Title of Invention

APPARATUS FOR NONINVASIVE MEASUREMENT OF GLUCOSE THROUGH NEAR-INFRARED SPECTROSCOPY

Abstract This invention discloses an apparatus for noninvasive measurement of glucose concentration through near-infrared spectroscopy, comprising: a base module comprising a grating and a detector array, said base module comprising: means for bias correcting one or more of spectral data collected in (X) and glucose concentration data (Y); a sampling module, securely and removeably attachable to a sample site, and coupled to said base module, said sampling module comprising an illumination source; and a communication bundle for carrying optical and/or electrical signals between said base module and said sampling module, and for carrying power to said sampling module from said base module, wherein said base module further comprises 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.
Full Text Apparatus for Noninvasive Measurement
of Glucose through Near-Infrared Spectroscopy
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Patent Application Nos.
60/362,885. filed on March 8. 2002. entitled Apparatus For Noninvasive Blood
Analyte Determination; and 60/362.899. filed on March 8. 2002 entitled Calibration
Methods In Noninvasive Blood Analyte Determination; and **Unassigned**, filed on
February 19, 2003, entitled Compact Apparatus for Noninvasive Measurement of
Glucose through Near-Infrared Spectroscopy.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
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.
DISCUSSION OF THE PRIOR ART
DIABETES
Diabetes is a chronic disease that results in improper production and use of insulin, a
hormone that facilitates glucose uptake into ceils. 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
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, Nov. 1997).

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
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 colorimetric 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 + O2 → gluconolactone + H2O2 eq. 1
H2O2→2H+ + O2 + 2e. eq. 2

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
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
There are several alternative invasive methods of determining glucose
concentrations.
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® Freestyle

Meter™ 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.
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.
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.

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:
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.
B. Applied current: In these systems, a small electrical current is applied to the skin
allowing interstitial fluid to permeate through the skin.
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.
For example, a device that acquires a sample via iontophoresis, such as Cygnus
GlucoWatch™, is an alternative invasive technique.
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

biosampies from the skin without the use of a lancet on the fingertip or toes is
referred to as an alternative invasive technique.
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.
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 _ microliter, are considered to be alternative invasive
glucose determination techniques as defined above. Examples of alternative
invasive techniques include the TheraSense® FreeStyle™ when not sampling
fingertips or toes, the Cygnus® GlucoWatch™, the One Touch® Ultra™, and
equivalent technologies.

Biosamples collected with alternative invasive techniques are analyzed via a large
range of technologies. The most common of these technologies are summarized
below:
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 colorimetric approaches. For example, the enzymatic and
colorimetric approaches described above may also be used to determine the
glucose concentration in interstitial fluid samples.
B. Spectrophotometry: 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-JR (700 to 2500
nm or 14,286 to 4000 cm-1), and infrared (2500 to 14,285 nm or 4000 to 700 cm
1)].
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
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.
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 cm1), and infrared
(2500 to 14,285 nm or 4000 to 700 cm"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.
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.
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
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.

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® 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.
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
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; Bemer, 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. Patent # 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. Patent #
6,326,160, December 4, 2001; Kurnik, Ronald T. "Method and Device for Predicting

