U.S. patent application number 10/900062 was filed with the patent office on 2005-03-31 for sample adapter.
Invention is credited to Braig, James R., Gable, Jennifer H., Hartstein, Philip C., Rule, Peter.
Application Number | 20050070771 10/900062 |
Document ID | / |
Family ID | 26687965 |
Filed Date | 2005-03-31 |
United States Patent
Application |
20050070771 |
Kind Code |
A1 |
Rule, Peter ; et
al. |
March 31, 2005 |
Sample adapter
Abstract
An adapter presents a sample of bodily fluid, such as whole
blood, including an analyte to an analyzer window of a non-invasive
monitor. The adapter comprises a base material that comprises a
first side and a second side. The adapter also comprises a sample
accommodating volume extending between an opening in the second
side of the base material and an opening in the first side of the
base material.
Inventors: |
Rule, Peter; (Los Altos
Hills, CA) ; Braig, James R.; (Piedmont, CA) ;
Hartstein, Philip C.; (Cupertino, CA) ; Gable,
Jennifer H.; (Walnut Creek, CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
26687965 |
Appl. No.: |
10/900062 |
Filed: |
July 27, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10900062 |
Jul 27, 2004 |
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10219996 |
Aug 15, 2002 |
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6771993 |
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10219996 |
Aug 15, 2002 |
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10015932 |
Nov 2, 2001 |
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6678542 |
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60313082 |
Aug 16, 2001 |
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Current U.S.
Class: |
600/316 ;
600/322 |
Current CPC
Class: |
A61B 5/14532 20130101;
A61B 5/1455 20130101; A61B 5/1495 20130101; A61B 5/1491
20130101 |
Class at
Publication: |
600/316 ;
600/322 |
International
Class: |
A61B 005/00 |
Claims
1-27. (cancelled)
28. A method for calibrating a noninvasive detection unit, said
method comprising: placing a noninvasive sensor portion of said
noninvasive detection unit in operative engagement with the skin of
a patient; analyzing a property of an analyte within said patient
with said noninvasive detection unit and generating a first monitor
output representing said property of said analyte; withdrawing an
amount of bodily fluid from a patient; placing said noninvasive
sensor portion of said noninvasive detection unit in operative
engagement with at least some of said withdrawn amount of bodily
fluid; analyzing said property of said analyte in said withdrawn
amount of bodily fluid with said noninvasive detection unit and
generating a second monitor output representing said property of
said analyte, without reference to a prepared standard in which
said property of said analyte is predetermined; comparing said
first monitor output and said second monitor output to estimate an
error; and correcting said first monitor output based on said
error.
29. The method of claim 28, wherein said bodily fluid is whole
blood.
30. The method of claim 29, wherein analyte is glucose and said
property is concentration.
31. The method of claim 28, wherein said noninvasive sensor portion
comprises an analyzer window of said noninvasive detection
unit.
32. The method of claim 28, wherein analyzing said property of said
withdrawn amount of bodily fluid in thermal communication with a
thermal gradient inducing element of said noninvasive detection
unit.
33. The method of claim 32, wherein analyzing said property of said
analyte within said patient comprises placing said thermal gradient
inducing element in thermal communication with the skin of said
patient.
34. A method for calibrating a noninvasive detection unit, said
method comprising: placing a noninvasive sensor portion of said
noninvasive detection unit in operative engagement with the skin of
a patient; analyzing a concentration of an analyte within said
patient with said noninvasive detection unit and generating a first
monitor output representing said concentration of said analyte;
withdrawing an amount of whole blood from a patient; placing said
noninvasive sensor portion of said noninvasive detection unit in
operative engagement with at least some of said withdrawn amount of
whole blood; analyzing said property of said analyte in said
withdrawn amount of whole blood with said noninvasive detection
unit and generating a second monitor output representing a
concentration of said analyte in said whole blood; comparing said
first monitor output and said second monitor output to estimate an
error; and correcting said first monitor output based on said
error.
35. The method of claim 34, wherein analyte is glucose.
36. The method of claim 34, wherein said noninvasive sensor portion
comprises an analyzer window of said noninvasive detection
unit.
37. The method of claim 34, wherein analyzing said concentration of
said analyte in said withdrawn amount of whole blood comprises
placing at least some of said withdrawn amount of whole blood in
thermal communication with a thermal gradient inducing element of
said noninvasive detection unit.
38. The method of claim 37, wherein analyzing said concentration of
said analyte within said patient comprises placing said thermal
gradient inducing element in thermal communication with the skin of
said patient.
39. A method for calibrating a noninvasive detection unit, said
method comprising: placing a noninvasive sensor portion of said
noninvasive detection unit in operative engagement with the skin of
a patient; analyzing a property of an analyte within said patient
with said noninvasive detection unit and generating a first monitor
output representing said property of said analyte; withdrawing an
amount of bodily fluid from a patient; placing said noninvasive
sensor portion of said noninvasive detection unit in operative
engagement with said withdrawn amount of bodily fluid, without
mixing said bodily fluid with other fluids; analyzing said property
of said analyte in said withdrawn amount of bodily fluid with said
noninvasive detection unit and generating a second monitor output
representing said property of said analyte; comparing said first
monitor output and said second monitor output to estimate an error;
and correcting said first monitor output based on said error.
40. The method of claim 39, wherein said bodily fluid is whole
blood.
41. The method of claim 40, wherein analyte is glucose and said
property is concentration.
42. The method of claim 39, wherein said noninvasive sensor portion
comprises an analyzer window of said detection unit.
43. The method of claim 39, wherein analyzing said property of said
analyte in said withdrawn amount of bodily fluid comprises placing
at least some of said withdrawn amount of bodily fluid in thermal
communication with a thermal gradient inducing element of said
noninvasive detection unit.
44. The method of claim 43, wherein analyzing said property of said
analyte within said patient comprises placing said thermal gradient
inducing element in thermal communication with the skin of said
patient.
Description
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 10/015,932, filed Nov. 2, 2001, entitled
CALIBRATOR, and also claims the benefit of U.S. Provisional Patent
Application No. 60/313,082, filed Aug. 16, 2001, entitled ANALYTE
MEASUREMENT ERROR CORRECTION METHOD AND DEVICE, the entire contents
of both of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates generally to determining analyte
concentrations within living tissue.
[0004] 2. Description of the Related Art
[0005] Millions of diabetics are forced to draw blood on a daily
basis to determine their blood glucose levels. A search for a
non-invasive methodology to accurately determine blood glucose
levels has been substantially expanded in order to alleviate the
discomfort of these individuals.
SUMMARY OF THE INVENTION
[0006] A significant advance in the state of the art of
non-invasive blood glucose analysis has been realized by an
apparatus taught in U.S. Pat. No. 6,198,949, titled SOLID-STATE
NON-INVASIVE INFRARED ABSORPTION SPECTROMETER FOR THE GENERATION
AND CAPTURE OF THERMAL GRADIENT SPECTRA FROM LIVING TISSUE, issued
Mar. 6, 2001; and by methodology taught in U.S. Pat. No. 6,161,028,
titled METHOD FOR DETERMINING ANALYTE CONCENTRATION USING PERIODIC
TEMPERATURE MODULATION AND PHASE DETECTION, issued Dec. 12, 2000;
and in the Assignee's U.S. patent application Ser. No. 09/538,164,
titled METHOD AND APPARATUS FOR DETERMINING ANALYTE CONCENTRATION
USING PHASE AND MAGNITUDE DETECTION OF A RADIATION TRANSFER
FUNCTION. Additional information relating to calibration of such
non-invasive blood analysis is taught in U.S. Pat. No. 6,049,081,
titled SUBSURFACE THERMAL GRADIENT SPECTROMETRY, issued Apr. 11,
2000; and by U.S. Pat. No. 6,196,046 B1, titled DEVICES AND METHODS
FOR CALIBRATION OF A THERMAL GRADIENT SPECTROMETER, issued Mar. 6,
2001. The entire disclosure of all of the above mentioned patents
and patent applications are hereby incorporated by reference herein
and made a part of this specification.
[0007] U.S. Pat. No. 6,198,949 discloses a spectrometer for
non-invasive measurement of thermal gradient spectra from living
tissue. The spectrometer includes an infrared transmissive thermal
mass, referred to as a thermal mass window, for inducing a
transient temperature gradient in the tissue by means of conductive
heat transfer with the tissue, and a cooling system in operative
combination with the thermal mass for the cooling thereof. Also
provided is an infrared sensor for detecting infrared emissions
from the tissue as the transient temperature gradient progresses
into the tissue, and for providing output signals proportional to
the detected infrared emissions. A data capture system is provided
for sampling the output signals received from the infrared sensor
as the transient temperature gradient progresses into to the
tissue. The transient thermal gradients arising due to the
intermittent heating and cooling of the patient's skin generate
thermal spectra which yield very good measurements of the patient's
blood glucose levels.
[0008] Although the apparatus taught in the above-mentioned U.S.
Pat. No. 6,198,949 has led to a significant advance in the state of
the art of non-invasive blood glucose analysis, one possible source
of error in such analysis arises due to physiological variation
across the patient population. This variation, as well as other
factors, can introduce systematic error into the measurements being
performed.
[0009] In one embodiment, there is provided an adapter for
presenting a sample of body fluid including an analyte to a window
of a noninvasive analyte detection system. The adapter comprises a
base material comprising a first side and a second side, and a
sample accommodating volume extending between an opening in the
second side of the base material and an opening in the first side
of the base material.
[0010] In another embodiment, there is provided an adapter for
presenting a sample of whole blood including an analyte to a window
of a noninvasive analyte detection system. The adapter comprises a
base material comprising a first side and a second side, and an
optically transparent layer comprising a first side and a second
side. The second side of the optically transparent layer is
positioned proximate the first side of the base material. The
adapter further comprises a sample accommodating volume extending
between the second side of the optically transparent layer and an
opening in the second side of the base material.
[0011] In another embodiment, there is provided an adapter for
presenting a sample of whole blood including an analyte to a window
of a noninvasive analyte detection system. The adapter comprises a
base material comprising a first side having a first opening and a
second side having a second opening, and a sample accommodating
volume formed in the base material and extending between the first
opening and the second opening.
