U.S. patent application number 11/335067 was filed with the patent office on 2006-06-01 for compact apparatus for noninvasive measurement of glucose through near-infrared spectroscopy.
Invention is credited to N. Alan Abul Haj, George M. Acosta, Thomas B. Blank, Kevin H. Hazen, James R. Henderson, Stephen L. Monfre, Timothy L. Ruchti.
Application Number | 20060116562 11/335067 |
Document ID | / |
Family ID | 29587644 |
Filed Date | 2006-06-01 |
United States Patent
Application |
20060116562 |
Kind Code |
A1 |
Acosta; George M. ; et
al. |
June 1, 2006 |
Compact apparatus for noninvasive measurement of glucose through
near-infrared spectroscopy
Abstract
The invention involves the monitoring of a biological parameter
through a compact analyzer. The preferred apparatus is a
spectrometer based system that is attached continuously or
semi-continuously to a human subject and collects spectral
measurements that are used to determine a biological parameter in
the sampled tissue. The preferred target analyte is glucose. The
preferred analyzer is a near-IR based glucose analyzer for
determining the glucose concentration in the body.
Inventors: |
Acosta; George M.; (Phoenix,
AZ) ; Henderson; James R.; (Phoenix, AZ) ;
Abul Haj; N. Alan; (Mesa, AZ) ; Ruchti; Timothy
L.; (Gilbert, AZ) ; Monfre; Stephen L.;
(Gilbert, AZ) ; Blank; Thomas B.; (Chandler,
AZ) ; Hazen; Kevin H.; (Gilbert, AZ) |
Correspondence
Address: |
GLENN PATENT GROUP
3475 EDISON WAY, SUITE L
MENLO PARK
CA
94025
US
|
Family ID: |
29587644 |
Appl. No.: |
11/335067 |
Filed: |
January 18, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10472856 |
Sep 18, 2003 |
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PCT/US03/07065 |
Mar 7, 2003 |
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11335067 |
Jan 18, 2006 |
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60362885 |
Mar 8, 2002 |
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60362899 |
Mar 8, 2002 |
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60448840 |
Feb 19, 2003 |
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Current U.S.
Class: |
600/316 ;
128/903; 600/310 |
Current CPC
Class: |
A61B 5/6833 20130101;
A61B 2560/0252 20130101; G01N 21/49 20130101; A61B 5/7203 20130101;
A61B 5/726 20130101; G01N 21/359 20130101; A61B 2560/0456 20130101;
A61B 2562/146 20130101; A61B 2560/0412 20130101; A61B 5/14532
20130101; A61B 5/0075 20130101; A61B 5/7225 20130101; A61B 5/1495
20130101; A61B 2562/0242 20130101; A61B 2560/0443 20130101; A61B
2560/0223 20130101; A61B 2562/227 20130101; A61B 2560/0233
20130101; A61B 2562/228 20130101; A61B 5/1455 20130101 |
Class at
Publication: |
600/316 ;
600/310; 128/903 |
International
Class: |
A61B 5/00 20060101
A61B005/00 |
Claims
1. An apparatus for noninvasive measurement of an analyte property
using spectroscopy, comprising: a sample module; that is positioned
proximate to a sample site during collection of a sample spectrum;
a base module, physically separated from said sample module, said
base module and said sample module each comprising a wireless
communication system for communication there between; and a source
located in said sample module; said base module comprising means
for any of generating said analyte property using said spectrum and
recording said analyte property generated from said sample
spectrum.
2. The apparatus of claim 1, said wireless communication system
comprising a two-way wireless communication system.
3. The apparatus of claim 2, wherein said base module is worn by a
person.
4. The apparatus of claim 3, said base module comprising a remote
display and receiving unit.
5. The apparatus of claim 4, said base module comprising a data
processing system.
6. The apparatus of claim 1, said sample module comprising a data
collection system.
7. The apparatus of claim 6, said sample module further comprising:
an optic that is positioned in close proximity to said sample site
to reduce specular reflectance.
8. The apparatus of claim 7, said sample module further comprising:
a detector array.
9. The apparatus of claim 8, further comprising: a first optic
located in an optical train after said source to remove photonic
heat from said optical train; and a second optic located in said
optical train after said first optic and before a sample site.
10. The apparatus of claim 9, wherein at least one of said first
optic and said second optic removes source light otherwise detected
by said detector as second order light from said grating.
11. The apparatus of claim 8, wherein said detector array is
optically coupled to a wavelength separation device.
12. The apparatus of claim 1, said analyte property comprising:
glucose concentration.
13. The apparatus of claim 12, said analyzer either continuously or
semi-continuously monitoring said glucose concentration.
14. The apparatus of claim 13, further comprising: means for
enhancing equilibration in glucose concentration between said
sample site and finger blood glucose concentration.
15. The apparatus of claim 13, further comprising: means for bias
correcting at least one of spectra (X) and glucose concentration
data (Y).
16. The apparatus of claim 1, said sample module either
continuously or semi-continuously samples said sample site in an
automated fashion, wherein time between sampling comprises any of
about: seconds; one minute; five minutes; ten minutes; twenty
minutes; a half hour; and one hour.
17. The apparatus of claim 1, said source comprising an
incandescent lamp.
18. The apparatus of claim 1, said source comprising at least one
light emitting diode.
19. The apparatus of claim 1, further comprising: means for
automated delivery of a coupling fluid to said sample site prior to
sampling.
20. The apparatus of claim 1, further comprising: means for
optically detecting proximate contact of said sample module with
said sample site.
21. The apparatus of claim 1, further comprising: means for
performing an indirect determination of said analyte property using
said sample spectrum.
22. The apparatus of claim 1, further comprising: means for
measuring a reference spectrum and a wavelength standardization
spectrum through spectroscopic measurement of a minimally absorbing
substance and a material with known and immutable spectral
absorbance bands.
23. The apparatus of claim 1, said base module further comprising:
means for calibrating to an individual or a group of individuals
based upon a calibration data set comprised of paired data points
of processed spectral measurements and reference biological
parameter values.
24. The apparatus of claim 1, wherein said sample module is
replaceably attached to a docking station: wherein said docking
station comprises a computer and an analyte property management
center; and wherein said analyte property management center keeps
track of events occurring over time.
25. The apparatus of claim 1, further comprising: means for taking
any of continuous and semi-continuous measurements when said sample
module is in proximate contact with said sample site.
26. The apparatus of claim 1, wherein said sample module is
supported by said sample site during collection of said sample
spectrum.
27. The apparatus of claim 1, said spectroscopy comprising
near-infrared spectroscopy.
28. The apparatus of claim 1, said sample module further
comprising: a Fabry-Perot interferometer.
29. A method for noninvasive measurement of an analyte property
using near-infrared spectroscopy, comprising the steps of:
providing an analyzer for collecting a near-infrared spectrum of a
human tissue sample site; and estimating said analyte property
through application of a multivariate calibration model on said
spectrum; wherein the step of providing said analyzer comprises the
steps of: providing a base module and a sample module that is
positioned proximate a sample site during collection of a sample
spectrum, and: that is physically separated from said base module,
said base module and said sample module each comprise a wireless
communication system for communication there between; and providing
a source located in said sample module; said base module either of
generating said analyte property using said spectrum and recording
said analyte property generated from said sample spectrum.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/472,856 filed Mar. 3, 2003, which
claims:
[0002] priority to PCT application no. PCT/US03/07065 filed Mar. 3,
2003, which claims benefit of U.S. provisional patent application
No. 60/362,885, filed on Mar. 8, 2002;
[0003] benefit of U.S. provisional patent application No.
60/362,899, filed on Mar. 8, 2002; and
[0004] benefit of U.S. provisional patent application No.
60/448,840 filed on Feb. 19, 2003;
[0005] each of which is incorporated by its entirety by this
reference thereto.
BACKGROUND OF THE INVENTION
[0006] 1. Field of the Invention
[0007] This invention relates generally to the noninvasive
measurement of biological parameters through near-infrared
spectroscopy. In particular, an apparatus and a method are
disclosed for noninvasively, and continuously or semi-continuously,
monitoring a biological parameter, such as glucose in tissue.
[0008] 2. Discussion of the Prior Art
Diabetes
[0009] Diabetes is a chronic disease that results in improper
production and use of insulin, a hormone that facilitates glucose
uptake into cells. Diabetes can be broadly categorized into four
forms: diabetes, impaired glucose tolerance, normal physiology, and
hyperinsulinemia (hypoglycemia). While a precise cause of diabetes
is unknown, genetic factors, environmental factors, and obesity
appear to play roles. Diabetics have increased risk in three broad
categories: cardiovascular heart disease, retinopathy, and
neuropathy. Diabetics may have one or more of the following
complications: heart disease and stroke, high blood pressure,
kidney disease, neuropathy (nerve disease and amputations),
retinopathy, diabetic ketoacidosis, skin conditions, gum disease,
impotence, and fetal complications. Diabetes is a leading cause of
death and disability worldwide.
Diabetes Prevalence and Trends
[0010] Diabetes is a common and growing disease. The World Health
Organization (WHO) estimates that diabetes currently afflicts one
hundred fifty-four million people worldwide. Fifty-four million
diabetics live in developed countries. The WHO estimates that the
number of people with diabetes will grow to three hundred million
by the year 2025. In the United States, 15.7 million people or 5.9%
of the population are estimated to have diabetes. Within the United
States, the prevalence of adults diagnosed with diabetes increased
by six percent in 1999 and rose by thirty-three percent between
1990 and 1998. This corresponds to approximately eight hundred
thousand new cases every year in America. The estimated total cost
to the United States economy alone exceeds $90 billion per year
(Diabetes Statistics. Bethesda, Md.: National Institute of Health,
Publication No. 98-3926, November 1997).
[0011] Long-term clinical studies show that the onset of diabetes
related complications can be significantly reduced through proper
control of blood glucose concentrations (The Diabetes Control and
Complications Trial Research Group. The effect of intensive
treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. N
Eng J of Med 1993;329:977-86; U.K. Prospective Diabetes Study
(UKPDS) Group, "Intensive blood-glucose control with sulphonylureas
or insulin compared with conventional treatment and risk of
complications in patients with type 2 diabetes," Lancet, vol. 352,
pp. 837-853, 1998; Ohkubo, Y., H. Kishikawa, E. Araki, T. Miyata,
S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, and M. Shichizi,
"Intensive insulin therapy prevents the progression of diabetic
microvascular complications in Japanese patients with
non-insulin-dependent diabetes mellitus: a randomized prospective
6-year study," Diabetes Res Clin Pract, vol. 28, pp. 103-117,
1995). A vital element of diabetes management is the
self-monitoring of blood glucose levels by diabetics in the home
environment. However, current monitoring techniques discourage
regular use due to the inconvenient and painful nature of drawing
blood through the skin prior to analysis (The Diabetes Control and
Complication Trial Research Group, "The effect of intensive
treatment of diabetes on the development and progression of
long-term complications of insulin-dependent diabetes mellitus", N.
Engl. J. Med., 329, 1993, 997-1036). Unfortunately, recent reports
indicate that even periodic measurement of glucose by individuals
with diabetes, (e.g. seven times per day) is insufficient to detect
important glucose fluctuations and properly manage the disease. In
addition, nocturnal monitoring of glucose levels is of significant
value but is difficult to perform due to the state of existing
technology. Therefore, a device that provides noninvasive,
automatic, and nearly continuous measurements of glucose levels
would be of substantial value to people with diabetes. Implantable
glucose analyzers eventually coupled to an insulin delivery system
providing an artificial pancreas are also being pursued.
Description of Related Technology
[0012] Common technologies are used to analyze the blood glucose
concentration of samples collected by venous draw and with
capillary stick approaches. Glucose analysis includes techniques
such as colorimetric and enzymatic glucose analysis. Many of the
invasive, traditional invasive, alternative invasive, and minimally
invasive glucose analyzers use these technologies. The most common
enzymatic based glucose analyzers use glucose oxidase, which
catalyzes the reaction of glucose with oxygen to form
gluconolactone and hydrogen peroxide, equation 1. Glucose
determination may be achieved by techniques based upon depletion of
oxygen in the sample, through the changes in sample pH, or via the
formation of hydrogen peroxide. A number of calorimetric and
electro-enzymatic techniques further use the reaction products as a
starting reagent. For example, hydrogen peroxide reacts in the
presence of platinum to form the hydrogen ion, oxygen, and current
any of which may be used to determine the glucose concentration,
equation 2. glucose+O.sub.2.fwdarw.gluconolactone+H.sub.2O.sub.2
eq. 1 H.sub.2O.sub.2.fwdarw.2H.sup.++O.sub.2+2e.sup.- eq. 2
[0013] Due to the wide and somewhat loose terminology in the field,
the terms traditional invasive, alternative invasive, noninvasive,
and implantable are here outlined:
Traditional Invasive Glucose Determination
[0014] There are three major categories of traditional (classic)
invasive glucose determinations. The first two methodologies use
blood drawn with a needle from an artery or vein, respectively. The
third group consists of capillary blood obtained via lancet from
the fingertip or toes. Over the past two decades, this last method
has become the most common method for self-monitoring of blood
glucose at home, at work, or in public settings.