Physiological Values", U.S. Patent # 6,272,364, August 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. Patent #
6,180,416, January 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 GJucoWatch™", Diabetes Technology & Therapeutics, g,
2000, 115-116; and "GlucoWatch Automatic Glucose Biographer and AutoSensors",
Cygnus Inc., Document #1992-00, Rev. March 2001) The Cygnus Glucose Watch®
uses this technology. The GlucoWatch® 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.
One class of semi-implantable glucose analyzers are those based upon open-flow
microperfusion (Trajanowski, Zlatko; Brunner, Gemot 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, H, 1996, 479-487). A common issue with semi-
implantable and implantable devices is coating by proteins. The MiniMed®
continuous glucose monitoring system, a short-term implantable, is the first
commercially available semi-continuous glucose monitor in this class. The MiniMed®
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® 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® 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).
Other approaches, such as the continuous monitoring system reported by Gross, et
al. (Gross, T.M., B.W. Bode, D. Einhom, D.M. Kayne, J.H. Reed, N.H. White and J.J.
Mastrototaro, "Performance Evaluation of the MiniMed® 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.
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. Patent # 6,304,766, October 16, 2001; Colvin, Arthur E.; Dale,
Gregory A.; Zerwekh, Samuel, Lesho, Jeffery C; Lynn, Robert W. "Optical-Based
Sensing Devices", U.S. Patent # 6,330,464, December 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. Patent #6,334,360,
February 5, 2002; and Lesho, Jeffery "Implanted Sensor Processing System and
Method for Processing Implanted Sensor Output", U.S. Patent # 6,400,974, June 4,
2002).
Notably, none of these technologies are noninvasive. Further, none of these
technologies offer continuous glucose determination.
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.
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. Patent #6,152,876, November 28, 2000;
Messerschmidt, Robert G.; Robinson, Mark Ries "Diffuse Reflectance Monitoring
Apparatus", U.S. Patent # 5,935,062, August 10, 1999; Messerschmidt, Robert G.
"Method for Non-invasive Analyte Measurement with Improved Optical Interface",
U.S. Patent # 5,823,951, October 20, 1998; Messerschmidt, Robert G. "Method for
Non-invasive Blood Analyte Measurement with Improved Optical Interface", U.S.
Patent # 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. 6,240,306, May 29, 2001; Messerschmidt, Robert
G.; Robinson, Mark Ries "Diffuse Reflectance Monitoring Apparatus", U.S. Patent

#6,230,034, May 8, 2001; Barnes, Russell H.; Brasch, Jlmmie W. "Non-invasive
Determination of Glucose Concentration in Body of Patients", U.S. Patent
#5,070,874, December 10,1991; and Hall, Jeffrey; Cadell, T.E. "Method and Device
for Measuring Concentration Levels of Blood Constituents Non-invasively", U.S.
Patent #5,361,758, November 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. 4,882,492, November
21, 1989.; Malin, Stephen; Khalil, Gamal "Method and Apparatus for Multi-Spectral
Analysis in Noninvasive Infrared Spectroscopy", U.S. 6,040,578, March 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. 6,411,373, June 25,2002; Blank,
Thomas B.; Acosta, George; Mattu, Mutua; Monfre, Stephen L. "Fiber Optic Probe
and Placement Guide", U.S. 6,415,167, July 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. 6,442,408, August 27, 2002..
Mode of Analysis
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.
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.
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.
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.
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
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'1), and
infrared (2500 to 14,285 nm or 4000 to 700 cm-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.

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.

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.
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.
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.

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
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, NJ: 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 lllman 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.
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
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.
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 = ε b C eq. 3
where A is the absorbanee/reflectance measurement at a given wavelength of light, e
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).
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.
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.
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.
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
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
Figure 1 shows a sampling module, a communication bundle and a base module;
Figure 2 shows a preferred embodiment with a grating and detector array;
Figure 3 shows a preferred embodiment of the sampling module;
Figure 4 shows a low profile embodiment of the sampling module;
Figure 5 shows a single filter embodiment of the sampling module;
Figure 6 shows an alternative embodiment of the sampling module;
Figure 7 shows noninvasive glucose predictions in a concentration correlation plot;

Figure 8 shows an LED based embodiment of the sampling module;
Figure 9 shows a possible LED reflector; and
Figure 10 shows filter shapes optionally coupled to the LED.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
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 Figure 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.
A block diagram of the noninvasive glucose analyzer is provided in Figure 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 Figure 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.
The sampling module, base module, and communication bundle are further
described herein. Key features of the invention may include but are not limited to:
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.
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.

