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Patent 2383727 Summary

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(12) Patent Application: (11) CA 2383727
(54) English Title: METHOD FOR DETERMINATION OF ANALYTES USING NEAR INFRARED, ADJACENT VISIBLE SPECTRUM AND AN ARRAY OF LONGER NEAR INFRARED WAVELENGTHS
(54) French Title: PROCEDE DE DETERMINATION D'ANALYTES AU MOYEN D'UN SPECTRE VISIBLE ADJACENT, A INFRAROUGE PROCHE ET RESEAU DE LONGUEURS D'ONDE PLUS LONGUES A INFRAROUGE PROCHE
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • G01N 21/25 (2006.01)
  • A61B 5/00 (2006.01)
  • G01J 3/36 (2006.01)
(72) Inventors :
  • PAWLUCZYK, ROMUALD (Canada)
  • SCECINA, THOMAS (United States of America)
  • CADELL, THEODORE E. (Canada)
(73) Owners :
  • NIRESULTS INC. (Canada)
(71) Applicants :
  • CME TELEMETRIX INC. (Canada)
(74) Agent: GOWLING LAFLEUR HENDERSON LLP
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2000-08-31
(87) Open to Public Inspection: 2001-03-08
Examination requested: 2005-08-19
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/CA2000/001003
(87) International Publication Number: WO2001/016578
(85) National Entry: 2002-02-28

(30) Application Priority Data:
Application No. Country/Territory Date
60/151,685 United States of America 1999-08-31

Abstracts

English Abstract




Described is a method which uses spectral data simultaneously collected in a
continuous array of discrete wavelength points of the visible spectrum
adjacent to the infrared and near infrared part of the light spectrum. The
spectral data is collected using a number of detectors with different
sensitivity ranges. Some detectors may be sensitive to visible and, possibly,
to part of the near infrared portion of radiation. Spectral data from the
infrared spectrum is collected with the infrared detectors, and are in some
embodiments insensitive to the visible light.


French Abstract

L'invention porte sur un procédé qui utilise des données spectrales recueillies simultanément dans un réseau continu de points de longueurs d'onde distincts du spectre visible adjacent à la partie infrarouge et à la partie infrarouge proche du spectre lumineux. Les données spectrales sont recueillies au moyen d'un certain nombre de détecteurs présentant des plages de sensibilité différentes. Certains détecteurs peuvent être sensibles à la partie infrarouge visible, et éventuellement, à la partie infrarouge proche du rayonnement. Les données spectrales du spectre infrarouge sont recueillies par des détecteurs d'infrarouges et sont, dans certaines réalisations, insensibles à la lumière visible.

Claims

Note: Claims are shown in the official language in which they were submitted.





-21-

WE CLAIM:

1. A method for determining a concentration of a constituent in a
sample comprising the steps of:
irradiating the sample with a broad spectrum of radiation from
the adjacent visible and near infrared (AV/NIR) region;
collecting radiation after the radiation has been directed onto
the sample;
dispersing the collected radiation into a dispersed spectrum of
component wavelengths onto a detector of the AV/NIR, the detector
of the AV/NIR taking measurements of at least one of transmitted or
reflected radiation from the collected radiation; and transferring the
measurements to a processor;
irradiating the sample with a broad spectrum of radiation in the
longer wavelength near infrared (LWNIR) region; detecting one or
more bands of radiation after the radiation has been directed onto the
sample with a detector of the LWNIR, the detector of the LWNIR
taking measurements of at least one of transmitted or reflected
radiation ; and
transferring the measurements to a processor;
based on the measurements and one or more calibration algorithms,
the processor calculating the concentration of said constituent in said
sample.

2. A method according to claim 1 wherein one or more separate
energy sources are used to provide radiation.

3. A method according to either claim 1 or 2 wherein the detector
of the AV/NIR is one or more spectral instruments with an array of
silicon detectors and the detector of LWNIR is one or more spectral
instruments with a separate array of infrared sensitive detectors for
each band of radiation.

4. A method according to either claim 1 or 2 wherein the detector
of the AV/NIR is one or more spectral instruments with an array of
silicon detectors and the detector of LWNIR is one or more spectral




-22-

instruments with an array of infrared sensitive detectors and
measurements for each band of radiation are taken from appropriate
members of the array of infrared sensitive detectors.

5. A method according to any one of claims 1-4 wherein the
infrared sensitive detectors are InGaAs detectors.

6. A method according to any of claims 1-5 wherein the
spectrometers with silicon detectors arrays register light in the all of
the visible, visible/infrared and adjacent to visible infrared ranges
within the spectral sensitivity range of the detectors.

7. A method according to any of claims 1-6 wherein the
spectrometers with infrared sensitive detectors register light in the
separate infrared ranges within their spectral sensitivity range.

8. A method according to any of claims 1-7 wherein all detectors
register light in their respectable sensitivity ranges virtually
simultaneously.

9. A method for determining a concentration of a constituent in a
sample comprising the steps of:
irradiating the sample with a broad spectrum of radiation from
the AV/NIR region;
collecting radiation after the radiation has been directed onto
the sample;
dispersing the collected radiation into a dispersed spectrum of
component wavelengths onto a detector of the AV/NIR, the detector
of the AV/NIR taking measurements of at least one of transmitted and
reflected radiation from the collected radiation; and transferring the
measurements to a processor;
irradiating the sample with one or more bands of radiation in
the LWNIR region; detecting the one or more bands of radiation after
the radiation has been directed onto the sample with a detector of the
LWNIR, the detector of the LWNIR taking measurements of at least
one of transmitted and reflected radiation; and




-23-

transferring the measurements to a processor;
based on the measurements and one or more calibration algorithms,
the processor calculating the concentration of said constituent in said
sample.

