U.S. patent number 5,533,509 [Application Number 08/411,631] was granted by the patent office on 1996-07-09 for method and apparatus for non-invasive measurement of blood sugar level.
This patent grant is currently assigned to Kurashiki Boseki Kabushiki Kaisha. Invention is credited to Katsue Koashi, Shigeo Minami.
United States Patent |
5,533,509 |
Koashi , et al. |
July 9, 1996 |
Method and apparatus for non-invasive measurement of blood sugar
level
Abstract
To intensity-modulate laser light periodically
wavelength-modulated by and emitted from a wavelength-variable
semiconductor laser 11. To separate the laser light into optical
paths 13a, 13b with a beam splitter 14 to irradiate an examined
location 17 for assessing blood sugar through path 13a. To detect
the intensity of transmitted or reflected light from examined
location 17 with a first detector 21 and the intensity of laser
light passing through path 13b with a second detector 22 to detect
the ratio of the former intensity to the latter intensity with a
logarithmic ratio amplifier 25. To detect the rate of change in the
ratio with respect to the change in wavelength of the wavelength
modulation with a lock-in amplifier 26 to obtain a derivative
spectral signal of the absorption spectrum of glucose. An
arithmetic processor 27 detects blood sugar in the examined
location from the derivative spectrum.
Inventors: |
Koashi; Katsue (Toyonaka,
JP), Minami; Shigeo (Ashiya, JP) |
Assignee: |
Kurashiki Boseki Kabushiki
Kaisha (Okayama, JP)
|
Family
ID: |
25677900 |
Appl.
No.: |
08/411,631 |
Filed: |
April 10, 1995 |
PCT
Filed: |
August 12, 1993 |
PCT No.: |
PCT/JP93/01140 |
371
Date: |
April 10, 1995 |
102(e)
Date: |
April 10, 1995 |
PCT
Pub. No.: |
WO95/05120 |
PCT
Pub. Date: |
February 23, 1995 |
Current U.S.
Class: |
600/316;
356/41 |
Current CPC
Class: |
A61B
5/14532 (20130101); A61B 5/1455 (20130101); G01N
21/39 (20130101); A61B 5/7239 (20130101); G01N
2201/065 (20130101) |
Current International
Class: |
A61B
5/00 (20060101); G01N 21/31 (20060101); G01N
21/39 (20060101); A61B 005/00 () |
Field of
Search: |
;128/633,664-6
;351/41 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
1-131436 |
|
May 1989 |
|
JP |
|
612271 |
|
Jul 1979 |
|
CH |
|
2033575 |
|
May 1980 |
|
GB |
|
2075668 |
|
Nov 1981 |
|
GB |
|
WO81/00622 |
|
Mar 1981 |
|
WO |
|
Other References
Clinical Chemistry, vol. 25, No. 9 (1979), T. C. O'Haver,
"Potential Clinical Applications of Derivative and
Wavelength-Mofulation Spectrometry". .
Nikkei Electronics, No. 423, (1987), K. Kobayashi and I.
Mito..
|
Primary Examiner: Sykes; Angela D.
Assistant Examiner: Nasser, Jr.; Robert L.
Attorney, Agent or Firm: Wenderoth, Lind & Ponack
Claims
What is claimed is:
1. A method for non-invasive measurement of blood sugar levels
comprising the steps of:
providing light which is intensity-modulated with a plurality of
intensities as well as being wavelength-modulated;
applying the modulated light to an examined portion;
detecting an intensity of reflected light from said examined
portion and an intensity of the incident light onto said examined
portion for each intensity of said modulated light;
detecting the ratio of an intensity of said reflected light and
said incident light;
detecting the rate of change in said ratio with respect to the
change in wavelength due to the wavelength modulation;
extracting a derivative spectrum of an absorbance spectrum of
glucose in said examined portion, and
detecting the blood sugar level of said examined portion.
2. The method for non-invasive measurement of blood sugar levels as
defined in claim 1, including extracting said derivative spectrum
by accumulating and averaging in correspondence with the iteration
of said wavelength modulation.
3. An apparatus for non-invasive measurement of blood sugar levels
comprising:
a wavelength-modulated light generator for generating a
wavelength-modulated light;
an intensity-modulator for intensity-modulating the
wavelength-modulated light output from said wavelength-modulated
light generator with a plurality of intensities;
a beam splitter for separating the optical path of the
wavelength-modulated and intensity-modulated light emitted from
said intensity modulator into two optical paths;
an optical collector for collecting the light passing along one of
the two optical paths separated by said beam splitter, being
incident on an examined location for assessing the blood sugar
level, and being reflected therefrom;
a first optical detector for detecting an intensity of the light
collected by said optical collector;
a second optical detector for detecting an intensity of the light
passing along the other optical path separated by said beam
splitter;
a ratio detector for detecting the ratio of the output of said
first optical detector to the output of said second optical
detector;
a derivative spectral signal detector for receiving a ratio signal
from said ratio detector and for detecting the rate of change in
said ratio signal with respect to the change in wavelength due to
the wavelength modulation to detect a derivative spectral signal of
an absorbance spectrum of glucose in said examined portion;
an arithmetic means for calculating the blood sugar level in said
examined location based on the derivative spectral signal detected
by said derivative spectral signal detector.