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® 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.
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.
One version of the sampling module of the invention is presented in Figure 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® 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 µm 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.
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.

In the preferred embodiment, the base module resides on a table, the sampling
module interfaces through a semi-permanentiy 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
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.

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.
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.
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.
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-permanentiy 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 Figure 4.
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 µm fiber 40 is used as the
collection optic. The 600 µm fiber is fixed into the sampling module 41. The
sampling module has a connector for accepting a 300 µm 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.
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.
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.

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.
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 Figure 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 Jess 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.
An alternative embodiment of the source/reflector/filter is shown in Figure 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.
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.
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.
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

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.
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.
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.
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.

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.
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.
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.
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 µm in a continuous or duty cycle fashion.
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.
It is recognized that the sampling module can interface directly to a skin sampling
without the use of a guide.
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°F,
preferably to 92°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.
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.
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 µm 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 µm 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 µm
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
optica] glass.
In the preferred embodiment, the collected signal is turned 90° 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.
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 µm

collection fiber may be downsized to a 300 µm 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.
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
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.
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.
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.
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.
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
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.
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.
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
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.
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 Figure 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.
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.
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 reference.
For an internal reference, a similar arrangement may be used, but a transmittance
spectrum is preferred.
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

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.
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.
Additional preprocessing techniques are covered in the introductory section. These
techniques are well understood by those skilled in the art.
Modeling
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.
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 Figure 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
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.
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
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.
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.

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.
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.
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.

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
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.
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.
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.
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
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.
In the simplest embodiment, the LEDs may illuminate the sample directly, as in
Figure 8. In Figure 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
Figure 9.
In this scenario, two arrangements are used. First, a mixing chamber is present as
shown in Figure 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.
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.
In the preferred embodiment, groups of LEDs (Figure 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 (se e
Figure 10). In one embodiment (Figure 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 (Figure 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.
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.
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.
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.
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.
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.

We Claim:
1. An apparatus for noninvasive measurement of glucose concentration through near-
infrared spectroscopy, comprising:
a base module comprising a grating and a detector array, said base module
comprising:
means for bias correcting one or more of spectral data collected in (X) and
glucose concentration data (Y);
a sampling module, securely and removeably attachable to a sample site, and
coupled to said base module, said sampling module comprising an illumination
source; and
a communication bundle for carrying optical and/or electrical signals between
said base module and said sampling module, and for carrying power to said sampling
module from said base module,
wherein said base module further comprises 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.
2. The apparatus as claimed in Claim 1, optionally comprising:
an optic system located before and/or after said sample site for coupling said
illumination source to said sample and said sample to said detector array.
3. The apparatus as claimed in Claim 2, said optic system comprising any of:
an optical filter, a light blocker, and a standardization material.
4. The apparatus as claimed in Claim 1, said sampling module optionally comprising
at least one of:
a low profile sampling interface;
a low wattage stabilized source in close proximity to said sampled site;
an excitation collection cavity or optics;
a guide;
a preheated interfacing solution;
means for maintaining a temperature controlled skin sample;
a mechanism for constant pressure and/or displacement of sampled skin tissue;
a photonic stimulation source; and
collection optics or fiber.