10. A method according to claim 9 wherein one or more separate
energy sources are used to provide radiation of required spectral
content.

11. A method according to either claim 9 or 10 wherein the detector
of the AV/IVIR is one or more spectral instruments with an array of
silicon detectors and the detector of LWNIR is one or more spectral
instruments with a separate array of infrared sensitive detectors for
each band of radiation.

12. A method according to either claim 9 or 10 wherein the detector
of the AV/IVIR is one or more spectral instruments with an array of
silicon detectors and the detector of LWNIR is one or more spectral
instruments with an array of infrared sensitive detectors and
measurements for each band of radiation are taken from appropriate
members of the array of infrared sensitive detectors.

13. A method according to any one of claims 9-12 wherein the
infrared sensitive detectors are InGaAs detectors.

14. A method according to any of claims 9-13 wherein the
spectrometers with silicon detectors arrays register light in the all of
the visible, visible/infrared and adjacent to visible infrared ranges
within the spectral sensitivity range of the detectors.

15. A method according to any of claims 9-14 wherein the
spectrometers with infrared sensitive detectors register light in the
separate infrared ranges within their spectral sensitivity range.




-24-

16. A method according to any of claims 9-15 wherein all detectors
register light in their respectable sensitivity ranges virtually
simultaneously.

17. A method for determining a concentration of a constituent in a
sample comprising the steps of:
irradiating the sample with a broad spectrum of radiation from
the AV/NIR region;
collecting radiation after the radiation has been directed onto
the sample;
dispersing the collected radiation into a dispersed spectrum of
component wavelengths onto a detector of the AV/NIR, the detector
of the AV/NIR taking measurements of at least one of transmitted and
reflected radiation from the collected radiation; and transferring the
measurements to a processor;
irradiating the sample with a broad spectrum of radiation from
the LWNIR region; collecting radiation after the radiation has been
directed onto the sample;
dispersing the collected radiation into a dispersed spectrum of
bands of radiation onto a detector of the LWNIR, the detector of the
LWNIR taking measurements of at least one of transmitted and
reflected radiation ; and
transferring the measurements to a processor;
based on the measurements and one or more calibration algorithms,
the processor calculating the concentration of said constituent in said
sample.

18. A method according to claim 17 wherein one or more separate
energy sources are used to provide radiation of required spectral
content.

19. A method according to either claim 17 or 18 wherein the
detector of the AV/NIR is one or more spectral instruments with an
array of silicon detectors and the detector of LWNIR is one or more
spectral instruments with a separate array of infrared sensitive
detectors for each band of radiation.



-25-

20. A method according to either claim 17 or 18 wherein the
detector of the AV/NIR is one or more spectral instruments with an
array of silicon detectors and the detector of LWNIR is one or more
spectral instruments with an array of infrared sensitive detectors and
measurements for each band of radiation are taken from appropriate
members of the array of infrared sensitive detectors.

21. A method according to any one of claims 17-20 wherein the
infrared sensitive detectors are InGaAs detectors.

22. A method according to any of claims 17-21 wherein the
spectrometers with silicon detectors arrays register light in the all of
the visible, visible/infrared and adjacent to visible infrared ranges
within the spectral sensitivity range of the detectors.

23. A method according to any of claims 17-22 wherein the
spectrometers with infrared sensitive detectors register light in the
separate infrared ranges within their spectral sensitivity range.

24. A method according to any of claims 17-23 wherein all detectors
register light in their respectable sensitivity ranges virtually
simultaneously.

25. A method according to any one of claims 1-24 wherein the
sample is a finger of a subject.

Description

Note: Descriptions are shown in the official language in which they were submitted.



WD ~l/16$78 CA 02383727 2002-02-28 PCT/CA00/01003
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Title: METHOD FOR DETERMINATION OF ANALYTES USING
NEAR INFRARED, ADJACENT VISIBLE SPECTRUM AND AN
ARRAY OF LONGER NEAR INFRARED WAVELENGTHS
FIELD OF INVENTION
This invention relates to a device and method for determining
and monitoring concentration levels of one or more constituents
within a varying in time, complex mufti component structure, (for
example blood constituents in blood sample, tissue or body parts) or,
in particular, blood and tissue constituents in living subjects such as
humans or animals.
BACKGROUND OF INVENTION
The application of spectroscopy for chemical analysis is well
known. For many years, however, it was mainly used for atomic
analysis because sufficiently sensitive detectors did not exist for
infrared, where information on vibration states of the molecules
(especially those of organic origin) is located. Advances in technology
of IR detectors have dramatically changed the situation and presently a
large number of detectors, instruments and methods exist for such
2 0 applications. This has also opened the way for new applications, but
has imposed new requirements on the technology. One of the most
important applications is a noninvasive analysis of chemical
compositions of living subjects.
It is generally appreciated that light in spectral range 500nm to
2 5 770nm belongs to the visible part of the spectrum but, since it does not
cover whole visible range and it is directly adjacent to the infrared part
of the spectrum, herein it is referred to as adjacent visible (AV). It is
widely accepted that of the infrared part of the electromagnetic
spectrum (IR) is divided into the near infrared (NIR), which expands
3 0 beyond the visible to about 2700 nm, the middle infrared radiation
(MIR), which expands beyond the NIR range and a further expanding
far infrared range (FIR). There are some photodetectors (mainly
silicon) whose sensitivity covers the visible part of spectrum and initial
part of NIR. Therefore, part of visible range adjacent to NIR and part


