U.S. patent application number 11/120050 was filed with the patent office on 2005-09-01 for non-invasive blood analyte measuring system and method utilizing optical absorption.
This patent application is currently assigned to Minformed, L.L.C.. Invention is credited to Wuori, Edward R..
Application Number | 20050192493 11/120050 |
Document ID | / |
Family ID | 28452389 |
Filed Date | 2005-09-01 |
United States Patent
Application |
20050192493 |
Kind Code |
A1 |
Wuori, Edward R. |
September 1, 2005 |
Non-invasive blood analyte measuring system and method utilizing
optical absorption
Abstract
A device and method for measuring the concentration of analytes
in the blood of a portion of tissue. The device includes a sensor
module, a monitor, and a processor (separate from or integral with
the sensor module). The sensor module includes a radiation source
for emitting radiation to the tissue; a collimator and narrow band
filter for processing the radiation after it has transmitted
through or been reflected by the tissue; and one or more sensors
for sensing the transmitted or reflected radiation. The one or more
sensors send a signal to the processor which algorithmically
converts the radiation using linear regression or orthogonal
functions to determine the concentration of one or more blood
analytes. The device self-calibrates to eliminate error caused by
variables such as skin character. The sensor module is integrated
to reduce size and weight such that it is inobtrusive, and the
monitor is compact for transport.
Inventors: |
Wuori, Edward R.; (Mounds
View, MN) |
Correspondence
Address: |
INTELLECTUAL PROPERTY GROUP
FREDRIKSON & BYRON, P.A.
200 SOUTH SIXTH STREET
SUITE 4000
MINNEAPOLIS
MN
55402
US
|
Assignee: |
Minformed, L.L.C.
|
Family ID: |
28452389 |
Appl. No.: |
11/120050 |
Filed: |
May 2, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11120050 |
May 2, 2005 |
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10104782 |
Mar 21, 2002 |
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6898451 |
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60277758 |
Mar 21, 2001 |
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Current U.S.
Class: |
600/322 ;
600/310 |
Current CPC
Class: |
A61B 5/0002 20130101;
A61B 5/14532 20130101; A61B 5/1455 20130101 |
Class at
Publication: |
600/322 ;
600/310 |
International
Class: |
A61B 005/00 |
Claims
What is claimed is:
1. A mobile apparatus for the non-invasive measurement of the
concentration of one or more blood analytes in the blood of a
portion of tissue comprising: a light source for generating a
spectrum of infrared radiation and transmitting the spectrum of
radiation to the portion of tissue; one or more sensors for
detecting radiation from the portion of tissue over a broad
spectrum and generating an output regarding the detected radiation;
a mounting device for positioning the light source and the one or
more sensors approximately adjacent to the portion of tissue; a
processor for receiving the output from the sensors, the processor
being configured for performing orthogonal analysis using weighting
functions to determine the concentration of one or more blood
analytes in the blood of the portion of tissue using self
calibration in which the ratio of blood analyte to a blood
reference material is used; and a display for displaying the
concentration of the one or more blood analytes.
2. The mobile apparatus of claim 1, wherein the one or more sensors
are configured for detecting infrared radiation reflected from the
portion of tissue.
3. The mobile apparatus of claim 1, wherein the one or more sensors
are configured for detecting infrared radiation transmitted through
the portion of tissue.
4. The mobile apparatus of claim 1, further including a source
optics device for focusing the infrared radiation from the light
source onto a measurement point on the portion of tissue.
5. The mobile apparatus of claim 4, further including a collimator
for focusing infrared radiation onto the one or more sensors after
it has passed through or reflected from the portion of tissue.
6. The mobile apparatus of claim 1, wherein the one or more sensors
are capable of detecting near infrared regions of wavelengths of
about 700 nm to about 2500 nm.
7. The mobile apparatus of claim 1, wherein the sensors comprise
direct silicon sensors sensitive to radiation of a wavelength range
from about 0.4 to 1.1 microns and infrared sensors sensitive to
radiation of a wavelength range from about 1 to 10 microns.
8. The mobile apparatus of claim 5, wherein the mobile apparatus
comprises a pocket monitor module and a sensor module capable of
communication with the pocket monitor module.
9. The mobile apparatus of claim 8, wherein the sensor module
comprises the light source, the one or more sensors, the source
optics device, the collimator, and the mounting device.
10. The mobile apparatus of claim 9, wherein the sensor module
comprises a radio frequency transmitter and the pocket monitor
module comprises a radio frequency receiver.
11. An ambulatory system for the rapid and continuous, non-invasive
measurement of the concentration of one or more blood analytes
comprising a sensor module and a pocket monitor module, wherein the
sensor module comprises: a light source for generating and
transmitting infrared radiation to an ear lobe; a focusing device
for focusing the infrared radiation from the light source onto a
measurement point on the ear lobe; a filter for separating the
infrared radiation into separate wavelengths; one or more sensors
for detecting infrared radiation transmitted or reflected from the
measurement point and generating spectral data corresponding to the
detected infrared radiation received; a means for mounting the
light source, the focusing device, the filter, and the one or more
sensors on the ear lobe to facilitate the transmission of infrared
radiation through the earlobe and to the one or more sensors; a
processor for receiving spectral data from the sensors, the
processor being configured for performing orthogonal analysis to
determine blood analyte concentration data using self calibration
in which the ratio of one or more blood analytes to a blood
reference material is used; and a radio frequency transmitter for
transmitting the blood analyte concentration data over a short
distance; and wherein the pocket monitor module comprises: a radio
frequency receiver for obtaining blood analyte concentration data
from the sensor module; and a monitor for displaying the blood
analyte concentration data.
12. The mobile ambulatory system of claim 11, wherein the sensor
module further includes a collimator for refocusing the infrared
radiation after scattering in the ear lobe.
13. A method of non-invasively measuring the concentration of one
or more blood analytes in a portion of tissue of a human or animal
comprising the steps of: positioning the portion of tissue near a
light source and one or more sensors such that infrared radiation
transmitted by the light source is reflected from or transmitted
through the portion of tissue and onto the one or more sensors;
exposing the portion of tissue to infrared radiation from the light
source; detecting the infrared radiation transmitted or reflected
from the portion of tissue with the one or more sensors; generating
spectral data from the one or more sensors in response to receiving
the infrared radiation and communicating the spectral data to a
processor; determining the concentration of one or more blood
analytes by orthogonal analysis using self calibration of the
spectral data in which the ratio of blood analyte to a blood
reference material is used; and displaying the concentration of the
one or more blood analytes.
14. The method of claim 13, wherein the step of determining the
concentration of one or more blood analytes by orthogonal analysis
further includes using weighting functions.
15. The method of claim 14, further including the step of filtering
the radiation from the tissue into a plurality of wavelengths
before it is detected by the one or more sensors.
16. The method of claim 14, wherein the portion of tissue is an
earlobe.
17. The method of claim 14, wherein the blood analyte is lactic
acid.
18. The method of claim 14, wherein the blood reference material is
selected from the group consisting of water and hemoglobin.
19. The method of claim 14, further including the step of
separating the one or more blood analytes by using a ratio of
pulsatile hemoglobin to total hemoglobin.
20. The method of claim 14, wherein the steps of: exposing the
tissue to infrared radiation, detecting the infrared radiation,
generating spectral data and communicating it to a processor,
determining the concentration of one or more blood analytes by
orthogonal analysis using weighting functions and self calibration
of the spectral data in which the ratio of blood analyte to a blood
reference material is used, and displaying the concentration of the
one or more blood analytes, are rapidly repeated to provide
continuous information on blood analyte concentrations.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of patent
application having U.S. Ser. No. 10/104,782, filed Mar. 21, 2002,
which in turn is entitled to the benefit of Provisional Patent
Application Ser. No. 60/277,758, filed Mar. 21, 2001, entitled
"Noninvasive Infrared Blood Analyte Measuring System and
Methods."
FIELD OF THE INVENTION
[0002] The present invention relates to a method and apparatus for
non-invasive monitoring of various blood analytes in humans and
other animals in the fields of medicine, sports medicine, military
hardware, anemia treatment, diabetes treatment, and traumatic
injury treatment.
BACKGROUND OF THE INVENTION
[0003] This invention relates to a non-invasive apparatus and
methods for in vivo monitoring of the concentration levels of
various blood analytes within a living subject, using optical
absorption spectrophotometry. The device and methods may be used to
simultaneously monitor several analytes found in the blood outside
of a laboratory setting. The device and methods are able to resolve
analytes down to approximately one mg/dL. Further, the device and
methods are able to measure all blood analytes present at
approximately one mg/dL, including glucose and lactate, for
example.
[0004] Information concerning the concentrations of blood analytes
is widely used to assess the health characteristics of people. For
example, lactate is becoming the measurement of choice in sports
and coaching to assess levels of conditioning for athletes and to
prevent over-training. Lactate threshold and other related
parameters are used to assess the aerobic and anaerobic status of
athletes, are correlated to athletic performance, and may be used
to "rank" athletes according to actual performance history. Lactate
monitoring, as used in athletics, may also be useful for Military
Academies, Army boot camps, and other physical training operations
to assess the physical condition of trainees, to improve training
programs, and to evaluate the effectiveness of training regimens on
specific individuals. Lactate is also widely used to assess the
medical condition of injured people. When serum lactate elevates
after an injury, whether or not the lactate clears is correlated
strongly with mortality, thus, measurement of serum lactate levels
is a key tool in assessing treatment.
[0005] Likewise, the monitoring of blood glucose has long been an
important tool in controlling diabetes in diabetic patients.