[0012] In another embodiment, there is provided a method for
calibrating a noninvasive detection unit including a window. The
method comprises withdrawing a sample of bodily fluid from a
patient, positioning the sample over the window, analyzing the
sample with the noninvasive detection unit and generating an
invasive-measurement output representing the concentration of an
analyte. The method further comprises placing the window in contact
with the skin of the patient, analyzing the patient's tissue with
the noninvasive detection unit and generating a
noninvasive-measurement output representing the concentration of
the analyte. The method further comprises comparing the
invasive-measurement output and the noninvasive-measurement output
to estimate an error, and correcting the noninvasive-measurement
output based on the error.
[0013] In another embodiment, there is provided a method for
calibrating a noninvasive detection unit including a window. The
method comprises determining whether there is a restricted period
in effect, selecting an on-site or an alternative site measurement
location based on whether a restricted period is in effect, and
withdrawing an sample of bodily fluid from a patient at the
selected measurement location, wherein the sample comprises at
least one analyte. The method further comprises positioning the
sample over the window, analyzing the analyte in the sample using
the noninvasive detection unit and generating an
invasive-measurement output representing a characteristic of the
analyte. The method further comprises placing the window of the
noninvasive detection unit in contact with the skin of the patient,
analyzing the analyte in the tissue of the patient with the
noninvasive detection unit, and generating a
noninvasive-measurement output representing the characteristic of
the analyte. The method further comprises comparing the
invasive-measurement output and the noninvasive-measurement output
to estimate an error, and correcting the noninvasive-measurement
output based on the error.
[0014] All of these embodiments are intended to be within the scope
of the invention herein disclosed. These and other embodiments of
the present invention will become readily apparent to those skilled
in the art from the following detailed description of the preferred
embodiments having reference to the attached figures, the invention
not being limited to any particular preferred embodiment(s)
disclosed.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Having thus summarized the general nature of the invention,
certain preferred embodiments and modifications thereof will become
apparent to those skilled in the art from the detailed description
herein having reference to the figures that follow, of which:
[0016] FIG. 1 is a schematic view of a noninvasive optical
detection system.
[0017] FIG. 2 is a perspective view of a window assembly for use
with the noninvasive detection system.
[0018] FIG. 3 is an exploded schematic view of an alternative
window assembly for use with the noninvasive detection system.
[0019] FIG. 4 is a plan view of the window assembly connected to a
cooling system.
[0020] FIG. 5 is a plan view of the window assembly connected to a
cold reservoir.
[0021] FIG. 6 is a cutaway view of a heat sink for use with the
noninvasive detection system.
[0022] FIG. 6A is a cutaway perspective view of a lower portion of
the noninvasive detection system of FIG. 1.
[0023] FIG. 7 is a schematic view of a control system for use with
the noninvasive optical detection system.
[0024] FIG. 8 depicts a first methodology for determining the
concentration of an analyte of interest.
[0025] FIG. 9 depicts a second methodology for determining the
concentration of an analyte of interest.
[0026] FIG. 10 depicts a third methodology for determining the
concentration of an analyte of interest.
[0027] FIG. 11 depicts a fourth methodology for determining the
concentration of an analyte of interest.
[0028] FIG. 12 depicts a fifth methodology for determining the
concentration of an analyte of interest.
[0029] FIG. 13 is a schematic view of a reagentless whole-blood
detection system.
[0030] FIG. 14 is a perspective view of one embodiment of a cuvette
for use with the reagentless whole-blood detection system.
[0031] FIG. 15 is a plan view of another embodiment of a cuvette
for use with the reagentless whole-blood detection system.
[0032] FIG. 16 is a disassembled plan view of the cuvette shown in
FIG. 15.
[0033] FIG. 16A is an exploded perspective view of the cuvette of
FIG. 15.
[0034] FIG. 17 is a side view of the cuvette of FIG. 15.
[0035] FIG. 18 shows a pictorial representation of a monitor that
includes a non-invasive detection unit and a traditional
measurement system.
[0036] FIG. 19 shows a process flow for calibrating the monitor of
FIG. 18.
[0037] FIG. 20 shows a variation of the process flow of FIG. 19
wherein a restricted period may be applied after the subject
eats.
[0038] FIG. 21 shows a top view of a whole blood adapter.
[0039] FIG. 22 shows a cross-sectional view of the whole blood
adapter of FIG. 21.
[0040] FIG. 23 shows a top view of a variation of the whole blood
adapter.
[0041] FIG. 24 shows a cross-sectional view of the whole blood
adapter of FIG. 23.
[0042] FIG. 25 shows a top view of another variation of the whole
blood adapter.
[0043] FIG. 26 shows a cross-sectional view of the whole blood
adapter of FIG. 25.
[0044] FIG. 27 shows a top view of another variation of the whole
blood adapter.
[0045] FIG. 28 shows a cross-sectional view of the whole blood
adapter of FIG. 27.
[0046] FIG. 29 shows a process flow for calibrating the
non-invasive detection unit of FIG. 1.
[0047] FIG. 30 shows a variation of the process flow of FIG. 29
wherein a restricted period may be applied after the subject
eats.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0048] Although certain preferred embodiments and examples are
disclosed below, it will be understood by those skilled in the art
that the invention extends beyond the specifically disclosed
embodiments to other alternative embodiments and/or uses of the
invention and obvious modifications and equivalents thereof. Thus,
it is intended that the scope of the invention herein disclosed
should not be limited by the particular disclosed embodiments
described below.
I. Overview of Analyte Detection Systems
[0049] Disclosed herein are analyte detection systems, including a
noninvasive system discussed largely in part A below and a
whole-blood system discussed largely in part B below. Also
disclosed are various methods, including methods for detecting the
concentration of an analyte in a material sample. The noninvasive
system/method and the whole-blood system/method are related in that
they both can employ optical measurement. As used herein with
reference to measurement apparatus and methods, "optical" is a
broad term and is used in its ordinary sense and refers, without
limitation, to identification of the presence or concentration of
an analyte in a material sample without requiring a chemical
reaction to take place. As discussed in more detail below, the two
approaches each can operate independently to perform an optical
analysis of a material sample. The two approaches can also be
combined in an apparatus, or the two approaches can be used
together to perform different steps of a method.
[0050] In one embodiment, the two approaches are combined to
perform calibration of an apparatus, e.g., of an apparatus that
employs a noninvasive approach. In another embodiment, an
advantageous combination of the two approaches performs an invasive
measurement to achieve greater accuracy and a whole-blood
measurement to minimize discomfort to the patient. For example, the
whole-blood technique may be more accurate than the noninvasive
technique at certain times of the day, e.g., at certain times after
a meal has been consumed, or after a drug has been
administered.
[0051] It should be understood, however, that any of the disclosed
devices may be operated in accordance with any suitable detection
methodology, and that any disclosed method may be employed in the
operation of any suitable device. Furthermore, the disclosed
devices and methods are applicable in a wide variety of situations
or modes of operation, including but not limited to invasive,
noninvasive, intermittent or continuous measurement, subcutaneous
implantation, wearable detection systems, or any combination
thereof.
[0052] Any method which is described and illustrated herein is not
limited to the exact sequence of acts described, nor is it
necessarily limited to the practice of all of the acts set forth.
Other sequences of events or acts, or less than all of the events,
or simultaneous occurrence of the events, may be utilized in
practicing the method(s) in question.
[0053] A. Noninvasive System
[0054] 1. Monitor Structure
[0055] FIG. 1 depicts a noninvasive optical detection system
(hereinafter "noninvasive system") 10 in a presently preferred
configuration. The depicted noninvasive system 10 is particularly
suited for noninvasively detecting the concentration of an analyte
in a material sample S, by observing the infrared energy emitted by
the sample, as will be discussed in further detail below.
[0056] As used herein, the term "noninvasive" is a broad term and
is used in its ordinary sense and refers, without limitation, to
analyte detection devices and methods which have the capability to
determine the concentration of an analyte in in-vivo tissue samples
or bodily fluids. It should be understood, however, that the
noninvasive system 10 disclosed herein is not limited to
noninvasive use, as the noninvasive system 10 may be employed to
analyze an in-vitro fluid or tissue sample which has been obtained
invasively or noninvasively. As used herein, the term "invasive" is
a broad term and is used in its ordinary sense and refers, without
limitation, to analyte detection methods which involve the removal
of fluid samples through the skin. As used herein, the term
"material sample" is a broad term and is used in its ordinary sense
and refers, without limitation, to any collection of material which
is suitable for analysis by the noninvasive system 10. For example,
the material sample S may comprise a tissue sample, such as a human
forearm, placed against the noninvasive system 10. The material
sample S may also comprise a volume of a bodily fluid, such as
whole blood, blood component(s), interstitial fluid or
intercellular fluid obtained invasively, or saliva or urine
obtained noninvasively, or any collection of organic or inorganic
material. As used herein, the term "analyte" is a broad term and is
used in its ordinary sense and refers, without limitation, to any
chemical species the presence or concentration of which is sought
in the material sample S by the noninvasive system 10. For example,
the analyte(s) which may be detected by the noninvasive system 10
include but not are limited to glucose, ethanol, insulin, water,
carbon dioxide, blood oxygen, cholesterol, bilirubin, ketones,
fatty acids, lipoproteins, albumin, urea, creatinine, white blood
cells, red blood cells, hemoglobin, oxygenated hemoglobin,
carboxyhemoglobin, organic molecules, inorganic molecules,
pharmaceuticals, cytochrome, various proteins and chromophores,
microcalcifications, electrolytes, sodium, potassium, chloride,
bicarbonate, and hormones. As used herein to describe measurement
techniques, the term "continuous" is a broad term and is used in
its ordinary sense and refers, without limitation, to the taking of
discrete measurements more frequently than about once every 10
minutes, and/or the taking of a stream or series of measurements or
other data over any suitable time interval, for example, over an
interval of one to several seconds, minutes, hours, days, or
longer. As used herein to describe measurement techniques, the term
"intermittent" is a broad term and is used in its ordinary sense
and refers, without limitation, to the taking of measurements less
frequently than about once every 10 minutes.