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of NIR adjacent to visible will be referred here as AV/NIR, while the
remaining part of NIR range will be referred to as the "longer
wavelength NIR region' or "LWNIR".
Non-Invasive Techniques
Previous devices for non-invasively monitoring concentration of
blood constituents of a patient are known. Usually, a sensor is used to
externally measure either the concentration of the constituents in gases
emitted by the body or contained in the perspiration, or the
concentration of the constituents contained in body fluids such as tears,
saliva, or urine. Alternatively, the blood constituents are identified by
measurement of attenuation of some radiation passed through a part
of a patient's body such as an earlobe, a finger or skin. In majority
cases, radiation is measured at one, two or limited number of relatively
narrow spectral bands obtained from separate, narrow band light
sources (see for example US 4,655,225; US 4,883,953; and US 4,882,492).
Some of these devices perform measurements at limited number
relatively narrow spectral bands consecutively selected from spectrally
broad light by a set of exchangeable narrow-band spectral filters.
Analysis of absolute and relative changes in light intensity at these
2 0 bands under certain conditions may provide important information on
body constituents. Exchange of the filters and time required for their
stabilization to obtain precise measurement, very often significantly
increase duration of the measurement process and as a result, the
measurement in different bands are taken with significant time delays.
2 5 Because of physiological variability of physical state of the alive
person,
this leads to situation when measurements at different wavelengths are
taken under changed physical conditions of the body, making
impossible to measure the constituents of the body. Another source of
the error in the systems with limited number of discrete spectral bands
3 0 is wavelength shift of the selected bands from measurement to the
measurement and from instrument to the instrument. There are
some medical and other applications when these two sources of the
error make measurement of constituents impossible. In such a case it


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becomes important to make the measurement in whole spectrum
virtually simultaneously and to preserve as complete as possible
information on whole spectrum. This is achieved applying other
techniques, which measure either a full spectrum of light interacting
with sample, with a large number (for example, 128 or 256) of
wavelengths in a specific range and those that measure a limited
number of wavelengths. Those that measure full spectra typically use
the wavelengths in the AV/hTIR range (see for examples US 5,361,758
and US 4,975,581), where arrays of the photodetectors, produced with
application of well established silicon technology, have been available
for long time for simultaneous registration of the spectra in large
number of discrete points. There are several advantages in
measurement of whole spectrum. One of them consists in that the
spectra provide information about the desired analyte as well as
information about interfering substances (e.g., other analytes) and
effects (e.g., light scattering). The second advantage is capability to
register a complete information on spectrum even if it is shifted due to
temperature changes of sample. Finally, the third advantage is that
even if the instrument loses wavelength calibration, whole information
2 0 is still preserved in the spectrum and can be easily extracted once new
wavelength calibration data is available. In some cases, however, there
is not enough information available in the above range or available
information is insufficient for precise measurement of body
constituents and additional information outside the above mentioned
2 5 spectral range (usually at longer wavelengths) is required.
In some cases, the methods that take measurements at limited
number of wavelengths only within the 1100 to 1700nm region can be
sufficient, because of the sharper analyte spectra that exist in this
region. In majority cases, however, while they provide information
3 0 relating to the analyte of interest, there is not enough independent
information on other analytes whose absorption spectra interferes
with that of the desired analyte. In some cases additional information
obtained in earlier mentioned spectral range 580nm to 1100nm helps to


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eliminate ambiguity introduced by interfering analytes. It is clear that if
the sample demonstrates a temporal variability, a simultaneous
measurement in whole spectral range of the interest is preferred, to
eliminate possible errors caused by changes in the sample.
Furthermore, as in earlier discussed cases for shorter spectral
range, spectral measurement in limited number of points within
1100nm to 1700nm spectral range in some cases may not be sufficient
for recognition of desired analyte. In addition, the measurements
usually are very sensitive to both: variations of spectral position of the
selected points and width and shape of spectral bands measured at
those points. Thus, the methods when measurement in different parts
of spectrum are taken at different time, or from different part of
samples or within limited number of points may not be sufficient for
precise analysis of constituents of the samples and more advanced
instruments are required. The way to eliminate these limitations and
provide instrument suitable for such measurements is given it this
invention. Overall, previous non-invasive devices and techniques
have not been sufficiently accurate to be used in place of invasive
techniques in the measurement of blood constituent concentration in
2 0 patients. Some of them have been designed to measure one
component only and physical changes to the instrument have to be
applied to adapt them to measurement of different components. For
some devices it takes unreasonably long time to produce a results; or,
some other cannot produce results in an easy-to-use form; or, they
2 5 cannot measure concentration of two or more constituents
simultaneously. Obviously, if the device gives an inaccurate reading,
disastrous results could occur for the patient using the device to
calculate, for example, dosages for insulin administration.
It has been recognized that simultaneous spectrum collection is
3 0 possible only by applying a large number of photodetectors.
Technically this is brought about by spatial dispersion of radiation,
composed of different wavelengths, by means of a dispersing device
(diffraction grating, for example) and registration of its intensity with