Diabetes is a high maintenance disease, generally requiring several
measurements of blood glucose daily. At present, this is typically
accomplished using a glucometer, in which a fresh blood sample must
be obtained for each measurement. Each measurement typically
requires a new "test strip" for receiving the blood sample, the
test strips characteristically being relatively expensive. Such
measurements are often painful, cumbersome, and moderately
time-consuming. The method of testing blood glucose using a test
strip is generally referred to as the "finger stick" method. It
specifically involves applying a drop of blood to the test strip,
the test strip using molecular sieves to block molecules larger
than molecular weight of about 200. The sieves consequently block,
for example, large glycosylated proteins from being included in the
blood glucose measurement. Due to the inconvenience and expense,
many diabetic patients do not monitor their blood glucose levels as
often as recommended. About 16 million diabetic patients in the
United States need to regularly monitor their blood glucose
levels.
[0006] A non-invasive device enabling painless and convenient
monitoring of blood glucose would be of great benefit to diabetic
patients. The relative ease of measurement may contribute to a more
regular blood glucose monitoring regime by diabetic patients.
Various attempts have been made at a blood glucose measurement
device using spectroscopy. However, those attempts have generally
had problems with "baseline drift" of unknown origin. It is
hypothesized that the absorption method used in most spectroscopy
devices for measuring glucose in the blood measures all glucose in
the blood, both the bound glucose and the free glucose. For the
purpose of diabetes management, measurement of the concentration of
free glucose is desired. That is, the concentration of free glucose
in the blood is generally recommended to be in the range of 80
mg/dL and 120 mg/dL. A diabetic patient will measure their blood
glucose level to determine whether the level is within the
recommended range. If the blood glucose level is outside of the
recommended range, the diabetic patient will typically inject
insulin to reduce the blood glucose level. Again, it is the free
glucose concentration level that is relevant to determining whether
the patient's blood glucose concentration is within the recommended
range. Because absorption techniques may measure both free and
bound glucose levels as one measurement, there may be an
overstatement of the blood glucose level that results in faulty
treatment by the patient. The molecular sieves of the test strip
glucometers described above correct for the possibility of
measuring bound and free glucose by preventing the bound glucose,
with a relatively high molecular weight, from passing through the
sieve.
[0007] It is notable, however, that the finger stick methods take
only one measurement of the glucose concentration level in the
blood and, for a series of measurements, require a series of blood
samples, generally obtained by a series of finger pricks.
Consequently, the finger stick methods do not offer an appealing
method of continuous measurement of blood glucose concentration in
the blood. Continuous measurement of blood glucose levels enable
near instant recognition of abnormal blood glucose levels whereas a
series of individual measurements inevitably includes periods of
time where the precise blood glucose level is unknown. Thus, a
diabetic patient may be better able to control blood glucose
levels. It may also assist the person in adjusting their lifestyle,
diet, and medication for optimum benefits. Providing the easy,
non-invasive, and optionally continuous monitoring provides a great
improvement in the treatment of the diabetes and allows the
treatment to be tailored to the individual.
[0008] Many other blood analytes with concentrations similar to or
greater than lactate and glucose are of fundamental importance; for
example, hemoglobin and its sub-types, albumin, globulins,
electrolytes, and others. Hemoglobin is important especially in the
monitoring of anemia caused by various various factors such as HIV
infection and chemotherapy. Anemia treatments need frequent
monitoring of hemoglobin to assess effectiveness of various
treatments such as Epoetin-Alpha therapy.
[0009] Spectrophotometry provides a useful method for determining
the presence of analytes in a system. A typical spectrometer
exposes a dissolved compound to a continuous wavelength range of
electromagnetic radiation. The radiation is selectively absorbed by
the compound, and a spectrograph is formed of radiation transmitted
(or absorbed) as a function of wavelength or wave number.
Absorption peaks are usually plotted as minima in optical
spectrographs because transmittance or reflectance is plotted with
the absorbance scale superimpose, creating IR absorption bands.
[0010] At a given wavelength the absorption of radiation follows
Beers' Law, an exponential law of the form:
A=.epsilon.Cb Where: A=absorbance=-log.sub.10(t).
[0011] t=fraction of radiation transmitted (or reflected).
[0012] .epsilon.=molar extinction coefficient, cm.sup.2/mol.
[0013] C=concentration, mol/cc.
[0014] b=thickness presented to radiation, cm.
[0015] The wavelengths of maximum absorption, .lambda..sub.max, and
the corresponding maximum molar extinction coefficient,
.epsilon..sub.max, are identifying properties of a compound.
Radiation causes excitation of the quantized molecular vibration
states. Several kinds of bond stretching and bond bending modes may
be excited, each causing absorption at unique wavelengths. Only
vibrations that cause a change in dipole moment give rise to an
absorption band. Absorption is only slightly affected by molecular
environment of the bond or group. Nevertheless, these small
chemical shifts may aid in uniquely identifying a compound. A
"fingerprint region" exists between 42 and 24 THz (1400 and 800
cm.sup.-1) because of the many absorption peaks that occur in this
region. It is virtually impossible for two different organic
compounds to have the same infrared (IR) spectrum, because of the
large number of peaks in the spectrum. While the peaks and valleys
are the traditional features used in this type of
spectrophotometry, the overall shape of the spectra may also
provide useful information, especially in mathematically separating
mixed spectra where more than one analyte is present.
[0016] In addition to the IR absorption bands, absorption peaks
also occur in the near-IR region (700-2500 nm). Absorptions in this
region are most often associated with the overtone and combination
bands of the fundamental molecular vibrations of --OH, --NH, and
--CH functional groups that are also seen in the mid IR region. As
a result, most biochemical species will exhibit unique absorptions
in the near-IR. In addition, a few weak electronic transitions of
organometallic molecules, such as hemoglobin, myoglobin, and
cytochrome, also appear in the near-IR. These highly overlapping,
weakly absorbing bands were initially perceived to be too complex
for interpretation and too weak for practical application. However,
recent improvements in instrumentation and advances in multivariate
chemometric data analysis techniques, which may extract vast
amounts of chemical information from near-IR spectra, allow
meaningful results to be obtained from a complex spectrum.
Absorption bands also occur in the visible range (400-700 nm). For
example, hemoglobin and bilirubin absorb strongly in this
region.
[0017] Traditionally, Near Infrared Spectroscopy (NIRS) has been
used to estimate the nutrient content of agricultural commodities.
More recently NIRS has become widely applied in the food
processing, chemical, pulp and paper, pharmaceutical, polymer, and
petrochemical industries.
[0018] Invasive devices and methods of quantifying and classifying
blood analytes using IR and other optical spectrophotometry methods
are very commonly known. Invasive procedures are those where a
sample such as blood is taken from the body by puncture or other
entry into the body before analysis. Invasive procedures are
undesirable because they cause pain and increase the risk of spread
of communicable, blood-borne diseases. Further, after the invasive
collection of body samples, these samples may need to be further
prepared in the laboratory by adding water or ions to the samples
to increase the accuracy of the spectrophotometry readings. Thus,
these commonly known devices and methods are often only suitable
for use under laboratory in vitro conditions and are too difficult
to be practically applied in athletic training and military
situations. It is noted, of course, that the finger stick method of
measuring blood glucose concentration levels using a glucometer has
been adapted for home use.
[0019] Recently, non-invasive devices for monitoring levels of
blood analytes using infrared spectroscopy have been developed. For
example, U.S. Pat. No. 5,757,002 by Yamasaki relates to a method of
and an apparatus for measuring lactic acid in an organism in the
field of sports medicine or exercise physiology. Also, U.S. Pat.
No. 5,361,758 by Hall relates to a non-invasive device and method
for monitoring concentration levels of blood and tissue
constituents within a living subject.
[0020] Previous non-invasive devices and methods typically require
time-consuming custom calibrations to account for the differences
between individuals and environmental factors which cause variation
in energy absorption. There are several factors that may result in
variation in energy absorption; for example, environmental factors
such as temperatures and humidity that may affect the equipment,
and individual factors such as skin coloration, skin weathering,
skin blemishes or other physical or medical conditions. This need
for custom calibration to each individual makes it impractical to
use previous devices on demand in training situations or at the
scene of accidents. A universal or self-calibrating device that is
capable of taking into account these variations would be
useful.
[0021] Further, many previous non-invasive devices and methods
accurately measure only a single blood analyte at a time. Most
typically, the devices are designed to measure blood glucose. To
measure a different analyte, the device must be reprogrammed or
otherwise altered. Even with such reprogramming or alteration, the
devices maynot typically measure the results of two or more
analytes at the same time without significant inaccuracies. Each
analyte in the blood sample contributes a unique absorption pattern
to the overall infrared spectrum, governed by the unique set of
molecular vibrations characteristic of each distinct molecular
species. The infrared spectral range extends from 780 nm to 25,000
nm and is commonly subdivided further into the near-infrared and
mid-infrared regions. Most devices obtain an measurement of an
analyte by using only a small portion of the IR spectrum reflecting
the particular analyte of interest. In those devices that do
attempt to use a wider spectrum to obtain multiple analyte
readings, relatively ineffective methods are used to separate and
account for multiple analyte spectral interferences, leading to
decreased accuracy. Thus, there exists a need for a device that may
successfully use a wider spectrum to accurately and simultaneously
isolate and determine the concentrations of multiple analytes.
[0022] IR spectroscopy typically involves radiating light onto a
portion of tissue for either transmission through the tissue or
reflection from the tissue. The transmitted or reflected radiation
is then analyzed to determine concentrations of analytes. However,
the radiation that is transmitted or reflected is not just
transmitted through or reflected from the blood, but instead
includes transmissions or reflection from the skin, subdermal
tissue, and blood. Thus, the received radiation is a mixture of
absorption signals from skin and tissues and blood. The signals
contributed by the skin and tissues make it difficult to accurately
measure the presence of blood analytes. These signals need to be
separated to eliminate the effects of skin and tissue in order to
measure the analytes in the blood. Previous non-invasive devices
and methods were unable to separate blood-related readings from
body tissue readings. Therefore, there is a need for a device
capable of separating the blood-related component of the signal
from the tissue component.