5. The apparatus as claimed in Claim 1, said sampling module optionally comprising:
a guide that is securely and removeably attached to said sampling site, said
guide continuously and/or periodically physically and optically locating said sampling
module relative to said sample site in a repeatable manner and with minimal
disturbance to said sampling site.
6. The apparatus as claimed in Claim 5, optionally comprising:
means for pretreatment of said sample site to provide appropriate contact of
said sampling module to said sampling site to reduce specular reflectance, to approach
and maintain appropriate sampling site temperature variation, and to minimize
sampling site hydration changes.
7. The apparatus as claimed in Claim 1, wherein said sampling module collects a
diffusely reflected or transflected signal from said sampling site.
8. The apparatus as claimed in Claim 1, either of said base module and said sampling
module comprising any of:
a wavelength reference standard; and
an intensity reference standard.
9. The apparatus as claimed in Claim 1, wherein said communication bundle is
integrated between said sampling module and said base module.
10. The apparatus as claimed in Claim 1, wherein said sampling module and said base
module are integrated together into a handheld unit.
11.The apparatus as claimed in Claim 1. said sampling module comprising:
a housing;
a reflector;
a lamp comprising a tungsten halogen source, said lamp coupled to said
reflector; and
a photodiode for monitoring said lamp and for maintaining said lamp's output
stable by means of a lamp output controller.
12. The apparatus as claimed in Claim 11, wherein said reflector, and hence incident
light emanating therefrom, is centered on an angle off of a normal to said sample site
to allow room for a collection fiber.
13. The apparatus as claimed in Claim 11, wherein light is focused through a silicon
window onto an aperture at said sample site, wherein said silicon window comprises a
longpass filter.

14. The apparatus as claimed in Claim 5. wherein said sampling module reversibly
couples into said guide for reproducible contact pressure and/or sampling location.
15. The apparatus as claimed in Claim 14, said guide optionally comprising:
at least one magnet for aiding in positioning a sampling module probe to
ensure proper penetration of said probe into a guide aperture, and to enable a constant
pressure and/or displacement interface of said sampling site; wherein said magnet is
optionally electrically activated to facilitate controlled movement into a guide aperture
and to allow, through reversal of said magnet poles, withdrawal from said guide
aperture without pulling.
16. The apparatus as claimed in Claim 14, wherein said reversible coupling of said
sampling module into said guide allows said sampling module to be removed and
coupled to an intensity reference and/or a wavelength reference that have a same guide
interface.
17. The apparatus as claimed in Claim 16, wherein said intensity reference comprises
a 99% reflective material, and wherein said wavelength reference is polystyrene.
18. The apparatus as claimed in Claim 1, said sampling module optionally
comprising:
a heater for maintaining said sampling site at a constant temperature.
19. The apparatus as claimed in Claim 1, said sampling module optionally
comprising:
a detection fiber for collecting diffusely reflected light.
20. The apparatus as claimed in Claim 1, wherein said base module either resides on a
support surface, or said base module may be worn by a person.
21. The apparatus as claimed in Claim 1, wherein said sampling module 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.
22. The apparatus as claimed in Claim 1, optionally comprising:
a docking station for said base module.
23. The apparatus as claimed in Claim 1, wherein said base module is coupled directly
to said sampling module, with said communication bundle forming an integral part
thereof.
24. The apparatus as claimed in Claim 1. wherein said sampling module further
comprises:

a housing, providing light blocking in ultraviolet wavelengths, visible
wavelengths, and near-infrared wavelengths from 700 to 1000 nm.
25. The apparatus as claimed in Claim 24, wherein said housing is constructed of
silicon, and has a thickness of about 1mm.
26. The apparatus as claimed in Claim 1, said illumination source comprising:
a tungsten halogen source ranging in power from 0.05 W to 5 W.
27. The apparatus as claimed in Claim 1, said illumination source comprising:
at least one light emitting diode (LED).
28. The apparatus as claimed in Claim 1, optionally comprising:
a photodiode; and
a feedback controller for allowing said illumination source to be driven at
different levels at different points in time during and prior to data acquisition;
wherein said photodiode is placed before an optional order sorter to detect
visible light from said illumination source; and
wherein said photodiode comprises any of a silicon, InGaAs, InPGaAs. PbS.
and PbSe detector.
29. The apparatus as claimed in Claim 1, said illumination source further comprises:
a reflector having any of a parabolic, elliptical, and spherical shape.
30. The apparatus as claimed in Claim 29. wherein said source, said housing, and said
reflector are arranged to bring in source light nearly parallel to said sample site
surface.
31. The apparatus as claimed in Claim 1, wherein said sampling module optionally
comprising:
folding optics for bringing light in at a low angle relative to said sampling site
surface, wherein said folding optics optionally comprise any of a mirror and a
focusing mirror.
32. The apparatus as claimed in Claim 1, said communication bundle optionally
comprising:
quick connect optics which comprise:
a first collection optic that is fixed into said communication bundle; and
a connector in said communication bundle for accepting a second collection
optic that in turn couples to said base module.
33. The apparatus as claimed in Claim 32, optionally comprising:
at least one optical device for coupling light by any of magnifying and de-