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an array of photodetectors. In such cases, the signal registered by each
detector of the array can be read virtually simultaneously. This
technique has been recognized and many spectrometers with an array
of photodetectors are available on the market. Unfortunately, the
available arrays systems have various limitations, therefore, the
capabilities of such spectrometers are limited.
The most important limitation for each array is its sensitivity
range, which is determined by the material used to produce an array.
The sensitivity range determines in what spectral range the instrument
built with an application of a particular array can work. Grating
spectrometers designed with the application of arrays of
photodetectors have further intrinsic limitations, which put even
stronger constrains on the performance of the instruments. One such
constraint is the existence of additional diffraction orders in light
diffracted by a grating. The existence of the second order imposes the
condition that the spectral range of an array-based instrument cannot
be wider than one octave, unless a special filter is placed in front of the
array. Production of such filters is not easy, hence, instruments are
built to cover less than one octave and a cut-off filter, eliminating
2 0 radiation with shorter wavelengths is normally used to eliminate the
impact of that order. As a result, the spectral range of existing array-
based instruments is such that the longest measured wavelength of
analyzed light is always smaller than the doubled length of the shortest
wavelength analyzed by the spectrometer
2 5 Finally, since the number of elements in an array and length of
an array are limited, very often it is impossible to achieve high
resolution even in that limited spectral range. As a result, the
performance of array-based instruments is a compromise between
such factors and consequently spectrometers very often cannot
3 0 provide information needed for particular applications. If, in addition,
these applications require simultaneous registration of the wider
spectrum (as, for example, non-invasive in-vivo diagnostic), the
measurement problem remains unsolved.


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SUMMARY OF THE INVENTION
While for some applications relatively simple instruments,
measuring of infrared radiation at one or small number of
wavelengths are sufficient, it was discovered that for more demanding
applications, such as, for example, glucose concentration in blood in a
human body, significantly more advanced instruments are required. In
particular it has been found that for such applications it is important to
collect data in a wide spectral range covering at least part of near
infrared and adjacent to it visible part of the spectrum. It has been also
discovered that for living subject it is crucial that information is
collected simultaneously in whole spectral range of the interest,
otherwise physiological changes in the organism during measurement
may significantly contribute to the measurement error. Finally, it has
been found that because of dependence of the molecular vibration
spectrum on temperature it is important to have as complete
information on the spectrum as possible. Therefore a need has arisen
to build a spectroscopic system able to simultaneously collect
information in as wide spectrum as possible. This approach excludes
techniques when a spectrum of light is collected with the application of
2 0 any scanning instrument like those with rotated gratings or Fourier
transform spectrometers.
Accordingly, the present invention provides a method for
monitoring the concentration level of a particular constituent in a
sample or, alternatively, of measuring the concentration level of one or
2 5 more different constituents using a non-invasive device with higher
precision and in a short period of time, through simultaneous
measurement of light signal in several different spectral ranges using
separate array-based spectrometers.
The present inventors have determined that analyte
3 0 measurement accuracy with spectral devices measuring full spectra
absorption/reflectance in the AV/NIR region, is enhanced by adding
to such measurement, measurements from one or more arrays of
wavelength in the infrared region


W~ 01/16$78 CA 02383727 2002-02-28 pCT/CA00/01003
_ 'j _
In its broad aspect the present invention provides a method for
monitoring the concentration level of a constituent in sample
comprising placing the sample in a non-invasive device capable of
emitting radiation; directing the radiation onto the sample; measuring
radiation collected from the sample; calculating the concentration level
based on the measured radiation wherein the radiation directed onto
the tissue and collected from the tissue is of the wavelengths starting at
500nm and expanding into AV/NIR range, and wavelengths in the LIR
range possible from 1100 to 1700nm.
According to one embodiment, the present invention provides a
method for measuring concentration levels of blood constituents
within a living subject such as humans or animals, wherein, a
polychromatic light source or other single or multiplicity of radiation
sources are used that emit a broad spectrum of light in the required
range. A number of spectrum analyzing systems containing
photodetector arrays, possible sensitive in different spectral ranges
provide sensitivity and resolution over portions of the range of the
interest, preferably one from 500-1100nm and one from 900-1700nm
and further spectral ranges. The method comprises the steps of:
- directing light at a continuum wavelengths (whether from one or
more sources) simultaneously onto a sample or a part of a subject;
- collecting the continuum of light after the light has been directed onto
and interacted with the sample or the part;
- dividing of collected light into at least two parts separately directed to
2 5 the corresponding number of spectrum analyzing systems, at least one
for AV/NIR and at least another one for WNIR,
- forming of each part of light into a light beam, suitable for
simultaneous analysis of corresponding spectral content of each part,
preferably by means of a dispersing element, preferable diffraction
3 0 grating,
- spatially dispersing a portion of the continuum of light predestined
for analysis with separate spectrum analyzing systems into a dispersed
spectrum of component wavelengths in each selected part,


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_ g _
- forming of dispersed light in each part into light beam suitable for
detection with a suitable array of photodetectors,
- the arrays of the photodetectors taking measurement of dispersed
light in selected part or whole AV/1VIR spectral range and at least one
or more arrays applied for measurements of at least selected part or
whole LWIVIR spectral range.
Preferably these measurements are taken simultaneously or
sequentially, or in any combination thereof. The measurement results
are transferred to a microprocessor, and the concentration level of said
at least one constituent of the sample, in particular of said blood or
tissue is calculated and a result of each concentration level is produced.
According to another embodiment of the invention, there is
provided a non-invasive device measuring concentration levels of
constituents occurring in the sample in particular in blood and tissue in
a subject such as a human or animal uses one or more radiation
sources. The broad spectrum of light in the adjacent visible spectrum
and near infrared range provided by the radiation or light sources)
is/are powered by one or a required number of stabilized power
sources . The device (or devices) has a receptor shaped so that a
2 0 sample or a part of the subject can be placed in contact with the
receptor. The receptor has means for eliminating extraneous light and
is located relative to the light source (or sources) so that when a sample
or body part (or tissue) is placed in contact with the receptor, the
sources) can be activated and light with continuum of wavelengths, is
2 5 directed onto the part. The device is equipped with means for
collecting light in the AV/I~TIR and LWNIR spectral regions after the
light has been directed onto the sample or the part. There are also
means for dispersing the collected light over said broad spectrum into
a dispersed spectrum of component wavelengths and means for taking
3 0 measurements of a light signal at many different wavelengths in the
AV/I~TIR and LWIVIR regions simultaneously or sequentially. There
are also means for transforming results of these measurements over
the dispersed spectrum into the concentration of at least one