[0057] The noninvasive system 10 preferably comprises a window
assembly 12, although in some embodiments the window assembly 12
may be omitted. One function of the window assembly 12 is to permit
infrared energy E to enter the noninvasive system 10 from the
sample S when it is placed against an upper surface 12a of the
window assembly 12. The window assembly 12 includes a heater layer
(see discussion below) which is employed to heat the material
sample S and stimulate emission of infrared energy therefrom. A
cooling system 14, preferably comprising a Peltier-type
thermoelectric device, is in thermally conductive relation to the
window assembly 12 so that the temperature of the window assembly
12 and the material sample S can be manipulated in accordance with
a detection methodology discussed in greater detail below. The
cooling system 14 includes a cold surface 14a which is in thermally
conductive relation to a cold reservoir 16 and the window assembly
12, and a hot surface 14b which is in thermally conductive relation
to a heat sink 18.
[0058] As the infrared energy E enters the noninvasive system 10,
it first passes through the window assembly 12, then through an
optical mixer 20, and then through a collimator 22. The optical
mixer 20 preferably comprises a light pipe having highly reflective
inner surfaces which randomize the directionality of the infrared
energy E as it passes therethrough and reflects against the mixer
walls. The collimator 22 also comprises a light pipe having
highly-reflective inner walls, but the walls diverge as they extend
away from the mixer 20. The divergent walls cause the infrared
energy E to tend to straighten as it advances toward the wider end
of the collimator 22, due to the angle of incidence of the infrared
energy when reflecting against the collimator walls.
[0059] From the collimator 22 the infrared energy E passes through
an array of filters 24, each of which allows only a selected
wavelength or band of wavelengths to pass therethrough. These
wavelengths/bands are selected to highlight or isolate the
absorptive effects of the analyte of interest in the detection
methodology discussed in greater detail below. Each filter 24 is
preferably in optical communication with a concentrator 26 and an
infrared detector 28. The concentrators 26 have highly reflective,
converging inner walls which concentrate the infrared energy as it
advances toward the detectors 28, increasing the density of the
energy incident upon the detectors 28.
[0060] The detectors 28 are in electrical communication with a
control system 30 which receives electrical signals from the
detectors 28 and computes the concentration of the analyte in the
sample S. The control system 30 is also in electrical communication
with the window 12 and cooling system 14, so as to monitor the
temperature of the window 12 and/or cooling system 14 and control
the delivery of electrical power to the window 12 and cooling
system 14.
[0061] a. Window Assembly
[0062] A preferred configuration of the window assembly 12 is shown
in perspective, as viewed from its underside (in other words, the
side of the window assembly 12 opposite the sample S), in FIG. 2.
The window assembly 12 generally comprises a main layer 32 formed
of a highly infrared-transmissive material and a heater layer 34
affixed to the underside of the main layer 32. The main layer 32 is
preferably formed from diamond, most preferably from
chemical-vapor-deposited ("CVD") diamond, with a preferred
thickness of about 0.25 millimeters. In other embodiments
alternative materials which are highly infrared-transmissive, such
as silicon or germanium, may be used in forming the main layer
32.
[0063] The heater layer 34 preferably comprises bus bars 36 located
at opposing ends of an array of heater elements 38. The bus bars 36
are in electrical communication with the elements 38 so that, upon
connection of the bus bars 36 to a suitable electrical power source
(not shown) a current may be passed through the elements 38 to
generate heat in the window assembly 12. The heater layer 34 may
also include one or more temperature sensors (not shown), such as
thermistors or resistance temperature devices (RTDs), to measure
the temperature of the window assembly 12 and provide temperature
feedback to the control system 30 (see FIG. 1).
[0064] Still referring to FIG. 2, the heater layer 34 preferably
comprises a first adhesion layer of gold or platinum (hereinafter
referred to as the "gold" layer) deposited over an alloy layer
which is applied to the main layer 32. The alloy layer comprises a
material suitable for implementation of the heater layer 34, such
as, by way of example, 10/90 titanium/tungsten, titanium/platinum,
nickel/chromium, or other similar material. The gold layer
preferably has a thickness of about 4000 .ANG., and the alloy layer
preferably has a thickness ranging between about 300 .ANG. and
about 500 .ANG.. The gold layer and/or the alloy layer may be
deposited onto the main layer 32 by chemical deposition including,
but not necessarily limited to, vapor deposition, liquid
deposition, plating, laminating, casting, sintering, or other
forming or deposition methodologies well known to those or ordinary
skill in the art. If desired, the heater layer 34 may be covered
with an electrically insulating coating which also enhances
adhesion to the main layer 32. One preferred coating material is
aluminum oxide. Other acceptable materials include, but are not
limited to, titanium dioxide or zinc selenide.
[0065] The heater layer 34 may incorporate a variable pitch
distance between centerlines of adjacent heater elements 38 to
maintain a constant power density, and promote a uniform
temperature, across the entire layer 34. Where a constant pitch
distance is employed, the preferred distance is at least about
50-100 microns. Although the heater elements 38 generally have a
preferred width of about 25 microns, their width may also be varied
as needed for the same reasons stated above.
[0066] Alternative structures suitable for use as the heater layer
34 include, but are not limited to, thermoelectric heaters,
radiofrequency (RF) heaters, infrared radiation heaters, optical
heaters, heat exchangers, electrical resistance heating grids, wire
bridge heating grids, or laser heaters. Whichever type of heater
layer is employed, it is preferred that the heater layer obscures
about 10% or less of the window assembly 12.
[0067] In a preferred embodiment, the window assembly 12 comprises
substantially only the main layer 32 and the heater layer 34. Thus,
when installed in an optical detection system such as the
noninvasive system 10 shown in FIG. 1, the window assembly 12 will
facilitate a minimally obstructed optical path between a
(preferably flat) upper surface 12a of the window assembly 12 and
the infrared detectors 28 of the noninvasive system 10. The optical
path 32 in the preferred noninvasive system 10 proceeds only
through the main layer 32 and heater layer 34 of the window
assembly 12 (including any antireflective, index-matching,
electrical insulating or protective coatings applied thereto or
placed therein), through the optical mixer 20 and collimator 22 and
to the detectors 28.
[0068] FIG. 3 depicts an exploded side view of an alternative
configuration for the window assembly 12, which may be used in
place of the configuration shown in FIG. 2. The window assembly 12
depicted in FIG. 3 includes near its upper surface (the surface
intended for contact with the sample S) a highly
infrared-transmissive, thermally conductive spreader layer 42.
Underlying the spreader layer 42 is a heater layer 44. A thin
electrically insulating layer (not shown), such as layer of
aluminum oxide, titanium dioxide or zinc selenide, may be disposed
between the heater layer 44 and the spreader layer 42. (An aluminum
oxide layer also increases adhesion of the heater layer 44 to the
spreader layer 42.) Adjacent to the heater layer 44 is a thermal
insulating and impedance matching layer 46. Adjacent to the thermal
insulating layer 46 is a thermally conductive inner layer 48. The
spreader layer 42 is coated on its top surface with a thin layer of
protective coating 50. The bottom surface of the inner layer 48 is
coated with a thin overcoat layer 52. Preferably, the protective
coating 50 and the overcoat layer 52 have antireflective
properties.
[0069] The spreader layer 42 is preferably formed of a highly
infrared-transmissive material having a high thermal conductivity
sufficient to facilitate heat transfer from the heater layer 44
uniformly into the material sample S when it is placed against the
window assembly 12. Other effective materials include, but are not
limited to, CVD diamond, diamondlike carbon, gallium arsenide,
germanium, and other infrared-transmissive materials having
sufficiently high thermal conductivity. Preferred dimensions for
the spreader layer 42 are about one inch in diameter and about
0.010 inch thick. As shown in FIG. 3, a preferred embodiment of the
spreader layer 42 incorporates a beveled edge. Although not
required, an approximate 45-degree bevel is preferred.
[0070] The protective layer 50 is intended to protect the top
surface of the spreader layer 42 from damage. Ideally, the
protective layer is highly infrared-transmissive and highly
resistant to mechanical damage, such as scratching or abrasion. It
is also preferred that the protective layer 50 and the overcoat
layer 52 have high thermal conductivity and antireflective and/or
index-matching properties. A satisfactory material for use as the
protective layer 50 and the overcoat layer 52 is the multi-layer
Broad Band Anti-Reflective Coating produced by Deposition Research
Laboratories, Inc. of St. Charles, Mo. Diamondlike carbon coatings
are also suitable.
[0071] Except as noted below, the heater layer 44 is generally
similar to the heater layer 34 employed in the window assembly
shown in FIG. 2. Alternatively, the heater layer 44 may comprise a
doped infrared-transmissive material, such as a doped silicon
layer, with regions of higher and lower resistivity. The heater
layer 44 preferably has a resistance of about 2 ohms and has a
preferred thickness of about 1,500 angstroms. A preferred material
for forming the heater layer 44 is a gold alloy, but other
acceptable materials include, but are not limited to, platinum,
titanium, tungsten, copper, and nickel.
[0072] The thermal insulating layer 46 prevents the dissipation of
heat from the heater element 44 while allowing the cooling system
14 to effectively cool the material sample S (see FIG. 1). This
layer 46 comprises a material having thermally insulative (e.g.,
lower thermal conductivity than the spreader layer 42) and infrared
transmissive qualities. A preferred material is a germanium
arsenic-selenium compound of the calcogenide glass family known as
AMTIR-1 produced by Amorphous Materials, Inc. of Garland, Tex. The
pictured embodiment has a diameter of about 0.85 inches and a
preferred thickness in the range of about 0.005 to about 0.010
inches. As heat generated by the heater layer 44 passes through the
spreader layer 42 into the material sample S, the thermal
insulating layer 46 insulates this heat.
[0073] The inner layer 48 is formed of thermally conductive
material, preferably crystalline silicon formed using a
conventional floatzone crystal growth method. The purpose of the
inner layer 48 is to serve as a cold-conducting mechanical base for
the entire layered window assembly.