magnifying lenses and folding mirrors.
34. The apparatus as claimed in Claim 33, wherein said second collection optic is
readily removed from said sampling module, allowing said sampling module to
remain in contact with said sampling site.
35. The apparatus as claimed in Claim 1, wherein said illumination source further
comprises a heat source.
36. The apparatus as claimed in Claim 1, optionally comprising:
an optical filter located between said illumination source and said sampling
site.
37. The apparatus as claimed in Claim 36, wherein said optical filter is located after
said illumination source but not in contact with any of said sampling site and a
coupling fluid.
38. The apparatus as claimed in Claim 36, wherein said optical filter comprises:
at least two filters located between said illumination source and said sampling
site, wherein a first filter removes heat, and wherein a second filter reduces spectral
reflectance.
39. The apparatus as claimed in Claim 36, wherein said optical filter comprises:
a silicon filter for removing light under 1050 nm. wherein a grating can be
used in the 1150 to 1850 nm region without detection of second or higher order light
off of said grating, wherein said silicon filter is placed before the grating and after said
sampling site.
40. The apparatus as claimed in Claim 36, wherein said optical filter comprises:
a filter comprising of any of the following:
a filter that is a silicon longpass optic;
a filter that is coated to block about 1900 to 2500 nm;
a filter that is antireflection-coated to match refractive indices and increase
light throughput, and/or used in combination with a shortpass filter;
a filter that is coated with a blocker for removing a largest intensity of a black
body curve of a typical tungsten halogen source that is not blocked by silicon, wherein
said blocking band may cover any region from about 1800 nm on up to 3000 nm; and
a filter that is used in combination with an RG glass that cuts off at about 2500
nm to provide a bandpass filter passing light from approximately 1100 to 2500 nm,
wherein said filter combination is optionally used in conjunction with a
coating layer to provide a bandpass from about 1100 to 1900 nm.

41. The apparatus as claimed in Claim 1, said sampling module optionally
comprising:
a member shaped into a parabolic optic surrounding part of said illumination
source, wherein an outside of said member is coated with a reflector.
42. The apparatus as claimed in Claim 41, wherein said member comprises any of
silicon and plastic parts.
43. The apparatus as claimed in Claim 1, said sampling module optionally
comprising:
an illumination source filament that is wrapped around a collection fiber; and
a reflector for directing light into an aperture for admission therethrough to
said sampling site, wherein said reflector optionally is any of surface coated for
reflectance on an incident light surface, and transmissive with an outer surface of said
reflector being reflectively coated.
44. The apparatus as claimed in Claim 43, optionally comprising:
a window defined between said illumination source and said sampling site,
said window optionally comprising a filter.
45. The apparatus as claimed in Claim 1, said sampling module optionally
comprising:
a broadband source operatively combined with a single element detector.
46. The apparatus as claimed in Claim 1, said sampling module optionally
comprising:
a Fabry-Perot interferometer.
47. The apparatus as claimed in Claim 1, said sampling module comprising:
a surface defining an aperture for providing optical pathlengths within a
sample for indirectly monitoring glucose concentrations within a body, providing
acceptable energy delivery to said sampling site, and providing appropriate
heating/temperature control of said sampling site;
wherein variation of said aperture affects a net analyte signal of a sampled
tissue.
48. The apparatus as claimed in Claim 47, optionally comprising:
a fiber optic collection fiber placed in a center of an illumination area defined
by said aperture.
49. The apparatus as claimed in Claim 47, optionally comprising:
means for performing an indirect determination of glucose from sample