Alternative Invasive Glucose Determination
[0015] There are several alternative invasive methods of
determining glucose concentrations.
[0016] A first group of alternative invasive glucose analyzers have
a number of similarities to traditional invasive glucose analyzers.
One similarity is that blood samples are acquired with a lancet.
Obviously, this form of alternative invasive glucose determination
may not be used to collect venous or arterial blood for analysis,
but may be used to collect capillary blood samples. A second
similarity is that the blood sample is analyzed using chemical
analyses that are similar to the colorimetric and enzymatic
analyses describe above. The primary difference is that in an
alternative invasive glucose determination the blood sample is not
collected from the fingertip or toes. For example, according to
package labeling the TheraSense.RTM. FreeStyle Meter.TM. may be
used to collect and analyze blood from the forearm. This is an
alternative invasive glucose determination due to the location of
the lancet draw.
[0017] In this first group of alternative invasive methods based
upon blood draws with a lancet, a primary difference between the
alternative invasive and traditional invasive glucose determination
is the location of blood acquisition from the body. Additional
differences include factors such as the gauge of the lancet, the
depth of penetration of the lancet, timing issues, the volume of
blood acquired, and environmental factors such as the partial
pressure of oxygen, altitude, and temperature. This form of
alternative invasive glucose determination includes samples
collected from the palmar region, base of thumb, forearm, upper
arm, head, earlobe, torso, abdominal region, thigh, calf, and
plantar region.
[0018] A seond group of alternative invasive glucose analyzers are
distinguished by their mode of sample acquisition. This group of
glucose analyzers has a common characteristic of acquiring a
biological sample from the body or modifying the surface of the
skin to gather a sample without use of a lancet for subsequent
analysis. For example, a laser poration based glucose analyzer
would use a burst or stream of photons to create a small hole in
the surface of the skin. A sample of basically interstitial fluid
would collect in the resulting hole. Subsequent analysis of the
sample for glucose would constitute an alternative invasive glucose
analysis whether or not the sample was actually removed from the
created hole. A second common characteristic is that a device and
algorithm are used to determine glucose from the sample.
[0019] A number of methodologies exist for the collection of the
sample for alternative invasive measurements including laser
poration, applied current, and suction. The most common are
summarized here: [0020] A. Laser poration: In these systems,
photons of one or more wavelengths are applied to skin creating a
small hole in the skin barrier. This allows small volumes of
interstitial fluid to become available to a number of sampling
techniques. [0021] B. Applied current: In these systems, a small
electrical current is applied to the skin allowing interstitial
fluid to permeate through the skin. [0022] C. Suction: In these
systems, a partial vacuum is applied to a local area on the surface
of the skin. Interstitial fluid permeates the skin and is
collected.
[0023] For example, a device that acquires a sample via
iontophoresis, such as Cygnus'.RTM. GlucoWatch.TM., is an
alternative invasive technique.
[0024] In all of these techniques, the analyzed sample is
interstitial fluid. However, some of the techniques can be applied
to the skin in a fashion that draws blood. Herein, the term
alternative invasive includes techniques that analyze biosamples
such as interstitial fluid, whole blood, mixtures of interstitial
fluid and whole blood, and selectively sampled interstitial fluid.
An example of selectively sampled interstitial fluid is collected
fluid in which large or less mobile constituents are not fully
represented in the resulting sample. For this group of alternative
invasive glucose analyzers sampling sites include: the hand,
fingertips, palmar region, base of thumb, forearm, upper arm, head,
earlobe, eye, chest, torso, abdominal region, thigh, calf, foot,
plantar region, and toes. In this document, any technique that
draws biosamples from the skin without the use of a lancet on the
fingertip or toes is referred to as an alternative invasive
technique.
[0025] In addition, it is recognized that the alternative invasive
systems each have different sampling approaches that lead to
different subsets of the interstitial fluid being collected. For
example, large proteins might lag behind in the skin while smaller,
more diffusive, elements may be preferentially sampled. This leads
to samples being collected with varying analyte and interferent
concentrations. Another example is that a mixture of whole blood
and interstitial fluid may be collected. Another example is that a
laser poration method can result in blood droplets. These
techniques may be used in combination. For example the Soft-Tact,
SoftSense in Europe, applies a suction to the skin followed by a
lancet stick. Despite the differences in sampling, these techniques
are referred to as alternative invasive techniques sampling
interstitial fluid.
[0026] Sometimes, the literature refers to the alternative invasive
technique as an alternative site glucose determination or as a
minimally invasive technique. The minimally invasive nomenclature
derives from the method by which the sample is collected. In this
document, the alternative site glucose determinations that draw
blood or interstitial fluid, even 1/4 microliter, are considered to
be alternative invasive glucose determination techniques as defined
above. Examples of alternative invasive techniques include the
TheraSense.RTM. FreeStyle.TM. when not sampling fingertips or toes,
the Cygnus.RTM. GlucoWatch.TM., the One Touch.RTM. Ultra.TM., and
equivalent technologies.
[0027] Biosamples collected with alternative invasive techniques
are analyzed via a large range of technologies. The most common of
these technologies are summarized below: [0028] A. Conventional:
With some modification, the interstitial fluid samples may be
analyzed by most of the technologies used to determine glucose
concentrations in serum, plasma, or whole blood. These include
electrochemical, electroenzymatic, and calorimetric approaches. For
example, the enzymatic and calorimetric approaches described above
may also be used to determine the glucose concentration in
interstitial fluid samples. [0029] B. Spectrophotometric: A number
of approaches, for determining the glucose concentration in
biosamples, have been developed that are based upon
spectrophotometric technologies. These techniques include: Raman
and fluorescence, as well as techniques using light from the
ultraviolet through the infrared [ultraviolet (200 to 400 nm),
visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000
cm.sup.-1), and infrared (2500 to 14,285 nm or 4000 to 700
cm.sup.-1)].
[0030] In this document, an invasive glucose analyzer is the genus
of both the traditional invasive glucose analyzer species and the
alternative invasive glucose analyzer species.
Noninvasive Glucose Determination
[0031] There exist a number of noninvasive approaches for glucose
determination. These approaches vary widely, but have at least two
common steps. First, an apparatus is used to acquire a reading from
the body without obtaining a biological sample. Second, an
algorithm is used to convert this reading into a glucose
determination.
[0032] One species of noninvasive glucose analyzers are those based
upon the collection and analysis of spectra. Typically, a
noninvasive apparatus uses some form of spectroscopy to acquire the
signal or spectrum from the body. Used spectroscopic techniques
include but are not limited to Raman, fluorescence, as well as
techniques using light from ultraviolet through the infrared
[ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700
to 2500 nm or 14,286 to 4000 cm.sup.-1), and infrared (2500 to
14,285 nm or 4000 to 700 cm.sup.-1)]. A particular range for
noninvasive glucose determination in diffuse reflectance mode is
about 1100 to 2500 nm or ranges therein (Hazen, Kevin H. "Glucose
Determination in Biological Matrices Using Near-Infrared
Spectroscopy", doctoral dissertation, University of Iowa, 1995). It
is important to note, that these techniques are distinct from the
traditionally invasive and alternative invasive techniques listed
above in that the sample analyzed is a portion of the human body
in-situ, not a biological sample acquired from the human body.
[0033] Typically, three modes are used to collect noninvasive
scans: transmittance, transflectance, and/or diffuse reflectance.
For example the light, spectrum, or signal collected may be light
transmitting through a region of the body, diffusely transmitting,
diffusely reflected, or transflected. Transflected here refers to
collection of the signal not at the incident point or area (diffuse
reflectance), and not at the opposite side of the sample
(transmittance), but rather at some point or region of the body
between the transmitted and diffuse reflectance collection area.
For example, transflected light enters the fingertip or forearm in
one region and exits in another region. When using the near-IR, the
transflected radiation typically radially disperses 0.2 to 5 mm or
more away from the incident photons depending on the wavelength
used. For example, light that is strongly absorbed by the body such
as light near the water absorbance maxima at 1450 or 1950 nm must
be collected after a small radial divergence in order to be
detected and light that is less absorbed such as light near water
absorbance minima at 1300, 1600, or 2250 nm may be collected at
greater radial or transflected distances from the incident
photons.
[0034] Noninvasive techniques are not limited to the fingertip.
Other regions or volumes of the body subjected to noninvasive
measurements are: a hand, finger, palmar region, base of thumb,
forearm, volar aspect of the forearm, dorsal aspect of the forearm,
upper arm, head, earlobe, eye, tongue, chest, torso, abdominal
region, thigh, calf, foot, plantar region, and toe. It is important
to note that noninvasive techniques do not have to be based upon
spectroscopy. For example, a bioimpedence meter would be a
noninvasive device. In this document, any device that reads glucose
from the body without penetrating the skin and collecting a
biological sample is referred to as a noninvasive glucose analyzer.
For the purposes of this document, X-rays and MRI's are not
considered to be defined in the realm of noninvasive
technologies.
Implantable Sensor for Glucose Determination
[0035] There exist a number of approaches for implanting a glucose
sensor into the body for glucose determination. These implantables
may be used to collect a sample for further analysis or may acquire
a reading of the sample directly or based upon direct reactions
occurring with glucose. Two categories of implantable glucose
analyzers exist: short-term and long-term.
[0036] In this document, a device or a collection apparatus is
referred to as a short-term implantable (as opposed to a long-term
implantable) if part of the device penetrates the skin for a period
of greater than three hours and less than one month. For example, a
wick placed subcutaneously to collect a sample overnight that is
removed and analyzed for glucose content representative of the
interstitial fluid glucose concentration is referred to as a short
term implantable. Similarly, a biosensor or electrode placed under
the skin for a period of greater than three hours that reads
directly or based upon direct reactions occurring with glucose
concentration or level is referred to as a short-term implantable
device. Conversely, devices such as a lancet, applied current,
laser poration, or suction are referred to as either a traditional
invasive or alternative invasive technique as they do not fulfill
both the three hour and penetration of skin parameters. An example
of a short-term implantable glucose analyzer is MiniMed's.RTM.
continuous glucose monitoring system. In this document, long-term
implantables are distinguished from short-term implantables by
having the criteria that they must both penetrate the skin and be
used for a period of one month or longer. Long term implantables
may be in the body for greater than one month, one year, or many
years.
[0037] Implantable glucose analyzers vary widely, but have at least
several steps in common. First, at least part of the device
penetrates the skin. More commonly, the entire device is imbedded
into the body. Second, the apparatus is used to acquire either a
sample of the body or a signal relating directly or based upon
direct reactions occurring with the glucose concentration within
the body. If the implantable device collects a sample, readings or
measurements on the sample may be collected after removal from the
body. Alternatively, readings may be transmitted out of the body by
the device or used for such purposes as insulin delivery while in
the body. Third, an algorithm is used to convert the signal into a
reading directly or based upon direct reactions occurring with the
glucose concentration. An implantable analyzer may read from one or
more of a variety of body fluids or tissues including but not
limited to: arterial blood, venous blood, capillary blood,
interstitial fluid, and selectively sampled interstitial fluid. An
implantable analyzer may also collect glucose information from skin
tissue, cerebral spinal fluid, organ tissue, or through an artery
or vein. For example, an implantable glucose analyzer may be placed
transcutaneously, in the peritoneal cavity, in an artery, in
muscle, or in an organ such as the liver or brain. The implantable
glucose sensor may be one component of an artificial pancreas.
Description of Related Technology
[0038] One class of alternative invasive continuous glucose
monitoring systems are those based upon iontophoresis. Using the
iontophoresis process, uncharged molecules such as glucose may be
moved across the skin barrier with the application of a small
electric current. Several patents and publications in this area are
available (Tamada, J. A., S. Garg, L. Jovanovic, K. R. Pitzer, S.
Fermi, R. O. Potts, "Noninvasive Glucose Monitoring Comprehensive
Clinical Results," JAMA, Vol. 282, No. 19, pp. 1839-1844, Nov. 17,
1999; Berner, Bret; Dunn, Timothy c.; Farinas, Kathleen C.;
Garrison, Michael D.; Kurnik, Ronald T.; Lesho, Matthew J.; Potts,
Russell O.; Tamada, Janet A.; Tierney, Michael J. "Signal
Processing for Measurement of Physiological Analysis", U.S. Pat.
