reduce the cost of implementation and to improve accuracy.

WO 2014/125355 discloses a PFILIM which has greatly improved performance compared to that of the MUM of claim 25 of WO 2013/001265. It exploits more effectively a second degree of correlation to improve specificity. WO 2014/125355 teaches that the signal related to the concentration of the amble may be correlated with the pulse, so as to make the signal preferentially sensitive to the change in the amount of analyte when the artery expands with each pulse. It further teaches that the change may be maximised by applying pressure to the body part so as to cause the pressure around the artery to be similar to diastolic blood pressure. It further teaches that one of the optical cells may include a material that mimics the absorption spectrum of the analyte to be detected.

The PHHM of WO 2014/125355 represents a considerable advance on the prior art and allows accurate measurements to be made of the total amount of amble in the field of view of the instrument. WO 2017/198981 discloses a further invention which reduces the size and cost of the device and improves the accuracy of the estimate of concentration. The size and cost of a product embodying the PHIAM described in WO 2014/125355 is limited by the size and heat dissipation of the photo-emitter and the mechanical or other means of switching between the two beams. The accuracy is limited by the information available to normalise the measured signal to find the concentration of analyte from a measurement of the total quantity of analyte. The invention of WO 2017/198981 is to miniaturise the device using multiple solid state components and a physical configuration that allows it to be small, robust and inexpensive.

WO 2017/198981 discloses a PHHIM which is a considerable advance on the prior art. The PHHM is a sensitive and accurate detector of analyte in the field of view, provided that the tissue in the field of view is homogeneous. However, extensive computer simulation by the inventors has found that this is not always the case. Any inhomogeneity in the body part, for example if there is a single large artery in the field of view, means that the different beams may have different exposure to the change in the luminal area of the artery.

The computer simulations found that reliable high accuracy requires that each beam penetrates the same volume of tissue.

The accuracy of the PHHM disclosed in -WO 201 7/1 98981 is limited because the optical path is not the same for each beam because either the photo-emitters or the photo-detectors, or both, are not co-located. The simulations found that the accuracy could be increased by ensuring that both or all of the beams follow the same path. The simulations also showed an important thriller property, that the direction of the beams when they are outside the body part is not critical, provided that the beams illuminate or receive light from the same area of skin over the body part. Thus, it is not necessary for the beams to be parallel. This unexpected result is a consequence of the isotropic scattering when the light enters the body part. The present invention draws on this simulation result in order to improve the accuracy of the measurement of the analyte.

The Present Invention The present invention provides a personal hand-held monitor (PI-11-IND of the type described in WO 2017/198981 wherein one or more beam splitters is employed to ensure that there is a single optical path between each photo-emitter and each photo-detector. The disclosure of WO 2017/198981 is incorporated into this application in its entirety by reference.

A PHHM according to the present invention is defined in independent claims 1, 11, 14 and 16. Preferred features of the invention are defined in the dependent claims.

The Drawings In the accompanying drawings: Figure 1 shows the operation of a beam splitter; Figure 2 shows three examples of beam splitters; Figure 3 shows an embodiment of a beam splitter in which a second mirror has been added to reduce the size of the device; Figure 4 shows how curved surfaces may be used to focus the beams; and Figure 5 shows a collimator used to act as a beam splitter.

The present invention is described below with reference to the accompanying drawings by way of example only. The invention is not limited to the embodiment(s) shown in the accompanying drawings. The scope of the invention is defined in the accompanying claims.

The PHEIM according to the present invention is based on the PHFIM described in WO 2017/198981 and the specific description of WO 2017/198981 is hereby incorporated into this description by reference.

In addition to the features of a P1-It-TM as shown in WO 2017/198981, the PHHM of the present invention uses one or more beam splitters to ensure that, in use, the multiple photo-emitters or the multiple photo-detectors emit to or detect light from a single location on the surface of the skin of the body part being illuminated. A beam splitter is an optical device that directs a fraction of the light in one direction and the remainder of the light in another direction. A beam splitter is reciprocal in that the light may pass in either direction through the beam splitter. Figure 1 is a schematic representation of a simple beam splitter. Incoming light 102 hits the surface of the beam splitter 101. The surface is semi-reflective so around half the incoming light is reflected 103. The beam splitter is semi-transparent so the rest of the light 104 passes through the beam splitter.

It is apparent that the beam splitter does not ensure that the two beams are parallel but, as was found from the computer simulations, this is not essential.

Figure 2 shows two embodiments of a semi-reflective surface of a beam splitter 201, 202. The surface is silvered with a pattern of reflecting material, constructed so that the silvered area is approximately half the total area and the gaps between the silvered areas are small compared with the width of the incoming light beam. Figure 2 also shows a further embodiment 203 in which two bundles of fibre-optic cables 204, 205 (205 shown with dashed lines to make the separation clear) are configured so that they either split the light coming from above into two beams at the sides, or merge the light coming from the sides into a single beam at the top. This is not restricted to two beams; other embodiments may have more than two bundles of co-mingled fibre-optic cables. it also is not restricted to a bundle of cables; the bundles may be formed of one cable.

