 |
Description  |
|
|
BACKGROUND OF THE INVENTION
The technical field of this invention is material analysis and, in
particular, the invention relates to the detection and quantification of
analytes in materials by measuring the absorption of near infrared light.
Material analysis, especially the analysis of liquid materials for the
presence of solutes, can be a tedious and complex task. In many instances,
it would be more desirable to be able to analyze materials quickly, easily
and non-invasively. One example of such an application is blood analysis.
Treatment of many medical disorders, such as diabetes and other hormonal or
metabolic disorders, requires accurate blood analysis. Additionally, in
some situations, repeated or even continuous blood monitoring is
desirable, for example, when monitoring drug dosage changes or variations
in metabolic factors, such as glucose or cholesterol.
Conventionally, blood is analyzed by withdrawing a sample from the body of
a subject and examining it, using one or more techniques, such as
immunoassays, activity assays, chromatographic assays and
spectrophotometric assays. These conventional methods suffer from several
common disadvantages. One such disadvantage is that these tests are
invasive and raise the risk of patient infection and discomfort. Also,
such tests can be time-consuming. This time delay between when the blood
is drawn and when the analysis is completed provides a window during which
the subject's blood content may have changed, possibly leading to
erroneous test results. A further disadvantage to conventional blood
testing techniques is that the people drawing and testing the blood sample
are put at risk for exposure to infectious disease agents.
Accordingly, it is the object of the present invention to provide an
analytic apparatus for non-invasively, quickly and continuously detecting
and quantifying analytes in a blood sample.
It is another object of this invention to provide a method and apparatus
for non-invasive detection of blood-glucose levels but which avoids the
problems of non-continuous test results, subject discomfort and potential
technician exposure to infectious agents.
SUMMARY OF THE INVENTION
Systems and methods for non-invasive blood analysis are disclosed in which
a blood sample is non-invasively illuminated through a patient's tissue,
such as the skin, at a plurality of wavelengths, including a reference and
a data wavelength, for a target analyte. These wavelengths are preferably
selected from the near infrared spectrum, and are also preferably closely
spaced to each other in order to minimize interference from other solutes
in the blood. Non-invasive measurements of the absorption of light at such
wavelengths are taken (e.g., by measuring reflectance or transmittance),
and a non-invasive analysis of absorption ratios is performed for various
sets of these wavelengths. Changes in the detected reflectance or
transmittance ratios are then correlated with specific material
properties, such as the concentration of glucose, urea or cholesterol in a
subject's circulatory system.
One problem in obtaining reliable blood-analyte data is that the light
impinged on the sample is scattered by various local properties of the
subject. However, by performing a ratio analysis in a narrow window, the
present invention eliminates (or at least reduces) the effect of light
scattering caused by blood solutes other than the analyte as well as the
scattering effects of background and patient-dependent factors (e.g.,
pigmentation, thickness and vascularization of the skin) that might
otherwise interfere with accurate measurements.
It has been discovered that particular advantages can be obtained when
closely-spaced data and reference wavelengths are selected, because when
greater distances separate the analyte data wavelength from the reference
wavelength, the effects of scattering on the measured ratio typically will
be larger and more erratic. Thus, having a narrow detection window within
which all the measurements are taken can limit the range of variation and,
therefore, the effect of these phenomena, yielding a more accurate
determination of in vivo blood-analyte levels.
Furthermore, it has also been discovered that scattering increases as
wavelength approaches the visible light range. Therefore, in practice of
the invention, two wavelengths are selected as close together as possible,
to assure a narrow window, and the window is located at a relatively long
wavelength, e.g., over 1000 nm.
For example, to measure glucose levels in a circulating bloodstream within
a subject, glucose absorbance data is reliably obtained at about 1600 nm
+/-15 nm, and reliably evaluted when selected in combination with a
reflectance reference wavelength in the close by range of 1630-1660 nm,
the latter being relatively insensitive to glucose content. In the case of
glucose measurement, a reference reading above the 1600 nm data point
(e.g., in the 1630 to 1660 nm range) is preferable over a reference
measurement below the data point (e.g., in the 1540 to 1570 nm range)
because of urea and water measurement peaks at about 1500 nm can cause
interference. The absorption of light by other analytes at 1600 nm and in
the 1630 1660 range is relatively low, or the differences are small,
thereby minimizing interference due to such other analytes.