4. The apparatus for non-invasive measurement of blood sugar levels
as defined in claim 3, wherein said wavelength-modulated light
generator is a wavelength-variable semiconductor laser.
5. An apparatus for non-invasive measurement of blood sugar levels
comprising:
a wavelength-variable light source for wavelength-modulated
light;
an attenuator for periodically varying the intensity of the light
output from the light source;
a beam splitter for separating light output from the attenuator
into a reference light beam and a measuring light beam;
an integrating sphere for collecting light reflected from an
examined portion of skin in which the blood sugar level is to be
measured, the reflected light caused by the measuring light beam
being projected on the examined portion of skin;
a first detector for detecting the intensity of the light collected
by the integrating sphere;
a second detector for detecting the intensity of the reference
light beam;
first and second amplifiers for respectively amplifying outputs of
said first and second detectors;
a logarithmic ratio amplifier for receiving outputs from said first
and second amplifiers and for outputting a logarithm of a ratio
between outputs of the first and second amplifiers;
a lock-in amplifier for receiving an output from said logarithmic
ratio amplifier and for detecting a derivative spectral signal of a
glucose absorbance spectrum for the examined portion from a rate of
change of the output of the logarithmic ratio amplifier with
respect to a change in wavelength;
a processing means for receiving an output from said lock-in
amplifier and for calculating a blood sugar level in the examined
portion by processing the derivative spectral signal detected by
said lock-in amplifier.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method and apparatus for
non-invasively measuring a blood sugar level on an in vivo and in
situ basis using spectroscopic techniques. More specifically, the
invention relates to a method and apparatus for non-invasively
measuring the concentration of glucose in the blood stream or
tissue of a patient suspected of suffering from diabetes based on a
combination of wavelength modulation and intensity modulation of
light.
2. Description of the Related Art
Various methods and apparatus for measuring the concentration of
glucose in vitro and in vivo using spectroscopic techniques have
been proposed.
For example, International application No. WO 81/00,622 discloses a
method and apparatus for measuring the absorption of infrared light
by glucose in body fluid using CO.sub.2 laser light as an
irradiation light source. The method and apparatus measure the
absorption spectra of serum and urine by transmittance and
reflectance, i.e.--back scattering effects, at different
wavelengths .lambda..sub.1 and .lambda..sub.2. Here, .lambda..sub.2
is a characteristic absorption wavelength of the substance to be
measured, e.g. glucose, and .lambda..sub.1 is a wavelength at which
absorption is independent of the concentration of the substance to
be measured. The measurements are obtained by calculating the ratio
of the absorbance at .lambda..sub.1 to the absorbance at
.lambda..sub.2. The absorption band of the substance to be measured
is between 940 cm.sup.-1 : and 950 cm.sup.-1 ; ie. between 10.64
and 10.54 .mu.m for wavelength .lambda..sub.1, and the absorption
band is between 1090 cm.sup.-1 ; and 1095 cm.sup.-1 ; i.e.--between
9.17 .mu.m and 9.13 .mu.m for wavelength .lambda..sub.2.
U.S. Pat. No. 4,169,676 discloses an non-invasive examining method
for detecting biological substances through skin using an
attenuated-total-reflectance (ATR) prism. The method attaches the
wave guide (ATR prism) directly to the surface of a sample under
examination (e.g. a lip or tongue) and guides in infrared light.
The refractive index of the wave guide is greater than that of the
sample medium, ie. an optically thin layer of the surface, and the
infrared light is made to pass through the prism along the
total-reflection path. The infrared light interacts with the thin
layer of the surface, and the interaction is related to the
frustrated attenuation component of the light at the reflecting
part (see Hormone & Metabolic Res. Suppl. Ser. (1979) pp. 30-
35). If infrared light of a wavelength related to the absorption of
glucose is used, then the light passing through the prism is
attenuated depending on the concentration of glucose in the
optically thin layer of the surface. Therefore, the attenuated
quantity is detected and processed into data on the glucose
concentration.
U.S. Pat. No. 3,958,560 discloses a non-invasive detection
apparatus that detects glucose in a patient's eye. Specifically,
the apparatus of this U.S. patent is a sensor apparatus in shape of
a contact lens comprising a light source that applies infrared
light to one side of cornea and a detector that detects the
transmitted light on the opposite side. When infrared light is
applied to a measured location, the infrared light passes through
the cornea and the aqueous humor and reaches the detector. The
detector converts the quantity of transmitted light into an
electric signal and provides it to a remote receiver. Then the
reader of the receiver outputs the concentration of glucose in the
patient's eye as a function of the individual change of quantity in
the applied infrared light passing through the eye.
British Pat. application No. 2,035,557 discloses a detecting
apparatus for assessing substances near the blood stream of a
patient such as CO.sub.2, oxygen, or glucose. The detecting
apparatus comprises an optical source and an optical receiving
means that detects attenuated light back-scattered or reflected
from inside a patient's body, i.e.--from the hypoderma, and uses
ultraviolet or infrared light as the irradiation light.
