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1. A method for measuring the concentration of blood compo- nents such as but not limited to blood glucose in a non-invasive manner, characterized in that the method employs the measurement and analysis of spectra including but not limited to reflectance spectra in at least both the infra-red and the terahertz regions of the electromagnetic spectrum, in each case across a range of, or at least at several significant, frequencies.
2. The method according to claim 1, further characterized in that this method is used to measure blood component concentrations of some or all of glucose, cholesterol, urea, total pro- tein, triglycerides and creatinine.
3. The method according to claim 1 or 2 , further characterized in that this method provides more accurate measurements of blood components than methods employing frequencies limited to the infra-red region alone or frequencies limited to the terahertz region alone.
4. The method according to one of claims 1 to 3 , characterized in that the method may be used either in vitro or in vivo.
5. The method according to one of claims 1 to 4, characterized that if the method is used in vivo this may be done without penetrating the skin or mucosa, that is, the measurement is termed non-invasive.
6. The method according to one of claims 1 to 5, characterized in that the method is preferably used in vivo and non- invasively where there is a large amount of blood flowing just
below the surface.
7. The method according to one of claims 1 to 6, characterized in that the method is preferably used in vivo and non- invasively where there is a large amount of blood flowing just below the surface and further characterized in that a preferred measurement site is the inside of the wrist, inside of the ankle, or other sites where the wearing of an externally placed measurement instrument for extended periods of time is accept- able to the user.
8. The method according to claim 1 , for measuring the concentration of a chemical compound in a liquid, the liquid being contained in a container, comprising the steps: - providing a radiation source across a range of, or at least at several significant, frequencies within a given frequency band, directing the emission of said source onto said liquid through the wall of said container, - receiving the radiation, transmitted or reflected by the liquid and/or the container, evaluating the concentration of the compound through comparison of the obtained frequency spectrum with a signature of said chemical compound for the used frequency band, characterized in that two different radiation sources are providing infra-red and terahertz radiation of the electromagnetic spectrum.
9. The method according to claim 8, characterized in that the step of emission of said radiation sources and/or the measurement step is conducted intermittently or continuously.
10. The method according to claim 9, characterized in that
the step of emission of each of said radiation sources and the corresponding measurement step is conducted intermittently and alternating for the two different radiation sources and corre ¬ sponding measurement steps .
11. A device incorporating the method as in claims 1 to 10.
12. The device according to claim 11, characterized in that these device may be worn continually on the body.
13. The device according to claim 11 or 12, characterized in that they may monitor blood components concentration in a continuous or semi-continuous (time-based sampling) manner, where this sampling may be at regular or irregular intervals of time.
14. The device according to claim 11, 12 or 13, further characterized in that the devices may include or be linked to some or all of a direct data-logger, an electromagnetic radiation (e.g., radio) link to an external or remote data-logger, data analysis means such as but not limited to software and comparative data systems, which may or may not take further data inputs (e.g., body temperature) from further devices on or near the user, and data-presentation means such as but not limited to digital displays.
15. The device according to one of claims 11 to 14, further characterized in that the device may include alarms or other signals to the device or to remote devices to alert the device user or others to situations outside pre-set limits, such as but not limited to above- λ normal' or below- λ normal' blood glucose or other blood component concentrations .
16. The device according to one of claims 11 to 15, charac-
terized in that the devices may be used to trigger release of pharmaceuticals e.g., insulin, into the body of the user from an associated device.
17. The device according to one of claims 11 to 16, characterized in that the user may be human or non-human, (e.g., dogs, horses) .
18. Device for measuring the concentration of a chemical com- pound in a liquid, the liquid being contained in a container, according to claim 11, comprising a radiation source for emitting radiation across a range of, or at least at several significant, frequencies within a given frequency band, - a window transparent for the said radiation directed onto said liquid through the wall of said container, a receiver to receive the radiation, transmitted or reflected by the liquid and/or the container, a calculation unit to evaluate the concentration of the compound through comparison of the obtained frequency spectrum with a signature of said chemical compound for the used frequency band, characterized in that the device comprises two different radiation sources for providing infra-red and terahertz radiation of the electromagnetic spectrum.
BLOOD GLUCOSE SENSOR BASED ON REFLECTION OR TRANSMISSION SPECTROSCOPY AT FREQUENCIES IN THE TERAHERTZ REGION AND ABOVE THE TERAHERTZ REGION
Field of the invention
The invention relates to a non-invasive blood glucose sensor.
Diabetes is a disease of growing consequence. A 2002 survey found that there were approximately 150 million diabetics in the world and it is estimated that there will be as many as 300 mil- lion by 2025. According to the American Diabetes Association, there are 16 million individuals in the U.S. who have diabetes.