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constituent by using a calibration equation for the at least one
constituent. There are also means for determining the concentration
level of the at least one constituent of said blood or tissue and then
producing a result for each concentration level determined.
According to one embodiment of the present invention there is
provided a method for determining a concentration of a constituent in
a sample comprising the steps of:
irradiating the sample with a continuum of wavelengths from
the adjacent visible and near infrared (AV/NIR) region;
collecting radiation after the radiation has been directed onto
the part;
dispersing the continuum of collected radiation into a dispersed
spectrum of component wavelengths onto a detector, the detector
taking measurements of at least one of transmitted or reflected
radiation from the collected radiation; and transferring the
measurements to a processor;
irradiating the sample with a continuum of wavelengths in the
longer wavelength near infrared (LWNIR) region; detecting one or
more bands of radiation after the radiation has been directed onto the
2 0 sample with a detector, the detector taking measurements of at least
one of transmitted or reflected radiation ; and
transferring the measurements to a processor;
based on the measurements and one or more calibration algorithms,
the processor calculating the concentration of said constituent in said
2 5 sample, preferably one or more separate energy sources are used to
provide radiation.
According to another embodiment of the method of the
invention the detector of the AV/NIR is one or more spectral
instruments with an array of silicon detectors and the detector of
LWNIR is one or more spectral instruments with a separate array of
infrared sensitive detectors for each band of radiation.
According to yet another embodiment the detector of the
AV/NIR is one or more spectral instruments with an array of silicon


WO 01/16578 CA 02383727 2002-02-28 pCT/CA00/01003
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detectors and the detector of LWIVIR is one or more spectral
instruments with an array of infrared sensitive detectors and
measurements for each band of radiation are taken from appropriate
members of the array of infrared sensitive detectors, preferably the
infrared sensitive detectors are InGaAs detectors.
According to another embodiment the spectrometers with
silicon detectors arrays register light in the all of the visible,
visible/infrared and adjacent to visible infrared ranges within the
spectral sensitivity range of the detectors, and preferably the
spectrometers with infrared sensitive detectors register light in the
separate infrared ranges within their spectral sensitivity range.
According to another embodiment of the method all detectors
register light in their respectable sensitivity ranges virtually
simultaneously.
In another aspect of the present invention there is provided a
method for determining a concentration of a constituent in a sample
comprising the steps of:
irradiating the sample with a continuum of wavelengths from
the AV/1~TIR region;
2 0 collecting radiation after the radiation has been directed onto
the part;
dispersing the continuum of collected radiation into a dispersed
spectrum of component wavelengths onto a detector, the detector
taking measurements of at least one of transmitted or reflected
2 5 radiation from the collected radiation; and transferring the
measurements to a processor;
irradiating the sample with one or more bands of wavelengths
in the LW1VIR region; detecting the one or more bands of radiation
after the radiation has been directed onto the sample with a detector,
3 0 the detector taking measurements of at least one of transmitted or
reflected radiation ; and
transferring the measurements to a processor;


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based on the measurements and one or more calibration algorithms,
the processor calculating the concentration of said constituent in said
sample, preferably one or more separate energy sources are used to
provide radiation.
According to another embodiment of the method of the
invention the detector of the AV/NIR is one or more spectral
instruments with an array of silicon detectors and the detector of
LWNIIZ is one or more spectral instruments with a separate array of
infrared sensitive detectors for each band of radiation.
According to yet another embodiment the detector of the
AV/NIR is one or more spectral instruments with an array of silicon
detectors and the detector of LWNIR is one or more spectral
instruments with an array of infrared sensitive detectors and
measurements for each band of radiation are taken from appropriate
members of the array of infrared sensitive detectors, preferably the
infrared sensitive detectors are InGaAs detectors.
According to another embodiment the spectrometers with
silicon detectors arrays register light in the all of the visible,
visible/infrared and adjacent to visible infrared ranges within the
2 0 spectral sensitivity range of the detectors, and preferably the
spectrometers with infrared sensitive detectors register light in the
separate infrared ranges within their spectral sensitivity range.
According to another embodiment of the method all detectors
register light in their respectable sensitivity ranges virtually
2 5 simultaneously.
In yet another aspect of the present invention there is provided
a method for determining a concentration of a constituent in a sample
comprising the steps of:
irradiating the sample with a continuum of wavelengths from
3 0 the AV /NIR region;
collecting radiation after the radiation has been directed onto
the part;


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dispersing the continuum of collected radiation into a dispersed
spectrum of component wavelengths onto a detector, the detector
taking measurements of at least one of transmitted or reflected
radiation from the collected radiation; and transferring the
measurements to a processor;
irradiating the sample with a continuum of wavelengths from
the LWNIR region; collecting radiation after the radiation has been
directed onto the part;
dispersing the continuum of collected radiation into a dispersed
spectrum of bands of radiation onto a detector, the detector taking
measurements of at least one of transmitted or reflected radiation ; and
transferring the measurements to a processor;
based on the measurements and one or more calibration algorithms,
the processor calculating the concentration of said constituent in said
sample, preferably one or more separate energy sources are used to
provide radiation.
According to another embodiment of the method of the
invention the detector of the AV/NIR is one or more spectral
instruments with an array of silicon detectors and the detector of
LWNIR is one or more spectral instruments with a separate array of
infrared sensitive detectors for each band of radiation.
According to yet another embodiment the detector of the
AV/NIR is one or more spectral instruments with an array of silicon
detectors and the detector of LWNIR is one or more spectral
2 S instruments with an array of infrared sensitive detectors and
measurements for each band of radiation are taken from appropriate
members of the array of infrared sensitive detectors, preferably the
infrared sensitive detectors are InGaAs detectors.
According to another embodiment the spectrometers with
3 0 silicon detectors arrays register light in the all of the visible,
visible/infrared and adjacent to visible infrared ranges within the
spectral sensitivity range of the detectors, and preferably the