On the other hand, there are following apparatus that measure or
monitor the flow of blood and organism-activating parameters or
components such as oxygenated hemoglobin and reduced
oxyhemoglobin.
U.S. Pat. No. 3,638,640 discloses a method and apparatus for
measuring oxygen and other substances in blood and the tissue. The
U.S. Pat. apparatus comprises an irradiation light source and a
detector placed on a patient's body. If the detector is placed on
an ear, then the intensity of light passing through the ear is
measured, and if the detector is placed on a forehead, then the
intensity of light reflected after passing through blood and the
hypoderma is measured. The wavelengths between red light and
near-infrared light are used as the irradiation light, i.e.--660
nm, 715 nm, and 805 nm. The number of wavelengths used at the same
time is 1 plus the number of wavelengths characteristic of
substances existing in the examined location. Signals obtained by
detecting from absorption at various wavelengths are processed by
an electric circuit, so that quantitative data concerning the
concentration of the substance to be measured is obtained without
being influenced by the fluctuation of measuring conditions such as
the fluctuation of the detector, the deviation of the intensity,
the direction and angle of irradiation, and the fluctuation of the
flow of blood in the examined location.
Further, British pat. No. 2,075,668 discloses a spectrophotometric
apparatus for measuring and monitoring metabolic functions of an
organism such as changes in oxidation and reduction of hemoglobins
and cytochromes or changes in the blood flow in an organ such as
the brain, heart, lever on an in vivo and in situ basis. The
apparatus uses an irradiation light of wavelengths between 700 nm
and 1,300 nm, which effectively penetrates several mm deep under
skin.
FIG. 14 of the British patent application illustrates an apparatus
for measuring reflectance comprising a wave guide (optical fiber
tube) to be abutted to an organism and a light source. The wave
guide is abutted to an organism so that irradiation light is
applied to the surface of skin in an oblique direction, and the
oriented irradiation light is made to penetrate into the body
through skin and to be reflected or back-scattered from the tissue
at a distance apart from the light source. Some of the light energy
is absorbed and the rest is incident on a first detector placed on
skin and apart from the light source. Also a second detector is
placed and detects a backward-radiated reference signal. The
analytical signal from the first detector and the reference signal
from the second detector are output into an arithmetic operation
circuit, and the data of analytical information is obtained as the
output of the arithmetic operation circuit.
In measurement of the concentration of glucose and the like
described above, the quality of the spectroscopic data obtained by
a near-infrared spectrometer is determined by the performance of
hardware constituting the near-infrared spectrometer. At present,
the signal to noise ratio S/N of the best performance is
approximately on the order between 10.sup.5 to 10.sup.6. On the
other hand, for example, the prior methods of measuring the
absolute intensity of the spectrum requires 10.sup.5 to 10.sup.6
order as the S/N ratio of the spectral signal to measure 100 mg/dL,
which is the physiological concentration of glucose in blood, with
spectroscopically practical precision, so that the measurement must
be done near the maximum precision limit attainable by the
spectrometer.
Therefore, methods of measuring the concentrations of sugar and
glucose and the like using spectroscopic techniques have less
sensitivity, precision and accuracy than chemical analysis that
analyzes the concentrations of these substances using reagents, and
a near-infrared spectrometer of high performance having a high S/N
ratio is made with complex construction at great cost. Thus, if a
variation of glucose concentration from the physiological
concentration of glucose, 100 mg/dL, can be measured with the
precision of 2 to 3 digits by a reference method, instead of simply
measuring the absolute intensity of a spectrum, then we can find
how much the blood sugar of a patient deviates from a normative
value, so that the measurement can be favorably used for
controlling the blood sugar of the patient.
SUMMARY OF THE INVENTION
The object of the present invention is therefore to provide a
method of measuring blood sugar that easily and non-invasively
measures the variation of the blood sugar of a patient suspected of
suffering from diabetes from a normative value independent of the
patient's individual differences using a modulation means that
combines wavelength modulation with intensity modulation.
Another object of the present invention is to provide a compact and
inexpensive apparatus for measuring blood sugar that easily and
non-invasively measures the variation of the blood sugar of a
patient suspected of suffering from diabetes from a normative value
independent of the patient's individual differences with a simple
construction comprising a wavelength modulation means and an
intensity modulation means.
In order to achieve the aforementioned objectives, the present
invention intensity-modulates light with several intensities as
well as wavelength-modulating, applies the modulated light to an
examined location for assessing blood sugar, detects, for each
intensity-modulated light, the intensity of the transmitted and
reflected light from a portion to be examined and the intensity of
the incident light onto the portion to be examined, detects the
ratio of the two intensities, detects the rate of change in the
ratio with respect to the change in the wavelength due to the above
wavelength-modulation, extracts the derivative spectrum of the
absorption spectrum of glucose in that portion, and detects the
blood sugar of that portion based on these derivative spectra for
all modulating intensities of light.
In this way, light which is intensity-modulated as well as being
wavelength-modulated with a small modulation width .DELTA..lambda.
around a considered wavelength is applied to the examined portion,
and the depth of penetration into skin is varied by the intensity
modulation of the incident light on the examined location, so that
information concerning the concentration of glucose in the examined
portion, where body fluid including blood components exists, is
extracted, and determination of glucose in the examined location is
performed based on the derivative spectra of the absorption
spectra. Therefore, the concentration of glucose is easily and
securely detected independently of individual differences of the
patient.