Until recently self-administered blood glucose sensing, which has to be done several times daily or more for accurate results, has been done by finger pricking. This costs -$1700 per patient per year (in the U.S.) .
A reliable non-invasive method which is both cheap and convenient, and which provides the potential for continuous or semi- continuous (frequent) blood glucose measurement has thus been sought for many years. The present invention provides this.
Technological Background: Other approaches
Various methods of non-invasive monitoring have been attempted and are under development. Some 69 programmes are reviewed by Diabetes Monitor (update October 3rd 2005) . These include:
Shining a beam of light onto the skin or through body tissues,
Measuring the infrared radiation emitted by the body, - Applying radio waves to the fingertips,
Using ultrasound, and
Checking the viscosity of fluids in tissue underneath the skin.
So far as can be identified the FDA has approved only one truly non-invasive blood glucose monitoring device: The GlucoWatch G2 Biographer, manufactured by Cygnus Inc., approved to detect glu- cose level trends and track patterns in people with diabetes (it must be used along with conventional blood glucose monitoring of blood samples) . The device, which looks like a wristwatch, pulls body fluid (interstitial fluid) from the skin using small electric currents . It can provide six measurements per hour for 13 hours.
Other approved or about-to-be devices include:
The Medtronic MiniMed, also FDA approved, involves placing a subcutaneous sensor and then having this interface with a remote-readable 'black box' . This is not truly non-invasive, does not provide continuous measurements, works only for 3 days, and needs to be used with a docking station to read-out.
The 'Navigator' from Abbott Diabetes Care is still under development, but will be seeking a CE mark in 2005 and is under review by the FDA. It measures once every 60 seconds. Like the
Medtronic MiniMed, it uses a subcutaneously placed probe and runs for 3 days.
A wristwatch-style device from Glucon Inc. (est. 2000: 19 staff) uses tiny lasers that resonate with blood glucose to pro- duce ultrasound and give 24-hour measurements (photo-acoustic: origin Tel Aviv University: US patent granted Feb. 2005 for "the use of photoacoustic waves originating in the blood vessel to calculate the concentration of glucose in the blood vessel") . Also important is the location or measurement of blood volume to be able to measure concentration. Glucon "uses the acoustics e- lement to localize measured volume inside a blood vessel, as well as removing the influence of the outer layers of the skin, and the optics element provides the specificity to glucose by
using several light wavelengths" . It claims to be as accurate as skin pricking, and is in the process of clinical trials and approval by the FDA. Launch ~2008, anticipated price >$1700.
Hitachi has determined that it is possible to compute the level of blood sugar by measuring parameters such as the thermal energy generated by metabolic reactions, the level of oxygen saturation of hemoglobin, and blood flow. The device is undergoing clinical testing to support a premarket submission to the FDA and the Japan Ministry of Health, Labour and Welfare. Plans call for the device to go on sale in 2005, subject to regulatory approval .
Other companies e.g., GlucoStats System (Singapore) have non-invasive IR probes: currently undergoing clinical trials.
The present invention is characterized in that it combines the use of terahertz radiation and the use of infra-red radiation for detecting blood glucose and measuring its concentration by means of a multi-frequency radiation analysis, the radiation be- ing measured in reflected mode as well as potentially in transmitted and absorptive modes . It thus provides a more accurate reading than that possible with the use of any narrower frequency band such as IR or terahertz alone.
It is further characterized in that it uses small, low cost terahertz emitters, thus enabling realizations of the device to be made in a hand-held or body-wearable (e.g., wristwatch) format. It will be able to take more and more frequent measurements, o- ver a longer time-span, and more accurately, than the hitherto known systems such as are described above.
The use of terahertz radiation alone for detecting blood glucose
is, rather surprisingly, not immediately identifiable in the EPO database. However this is not considered to be novel, since two companies have been identified which have targeted terahertz radiation as a means of detecting blood glucose.
It is known that Spire Corp. received August 22, 2004 a $99k grant from the U.S. Army Medical Research and Material Command based under the Deputy Under-Secretary of Defense for Science and Technology SBIR Program to carry out research towards devel- opment of a non-invasive blood-glucose monitor based on a terahertz quantum cascade laser.
λ Spire 1 S quantum cascade laser device consists of hundreds of nanometer-thick gallium arsenide-based layers. Terahertz radia- tion has wavelengths that are longer than visible and infrared, but shorter than microwaves, and may be the only radiation source that can separate glucose from other substances . Spire ' s terahertz quantum cascade laser instrument eliminates the need to draw blood samples by finger pricking . Thus , Spire ' s painless, non-invasive method of glucose detection using terahertz radiation may encourage diabetics to monitor their blood sugar levels more frequently' .