[0023] One method of achieving the separation of a blood-related
component of the signal is to accept only the portion of the mixed
signal which has a pulse synchronized with the heart pulse, known
as a pulsatile technique or synchronous detection. The pulsatile
signal is the time varying portion of the whole signal that is
synchronized with the heart beat. This method presumes that the
pulsations come from the movement of arterial blood or closely
related volume and allows a signal associated with the blood to be
separated from that of tissue. The synchronous method is widely
used for separating blood-related components in pulse
oximeters.
[0024] Another possible method for achieving separation of the
blood related components of the signal from tissue and skin related
components uses a hematocrit-type method to determine the portion
of the signal associated with the blood. The hematocrit is the
proportion, by volume, of the blood that consists of red blood
cells. The hematocrit is typically measured from a blood sample by
an automated machine that makes several other measurements at the
same time. Most of these machines do not directly measure the
hematocrit, but instead calculate it based on the determination of
the amount of hemoglobin and the average volume of the red blood
cells. Using a hematocrit method generally is faster than using a
synchronous method because there is no need to wait for heart
beats. Further, there is less signal loss associated with
hematocrit methods than with the synchronous method, the
synchronous method removing some blood associated signal
unnecessarily.
[0025] Finally, many non-invasive devices for in vivo monitoring of
blood analyte concentrations do not allow for an ambulatory
application. They typically utilize permanent equipment set up in a
laboratory or other test site, which makes it impossible to use
while away from the laboratory or other test site. Thus, there is a
need for a device that may be easily transported and used away from
the laboratory. The device would preferably not interfere with the
user's normal functioning and would greatly increase the utility
and range of analyte concentration monitoring beyond the laboratory
setting.
SUMMARY OF THE INVENTION
[0026] The present invention provides an improved apparatus and
method for the rapid, non-intrusive determination of the
concentration of blood analytes. In one embodiment, it provides a
portable tabletop unit for measurement of blood analyte
concentrations where the subject may walk up to the device for
measurement from a body part, such as a finger. However, there are
many situations where blood analyte measurement must be done
outside of a domestic or laboratory environment. Thus, another
embodiment of the present invention provides a portable system
which may be positioned on body tissue and transported on the
user's person. Features such as small size, a wireless sensor,
battery operation, portability, and downloadability demonstrably
increase the utility and range of the analyte measurement apparatus
of the present invention beyond the hospital or laboratory
setting.
[0027] The present invention also provides a method and apparatus
with increased sensitivity and accuracy. A problem encountered in
the area of blood analyte measurement via IR spectroscopy is
accuracy and drift. In general, other analytes and various other
substances present interfere with the IR measurement of the desired
analyte. These analytes vary in concentration and thus vary the IR
spectrum in the regions being used to determine specific analyte
concentration. The present invention corrects for all other
analytes with concentrations sufficient to interfere in the
determination of the concentration of the analyte or analytes of
interest. Measuring the entire visible and IR spectrum provides
enough data to simultaneously determine all of the analytes and
thereby compensate for any accuracy or drift problems their
concentration may cause in measuring the concentration of the
analyte(s) of interest. Data processing using orthogonal functions
is used to accomplishing this task. Other properties of blood may
also effect the IR measurement of the desired analyte. For example,
turbidity of the blood, as may be caused by elevated white cell
count or high blood lipids, may affect the measurement. These
factors appear in the spectra and are compensated for by the
present invention. The analyte measurement apparatus of the present
invention is sufficiently sensitive to detect blood glucose or
lactate with accuracy within, approximately, 10% of the level
actually present, and may do so in a short period of time (e.g. 5
seconds or less). Due to the non-intrusive nature of the
measurement and its relative rapidity, it is also possible to
monitor blood analyte levels essentially continuously.
[0028] The blood analyte measurement apparatus of the present
invention includes a radiation source for generating and
transmitting a spectrum of radiation onto a portion of tissue (for
transmission therethrough or reflection therefrom), one or more
sensors for detecting the radiation either transmitted through or
reflected from the tissue over a broad spectrum and generating an
output in response to the detected radiation, and a processor for
receiving output from the sensors to determine the concentration of
blood analytes in the portion of tissue. In a preferred embodiment,
the apparatus also makes use of a mounting device to position the
radiation source and the sensors relative to a portion of tissue so
the one or more sensors may receive a substantial portion of the
radiation produced by the radiation source and transmitted through
or reflected by the portion of tissue. In a further preferred
embodiment, the information regarding absorption of the radiation
is then algorithmically processed to clarify the signal(s) of the
desired blood analytes. Thus, the invention, in a typical
configuration, includes a sensor module which is preferably
attached to an earlobe, a pocket monitor for immediate readout and
data logging, and a data link to a PC for long term storage and
compilation of data. Thus, blood analyte levels may be continuously
monitored without the constraints of attachment wires or bulky
apparatus.
[0029] The blood analyte sensor module is integrated as much as
possible to reduce the size and weight. In one embodiment, the
sensor module is completely self-contained. The sensor module
illuminates the measurement site with a built-in radiation source
tailored to the spectral region of interest. The radiation source
and the sensors are each positioned on a chip. The radiation source
may be integrated onto a custom chip in transmission mode, or onto
the same chip as the sensors in reflection mode. That is, when it
is desired to receive and interpret radiation transmitted through
the tissue, the apparatus is working in transmission mode and the
radiation source is positioned on a chip separate from the chip on
which the sensors are positioned. In contrast, when it is desired
to receive and interpret radiation that is reflected from the
tissue, the apparatus is working in reflection mode and the
radiation source may be positioned on the same chip as the chip on
which the sensors are positioned. Preferably, the radiation source
is a thermal radiator made up of tungsten or tantalum positioned
over a reflective heat shield.
[0030] The blood analyte measurement apparatus also optionally
includes a focusing device for focusing the radiation from the
radiation source onto a point on the tissue. A fresnel lens, for
example, works well in this capacity. The apparatus also optionally
includes a collimator to compensate for the scattering that
typically occurs when the radiation passes through tissue. The beam
divergence of the collimator, if used, should be approximately 5
degrees or less.
[0031] A filter may also be included to separate the radiation
received by the sensors into various wavelengths subsequent to
collimation. The preferred filter for this separation is a
Fabry-Perot narrow band interference filter comprising a dielectric
film between two metal films, where the dielectric film has a
graded thickness running from a short wavelength end with a
thickness of about 100 nm to a long wavelength end with a thickness
of about 2.5 microns. Between the narrow band interference filter
and the sensors is a planarizing layer. The spectrophotometer bears
sensors which are preferably sensitive to radiation from
wavelengths of about 700 nm to about 2500 nm.
[0032] The sensors within the sensor module are divided into two
groups: direct silicon sensors sensitive to radiation of a
wavelength range from about 0.4 to 1.1 microns, and infrared
sensors sensitive to radiation of a wavelength range from 1 to 10
microns. Using both types of sensors, the apparatus of the present
invention preferably uses an array of approximately 1024 elements,
for an overall filter passband of about 0.22 percent of its center
wavelength or frequency. The direct silicon sensors may be, for
example, either photodiodes or charge coupled devices. A charge
coupled device array made up of multiple elements sensitive to
differing portions of the wavelength range is preferred. The
infrared sensors making up the rest of the array may, for example,
be extrinsic silicon, pyroelectric, photoconductor, or thermocouple
sensors. Thermocouples comprising two layers of metal with an
additional layer of gold black are preferred, where the two metal
layers may be either nickel-chromium alloy on nickel-copper alloy,
for example. The sensor module may include a replaceable,
rechargeable battery and use a unique ID code if desired.
[0033] A processor is provided for processing the output from the
sensors. If desired, an RF transmitter or other device may be
provided for wirelessly transmitting the signals from the sensors
to the processor. This processor is preferably a CMOS
microprocessor, which uses a Boolean algorithm to process the
output from the sensors. Various processing algorithms are used to
enhance the value of the data obtained from the sensors. The blood
analyte measurement apparatus may also include a display, typically
a liquid crystal display, for the immediate display of data to the
user. The data may be downloaded to a computer or other device via
an I/O port, typically an RS-232 port.
[0034] The present invention also discloses a method for measuring
the concentration of one or more blood analytes in a portion of
tissue with a non-invasive measuring apparatus. The method involves
positioning a portion of tissue approximately adjacent one or more
sensors and a radiation source, exposing the tissue to radiation
from the radiation source, detecting radiation transmitted through
or reflected from the tissue with the one or more sensors,
generating a signal from the one or more sensors in response to the
detected radiation, communicating the signal to the processor, and
finally interpreting the signal communicated to the processor to
determine the concentration of one or more blood analytes.
Preferably, the method of the present invention also includes the
step of displaying the results so they may be perceived by the
user.
[0035] The preferred tissue exposed to the radiation in the method
is either an earlobe or a finger. Preferably, the positioning of
the tissue is carried out so that the sensors and the radiation
source have minimal or no contact with the tissue itself. While any
analyte which has infrared absorption may be measured by this
method, specific examples are lactate/lactic acid, glucose,
insulin, ethanol, triglycerides, albumin, proteins, hemoglobin,
immunoglobulins, cholesterol, and urea.
[0036] An important aspect of the present invention is the
interpreting of the signals communicated to the processor by an
algorithm. One type of algorithm used to interpret this data is
linear regression. A more preferred algorithm makes use of
orthogonal functions. The concept is to use the reference spectrum
for each blood analyte as basis functions and determine a weighting
function or functions that create an orthogonal set. This permits
easy separation algorithms for mixed spectra. The use of algorithms
is very helpful for self-calibrating to eliminate data artifacts
caused by individual variation in tissue character.
[0037] The least squares method of orthogonal functions is
preferably used to separate the concentrations of the individual
analytes from the total spectrum measured. This is also referred to
as "principle component analysis" and is similar to "Fourier series
decomposition." Separating the various analyte concentrations is
statistically challenging because of an overlap of the spectra
which causes interactions and cross-coupling. Trying to evaluate
one analyte concentration is affected by the other overlapping
concentrations. The orthogonal decomposition is a mathematical way
of processing the overlapping concentrations so that they are
non-interacting.
