Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
2146856
Method and Apparatus for Non-Invasive
Measurement of Blood Sugar Level
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.
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 a body fluid using COz 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 ~l and ~z.
Here, az is a characteristic absorption wavelength of the
substance to be measured, e.g. glucose, and ~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 ~1 to the absorbance
at ~z. The absorption band of the substance to be measured is
between 940 cm-1 and 950 cm-1, i . a . between 10 . 64 and 10 . 54 ~,m
for wavelength ~1, and the absorption band is between 1090 cm-1
and 1095 cm-1, i . a . between 9 . 17 ~,m and 9 . 13 ~,m for wavelength
~z~
Swiss Patent No. CH-612,271 discloses a non-invasive
examining method for detecting biological substances through
skin, using an attenuated-total-reflectance (ATR) prism. The
method attaches a wave guide (ATR prism) directly to the
surface of a sample under examination (e. g. a lip or tongue)
to introduce infrared light. The refractive index of the wave
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guide is greater than that of the sample medium, i.e. 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 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 obtained
data on glucose.
U.S. Patent No. 3,958,560 disclosed 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 the shape of a contact lens comprising a light
source that applies infrared light to one side of the 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 Patent Application No. 2,035,557 discloses a
detecting apparatus for assessing substances near the blood
stream of a patient, such as CO2, 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 devices that measure or
monitor the flow of blood and organism-activating parameters
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or components such as oxygenated hemoglobin and reduced
oxyhemoglobin.
U.S. Patent No. 3,638,640 discloses a method and
apparatus for measuring oxygen and other substances in blood
and tissue. This 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.
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 absorption
detection 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 fluctuations of measuring
conditions, such as fluctuations of the detector, deviation of
the intensity, the direction and angle of irradiation, and
fluctuations of the flow of blood in the examined location.
Further, British Patent No. 2,075,668 disclosed 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, liver 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
the 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 organ, and a light
source. The wave guide is abutted to an organ so that
irradiation light is applied to the surface of the skin in an
oblique direction, and the oriented irradiation light is made
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to penetrate into the body through the skin and to be
reflected or back-scattered from the tissue at a distance from
the light source. Some of the light energy is absorbed and
the rest is incident on a first detector placed on the skin
spaced from the light source. A second detector is placed to
detect 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 the measurements 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 the hardware constituting the near-infrared
spectrometer. At present, the signal to noise rat_Lo S/N of
the best performance is approximately in the order between 105
to 106. On the other hand, for example, the prior methods of
measuring the absolute intensity of the spectrum requires a 105
to 106 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, the methods of measuring the concentrations of
sugar and glucose and the like using spectroscopic techniques
have less sensitivity, precision and accuracy than chemical
analysis of these concentrations of substances using reagents,
and a near-infrared spectrometer of high performance having a
high S/N ratio requires complex construction and high cost.
Thus, if a variation of glucose concentration from the
physiological concentration of glucose, 100 mg/dL, can be
measured with a precision of 2 to 3 digits by a reference
method, instead of simply measuring the absolute intensity of
a spectrum, we can find out 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.
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. An 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, independently 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 a variation of blood
sugar of a patient suspected of suffering from diabetes from a
normative value, independently of the patient's individual
differences, with a simple construction comprising wavelength
modulation means and 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 portion far assessing blood
sugar, detects, for each intensity-modulated light, the
2 0 intensity of reflected light from a portion being examined and the
intensity
of the incident light onto the portion being examined, detects the ratio of
an intensity of said reflected light and said incident light, detects the
rate of change in the ratio with respect to the change in the wavelength due
2 5 to the wavelength-modulation, extracts a 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
30 as being wavelength-modulated with a small modulation width
around a considered wavelength is applied to the examined
portion, e.g skin 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
35 concentration of glucose in the examined portion, where body
fluid including blood components exists, is extracted, and a
determination of the glucose in the examined portion is
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performed based on the derivative spectra of the absorption
spectra. Therefore, the concentration of glucose is easily
and securel y detected independent of individual differences of
the patient.
The above derivative spectra are preferably accumulated
and averaged corresponding to 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
accumulations, so that the signal to noise ratio S/N is
improved.