The above derivative spectra are preferably accumulated and
averaged corresponding to the iteration of the above wavelength
modulation. If, in this way, the derivative spectra are accumulated
and averaged, then the noise component is reduced in proportion to
the square root of the number of accumulation, so that the signal
to noise ratio S/N is improved.
The present invention provides an apparatus comprising a
wavelength-modulated light generator that generates
wavelength-modulated light, an intensity modulator that
intensity-modulates the wavelength-modulated light output from the
wavelength-modulated light generator into several intensities, a
beam splitter that separates the optical path of the
wavelength-modulated and intensity modulated light emitted from the
intensity modulator, an optical collector that collects the light
passing along one of the optical paths separated by the beam
splitter, made incident on the examined location for assessing
blood sugar, and being transmitted or reflected thereby, a first
photo detector that detects the intensity of the light collected by
the optical collector, a second photo detector that detects the
intensity of the light passing along the other path separated by
the beam splitter, a ratio detector that detects the ratio of the
output of the first photo detector to the output of the second
photo detector, a derivative spectral signal detector that reads a
ratio signal output from the ratio detector, detects the rate of
change in the ratio signal with respect to the change in wavelength
due to the above wavelength modulation, and detects the derivative
spectral signal of the absorption spectrum of glucose in the
examined portion, an arithmetic means that calculates blood sugar
in the examined portion for each intensity of the
intensity-modulated light based on the derivative spectral signal
detected by the derivative spectral signal detector.
The present invention wavelength-modulates light in the
wavelength-modulated light generator and intensity-modulates the
wavelength-modulated light to make it incident on the examined
portion and detects the difference spectrum of the absorption
spectrum of glucose, so that derivative data of high quality is
obtained in real time without requiring computer processing.
Further, the speed of iterative scanning is higher than an ordinary
spectrometer, which scans a wide range of wavelengths, so that
measured data on the concentration of glucose can be obtained by
short-time photometry without being much influenced by a drift of
the optical system.
The above wavelength-modulated light generator is preferably a
wavelength-variable semiconductor laser. A semiconductor laser
developed for use in optical fiber communications can be employed
as the wavelength-variable semiconductor laser, so that the
characteristics of a wavelength-variable semiconductor laser can be
effectively utilized at its maximum performance, and the
construction of the means for wavelength-modulating the measured
light is extremely simplified. Therefore, the construction of the
apparatus for non-invasive measurement of blood sugar becomes
simple and compact.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other objects and features of the present invention will
become clear from the following description taken in conjunction
with the preferred embodiments thereof with reference to the
accompanying drawings throughout which like parts are designated by
like reference numerals, and in which:
FIG. 1 shows a single peak spectrum, its first derivative spectrum,
and its second derivative spectrum.
FIG. 2 shows the generation of a derivative spectrum by
wavelength-modulation spectroscopy.
FIG. 3 shows an absorbance spectrum of an aqueous solution of
glucose.
FIG. 4 shows the first derivative spectrum of FIG. 3.
FIG. 5 shows the difference absorbance spectra with respect to
standard pure water.
FIG. 6 shows the difference of the first derivative spectra.
FIG. 7. shows the difference of the first derivative spectra.
FIG. 8 shows the difference of the first derivative spectra.
FIG. 9 shows the difference of the first derivative spectra.
FIG. 10 shows the relationship between the concentration of glucose
and the first derivative of an absorbance spectrum.
FIG. 11 shows the structure of human skin for describing its
optical properties.
FIG. 12 shows a graph for describing the relationship between the
intensity of incident light and the depth of light penetration.
FIG. 13 shows a block diagram of an apparatus for non-invasive
measurement of blood sugar.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The preferred embodiments according to the present invention will
be described below with reference to the appended drawings.
Items [1] and [2] below describe the derivative spectroscopy
necessary for understanding the present invention and a method of
wavelength modulation for obtaining derivative spectra.
Furthermore, items [3], [4], and [5] respectively described the
verification of determining glucose from the first derivative
spectra, the choice of optimal wavelength, and the diffuse
reflectance spectra of skin and intensity-modulation spectroscopy.
Finally the configuration of an apparatus for non-invasive
measurement of blood sugar in accordance with the present invention
is described in item [6].
[1] Derivative spectroscopy
Wavelength modulation is generally used to obtain derivative
spectra. The method of wavelength modulation is described in T. C.
O'Haver, "Potential clinical applications of derivative and
wavelength-modulation spectroscopy", (Clinical Chemistry, Vol 25,
No. 9 (1979), pp. 1548-1553). The concept of wavelength-modulation
spectroscopy is closely connected to the concept of derivative
spectroscopy, and they are both based on the measurements of
changes in intensity and absorbance with respect to a change in
wavelength.
First, derivative spectroscopy is described. Derivative
spectroscopy obtains the first or higher-order derivatives of the
intensity or absorbance spectrum with respect to wavelength and
plots the results. The purposes of the derivative spectroscopy
are:
(a) the compensation and correction of the baseline shift, and
(b) the effective increase in sensitivity to subtle changes in the
shape of the spectral band.