[0038] Beers' law, described above, may be used to describe blood
as a series where each term in the series represents aborbance of
one of the blood analytes. As an example, if the blood contains
fixed known concentrations of the analytes, and if the absorption
spectrum is known for each of these analytes, then the composite
spectrum CS can be calculated directly. The method of the present
invention measures the composite spectrum and the reference
spectra. Concentration coefficients are determined using the
orthogonal function decomposition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] FIG. 1 is a drawing illustrating the overall concept of the
non-invasive blood analyte micromonitor;
[0040] FIG. 2 is a drawing illustrating one possible construction
for the sensor module;
[0041] FIG. 3 is a drawing illustrating the positioning of the
basic components of the sensor module with respect to an ear
lobe;
[0042] FIG. 4 is a perspective view of an integrated radiation
source element;
[0043] FIG. 5 is a drawing illustrating the operation of the
collimator;
[0044] FIG. 6 is a drawing illustrating the layered components of a
narrow band filter integrated directly onto a sensor chip;
[0045] FIG. 7 is a drawing illustrating the layout of the sensor
circuit and related components;
[0046] FIG. 8 is a perspective view of the thermocouple sensor
cell;
[0047] FIG. 9 is a block diagram of the preliminary schematic
diagram for the sensor module;
[0048] FIG. 10 is a block diagram of the CMOS custom chip for the
sensor arrays; and
[0049] FIG. 11 is a block diagram of the inputs and outputs for the
pocket monitor.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0050] The following detailed description is to be read with
reference to the drawings, in which like elements in different
drawings have been given like reference numerals. The drawings,
which are not necessarily to scale, depict selected embodiments and
are not intended to limit the scope of the invention.
[0051] One preferred embodiment of the present invention is a blood
analyte measurement apparatus for measuring the concentration of
blood analytes outside of a laboratory setting. The blood analyte
measurement apparatus utilizes a sensing unit 1, such as a
micromonitor sensor module, that is preferably small and
inobtrusive and does not interfere with a user's normal
functioning. FIG. 1 shows an embodiment of the analyte measurement
apparatus, with the sensor module 1, support hardware such as a
pocket monitor 2 and an optional computer interface 3. The sensor
module contains a small spectrophotometer, which comprises two
sensor arrays and a custom graded narrow band interference filter.
The sensor module also preferably contains an RF radio transmitter
to broadcast the data produced by the sensor, typically only over a
limited range, and a rechargeable battery as well as custom optics.
The sensor module may be used in an ambulatory application where
the user simply clips the sensor module 1 onto an appropriate
tissue region, puts the pocket monitor 2 in a pocket/purse and goes
about their business. The pocket monitor display give the user
immediate data, and stores the data, optionally for later
downloading to a computer 3.
[0052] The micromonitor sensor module 1 shown in detail in FIG. 2
is integrated to reduce its size and weight. The sensor module may
also be completely self-contained. As shown, the sensor module is
configured for attachment to the user's ear lobe, the ear lobe
being the preferred measurement site. Of course, sensor modules
intended for attachment to other measuring sites may be configured
differently. The target sensor volume is preferably 5 to 10 cc for
lactate monitoring, and 1 to 2 cc for glucose monitoring. The
sensor module, as shown, is configured to illuminate the
measurement site and to receive the reflected radiation from the
measurement site.
[0053] The configuration of the sensor module or modules may vary
for receiving transmitted radiation from the measurement site. The
sensor module of FIG. 2 illuminates the measurement site with a
radiation source 4 configured to generate radiation in the spectral
region of interest. As wide a spectrum as practical is generated,
preferably with a wavelength range as wide as 0.4-10 microns.
Adjacent to the radiation source 4 are source optics 5 which help
to direct and focus the radiation. As shown, the sensor also has
collimator optics 6, as well as an integrated narrow band filter,
and individual sensors. The individual sensors may be, for example,
thermocouple sensors and/or charge couple device (CCD) sensors 7.
The sensors are preferably built directly onto a CMOS chip 8. If
desired, each sensor module may have a unique ID code.
[0054] The sensor module also preferably contains an RF radio
transmitter 9 to broadcast the data received by the sensor as
reflection or transmittal of the radiation, that is the transmitted
or reflected radiation from the measurement site, and a
rechargeable battery 10 as well as custom optics. Typically, only a
weak RF source is provided since the signal is generally broadcast
over only a few feet. Preferably, as much functionality as possible
is integrated onto the custom CMOS chip 8 (e.g., preamplification,
data processing, IR data output). The sensor module may analyze the
blood spectra, that is illuminate the mearsurement site and receive
the transmitted or reflected radiation therefrom, at fixed time
intervals, such as once every minute, and is capable of running an
analysis in less than five seconds. A further preferred embodiment
of this blood analyte measurement device includes a non-invasive
sensor module that utilizes infrared spectrophotometric
techniques.
[0055] A narrow-band interference filter 11 is used as a color
separation device in the sensor module. This type of filter is
preferred due to its small volume, minimal needs for optics to
collimate the radiation, and inherent compatibility with integrated
circuit processing techniques. A very small spectrophotometer
results when this filter is combined with a CMOS chip bearing an
array of sensors.
[0056] The radiation (typically, visible and IR or near-IR light)
sources 4 of the sensor module may be integrated onto a different
chip from that bearing the sensor array for transmission mode or
onto the same chip for reflection mode. In one embodiment, the
radiation source comprises a series of incandescent elements
integrated onto a silicon chip. Existing tungsten/tantalum
technology (used in fusible link type EE Prom's) may be combined
with Micro-Electro-Mechanical Systems (MEMS) to form an array of
radiation sources tailored to the specific needs of this
spectrometer. MEMS technology is the integration of mechanical
elements, sensors, actuators, and electronics on a common silicon
substrate through the utilization of microfabrication
technology.
[0057] FIG. 3 illustrates the relationship between the sensor
components and a portion of tissue, an ear lobe 13, which is a
preferred measurement site. These components are the radiation
source 4, the source optics 5, the light collimator 6, the narrow
band filter 11, and the integrated sensors 12. The ear lobe is a
rich source of blood, and attachment of the sensor module thereto
meets the ambulatory monitoring goals to be unobtrusive and not
interfere with normal user activity. FIG. 3 shows a configuration
where radiation is transmitted through the ear lobe 13, rather than
reflected from it. This configuration requires components on both
sides of the ear lobe, but generally uses the available radiation
more efficiently than a configuration where the radiation reflected
from the ear lobe is sensed. A configuration for sensing radiation
reflected from the ear lobe, not illustrated, includes the same
components as the configuration illustrated in FIG. 3 (a radiation
source, source optics, a light collimator, a narrow band filter,
and integrated sensors) where all of the components are positioned
on one side of the ear lobe. The reflection mode generally requires
a stronger radiation source than the transmission mode.
[0058] FIG. 3 also illustrates the positioning of the source optics
5. A cylindrical Fresnel style lens is preferred for the source
optics for the analyte measurement apparatus. The source optics
focus the radiation from the radiation source onto a point at the
center of the ear lobe. A Fresnel lens also has a relatively small
volume. Once the radiation has been transmitted or reflected from
the measurement site, it is run through a collimator 6, followed by
a narrow band filter 11, and then finally is received by the
integrated sensors 12.
[0059] The integrated sensors are directly adjacent to the narrow
band filter 11 and consist of two types of infrared detectors
sensitive to discrete portions of the spectrum: direct silicon
sensors sensitive to radiation of a wavelength range from about 0.4
to 1.1 microns, and infrared sensors sensitive to radiation of a
wavelength range from 1 to 10 microns. Using both types of sensors,
the apparatus of the present invention preferably uses an array of
approximately 1024 elements, for an overall filter passband of
about 0.22 percent of its center wavelength or frequency. The
direct silicon sensors may be, for example, either photodiodes or
charge coupled devices. A charge coupled device array made up of
multiple elements sensitive to differing portions of the wavelength
range is preferred. The infrared sensors making up the rest of the
array may, for example, be extrinsic silicon, pyroelectric,
photoconductor, or thermocouple sensors. Thermocouples comprising
two layers of metal with an additional layer of gold black are
preferred, where the two metal layers may be either nickel-chromium
alloy on nickel-copper alloy, for example.
[0060] The integrated radiation source illustrated in FIG. 4
provides rapid turn on and off times, a tailored emission spectrum,
and may be configured to a relatively small size. Preferably, the
radiation source 4 utilizes a high melting temperature metal such
as tungsten or tantalum to form a thermal radiator 14. The radiator
is spaced above a silicon wafer by MEMS techniques and supported by
the electrical connections and/or auxiliary supports 16. If
serpentine construction is used, the resistance may be adjusted to
a convenient value such that it may readily match driver
characteristics.
[0061] Presuming that sufficient thermal isolation is achieved, the
element is allowed to become very hot. A metal reflector layer 15
on the wafer under the thermal radiator element 14 boosts emission
efficiency and reduces the heat load to the silicon wafer. The
optical color of the emission is set by the temperature of the
element, and optical power by the emitting area. Using an array of
such elements, each with a different temperature and area, the
total emission spectrum may be adjusted to be reasonably flat over
the spectrum of interest.
[0062] The integrated radiation source allows control over the heat
leak associated with the supports. The heat leak may be adjusted to
achieve almost any desired turn on and turn off times of the light.
Each element, when hot, has a relatively small heat capacity,
permitting switching times in the millisecond range without
exorbitant power expenditure. With rapid turn on and turn off
times, an electronic "chopper-wheel" with modulation frequency in
the range of 1 Khz, may be used to reject unwanted background
signals.