In the event that problems are encountered in measuring glucose in this
range, then a reference reflectance reading may be obtained at about 1300
nm, as an alternative or supplemental reference reading. While the latter
reference wavelength is further removed from 1600 nm, and typically will
result in lower precision due to increased scattering effects, it provides
an alternative or supplemental reference wavelength which will still yield
favorable results.
In another example of the invention, cholesterol levels can be measured in
a circulating bloodstream within a subject, by obtaining light absorbance
data at about 1720 nm+/-15 nm, or at about 2300 nm+/-15 nm, in combination
with a closely spaced reference wavelength, the latter being relatively
insensitive to cholesterol content.
In yet another example of the invention, urea levels can be measured in a
circulating bloodstream within a subject, by obtaining light absorbance
data at about 1500 nm+/-15 nm, in combination with a closely spaced
reference wavelength, the latter being relatively insensitive to urea
content.
As used herein the term "near infrared" or "near IR" is intended to
encompass light in a spectrum ranging from about 1000 to about 2500 nm,
more preferably from about 1300 to about 2300 nm, and, in some instances,
most preferably from about 1500 to about 1800 nm.
As used herein the terms "closely spaced" or "narrow window" are intended
to describe paired wavelengths for measurement of an analyte, with a first
wavelength being chosen proximal to a near infrared (IR) absorption peak
for the analyte which varies with concentration of the analyte (the data
wavelength) and the a second (reference) wavelength being sufficiently
removed from the first so that measurements of light absorption at this
second wavelength are relatively insensitive to the concentration of the
analyte and yet the second wavelength is sufficiently close to the first
wavelength to minimize interference from scattering effects and the like.
Typically, the window bracketing these closely spaced wavelengths will be
less than about 300 nm and preferably less than about 60 nm wide and, in
some instances, more preferably less than about 30 nm wide.
By choosing a data wavelength that is highly specific for a particular
analyte (i.e., with no competing nearby absorption peaks), the use of a
narrow window also assures that non-analyte absorption effects as well as
scattering effects are minimized.
In another aspect of the invention, an analytic apparatus and method are
described employing a multi-wavelength illumination source, a
wavelength-specific detector array and a reflection ration analyzer. The
illumination source illuminates material sample at a plurality of discrete
wavelengths selected from the near infrared region, in a narrow window as
described above, e.g., less than about 300 nm or preferably less than
about 60 nm wide and, in some instances, more preferably less than about
30 nm wide.
The detector array detects the IR light absorbed by the sample, converts
the detected light into electrical signals indicative of the intensity of
the reflected (or transmitted) light at each selected wavelength. These
signal can then be processed by a absorption ratio analyzer. The ratio
analyzer then derives a ratio for at least two of the detected
wavelengths, for example, in the case of glucose, selecting a reference
wavelength at approximately 1630-1660 nanometers and a glucose data
wavelength at approximately 1600 nanometers, such that the ratio can be
compared with predetermined values to non-invasively detect the
concentration of glucose in a subject's circulatory system.
In one particular embodiment of the invention, the illumination source
further includes at least two laser diodes, producing light at distinct
wavelengths, to illuminate the subject's skin with IR light at both a
reference and a data wavelength. This embodiment is particularly
well-suited to providing a system for detecting glucose in blood
circulating through a surface vein, or in a nailbed of a finger, due to
the penetration of near infrared wavelengths of light through human
tissue.
The methods of the invention utilizes the observation that analytes
differentially absorb near IR light at various wavelengths and that data
and reference wavelength can be chosen to quantify the presence of the
analyte, non-invasive reflectance or transmittance measurements. For
example, a surface vein in a human subject, or a fingernail bed, can be
illuminated with light at a first data wavelength, and a non-invasive
reading is taken so as to establish a blood analyte level. The vein or bed
is also either concurrently or sequentially illuminated with light at a
second reference wavelength and a second non-invasive reading is taken, so
as to establish a baseline background value. The ratio of these
reflectance readings is compared to known (e.g., stored in a look-up
table) ratios relating to known analyte levels, and an analyte level is
thereby determined.
The present invention is an improvement over the prior art in that it can,
with improved accuracy, non-invasively, quickly and easily detect and/or
quantify blood analyte levels. In this way, the invention eliminates the
problems of non-continuous data, subject discomfort and/or potential
exposure to infectious diseases.