Other types of beam splitter will be known to a person skilled in the art.

Figure 3 shows a typical embodiment of how a beam splitter is used in a P1-11-IM of the present invention. Incoming light 302 is split by the beam splitter into two beams 303, 304. The first beam 303 is received by a photo-detector 305. The second beam is reflected by a conventional mirror 307 to a second photo-detector 306. The second mirror is not essential but is preferable because it reduces the size of the complete device and allows the two photo-detectors to lie in a single plane. Preferably, the path length from the beam splitter 301 to the photo-detector 305 is the same as the path length from the beam splitter 301 to the second photo-detector 306 because this creates an equal field of view for the two photo-detectors. The second mirror may lie at an angle with respect to the beam splitter that is not 90 degrees, as illustrated in Figure 3.

Figure 4 shows a further embodiment wherein the beam splitter 401 and the conventional mirror 407 are curved to focus their respective beams of Fight 403, 404. It is apparent in Figure 2 that the fibre-optic cables may also be configured to focus the It will be apparent to a person skilled in the art that similar geometries may be constructed in which the photo-detectors are replaced by photo-emitters and the path of the light is in the opposite direction.

The beam splitter and the second mirror may be constructed as discrete components. Preferably, they are further miniaturised by constructing them using integrated optics, wherein they are created from a single block of plastic with appropriate silvering applied to the surfaces. This permits small and precise physical dimensions to be created; the parts can be as small as around 1 mm in each direction.

Figure 5 shows another embodiment in which a block of material 501 forms a collimator that acts as a beam splitter. The block of material 501 has a conical hole, the inside surfaces of which are silvered.

At the bottom of the conical hole are located two optical devices 502, 503, which may both be either photo-emitters or photo-detectors. The silvered cone ensures that all the light from or to the optical devices passes through the hole 504. Although the light will not be essentially parallel as with the other forms of beam splitter, this does not affect the effectiveness of the device because the light is scattered isotropically when it enters the skin. This embodiment is also preferably constructed using integrated optics. The reflecting surfaces may be curved 505 to direct or focus the light, as with the other beam splitters. it will be apparent to a person skilled in the art that the collimator does not have to be linear and that flat or curved mirrors may be used in a way analogous to conventional mirror 307. It is also apparent that more than two photo-emitters or more than two photo-detectors may be placed in one collimator.

Preferably, the collimator may be combined with a beam splitter that uses a semi-reflective minor, especially if more than two beams are required.

Integrated optical components may be made using injection moulding or, for prototyping and small production quantities, using additive manufacture ("3D printing"). The reflective surfaces may be applied using ink-jet printing, sputtering or other techniques that will be well known to a person skilled in the art.

Any of the beam splitters described above may be used in a P1-IBM constructed as described in WO 2017/198981, immediately after the or each photo-emitter and/or immediately before the or each photo-detector, to ensure that there is a single optical path between each photo-emitter and each photo-detector.