[0063] Heat transfer calculations are provided using tungsten
(3370.degree. C. melting temperature) film 1000 angstroms thick. A
hot resistance in the range of 10-100 ohms is obtained with a
resistor length of 10000 to 30000 squares, well within IC
capability. An element temperature of 2000.degree. C. emits 2 to 50
mw radiant energy centered at about 1.5 micron wavelength using
photolithographic line widths of 1-5 microns. Heat loads due to
supports, electrical connections, and other losses may be held to
the range of 1-10 mw. Air conduction loss is eliminated by
evacuating the hot zone. The small element heat capacitance the
order of 30-770 njoules/.degree. C. results in thermal time
constants of 0.2-4 milliseconds. Tantalum (2996.degree. C. melting
temperature) gives similar results but has less severe inrush
currents than tungsten. Thus, an integrated radiation source with a
total power dissipation in the range of 10-100 mw, battery
compatible resistance, millisecond response times, and
compatibility with IC processing is clearly possible using tungsten
or tantalum.
[0064] The ear lobe 13 is shown in both FIG. 3 and FIG. 5. The
analyte measurement device of the present invention compensates for
complications of IR spectroscopy inherent in measurement through
skin and tissue. The ear lobe infrared absorption spectrum
corresponds roughly to two layers of skin; one on the backside of
the ear and the other on the front side. The transmission of light
through skin is fairly complicated. The skin includes a stratum
corneum, about 10 microns thick, an epidermis, about 100 microns
thick, and a dermis, about 3 mm thick. The incident radiation
suffers a 4% to 7% reflection at the stratum corneum due to change
in index of refraction (1.0 for air to 1.55) over the whole
spectral range up to 3 microns wavelength for both white and black
skin. The stratum corneum also contributes to scattering since it
is not flat, and has a certain roughness. The chromophores of the
epidermis especially melatonin determine attenuation in the visible
range in this layer. Psoriatic skin may also be a significant
interfering factor, perhaps requiring clear lipophilic liquids to
enhance light penetration in some individuals. In the dermis, blood
chromophores Hb, HbO.sub.2 and biliruben are the primary absorbers.
Scattering by collagen fibers in the dermis is a strong influence
on transparency. Attenuation exceeding 90% may be expected. An
optical window exists between 0.6 and 1.8 microns wavelengths where
the skin is most transparent. While the ear lobe is a preferable
portion of tissue for the measurement site, the present invention
is by no means limited to this particular tissue.
[0065] FIGS. 3 and 5 both illustrate the use of a collimator 6 with
the analyte measurement device as well. The radiation received from
the illuminated ear lobe 13, either by transmission or reflection,
may be scattered. The narrow band filter works more effectively
when the radiation has been collimated. A beam divergence of 5
degrees or less is preferred. One method is to use a standard
condenser 17 and projector 18 lens arrangement, as illustrated in
FIG. 5.
[0066] Considering the source of radiation for the collimator to be
the spot illuminated inside the ear lobe, this spot is imaged by
the condenser lens 17 onto the projector 18 lens aperture, and
projected in a beam. The scheme illustrated in FIG. 5 has a minimum
volume of about 2 cc. Microlens arrays may be used to reduce the
volume. For example, an array of microlenses may be configured at a
fraction of a cubic centimeter.
[0067] FIG. 6 portrays a preferred narrow band filter. The narrow
band filter separates the wavelengths of radiation transmitted
through the tissue at the measurement site and directs the various
wavelengths to the sensing array, which is preferably a linear
array of elements. The sensors at one end of the array sense only
radiation from one end of the spectrum, for example 0.4 microns,
while the sensors at the other end of the array sense only
radiation from the other end of the spectrum for example 10
microns. Using a linear graded filter, each sensor measures a
different color, with color varying linearly with sensor position.
A Fabry-Perot narrow band interference filter 19 with a graded
dielectric thickness is preferred, where the dielectric film has a
graded thickness running from a short wavelength end with a
thickness of about 100 nm to a long wavelength end with a thickness
of about 2.5 microns. Between the narrow band interference filter
and the sensors is a planarizing layer. The spectrophotometer bears
sensors which are preferably sensitive to radiation from
wavelengths of about 700 nm to about 2500 nm. FIG. 6 shows a
preferred form of filter, a metal-dielectric-metal sandwich.
[0068] The vertical dimension of the dielectric is a quarter
wavelength. Additional layers may be used to suppress higher order
resonance modes. The filter may be fabricated on a separate
substrate and then affixed to the CMOS chip. Since the sensor array
may be only one cm long, a separate filter is manageable. The
allowable separation between filter and sensor element is
determined by the amount of optical cross-talk tolerable between
adjacent sensors. For example, if the sensor dimension is
approximately 10 microns and the incoming light has a divergence of
5 degrees, then a separation of 25 microns (1 mil) would result in
up to 22% cross talk between adjacent elements due to the parallax
effects. If a larger separation or lower cross talk is needed, then
the incoming light may be better collimated.
[0069] FIG. 6 shows the narrow band filter integrated directly onto
the CMOS chip 12, rather than as a separate substrate. Compared to
the example above, filter-to-sensor spacing is very small, and
cross talk between adjacent elements due to parallax is less than
10% for the layer thickness' used. With typical semiconductor
processing, a planarizing layer may be preferable to accommodate
the filter. The first partially transmitting metal layer 22 of the
optical filter is then placed on the planarizing layer 23, followed
by the dielectric layer 21 and then the top partially transmitting
metal layer 20. A wide range of pass band widths may be obtained.
Such a filter typically resonates at 1/4 wavelength, corresponding
to the dielectric thickness. Hence, typical dielectric thickness is
100 nm at the short wavelength end and 2.5 microns at the long
wavelength end, for the preferred spectral range of 0.4 to 10
microns. Typically, most metals, e.g. gold or aluminum, are
partially transmissive at layer thicknesses of 500 to 1000
angstroms. The tapered dielectric layer may be readily fabricated
using fixturing (i.e. using a moving aperture) with standard
semiconductor equipment. The expected thicknesses and materials may
be patterned if desired by standard semiconductor processes.
[0070] The sensing array operates over a wide wavelength range of
0.4 to 10 microns. Silicon sensors are sensitive to radiation only
over a wavelength range of about 0.4 to 1.1 microns. Beyond 1.1
microns, silicon is generally not useful as a radiation sensor and
other methods than direct silicon sensing must be used. Two kinds
of arrays are preferably used in the present invention, a direct
silicon photo-sensing array and a thermocouple array. Over its
range, silicon generates a much stronger signal than other sensing
means. The rest of the wavelength range, from 1 to 10 microns, is
sensed by the thermocouple array.
[0071] Both photodiodes and CCDs may be used for direct silicon
sensing. The present invention uses CCDs because of their very
large dynamic range (more than 1000:1), very low noise capability,
easy handling of the small analog signals, inherent CMOS
(Complementary Metal Oxide Semiconductor) compatibility, and high
quantum efficiency (in the range of 0.5%). FIG. 7 illustrates a
preferred CCD structure 24 for use in the present invention. The
CCD may be viewed as a collection of MOS capacitors that collect
photo-induced charges over a controlled integration time, then
transfer the collected charges into readout registers 25 (also
CCDs) which shift the data serially to an output port 26 where the
analog signal is connected to an analog-to-digital converter.
Photo-sites 27 are indicated in the figure with radiation impinging
on the silicon through transparent polysilicon electrodes. Various
clocking schemes (eg. two, three and four phase) may be used,
depending on the geometry.
[0072] FIG. 8 illustrates a thermocouple IR sensor cell 28. A
variety of devices may be utilized for sensing over the IR part of
the range (1 to 10 microns): extrinsic silicon, pyroelectric
sensors (such as LiTaO.sub.3), various photoconductors, and
thermocouples, for example. The preferred embodiment of the present
invention uses thin film thermocouple sensors. D*, the normalized
detectivity figure, may be very high in integrated thermocouples,
as high as 1016. Thin film thermocouple sensors are very compatible
with IC processing and may be patterned using standard
photolithographic techniques. The sensitivity to infrared energy is
constant over the entire IR range from about 0.7-50 microns. The
signal levels are good at 63 .mu.v/.degree. C. with very low source
impedance, since they are metal films. In a preferred embodiment
the two metal layers of the thermocouple are nickel--chromium 29
and copper--nickel 30 alloys, as shown, with an additional layer of
about 60 .mu.g/cm.sup.2 of gold black 31. The thermocouple sensor
is thermally isolated from the substrate and exposed to the
incident radiation. The cold junctions, not shown, are thermally
connected to the substrate as a heat sink and shielded from the
light. Additional layers may be used to connect several
thermocouples in series to produce larger signals. The thin film
thermocouples have a low heat capacity which produces fast response
times of about a millisecond. This fast response time allows use of
an amplifier tuned to the "chopper" frequency to reduce unwanted
background signals. In an alternative embodiment, 2D thermal
imaging may be used. An array of such elements are placed on the
photo sites 27 of FIG. 7 and inject charge into the CCD.
[0073] A total of 2048 sensor elements are used to read 1024 band
width increments similar to those disclosed by Hall and Pollard.
Hall J. W. and Pollard A., Near-infrared Spectrophotometry: A New
Dimension in Clinical Chemistry. Clin. Chem. 38, 1623 (1992). See
also Hall et. al, U.S. Pat. No. 5,361,758, the disclosure of which
is hereby incorporated by reference. The 1024 band increments are
spread over the wavelength range of 0.4-10 microns. The passband
width is expressed as a percentage rather that an absolute
wavelength width. Dividing the wavelength range from 0.4-10 microns
into 1024 equal percent age increments results in a pass band of
0.22% wavelength.
[0074] This corresponds to 162 wavelength "slots" for the visible
range (0.4 to 1.1 microns) and 862 "slots" for the IR range (1.1 to
10 microns). Using two sensors per "slot" results in 2048 elements
(324 for visible and 1724 for IR). Holding the chip size to one
centimeter length results in a sensor element length of about 5
microns. A larger sensor length requires a staggered arrangement.