[0074] The overall optical transmission of the window assembly 12
shown in FIG. 3 is preferably at least 70%. The window assembly 12
of FIG. 3 is preferably held together and secured to the
noninvasive system 10 by a holding bracket (not shown). The bracket
is preferably formed of a glass-filled plastic, for example Ultem
2300, manufactured by General Electric. Ultem 2300 has low thermal
conductivity which prevents heat transfer from the layered window
assembly 12.
[0075] b. Cooling System
[0076] The cooling system 14 (see FIG. 1) preferably comprises a
Peltier-type thermoelectric device. Thus, the application of an
electrical current to the preferred cooling system 14 causes the
cold surface 14a to cool and causes the opposing hot surface 14b to
heat up. The cooling system 14 cools the window assembly 12 via the
situation of the window assembly 12 in thermally conductive
relation to the cold surface 14a of the cooling system 14. It is
contemplated that the cooling system 14, the heater layer 34, or
both, can be operated to induce a desired time-varying temperature
in the window assembly 12 to create an oscillating thermal gradient
in the sample S, in accordance with various analyte-detection
methodologies discussed herein.
[0077] Preferably, the cold reservoir 16 is positioned between the
cooling system 14 and the window assembly 12, and functions as a
thermal conductor between the system 14 and the window assembly 12.
The cold reservoir 16 is formed from a suitable thermally
conductive material, preferably brass. Alternatively, the window
assembly 12 can be situated in direct contact with the cold surface
14a of the cooling system 14.
[0078] In alternative embodiments, the cooling system 14 may
comprise a heat exchanger through which a coolant, such as air,
nitrogen or chilled water, is pumped, or a passive conduction
cooler such as a heat sink. As a further alternative, a gas coolant
such as nitrogen may be circulated through the interior of the
noninvasive system 10 so as to contact the underside of the window
assembly 12 (see FIG. 1) and conduct heat therefrom.
[0079] FIG. 4 is a top schematic view of a preferred arrangement of
the window assembly 12 (of the type shown in FIG. 2) and the cold
reservoir 16, and FIG. 5 is a top schematic view of an alternative
arrangement in which the window assembly 12 directly contacts the
cooling system 14. The cold reservoir 16/cooling system 14
preferably contacts the underside of the window assembly 12 along
opposing edges thereof, on either side of the heater layer 34. With
thermal conductivity thus established between the window assembly
12 and the cooling system 14, the window assembly can be cooled as
needed during operation of the noninvasive system 10. In order to
promote a substantially uniform or isothermal temperature profile
over the upper surface of the window assembly 12, the pitch
distance between centerlines of adjacent heater elements 38 may be
made smaller (thereby increasing the density of heater elements 38)
near the region(s) of contact between the window assembly 12 and
the cold reservoir 16/cooling system 14. As a supplement or
alternative, the heater elements 38 themselves may be made wider
near these regions of contact. As used herein, "isothermal" is a
broad term and is used in its ordinary sense and refers, without
limitation, to a condition in which, at a given point in time, the
temperature of the window assembly 12 or other structure is
substantially uniform across a surface intended for placement in
thermally conductive relation to the material sample S. Thus,
although the temperature of the structure or surface may fluctuate
over time, at any given point in time the structure or surface may
nonetheless be isothermal.
[0080] The heat sink 18 drains waste heat from the hot surface 14b
of the cooling system 16 and stabilizes the operational temperature
of the noninvasive system 10. The preferred heat sink 18 (see FIG.
6) comprises a hollow structure formed from brass or any other
suitable material having a relatively high specific heat and high
heat conductivity. The heat sink 18 has a conduction surface 18a
which, when the heat sink 18 is installed in the noninvasive system
18, is in thermally conductive relation to the hot surface 14b of
the cooling system 14 (see FIG. 1). A cavity 54 is formed in the
heat sink 18 and preferably contains a phase-change material (not
shown) to increase the capacity of the sink 18. A preferred phase
change material is a hydrated salt, such as calciumchloride
hexahydrate, available under the name TH29 from PCM Thermal
Solutions, Inc., of Naperville, Ill. Alternatively, the cavity 54
may be omitted to create a heat sink 18 comprising a solid, unitary
mass. The heat sink 18 also forms a number of fins 56 to further
increase the conduction of heat from the sink 18 to surrounding
air.
[0081] Alternatively, the heat sink 18 may be formed integrally
with the optical mixer 20 and/or the collimator 22 as a unitary
mass of rigid, heat-conductive material such as brass or aluminum.
In such a heat sink, the mixer 20 and/or collimator 22 extend
axially through the heat sink 18, and the heat sink defines the
inner walls of the mixer 20 and/or collimator 22. These inner walls
are coated and/or polished to have appropriate reflectivity and
nonabsorbance in infrared wavelengths as will be further described
below. Where such a unitary heat sink-mixer-collimator is employed,
it is desirable to thermally insulate the detector array from the
heat sink.
[0082] It should be understood that any suitable structure may be
employed to heat and/or cool the material sample S, instead of or
in addition to the window assembly 12/cooling system 14 disclosed
above, so long a proper degree of cycled heating and/or cooling are
imparted to the material sample S. In addition other forms of
energy, such as but not limited to light, radiation, chemically
induced heat, friction and vibration, may be employed to heat the
material sample S. It will be further appreciated that heating of
the sample can achieved by any suitable method, such as convection,
conduction, radiation, etc.
[0083] c. Optics
[0084] As shown in FIG. 1, the optical mixer 20 comprises a light
pipe with an inner surface coating which is highly reflective and
minimally absorptive in infrared wavelengths, preferably a polished
gold coating, although other suitable coatings may be used where
other wavelengths of electromagnetic radiation are employed. The
pipe itself may be fabricated from a another rigid material such as
aluminum or stainless steel, as long as the inner surfaces are
coated or otherwise treated to be highly reflective. Preferably,
the optical mixer 20 has a rectangular cross-section (as taken
orthogonal to the longitudinal axis A-A of the mixer 20 and the
collimator 22), although other cross-sectional shapes, such as
other polygonal shapes or circular or elliptical shapes, may be
employed in alternative embodiments. The inner walls of the optical
mixer 20 are substantially parallel to the longitudinal axis A-A of
the mixer 20 and the collimator 22. The highly reflective and
substantially parallel inner walls of the mixer 20 maximize the
number of times the infrared energy E will be reflected between the
walls of the mixer 20, thoroughly mixing the infrared energy E as
it propagates through the mixer 20. In a presently preferred
embodiment, the mixer 20 is about 1.2 inches to 2.4 inches in
length and its cross-section is a rectangle of about 0.4 inches by
about 0.6 inches. Of course, other dimensions may be employed in
constructing the mixer 20. In particular it is be advantageous to
miniaturize the mixer or otherwise make it as small as possible
[0085] Still referring to FIG. 1, the collimator 22 comprises a
tube with an inner surface coating which is highly reflective and
minimally absorptive in infrared wavelengths, preferably a polished
gold coating. The tube itself may be fabricated from a another
rigid material such as aluminum, nickel or stainless steel, as long
as the inner surfaces are coated or otherwise treated to be highly
reflective. Preferably, the collimator 22 has a rectangular
cross-section, although other cross-sectional shapes, such as other
polygonal shapes or circular, parabolic or elliptical shapes, may
be employed in alternative embodiments. The inner walls of the
collimator 22 diverge as they extend away from the mixer 20.
Preferably, the inner walls of the collimator 22 are substantially
straight and form an angle of about 7 degrees with respect to the
longitudinal axis A-A. The collimator 22 aligns the infrared energy
E to propagate in a direction that is generally parallel to the
longitudinal axis A-A of the mixer 20 and the collimator 22, so
that the infrared energy E will strike the surface of the filters
24 at an angle as close to 90 degrees as possible.
[0086] In a presently preferred embodiment, the collimator is about
7.5 inches in length. At its narrow end 22a, the cross-section of
the collimator 22 is a rectangle of about 0.4 inches by 0.6 inches.
At its wide end 22b, the collimator 22 has a rectangular
cross-section of about 1.8 inches by 2.6 inches. Preferably, the
collimator 22 aligns the infrared energy E to an angle of incidence
(with respect to the longitudinal axis A-A) of about 0-15 degrees
before the energy E impinges upon the filters 24. Of course, other
dimensions or incidence angles may be employed in constructing and
operating the collimator 22.
[0087] With further reference to FIGS. 1 and 6A, each concentrator
26 comprises a tapered surface oriented such that its wide end 26a
is adapted to receive the infrared energy exiting the corresponding
filter 24, and such that its narrow end 26b is adjacent to the
corresponding detector 28. The inward-facing surfaces of the
concentrators 26 have an inner surface coating which is highly
reflective and minimally absorptive in infrared wavelengths,
preferably a polished gold coating. The concentrators 26 themselves
may be fabricated from a another rigid material such as aluminum,
nickel or stainless steel, so long as their inner surfaces are
coated or otherwise treated to be highly reflective.
[0088] Preferably, the concentrators 26 have a rectangular
cross-section (as taken orthogonal to the longitudinal axis A-A),
although other cross-sectional shapes, such as other polygonal
shapes or circular, parabolic or elliptical shapes, may be employed
in alternative embodiments. The inner walls of the concentrators
converge as they extend toward the narrow end 26b. Preferably, the
inner walls of the collimators 26 are substantially straight and
form an angle of about 8 degrees with respect to the longitudinal
axis A-A. Such a configuration is adapted to concentrate infrared
energy as it passes through the concentrators 26 from the wide end
26a to the narrow end 26b, before reaching the detectors 28.
[0089] In a presently preferred embodiment, each concentrator 26 is
about 1.5 inches in length. At the wide end 26a, the cross-section
of each concentrator 26 is a rectangle of about 0.6 inches by 0.57
inches. At the narrow end 26b, each concentrator 26 has a
rectangular cross-section of about 0.177 inches by 0.177 inches. Of
course, other dimensions or incidence angles may be employed in
constructing the concentrators 26.