constituents which comprise any of fat, protein, and water and that are distributed as a
function of depth in a sample, wherein a magnitude of an indirect signal varies with
said aperture.
50. The apparatus as claimed in Claim 1, wherein said sampling module is semi-
permanently attached to said sampling site with a replaceable adhesive.
51. The apparatus as claimed in Claim 47, optionally comprising:
a removable plug for placement in said aperture to stabilize tissue at said
sampling site by providing a same tissue displacement as a probe.
52. The apparatus as claimed in Claim 47, optionally comprising:
a contact window for allowing a continuous barrier for hydration of said
sampling site and a constant pressure interface.
53. The apparatus as claimed in Claim 1, said sampling module optionally comprising
any of:
means for any of photonic stimulation, ultrasound pretreatment, mechanical
stimulation, cooling, and heating.
54. The apparatus as claimed in Claim 1, said sampling module optionally comprising
any of:
an LED for providing photonic stimulation to induce capillary blood vessel
dilation.
55. The apparatus as claimed in Claim 1, optionally comprising:
a coupling fluid disposed between said sampling module and said sampling
site for coupling incident photons into a tissue sample, wherein said coupling fluid is
optionally preheated to minimize changes to a surface temperature of said sampling
site, and minimize spectral changes observed from said tissue sample, wherein said
coupling fluid, if preheated, is preheated using any of illumination source energy,
sampling site heater energy, and an auxiliary heat source.
56. The apparatus as claimed in Claim 55, optionally comprising:
means for automated delivery of said coupling fluid prior to sampling.
57. The apparatus as claimed in Claim 1, said sampling module optionally
comprising:
a collection fiber placed into an aperture formed through a base, said collection
fiber being in contact with a sampling site surface.
58. The apparatus as claimed in Claim 1, optionally comprising:
means for using any of a signal and an absence of observed intensity at large

water absorbance bands near 1450, 1900, and 2500 nm to determine when said
sampling module is in good spectral contact with a sampling site surface.
59. The apparatus as claimed in Claim 1, wherein said base module further comprises:
a two-way wireless communication system for transferring data between said
base module and any of said sampling module and a data collection/processing
system.
60. The apparatus as claimed in Claim 1, optionally comprising:
means for standardizing a near-infrared wavelength based on a comparative
analysis of a master and slave spectra of a standardization material.
61. The apparatus as claimed in Claim 60, said means for standardizing comprising:
a material having absorption bands in a targeted wavelength region for
determining said x-axis, said material comprising any of polystyrene, erbium oxide,
dysprosium oxide, and holmium oxide.
62. The apparatus as claimed in Claim 61, wherein said material used for
standardization is any of:
measured external to said base module;
measured continuously and mounted within said base module in a separate
light path, wherein said internal wavelength standard is measured simultaneously with
said sample;
moved through an actuator into a main optical train at an appropriate time;
wherein a reference spectrum is collected in any of a transmittance mode,
reflectance mode, or a diffuse reflectance mode.
63. The apparatus as claimed in Claim 60, optionally comprising:
means for measuring a reference spectrum and a (wavelength) standardization
spectrum through spectroscopic measurement of a non-absorbing material and a
material with known and immutable spectral absorbance bands, respectively.
64. The apparatus as claimed in Claim 63, said means for measuring optionally
comprising:
a master spectrum of a standardization material, and
means for determining a discrepancy between said master spectrum and an
instrument standardization spectrum;
wherein said master spectrum and wavelength regions are optionally stored in
a nonvolatile memory.