The present invention also 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 with a plurality
of 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 sputter, being incident.on an examined
portion for assessing blood sugar, and being transmitted or
reflected thereby, a first optical detector that detects the
intensity of the light collected by the optical collector, a
second optical detector that detects the intensity of the
light passing along the other optical path separated by the beam
splitter, a ratio detector that detects the ratio of the
output of the first optical detector to the output of the
second optical 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 to detect a derivative spectral signal of the
absorption spectrum of glucose in the examined portion, and
arithmetic means that calculates blood sugar in the examined
portion for each intensity of the intensity-modulated light
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based on the derivative spectral signal detected by the
derivative spectral signal detector.
As a result, derivative data of high quality is obtained
in real time without requiring computer processing. Further,
the speed of iterative scanning is higher than in 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 significantly
influenced by 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 so that its characteristics can
be effectively utilized for maximum performance, the
construction of the means for wavelength-modulating the
measured light being extremely simplified. Therefore, the
construction of the apparatus becomes simple and compact.
In the drawings:
Fig. 1 shows a single peak spectrum, its first derivative
spectrum, and its second derivative spectrum.
Fig. 2 shows 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 difference absorbance spectra with respect
to standard pure water.
Fig. 6 shows a comparison of the first derivative
spectra.
Fig. 7 shows a further comparison of first derivative
spectra.
Fig. 8 shows a further comparison of first derivative
spectra.
Fig. 9 shows a further comparison of first derivative
spectra.
Fig. 10 shows the relation between the concentration of
glucose and the first derivative of an absorbance spectrum.
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Fig. 11 shows the structure of human skin for describing
its optical properties.
Fig. 12 shows a graph for describing the relation 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.
The preferred embodiments of the present invention will
be described below with reference to the appended drawings.
In the following items [1] and [2] there are described
the derivative spectroscopy necessary for understanding the
present invention and a method of wavelength modulation for
obtaining derivative spectra. Further, in items [3], [4], and
[5] there are respectively described the verification of
determining glucose from 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's,
(Clinical Chemistry, Vol. 25, No. 9 (1979), pp. 1548-1553).
The concept of wavelength-modulation spectroscopy is closely
connected with 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.
Derivative spectroscopy is first 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:
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(a) compensation and correction of the baseline shift,
and
(b) effective increase in sensitivity to subtle changes
in the shapes of the spectral band.
Fig. 1 shows a single peak spectrum and its first and
second derivative spectra. The peak maximum point PmaX
corresponds to the zero-crossing point Pol of the first
derivative and the central peak point P~ of the second
derivative. The peak maximum point PdmaX and the peak minimum
point Pdmi,., of the second derivative respectively correspond to
the maximum slope points PS1 and Pg2 of the original spectrum
and also respectively correspond to the zero-crossing points
Po2 and Po3 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~/dt is constant, the
derivative dI/d~ of the intensity I with respect to wavelength
~ is proportional to the derivative dI/dt of the intensity I
with respect to time t, as is clear from the following
equation (1). By means of an electronic differentiator the
following equation (1) can be calculated.
dI/d~ _ (dI/dt)/(d~/dt) (1)
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 ~~. around a particular wavelength
and detects the transmitted or reflected light by 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 0~ is sufficiently less
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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 also be 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 to
be continuous and allows jumps between longitudinal modes, 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, oscillation
occurs at an arbitrarily set wavelength in a single mode.
This apparatus is called a tunable semiconductor laser of the
external resonance type.
Further, a wavelength-variable semiconductor laser
developed for use in coherent optical communications is
described in Nikkei electronics, No. 423 (6/15/1987), pp. 149-
161. In this article, semiconductor lasers that control the
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 the wavelength in a single longitudinal mode within a
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wavelength range of 3.1 nm. If the longitudinal mode is
allowed to change in the middle, the wavelength range is about
6 nm.
[2] Method of wavelength modulation for obtaining
derivative spectra.
If, in wavelength modulation, the modulation width
(_ ~z - ~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 ~I/~~, i.e. a derivative spectrum D
expressed by the following equation (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 electric system.
D = ~I/~A = (Iz - I1) / (~z - ~1) (2;
In general, the direct-current component is greater than
the alternating-current component in the measurement of a low
concentration of glucose. Since the direct-current-component
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.
4~lavelength modulation is performed by scanning
periodically upward and downward within a narrow modulation
width ~~, so that the scanning can be repeated at a higher
speed than by an ordinary spectrometer which scans a wide
range of wavelength. Therefore, accumulation and averaging
are easily performed. Since the noise component can be
reduced in proportion to the square root of the number of
accumulations, the signal to noise ratio (S/N) can be improved
by making the number of accumulations large. Further,
measurement in a short time effectively suppresses drift of
the optical system of the spectrometer.