[0090] d. Filters
[0091] The filters 24 preferably comprise standard
interference-type infrared filters, widely available from
manufacturers such as Optical Coating Laboratory, Inc. ("OCLI") of
Santa Rosa, Calif. In the embodiment illustrated in FIG. 1, a
3.times.4 array of filters 24 is positioned above a 3.times.4 array
of detectors 28 and concentrators 26. As employed in this
embodiment, the filters 24 are arranged in four groups of three
filters having the same wavelength sensitivity. These four groups
have bandpass center wavelengths of 7.15 .mu.m.+-.0.03 .mu.m, 8.40
.mu.m.+-.0.03 .mu.m, 9.48 .mu.m.+-.0.04 .mu.m, and 11.10
.mu.m.+-.0.04 .mu.m, respectively, which correspond to wavelengths
around which water and glucose absorb electromagnetic radiation.
Typical bandwidths for these filters range from 0.20 .mu.m to 0.50
.mu.m.
[0092] In an alternative embodiment, the array of
wavelength-specific filters 24 may be replaced with a single
Fabry-Perot interferometer, which can provide wavelength
sensitivity which varies as a sample of infrared energy is taken
from the material sample S. Thus, this embodiment permits the use
of only one detector 28, the output signal of which varies in
wavelength specificity over time. The output signal can be
de-multiplexed based on the wavelength sensitivities induced by the
Fabry-Perot interferometer, to provide a multiple-wavelength
profile of the infrared energy emitted by the material sample S. In
this embodiment, the optical mixer 20 may be omitted, as only one
detector 28 need be employed.
[0093] In still other embodiments, the array of filters 24 may
comprise a filter wheel that rotates different filters with varying
wavelength sensitivities over a single detector 24. Alternatively,
an electronically tunable infrared filter may be employed in a
manner similar to the Fabry-Perot interferometer discussed above,
to provide wavelength sensitivity which varies during the detection
process. In either of these embodiments, the optical mixer 20 may
be omitted, as only one detector 28 need be employed.
[0094] e. Detectors
[0095] The detectors 28 may comprise any detector type suitable for
sensing infrared energy, preferably in the mid-infrared
wavelengths. For example, the detectors 28 may comprise
mercury-cadmium-telluride (MCT) detectors. A detector such as a
Fermionics (Simi Valley, Calif.) model PV-9.1 with a PVA481-1
pre-amplifier is acceptable. Similar units from other manufacturers
such as Graseby (Tampa, Fla.) can be substituted. Other suitable
components for use as the detectors 28 include pyroelectric
detectors, thermopiles, bolometers, silicon microbolometers and
lead-salt focal plane arrays.
[0096] f. Control System
[0097] FIG. 7 depicts the control system 30 in greater detail, as
well as the interconnections between the control system and other
relevant portions of the noninvasive system. The control system
includes a temperature control subsystem and a data acquisition
subsystem.
[0098] In the temperature control subsystem, temperature sensors
(such as RTDs and/or thermistors) located in the window assembly 12
provide a window temperature signal to a synchronous
analog-to-digital conversion system 70 and an asynchronous
analog-to-digital conversion system 72. The A/D systems 70, 72 in
turn provide a digital window temperature signal to a digital
signal processor (DSP) 74. The processor 74 executes a window
temperature control algorithm and determines appropriate control
inputs for the heater layer 34 of the window assembly 12 and/or for
the cooling system 14, based on the information contained in the
window temperature signal. The processor 74 outputs one or more
digital control signals to a digital-to-analog conversion system 76
which in turn provides one or more analog control signals to
current drivers 78. In response to the control signal(s), the
current drivers 78 regulate the power supplied to the heater layer
34 and/or to the cooling system 14. In one embodiment, the
processor 74 provides a control signal through a digital I/O device
77 to a pulse-width modulator (PWM) control 80, which provides a
signal that controls the operation of the current drivers 78.
Alternatively, a low-pass filter (not shown) at the output of the
PWM provides for continuous operation of the current drivers
78.
[0099] In another embodiment, temperature sensors may be located at
the cooling system 14 and appropriately connected to the A/D
system(s) and processor to provide closed-loop control of the
cooling system as well.
[0100] In yet another embodiment, a detector cooling system 82 is
located in thermally conductive relation to one or more of the
detectors 28. The detector cooling system 82 may comprise any of
the devices disclosed above as comprising the cooling system 14,
and preferably comprises a Peltier-type thermoelectric device. The
temperature control subsystem may also include temperature sensors,
such as RTDs and/or thermistors, located in or adjacent to the
detector cooling system 82, and electrical connections between
these sensors and the asynchronous A/D system 72. The temperature
sensors of the detector cooling system 82 provide detector
temperature signals to the processor 74. In one embodiment, the
detector cooling system 82 operates independently of the window
temperature control system, and the detector cooling system
temperature signals are sampled using the asynchronous A/D system
72. In accordance with the temperature control algorithm, the
processor 74 determines appropriate control inputs for the detector
cooling system 82, based on the information contained in the
detector temperature signal. The processor 74 outputs digital
control signals to the D/A system 76 which in turn provides analog
control signals to the current drivers 78. In response to the
control signals, the current drivers 78 regulate the power supplied
to the detector cooling system 14. In one embodiment, the processor
74 also provides a control signal through the digital I/O device 77
and the PWM control 80, to control the operation of the detector
cooling system 82 by the current drivers 78. Alternatively, a
low-pass filter (not shown) at the output of the PWM provides for
continuous operation of the current drivers 78.
[0101] In the data acquisition subsystem, the detectors 28 respond
to the infrared energy E incident thereon by passing one or more
analog detector signals to a preamp 84. The preamp 84 amplifies the
detector signals and passes them to the synchronous A/D system 70,
which converts the detector signals to digital form and passes them
to the processor 74. The processor 74 determines the concentrations
of the analyte(s) of interest, based on the detector signals and a
concentration-analysis algorithm and/or phase/concentration
regression model stored in a memory module 88. The
concentration-analysis algorithm and/or phase/concentration
regression model may be developed according to any of the analysis
methodologies discussed herein. The processor may communicate the
concentration results and/or other information to a display
controller 86, which operates a display (not shown), such as an LCD
display, to present the information to the user.
[0102] A watchdog timer 94 may be employed to ensure that the
processor 74 is operating correctly. If the watchdog timer 94 does
not receive a signal from the processor 74 within a specified time,
the watchdog timer 94 resets the processor 74. The control system
may also include a JTAG interface 96 to enable testing of the
noninvasive system 10.
[0103] In one embodiment, the synchronous A/D system 70 comprises a
20-bit, 14 channel system, and the asynchronous A/D system 72
comprises a 16-bit, 16 channel system. The preamp may comprise a
12-channel preamp corresponding to an array of 12 detectors 28.
[0104] The control system may also include a serial port 90 or
other conventional data port to permit connection to a personal
computer 92. The personal computer can be employed to update the
algorithm(s) and/or phase/concentration regression model(s) stored
in the memory module 88, or to download a compilation of
analyte-concentration data from the noninvasive system. A real-time
clock or other timing device may be accessible by the processor 74
to make any time-dependent calculations which may be desirable to a
user.
[0105] 2. Analysis Methodology
[0106] The detector(s) 28 of the noninvasive system 10 are used to
detect the infrared energy emitted by the material sample S in
various desired wavelengths. At each measured wavelength, the
material sample S emits infrared energy at an intensity which
varies over time. The time-varying intensities arise largely in
response to the use of the window assembly 12 (including its heater
layer 34) and the cooling system 14 to induce a thermal gradient in
the material sample S. As used herein, "thermal gradient" is a
broad term and is used in its ordinary sense and refers, without
limitation, to a difference in temperature and/or thermal energy
between different locations, such as different depths, of a
material sample, which can be induced by any suitable method of
increasing or decreasing the temperature and/or thermal energy in
one or more locations of the sample. As will be discussed in detail
below, the concentration of an analyte of interest (such as
glucose) in the material sample S can be determined with a device
such as the noninvasive system 10, by comparing the time-varying
intensity profiles of the various measured wavelengths.
[0107] Analysis methodologies are discussed herein within the
context of detecting the concentration of glucose within a material
sample, such as a tissue sample, which includes a large proportion
of water. However, it will evident that these methodologies are not
limited to this context and may be applied to the detection of a
wide variety of analytes within a wide variety of sample types. It
should also be understood that other suitable analysis
methodologies and suitable variations of the disclosed
methodologies may be employed in operating an analyte detection
system, such as the noninvasive system 10.
[0108] As shown in FIG. 8, a first reference signal P may be
measured at a first reference wavelength. The first reference
signal P is measured at a wavelength where water strongly absorbs
(e.g., 2.9 .mu.m or 6.1 .mu.m). Because water strongly absorbs
radiation at these wavelengths, the detector signal intensity is
reduced at those wavelengths. Moreover, at these wavelengths water
absorbs the photon emissions emanating from deep inside the sample.
The net effect is that a signal emitted at these wavelengths from
deep inside the sample is not easily detected. The first reference
signal P is thus a good indicator of thermal-gradient effects near
the sample surface and may be known as a surface reference signal.
This signal may be calibrated and normalized, in the absence of
heating or cooling applied to the sample, to a baseline value of 1.
For greater accuracy, more than one first reference wavelength may
be measured. For example, both 2.9 .mu.m and 6.1 .mu.m may be
chosen as first reference wavelengths.
[0109] As further shown in FIG. 8, a second reference signal R may
also be measured. The second signal R may be measured at a
wavelength where water has very low absorbance (e.g., 3.6 .mu.m or
4.2 .mu.m). This second reference signal R thus provides the
analyst with information concerning the deeper regions of the
sample, whereas the first signal P provides information concerning
the sample surface. This signal may also be calibrated and
normalized, in the absence of heating or cooling applied to the
sample, to a baseline value of 1. As with the first (surface)
reference signal P, greater accuracy may be obtained by using more
than one second (deep) reference signal R.