65. The apparatus as claimed in Claim 64, wherein at least one window across a
spectrum of said x-axis phase shift between said master spectrum and an acquired
spectrum are determined through a cross-correlation function after removing
instrument related baseline variations, wherein said phase shift is used to correct
(standardize) said x-axis of said acquired spectrum to said master spectrum.
66. The apparatus as claimed in Claim 1, wherein for glucose measurement, said
reference values comprise at least one of the following: finger capillary blood
glucose, alternate site capillary blood glucose at a site on the body other than the
finger, interstitial glucose, or venous blood glucose.
67. The apparatus as claimed in Claim 1, wherein said base module is integrally
connected to a docking station; wherein said docking station comprises a computer
and a glucose management center; wherein said glucose management center keeps
track of events occurring in time comprising any of glucose intake, insulin delivery,
and determined glucose concentration.
68. The apparatus as claimed in Claim 1, said base module optionally comprising:
means for estimating precision of measurement through a statistical analysis of
repeated or successive measurements; and
means for determining when a biological parameter is close to a preset level
through a statistical estimate of confidence limits of a future analyte prediction made
through a simple slope (change in said biological parameter over change in time)
estimate based on an exponentially moving average, where said confidence limits are
based upon said estimate of precision.
69. The apparatus as claimed in Claim 1, said base module optionally comprising:
means for determining when a biological parameter is close to a preset level
through a standard time series analysis; wherein an alarm is invoked if an associated
present alarm level is within a confidence interval of a future biological parameter
prediction.
70. The apparatus as claimed in Claim 1, either of said sampling module and said base
module optionally comprising:
means for taking any of continuous and semi-continuous measurements when
said sampling module is in contact with said sampling site.
71. The apparatus as claimed in Claim 1, said base module optionally comprising:
means for using time based information and trends to perform various
functions comprising any of:

estimation of precision-;
estimation of a confidence intervals; and
prediction of future events.
72. The apparatus as claimed in Claim 1, optionally comprising:
a link provided to an insulin delivery system to provide a feedback mechanism
for control purposes.
73. The apparatus as claimed in Claim 1, any of said base module and said sampling
module comprising:
a spectrometer system comprising LEDs to provide near-infrared radiation to
said sample site over predefined wavelength ranges, wherein each of said LEDs
provides near-infrared radiation over a band of wavelengths.
74. The apparatus as claimed in Claim 73, wherein wavelengths of said LEDs are
selected specifically to optimize a signal-to-noise ratio of a net analyte signal of a
target analyte, and are arranged at various distances with respect to detection elements
to provide a means for sampling various tissue volumes for purposes of averaging and
determination of a differential measurement.
75. The apparatus as claimed in Claim 73, wherein said LEDs are sequentially
energized one at a time and/or in groups to obtain various estimates of diffuse
reflectance of various tissue volumes at specific wavelengths or bands of wavelengths.
76. The apparatus as claimed in Claim 73, wherein said LEDs are pulsed to provide
short measurements with high signal-to-noise ratios to provide greater illumination
intensity while avoiding photo heating of a sampled tissue volume.
77. The apparatus as claimed in Claim 73, wherein said LEDs are modulated at a
particular duty cycle and frequency to remove additive noise and to provide
simultaneous measurement of multiple wavelengths.
78. The apparatus as claimed in Claim 73, wherein said LEDs illuminate said sample
site directly.
79. The apparatus as claimed in Claim 73, optionally comprising:
a mixing chamber with a reflective surface located between said LEDs and an
optical window to provide a nearly uniform distribution onto a sample tissue region
surrounding a detection fiber, wherein each LED is optionally recessed into a material
having a reflective surface.
80. The apparatus as claimed in Claim 73, wherein groups of LEDs are employed with
each group associated with a single filter type, and wherein said LEDs are arranged at