No. 6,233,471, May 15, 2001; Dunn, Timothy C.; Jayalakshmi, Yalia;
Kurnik, Ronald T.; Lesho, Matthew J.; Oliver, Jonathan James;
Potts, Russell O.; Tamada, Janet A.; Waterhouse, Steven Richard;
Wei, Charles W. "Microprocessors for use in a Device Predicting
Physiological Values", U.S. Pat. No. 6,326,160, Dec. 4, 2001;
Kurnik, Ronald T. "Method and Device for Predicting Physiological
Values", U.S. Pat. No. 6,272,364, Aug. 7, 2001; Kurnik, Ronald T.;
Oliver, Jonathan James; Potts, Russell O.; Waterhouse, Steven
Richard; Dunn, Timothy C.; Jayalakshmi, Yalia; Lesho, Matthew J.;
Tamada, Janet A.; Wei, Charles W. "Method and Device for Predicting
Physiological Values", U.S. Pat. No. 6,180,416, Jan. 30, 2001;
Tamada, Janet A.; Garg, Satish; Jovanovic, Lois; Pitzer, Kenneth
R.; Fermi, Steve; Potts, Russell O. "Noninvasive Glucose
Monitoring", JAMA, 282, 1999, 1839-1844; Sage, Burton H. "FDA Panel
Approves Cygnus's Noninvasive GlucoWatch.TM.", Diabetes Technology
& Therapeutics, 2, 2000, 115-116; and "GlucoWatch Automatic
Glucose Biographer and AutoSensors", Cygnus Inc., Document
#1992-00, Rev. March 2001) The Cygnus Glucose Watch.RTM. uses this
technology. The GlucoWatch.RTM. provides only one reading every
twenty minutes, each delayed by at least ten minutes due to the
measurement process. The measurement is made through an alternative
invasive electrochemical-enzymatic sensor on a sample of
interstitial fluid which is drawn through the skin using
iontophoresis. Consequently, the limitations of the device include
the potential for significant skin irritation, collection of a
biohazard, and a limit of three readings per hour.
[0039] One class of semi-implantable glucose analyzers are those
based upon open-flow microperfusion (Trajanowski, Zlatko; Brunner,
Gernot A.; Schaupp, Lucas; Ellmerer, Martin; Wach, Paul; Pieber,
Thomas R,; Kotanko, Peter; Skrabai, Falko "Open-Flow Microperfusion
of Subcutaneous Adipose Tissue for ON-Line Continuous Ex Vivo
Measurement of Glucose Concentration", Diabetes Care, 20, 1997,
1114-1120). Typically these systems are based upon biosensors and
amperometric sensors (Trajanowski, Zlatko; Wach, Paul; Gfrerer,
Robert "Portable Device for Continuous Fractionated Blood Sampling
and Continuous ex vivo Blood Glucose Monitoring", Biosensors and
Bioelectronics, 11, 1996, 479-487). A common issue with
semi-implantable and implantable devices is coating by proteins.
The MiniMed.RTM. continuous glucose monitoring system, a short-term
implantable, is the first commercially available semi-continuous
glucose monitor in this class. The MiniMed.RTM. system is capable
of providing a glucose profile for up to seventy-two hours. The
system records a glucose value every five minutes. The technology
behind the MiniMed.RTM. system relies on a probe being invasively
implanted into a subcutaneous region followed by a glucose oxidase
based reaction producing hydrogen peroxide, which is oxidized at a
platinum electrode to produce an analytical current. Notably, the
MiniMed.RTM. system automatically shifts glucose determinations by
ten minutes in order to accommodate for a potential dynamic lag
between the blood and interstitial glucose (Gross, Todd M.; Bode,
Bruce W.; Einhorn, Daniel; Kayne, David M.; Reed, John H.; White,
Neil H.; Mastrototaro, John J. "Performance Evaluation of the
MiniMed Continuous Glucose Monitoring System During Patient Home
Use", Diabetes Technology & Therapeutics, 2, 2000, 49-56.;
Rebrin, Kerstin; Steil, Gary M.; Antwerp, William P. Van;
Mastrototaro, John J. "Subcutaneous Glucose Predicts Plasma Glucose
Independent of Insulin: Implications for Continuous Monitoring",
Am., J. Physiol., 277, 1999, E561-E571, 0193-1849/99, The American
Physiological Society, 1999).
[0040] Other approaches, such as the continuous monitoring system
reported by Gross, et. al. (Gross, T. M., B. W. Bode, D. Einhorn,
D. M. Kayne, J. H. Reed, N. H. White and J. J. Mastrototaro,
"Performance Evaluation of the MiniMed.RTM. Continuous Glucose
Monitoring System During Patient Home Use," Diabetes Technology
& Therapeutics, Vol. 2, Num. 1, 2000), involve the implantation
of a sensor in tissue with a transcutaneous external connector.
Inherent in these approaches are health risks due to the sensor
implantation, infections, patient inconvenience, and measurement
delay.
[0041] Another approach towards continuous glucose monitoring is
through the use of fluorescence. For example Sensors for Medicine
and Science Incorporated (S4MS) is developing a glucose selective
indicator molecule combined into an implantable device that is
coupled via telemetry to an external device. The device works via
an indicator molecule that reversibly binds to glucose. With an LED
for excitation, the indicator molecule fluoresces in the presence
of glucose. This device is an example of a short-term implantable
with development towards a long-term implantable (Colvin, Arthur E.
"Optical-Based Sensing Devices Especially for In-Situ Sensing in
Humans", U.S. Pat. No. 6,304,766, Oct. 16, 2001; Colvin, Arthur E.;
Dale, Gregory A.; Zerwekh, Samuel, Lesho, Jeffery C.; Lynn, Robert
W. "Optical-Based Sensing Devices", U.S. Pat. No. 6,330,464, Dec.
11, 2001; Colvin, Arthur E.; Daniloff, George Y.; Kalivretenos,
Aristole G.; Parker, David; Ullman, Edwin E.; Nikolaitchik,
Alexandre V. "Detection of Analytes by fluorescent Lanthanide Metal
Chelate Complexes Containing Substituted Ligands", U.S. Pat. No.
6,334,360, Feb. 5, 2002; and Lesho, Jeffery "Implanted Sensor
Processing System and Method for Processing Implanted Sensor
Output", U.S. Pat. No. 6,400,974, Jun. 4, 2002).
[0042] Notably, none of these technologies are noninvasive.
Further, none of these technologies offer continuous glucose
determination.
[0043] Another technology, near-infrared spectroscopy, provides the
opportunity to measure glucose noninvasively with a relativity
short sampling interval. This approach involves the illumination of
a spot on the body with near-infrared electromagnetic radiation
(light in the wavelength range 700 to 2500 nm). The incident light
is partially absorbed and scattered, according to its interaction
with the constituents of the tissue. The actual tissue volume that
is sampled is the portion of irradiated tissue from which light is
diffusely reflected, transflected, or transmitted by the sample and
optically coupled to the spectrometer detection system. The signal
due to glucose is extracted from the spectral measurement through
various methods of signal processing and one or more mathematical
models. The models are developed through the process of calibration
on the basis of an exemplary set of spectral measurements and
associated reference blood glucose values (the calibration set)
based on an analysis of capillary (fingertip), alternative invasive
samples, or venous blood. To date, only discrete glucose
determinations have been reported using near-IR technologies.
[0044] There exists a body of work on noninvasive glucose
determination using near-IR technology, the most pertinent of which
are referred here (Robinson, Mark Ries; Messerschmidt, Robert G
"Method for Non-invasive Blood Analyte Measurement with Improved
Optical Interface", U.S. Pat. No. 6,152,876, Nov. 28, 2000;
Messerschmidt, Robert G.; Robinson, Mark Ries "Diffuse Reflectance
Monitoring Apparatus", U.S. Pat. No. 5,935,062, Aug. 10, 1999;
Messerschmidt, Robert G. "Method for Non-invasive Analyte
Measurement with Improved Optical Interface", U.S. Pat. No.
5,823,951, Oct. 20, 1998; Messerschmidt, Robert G. "Method for
Non-invasive Blood Analyte Measurement with Improved Optical
Interface", U.S. Pat. No. 5,655,530; Rohrscheib, Mark; Gardner,
Craig; Robinson, Mark R. "Method and Apparatus for Non-invasive
Blood Analyte Measurement with Fluid Compartment Equilibration",
U.S. Pat. No. 6,240,306, May 29, 2001; Messerschmidt, Robert G.;
Robinson, Mark Ries "Diffuse Reflectance Monitoring Apparatus",
U.S. Pat. No. 6,230,034, May 8, 2001; Barnes, Russell H.; Brasch,
Jimmie W. "Non-invasive Determination of Glucose Concentration in
Body of Patients", U.S. Pat. No. 5,070,874, Dec. 10, 1991; and
Hall, Jeffrey; Cadell, T. E. "Method and Device for Measuring
Concentration Levels of Blood Constituents Non-invasively", U.S.
Pat. No. 5,361,758, Nov. 8, 1994). Several Sensys Medical patents
also address noninvasive glucose analyzers: Schlager, Kenneth J.
"Non-invasive Near Infrared Measurement of Blood Analyte
Concentrations", U.S. Pat. No. 4,882,492, Nov. 21, 1989.; Malin,
Stephen; Khalil, Gamal "Method and Apparatus for Multi-Spectral
Analysis in Noninvasive Infrared Spectroscopy", U.S. Pat. No.
6,040,578, Mar. 21, 2000; Garside, Jeffrey J.; Monfre, Stephen;
Elliott, Barry C.; Ruchti, Timothy L.; Kees, Glenn Aaron "Fiber
Optic Illumination and Detection Patterns, Shapes, and Locations
for Use in Spectroscopic Analysis", U.S. Pat. No. 6,411,373, Jun.
25, 2002; Blank, Thomas B.; Acosta, George; Mattu, Mutua; Monfre,
Stephen L. "Fiber Optic Probe and Placement Guide", U.S. Pat. No.
6,415,167, Jul. 2, 2002; and Wenzel, Brian J.; Monfre, Stephen L.;
Ruchti, Timothy L.; Meissner, Ken; Grochocki, Frank "A Method for
Quantification of Stratum Corneum Hydration Using Diffuse
Reflectance Spectroscopy", U.S. Pat. No. 6,442,408, Aug. 27,
2002.
Mode of Analysis
[0045] A measurement of glucose is termed "direct" when the net
analyte due to the absorption of light by glucose in the tissue is
extracted from the spectral measurement through various methods of
signal processing and/or one or more mathematical models. In this
document, an analysis is referred to as direct if the analyte of
interest is involved in a chemical reaction. For example, in
equation 1 glucose reacts with oxygen in the presence of glucose
oxidase to form hydrogen peroxide and gluconolactone. The reaction
products may be involved in subsequent reactions such as that in
equation 2. The measurement of any reaction component or product is
a direct reading of glucose, herein. In this document, a direct
reading of glucose would also entail any reading in which the
electromagnetic signal generated is due to interaction with glucose
or a compound of glucose. For example, the fluorescence approach
listed above by Sensors for Medicine and Science is termed a direct
reading of glucose, herein.
[0046] A measurement of glucose is termed "indirect" when movement
of glucose within the body affects physiological parameters. In
brief, an indirect glucose determination may be based upon a change
in glucose concentration causing an ancillary physiological,
physical, or chemical response that is relatively large. A key
finding related to the noninvasive measurement of glucose is that a
major physiological response accompanies changes in glucose and can
be detected noninvasively through the resulting changes in tissue
properties.
[0047] An indirect measurement of blood glucose through assessment
of correlated tissue properties and/or physiological responses
requires a different strategy when compared with the direct
measurement of glucose spectral signals. Direct measurement of
glucose requires the removal of spectral variation due to other
constituents and properties in order to enhance the net analyte
signal of glucose. Because the signal directly attributable to
glucose in tissue is small, an indirect calibration to correlated
constituents or properties, e.g. the physiological response to
glucose, is attractive due to a gain in relative signal size. For
example, changes in the concentration of glucose alters the
distribution of water in the various tissue compartments. Because
water has a large NIR signal that is relatively easy to measure
compared to glucose, a calibration based at least in part on the
compartmental activity of water has a magnified signal related to
glucose. An indirect measurement may be referred to as a
measurement of an ancillary effect of the target analyte. An
indirect measurement means that an ancillary effect due to changes
in glucose concentration is being measured.