[0110] In order to determine analyte concentration, a third
(analytical) signal Q is also measured. This signal is measured at
an IR absorbance peak of the selected analyte. The IR absorbance
peaks for glucose are in the range of about 6.5 .mu.m to 11.0
.mu.m. This detector signal may also be calibrated and normalized,
in the absence of heating or cooling applied to the material sample
S, to a baseline value of 1. As with the reference signals P, R,
the analytical signal Q may be measured at more than one absorbance
peak.
[0111] Optionally, or additionally, reference signals may be
measured at wavelengths that bracket the analyte absorbance peak.
These signals may be advantageously monitored at reference
wavelengths which do not overlap the analyte absorbance peaks.
Further, it is advantageous to measure reference wavelengths at
absorbance peaks which do not overlap the absorbance peaks of other
possible constituents contained in the sample.
[0112] a. Basic Thermal Gradient
[0113] As further shown in FIG. 8, the signal intensities P, Q, R
are shown initially at the normalized baseline signal intensity of
1. This of course reflects the baseline radiative behavior of a
test sample in the absence of applied heating or cooling. At a time
t.sub.C, the surface of the sample is subjected to a temperature
event which induces a thermal gradient in the sample. The gradient
can be induced by heating or cooling the sample surface. The
example shown in FIG. 8 uses cooling, for example, using a
10.degree. C. cooling event. In response to the cooling event, the
intensities of the detector signals P, Q, R decrease over time.
[0114] Since the cooling of the sample is neither uniform nor
instantaneous, the surface cools before the deeper regions of the
sample cool. As each of the signals P, Q, R drop in intensity, a
pattern emerges. Signal intensity declines as expected, but as the
signals P, Q, R reach a given amplitude value (or series of
amplitude values: 150, 152, 154, 156, 158), certain temporal
effects are noted. After the cooling event is induced at t.sub.C,
the first (surface) reference signal P declines in amplitude most
rapidly, reaching a checkpoint 150 first, at time t.sub.P. This is
due to the fact that the first reference signal P mirrors the
sample's radiative characteristics near the surface of the sample.
Since the sample surface cools before the underlying regions, the
surface (first) reference signal P drops in intensity first.
[0115] Simultaneously, the second reference signal R is monitored.
Since the second reference signal R corresponds to the radiation
characteristics of deeper regions of the sample, which do not cool
as rapidly as the surface (due to the time needed for the surface
cooling to propagate into the deeper regions of the sample), the
intensity of signal R does not decline until slightly later.
Consequently, the signal R does not reach the magnitude 150 until
some later time t.sub.R. In other words, there exists a time delay
between the time t.sub.P at which the amplitude of the first
reference signal P reaches the checkpoint 150 and the time t.sub.R
at which the second reference signal R reaches the same checkpoint
150. This time delay can be expressed as a phase difference
.PHI.(.lambda.). Additionally, a phase difference may be measured
between the analytical signal Q and either or both reference
signals P, R.
[0116] As the concentration of analyte increases, the amount of
absorbance at the analytical wavelength increases. This reduces the
intensity of the analytical signal Q in a concentration-dependent
way. Consequently, the analytical signal Q reaches intensity 150 at
some intermediate time t.sub.Q. The higher the concentration of
analyte, the more the analytical signal Q shifts to the left in
FIG. 8. As a result, with increasing analyte concentration, the
phase difference .PHI.(.lambda.) decreases relative to the first
(surface) reference signal P and increases relative to the second
(deep tissue) reference signal R. The phase difference(s)
.PHI.(.lambda.) are directly related to analyte concentration and
can be used to make accurate determinations of analyte
concentration.
[0117] The phase difference .PHI.(.lambda.) between the first
(surface) reference signal P and the analytical signal Q is
represented by the equation:
.PHI.(.lambda.)=.vertline.t.sub.P-t.sub.Q.vertline.
[0118] The magnitude of this phase difference decreases with
increasing analyte concentration.
[0119] The phase difference .PHI.(.lambda.) between the second
(deep tissue) reference signal R and the analytical signal Q signal
is represented by the equation:
.PHI.(.lambda.)=.vertline.t.sub.Q-t.sub.R.Arrow-up bold.
[0120] The magnitude of this phase difference increases with
increasing analyte concentration.
[0121] Accuracy may be enhanced by choosing several checkpoints,
for example, 150, 152, 154, 156, and 158 and averaging the phase
differences observed at each checkpoint. The accuracy of this
method may be further enhanced by integrating the phase
difference(s) continuously over the entire test period. Because in
this example only a single temperature event (here, a cooling
event) has been induced, the sample reaches a new lower equilibrium
temperature and the signals stabilize at a new constant level
I.sub.F. Of course, the method works equally well with thermal
gradients induced by heating or by the application or introduction
of other forms of energy, such as but not limited to light,
radiation, chemically induced heat, friction and vibration.
[0122] This methodology is not limited to the determination of
phase difference. At any given time (for example, at a time
t.sub.X) the amplitude of the analytical signal Q may be compared
to the amplitude of either or both of the reference signals P, R.
The difference in amplitude may be observed and processed to
determine analyte concentration.
[0123] This method, the variants disclosed herein, and the
apparatus disclosed as suitable for application of the method(s),
are not limited to the detection of in-vivo glucose concentration.
The method and disclosed variants and apparatus may be used on
human, animal, or even plant subjects, or on organic or inorganic
compositions in a non-medical setting. The method may be used to
take measurements of in-vivo or in-vitro samples of virtually any
kind. The method is useful for measuring the concentration of a
wide range of additional chemical analytes, including but not
limited to, glucose, ethanol, insulin, water, carbon dioxide, blood
oxygen, cholesterol, bilirubin, ketones, fatty acids, lipoproteins,
albumin, urea, creatinine, white blood cells, red blood cells,
hemoglobin, oxygenated hemoglobin, carboxyhemoglobin, organic
molecules, inorganic molecules, pharmaceuticals, cytochrome,
various proteins and chromophores, microcalcifications, hormones,
as well as other chemical compounds. To detect a given analyte, one
needs only to select appropriate analytical and reference
wavelengths.
[0124] The method is adaptable and may be used to determine
chemical concentrations in samples of body fluids (e.g., blood,
urine or saliva) once they have been extracted from a patient. In
fact, the method may be used for the measurement of in-vitro
samples of virtually any kind.
[0125] b. Modulated Thermal Gradient
[0126] In a variation of the methodology described above, a
periodically modulated thermal gradient can be employed to make
accurate determinations of analyte concentration.
[0127] As previously shown in FIG. 8, once a thermal gradient is
induced in the sample, the reference and analytical signals P, Q, R
fall out of phase with respect to each other. This phase difference
.PHI.(.lambda.) is present whether the thermal gradient is induced
through heating or cooling. By alternatively subjecting the test
sample to cyclic pattern of heating, cooling, or alternately
heating and cooling, an oscillating thermal gradient may be induced
in a sample for an extended period of time.
[0128] An oscillating thermal gradient is illustrated using a
sinusoidally modulated gradient. FIG. 9 depicts detector signals
emanating from a test sample. As with the methodology shown in FIG.
8, one or more reference signals J, L are measured. One or more
analytical signals K are also monitored. These signals may be
calibrated and normalized, in the absence of heating or cooling
applied to the sample, to a baseline value of 1. FIG. 9 shows the
signals after normalization. At some time t.sub.C, a temperature
event (e.g., cooling) is induced at the sample surface. This causes
a decline in the detector signal. As shown in FIG. 8, the signals
(P, Q, R) decline until the thermal gradient disappears and a new
equilibrium detector signal I.sub.F is reached. In the method shown
in FIG. 9, as the gradient begins to disappear at a signal
intensity 160, a heating event, at a time t.sub.W, is induced in
the sample surface. As a result the detector output signals J, K, L
will rise as the sample temperature rises. At some later time
t.sub.C2, another cooling event is induced, causing the temperature
and detector signals to decline. This cycle of cooling and heating
may be repeated over a time interval of arbitrary length. Moreover,
if the cooling and heating events are timed properly, a
periodically modulated thermal gradient may be induced in the test
sample.
[0129] As previously explained in the discussions relating to FIG.
8, the phase difference .PHI.(.lambda.) may be measured and used to
determine analyte concentration. FIG. 9 shows that the first
(surface) reference signal J declines and rises in intensity first.
The second (deep tissue) reference signal L declines and rises in a
time-delayed manner relative to the first reference signal J. The
analytical signal K exhibits a time/phase delay dependent on the
analyte concentration. With increasing concentration, the
analytical signal K shifts to the left in FIG. 9. As with FIG. 8,
the phase difference .PHI.(.lambda.) may be measured. For example,
a phase difference .PHI.(.lambda.) between the second reference
signal L and the analytical signal K, may be measured at a set
amplitude 162 as shown in FIG. 9. Again, the magnitude of the phase
signal reflects the analyte concentration of the sample.
[0130] The phase-difference information compiled by any of the
methodologies disclosed herein can correlated by the control system
30 (see FIG. 1) with previously determined phase-difference
information to determine the analyte concentration in the sample.
This correlation could involve comparison of the phase-difference
information received from analysis of the sample, with a data set
containing the phase-difference profiles observed from analysis of
wide variety of standards of known analyte concentration. In one
embodiment, a phase/concentration curve or regression model is
established by applying regression techniques to a set of
phase-difference data observed in standards of known analyte
concentration. This curve is used to estimate the analyte
concentration in a sample based on the phase-difference information
received from the sample.
[0131] Advantageously, the phase difference .PHI.(.lambda.) may be
measured continuously throughout the test period. The
phase-difference measurements may be integrated over the entire
test period for an extremely accurate measure of phase difference
.PHI.(.lambda.). Accuracy may also be improved by using more than
one reference signal and/or more than one analytical signal.
[0132] As an alternative or as a supplement to measuring phase
difference(s), differences in amplitude between the analytical and
reference signal(s) may be measured and employed to determine
analyte concentration. Additional details relating to this
technique and not necessary to repeat here may be found in the
Assignee's U.S. patent application Ser. No. 09/538,164,
incorporated by reference below.