The sensing arrays are made as wide as practical, perhaps 100
microns or more, to maximize sensitivity. The wavelength of the
incident light is measured along the direction of propagation, not
laterally, so that sensors may have lateral dimensions smaller than
a wavelength and still sense the radiation. Using absorbing layers
like gold black, radiation is absorbed in layers less than a
wavelength thick.
[0075] The measurement accuracy of the present invention is quite
high. Each component shown FIG. 3 has a characteristic that is
strongly dependent on wavelength. To achieve the desired accuracy
(e.g. 10% for glucose) these dependencies must be accounted for.
Integrated radiation sources may easily have an emission spectrum
that varies by a factor of 10 or more over wavelength range. This
variation is partially compensated for by the design of the
emitting array. Use of the narrow band filter with constant
percentage passband significantly compensates at the IR end of the
spectrum.
[0076] The ear lobe has absorbances that are strongly wavelength
dependent and have both skin tissue and blood components. The
analyte measurement device of the present invention uses an
automatic compensation scheme to account for the varying skin
dependencies among individuals. In one embodiment, a ratiometric
technique against a known spectral shape component such as water or
albumin yields suitable correction factors. The source optics,
collimator optics, narrow band filter and sensor wavelength
dependencies are calibrated and thereby taken into account.
[0077] Non-invasive glucose monitoring in diabetic patients has
shown a more than 50% variation of transmittance in some cases at
900 nm for glucose over the physiological range (2.7 to 27.7
mmol/L). Achieving a glucose measurement accurate to within 10%
thus implies a transmittance accuracy of at least 2%. To achieve
this accuracy, absorbance measurements accurate or repeatable to
0.1% give a sufficient margin. A 13 bit analog to digital converter
is therefore recommended. In a preferred embodiment of the present
invention, a 16 bit integrated converter is used.
[0078] The present invention uses radiation either reflected or
transmitted through tissue at the measuring site, including skin,
sub-dermal tissue, and blood, so the received signal is a mixture
of signals from blood and tissue. One embodiment of the present
invention achieves the separation of the blood-related component of
the signal from the tissue component of the signal by accepting
only the portion of the mixed signal which has a pulse synchronized
with the heart pulse. This presumes that the pulsations come from
the moving arterial blood or closely related matter and thus allows
a signal associated with the blood to be separated from that
associated with the tissue. Pulse oximeters, for example, operate
using this method. In a preferred embodiment, hematocrit is used to
determine the portion of the signal associated with the blood. This
technique has two advantages. First, it results in a faster
response time because there is no need to wait for heart beats.
Second, there is less signal loss due to synchronous signal
extraction (the synchronous method removes some blood associated
signal unnecessarily).
[0079] FIG. 9 shows a preliminary schematic diagram for a sensor
module. The sensor module is the portion of the analyte measuring
device which is positioned on the target tissue and bears the
radiation source and sensors, among other things. Everything is
integrated onto a single CMOS chip 8 as shown, except the battery
10, radio antenna 9, and one or more capacitors (used, for example,
as power filter and charge pump). FIG. 9 shows the sensor arrays
integrated on the chip as well. Earlier, FIG. 3 depicted a separate
light source mounted on the other side of the ear for measuring the
transmission IR spectra transmitted. The schematic shown in FIG. 9
depicts the alternate embodiment, in which the light sources are
also integrated onto the chip. While FIG. 3 shows transmission and
FIG. 9 implies a reflection mode, both embodiments are fully
encompassed by the present invention.
[0080] FIG. 10 shows a block diagram of functions incorporated into
the CMOS chip and the sensor arrays; one for visible light (e.g. a
silicon CCD array), and one for the IR region (e.g. a thermocouple
array). Preamplifiers are included for each sensor. The spectral
data output from the sensors is digitized by the analog-to-digital
converter. A charge pump to stabilize operating voltages and a
gated RIP oscillator for the data transmitter are preferably
included in the CMOS chip as well. One embodiment also includes
integrated light sources. The block diagram shows a microprocessor
embedded in the chip. However, a state table design is a viable
alternative embodiment.
[0081] A "pocket monitor" is provided in a preferred embodiment for
displaying analyte measurements in the field. A block diagram for
the pocket monitor is shown in FIG. 11. For situations that require
continuous monitoring, a pocket monitor may be dedicated to a
specific individual for data logging and downloading (optional) to
a computer at a more convenient time. The pocket monitor contains a
radio receiver tuned to a specific sensor transmitter frequency.
Data from the sensor module is received and processed for prompt
display and storage. The pocket monitor also preferably utilizes an
LCD display screen where data may be presented. A graphics mode
showing analyte readings for the recent past can also be
displayed.
[0082] Two preferred embodiments of the pocket monitor are
described. The first utilizes existing IRDa hardware available in
some personal computers. This embodiment eliminates the need for a
separate receiver to be supplied by the personal computer. The
second embodiment has a separate receiver that plugs into an
existing I/O port in the personal computer. In this embodiment, the
receiver accepts the low-power radio frequency transmissions either
from the sensor module directly or from the pocket monitor,
translates the tramsission into an acceptable I/O format (e.g.
RS-232), and then sends the information to the host personal
computer via an I/O port. These two embodiments may alternately be
combined for maximum flexibility.
[0083] The software package for the personal computer is based on a
user-friendly platform (e.g. Windows 95). The software uses simple
GUI (Graphic User Interface, e.g. Visual Basic) that allows for
quick and easy results evaluation. The software takes the
information received from the I/O port (e.g. an IRDa port or RS-232
port) and imports this information into a database. Algorithms
evaluate the spectra data and provide the individual with readily
understood information on concentrations of the analytes of
interest. These results may be displayed on a "screen" on the
personal computer monitor. Preferably, the software enables further
analysis and manipulation of the analyte measurement data on the
display. An alternative embodiment incorporates a modem feature
that would allow a personal computer to transmit some or all of the
information to a main computing center via information transmission
means (e.g. a phone line). Data archiving would permit long term
trending analysis of analyte concentration levels.
[0084] Spectrophotometry is an important aspect of the present
invention. Currently many spectroscopic methods are in use covering
all regions of the electromagnetic spectrum from x-ray to radio
wavelengths. For the present invention, the x-ray and UV regions
are not preferred because of the greater possibility of damage to
the region of the body being tested. Although interesting, the
radio region of the spectrum is also not preferred because the
physical structures required to generate and sense radio signals
differ substantially from those of the preferred embodiments. The
preferred spectral regions for use by the analyte measuring device
are thus the visible, near-infrared, and infrared regions of the
spectrum.
[0085] Direct spectroscopic measurements of unmodified body fluids
with the more traditional speactral regions (ultraviolet, visible
and infrared) generally have limited penetration depths, and are
hindered by interfering absorption and excessive scattering with
inhomogeneous samples. Body fluids and soft tissues, in contrast,
are relatively transparent at near-IR wavelengths. Thus, near-IR
spectroscopy is preferred with the analyte measuring device of the
present invention.
[0086] The spectral complexity of typical analytes helps isolate
particular species out of the total spectra. For example,
.beta.-D-glucopyranose shows absorption peaks in the IR fingerprint
region at 1458, 1435, 1365, 1325, 1235, 1205, 1152, 1109, 1080,
1035, and 996 cm.sup.-1, and a mere listing of the peaks leaves out
a great deal of the complexity of the actual spectra. Very high
order polynomials (for example, with hundreds of terms) or tabular
methods fitted to individual species spectra are used alongside
multivariate analysis techniques or orthogonal function methods to
capitalize on this inherent complexity. Effects of interfering
compounds and overlapping peaks are part of the analysis and, due
to the spectra complexity, tend to be compensated and even
separated, if desired.
[0087] Because blood is a complex mixture, there are various ways
of categorizing its many constituents. Table 1, for example, shows
the basic separation of blood constituents into solids (formed
elements) and liquids (blood plasma). The solids represent about
45% of the blood while liquids (55%) represents the rest. The
components of interest for the present invention are contained in
the plasma. As seen in Table 1, plasma is about 90% water, with
another 8% as plasma proteins, leaving about 2% of the plasma for
the analytes of interest. That is, 2% of 55% or roughly 1% of whole
blood. Thus, the sensor module is configured to measure spectral
amplitude significantly better than 1% (first estimate) in order to
obtain data sufficiently accurate to resolve the analytes of
interest.