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spectrometers with infrared sensitive detectors register light in the
separate infrared ranges within their spectral sensitivity range.
According to another embodiment of the method all detectors
register light in their respectable sensitivity ranges virtually
simultaneously.
In accordance with a preferred embodiment of any of the
forgoing methods the sample is a finger of a subject.
Other features and advantages of the present invention will
become apparent from the following detailed description. It should be
understood, however, that the detailed description and the specific
examples, while indicating preferred embodiments of the invention,
are given by way of illustration only, since various changes and
modifications within the spirit and scope of the invention will become
apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described in relation to the drawing in
which:
Figure 1 shows absorbance spectra from 500-1380 nm for
globulins, glucose, urea, creative, cholesterol and human serum
2 0 albumin with water displacement compensation.
Figure 2 presents a general concept for simultaneous collection
of spectra in a wide spectral range by many array-based instruments,
each of which covers a separate spectral range.
DETAILED DESCRIPTION OF THE INVENTION
2 5 As used herein "concentration" or "concentration level" means
the amount or quantity of a constituent in a solution whether the
solution is in vitro or in vivo.
As used herein, "constituent" means a substance, or analyte
found in a tissue and includes carbohydrates such as for example
3 0 glucose, bilirubin, a protein, for examples albumin or , hemoglobin.
As used herein, "in a solution' means in a liquid environment
such as, for examples interstitial, or other bodily fluid


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As used herein, "tissue" means any tissue of the body of a subject
including for example, blood, extracellular spaces, and can mean the
entire composition of a body part such as a finger or ear lobe.
As used herein "subject" means any member of the animal
kingdom including, preferably, humans.
As noted previously, light in spectral range 500nm to 770nm is
referred to herein as adjacent visible (AV). As used herein, the infrared
part of the electromagnetic spectrum (IR) is divided into the near
infrared (NIR), which expands beyond the visible to about 2700 nm,
the middle infrared radiation (MIR), which expands beyond the NIR
range and a further expanding far infrared range (FIR). Also, part of
visible range adjacent to NIR and part of NIR adjacent to visible will be
referred here as AV/NIR, while the remaining part of NIR range will
be referred to as the "longer wavelength NIR region" or "LWNIR".
According to a preferred embodiment, in each case, it is
assumed that measurement of the light intensity at any given spectral
band with given central wavelengths is at a sufficiently high signal to
noise ratio in order to achieve the desired results.
As discussed above, the present inventors have determined that
2 0 significant improvement of the ability to measure analytes in various
samples (in tissue in particular) using a non-invasive spectral device
can be achieved by adding; it is only necessary to add one or more
arrays of wavelength measurements in the LWNIR or IR region to a
full spectra absorption measurement in the 500 to 1100nm region to
2 5 gain a significant improvement in analyte measurement accuracy. In
particular analyte measurement accuracy achieved through previous
methods is enhanced by adding a full spectra absorption measurement
in the 1100 to 1300nm (the "First region") and/or by adding a full
spectra absorption measurement in the 1590 to 1700nm (the "Second
3 0 region") region to a full spectra absorption measurement in the 500 to
1100nm region, preferably in the AV/NIR region, more preferably the
addition of the First region to the Second region is performed. The
result provides a significant improvement in analyte measurement


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- 15 -
accuracy. It will be readily appreciated that the method includes
addition of measurements of full spectra absorption from other
regions or whole range in the LWNIR or IR.
The AV/NIR range has been used because, among other
reasons, silicon detectors are sensitive in that range. Silicon detectors,
particularly silicon-based detector arrays provide superior noise and
dynamic range performance, are readily available, and, are relatively
inexpensive. However, the 900 to 1700nm and further IR wavelength
ranges provide sharper spectra for many of the analytes of interest as
may be seen by referring to Figure 1. An Indium Gallium Arsenite
(InGaAs) detector may be used to measure spectra in this region while
other detectors array can cover further IR ranges. Unfortunately,
these detectors provide inferior noise and dynamic range performance
in comparison with silicon, consequently the lower signal to noise ratio
offsets some of the advantage of the sharper spectra.
To achieve the advantages of measuring spectra in the IR, one or
more arrays of spectra are added to measurements in the AV/ NIR
region. The results are significantly better than those achieve with
measurements of spectra in either range separately.
2 0 The light is delivered to the sample or to the tissue, such as a
finger, by a suitable conduit such as fiber optics bundle. The light
emerging from the finger is collected and delivered to separate sets of
detectors by another conduit such as another fiber optics bundle. As
just mentioned, a silicon diode array is used to detect light in the
2 5 AV /NIR region and an InGaAs photodiode array can be used to detect
light in the LWNIR region and other detector arrays in further IR
ranges. As used herein, "light", "illumination', "radiation' all refer to the
light energy provided by a source which is capable of delivering
sufficient radiation of a desired wavelength.
3 0 Any device which is capable of delivering radiation in the ranges
of the invention may be utilized and are within the scope of the present
invention.