The wavelength range in wavelength modulation is limited
to a narrow ~7~, but derivative spectra of high quality are
obtained in real time without any computer processing.
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Therefore, wavelength modulation is suitable for 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~ 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 the measurement of a sample of low
absorption, unless the numerical precision or the number of
significant digits of the intensity Ii of an original spectrum
is great, a significant change in the desired derivative
spectrum cannot be obtained. That is, the S/N ratio needs to
be significantly 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, we used pure water, aqueous solutions of
glucose 1,000 mg/dL, 3,000 mg/dL, 5,000 mg/dL.
Since it is difficult to observe 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 of the absorbance spectrum and the difference
of the first derivative spectrum of each sample to make the
differences observable. The derivative operation was
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performed in the direction from longer wavelength to shorter
wavelength.
First, consider the glucose absorption band between the
absorption peaks 1.43 ~,m and 1.93 ~,m of pure water. Fig. 3
shows the absorbance spectrum, and Fig. 4 shows its first
derivative spectrum. Further, Fig. 5 shows the difference of
absorbance spectra. In the difference absorbance spectra of
Fig. 5, the absorption by glucose is observed between 1.55 ~.m
and 1.85 ~,m. Also, S-shaped characteristics are observed
between 1.35 ~.m and 1.45 Vim. These are due to the shift of
the absorbance peak 1.43 ~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 ~,m and
1.58 Vim, which is around the noninterference zero-crossing
point, one between 1.6 ~.m and 1.67 ~,m, and one between 1.75 ~m
and 1.85 ~,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 relation between the first derivative of the
absorbance and the glucose concentration at wavelength
1.555 ~,m.
Since wavelength-variable semiconductor lasers can be
employed for the 1.5 ~m band, the construction of the
apparatus is easy. If wavelength-variable semiconductor
lasers are applied to wavelength modulation, the
characteristics of the wavelength-variable semiconductor
lasers can be effectively used to the maximum performance
limit.
Beyond the absorption peak 1.93 ~m of pure water, there
are absorption bands of glucose at 2.1 Vim, 2.2.7 Vim, and
2.33 ~,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
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2.06 ~ 2.1 ~m
2.1 ~ 2.24 ~,m
2.24 ~ 2.27 ~,m
2.27 ~ 2.3 ~,m
2.3 ~ 2.32 ~.m
2.32 ~ 2.38 ~.m
Similarly, between the absorption peaks 0.96 ~,m and
1.15 ~m of pure water, there is a broad absorption band of
glucose at 1.06 ~.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 ~m and
1.25 ~,m and the range between 1.00 ~,m and 1.05 Vim.
Similarly, between the absorption peaks 1.15 ~,m and
1.43 ~,m of pure water, there is a broad absorption band of
glucose at 1.25 ~,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 ~m and
1.36 ~m and the range between 1.18 ~,m and 1.23 ~,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 a 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 as follows.
In the longer-wavelength region, light energy is absorbed
strongly by water existing in the organ, so that it is hard to
penetrate into a deeper part of the organ (skin). However,
light is difficult to attenuate, since it is less affected by
scattering. Also, since the absorption coefficient of glucose
in its existing absorption band is greater, the path length
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can be short, i.e. the depth of light penetration can be
relatively small.
In the shorter-wavelength region near visible light, the
light is less absorbed by water to reach a deep part of the
skin. However, light is easily affected and attenuated by
scattering. Also, since the absorption coefficients of
glucose in its absorption band are small, the pathlength must
be large to raise the sensitivity of measurement.
In this way, there are various related factors for
choosing optimal wavelength. An optimal wavelength for the
measurement of glucose is preferably chosen from the range
between 1.45 ~m and 1.85 ~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 these fluctuating factors.
A diffuse reflectance spectrum of skin is based on a
signal obtained from the weak diffuse reflection of light that
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:
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(a) Spectral components of regularly reflected light 7
on the surface of skin.
(b) Spectral components of diffuse-reflected light 8
from 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
exists.
(d) Spectrum components of transmitted light through
deeper tissue.
In general, the contribution of the spectral components
near the surface of the skin is great, and the contribution of
the spectral components in part 4 where body fluid containing
blood components exists 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 the following technique of
light-intensity modulation in Japanese Patent Application No.