The invention will next be described in connection with certain preferred
embodiments; however, it should be clear that various additions,
subtractions and modifications can be made without departing from the
spirit or scope of the invention. For example, although the invention is
illustrated in connection with a blood analysis system, various
alternative embodiments can also be devised. Furthermore, while
reflectance measurements are primarily discussed, transmittance
measurements may be employed in a similar manner as an alternative in
practice of the invention.
Although the illustrated embodiment shows a system with a fiber optic
bundle for delivery of six distinct wavelengths of light, it should be
clear that the number of interrogation wavelengths, the size and shape of
the sampling head, and the means for transmitting the light to and from
the sample, can be varied to meet particular needs and applications. For
example, in monitoring blood sugar levels, as few as two wavelengths may
be used to measure the glucose concentration. Moreover, a single fiber can
be used for transmission and detection of multiple interrogation
wavelengths. Additionally, although lasers are described as preferred
light sources, other illumination means, including non-coherent, discrete
wavelength light sources, can be employed.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic block diagram of an analytic apparatus according to
the invention;
FIG. 2 is a schematic diagram of the apparatus according to the invention
particularly adapted for non-invasive detection of glucose in a subject's
blood;
FIG. 3 is a detailed view of a sampling head assembly of the apparatus of
FIG. 2;
FIG. 3A is a schematic view of an alternative apparatus according to the
invention;
FIG. 4 is a more detailed illustration of an individual optical fiber and
its connection to an illumination source and a detector element according
to a reflection mode embodiment of the invention;
FIG. 5 is a graph of the reflectance spectrum of glucose, illustrating the
analytical techniques of the present invention;
FIG. 6 is a graph of absorbance versus glucose concentration for
illumination at 1586 nm for several concentrations of glucose;
FIG. 7 is a graph of glucose absorbance in arbitrary units versus
wavelength from about 1100 to 2500 nm, for two samples (curve 1 and 2)
having the same concentration of glucose in water, with one sample (curve
2) also including a scattering analyte; and
FIG. 8 is a graph of absorbance exhibited by albumin, glucose, urea, uric
acid and cholesterol in a blood sample illuminated over the range of 1000
to 2500 nm.
DETAILED DESCRIPTION
In FIG. 1, a schematic block diagram of an analytic apparatus 10 according
to the invention is shown. Apparatus 10 includes a multiple wavelength
illumination source 12, a wavelength specific detector array 14, and a
reflection ratio analyzer 16.
Illumination source 12 can be a single, multi-wavelength laser diode or a
series of discrete diode elements, each emitting a distinct wavelength of
light selected from the near infrared region to illuminate a blood sample
18 via optical path 20a. In some applications, illumination source 12 can
be a broadband near IR emitter, emitting both the data and reference
wavelengths as part of a broadband interrogation burst of IR light or
radiation.
Detector array 14 detects light reflected (or transmitted) by sample 18
through optical path 20b. The detector array 14 converts the reflected
light into electrical signals indicative of the degree of absorption light
at each wavelength and transfers the converted signals to the absorption
ratio analyzer 16. Analyzer 16 processes the electrical signals and
derives an absorption (e.g., a reflection or transmittance) ratio for at
least two of the wavelengths. Analyzer 16 then compares the calculated
ratio with predetermined values to detect the concentration and/or
presence of the analyte in the blood sample 18.
An embodiment of analytic apparatus 10 particularly adapted to provide
reflective measurements of analytes in blood circulating through a surface
vein is shown in FIG. 2. As can be seen from FIG. 2, laser diode elements
12a-12f comprise a multiple wavelength illumination source 12, which
provides light at a series of skin penetrating wavelengths. Diode elements
12a-12f can each transmit a predetermined wavelength of light via
corresponding optical fiber elements 24a-24f and sampling head 26, to vein
segment 28 of wrist 30. (Alternatively, light at various wavelengths can
be emitted by one multiple-wavelength laser diode and transmitted via a
single optical fiber.) The discrete wavelengths of laser light
automatically pass through the tissue of wrist 30 and illuminate the blood
circulating in surface vein 28.
For example, at least one of the diode elements 12a-12f can transmit
interrogating radiation in a wavelength range of about 1600 nm in order to
obtain glucose concentration data, and another of the diode elements
12a-12f can transmit radiation in at about 1630-1660 nm, or about
1540-1570 nm, to obtain qlucose reference measurements. In some instances,
it may also be preferable to take at least one further glucose reference
reading (e.g., at about 1300 nm) using another of the diode elements
12a-12f to provide additional baseline data for analyte discrimination.