FIG. 1 shows a single peak spectrum and its first and second
derivative spectra. The peak maximum point P.sub.max corresponds to
the zero-crossing point P.sub.01 of the first derivative and the
central peak point P.sub.c of the second derivative. The peak
maximum point P.sub.dmax and the peak minimum point P.sub.dmin of
the second derivative respectively correspond to the maximum slope
points P.sub.s1 and P.sub.s2 of the original spectrum and also
respectively correspond to the zero-crossing points P.sub.02 and
P.sub.03 of the second derivative.
There are several methods of obtaining derivative spectra as
follows.
First, if the spectral data are digital values and can be processed
by a computer, then the derivative spectra can be computed by
numerical differentiation in software.
Secondly, the derivative spectra can be acquired in real time
through time derivatives obtained by constant-speed scanning in
hardware. This technique is based on the fact that if the
wavelength scanning rate d.lambda./dt is constant, then the
derivative dI/d.lambda. of the intensity I with respect to
wavelength .lambda. is proportional to the derivative dI/dt of the
intensity I with respect to time t, as is clear from the following
(1). That is, by means of an electronic differentiator, the
following equation (1) can be calculated.
Thirdly, derivative spectra can be obtained by a wavelength
modulation described below.
As shown in FIG. 2, a technique of wavelength modulation irradiates
a sample with periodically modulated light having a narrow
modulation width .DELTA..lambda. around a particular wavelength
.lambda..sub.i and detects the transmitted or reflected light with
a detector. The ripple or the alternating-current component of the
output signal from the detector is separated or electrically
measured. If the modulation width .DELTA..lambda. is sufficiently
smaller than the bandwidth of the spectrum, then the
alternating-current component of the optoelectronic signal at the
modulation frequency generates an alternating-current signal,
i.e.--a derivative spectrum D, which has an amplitude proportional
to the slope of the spectrum within the modulation wavelength
width.
There are several techniques for the wavelength modulation
described above as follows:
(a) vibrating the slit, mirror, diffraction grating, or prism of a
monochromator.
(b) inserting a vibrating mirror or rotary refracting mirror.
(c) using a wavelength-continuous-variable filter.
(d) vibrating or tilting a diffraction filter.
(e) vibrating a Fabry-Perot interferometer. Besides,
(f) using a continuous-wavelength-variable semiconductor laser can
be also considered.
The method of installing a reflective diffraction grating outside a
semiconductor laser and controlling the angle of the diffraction
grating to vary the oscillatory wavelength has been known. This
method can vary the wavelength in a narrow spectral line width. If
the variation is not necessarily continuous and if jumps between
longitudinal modes are allowed, then the construction of the
apparatus can be simplified.
If a single-mode filter that is synchronous with a tuning
wavelength within a narrow bandwidth is added, then oscillation
occurs at an arbitrarily set wavelength in a single mode. This
apparatus is called a tunable semiconductor laser of the external
resonance type.
Furthermore, a wavelength-variable semiconductor laser developed
for use of coherent optical communications is described in Nikkei
electronics, No. 423 (Jun. 15, 1987), pp. 149-161. In this article,
semiconductor lasers that control wavelength with a tri-electrode
construction based on the distributive Bragg-reflection laser of
single mode are described. One of the semiconductor lasers
continuously varies wavelength in a single longitudinal mode within
a wavelength range of 3.1 nm. If the longitudinal mode is allowed
to change in a middle, then the wavelength range is about 6 nm.
[2] Method of wavelength modulation for obtaining derivative
spectra.
If, in wavelength modulation, the modulation width
.DELTA..lambda.(=.lambda..sub.2 -.lambda..sub.1) is sufficiently
less than the bandwidth of the spectrum, then the
alternating-current component of the optoelectronic signal at the
modulation frequency generates an alternating-current signal
.DELTA.I/.DELTA..lambda., i.e.--a derivative spectrum D expressed
by the following (2), which has an amplitude proportional to the
slope of the spectrum within the modulation wavelength width. The
amplitude of the alternating-current signal can be obtained in real
time by an appropriate electrical system.
In general, the direct-current component is greater than the
alternating-current component in measurement of a low concentration
of glucose. Since the direct-current-component having such
insignificant great values can be cut off, the dynamic range of the
A-D converter used in an apparatus for the measurement of blood
sugar described later can be efficiently used, and mathematical
processing is performed thereafter at an advantage.
Wavelength modulation is performed by scanning periodically upward
and downward within a narrow modulation width .DELTA..lambda., so
that the scanning can be repeated at a higher speed than by an
ordinary spectrometer, which scans a wide range of wavelength.
Therefore, the accumulation and averaging are easily performed.
Since the noise component can be reduced in proportion to the
square root of the number of accumulated measurements, the signal
to noise ratio (S/N) can be improved by making the number of
accumulated measurements large. Furthermore, short measurement
times effectively suppress a drift of the optical system of the
spectrometer.
The wavelength range in wavelength modulation is limited to a
narrow .DELTA..lambda., but derivative spectra of a high quality
are obtained in real time without any computer processing.