Sho-62-290821 and U.S. Patent 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, information of
greater depth is obtained, than when the intensity is small.
Therefore, if incident light of intensity Iol at which a
penetration depth of a detection limit is b1 is used, and the
intensity IS1 of diffuse-reflected light from depth b1/2 is
measured. Then the ratio between them is calculated by the
following equation (3) for normalization.
Ai = log (Io~/Isi) (3)
A1 has spectral information of only the part near the
surface of the skin.
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Next, if incident light of intensity Ioz in which the
penetration depth for the detection limit is bz, which is
greater than b2, is used, and the intensity ISZ of diffuse-
reflected light from depth bz/2 is measured, the ratio between
them is calculated by the following equation (4) for
normalization.
Az = log (Ioz/Isz) (4)
Az contains spectral information of a deeper part in from
the surface of the skin. Then the difference DA between A1 and
Az is calculated.
DA = Az - A1 = log (Ioz/Isz) - log (Ioi/Isi) (5)
The DA 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 present. Therefore, DA 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 = ~A/0~, we replace the absorbance A in equations
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(3), (4), and (5) with ~A/~~ 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.
This apparatus has a wavelength-variable semiconductor
laser 11, an attenuator 12 that periodically varies the
intensity of wavelength-modulated laser light output from the
laser 11, a beam splitter 14 that separates the optical path
13 of the wavelength-modulated and intensity-modulated light
emitted from the 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 which is made incident on an examined
portion 17 of skin 16 in which the blood sugar is to be
measured.
This apparatus also has 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 the 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 the
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 in the examined
portion by processing a derivative spectral signal obtained by
converting the analog derivative spectral signal detected by
the lock-in amplifier 26.
Laser light adjusted and controlled at the central
wavelength ~i and the wavelength-modulation width ~~. by the
wavelength-variable semiconductor laser 11 is separated into
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two beams by beam splitter 14 after being intensity-modulated
by attenuator 12.
One laser beam L2 passing through beam splitter 14 is
converted into an electric signal Io by the second detector 22,
so that the intensity of the incident light is monitored. The
other laser beam L1 is made incident on the examined portion 17
where the concentration of glucose is measured. The light
diffuse-reflected from examined location 17 is converted into
an electric signal IS by the first detector 21 after collection
by the integrating sphere 18.
The electric signals IS and Io are respectively amplified
by amplifiers 23 and 24, and are input to logarithmic ratio
amplifier 25, which outputs the normalized absorbance signal
expressed by the following equation (6).
A = log (Io/IS) (6)
Since the electric signals IS and Io have values measured
at the same time by the first detector 21 and the second
detector 22, after the same laser light has been separated by
the beam splitter 14, the values of the absorbance signal A
are accurate and 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.
D = DA/~~ (7)
The alternating-current component is a signal
proportional to the slope of the spectrum of a sample at the
central wavelength of the wavelength modulation.
As described earlier, attenuator 12 varies the intensity
of the incident light to vary the depth of light penetration
into the examined portion 17 of the skin 16 and switches
between two attenuator units 12a and 12b, or more than two, 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.
The lock-in amplifier 26 outputs an alternating-current
signal expressed by the following equation (8) corresponding
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to the intensity Iol of the incident light created by the
attenuator 12.
D~ _ ~Au ~~ (8)
The lock-in amplifier 26 also outputs an alternating-
current signal expressed by the following equation (9)
corresponding to the intensity Io2 of the incident light
created by the attenuator 12.
D~ = DA~/a~. (9)
The arithmetic processor 27 converts the above
alternating-current signals D1 and DZ 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.
~D = D2 - D1 = ~Az/0~ - ~Al/~~ ( 10 )
The 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 in the examined portion.
In this determination of glucose, if the process of
accumulation and averaging is performed for many cycles of the
switching of the attenuator units 12a and 12b of the
attenuator 12, the S/N ratio is improved.
Further, if the incident light is intensity-modulated in
more than 3 steps, an optimal range of intensities of the
incident light is found for the determination of glucose, so
that an optimal choice of the 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 the light penetrating the examined portion 17
does not leak from the bottom of the sample, i.e. the
condition of so-called infinite thickness of the sample, is
satisfied, then information on the thickness of the examined
portion is not necessary, unlike in 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
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various changes and modifications will be apparent to those
skilled in the art. Such changes and modifications are to be
understood as included within the scope of the present
invention as defined by the appended claims unless they depart
therefrom.
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