1TABLE 1 Blood Constituents Type Constituent
Characteristics/Functions Formed Erythrocytes anucleate, contain
hemoglobin; Elements (98-99%) O.sub.2 & CO.sub.2 transport
(45%) Leukocytes Neutrophils granulocytes, polymorphonuclear;
(0.1-0.3%) (60-70%) phagocytosis, wound healing Eosinophils
granulocytes, bilobed nucleus: (2-4%) phagocytosis Basophils
(0.5-1%) granulocytes, 2-5 lobed nucleus; release histamine
Lymphocytes agranulocytes, circular nucleus, (20-25%) T cells, B
cells; Monocytes immune response, antibodies (3-8%) agranulocytes,
large kidney- shaped nucleus; phagocytotic macrophages Thrombocytes
anucleate, megakaryocyte (platelets) (1-2%) fragments; blood
clotting Blood Water (90%) Plasma Plasma proteins Albumin (54%)
maintain osmotic pressure (55%) (8%) Globulins (38%) between
Fibrinogen (7%) blood & tissue Others (1%) lipid and metal ion
transporters, antibodies clotting factor enzymes, hormones,
clotting factors Electrolytes NA.sup.+, K.sup.+, Ca.sup.2+,
Mg.sup.2+, Cl.sup.-, HCO.sub.3-, SO.sub.4.sup.2-, HPO.sub.4.sup.2-
Gases O.sub.2, CO.sub.2, N.sub.2 Nutrients Glucose, other sources
of energy carbohydrates protein building blocks Amino acids fats,
steroids, phospholipids Lipids component of plasma Cholesterol
Membranes & steroid hormones Waste Products Urea From breakdown
of proteins Creatinine from breakdown of creatine phosphate (from
muscles) Uric acid from breakdown of nucleic acids Bilirubin from
breakdown of hemoglobin Hormones Various
[0088] There blood is a complex mixture; only 102 dominant
constituents are present with concentrations varying from
hemoglobin at about 15 g/dL to constituents such as insulin in the
nanogram range and lower. However, this listing by substance is
misleading because it does not differentiate between all of the
spectroscopically distinct species of a given constituent. For
example, glucose has three spectroscopically important species; the
open ring, .alpha.- and .beta.-pyranose forms. Similarly,
hemoglobin has four distinct subunits. The present invention
assumes that there are 102 important constituents, but the number
is actually higher when considering the effect of various
subspecies and subunits with distinct spectral characteristics. For
blood analytes with concentrations comparable to or greater than
glucose and lactate, Table 2 shows these blood components arranged
in order of molar concentration. The components are arranged this
way because the spectrum of each, as related by Beers' Law, is
typically normalized against molar concentration. Supposing that
the relative strength of the spectra correlates with molar
concentration (not always true), the table provides an approximate
ranking of the components that can be used to decide which ones
must be retained for compensation when measuring an analyte (such
as glucose). As seen in Table 2, glucose ranks 10.sup.th and
lactate ranks 16.sup.th. The other analyte ranking in Table 2 is by
mass concentration. The larger molecules, such as hemoglobin or
albumin, may have multiple absorbing sites per molecule. Such
multiple absorbing sites distort the molar ranking premise of only
one or a small number of absorbing sites. Thus, the top ranked
analytes, as ranked by mass concentration, are important as
well.
[0089] For an individual analyte, Beers' Law takes the form
A=.epsilon.Cb, where A is absorbance, .epsilon., is the molecular
extinction coefficient, C is the molar concentration, and b is the
optical path length. The absorbance, A, is the logarithm of the
transmittance. Preferably, the molar extinction coefficient,
.epsilon., is a function of wavelength, .lambda., alone. The molar
extinction coefficient .epsilon. is measured over a range of
wavelengths to form the absorption spectrum that would be
associated with the particular analyte. The molar extinction
coefficient, .epsilon., is measured for each analyte of interest to
form a set of spectra, (.epsilon..sub.1, .epsilon..sub.2, . . . ,
.epsilon..sub.N) over the wavelength range of interest. When more
than one analyte is present, Beers' Law allows simple addition of
the absorbance of each one.
A.sub.total=A.sub.1+A.sub.2+ . . .
+A.sub.N=C.sub.1b.epsilon..sub.1+C.sub.- 2b.epsilon..sub.2+ . . .
+C.sub.Nb.epsilon..sub.N
[0090] Presuming that the optical path length, b, is the same for
all the analytes, this relation becomes:
A.sub.total/b=C.sub.1.epsilon..sub.1+C.sub.2.epsilon..sub.2+ . . .
+C.sub.N.epsilon..sub.N
2TABLE 2 Proposed Blood Analytes to Compensate. Minimum Maximum a).
Dominant according to mass concentration in the blood. 1.
Hemogloblin 12000 18000 mg/dL 2. Albumin 3200 5600 mg/dL 3.
Globulins Total 2300 3500 mg/dL 4. Complement Proteins, Total 373
467 mg/dL 5. Fribrinogen 200 400 mg/dL 6. Phospholipids 150 380
mg/dL 7. Cholesterol 150 250 mg/dL 8. Triodothyronine 80 200 mg/dL
9. Triglyceriedes 10 190 mg/dL 10. Glucose 60 100 mg/dL 11.
Non-protein Nitrogen 25 50 mg/dL 12. Ceruloplasmin 23 50 mg/dL 13.
Protoporphyrin 15 50 mg/dL 14. Glutathione 24 37 mg/dL 15.
Prealbumin 15 36 mg/dL 16. Salicylates 15 30 mg/dL 17. Urea
Nitrogen 8 23 mg/dL 18. Lactate (Lactic Acid) 5 20 mg/dL b.
Dominant analytes according to molar concentration in the blood. 1.
Base, Total 145 160 mmol/L 2. Sodium 136 142 mmol/L 3. Chloride 95
103 mmol/L 4. Non-protein Nitrogen 18 36 mmol/L 5. Carbon Dioxide
19 30 mmol/L 6. Bicarbonate 21 28 mmol/L 7. Lipids, Fatty Acids 9
15 mmol/L 8. Urea Nitrogen 2.9 8.2 mmol/L 9. Cholesterol 3.9 6.5
mmol/L 10. Glucose 3.3 5.6 mmol/L 11. Potassium 3.8 5 mmol/L 12.
Alpha Amino Acid Nitrogen 2.6 5 mmol/L 13. Lipids, Phospholipid
Phosphorus 2.6 3.6 mmol/L 14. Calcium 2.3 2.7 mmol/L 15. Hemoglobin
1.9 2.5 mmol/L 16. Lactate (Lactic Acid) 0.3 2.2 mmol/L
[0091] The total absorbance divided by path length is seen to be a
linear superposition of spectra, .epsilon..sub.i, according to the
molar concentration of each one, C.sub.i. Note that the definition
can be shifted to use mass concentration rather than molar
concentration, even term-by-term, and Beers' law will still apply.
In the application of Beers' Law to an unknown mixture, the set of
spectra (.epsilon..sub.1, .epsilon..sub.2, . . . , .epsilon..sub.N)
is assumed to be known by prior laboratory measurement. The optical
path length, b, is also assumed to be known. (In the lab, blab can
be fixed precisely. But in the embodiment where analytes in the ear
lobe are being measured and focusing is used, b.sub.ear may be a
function of .lambda. also.
[0092] Rewriting the absorbance relation one more time for
composite spectrum (CS):
CS=A.sub.total/b=C.sub.1.epsilon..sub.1+C.sub.2.epsilon..sub.2+ . .
. +C.sub.N.epsilon..sub.N
[0093] In the method of the present invention, the composite
spectrum and reference spectra are measured. Thus, the
concentration coefficients are determined using Beers' law.
[0094] Table 2 lists about 28 primary blood components. A molar
extinction coefficient can be determined for each component so that
all 28 terms are included. Of course, analytes beyond those listed
in Table 2 may also be measured using the present invention.
Determination of all 28 molar extenction coefficients, .epsilon.,
is preferred. Alternately, the calculation may be limited to only
the components that are prominent with respect to the analyte of
interest. For example, glucose ranks 10.sup.th in Table 2 molar
concentration. Limiting the calculation to the analytes with 20% or
more prominence with respect to glucose will give a model with
sufficient accuracy for glucose determination, using perhaps only
25 or 30 terms.
[0095] Near IR spectroscopy has been used to extract the
concentration of blood analytes such as albumin, glucose,
triglycerides and others. Using this method, linear indications of
the analyte concentration can be obtained, provided that everything
is held constant except the analyte being measured. Usually a
"baseline" or reference level must be established through other
means. Attempts to measure glucose concentration using near IR
spectroscopy have encountered difficulty, primarily from "baseline
drift". As other analytes in the blood vary--for example,
albumin--the measurement of glucose changes also. The glucose
"baseline" shifts because of the albumin change, for example,
causing erroneous glucose readings. In fact, a least squares fit of
the albumin spectra, using the glucose spectra, yields a non-zero
result which adds to the glucose component, hence a variable
baseline. Other unknown components such as drugs can also cause
shifts in the spectra.
[0096] The present invention preferably uses self calibration to
compensate for the various problems encountered in the near-IR
determination of blood analyte concentration. Self calibration
relies on the ratio of analyte measurement against a reference
material. For analyte measurement in blood, there are two reference
materials present in all animals, namely hemoglobin and water.
Measuring the concentrations of hemoglobin and water simultaneously
with the analyte of interest, an arithmetic ratio may be
calculated. This provides a number of advantages. First, the ratio
conforms better to commonly accepted definition of concentration,
i.e., the amount of analyte per unit of blood. Hemoglobin and water
account for about 94% of blood, providing a good basis for the
assessing of the amount of blood in the test volume. Second,
measurement of hemoglobin and water at the same time as the analyte
of interest means that variations that affect the analyte
measurement also affects hemoglobin and water. Thus, the ratio
should automatically compensate a substantial part of these
variations. Third, since hemoglobin occurs only in the blood, it
can be used to make a hematocrit determination, based on the
proportion of blood by volume made up of erythrocytes, to separate
blood and tissue.
[0097] If the pulsatile method is used to determine a signal
associated with the arterial blood movement using the hemoglobin
signal, then a ratio of pulsatile hemoglobin to total hemoglobin
can be made. Call this ratio the P/B ratio. If the pulsatile
component of the analyte of interest is found, the same moving
volume is assumed and the P/B ratio used to determine how much of
the analyte is in the blood, and how much is in the tissue. For a
given analyte, once its fractions are known, the largest signal
(usually the tissue signal) can be used to imply blood
concentration because the fraction in the blood is not be expected
to change very rapidly. The smaller pulsatile signal may then be
re-measured over a longer time period, to improve accuracy, with
the analyte fraction updated periodically. This method improves
accuracy while allowing faster measurements and maintaining self
calibration.