[0048] A major component of the body is water. A re-distribution of
water between the vascular and extravascular compartments and the
intra- and extra-cellar compartments is observed as a response to
differences in glucose concentrations in the compartments during
periods of changing blood glucose. Water, among other analytes, is
shifted between the tissue compartments to equilibrate the osmotic
imbalance related to changes in glucose concentration as predicted
by Fick's law of diffusion and the fact that water diffuses much
faster in the body than does glucose. Therefore, a strategy for the
indirect measurement of glucose that exploits the near-infrared
signal related to fluid re-distribution is to design measurement
protocols that force maximum correlation between blood glucose and
the re-distribution of fluids. This is the opposite strategy of the
one required for the direct measurement of blood glucose in which
the near-infrared signals directly related to glucose and fluids
must be discriminated and attempts at equalizing glucose in the
body compartment are made. A reliable indirect measurement of
glucose based at least in part in the re-distribution of fluids and
analytes (other than glucose) and related changes in the optical
properties of tissue requires that the indirect signals are largely
due to the changing blood glucose concentration. Other variables
and sources that modify or change the indirect signals of interest
should be prevented or minimized in order to ensure a reliable
indirect measurement of glucose.
[0049] One interference to a determination of blood/tissue glucose
concentration measured indirectly is a rapid change in blood
perfusion, which also leads to fluid movement between the
compartments. This type of physiological change interferes
constructively or destructively with the analyte signal of the
indirect measurement. In order to preserve a blood glucose/fluid
shift calibration it is beneficial to control other factors
influencing fluid shifts including local blood perfusion.
Near-IR Instrumentation
[0050] A number of technologies have been reported for measuring
glucose noninvasively that involve the measurement of a tissue
related variable. One species of noninvasive glucose analyzers use
some form of spectroscopy to acquire the signal or spectrum from
the body. Examples include but are not limited to far-infrared
absorbance spectroscopy, tissue impedance, Raman, and fluorescence,
as well as techniques using light from the ultraviolet through the
infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm),
near-IR (700 to 2500 nm or 14,286 to 4000 cm.sup.-1), and infrared
(2500 to 14,285 nm or 4000 to 700 cm.sup.-1)]. A particular range
for noninvasive glucose determination in diffuse reflectance mode
is about 1100 to 2500 nm or ranges therein (Hazen, Kevin H.
"Glucose Determination in Biological Matrices Using Near-Infrared
Spectroscopy", doctoral dissertation, University of Iowa, 1995). It
is important to note, that these techniques are distinct from
invasive techniques in that the sample analyzed is a portion of the
human body in-situ, not a biological sample acquired from the human
body. The actual tissue volume that is sampled is the portion of
irradiated tissue from which light is diffusely reflected,
transflected, or diffusely transmitted to the spectrometer
detection system. These techniques share the common characteristic
that a calibration is required to derive a glucose concentration
from subsequent collected data.
[0051] A number of spectrometer configurations exist for collecting
noninvasive spectra of regions of the body. Typically a
spectrometer has one or more beam paths from a source to a
detector. A light source may include a blackbody source, a
tungsten-halogen source, one or more LED's, or one or more laser
diodes. For multi-wavelength spectrometers a wavelength selection
device may be used or a series of optical filters may be used for
wavelength selection. Wavelength selection devices include
dispersive elements such as one or more plane, concave, ruled, or
holographic grating. Additional wavelength selective devices
include an interferometer, successive illumination of the elements
of an LED array, prisms, and wavelength selective filters. However,
variation of the source such as varying which LED or diode is
firing may be used. Detectors may be in the form of one or more
single element detectors or one or more arrays or bundles of
detectors. Detectors may include InGaAs, extended InGaAs, PbS,
PbSe, Si, MCT, or the like. Detectors may further include arrays of
InGaAs, extended InGaAs, PbS, PbSe, Si, MCT, or the like. Light
collection optics such as fiber optics, lenses, and mirrors are
commonly used in various configurations within a spectrometer to
direct light from the source to the detector by way of a sample.
The mode of operation may be diffuse transmission, diffuse
reflectance, or transflectance. Due to changes in performance of
the overall spectrometer, reference wavelength standards are often
scanned. Typically, a wavelength standard is collected immediately
before or after the interrogation of the tissue or at the beginning
of the day, but may occur at times far removed such as when the
spectrometer was originally manufactured. A typical reference
wavelength standard would be polystyrene or a rare earth oxide such
as holmium, erbium, or dysprosium oxide. Many additional materials
exist that have stable and sharp spectral features that may be used
as a reference standard.
[0052] The interface of the glucose analyzer to the tissue includes
a module where light such as near-infrared radiation is directed to
and from the tissue either directly or through a light pipe,
fiber-optics, a lens system, or a light directing mirror system.
The area of the tissue surface to which near-infrared radiation is
applied and the area of the tissue surface the returning
near-infrared radiation is detected from are different and
separated by a defined distance and selected to target a tissue
volume conducive for the measurement of the property of interest.
The patient interface module may include an elbow rest, a wrist
rest, a hand support, and/or a guide to assist in interfacing the
illumination mechanism of choice and the tissue of interest.
Generally, an optical coupling fluid is placed on the sampling
surface to increase incident photon penetration into the skin and
to minimize specular reflectance from the surface of the skin.
Important parameters in the interface include temperature and
pressure.
[0053] The sample site is the specific tissue of the subject that
is irradiated by the spectrometer system and the surface or point
on the subject the measurement probe comes into contact with. The
ideal qualities of the sample site include homogeneity,
immutability, and accessibility to the target analyte. Several
measurement sites may be used, including the abdomen, upper arm,
thigh, hand (palm or back of the hand), ear lobe, finger, the volar
aspect of the forearm, or the dorsal part of the forearm.
[0054] In addition, while the measurement can be made in either
diffuse reflectance or diffuse transmittance mode, the preferred
method is diffuse reflectance. The scanning of the tissue can be
done continuously when pulsation effects do not affect the tissue
area being tested, or the scanning can be done intermittently
between pulses.
[0055] The collected signal (near-infrared radiation in this case)
is converted to a voltage and sampled through an analog-to-digital
converter for analysis on a microprocessor based system and the
result displayed.
Preprocessing
[0056] Several approaches exist that employ diverse preprocessing
methods to remove spectral variation related to the sample and
instrumental variation including normalization, smoothing,
derivatives, multiplicative signal correction (Geladi, P., D.
McDougall and H. Martens. "Linearization and Scatter-Correction for
Near-Infrared Reflectance Spectra of Meat," Applied Spectroscopy,
vol. 39, pp. 491-500, 1985), standard normal variate transformation
(R. J. Barnes, M. S. Dhanoa, and S. Lister, Applied Spectroscopy,
43, pp. 772-777, 1989), piecewise multiplicative scatter correction
(T. Isaksson and B. R. Kowalski, Applied Spectroscopy, 47, pp.
702-709, 1993), extended multiplicative signal correction (H.
Martens and E. Stark, J. Pharm Biomed Anal, 9, pp. 625-635, 1991),
pathlength correction with chemical modeling and optimized scaling
("GlucoWatch Automatic Glucose Biographer and AutoSensors", Cygnus
Inc., Document #1992-00, Rev. March 2001), and FIR filtering (Sum,
S. T., "Spectral Signal Correction for Multivariate Calibration,"
Doctoral Dissertation, University of Delaware, Summer 1998; Sum, S.
and S. D. Brown, "Standardization of Fiber-Optic Probes for
Near-Infrared Multivariate Calibrations," Applied Spectroscopy,
Vol. 52, No. 6, pp. 869-877, 1998; and T. B. Blank, S. T. Sum, S.
D. Brown and S. L. Monfre, "Transfer of near-infrared multivariate
calibrations without standards," Analytical Chemistry, 68, pp.
2987-2995, 1996). In addition, a diversity of signal, data or
pre-processing techniques are commonly reported with the
fundamental goal of enhancing accessibility of the net analyte
signal (Massart, D. L., B. G. M. Vandeginste, S. N. Deming, Y.
Michotte and L. Kaufman, Chemometrics: a textbook, New York:
Elsevier Science Publishing Company, Inc., 215-252, 1990;
Oppenheim, Alan V. and R. W. Schafer, Digital Signal Processing,
Englewood Cliffs, N.J.: Prentice Hall, 1975, pp. 195-271; Otto, M.,
Chemometrics, Weinheim: Wiley-VCH, 51-78, 1999; Beebe, K. R., R. J.
Pell and M. B. Seasholtz, Chemometrics A Practical Guide, New York:
John Wiley & Sons, Inc., 26-55, 1998; M. A. Sharaf, D. L.
Illman and B. R. Kowalski, Chemometrics, New York: John Wiley &
Sons, Inc., 86-112, 1996; and Savitzky, A. and M. J. E. Golay.
"Smoothing and Differentiation of Data by Simplified Least Squares
Procedures," Anal. Chem., vol. 36, no. 8, pp. 1627-1639, 1964). The
goal of all of these techniques is to attenuate the noise and
instrumental variation without affecting the signal of
interest.
[0057] While methods for preprocessing effectively compensate for
variation related to instrument and physical changes in the sample
and enhance the net analyte signal in the presence of noise and
interference, they are often inadequate for compensating for the
sources of tissue related variation. For example, the highly
nonlinear effects related sampling different tissue locations can't
be effectively compensated for through a pathlength correction
because the sample is multi-layered and heterogeneous. In addition,
fundamental assumptions inherent in these methods, such as the
constancy of multiplicative and additive effects across the
spectral range and homoscadasticity of noise are violated in the
non-invasive tissue application.
Near-IR Calibration
[0058] One noninvasive technology, near-infrared spectroscopy, has
been heavily researched for its application for both frequent and
painless noninvasive measurement of glucose. This approach involves
the illumination of a spot on the body with near-infrared (NIR)
electromagnetic radiation, light in the wavelength range of 700 to
2500 nm. The light is partially absorbed and scattered, according
to its interaction with the constituents of the tissue. With
near-infrared spectroscopy, a mathematical relationship between an
in-vivo near-infrared measurement and the actual blood glucose
value needs to be developed. This is achieved through the
collection of in-vivo NIR measurements with corresponding blood
glucose values that have been obtained directly through the use of
measurement tools such as the YSI, HemoCue, or any appropriate and
accurate traditional invasive or alternative invasive reference
device.
[0059] For spectrophotometric based analyzers, there are several
univariate and multivariate methods that can be used to develop
this mathematical relationship. However, the basic equation which
is being solved is known as the Beer-Lambert Law. This law states
that the strength of an absorbance/reflectance measurement is
proportional to the concentration of the analyte which is being
measured as in equation 3, A=.epsilon.bC eq. 3 where A is the
absorbance/reflectance measurement at a given wavelength of light,
.epsilon. is the molar absorptivity associated with the molecule of
interest at the same given wavelength, b is the distance (or
pathlength) that the light travels, and C is the concentration of
the molecule of interest (glucose).
[0060] Chemometric calibration techniques extract the glucose
related signal from the measured spectrum through various methods
of signal processing and calibration including one or more
mathematical models. The models are developed through the process
of calibration on the basis of an exemplary set of spectral
measurements known as the calibration set and an associated set of
reference blood glucose values based upon an analysis of fingertip
capillary blood, venous, or alternative site samples. Common
multivariate approaches requiring a set of exemplary reference
glucose concentrations and an associated sample spectrum include
partial least squares (PLS) and principal component regression
(PCR). Many additional forms of calibration are well known in the
art such as neural networks.
[0061] Because every method has error, it is beneficial that the
primary device, which is used to measure blood glucose be as
accurate as possible to minimize the error that propagates through
the mathematical relationship which is developed. While it appears
intuitive that any U.S. FDA approved blood glucose monitor could be
used, for accurate verification of the secondary method a monitor
which has an accuracy of less than 5% is desirable. Meters with
increased error such as 10% are acceptable, though the error of the
device being calibrated may increase.
[0062] Currently, no device using near-infrared spectroscopy for
the noninvasive measurement of glucose has been approved for use by
persons with diabetes due to technology limitations that include
poor sensitivity, sampling problems, time lag, calibration bias,
long-term reproducibility, stability, and instrument noise.
Fundamentally, however, accurate noninvasive estimation of blood
glucose is presently limited by the available near-infrared
technology, the trace concentration of glucose relative to other
constituents, and the dynamic nature of the skin and living tissue
of the patient. Further limitations to commercialization include a
poor form factor (large size, heavy weight, and no or poor
portability) and usability. For example, existing near-infrared
technology is limited to larger devices that do not provide
(nearly) continuous or automated measurement of glucose and are
difficult for consumers to operate.
[0063] Clearly, a need exists for a completely noninvasive approach
to the measurement of glucose that provides a nearly continuous
readings in an automated fashion.
SUMMARY OF THE INVENTION
[0064] The invention involves the monitoring of a biological
parameter through a compact analyzer. The preferred apparatus is a
spectrometer based system that is attached continuously or
semi-continuously to a human subject and collects spectral
measurements that are used to determine a biological parameter in
the sampled tissue. The preferred target analyte is glucose. The
preferred analyzer is a near-IR based glucose analyzer for
determining the glucose concentration in the body.