λ During Phase I of this program, Spire will synthesize a number of phantom samples containing various glucose concentrations, as well as samples containing potentially competing species such as sucrose and fructose, and measure their optical characteristics with terahertz radiation. The terahertz measurements will be carried out with the assistance of Dr. Tatiana Globus, Research Associate Professor in the Department of Electrical and Computer Engineering at the University of Virginia, at the Brookhaven National Laboratory in Upton, New York. Terahertz devices will be incorporated into a demonstration glucose monitoring instrument
during Phase II of the development project' .
Prof. Globus has not yet publicly reported any findings (Oct 5, 2005) . From this it is clear that the terahertz 'signature' is not yet publicly known (and see below). None of Spire's 87 identifiable patents appear specifically relevant to blood glucose sensing using terahertz radiation.
It is also known that Teraview (Cambridge, UK) also has aspira- tions towards using terahertz radiation for non-invasive blood glucose sensing, but it has made no recent announcements (since 2002) on this. Teraview has some 31 patents, but none specifically mentions x blood' or 'glucose' .
The use of infra-red radiation alone for detecting blood glucose is not considered to be novel .
That blood glucose has a distinctive IR spectrum is known from recent work in Fourier-transform infrared (FTIR) spectroscopy by Yaochun Shen at the Cavendish Laboratories, University of Cambridge .
The terahertz spectrum of blood glucose, as well as other blood components, was expected to be one of the outcomes of EU project QLK4-CT-2000-00129 coordinated by Dr. Gian Piero Gallerano of ENEA- FRASCATI (UTS Tecnologie Fisiche Avanzate, PO Box 65, Via Enrico Fermi 45, 00044, Frascati, Italy), initiated February 2001, reported January 2004. Measurements were made using quantum cascade lasers from three sources in the terahertz region 1.5THz to 100GHz. The project developed infrared assays for the biomedical analysis of blood samples by mid-IR spectroscopy to determine blood glucose, cholesterol, urea, total protein, triglycerides and creatinine, but not similar analysis means in-
corporating teraHertz measurements.
In the final report, available online at http : //www. frascati . enea. it/THz-BRIDGE/reports/THz- BRIDGE%20Final%20Report.pdf (see pp 11-20), the THz spectra of human haemoglobin, uric acid, glycine, tyrosine and phenylalanine are given, but not that of glucose or the other blood components noted above. A check made 8.12.2006 shows that the terahertz spectrum of glucose is still not readily identifiable as having been published.
Present Invention: Technical Details
The concept brings together five technical ideas, hitherto not combined, for unexpected benefit. 1.) Infra-red light emitting diodes capable of emitting different frequencies of infra-red radiation.
2.) Terahertz light-emitting-diodes capable of emitting different frequencies of terahertz radiation.
Terahertz emission is capable of penetrating skin non-invasively to register subcutaneous structures. The advantage utilized in the present invention is a small, cheap emitter device (LED type) , hitherto not achieved: it is tuneable, by magnetic field, and thus able to scan across a range of frequencies . 3.) The knowledge of the 'signature' spectrum on glucose and other components of interest in the IR region and how these can be distinguished from other blood component spectra. 4.) The knowledge of the 'signature' spectrum on glucose and other components of interest in the terahertz region and how these can be distinguished from other blood component spectra.
5.) Multi-frequency scanning analysis technology, which is capable of being trained to look for 'signatures' of specific compounds in the IR-to-microwave spectrum (and beyond) .
This has been used in the IR and the microwave region for various uses including the detection of CJD prions in blood supplies, and in the IR to UV region for imaging historic documents such as the Dead Sea Scrolls. Multi-frequency scanning in the terahertz region (alone) has been used for explosives and prohibited substances detection: it has not hitherto been used in combination with other non-terahertz frequencies for blood glucose or other blood component detection.
The technology involves the testing of samples with different frequencies / wavelengths of radiation, measuring (or imaging) the reflected signal digitally, and then combining these digital data to provide a composite where the presence or absence of a signal is dependant upon data taken at more than one frequency / wavelength.
A combination of the 'signature' scanning and analysis technology with the IR and the terahertz emitters/detectors has led to a device capable of measuring blood glucose levels (and those of certain other blood components of interest) sub-skin. - Key aspects are the sensitivity of measurements to the range of frequencies and energies possible.
Patentable features claimed are the particular components, frequencies and algorithms used.
This method can be made into a hand-held home-use product containing at least IR and terahertz LED emitters, a reflective multi-frequency sensor, and appropriate detection software. Such a device can in principle be used for continuous use if appropriately configured as a wristwatch- or similar type device. Such a device could be used in conjunction with other monitoring systems .