Claims

CLAIMSA personal hand-held monitor (PI-IHM) comprising a signal acquisition device for acquiring signals which can be used to derive a measurement of a parameter related to the health of the user, wherein the signal acquisition device comprises a blood photosensor having one or more photo-emitters for transmitting light to a body part of a user, one or more photo-detectors for detecting light transmitted through or scattered by the body part and two or more optical cells, at least one of which contains an analyte to be detected or which mimics the absorption spectrum of the analyte to be detected, through which the light that has been or will be transmitted through or scattered by the body part passes before it reaches the or each photo-detector, wherein the processor of the P1-IHM is adapted to process the signals received from the or each photo-detector to calculate the difference in intensity of light which has passed through the or each analyte cell and light which has passed through the or each non-analyte cell and to process signals obtained from the photosensor to provide a measurement of the concentration of the analyte in the user's blood, wherein the or each photo-emitter is a light-emitting diode (LED) and the PHHM includes one or more beam splitters arranged to ensure that there is a single optical path between each photo-emitter and each photo-detector.
2. The PHHM of claim 1, wherein the or each beam splitter splits light leaving the photo-emitters, before it penetrates the body part.
3. The PI-IHM of claim 1, wherein the or each beam splitter splits light entering the photo-detectors, after it leaves the body part.
4. The PHHM of any one of claims 1 to 3, wherein the reflecting surfaces of the or each beam splitter are curved in order to focus the light that strikes them.
5. The PHHM of any one of claims 1 to 3, wherein the or each beam splitter uses one or more fibre-optic cables to split or merge the light.
6, The PHHM of claim 5, wherein separate bundles of fibre-optic cables are arranged to focus the light that strikes them.
The PHHM of any one of claims I to 3, wherein the beam splitter uses a reflecting collimator.
8. The PHHM of any one of claims 1 to 7, wherein an optical cell that mimics the absorption spectrum of the analyte to be detected is used and is a manufactured optical filter.
9. The PHI-IM of any one of claims I to 6, wherein the PHHM is adapted to provide optical signals at one or more additional wavelengths for transmission to the body part, and the processor of the PHHM is adapted to process signals at the or each additional wavelength to estimate the volume of blood in the field of view of the blood photosensor.
10. The PHHM of any one of claims I to 9, wherein there is a ridge on the surface of the signal acquisition device between the photo-emitter(s) and the photo-detector(s).
I I. A personal hand-held monitor (PHHM) comprising a signal acquisition device for acquiring signals which can be used to derive a measurement of a parameter related to the health of the user, wherein the signal acquisition device comprises a blood photosensor having one or more photo-emitters for transmitting light to a body part of a user, one or more photo-detectors for detecting light transmitted through or scattered by the body part and two or more optical cells, at least one of which contains an analyte to be detected or which mimics the absorption spectrum of the analyte to be detected, through which the light that has been or will be transmitted through or scattered by the body part passes before it reaches the or each photo-detector. wherein the processor of the PHHM is adapted to process the signals received from the or each photo-detector to calculate the difference in intensity of light which has passed through the or each analyte cell and light which has passed through the or each non-analyte cell and to process signals obtained from the photosensor to provide a measurement of the concentration of the analyte in the user's blood, wherein an optical cell that mimics the absorption spectrum of the analyte to be detected is used and is a manufactured optical filter and the PHHM includes one or more beam splitters arranged to ensure that there is a single optical path between each photo-emitter and each photo-detector.
12, The PHHM of claim 8 or claim I I or any claim when dependent on claim 8, wherein the manufactured optical filter is a sheet of glass.
13. The PHHM of claim 12, wherein the sheet of glass has a thickness of from 1 to 2mm.
14. A personal hand-held monitor (PHHM) comprising a signal acquisition device for acquiring signals which can be used to derive a measurement of a parameter related to the health of the user, wherein the signal acquisition device comprises a blood photosensor having one or more photo-emitters for transmitting light to a body part of a user, one or more photo-detectors for detecting light transmitted through or scattered by the body part and two or more optical cells, at least one of which contains an analyte to be detected or which mimics the absorption spectrum of the analyte to be detected, through which the light that has been or will be transmitted through or scattered by the body part passes before it reaches the or each photo-detector, wherein the processor of the PHHM is adapted to process the signals received from the or each photo-detector to calculate the difference in intensity of light which has passed through the or each analyte cell and light which has passed through the or each non-analyte cell and to process signals obtained from the photosensor to provide a measurement of the concentration of the analyte in the user's blood, wherein the PHHM is adapted to provide optical signals at one or more additional wavelengths for transmission to the body part, the processor of the PHHM is adapted to process signals at the or each additional wavelength to estimate the volume of blood in the field of view of the blood photosensor and the PHHM includes one or more beam splitters arranged to ensure that there is a single optical path between each photo-emitter and each photo-detector.S
15. The PHHM of claim 9 or claim 15 or any claim when dependent on claim 9, wherein the additional wavelengths are chosen to optimize the estimation of haemoglobin content.
16. A personal hand-held monitor (PHHM) comprising a signal acquisition device for acquiring signals which can be used to derive a measurement of a parameter related to the health of the user, wherein the signal acquisition device comprises a blood photosensor having one or more photo-emitters for transmitting light to a body part of a user, one or more photo-detectors for detecting light transmitted through or scattered by the body part and two or more optical cells, at least one of which contains an analyte to be detected or which mimics the absorption spectrum of the analyte to be detected, through which the light that has been or will be transmitted through or scattered by the body part passes before it reaches the or each photo-detector, wherein the processor of the PHHM is adapted to process the signals received from the or each photo-detector to calculate the difference in intensity of light which has passed through the or each analyte cell and light which has passed through the or each non-analyte cell and to process signals obtained from the photosensor to provide a measurement of the concentration of the analyte in the user's blood, wherein there is a ridge on the surface of the signal acquisition device between the photo-emitter(s) and the photo-detector(s) and the PHHM includes one or more beam splitters arranged to ensure that there is a single optical path between each photo-emitter and each photo-detector.
17. The PHHM of any one of claims I to 16, wherein the signal acquisition device is integrated with a personal hand-held computing device (PHHCD).
18. The PHHM of any one of claims Ito 17, wherein: the PHHM is adapted to apply pressure to the body part or to have pressure applied to it by the body part so that, in use, an artery in the body part changes from occluded to patent during each pulse; the processor of the PHHM is adapted to determine the pulse of the user and to correlate the signals obtained from the photosensor with the pulse of the user; and the processor of the PHHM is adapted to derive a measurement of the change in the luminal area of the artery during each pulse and to correlate the signals received from the blood photosensor with the pulse and the change in the lurninal area of the artery to provide a measurement of the concentration of the analyte in the arterial blood.
19. The PHHM of any one of claims I to 18, wherein the wavelength(s) of the light and the wavelength(s) of the pass band(s) of any optical filter(s) are chosen to optimize the sensitivity of the measurements to the amount of analyte in the field of view by maximizing one or more of: the amplitude of the signal related to the analyte; or the ratio of the amplitude of the signal related to analyte to the signal due to the surrounding tissue; or the ratio of the amplitude of the signal related to analyte to the noise in the photodetector(s).S