[0098] The method and apparatus of the present invention
compensates for individual variation in measurement due to skin and
tissue characteristics. Since the spectra of water and hemoglobin
are well known, the spectrum of the skin and tissue may be
determined simultaneously with the measurement of other analytes. A
reference color is chosen corresponding to a prominent absorption
peak (e.g., of water). For example, if water is the dominant
absorber at a particular wavelength, then the rest of the spectrum
may be corrected based on the known spectrum of water, at least
over the wavelengths down to perhaps 700 nm where water becomes
transparent. Similarly, the spectra may be corrected using other
dominant absorbers at a particular wavelength. To continue with the
water example, below a wavelenth of 700 nm hemoglobin becomes the
dominant absorber and can be used to extend the correction based on
the known spectrum for hemoglobin down to near 450 nm. Correcting
factors are thereby used to extract the dominant features of the
skin and tissue. As additional analytes are extracted from the skin
and tissue spectrum, a large spectrum remains that is associated
only with the skin that exhibits a roughly constant absorbance of
about 2. This spectral pattern is associated with chemical
components not present in the blood. If the original reference
wavelength were to produce an appreciable absorbance error, this
would show up as a constant error over wavelength. Computing the
ratio for the analyte of interest would cause this type of error to
disappear since the analyte is affected the same way. The
calculation may be corroborated by performing a similar calculation
on the pulsatile spectra.
[0099] Overlapping peaks have previously made computing the
concentration of a particular analyte using IR spectroscopy
difficult, as it hard to distinguish between the portion of the
peak caused by the analyte and that caused by other components
present. One technique used to combat this problem is to compute
the second derivative of the spectra to sharpen the peaks. This
reduces the problem by reducing the amount of overlap, but does not
solve it completely, because of the very large ratio between the
concentration of interfering analytes and the analytes of interest.
This effect is typically the major source of error in attempting to
extract a single analyte such as glucose, or any analyte for that
matter. The apparatus and method of the present invention
preferably uses Linear Regression techniques (including partial
least squares methods) and Orthogonal functions to correct for the
problem of overlapping peaks and other spectral defects.
[0100] The present invention preferably utilizes linear regression
or least squares technique. These methods produce an accurate
measurement of analytes provided all the interaction terms are
included. Hall and Pollard, referenced earlier, includes an
excellent discussion of least squares fitting of data and the
method of partial least squares for including interactions. The
disclosure of this reference is hereby incorporated. These methods
are useful in their own right, and may be used to determine the
weighting function, w, described below.
[0101] A preferred embodiment of the present invention utilizes
orthogonal function techniques.
[0102] Orthogonal functions behave very much like vectors, and an
"inner product" may be defined,
<.epsilon..sub.1.vertline.w.vertline..epsilon..sub.2>,
where:
<.epsilon..sub.1.vertline.w.vertline..epsilon..sub.2>=.intg.w.epsilo-
n..sub.1.epsilon..sub.2d.lambda.
[0103] w=the weighting function (in .lambda.)
[0104] .epsilon..sub.1 and .epsilon..sub.2 are functions defined
over .lambda.
[0105] .lambda. is the common parameter (wavelength)
[0106] The two functions .epsilon..sub.1, and .epsilon..sub.2 are
said to be orthogonal if
<.epsilon..sub.1.vertline.w.vertline..epsilon..sub.2&- gt;=0
for the weighting function w. Thus, the weighting function, w, acts
to make the basis functions, or analyte spectra, orthogonal over
the wavelength, .lambda., of interest. The weighting function is
positive. Thus, adjustable candidate weighting functions include
quadratics. Further, for functions to be orthogonal to one another,
at least one of the basis functions must change sign over the
interval in order for the defining integral to be zero. The basis
functions, or analyte spectra in the present invention, are based
upon absorption, which is always a positive number. In order to
have a sign change, the first or second derivatives of the basis
functions, or analyte spectra, may be taken. Alternately, the "ac"
component (wherein the average value is subtracted) of the basis
function, or analyte spectra, may be used.
[0107] To make two functions orthogonal, a single adjustable
parameter is needed to find a weighting function. As an example,
the water spectrum (which absorbs primarily at long wavelengths)
can be made orthogonal to the deoxyhemoglobin spectrum (which
absorbs primarily in the 500-600 nm region) if the "ac" method is
used and the weighting function (x-a).sup.2 is used. The parameter,
a, is adjusted until the defining integral is zero. Further, the
four hemoglobin sub-types have sufficient features that they may
also be made mutually orthogonal. For 28 basis functions, or
analyte spectra, 378 (or 28.times.27/2) adjustable parameters are
necessary to find a weighting function. Other methods for finding
weighting functions may also be used. For example, one weighting
function can be found that makes water orthogonal to the other 27
basis functions, which then requires only 27 adjustable parameters.
This weighting function may then be used to decomponse the water
portion of the spectrum. Another weighting function may be found
which makes Hb orthogonal to the remaining 26 basis functions
(water already being removed). This second weighting function
requires only 26 adjustable parameters. And so on for the remaining
basis functions. The result is a set of 26 weighting functions
rather than just one which accomplishes the same decomposition.
Further, because the concentrations of the analytes drop off
quickly, another possibility is to remove the analytes in groups.
For example, water and the four kinds of hemoglobin may be removed
first and the residual spectrum examined thereafter for another
group of analytes.
[0108] There are many sets of orthogonal functions in common use
which are defined along these lines.
[0109] They include Legendre polynomials, Laguerre polynomials,
Hermite polynomials, Chebychev polynomials and Ultraspherical
polynomials, for example. Sin(n x) and cos(n x) form orthogonal
sets also. Each of these sets has the orthogonality property
<.epsilon..sub.N.vertline.w.vertli- ne..epsilon..sub.M>=0 if
N.noteq.M. The weighting function depends on the set used.
[0110] Generally, these sets of orthogonal functions
(.epsilon..sub.1, .epsilon..sub.2 . . . , .epsilon..sub.N) are used
to decompose a more complicated function CS into "components".
CS.dbd.C.sub.1.epsilon..sub.1+C.sub.2.epsilon..sub.2+ . . .
+C.sub.N.epsilon..sub.N+ . . .
[0111] The value of any specific coefficient of interest, for
example, the molar concentration of the nth component, C.sub.N, is
determined by using the orthogonality property. The composite
spectrum, CS, is multiplied by the weighting function w and by the
basis function, in the present invention the analyte spectra,
associated with the coefficient of interest, for example, the molar
extinction coefficient of the nth component, .epsilon..sub.N. The
result is integrated over .lambda., in the present invention, the
wavelength of interest. All the terms on the right side of the
equation are zero by orthogonality, except the one of interest, the
molar extinction coefficient of the nth component, EN. 1 wCS N = C
N w N N And , C N = wCS N wCS N = < CS w N > < _ N _ w N
>
[0112] All of the coefficients may be determined this fashion.
[0113] IR and near-IR spectra may be analyzed using orthogonal
functions as described above. The spectra for the blood analytes
are used as basis functions and made orthogonal by proper selection
of weighting function w. As explained above, the weighting function
or functions are found that make the basis functions orthogonal
over the wavelength range of interest. Note that the bulk of the
calculations involving reference spectra and weighting functions
are performed in the laboratory. The processor of the analyte
measuring device can then calculate the result in as little time as
a few seconds. The calculations necessary "in the field" consist of
only one integration of the spectrum for each analyte. If 28
analytes are being considered, for example, and the integrations
take only a millisecond or so (which is within the capacity of
available processors), the 28 integrations necessary may be
accomplished in under one second.
[0114] Because of the complexity of the individual spectra, high
order polynomials are needed to fit them. The method and apparatus
of the present invention can account for perhaps 100 analytes or
more. The number of coefficients needed to determine the weighting
function may then be on the order of several thousand. Thus the
invention makes use of a matrix that is 1000.times.1000 or larger
that must be inverted to determine the weighting function. This may
be readily accomplished, as SPICE circuit simulations, for example,
routinely invert matrices this size and larger, especially for
transient simulations where the typical simulation inverts large
matrices thousands of times in a typical run. Polynomial fitting of
the spectra for glucose and albumin has also been accomplished
using the Microsoft EXCEL matrix inverter. Microsoft EXCEL has
built in functions to invert matrices up to 256.times.256 elements,
which allows up to 256 data points to fit the spectra.
[0115] The use of orthogonal polynomials in this invention provides
a distinct advantage over the use of linear regression. Using
orthogonal polynomials, once the weighting function is known,
<.epsilon..sub.N.vertline.w.vertline..epsilon..sub.N> is
determined at the lab or factory, and only one integration,
<CS.vertline.w.vertli- ne..epsilon..sub.N>, is performed at
the site "in the field" to determine the concentration of a
specific analyte, such as glucose. In contrast, linear regression
requires an iterative solution of multiple analytes simultaneously
to extract the one of interest. It should be noted that the
orthogonal function method also yields a weighted least squares fit
of the data. Any of the currently used techniques, such as second
derivative peak sharpening, may also be used to improve performance
of the invention. Compensating for the 20 or 30 dominant background
components eliminates the accuracy and baseline drift issues
existing in previous efforts in this area.
[0116] The data processing of the present invention resolves
numerous other problems as well. For example, overlapping peaks are
corrected for by using orthogonal functions. Sample density
variations are dealt with by measuring the sample average
concentration. Over-fitting of the data may be a statistical
problem and should be avoided in determining which .epsilon.s
should be used.
[0117] Computational problems may also have a negative impact on
accuracy. A significant example of this is large concentration
differences. For example, comparing albumin at 5 g/dL and glucose
at 100 mg/dL represents a 50:1 concentration ratio. This has
implications on the measurement accuracy required. Glucose absorbs
at wavelengths where albumin does not, for example, so that the
problem in this particular case is abated somewhat. The net
numerical effect may be that albumin, measured at its absorption
peaks, is used to compensate for albumin effects at the glucose
peaks. Since .epsilon. for albumin is known, the method of
orthogonal functions provides a strong advantage because it
inherently compensates for the albumin effects at the glucose peak.
Obtaining 10% glucose accuracy requires spectral absorbance
measurements of 1% or better because of the concentration
differences, but as mentioned earlier this is within the capability
of the method and apparatus of the present invention.
[0118] While the embodiments and applications of this invention
have been shown and described in detail, it will be apparent to
those skilled in the art that many more modifications than
mentioned above are possible without departing from the inventive
concepts described herein. The scope of the present invention is
thus limited only by the terms of the appended claims.
* * * * *