[0133] Additionally, these methods may be advantageously employed
to simultaneously measure the concentration of one or more
analytes. By choosing reference and analyte wavelengths that do not
overlap, phase differences can be simultaneously measured and
processed to determine analyte concentrations. Although FIG. 9
illustrates the method used in conjunction with a sinusoidally
modulated thermal gradient, the principle applies to thermal
gradients conforming to any periodic function. In more complex
cases, analysis using signal processing with Fourier transforms or
other techniques allows accurate determinations of phase difference
.PHI.(.lambda.) and analyte concentration.
[0134] As shown in FIG. 10, the magnitude of the phase differences
may be determined by measuring the time intervals between the
amplitude peaks (or troughs) of the reference signals J, L and the
analytical signal K. Alternatively, the time intervals between the
"zero crossings" (the point at which the signal amplitude changes
from positive to negative, or negative to positive) may be used to
determine the phase difference between the analytical signal K and
the reference signals J, L. This information is subsequently
processed and a determination of analyte concentration may then be
made. This particular method has the advantage of not requiring
normalized signals.
[0135] As a further alternative, two or more driving frequencies
may be employed to determine analyte concentrations at selected
depths within the sample. A slow (e.g., 1 Hz) driving frequency
creates a thermal gradient which penetrates deeper into the sample
than the gradient created by a fast (e.g., 3 Hz) driving frequency.
This is because the individual heating and/or cooling events are
longer in duration where the driving frequency is lower. Thus, the
use of a slow driving frequency provides analyte-concentration
information from a deeper "slice" of the sample than does the use
of a fast driving frequency.
[0136] It has been found that when analyzing a sample of human
skin, a temperature event of 10.degree. C. creates a thermal
gradient which penetrates to a depth of about 150 .mu.m, after
about 500 ms of exposure. Consequently, a cooling/heating cycle or
driving frequency of 1 Hz provides information to a depth of about
150 .mu.m. It has also been determined that exposure to a
temperature event of 10.degree. C. for about 167 ms creates a
thermal gradient that penetrates to a depth of about 50 .mu.m.
Therefore, a cooling/heating cycle of 3 Hz provides information to
a depth of about 50 .mu.m. By subtracting the detector signal
information measured at a 3 Hz driving frequency from the detector
signal information measured at a 1 Hz driving frequency, one can
determine the analyte concentration(s) in the region of skin
between 50 and 150 .mu.m. Of course, a similar approach can be used
to determine analyte concentrations at any desired depth range
within any suitable type of sample.
[0137] As shown in FIG. 11, alternating deep and shallow thermal
gradients may be induced by alternating slow and fast driving
frequencies. As with the methods described above, this variation
also involves the detection and measurement of phase differences
.PHI.(.lambda.) between reference signals G, G' and analytical
signals H, H'. Phase differences are measured at both fast (e.g., 3
Hz) and slow (e.g., 1 Hz) driving frequencies. The slow driving
frequency may continue for an arbitrarily chosen number of cycles
(in region SL1), for example, two full cycles. Then the fast
driving frequency is employed for a selected duration, in region
F.sub.1. The phase difference data is compiled in the same manner
as disclosed above. In addition, the fast frequency (shallow
sample) phase difference data may be subtracted from the slow
frequency (deep sample) data to provide an accurate determination
of analyte concentration in the region of the sample between the
gradient penetration depth associated with the fast driving
frequency and that associated with the slow driving frequency.
[0138] The driving frequencies (e.g., 1 Hz and 3 Hz) can be
multiplexed as shown in FIG. 12. The fast (3 Hz) and slow (1 Hz)
driving frequencies can be superimposed rather than sequentially
implemented. During analysis, the data can be separated by
frequency (using Fourier transform or other techniques) and
independent measurements of phase delay at each of the driving
frequencies may be calculated. Once resolved, the two sets of phase
delay data are processed to determine absorbance and analyte
concentration.
[0139] Additional details not necessary to repeat here may be found
in U.S. Pat. No. 6,198,949, titled SOLID-STATE NON-INVASIVE
INFRARED ABSORPTION SPECTROMETER FOR THE GENERATION AND CAPTURE OF
THERMAL GRADIENT SPECTRA FROM LIVING TISSUE, issued Mar. 6, 2001;
U.S. Pat. No. 6,161,028, titled METHOD FOR DETERMINING ANALYTE
CONCENTRATION USING PERIODIC TEMPERATURE MODULATION AND PHASE
DETECTION, issued Dec. 12, 2000; U.S. Pat. No. 5,877,500, titled
MULTICHANNEL INFRARED DETECTOR WITH OPTICAL CONCENTRATORS FOR EACH
CHANNEL, issued on Mar. 2, 1999; U.S. patent application Ser. No.
09/538,164, filed Mar. 30, 2000 and titled METHOD AND APPARATUS FOR
DETERMINING ANALYTE CONCENTRATION USING PHASE AND MAGNITUDE
DETECTION OF A RADIATION TRANSFER FUNCTION; U.S. patent application
Ser. No. 09/427,178 (published as WIPO PCT Publication No. WO
01/30236 on May 3, 2001), filed Oct. 25, 1999, titled SOLID-STATE
NON-INVASIVE THERMAL CYCLING SPECTROMETER; U.S. Provisional Patent
Application No. 60/336,404, filed Oct. 29, 2001, titled WINDOW
ASSEMBLY; U.S. Provisional Patent Application No. 60/340,794, filed
Dec. 11, 2001, titled REAGENT-LESS WHOLE-BLOOD GLUCOSE METER; U.S.
Provisional Patent Application No. 60/340,435, filed Dec. 12, 2001,
titled CONTROL SYSTEM FOR BLOOD CONSTITUENT MONITOR; U.S.
Provisional Patent Application No. 60/340,654, filed Dec. 12, 2001,
titled SYSTEM AND METHOD FOR CONDUCTING AND DETECTING INFRARED
RADIATION; U.S. Provisional Patent Application No. 60/340,773,
filed Dec. 11, 2001, titled METHOD FOR TRANSFORMING PHASE SPECTRA
TO ABSORPTION SPECTRA; U.S. Provisional Patent Application No.
60/332,322, filed Nov. 21, 2001, titled METHOD FOR ADJUSTING SIGNAL
VARIATION OF AN ELECTRONICALLY CONTROLLED INFRARED TRANSMISSIVE
WINDOW; U.S. Provisional Patent Application No. 60/332,093, filed
Nov. 21, 2001, titled METHOD FOR IMPROVING THE ACCURACY OF AN
ALTERNATE SITE BLOOD GLUCOSE MEASUREMENT; U.S. Provisional Patent
Application No. 60/332,125, filed Nov. 21, 2001, titled METHOD FOR
ADJUSTING A BLOOD ANALYTE MEASUREMENT; U.S. Provisional Patent
Application No. 60/341,435, filed Dec. 14, 2001, titled
PATHLENGTH-INDEPENDENT METHODS FOR OPTICALLY DETERMINING MATERIAL
COMPOSITION; U.S. Provisional Patent Application No. 60/339,120,
filed Dec. 7, 2001, titled QUADRATURE DEMODULATION AND KALMAN
FILTERING IN A BIOLOGICAL CONSTITUENT MONITOR; U.S. Provisional
Patent Application No. 60/339,044, filed Nov. 12, 2001, titled FAST
SIGNAL DEMODULATION WITH MODIFIED PHASE-LOCKED LOOP TECHNIQUES;
U.S. Provisional Patent Application No. 60/336,294, filed Oct. 29,
2001, titled METHOD AND DEVICE FOR INCREASING ACCURACY OF BLOOD
CONSTITUENT MEASUREMENT; U.S. SELECTION FOR DETERMINING ANALYTE
CONCENTRATION IN LIVING TISSUE; and U.S. Provisional Patent
Application No. 60/339,116, filed Nov. 7, 2001, titled METHOD AND
APPARATUS FOR IMPROVING CLINICALLY SIGNIFICANT ACCURACY OF ANALYTE
MEASUREMENTS. The entire disclosure of all of the above-mentioned
patents, patent applications and publications is hereby
incorporated by reference herein and made a part of this
specification.
[0140] B. Whole-Blood Detection System
[0141] FIG. 13 is a schematic view of a reagentless whole-blood
analyte detection system 200 (hereinafter "whole-blood system") in
a preferred configuration. The whole-blood system 200 may comprise
a radiation source 220, a filter 230, a cuvette 240 that includes a
sample cell 242, and a radiation detector 250. The whole-blood
system 200 preferably also comprises a signal processor 260 and a
display 270. Although a cuvette 240 is shown here, other sample
elements, as described below, could also be used in the system 200.
The whole-blood system 200 can also comprise a sample extractor
280, which can be used to access bodily fluid from an appendage,
such as the finger 290, forearm, or any other suitable
location.
[0142] As used herein, the terms "whole-blood analyte detection
system" and "whole-blood system" are broad, synonymous terms and
are used in their ordinary sense and refer, without limitation, to
analyte detection devices which can determine the concentration of
an analyte in a material sample by passing electromagnetic
radiation through the sample and detecting the absorbance of the
radiation by the sample. As used herein, the term "whole-blood" is
a broad term and is used in its ordinary sense and refers, without
limitation, to blood that has been withdrawn from a patient but
that has not been otherwise processed, e.g., it has not been
hemolysed, lyophilized, centrifuged, or separated in any other
manner, after being removed from the patient. Whole-blood may
contain amounts of other fluids, such as interstitial fluid or
intracellular fluid, which may enter the sample during the
withdrawal process or are naturally present in the blood. It should
be understood, however, that the whole-blood system 200 disclosed
herein is not limited to analysis of whole-blood, as the
whole-blood system 10 may be employed to analyze other substances,
such as saliva, urine, sweat, interstitial fluid, intracellular
fluid, hemolysed, lyophilized, or centrifuged blood or any other
organic or inorganic materials.
[0143] The whole-blood system 200 may comprise a near-patient
testing system. As used herein, "near-patient testing system" is
used in its ordinary sense and includes, without limitation, test
systems that are configured to be used where the patient is rather
than exclusively in a laboratory, e.g., systems that can be used at
a patient's home, in a clinic, in a hospital, or even in a mobile
environment. Users of near-patient testing systems can include
patients, family members of patients, clinicians, nurses, or
doctors. A "near-patient testing system" could also include a
"point-of-care" system.