WO 01/16578 CA 02383727 2002-02-28 pCT/CA00/01003
- 16-
As just mentioned the light source can emit light over a very
wide band-width including light in adjacent to infrared visible and the
near infrared spectrum. According to one embodiment, the light from
the light source (or sources) is delivered by any optical means to the
sample, which preferably is placed in an appropriate receptor. In
particular the light may pass first through a collimator (a collection of
lenses that concentrate the light into a narrow parallel beam directed at
the receptor). In another embodiment, when a light scattered sample is
tested, the light, in the form of a wide divergent light beam, is
delivered by a fiber-optics means directly to a sample or to a receptor
containing the sample. An appropriate receptor is shaped to receive a
measured sample. Such samples may be, for example, a part of subject
being measured, for example, a finger or arm of a human. An
appropriate receptor may also be a sample holder in a form of any
transparent container or, for some applications, in a form of calibrated
cuvette with parallel walls. Alternatively, a receptor could be shaped
so that the part of the human or animal, onto which the light is to be
directed, is placed near the receptor rather than within the receptor.
Further, an integrating cavity may play the role of sample receptor
2 0 with light coupled into the cavity either directly or by any optical
means including optical fibers. After interaction of the light with the
sample, the light is collected by any optical means. The light from the
sample can be light that has passed through the sample (body part or
tissue, for example) or has reflected off it , or a combination thereof.
2 5 Preferably, the collected light is light that has passed through the
sample.
The collected light is divided into a required number of light
beams and each of them is directed to a separate spectral analyzing
system, preferably an array-based spectrophotometer. Before
3 0 entering a spectrometer, each light beam may be optionally shaped to
a narrow light source by means of suitably distributed fibers or a set of
optical elements and a slit. The light from a narrow light source can be
either collimated or directly delivered to a diffraction means.


Wo ~l/1C)$7g CA 02383727 2002-02-28 pCT/CA00/01003
-17-
Radiation from a sample interacts with a dispersion means, such
as a grating, which disperses the radiation into its component
wavelengths so that the light in the AV/NIR region falls along
detectors, preferably a length of linear array of silicon of detectors such
that light from the LWNIR and other IR regions falls onto the array of
detectors, preferably InGaAs detectors. As is readily understood by
those skilled in the art, these arrays are comprised of individual
detectors and are sensitive in a range of wavelengths which
correspond to the AV and IR regions. Preferably, although not
necessarily, all detectors are electronically simultaneously scanned to
measure signal registered by each individual unit.
The results from the detector are directed to a microprocessor
for analysis of the measurements from the detectors and ultimately
produces a concentration result for each constituent by applying one of
many known chemometric methods such as form example PLS or
PCR. The results can be shown on a display and/or printed on a
printer. A keyboard allows a user to control the device, for example,
to specify a particular constituent to be measured. The timing and
control may be activated by the microprocessor to control the device,
2 0 for example, to determine number and timing of measurements.
The light source or sources can be a quartz-halogen or a
tungsten-halogen bulb, supported by any other light source such as a
laser or light emitting diodes (LED) (or other light sources able to emit
radiation in the required ranges of AV and IR). Any such source is (or
2 5 are) powered by a stabilized power source, for example, a DC power
supply, or by a battery. Preferably, each linear array detector has a
sufficient number of photosensitive elements to cover a required
spectral range to provide adequate spectral resolution.
A standard measurement procedure comprises taking reference
3 0 measurements of incident light (being the light generated in the device
when no part of the subject is in contact with the receptor) and taking
measurements while the sample is present in the receptor. The
negative logarithm of the ratio of sample measurement to reference


CA 02383727 2002-02-28
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- 18 -
measurements is then calculated and compared to reference
measurements.
Although it should not be construed as a limitation on the
method of the invention, the second derivative of measurements may
be taken in order to reduce any variation in the result that will be
caused by a change in path length for the light.
The noise level within the device may be reduced by a multiple
scanning technique whereby the detectors take a number of
measurements and then average the results. Preferably, the linear
array detector and IR detectors are scanned many times for several
repetitions and then the results averaged.
While measuring glucose concentrations is a preferred
embodiment of the present invention, the device and method can be
used to measure concentration levels of various other constituents
found within the blood of humans and animals, for example, amino
acids, nitrogen, blood oxygenation, carbon dioxide, cortisol, creative,
creatinine, glucose, ketones, lipids, fat, urea, amino acids, fatty acids,
glycosylated hemoglobin, cholesterol, alcohol, lactate, Ca++, K+, Cl-m
HC03- and HP04-, to name a few. Indeed, as will be apparent to those
2 0 skilled in the art, the method and device can be modified to measure
several constituents simultaneously, finally it can be also modified to
measure chemical composition of any other materials or samples
whose properties may vary in time, demonstrating specific spectral
features in AV and IR ranges..
2 5 The following is a non-limiting exemplary embodiment of the
present invention.
EXEMPLARY EMBODIMENT OF INVENTION
Referring now to Figure 2, a certain number (n1) of light sources
21 generate a broad spectrum of light covering all required spectral
3 0 ranges. The light sources contain power supplies, light sources, means
to collect light from these sources and means to concentrate light into
optical elements predestined to mix light from these sources and bring
it to the sample.