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] FIG. 1 shows a sampling module, a communication bundle and a
base module;
[0066] FIG. 2 shows a preferred embodiment with a grating and
detector array;
[0067] FIG. 3 shows a preferred embodiment of the sampling
module;
[0068] FIG. 4 shows a low profile embodiment of the sampling
module;
[0069] FIG. 5 shows a single filter embodiment of the sampling
module;
[0070] FIG. 6 shows an alternative embodiment of the sampling
module;
[0071] FIG. 7 shows noninvasive glucose predictions in a
concentration correlation plot;
[0072] FIG. 8 shows an LED based embodiment of the sampling
module;
[0073] FIG. 9 shows a possible LED reflector; and
[0074] FIG. 10 shows filter shapes optionally coupled to the
LED.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
[0075] The presently preferred embodiment of the invention uses a
sampling module coupled to a base module. The sampling module
includes an illumination system based upon an incandescent lamp.
The base module includes a grating and detector array. The base
module may be connected to the sampling module through a
communication bundle. In this document, the combined sampling
module, communication bundle, base module, and associated
electronics and software is referred to as a spectrometer and/or
glucose analyzer. In FIG. 1, the sampling module 10 is
semi-permanently attached to the forearm of a subject 12, a
communication bundle 14 carries optical and/or electrical signal to
and/or from a base module 16 located on a table, and the
communication bundle carries power to the sampling module from the
base module.
[0076] A block diagram of the noninvasive glucose analyzer is
provided in FIG. 2. Essential elements of the glucose analyzer are
the source 21, guiding optics 14 before and/or after the sample for
coupling the source to the sample and the sample to the detector(s)
23, detector(s) and associated electronics 24, and data processing
system 25. In FIG. 2, an optional optical filter 30, light blocker
31, and standardization material 32 are shown. These components may
also be positioned after the sample and before the detector.
Variations of this simple block diagram are readily appreciated and
understood by those skilled in the art.
[0077] The sampling module, base module, and communication bundle
are further described herein. Key features of the invention may
include but are not limited to:
[0078] a semi-permanent patient/instrument interface sampling
module 10 incorporating at least one of a low profile sampling
interface 34, a low wattage stabilized source 21 in close proximity
to the sampled site, an excitation collection cavity or optics, a
guide, a preheated interfacing solution such as fluorinert, a
temperature controlled skin sample, a mechanism for constant
pressure and/or displacement of the sampled skin tissue, a photonic
stimulation source, and collection optics or fiber.
[0079] In the preferred embodiment the sampling module protrudes
less than two centimeters from the skin measurement site. The
sampling module may interface with a guide that may be
semi-permanently attached to a sampling location on a human body.
The guide aids in continuously and/or periodically physically and
optically coupling the sampling module to the tissue measurement
site in a repeatable manner with minimal disturbance. In addition,
the guide in combination with the sampling module is responsible
for pretreatment of the sample site for providing appropriate
contact of the sampling device to the skin for the purpose of
reducing specular reflectance, approaching and maintaining
appropriate skin temperature variation, and inducing skin hydration
changes. The sampling module preferably collects a diffusely
reflected or transflected signal from the sampled region of
skin.
[0080] In the preferred embodiment, the base module or semi-remote
system includes at least a wavelength selection device such as a
grating 35 and a detector preferably a detector array with an
optional wavelength reference standard 36 such as polystyrene and
an optional intensity reference standard such as a 99% reflective
Labsphere.RTM. disk. The remote system is coupled to the sampling
module via a communication bundle 14 that carries as least the
optical signal and optionally power. Additionally, the
communication bundle may transmit control and monitoring signal
between the sampling module and the remote system. The remote
system has at least one of an embedded computer 25, a display 37,
and an interface to an external computer system. The remote system
may be in close proximity to the guide element.
[0081] In one version of the invention, the sampling module and
base module are integrated together into a compact handheld unit.
The communication bundle is integrated between the two systems.
[0082] One version of the sampling module of the invention is
presented in FIG. 3. The housing 301 is made of silicon. The lamp
302 is a 0.8 W tungsten halogen source (Welch-Allyn 01270) coupled
to a reflector 303. A photodiode 309 is used to monitor the lamp
and to keep its output stable through the use of a lamp output
control circuit, especially right after power-up. The reflector,
and hence the incident light, is centered on an angle six degrees
off of the skin's normal to allow room for a collection fiber. The
light is focused through a 1 mm thick silicon window 306 onto an
aperture at the skin. The silicon operates as a longpass filter.
The illuminated aperture of the skin has a 2.4 mm diameter.
Positioning onto a sampling site is performed through a guide. The
patient sampling module reversibly couples into the guide for
reproducible contact pressure and sampling location. Magnets 312
are used in the guide to aid in the positioning of the probe, to
ensure proper penetration of the probe into the guide aperture and
to enable a constant pressure and/or displacement interface of the
sampled skin 308. The reversible nature of coupling the sampling
module into the guide allows the sampling module to be removed and
coupled to an intensity reference and/or a wavelength reference
that have the same guide interface and are preferably housed with
the base module. The preferred intensity reference is a 99%
reflective Labsphere.RTM. material and the preferred wavelength
reference is polystyrene. The preferred sampling module uses a
heater 309 for maintaining the skin at a constant temperature. A
600 .mu.m detection fiber 310 collects diffusely reflected light
from the center of the silicon window. The detection fiber is
coated in a manner to block source photons from penetrating through
the cladding to the core. For example a metal sheath may be placed
around the detection fiber. In this configuration, the length of
the detection fiber is 0.7 meters. The communication bundle
includes a power supply from the base unit. A blocking mechanism
may be included to allow the detection of detector dark current or
baseline. The base module incorporating a grating, detected array,
associated electronics, and associated software is coupled to the
sampling module via this bundle. In this configuration, the
sampling module extends roughly three inches from the arm.
[0083] It should be appreciated that in the preferred embodiment,
many of the components are optional and/or variable. Some specific
variations are described in this section. It is recognized that the
components or properties discussed in this section may be varied or
in some cases eliminated without altering the scope and intent of
the invention.
[0084] In the preferred embodiment, the base module resides on a
table, the sampling module interfaces through a semi-permanently
attached guide to the dorsal aspect of the forearm, and a
communication bundle carries power and optical signal between the
two modules. Alternatively, the base module may be worn on the
person, for example on a belt. The sampling module could couple to
any of a hand, finger, palmar region, base of thumb, forearm, volar
aspect of the forearm, dorsal aspect of the forearm, upper arm,
head, earlobe, eye, tongue, chest, torso, abdominal region, thigh,
calf, foot, plantar region, and toe. When the base module is on the
table, it may plug into a standard wall outlet for power. When worn
on the person, the module may be battery powered. When the base
module is worn on the person, an optional docking station may be
provided as described below for power and data analysis. It is
noted here that the base module may couple directly to the sampling
module without a communication bundle. The combined base module and
sampling module may be integrated into a handheld near-IR based
glucose analyzer that couples to the sampling site through an
optional guide.
Sampling Module
[0085] The sampling module housing in the preferred embodiment was
selected to be constructed of silicon based upon a number of
factors including but not limited to: providing a minimum of 6 O.D.
blocking in the ultraviolet, visible, and near-IR from 700 to 1000
nm at a 1 mm thickness, low cost, manufacturability, durability,
water resistance, and availability. It is recognized that it is the
functionality of the housing that is important and that the above
listed properties may be obtained through a variety of materials
such as metals, composites, and plastics without altering the scope
and intent of the invention.
[0086] The 0.8 W tungsten halogen source is preferred for a number
of reasons including but not limited to its power requirements,
performance specifications such as color temperature, spectral
output, and lifetime as well as on parameters such as ruggedness,
portability, cost, and size. It is recognized that the source power
is selected based upon the total net analyte signal generated and
the amount of light reaching the detection system. It has been
determined that the 0.8 W source in conjunction with the aperture
and collection fiber of the preferred embodiment provides adequate
signal and depth of penetration of the photons for the indirect
determination of glucose using features in the 1150 to 1850 nm
range. However, sources ranging from 0.05 W to 5 W may be used in
this invention. As described in the alternative embodiment section,
light emitting diodes (LED's) may be used as the source. The source
is preferably powered by the base module through the connection
cable described below. However, especially with the smaller sources
a battery power supply may be incorporated into the sampling
module.
[0087] A photodiode is used in the preferred embodiment in
conjunction with feedback control electronics to maintain the
source at constant power output during data collection which is
desirable during data acquisition. The photodiode is placed before
the order sorter (the silicon longpass filter), in order to detect
visible light from the source. The preferred photodiode is a
silicon detector. Other less desirable photodiodes include but are
not limited to InGaAs, InPGaAs, PbS, and PbSe. This arrangement of
components is preferred due to the low cost, durability, and
availability of detectors available in the visible and near-IR from
700 to 1000 nm where the long pass filter discussed below used
later in the optical train blocks the optical signal used in the
feedback loop. The control electronics allow the source to be
driven at different levels at different points in time during and
prior to data acquisition. In the preferred embodiment, the source
is initially run at a higher power in order to minimize the
analyzer warm-up time. The photodiode and feedback electronics are
optional, but are used in the preferred embodiment. Many
spectrometers are common in the art that do not use a separate
detector for monitoring the source intensity.
[0088] The source housing/reflector combination in the preferred
embodiment was selected based upon a number of factors including
but not limited to: providing acceptable energy delivery to the
sample site, reflectivity, manufacturability, ruggedness, size,
cost, and providing appropriate heating/temperature control of the
sample site. The specific reflector in the preferred embodiment is
parabolic. The properties were optimized using standard ray trace
software to image the lamp filament onto the aperture defining the
sampling location. The optical prescription is tuned for a specific
spectral range (1100 to 1900 nm) and the coatings are designed to
reflect optimally in this range. It is recognized that the
reflector may be elliptical or even spherical and that the
mechanical and optical properties of the reflector may be varied
without altering the scope and intent of the invention. For
example, in the simplest embodiment the source may shine light
directly onto the sampled surface without the use of a reflector.
In such cases, in order to deliver similar energy to the sampled
skin through the aperture, a larger source is required. In another
example, the specific focal distance of the reflector may be
varied, which impacts the overall dimensions of the interface
without affecting functionality. Similarly, a different substrate
may be used as the reflector or metallized coatings such as gold,
silver, and aluminum may be applied to the substrate.
[0089] The source/housing reflector in the preferred embodiment may
be modified to bring in the source light nearly parallel to the
skin surface. One objective of a low profile design is to maintain
a sampling module that may be semi-permanently attached to the
sampling site. A low profile sampling module has the benefit of
increase acceptance by the consumer and is less susceptible to
bumping or jarring during normal wear. A semi-permanent interface
would allow consecutive glucose determinations in an automated
continuous or semi-continuous fashion as described below. Light
brought in at a low angle relative to the skin may be turned into
the skin with folding optics. A simple mirror may be used; however,
a focusing mirror is preferred in order to optimally couple light
into the aperture. A representative embodiment is provided in FIG.
4.
[0090] One feature that may be used in this embodiment and in the
other embodiments is the use of quick connect optics. In this case
a 600 .mu.m fiber 40 is used as the collection optic. The 600 .mu.m
fiber is fixed into the sampling module 41. The sampling module has
a connector for accepting a 300 .mu.m fiber 42 that in turn couples
to a slit prior to the grating in the base module. The coupling of
the light may be done by lenses, which may be magnifying or
de-magnifying or with folding mirrors 44 with appropriate attention
to matching numerical apertures. An important concept in this
design is that the second collection optic is readily removed from
the sampling module allowing the sampling module to remain in
contact with the arm. In addition, the quick connect optic allows
the user to travel remotely from the base module until the next
reading is desired.
[0091] Locating the source and reflector housing near the skin
allows for temperature control/warm-up of the skin. The optical
source is a heat source. Skin temperature is an important variable
in near-IR noninvasive glucose determination. A thermistor 45
sensing the sampling module or patient skin temperature and feeding
this information back to the source via feedback electronics prior
to sampling may be used prior spectral data acquisition in order
elevate the skin temperature to a desirable sampling range such as
30 to 40 degrees centigrade. The inclusion of a heater, thermistor,
and associated feedback electronics are optional to this invention.
In another embodiment, the skin temperature may be measured
spectrally by the relative positions of water, fat, and protein in
an acquired near-IR spectrum or through a multivariate
analysis.
[0092] In the preferred embodiment, an optical filter is placed
between the source and the sampling site. In the preferred
embodiment, the optical filter is silicon. The silicon window was
selected based upon a number of factors. One factor is that silicon
behaves as a longpass filter with blocking to at least six optical
density units with a 1 mm thickness from the ultraviolet through
the visible to 1000 nm. Second, the longpass characteristic of
silicon acts as an order sorter benefiting the grating detector
combination in the base module. Third, longpass characteristics of
silicon removes unwanted photons in the ultraviolet, visible, and
near-IR that would heat the skin at unwanted depths and to
undesirable temperatures due to conversion of the light into heat
via the process of absorbance. Instead, the silicon is heated by
these photons resulting in maintenance of skin temperature near the
surface via conduction. Fourth, silicon offers excellent
transmissive features in the near-IR over the spectral region of
interest of 1150 to 1850 nm. Notably, silicon is the same material
as the source housing and source reflector. Therefore, a single
molding or part may be used for all three components. In the
preferred embodiment, a silicon window is in contact with the skin
to minimize specular reflectance. In the preferred embodiment, this
window is anti-reflection coated based upon properties of air on
the photon incident side and based upon the optical properties of
the coupling fluid on the skin surface side of the optic.