distances surrounding a detection fiber and energized to enable detection of light
associated with different wavelength bands and different illumination to detection
distances.
81. The apparatus as claimed in Claim 80, wherein said groups of LEDs are arranged
in any of:
annuli (rings) at specific distances surrounding said detection fiber, wherein
said filters are arranged in rings surrounding said detection fiber and covering
associated LEDs; and
wedges surrounding said detection fiber, wherein said filters are either of a
wedged or triangular shape and are arranged to cover associated LEDs.
82. The apparatus as claimed in Claim 80, wherein each LED or group of LEDs has
an associated optical filter that is used to limit a bandwidth of emitted light, wherein a
different filter is mounted such that light emitted and delivered to said sampling site
from said LED passes through said filter, wherein a filter associated with an LED has
a specific bandwidth and is centered on a particular wavelength that is within a native
bandwidth of said LED, wherein groups of LEDs are optionally associated with a
same filter.
83. The apparatus as claimed in Claim 80, wherein said LEDs have a bandwidth
relatively broader than net analyte and interference signals.
84. The apparatus as claimed in Claim 80, wherein said LED's are used in a
spectrometer without a dispersive element and a single element detector, wherein thin
dielectric films are used as in Fabry-Perot interference filters and a filter is associated
with each LED.

This invention discloses an apparatus for noninvasive measurement of glucose
concentration through near-infrared spectroscopy, comprising:
a base module comprising a grating and a detector array, said base module
comprising:
means for bias correcting one or more of spectral data collected in (X) and
glucose concentration data (Y);
a sampling module, securely and removeably attachable to a sample site, and
coupled to said base module, said sampling module comprising an illumination
source; and
a communication bundle for carrying optical and/or electrical signals between
said base module and said sampling module, and for carrying power to said sampling
module from said base module,
wherein said base module further comprises 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.

Documents:

1183-kolnp-2004-granted-abstract.pdf

1183-kolnp-2004-granted-assignment.pdf

1183-kolnp-2004-granted-claims.pdf

1183-kolnp-2004-granted-correspondence.pdf

1183-kolnp-2004-granted-description (complete).pdf

1183-kolnp-2004-granted-drawings.pdf

1183-kolnp-2004-granted-examination report.pdf

1183-kolnp-2004-granted-form 1.pdf

1183-kolnp-2004-granted-form 18.pdf

1183-kolnp-2004-granted-form 3.pdf

1183-kolnp-2004-granted-form 5.pdf

1183-kolnp-2004-granted-gpa.pdf

1183-kolnp-2004-granted-reply to examination report.pdf

1183-kolnp-2004-granted-specification.pdf


Patent Number 228769
Indian Patent Application Number 1183/KOLNP/2004
PG Journal Number 07/2009
Publication Date 13-Feb-2009
Grant Date 10-Feb-2009
Date of Filing 16-Aug-2004
Name of Patentee SENSYS MEDICAL, INC.
Applicant Address 7470 WEST CHANDLER BLVD., CHANDLER, AZ 85226
Inventors:
# Inventor's Name Inventor's Address
1 ABUL-HAJ ALAN N 3464 N. PLATINA CIRCLE, MESA, AZ 85215
2 MONFRE STEPHEN L 1289, EAST PALO BLANCO WAY, GILBERT, AZ 85296
3 HAZEN KEVIN H 1534 W. ISLANDIA DRIVE, GILBERT, AZ 85233
4 ACOSTA GEORGE 1639 WEST WILDWOOD DRIVE, PHOENIX, AZ 85025
5 HENDERSON JAMES R 7043 S. 27TH WAY, PHOENIX, AZ 85040
6 RUCHTI TIMOTHY L 1501, WEST SEA HAZE DRIVE, GILBERT, AZ 85233
7 BLANK THOMAS B 2922 E. TULSA STREET, CHANDLER, AZ 85225
PCT International Classification Number G01J
PCT International Application Number PCT/US2003/07065
PCT International Filing date 2003-03-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/448,840 2003-02-19 U.S.A.
2 60/362,885 2002-03-08 U.S.A.
3 60/362,899 2002-03-08 U.S.A.