Other diode elements can be dedicated to the measurement of other analytes
(such as cholesterol, urea or ureic acid, using similar pairs of closely
spaced data and reference wavelengths, as described above).
Following irradiation by the diode elements 12a-12f, a fraction of the
transmitted light is reflected back from the blood circulating in surface
vein 28 along optical fiber elements 24a-24f. (In one embodiment, each
optical fiber element 24a-24f carries a reflected light signal having the
same wavelength as the light originally transmitted along it.) Diode
detectors 14a-14f receive the reflected light from the optical fiber
elements 24a-24f and convert these light waves into a series of electrical
signals indicative of the intensity of each of the reflected wavelengths
of light received from surface vein 28. For example, if laser diode
element 12a originally transmitted light of wavelength 1595 nm (a glucose
data measurement wavelength) along optical fiber element 14a, then optical
fiber element 14a can also carry reflected light of wavelength 1595 nm
back to diode detector element 22a.
As shown in FIG. 2, diode detector elements 14a-14f transmit the electrical
signals indicative of the intensity of the reflected light to reflection
ratio analyzer 16 along electrical connection 32. Analyzer 16 compares the
electrical signals received from diode detector elements 14a-14f to derive
a reflectance ratio for at least two of the transmitted wavelengths of
light, such that the ratio can be compared to predetermined values to
detect the presence of glucose in the blood flowing through vein 28.
Analyzer 16 then can be employed to determine the presence and
concentration of glucose, alone or along with other blood analytes.
FIG. 3 shows a more detailed view of the sampling held 26 of FIG. 2. As can
be seen from FIG. 3, optical fiber elements 24a-24f of optical fiber
bundle 24 are adapted to extend through a corresponding set of holes
32a-32f in the sampling head 26, thus, facilitating alignment of optical
fiber elements 24a-24f along a surface vein or other vascular region.
Sampling head 26 also comprises taping flanges 34a and 34b located at
opposed ends of sampling held 26, providing a means for affixing sampling
held 26 above the surface.
FIG. 3A shows an alternative embodiment of a sampling held 26 of FIG. 2.
Optical fiber elements 24'a-f optical fiber bundle 24' coupled to source
12 are adapted to extend through a corresponding set of holes in the
sampling head 26A, thus facilitating alignment of the optical fiber
elements at the surface 42 of a finger 44 immediately above a nailbed 46.
The light from fibers 24'a-f is transmitted through the finger and
absorption is measured by applying a detector 48 on the opposite side of
the finger. The detector 48 can employ a corresponding series of optical
fibers 24"a-f and, optionally, a corresponding set of wavelength-specific
filters 49 a-f, as shown, or, in a more simple embodiment, a broadband
detector can be used and rely, for example, on sequential emissions of
specific interrogation wavelengths by the illumination means.
The sampling head 26A and detector 48 can be attached to the fingertip by a
clip 51, as shown, or by straps located at opposed ends of sampling head
26A, in a manner similar the attachment means of FIG. 3, to provide a
means for affixing the apparatus about the finger. (In other transmittance
measuring embodiments, the sampling head 26A and detector 48 can be
disposed in other locations as well, such as an earlobe, toe or the like.)
FIG. 4 is a more detailed illustration of an individual optical fiber 24a
and its connection to an illumination source 12a and a detector element
14a in a reflection-mode analysis system according to the invention. Since
each of optical fiber elements 24a-24f is identically adapted, only
optical fiber element 24a is shown. Laser diode element 12a is connected
to optical fiber element 24a via optical fiber element 36a through optical
splitter 38a. Diode detector element 14a is connected to optical fiber
element 24a via optical fiber element 40a, also through optical splitter
38a. Optical splitter element 38a and corresponding elements 38b-38f, not
shown) enable dual usage of optical fiber elements 24a-24f so that the
light emitted by laser diode elements 12a-12f and not absorbed by the
tissue sample travels along the same optical fiber elements 24a-24f.
For example, in blood sugar analysis, it has been observed that glucose has
peaks in the near infrared that are in well-defined spectral regions and
differentiable from the blood background. FIG. 5 is a graph of the
reflectance spectrum of glucose. The wavelength of the source light is
show | | |