[0093] Many configurations exist in which the longpass filter is
not in direct contact with the skin. First, the longpass filter may
be placed after the source but not in contact with the skin. For
example, the filter may be placed in or about the pupil plane. In
this configuration, photons removed by the filter that result in
the heating of the filter do not result in direct heating of the
sample site via conduction. Rather, the much slower and less
efficient convection process conveys this heat. This reduces the
risk of over heating the skin. Alternatively, two filters may be
placed between the source and the skin. These filters may or may
not be the same. The first filter removes heat as above. The second
filter reduces spectral reflectance as above. In a third
configuration, the order sorter nature of the longpass filter is
central. Silicon removes light under 1050 nm. This allows a grating
to be used in the 1150 to 1850 nm region without the detection of
second or higher order light off of the grating as long as the
longpass filter, silicon, is placed before the grating. Therefore,
in the third configuration the longpass filter may be after the
sample.
[0094] It is recognized that many filter designs exist. In the
preferred embodiment a silicon longpass filter is used. The filters
may be coated to block particular regions such as 1900 to 2500 nm,
antireflection-coated in order to match refractive indices and
increase light throughput, and/or used in combination with other
filters such as shortpass filters. One configuration coats the
silicon with a blocker from 1900 to 2500 nm. This has the advantage
of removing the largest intensity of the blackbody curve of a
typical tungsten halogen source that is not blocked by silicon or
in the desirable region of 1150 to 1850 nm. This blocking band may
cover any region from about 1800 nm on up to 3000 nm. Another
configuration is a silicon longpass filter used in combination with
an RG glass such as RG-850 that cuts off at about 2500 nm. The
combination provides a very cost effective and readily reproduced
bandpass filter passing light from approximately 1100 to 2500 nm.
Notably this filter combination may be used in conjunction with a
coating layer such as a blocker from 1900 to 2500 nm in order to
provide a bandpass from 1100 to 1900 nm. Those skilled in the art
will recognize that there exist multiple configurations of off the
shelf and customized longpass, shortpass, and bandpass filter that
may be placed in one or more of the locations described above that
fulfill the utility requirements described above. An alternative
embodiment of the source/reflector/filter is shown in FIG. 5. In
this embodiment, silicon is shaped into a parabolic optic 50
surrounding part of the source 51. The outside of the silicon is
coated with a reflector 52 such as gold. This embodiment allows a
low profile source coupled to the skin. The total height off of the
skin may be less than 1 cm with this configuration. The shape of
the silicon optic in conjunction with coating the outside of the
silicon with a reflective material such as gold allows efficient
coupling of the photons into the skin. An additional optional
protective coating over the reflector material allows the silicon
optic to also act as a housing for the sampling module with the
benefits of silicon listed above. Notably, the initial surface of
the silicon (near the source) removes the higher energy photons
that results in heating of the source optics prior to contact with
the skin. The later part of the silicon (near the skin) in
combination with a collection fiber acts as a mechanism for
reducing specular reflectance. This configuration eliminates the
optional two filter system as heat and spectral reflectance are
dealt with in one optic. Essentially, the silicon is acting as a
turning optic to allow a very low profile sampling module, as a
longpass filter, as an order sorter, as a heat blocker, as a
spectral reflectance blocker, and as a very manufacturable, cheap,
and durable component.
[0095] An alternative embodiment of the source/reflector/filter is
shown in FIG. 6. In this embodiment, the source filament 60 is
wrapped around a collection fiber 61. The reflector now directs
light into the skin aperture through an optic 62. The optic may be
surface coated for reflectance on the incident light surface.
Alternatively, as above, the reflector may be transmissive and the
outer surface of the reflector may be reflectively coated. As
above, this allow the reflector to act as the housing. In this
embodiment, there exists a filter adjacent to the skin that in
conjunction with a collection optic, fiber, or tube adjacent to the
skin results in the blocking of specular reflectance.
[0096] An alternative embodiment combines a broadband source with a
single element detector without the use of a grating. In one case,
an interferometer composed of two parallel, highly reflecting
plates separated by an air gap may be used. One of the parallel
plates may be translated mechanically such that the distance
between the plates varies. Technically, this is a Fabry-Perot
interferometer. When the mirror distance is fixed and adjusted for
parallelism by a spacer such as invar or quartz, the system is
referred to as a Fabry-Perot etalon. This system allows narrow
excitation lines as a function of time. Therefore, no dispersive
element is required and a single element detector may be used. The
interferometer may be placed in one of multiple positions in the
optical train.
[0097] In the preferred embodiment, the illuminated aperture of the
skin has a 2.4 mm diameter. The aperture in the preferred
embodiment was selected based upon a number of factors including
but not limited to: providing optical pathlengths within the sample
for indirectly monitoring glucose concentrations within the body,
providing acceptable energy delivery to the sample site, and
providing appropriate heating/temperature control of the sample
site. As discussed below, a fiber optic collection fiber is placed
in the center of this illumination area. This allows the incident
photon approximately 1 mm of radial travel from the point of
illumination to the collection fiber. This translates into depths
of penetration that probe water, fat, and protein bands as well as
scattering effects that may be used for the indirect determination
of glucose. It is recognized that the dimensions of the aperture
need not be the exact dimensions of the preferred embodiment. An
important aspect is the ability to deliver photons to a skin
tissue, allow them to penetrate to depths that allow an indirect
measurement of glucose, and detect those photons.
[0098] It is recognized that these properties may be varied without
altering the scope and intent of the invention. For example, the
aperture of 2.4 mm may be varied. The aperture provides an outer
limit of where photons from the source may penetrate the skin. This
in turn defines the largest depth of penetration and optical
pathlengths observed. While the aperture may be varied from 1.2 to
5 mm in diameter, the 2.4 mm diameter allows collection of spectra
with excellent features for the indirect measurement of glucose. At
smaller apertures, the average depth of penetration of the
collected photons decreases. Therefore, variation of the aperture
affects the net analyte signal of the sampled tissue. Varying
aperture shapes are possible as the shape affects the distribution
of photons penetration depth and optical pathlength. The indirect
determination of glucose may be performed off of sample
constituents such as fat, protein, and water that are distributed
as a function of depth. Therefore, the magnitude of the indirect
signal varies with the aperture. In addition, multiple excitation
sites and collection sites are possible. This could aid, for
example, in sampling a representative section of the skin. For
example, if one probe was located on a hair follicle, the others
may be used independently or in conjunction with the first site in
order to acquire the analytical signal necessary to determine
glucose.
Guide
[0099] In the preferred embodiment, the entire PIM couples into a
guide that is semi-permanently attached to the skin with a
replaceable adhesive. The guide aids in sampling repeatability. The
guide is intended to surround interfacing optics for the purpose of
sampling in a precise location. Typically this is done with an
interface surrounding the interface probe. In the main embodiment,
the guide is attached for the waking hours of the subject. A guide
may be attached in a more permanent fashion such as for a week or a
month, especially in continuous monitoring glucose analyzers
discussed below. The guide allows improved precision in sampling
location. Precision in sampling location allows bias to be removed
if a process such as mean centering is used in the algorithm. This
is addressed in the preprocessing section below. Additionally, the
guide allows for a more constant pressure/constant displacement to
be applied to the sampling location which also enhances precision
and accuracy of the glucose determination. While the guide greatly
enhances positioning and allows associated data processing to be
simpler and more robust, the guide is not an absolute requirement
of the sampling module.
[0100] In the preferred embodiment of the invention, magnets are
used to aid in a user friendly mechanism for coupling the sampling
module to the sampled site. Further, the magnets allow the guide to
be reversibly attached to the sampling module. Further, the guide
aids in the optical probe adequately penetrating into the guide
aperture. In addition, the magnets allow a constant, known, and
precise alignment between the sampling probe and the sampled site.
In the preferred embodiment two magnets are used, one on each side
of the sampled site, in order to enhance alignment. One or more
magnets may provide the same effect. It is recognized that there
exist a large number of mechanical methods for coupling two devices
together, such as lock and key mechanisms, electro-magnets,
machined fits, VELCRO, adhesives, snaps, and many other techniques
commonly known to those skilled in the art that allow the key
elements described above to be provided. In addition, the magnets
may be electrically activated to facilitate a controlled movement
of the probe into the guide aperture and to allow, through reversal
of the magnet poles, the probe to be withdrawn from the guide
without pulling on the guide.
[0101] The guide may optionally contain a window in the aperture
that may be the longpass/bandpass filter. Alternatively, the
aperture may be filled with a removable plug. The contact of a
window or plug with the skin stabilizes the tissue by providing the
same tissue displacement as the probe and increases the localized
skin surface and shallow depth hydration. As opposed to the use of
a removable plug, use of a contact window allows a continuous
barrier for proper hydration of the sampling site and a constant
pressure interface. The use of a plug or contact window leads to
increased precision and accuracy in glucose determination by the
removal of issues associated with dry or pocketed skin at the
sampling site.
[0102] The guide may optionally contain any of a number of elements
designed to enhance equilibration between the glucose concentration
at the sampling site and a capillary site, such as the fingertip.
Rapidly moving glucose values with time can lead to significant
discrepancies between alternate site blood glucose concentration
and blood glucose concentration in the finger. The concentration
differences are directly related to diffusion and perfusion that
combine to limit the rate of the equilibrium process. Equilibrium
between the two sites allows for the use of glucose-related signal
measured at an alternate site to be more accurate in predicting
finger blood glucose values.
[0103] A number of optional elements may be incorporated into the
sampling module and/or guide to increase sampling precision and to
increase the net analyte signal for the indirect glucose
determination. These optional elements are preferably powered
through the base module and connection cable described below but
may be battery operated. Equalization approaches include photonic
stimulation, ultrasound pretreatment, mechanical stimulation, and
heating. Notably, equilibration of the glucose concentration
between the sampled site and a well-perfused region such as an
artery or the capillary bed of the fingertip is not required. A
minimization of the difference in glucose concentration between the
two regionsl aids in subsequent glucose determination.
[0104] The guide may optionally contain an LED providing photonic
stimulation about 890 nm, which is known to induce capillary blood
vessel dilation. This technique may be used to aid in equilibration
of alternative site glucose concentrations with those of capillary
blood. By increasing the vessel dilation, and thereby the blood
flow rate to the alternate site, the limiting nature of mass
transfer rates and their effect on blood glucose differences in
tissue is minimized. The resulting effect is to reduce the
differences between the finger and the alternate site blood glucose
concentrations. The preferred embodiment uses (nominally) 890 nm
LED's in an array with control electronics set into the arm guide.
The LED's can also be used in a continuous monitoring application
where they are located in the probe sensing tip at the tissue
interface. Due to the periods of excitation required for
stimulation, the 890 nm LED is preferably powered by a rechargeable
battery in the guide so that the LED may be powered when the
communication bundle is not used.
[0105] The guide may optionally contain an apparatus capable of
delivering ultrasound energy into the sample site. Again, this
technique may be used to aid in equilibration of alternative site
glucose concentrations with those of capillary blood by stimulating
perfusion and/or blood flow.
[0106] The guide may optionally contain an apparatus that provides
mechanical stimulation of the sampled site prior to spectral data
acquisition. One example is a piezoelectric modulator than pulses
in an out relative to the skin surface a distance of circa 20 to 50
.mu.m in a continuous or duty cycle fashion.
[0107] The guide may optionally contain a heating and/or cooling
element, such as a strip heater or an energy transfer pad. Heating
is one mechanism of glucose compartment equilibration. These
elements may be used to match the core body temperature, to
manipulate the local perfusion of blood, to avoid sweating and/or
to modify the distribution of fluids among the various tissue
compartments.
[0108] It is recognized that the sampling module can interface
directly to a skin sampling without the use of a guide.
[0109] In the preferred embodiment of the invention, a coupling
fluid is used to efficiently couple the incident photons into the
tissue sample. The preferred coupling fluid is fluorinert.
Different formulations are available including FC-40 and FC-70.