Therefore, wavelength modulation is suitable for a routine analysis
of samples whose characteristics are already well known, for
example, for quality control and clinical analysis.
On the other hand, if an original spectrum of digital values is
processed by a numerical derivative operation, the numerical
precision and quality of the intensity I.sub.i itself pose a
problem.
The process of obtaining a derivative spectrum tends to enhance
high-frequency noise in the original spectrum. If used improperly,
the S/N ratio is greatly reduced by a derivative operation of a
spectrum of low quality.
Further, in measurement of a sample of low absorption, unless the
numerical precision or the number of significant digits of the
intensity I.sub.i of an original spectrum is great, a significant
change in the desired derivative spectrum can not be obtained. That
is, the S/N ratio needs to be very large.
[3] The verification of determining glucose from first derivative
spectra
If the spectral data have digital values, then their derivative
spectra can be computed by numerical differentiation of the
absorbance spectra. Therefore, we obtained the first derivative
spectrum of an absorbance spectrum obtained by a Fourier-transform
spectrometer by numerical differentiation to test the validity of
the determination of glucose concentration by the wavelength
modulation technique.
As samples, and we used pure water, aqueous solutions of glucose of
1,000 mg/dL, 3,000 mg/dL, and 5,000 mg/dL.
Since it is difficult to observe the differences among samples in
detail in comparing the absorbance spectrum and the first
derivative spectrum of each sample with that of each other sample,
we calculated the differences between each sample and the standard
pure water. That is, we calculated the difference absorbance
spectrum and the difference of the first derivative spectrum of
each sample to make the differences observable. The derivative
operation was performed in the direction from longer wavelength to
shorter wavelength.
First, let us consider the glucose absorption band between the
absorption peaks 1.43 .mu.m and 1.93 .mu.m of pure water. FIG. 3
shows the absorbance spectrum, and FIG. 4 shows its first
derivative spectrum. Further, FIG. 5 shows the difference
absorbance spectra. In the difference absorbance spectra of FIG. 5,
the absorption by glucose is observed between 1.55 .mu.m and 1.85
.mu.m. Also, S-shaped characteristics are observed between 1.35
.mu.m and 1.45 .mu.m. These are due to the shift of the absorbance
peak 1.43 .mu.m of pure water caused by hydration. The central
wavelength of the wavelength modulation can be chosen from the
wavelength ranges, one between 1.45 .mu.m and 1.58 .mu.m, which is
around the noninterference zero-crossing point, one between 1.6
.mu.m and 1.67 .mu.m, and one between 1.75 .mu.m and 1.85 .mu.m,
which are less affected by interference and have steep slopes in an
absorption band.
As is observed from the difference of the first derivative spectra
shown in FIG. 6, it is clear that glucose can be determined by the
first derivative spectrum. FIG. 10 shows the relationship between
the first derivative of the absorbance and the glucose
concentration at wavelength 1.555 .mu.m.
Since wavelength-variable semiconductor lasers can be employed for
the 1.5-.mu.m band, the construction of the apparatus is easy. If
wavelength-variable semiconductor lasers are applied to wavelength
modulation, the characteristics of wavelength-variable
semiconductor lasers can be effectively used to the maximum
performance limit.
Beyond the absorption peak 1.93 .mu.m of pure water, there are
absorption bands of glucose at 2.1 .mu.m, 2.27 .mu.m, and 2.33
.mu.m. The slopes around these absorption peaks should be
considered carefully. As is observed from the derivatives of
difference absorbance spectra shown in FIG. 7, the central
wavelength can also be chosen from
2.06.about.2.1 .mu.m
2.1.about.2.24 .mu.m
2.24.about.2.27 .mu.m
2.27.about.2.3 .mu.m
2.3.about.2.32 .mu.m
2.32.about.2.38 .mu.m
Similarly, between the absorption peaks 0.96 .mu.m and 1.15 .mu.m
of pure water, there is a broad absorption band of glucose at 1.06
.mu.m. As is observed from the difference of the first derivative
spectra shown in FIG. 8. The central wavelength can be chosen from
the range between 1.07 .mu.m and 1.25 .mu.m and the range between
1.00 .mu.m and 1.05 .mu.m.
Similarly, between the absorption peaks 1.15 .mu.m and 1.43 .mu.m
of pure water, there is a broad absorption band of glucose at 1.25
.mu.m. As is observed from the difference of the first derivative
spectra shown in FIG. 9, the central wavelength can be chosen from
the range between 1.28 .mu.m and 1.36 .mu.m and the range between
1.18 .mu.m and 1.23 .mu.m.
[4] Choice of optimal wavelength,
Human skin consists of the cornified layer 1, epidermis 2, and
dermis 3 successively from the outside, as shown in FIG. 11, and
has an anisotropic structure in the direction of depth. In
measuring the concentration of glucose in the part in which body
fluid containing blood components exists, i.e.--the capillary bed
4, by means of diffuse reflection through skin, the wavelength
selection is important and inseparable from the method of
measuring.
A longer-wavelength region near middle-infrared light and a
shorter-wavelength region near visible light in the near-infrared
region are compared in the following.