CA 02383727 2002-02-28
WO 01/16578 PCT/CA00/01003
- 19-
Light from the light source is collected by light collecting means,
preferably by multiple fiber bundles 22, and is optionally delivered
through a light mixing device 23 (glass rod, for example) and,
optionally a light forming device 24 (light collimator, or focusing lens,
for example) to a sample receptor 25 (sample holder, finger holder,
integrating cavity or any other device to hold sample) containing a
sample 26 (human finger, for example). After interaction with sample
the light is collected by a light collecting device 27 (another light
bundle, or any other light collecting optical system, lens, for example)
and is divided into as many parts as required to cover all possible
spectral bands. Division can be performed either by simple splitting of
fibers into multiplicity of fiber optics legs or using wide-band or
dichroic beam splitters.
Each "part" of light is directed to separate spectrum analyzing
devices 28, preferably array-based spectrometers. The number (n2) of
spectrometers (generally different from the number of light sources) is
selected to cover an entire spectral range of interest for a tested sample
with demanded resolution.
The light delivering means together with the spectrum
2 0 analyzing device may optionally contain a light beam forming optical
system, specific for a given spectrum analyzing device, spectrum
specific dispersing or light filtering element, a light beam forming
system for dispersed light and a wavelength specific array of the
photodetectors.
2 5 The signal from each array is read by one or more specialized
electronics boards (29), usually specific for each kind of array or
detector, and in addition to collection of the signal, performs control of
the array by providing proper electrical signals. By means of electrical
cables 210 boards are connected to a computer 211 which "supervises"
3 0 the action of the boards, takes information from the boards, stores it
and processes using one of many available chemometric methods (for
example PLS or PCR) to convert information collected from arrays into
information concerning the chemical composition of the tested sample


WO 01/16578 CA 02383727 2002-02-28 pCT/CA00/01003
-20-
and to present it to user in required form (graphs or any other signal).
It is important to appreciate that number n1 and kind of light sources is
selected to provide illumination in all spectral bands of the interest in
both AV and IR ranges, and in general can be different from number
n2 of the spectrum analyzing devices (spectrometers, for example)
selected to secure detection in these spectral bands with required
resolution.
While the present invention has been described with reference
to what are presently considered to be preferred examples, it is to be
understood that the invention is not limited to the disclosed examples.
To the contrary, the invention is intended to cover various
modifications and equivalents included within the spirit and scope of
the appended claims.
All publications, patents and patent applications referred to
herein are incorporated by reference in their entirety to the same
extent as if each individual publication, patent or patent application was
specifically and individually indicated to be incorporated by reference
in its entirety.

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date Unavailable
(86) PCT Filing Date 2000-08-31
(87) PCT Publication Date 2001-03-08
(85) National Entry 2002-02-28
Examination Requested 2005-08-19
Dead Application 2012-08-31

Abandonment History

Abandonment Date Reason Reinstatement Date
2011-08-31 FAILURE TO PAY APPLICATION MAINTENANCE FEE
2011-09-12 FAILURE TO PAY FINAL FEE

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Registration of a document - section 124 $100.00 2002-02-28
Application Fee $300.00 2002-02-28
Maintenance Fee - Application - New Act 2 2002-09-03 $100.00 2002-08-16
Maintenance Fee - Application - New Act 3 2003-09-02 $100.00 2003-08-27
Maintenance Fee - Application - New Act 4 2004-08-31 $100.00 2004-08-17
Maintenance Fee - Application - New Act 5 2005-08-31 $200.00 2005-08-17
Request for Examination $800.00 2005-08-19
Registration of a document - section 124 $100.00 2006-01-27
Registration of a document - section 124 $100.00 2006-01-27
Maintenance Fee - Application - New Act 6 2006-08-31 $200.00 2006-08-28
Maintenance Fee - Application - New Act 7 2007-08-31 $200.00 2007-08-23
Maintenance Fee - Application - New Act 8 2008-09-02 $200.00 2008-08-18
Registration of a document - section 124 $100.00 2009-03-12
Maintenance Fee - Application - New Act 9 2009-08-31 $200.00 2009-07-22
Maintenance Fee - Application - New Act 10 2010-08-31 $250.00 2010-08-31
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
NIRESULTS INC.
Past Owners on Record
CADELL, THEODORE E.
CME TELEMETRIX INC.
NIR DIAGNOSTICS INC.
PAWLUCZYK, ROMUALD
SCECINA, THOMAS
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Description 
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Representative Drawing 2002-08-27 1 7
Description 2009-09-10 20 1,012
Claims 2009-09-10 2 69
Description 2002-02-28 20 1,019
Abstract 2002-02-28 1 56
Claims 2002-02-28 5 204
Drawings 2002-02-28 2 39
Cover Page 2002-08-30 1 42
PCT 2002-02-28 18 784
Assignment 2002-02-28 4 103
Assignment 2002-06-25 4 148
PCT 2003-03-01 2 95
Fees 2003-08-27 1 35
Prosecution-Amendment 2009-09-10 6 197
Fees 2006-08-28 1 41
Fees 2004-08-17 1 31
Correspondence 2006-09-28 2 41
Correspondence 2006-02-23 1 22
Fees 2002-08-16 1 33
Prosecution-Amendment 2005-08-19 1 34
Fees 2005-08-17 1 31
Assignment 2006-01-27 10 396
Assignment 2006-01-27 4 161
Fees 2007-08-23 1 42
Fees 2008-08-18 1 45
Prosecution-Amendment 2009-03-11 3 105
Assignment 2009-03-12 26 1,025
Correspondence 2009-03-12 7 195
Correspondence 2009-04-27 1 13
Correspondence 2009-04-27 1 19
Correspondence 2009-07-22 2 59
Correspondence 2009-08-04 1 16
Correspondence 2009-08-04 1 20
Fees 2009-07-22 1 44
Fees 2010-08-31 1 40