FC-40 is preferred. While many coupling fluids are available for
matching refractive indices, fluorinert is preferred due to its
non-toxic nature when applied to skin and due to its absence of
near-IR absorbance bands that would act as interferences. In the
preferred embodiment, the coupling fluid is preheated to between 90
and 95.degree. F., preferably to 92.degree. F. Preheating the
coupling fluid minimizes changes to the surface temperature of the
contacted site, thus minimizing spectral changes observed from the
sampled tissue. The coupling fluid may be preheated using the
source energy, the optional sample site heater energy, or through
an auxiliary heat source. Preheating FC-70 is preferable due to its
poorer viscosity. The preheated FC-70 is not as likely to run off
of the sample site. Automated delivery prior to sampling is an
option. Such a system could be a gated reservoir of fluorinert in
the sample module. Manual delivery of the coupling fluid is also an
option, such as a spray bottle delivery system. Coverage of the
sample site is a key criteria in any delivery system.
[0110] In the preferred embodiment of the invention, the sampling
site is the dorsal aspect of the forearm. In addition, the volar
and ventral aspect of the forearm are excellent sampling locations.
It is further recognized that the guide may be attached to other
sampling locations such as the hand, fingertips, palmar region,
base of thumb, forearm, upper arm, head, earlobe, chest, torso,
abdominal region, thigh, calf, foot, plantar region, and toes. It
is preferable but not required to sample regions of the skin that
do not vary due to usage as with the fingertips or near joints,
change with time due to gravity like the back of the upper arm, or
have very thick skin such as the plantar region, or abdominal
region.
[0111] There are a number of possible configurations for collection
optics. In the preferred embodiment, light is incident to the
sample through the longpass filter which is in contact with the
skin. In the preferred embodiment, there exists a hole in the
middle of the longpass filter. A collection fiber is placed into
the hole in contact with the skin. This configuration forces
incident photons into the sampled skin prior to collection into the
fiber optic. If the fiber optic were merely pushed up against the
filter, then light could bounce through the filter directly into
the collection fiber without entering the skin resulting in a
spectral reflectance term. Once the collection fiber is in contact
with the skin, the signal (or rather absence of observed intensity)
at the large water absorbance bands near 1450, 1900, and 2500 nm
may be used to determine when the apparatus is in good spectral
contact with the sampled skin. The preferred collection optic is a
single 600 .mu.m detection fiber. It is recognized that the hole
and the fiber may be altered in dimension to couple in another
sized fiber such as a 300 .mu.m detection fiber. As those skilled
in the art will appreciate, the fiber diameter is most efficient
when it is optimally optically coupled to the detection system.
Therefore, as detector systems slits and detector element sizes are
varied, the collection optics should also be varied. The center
collection fiber of 600 .mu.m combined with the aperture of 2.4 mm
is related to a central fiber collecting incident light from a
bundle. The collection optic is not necessarily limited to a fiber
optic. Additional configurations include but are not limited to a
light pipe or a solid piece of optical glass.
[0112] In the preferred embodiment, the collected signal is turned
90.degree. off axis to send the signal roughly parallel to the arm
in order to minimize the height of the sampling module. This may be
accomplished by such common means as a folding mirror or bending of
a fiber optic, as described above.
[0113] In one embodiment, the collected light is coupled to a
second collection that connects at its opposite end to the base
module. The purpose of this configuration is to allow the sampling
module to be worn on the person without the bulk of the rest of the
spectrometer here referred to as the base module. A quick connect
connector is used to allow rapid connection of the base module to
the sampling module in a reproducible and user friendly fashion.
The connecting cable carries at least the optical signal. In the
preferred embodiment, the connection cable also carries power to
the source and optional elements, such as the thermistor, heater,
or sample compartment glucose concentration equilibration
apparatus. This connector also allows the diameter of the
collection fiber to be changed. For example, the 600 .mu.m
collection fiber may be downsized to a 300 .mu.m connection fiber
with appropriate attention to coupling optics and numerical
apertures obvious to those skilled in the art. Some advantages of
the smaller diameter connection fiber are described here. First,
the smaller diameter fiber has a tighter bend radius. Second, if a
slit is used prior to the spectrometer then the fiber can be made
of appropriate dimension for coupling to the slit. Third, the
smaller diameter fiber is less susceptible to breakage. An
additional consideration is cost.
[0114] It is recognized that collection/detection elements may be
recessed away from the window in order to avoid the direct
detection of surface reflectance. It is further recognized that
coupling fluids may be used to increase the angle of collection to
the detection element.
Base Module
[0115] In the preferred embodiment, the base module includes at
least a spectrometer (grating and detector system). The grating is
optimized to deliver peak energy about 1600 nm. The detector is an
InGaAs array covering the range of 1100 to 1900 nm. A main purpose
of the spectrometer is wavelength separation and detection.
Variations in the grating/detector system are readily understood by
those skilled in the art.
[0116] In an alternative embodiment, a broadband source is combined
with a detector array without the use of a dispersive element. In
one case, filters are placed in from the detectors. One type of
filter are thin dielectric films, such as in Fabry-Perot
interference filters. These filters may be placed into a linear,
bundle, or rectangular pattern depending upon how the light is
coupled to the detector. For example, a slit may be used in
conjunction with a rectangular array of filters and detectors.
Alternatively, a fiber may be used in conjunction with a bundle of
filters and associated detectors. Another type of filter is a
linear variable filter. For example, a linear variable filter may
sit in from of a linear array of filters. Many variations on these
optical layouts are known to those skilled in the art.
[0117] The Power/Control Module may be coupled to the user's belt
or other location other than the measurement site. In an alternate
embodiment the patient interface module contains a battery and
two-way wireless communication system. In this configuration the
Control/Power module may be carried by the patient. For example, a
handheld computer or Palm computing platform can be equipped with a
two-way wireless communication system for receiving data from the
patient interface module and sending instructions. The computer
system then provides the system with analysis capabilities.
[0118] In an alternate embodiment the base module contains a
battery and two-way wireless communication system. In this
configuration the Control/Power module is contained a remote
location that is either carried by the patient or not. For example,
a handheld computer or Palm computing platform can be equipped with
a two-way wireless communication system for receiving data from the
patient interface module and sending instructions. The computer
system then provides the system with analysis capabilities.
[0119] The Control/Power Module contains the control electronics,
power system, batteries, embedded computer and interface
electronics. Control electronics provide a means for initiating
events from the embedded or attached computer system and
interfacing the detector electronics (amplifiers) which provide a
voltage that is related to the detected light intensity. Digitizing
the detected voltage through the use of an analog-to-digital
converter is performed. The signals detected are used to form a
spectrum which is represents the diffusely reflected and detected
light intensity versus wavelength. In addition, historical
measurements are made available through a display and/or an
external communication port to a computer or computer system, e.g.
a Palmtop. In an alternate embodiment, the measurement and
ancillary information is transferred to a remote display and
receiving unit, such as a handheld computer or stand-alone display
module through a wireless communication. In this latter system, a
display and receiving unit may be incorporated into a watch, pen,
personal desktop assistance, cell phone, or blood glucose
monitoring device.
Spectrometer
[0120] It is here noted, that variation of one component may affect
optimal or preferred characteristics of other components. For
example, variation in the source may affect the quality or design
of the reflector, the thickness of the filter, the used aperture
size, the time or power requirements for maintaining or heating the
skin and/or fluorinert, and the diameter of the collection fiber.
Similarly, changing another component such as the collection fiber
diameter impacts the other elements. Those skilled in the art will
appreciate the interaction of these elements. Those skilled in the
art will also immediately appreciate that one or more components of
the spectrometer may be changed without altering the scope of the
invention.
[0121] Important regions to detect are permutations and
combinations of bands due to water centered about 1450, 1900, or
2600 nm, protein bands centered about 1180, 1280, 1690, 1730, 2170,
or 2285 nm, fat bands centered about 1210, 1675, 1715, 1760, 2130,
2250, or 2320 nm, or glucose bands centered about 1590, 1730, 2150,
and 2272 nm.
[0122] A preferred physical orientation of the spectrometer is in a
vertical position. For example, when sampling on the dorsal aspect
of the forearm when the palm is face down on a support it is
preferable for the sampling module to come down onto the arm from
above. This allows the weight of the sampling module to be
reproducible.
Standards
[0123] Near-infrared devices are composed of optical and mechanical
components that vary due to manufacturing tolerances, vary in
optical alignment, and change with time due to mechanical factors
such as wear and strain, and environmental factors such as
temperature variation. This results in changes in the x-axis of a
given spectrometer with time as well as instrument-to-instrument
variation. When a calibration model is used to extract information
about a sample, such as the glucose concentration in the body,
these instrument related changes result in wavelength uncertainty
that reduces the accessibility of the signal related to the
property of interest. These variations also degrades the device
accuracy when a calibration model is transferred from one
instrument to another.
[0124] A system for standardizing the wavelength axis of near-IR
optical systems that measures light at a multiplicity of
wavelengths is described in this section. The preferred embodiment
is that presented in FIG. 2. The system described in this section
may be used with the instrument configurations described in the
remainder of this document. The spectrometer system detects the
transmitted or reflected near-infrared radiation from the sample
within a specified wavelength range and the analyzer determines the
absorbance at various wavelengths after a standardization
procedure. Methods for standardizing the x-axis of a spectrometer
based system rely on a comparative analysis of a master and slave
spectra of a standardization material. A material with absorption
bands in the targeted wavelength region is used for determining the
x-axis. Typically, the reference or standard absorbance bands are
reasonably sharp, stable, and distributed across the wavelength
region of interest (1100 to 1900 nm). Common materials for this
purpose are polystyrene, erbium oxide, dysprosium oxide, and
holmium oxide though a large number of plastics may be used.
Internal polystyrene has been used as a reference in the FOSS,
formerly NIRSystems spectrometers. However, in these systems,
polystyrene is used in conjunction with an actuated rotating
grating and a single detector. In the preferred embodiment of this
invention no actuated grating is used.
[0125] The material used for standardization may be measured
external to the spectrometer system with an external mounting
system. However, the material mounted in a separate standard
mounting system external to the spectrometer must be placed on the
device by the user at designated time periods. This process is
subject to positioning error and increases the complexity of the
measurement protocol from the standpoint of the user. This is
particularly a problem in consumer oriented devices, such as
non-invasive glucose sensors, in which the user may not be
technically oriented.
[0126] Alternatively, the reference may be continuously mounted
internal to the instrument in a separate light path. In this
configuration, the internal wavelength standard may be measured
simultaneously with the sample. Alternatively, the reference may be
moved through an actuator into the main optical train at an
appropriate time, optionally in an automated process. In either of
these systems, the reference spectrum may be collected in
transmittance of reflectance mode. However, it is preferable to
collected an external reference in diffuse reflectance mode. For
example a polystyrene disk placed at an angle to the incident light
to minimize specular reflectance may be backed by a reflector such
as a Labsphere.RTM. reference. For an internal reference, a similar
arrangement may be used, but a transmittance spectrum is
preferred.
[0127] The wavelength standardization system includes associated
methods for measurement of a reference spectrum and a (wavelength)
standardization spectrum through the spectroscopic measurement of a
non-absorbing material and a material with known and immutable
spectral absorbance bands respectively. The spectrum of the
standardization material is used in-conjunction with an associated
method for standardizing the x-axis of sample spectra that are
collected subsequently. The method includes a master spectrum of
the standardization material and a method for determining the
discrepancy between the master and instrument standardization
spectrum. The master spectrum and the wavelength regions are stored
in nonvolatile memory of the instrument computer system. One method
of calculating the phase difference or x-axis shift between the
master and slave spectra is through the use of cross correlation.
For example, one or more windows across the spectrum the x-axis
phase shift between the master and acquired spectrum are determined
through a cross-correlation function after removing instrument
related baseline variations. The phase shift is used to correct
(standardize) the x-axis of the acquired spectrum to the master
spectrum. Other approaches include interpolation or wavelet
transformation.
Preprocessing
[0128] After conversion of the photons into intensity and
optionally absorbance units, preprocessing occurs. The detected
spectrum may be processed through multiple preprocessing steps
including outlier analysis, standardization, absorbance
calculation, filtering, correction, and application to a linear or
nonlinear model for generation of an estimate (measurement) of the
targeted analyte or constituent which is displayed to the user.
[0129] Of particular note is the preprocessing step of bias
correcting the spectral data collected in one or both of the X
(spectra) and Y (glucose concentration) data. In particular, the
first scan of a day may have a reference glucose concentration
associated with it. This glucose concentration may be used as a
bias correction for glucose determinations collected until
subsequent calibration. Similarly, the first spectrum of the day
may be used to adjust calibration components from the X block.
Notably, the guide allows the same sampling location to be obtained
until the guide is removed. This directly impacts the use of the
first spectrum and reference glucose concentration to adjust the
model in terms of preprocessing and subsequent model
application.
[0130] Additional preprocessing techniques are covered in the
introductory section. These techniques are well understood by those
skilled in the art.