In the longer-wavelength region, light energy is absorbed strongly
by water existing in the organism, so that it is hard to penetrate
into a deeper part of the organism (skin). However, light is hard
to be attenuated since it is less affected by scattering. Also,
since the absorption coefficient of glucose in its existing
absorption band is greater, the path length can be short, ie. the
depth of light penetration can be relatively small.
In the shorter-wavelength region near visible light, light is less
absorbed by water to reach a deep part of skin. However, light is
easily affected and attenuated by scattering. Also, since the
absorption coefficients of glucose in its absorption band are
small, the path length must be large to raise the sensitivity of
measurement.
In this way, there are various related factors for choosing optimal
wavelength. In conclusion, an optimal wavelength for measurement of
glucose is preferably chosen from the range between 1.45.mu. and
1.85 .mu.m because of the chosen wavelength band described in [3]
and the characteristic absorption coefficients of glucose, the
depth of light penetrating skin, and a practical factor. The
practical factor means the fact that a wavelength-variable
semiconductor laser for coherent optical fiber communications can
be employed.
[5] Diffuse reflectance spectra of skin and intensity-modulation
spectroscopy
As described earlier, derivative data of high quality are obtained
in real time by wavelength modulation without requiring computer
processing. Derivative data are, in a way, data at one point, so
that, from a practical standpoint, it is important that data are
normalized and that various fluctuating factors such as changes in
the temperature of the sample and interaction of chemical
components are automatically compensated. The present invention
combines wavelength modulation with intensity modulation to
automatically compensate for these fluctuating factors.
A diffuse reflectance spectrum of skin is based on a signal
obtained from the weak diffuse reflection of light which has been
repeatedly absorbed and scattered inside skin and collected by an
integrating sphere and detected by a detector. In relation to the
anisotropic structure in the direction of depth, the diffuse
reflectance spectrum is a mixture spectrum comprising the following
spectral components of the incident light 5:
(a) Spectral components of regularly reflected light 7 on the
surface of skin.
(b) Spectral components of diffuse-reflected light 8 from the
cornified layer 1 or surface tissue that does not contain
glucose.
(c) Spectral components of diffuse-reflected light 9 from the part
4 where body fluid containing blood components exist.
(d) Spectrum components of transmitted light through deeper
tissue.
In general, the contribution of spectral components near the
surface of skin is great, and the contribution of spectral
components in part 4 where body fluid containing blood components
exist is small. This fact characterizes an ordinary diffuse
reflectance spectrum.
If we are concerned with the concentration of glucose in part 4
where body fluid containing blood components exists, and if we can
determine and analyze a spectrum not containing the spectral
components of the above (a) and (b), then clearly we can measure
the concentration of glucose more accurately.
As a technique to realize this possibility, the inventors of the
present application proposed a following technique of
light-intensity modulation in Japanese Patent Application No.
Sho-62-290821 and U.S. Pat. No. 4,883,953.
The technique controls the depth of light penetration by varying
the intensity of incident light. As shown in FIG. 12, when the
intensity of incident light is great, then more information of
greater depth is included than when the intensity is small.
Therefore, the incident light of intensity I.sub.01 at which
penetration depth for a detection limit is b.sub.1 is used, and the
intensity I.sub.s1 of diffuse-reflected light from depth b.sub.1 /2
is measured. Then the ratio between them is calculated by the
following equation (3) for normalization.
A.sub.1 has spectral information of only the part near the surface
of skin.
Next, the incident light of intensity I.sub.02 in which penetration
depth for detection limit is b.sub.2, which is greater than b2, is
used, and the intensity I.sub.s2 of diffuser-reflected light from
depth b.sub.2 /2 is measured. Then the ratio between them is
calculated by the following equation (4) for normalization.
A.sub.2 contains spectral information of deeper part from the
surface of skin. Then the difference .DELTA.A between A.sub.1 and
A.sub.2 is calculated.
The .DELTA.A of the above equation (5) expresses spectral
information from the baseline spectrum of an examined subject's
tissue near the surface of the skin in which no glucose is
contained. Therefore, .DELTA.A is free from the influence of the
subject's individual differences such as race, sex, and age.
The modulation of incident light can be performed by switching
attenuators having different attenuation ratios by a rotating disk.
The absorbances are normalized by calculating the above ratios (3)
and (4) for each cycle of the modulation of the intensity of
incident light, and the difference of the normalized absorbances is
calculated by (5). Then the differences are accumulated and
averaged for many cycles to improve the S/N ratio.
A regression equation is created using the averaged differences for
samples having different concentrations of glucose and reference
concentration values obtained by chemical analysis. Finally, using
this regression equation, glucose of an unknown sample is
determined.
We have described the algorithm of the technique of intensity
modulation of incident light using the spectral intensity I. It is
known by the method of regression that determinacy also exists
between the derivative intensity and the concentrations. Therefore,
in order to use the first derivative D=.DELTA.A/.DELTA..lambda., we
replace the absorbance A in equations (3), (4), and (5) with
.DELTA.A/.DELTA..lambda. to obtain the equations (8), (9), and (10)
described later.