Modeling
[0131] Subsequent data analysis may include a soft model or a
calibration such as PCR or PLS. Many other modes of data analysis
exist such as neural networks. A method has been invented for
calibrating the device to an individual or a group of individuals
based upon a calibration data set. The calibration data set is
comprised of paired data points of processed spectral measurements
and reference biological parameter values. For example, in the case
of glucose measurement, the reference values are one or more of the
following: finger capillary blood glucose, alternate site capillary
blood glucose, i.e. a site on the body other than the finger,
interstitial glucose or venous blood glucose. The calibration data
is subject to optimal sample selection to remove outliers, data
correlating to ancillary factors and data with excessive variation.
Spectral measurements are preprocessed prior to calibration through
filtering and scattering correction and normalized to a background
template collected each time the guide system is attached to the
skin tissue. Measurements are performed after preprocessing data
collected subsequent to calibration as discussed above through the
calibration or model to measure the variation of the biological
parameter relative to its value at the time the guide was attached.
The scope of these techniques was addressed in the prior art
section and are well known to those skilled in the art.
[0132] Results of a study using a noninvasive glucose analyzer are
presented here. The study used a custom built noninvasive near-IR
glucose analyzer. The analyzer is conceptually as presented in the
preferred embodiment with components including a tungsten halogen
source, a back-reflector, a bandpass optical filter, a fiber optic
illumination bundle, a guide, a fluorinert coupling fluid, a guide,
an aperture, a forearm sampling site, a collection fiber, a slit, a
dispersive grating, and an InGaAs array detector though the
spectrometer was larger in overall dimensions than in the preferred
embodiment. However, the miniaturized sampling module has been
demonstrated to deliver equivalent energy to the sample site. A
calibration model was built. A subsequent prediction data set was
initiated two weeks after all parameters were fixed in the
calibration model. Subsequent prediction data (spectra) were
collected with two spectrometers on seven people over a period of
seven weeks. Preprocessing included a Savitsky-Golay first
derivative with 27 points and mean centering. A PLS model was
applied with a fifteen factor model to the resulting data over a
range of 1200 to 1800 nm. A total of 976 glucose determinations
were made. The outlier analysis program was automated. The results
are presented in FIG. 7 in a concentration correlation plot
overlaid with a Clarke error grid. Overall, 99.9% of the glucose
predictions fell into the `A` or `B` region of the Clarke error
grid. These glucose predictions are considered clinically
accurate.
Docking Station
[0133] In the preferred embodiment, the base module is integrally
connected to the docking station. In addition to the grating,
detector assembly, and power supply, the docking station includes a
computer and a glucose management center. The glucose management
system may keep track of events occurring in time such as glucose
intake, insulin delivery, and determined glucose concentration.
These may be graphed with time or exported to exterior devices,
such as a doctor's computer.
[0134] A process is provided for estimating the precision of the
measurement through a statistical analysis of repeated or
successive measurements. A method is implemented for determining
when the biological parameter is close to a preset level through a
statistical estimate of the confidence limits of a future analyte
prediction. The prediction is made through a simple slope, e.g.
change in the biological parameter over the change in time,
estimate based on an exponentially moving average and the
confidence limits are based upon the estimate of precision.
Alternately, the prediction is made through a standard time series
analysis. An alarm is invoked if the associated present alarm level
is within the confidence interval of a future biological parameter
prediction. This process is used, for example, to detect the
potential for hypoglycemia in diabetics in the near future, e.g.
within 10-30 minutes. In addition, the process is used to detect
potential outliers through a determination of the statistical
consistency of a particular measurement with its expected
value.
Continuous/Semi-Continuous Glucose Determination
[0135] Continuous or semi-continuous measurements may be taken when
the sampling module is in contact with the sampling site.
Measurements of a biological parameter that are made at short
intervals relative to the change in the biological parameter such
that the measurement process is continuous. In the preferred
embodiment, measurements may be made every six seconds.
Realistically, the glucose concentration does not change to a
measurable level within six seconds. Therefore, readings taken at a
less frequent interval such as every 1, 5, 10, 20, 30, or 60
minutes can be made. Readings taken at this interval are still
referred to as continuous and/or semi-continuous. The continuous
readings may be performed in an automated fashion.
[0136] It is noted that when the biological parameter is slowly
varying, the guide can remain attached to the individual while the
rest of the system is intermittently attached at particular
intervals to make continuous or semi-continuous readings.
[0137] An element of the invention is the use of the time based
information and trends to perform other functions such as estimate
of the precision, confidence intervals and prediction of future
events.
[0138] A process is provided for estimating the precision of the
measurement through a statistical analysis of repeated or
successive measurements. A method is implemented for determining
when the biological parameter is close to a preset level through a
statistical estimate of the confidence limits of a future analyte
prediction. The prediction is made through a simple slope, e.g.
change in the biological parameter over the change in time,
estimate based on an exponentially moving average and the
confidence limits are based upon the estimate of precision.
Alternately, the prediction is made through a standard time series
analysis. An alarm is invoked if the associated present alarm level
is within the confidence interval of a future biological parameter
prediction. This process is used, for example, to detect the
potential for hypoglycemia in diabetics in the near future, e.g.
within 10-30 minutes. In addition, the process is used to detect
potential outliers through a determination of the statistical
consistency of a particular measurement with its expected
value.
[0139] In circumstances in which the Control/Power module can be
secured without disturbing the sample site the two modules are
merged into one that are attached to the subject through the guide
interface system. Finally, when the biological parameter is slowly
varying, the guide can remain attached to the individual while the
rest of the system is intermittently attached at particular
intervals.
[0140] A link is disclosed to an insulin delivery system. When the
monitored biological parameter is glucose, a link is provided to an
insulin delivery system to provide a feedback mechanism for control
purposes. The link is either a direct or a wireless connection. In
addition, a communication system is provided for transmitting the
patient's monitored glucose levels to his physician.
An Alternative Embodiments
[0141] As in the preferred embodiment, a primary alternative
embodiment of the invention includes two main modules: a sampling
module and base module connected though a communication bundle. The
modules are as described in the preferred embodiment with the
exception of the source and the associated wavelength
selection/detection components. In the alternative embodiment of
the invention, the spectrometer system uses LEDs to both provide
near-infrared radiation to the sample and to perform wavelength
selection over predefined wavelength ranges. This embodiment has
the significant advantage of not requiring a dispersive element or
interferometer based system for the purpose of wavelength
selection. Rather, each LED provides near-infrared radiation over a
band of wavelengths and thereby gives the necessary means for
wavelength selection.
[0142] The wavelengths of the LEDs are selected specifically to
optimize the signal-to-noise ratio of the net analyte signal of the
target analyte and are arranged at various distances with respect
to the detection elements to provide a means for sampling various
tissue volumes for the purpose of averaging and the determination
of a differential measurement. The LEDs are sequentially energized
one at a time and/or in groups to obtain various estimates of the
diffuse reflectance of various tissue volumes at specific
wavelengths or bands of wavelengths. In addition, the LEDs can be
pulsed to provide short measurements with high signal-to-noise
ratios. This provides greater illumination intensity, while
avoiding photo heating of the sampled tissue volume. Alternately,
the LEDs can be modulated at a particular duty cycle and frequency
to provide a means for removing additive noise and simultaneous
measurement of multiple wavelengths.
[0143] The wavelengths of the LED(s) are selected specifically to
optimize the signal-to-noise ratio of the net analyte signal of the
target biological parameter and are arranged at various distances
with respect to the detection elements to provide a means for
sampling various tissue volumes for the purpose of averaging and
the determination of a differential measurement. The LEDs are
sequentially energized one at a time and/or in groups to obtain
various estimates of the diffuse reflectance of various tissue
volumes. In addition, the LEDs can be pulsed to provided short
measurements with a high signal-to-noise ratio while avoiding photo
heating of the sampled tissue volume. Alternately, the LEDs can be
modulated at a particular duty cycle and frequency to provide a
means for removing additive noise and simultaneous measurement of
multiple wavelengths.
[0144] With an LED source, the remainder of the spectrometer
remains as in the preferred embodiment and its species. For
example, the LED's may be stabilized with control electronics,
optics may be used to guide the source intensity to the sampled
aperture, a guide may be used, a coupling fluid may be used,
temperature stabilization of the source and or sample may be used,
collection optics integrate with the sampled skin directly, a
communication bundle may be employed, and a base module is used
with or without a docking station. As in the preferred embodiment,
the detector may stare directly at the tissue.
Embodiments
[0145] A number of instrument configurations of the alternative
embodiment are presented below. Those skilled in the art will
recognize that permutations and combinations of these embodiments
are possible.
[0146] In the simplest embodiment, the LEDs may illuminate the
sample directly, as in FIG. 8. In FIG. 8, a coupling fluid 84, as
disclosed above, is shown provides between the device and the
tissue sample. An optional mixing chamber with a reflective surface
may be used between the LEDs 80 and the optical window 81 to
provide a nearly uniform distribution onto the tissue region 82
surrounding the detection fiber 83. A spacer 85 may also be
provided between the fiber and the LEDs. In this embodiment, the
LEDs are designed with a bandwidth enabling the measurement, and
the LEDs are arranged in a manner that allows the sampling and
detection of a particular tissue volume at a particular band of
wavelengths. Each LED may be recessed into a material 91 having a
reflective surface 90 as shown in FIG. 9.
[0147] In this scenario, two arrangements are used. First, a mixing
chamber is present as shown in FIG. 8 with the filter inserted in
the place of the optical window. This allows the LED's to be used
in much the same way as a broadband source.
[0148] Second, the illumination-to-detection distance may be used
for measurement purposes so the mixing chamber is removed and the
LEDs are put in close proximity or even touching the overall
sampling site via optional filters. In this second mode, the
distance from the illumination spot of the LED to the collection
optics is known. This allows the average depth of penetration of
the photons and average pathlength to be known. This allows
wavelength dependent scanning of depth and radial variation from
the collection spot, and allows wavelength specific information to
be used in an indirect reading of the glucose concentration.
[0149] In the preferred embodiment, groups of LEDs (FIG. 10; 100)
are employed with each group associated with a single filter type,
more than one physical filter may be necessary. The LEDs are
arranged at distances surrounding the detection fiber and energized
according to a strategy enabling the detection of light associated
with different wavelength bands and different illumination to
detection distances (see FIG. 10). In one embodiment (FIG. 10a) the
groups of LEDs are arranged in annuli (rings) at specific distances
surrounding the detection fiber. The filters are arranged in rings
surrounding the detection fiber and covering the associated LEDs.
Each annular ring of the filter may have its own filter
characteristics. In a second arrangement (FIG. 10b), groups of LEDs
are arranged in wedges surrounding the detection fiber. In the
second embodiment the filters may be of a wedged or triangular
shape and are arranged to cover their associated LEDs. Each wedge
filter may have its own filter characteristics.
[0150] In another embodiment, each LED or group of LEDs has an
associated optical filter that is used to limit the bandwidth of
emitted light. A different filter is mounted such that the light
emitted and delivered to the sample from the LED passes through the
filter. The filter associated with an LED is designed with a
specific bandwidth and is centered on a particular wavelength that
is within the native bandwidth of the LED. To provide for a broader
illumination pattern or to increase the light energy delivered to
the sample, groups of LEDs can be associated with the same filter.
Through alternate energization of the LEDs or by modulating each
LED or LED group at different frequencies (and demodulating after
detection), narrow wavelength bands on the order of 5-100 nm can be
distinguished and measured through a single element detector.
[0151] In another embodiment, the LEDs have a bandwidth relatively
broader than the net analyte and interference signals. The light
collected by the detection fiber is passed through a slit and
imaged onto dispersive element which disperses the band of detected
light onto an array of detector elements. In this configuration,
optical filters on the LEDs are not employed.
[0152] In another embodiment, the LED's are used in a spectrometer
without a dispersive element and a single element detector. In one
case, thin dielectric films are used as in Fabry-Perot interference
filters. A filter is associated with each LED. In a second case, an
interferometer composed of two parallel, highly reflecting plates
separated by an air gap may be used. One of the parallel plates may
be translated mechanically such that the distance between the
plates varies. Technically, this is a Fabry-Perot interferometer.
When the mirror distance is fixed and adjusted for parallelism by a
spacer such as invar or quartz, the system is referred to as a
Fabry-Perot etalon. Both cases allow narrow excitation lines and
may be used by sequentially firing the LED's as above.
[0153] A number of spectrometer configurations are possible for
this measurement as are outlined above. Basically the spectroscopic
measurement system includes a source of near-infrared radiation, a
wavelength selection system, an interface to the patient, photon
guiding optics, and a detector.
[0154] Although the invention has been described herein with
reference to certain preferred embodiments, one skilled in the art
will readily appreciate that other applications may be substituted
for those set forth herein without departing from the spirit and
scope of the present invention. Accordingly, the invention should
only be limited by the claims included below.
* * * * *