[6] apparatus for non-invasive measurement of blood sugar
FIG. 13 shows a block diagram of an apparatus for non-invasive
measurement of blood sugar in accordance with the present
invention.
The above apparatus for non-invasive measurement of blood sugar has
as its components a wavelength-variable semiconductor laser 11, an
attenuator 12 that periodically varies the intensity of
wavelength-modulated laser light output from semiconductor laser
11, a beam splitter 14 that separates the optical path 13 of the
wavelength-modulated and intensity-modulated light emitted from
attenuator 12 into an optical path 13a and an optical path 13b, and
an integrating sphere 18 that collects laser light transmitted or
reflected after passing along optical path 13a and made incident on
an examined portion 17 of skin 16 in which the blood sugar level is
measured.
The above apparatus for non-invasive measurement of blood sugar
levels also has as its components a first detector 21 that detects
the intensity of the laser light collected by the integrating
sphere 18, a second detector 22 that detects the intensity of laser
light passing along optical path 13b, an amplifier 23 that
amplifies the output of the first detector 21, an amplifier 24 that
amplifies the output of the second detector 22, a logarithmic ratio
amplifier 25 that outputs the logarithm of the ratio between the
outputs of amplifiers 23 and 24, a lock-in amplifier 26 that
detects the derivative spectral signal of a glucose absorbance
spectrum in above examined portion 17 from the rate of change of
the output of logarithmic ratio amplifier 25 with respect to a
change in wavelength, an arithmetic processor 27 containing a
microprocessor that calculates the blood sugar level in the above
examined portion by processing a derivative spectral signal, which
is a digital signal obtained by converting the above analog
derivative spectral signal detected by the lock-in amplifier
26.
Laser light adjusted and controlled at the central wavelength
.lambda..sub.i and the wavelength-modulation width .DELTA..lambda.
by wavelength-variable semiconductor laser 11 is separated into two
beams by beam splitter 14 after being intensity-modulated by
attenuator 12.
One laser beam L.sub.2 passing through beam splitter 14 is
converted into an electrical signal I.sub.0 by second detector 22,
so that the intensity of the incident light is monitored. The other
laser beam L.sub.1 is made incident on examined location 17 where
the concentration of glucose is measured. The light
diffuse-reflected from examined location 17 is converted into an
electrical signal I.sub.s by the first detector 21 after being
collected by integrating sphere 18.
The above electrical signals I.sub.s and I.sub.0 are respectively
amplified by the amplifiers 23 and 24, and is input to logarithmic
ratio amplifier 25, which outputs the normalized absorbance signal
expressed by the following equation (6).
Since the above electric signals I.sub.s and I.sub.0 are values
measured at the same time by the first detector 21 and the second
detector 22 after the same laser light is separated by the beam
splitter 14, the values of the above absorbance signal A are
accurate and are hardly affected by drift.
Then only the amplitude of an alternating-current signal expressed
by the following equation (7) is extracted by the lock-in amplifier
25.
The alternating-current component is a signal proportionate to the
slope of the spectrum of a sample at the central wavelength of the
wavelength modulation.
As described earlier, the attenuator 12 varies the intensity of the
incident light to vary the depth of light penetration into examined
location 17 of skin 16 and switches two attenuator units 12a and
12b or more than those by a rotating disk 12c. The concentration of
glucose in a part where body fluid containing blood components
exists is measured accurately by the variation of the intensity of
the incident light.
Lock-in amplifier 26 outputs an alternating-current signal
expressed by the following equation (8) corresponding to the
intensity I.sub.01 of the incident light created by attenuator
12.
Lock-in amplifier 26 also outputs an alternating-current signal
expressed by the following equation (9) corresponding to the
intensity I.sub.02 of the incident light created by attenuator
12.
Arithmetic processor 27 converts the above alternating-current
signals D.sub.1 and D.sub.2 from analog to digital format and
calculates the difference expressed by the following equation (10)
for each cycle of the intensity modulation of the incident
light.
Arithmetic processor 27 uses the values obtained by equation (10)
and the data of a regression equation, which is obtained beforehand
and not illustrated in FIG. 13, to determine the glucose
concentration level in the examined location.
In the above determination of the glucose concentration level, if
the processing of accumulation and averaging is performed for many
cycles of the switching of attenuator units 12a and 12b of
attenuator 12, then the S/N ratio is improved.
Further, if the incident light is intensity-modulated at more than
3 steps, then an optimal range of intensities of the incident light
is found for the determination of the glucose concentration level,
so that an optimal choice of attenuator 12 can be made, and the
accuracy of the present technique is further enhanced. As a result,
a standard diffuse plate used for calibration in prior diffuse
reflectance methods becomes unnecessary.
Further, if light penetrating examined portion 17 does not leak
from the bottom of the sample, ie. the condition of the so-called
infinite thickness of the sample, is satisfied, then the
information on the thickness of the examined location is not
necessary unlike the transmission method.
Although the present invention has been fully described in
connection with the preferred embodiments thereof with reference to
the accompanying drawings, it is to be noted that various changes
and modifications are apparent to those skilled in the art. Such
changes and modifications are to be understood as being included
within the scope of the present invention as defined by the
appended claims unless they depart therefrom.
* * * * *