[0144] The whole-blood system 200 may in one embodiment be
configured to be operated easily by the patient or user. As such,
the system 200 is preferably a portable device. As used herein,
"portable", is used in its ordinary sense and means, without
limitation, that the system 200 can be easily transported by the
patient and used where convenient. For example, the system 200 is
advantageously small. In one preferred embodiment, the system 200
is small enough to fit into a purse or backpack. In another
embodiment, the system 200 is small enough to fit into a pants
pocket. In still another embodiment, the system 200 is small enough
to be held in the palm of a hand of the user.
[0145] Some of the embodiments described herein employ a sample
element to hold a material sample, such as a sample of biological
fluid. As used herein, "sample element" is a broad term and is used
in its ordinary sense and includes, without limitation, structures
that have a sample cell and at least one sample cell wall, but more
generally includes any of a number of structures that can hold,
support or contain a material sample and that allow electromagnetic
radiation to pass through a sample held, supported or contained
thereby; e.g., a cuvette, test strip, etc. As used herein, the term
"disposable" when applied to a component, such as a sample element,
is a broad term and is used in its ordinary sense and means,
without limitation, that the component in question is used a finite
number of times and then discarded. Some disposable components are
used only once and then discarded. Other disposable components are
used more than once and then discarded.
[0146] The radiation source 220 of the whole-blood system 200 emits
electro-magnetic radiation in any of a number of spectral ranges,
e.g., within infrared wavelengths; in the mid-infrared wavelengths;
above about 0.8 .mu.m; between about 5.0 .mu.m and about 20.0
.mu.m; and/or between about 5.25 .mu.m and about 12.0 .mu.m.
However, in other embodiments the whole-blood system 200 may employ
a radiation source 220 which emits in wavelengths found anywhere
from the visible spectrum through the microwave spectrum, for
example anywhere from about 0.4 .mu.m to greater than about 100
sum. In still further embodiments the radiation source emits
electromagnetic radiation in wavelengths between about 3.5 .mu.m
and about 14 .mu.m, or between about 0.8 .mu.m and about 2.5 .mu.m,
or between about 2.5 .mu.m and about 20 .mu.m, or between about 20
.mu.m and about 100 .mu.m, or between about 6.85 .mu.m and about
10.10 .mu.m.
[0147] The radiation emitted from the source 220 is in one
embodiment modulated at a frequency between about one-half hertz
and about one hundred hertz, in another embodiment between about
2.5 hertz and about 7.5 hertz, in still another embodiment at about
50 hertz, and in yet another embodiment at about 5 hertz. With a
modulated radiation source, ambient light sources, such as a
flickering fluorescent lamp, can be more easily identified and
rejected when analyzing the radiation incident on the detector 250.
One source that is suitable for this application is produced by ION
OPTICS, INC. and sold under the part number NL5LNC.
[0148] The filter 230 permits electromagnetic radiation of selected
wavelengths to pass through and impinge upon the cuvette/sample
element 240. Preferably, the filter 230 permits radiation at least
at about the following wavelengths to pass through to the
cuvette/sample element: 3.9, 4.0 .mu.m, 4.05 .mu.m, 4.2 .mu.m,
4.75, 4.95 .mu.m, 5.25 .mu.m, 6.12 .mu.m, 7.4 .mu.m, 8.0 .mu.m,
8.45 .mu.m, 9.25 .mu.m, 9.5 .mu.m, 9.65 .mu.m, 10.4 .mu.m, 12.2
.mu.m. In another embodiment, the filter 230 permits radiation at
least at about the following wavelengths to pass through to the
cuvette/sample element: 5.25 .mu.m, 6.12 .mu.m, 6.8 .mu.m, 8.03
.mu.m, 8.45 .mu.m, 9.25 .mu.m, 9.65 .mu.m, 10.4 .mu.m, 12 .mu.m. In
still another embodiment, the filter 230 permits radiation at least
at about the following wavelengths to pass through to the
cuvette/sample element: 6.85 .mu.m, 6.97 .mu.m, 7.39 .mu.m, 8.23
.mu.m, 8.62 .mu.m, 9.02 .mu.m, 9.22 .mu.m, 9.43 .mu.m, 9.62 .mu.m,
and 10.10 .mu.m. The sets of wavelengths recited above correspond
to specific embodiments within the scope of this disclosure.
Furthermore, other subsets of the foregoing sets or other
combinations of wavelengths can be selected. Finally, other sets of
wavelengths can be selected within the scope of this disclosure
based on cost of production, development time, availability, and
other factors relating to cost, manufacturability, and time to
market of the filters used to generate the selected wavelengths,
and/or to reduce the total number of filters needed.
[0149] In one embodiment, the filter 230 is capable of cycling its
passband among a variety of narrow spectral bands or a variety of
selected wavelengths. The filter 230 may thus comprise a
solid-state tunable infrared filter, such as that available from
ION OPTICS INC. The filter 230 could also be implemented as a
filter wheel with a plurality of fixed-passband filters mounted on
the wheel, generally perpendicular to the direction of the
radiation emitted by the source 220. Rotation of the filter wheel
alternately presents filters that pass radiation at wavelengths
that vary in accordance with the filters as they pass through the
field of view of the detector 250.
[0150] The detector 250 preferably comprises a 3 mm long by 3 mm
wide pyroelectric detector. Suitable examples are produced by DIAS
Angewandte Sensorik GmbH of Dresden, Germany, or by BAE Systems
(such as its TGS model detector). The detector 250 could
alternatively comprise a thermopile, a bolometer, a silicon
microbolometer, a lead-salt focal plane array, or a
mercury-cadmium-telluride (MCT) detector. Whichever structure is
used as the detector 250, it is desirably configured to respond to
the radiation incident upon its active surface 254 to produce
electrical signals that correspond to the incident radiation.
[0151] In one embodiment, the sample element comprises a cuvette
240 which in turn comprises a sample cell 242 configured to hold a
sample of tissue and/or fluid (such as whole-blood, blood
components, interstitial fluid, intercellular fluid, saliva, urine,
sweat and/or other organic or inorganic materials) from a patient
within its sample cell. The cuvette 240 is installed in the
whole-blood system 200 with the sample cell 242 located at least
partially in the optical path 243 between the radiation source 220
and the detector 250. Thus, when radiation is emitted from the
source 220 through the filter 230 and the sample cell 242 of the
cuvette 240, the detector 250 detects the radiation signal strength
at the wavelength(s) of interest. Based on this signal strength,
the signal processor 260 determines the degree to which the sample
in the cell 242 absorbs radiation at the detected wavelength(s).
The concentration of the analyte of interest is then determined
from the absorption data via any suitable spectroscopic
technique.
[0152] As shown in FIG. 13, the whole-blood system 200 can also
comprise a sample extractor 280. As used herein, the term "sample
extractor" is a broad term and is used in its ordinary sense and
refers, without limitation, to or any device which is suitable for
drawing a sample of fluid from tissue, such as whole-blood or other
bodily fluids through the skin of a patient. In various
embodiments, the sample extractor may comprise a lance, laser
lance, iontophoretic sampler, gas-jet, fluid-jet or particle-jet
perforator, ultrasonic enhancer (used with or without a chemical
enhancer), or any other suitable device.
[0153] As shown in FIG. 13, the sample extractor 280 could form an
opening in an appendage, such as the finger 290, to make
whole-blood available to the cuvette 240. It should be understood
that other appendages could be used to draw the sample, including
but not limited to the forearm. With some embodiments of the sample
extractor 280, the user forms a tiny hole or slice through the
skin, through which flows a sample of bodily fluid such as
whole-blood. Where the sample extractor 280 comprises a lance (see
FIG. 14), the sample extractor 280 may comprise a sharp cutting
implement made of metal or other rigid materials. One suitable
laser lance is the Lasette Plus.RTM. produced by Cell Robotics
International, Inc. of Albuquerque, N. Mex. If a laser lance,
iontophoretic sampler, gas-jet or fluid-jet perforator is used as
the sample extractor 280, it could be incorporated into the
whole-blood system 200 (see FIG. 13), or it could be a separate
device.
[0154] Additional information on laser lances can be found in U.S.
Pat. No. 5,908,416, issued Jun. 1, 1999, titled LASER DERMAL
PERFORATOR; the entirety of this patent is hereby incorporated by
reference herein and made a part of this specification. One
suitable gas-jet, fluid-jet or particle-jet perforator is disclosed
in U.S. Pat. No. 6,207,400, issued Mar. 27, 2001, titled NON- OR
MINIMALLY INVASIVE MONITORING METHODS USING-PARTICLE DELIVERY
METHODS; the entirety of this patent is hereby incorporated by
reference herein and made a part of this specification. One
suitable iontophoretic sampler is disclosed in U.S. Pat. No.
6,298,254, issued Oct. 2, 2001, titled DEVICE FOR SAMPLING
SUBSTANCES USING ALTERNATING POLARITY OF IONTOPHORETIC CURRENT; the
entirety of this patent is hereby incorporated by reference herein
and made a part of this specification. One suitable ultrasonic
enhancer, and chemical enhancers suitable for use therewith, are
disclosed in U.S. Pat. No. 5,458,140, titled ENHANCEMENT OF
TRANSDERMAL MONITORING APPLICATIONS WITH ULTRASOUND AND CHEMICAL
ENHANCERS, issued Oct. 17, 1995, the entire disclosure of which is
hereby incorporated by reference and made a part of this
specification.
[0155] FIG. 14 shows one embodiment of a sample element, in the
form of a cuvette 240, in greater detail. The cuvette 240 further
comprises a sample supply passage 248, a pierceable portion 249, a
first window 244, and a second window 246, with the sample cell 242
extending between the windows 244, 246. In one embodiment, the
cuvette 240 does not have a second window 246. The first window 244
(or second window 246) is one form of a sample cell wall; in other
embodiments of the sample elements and cuvettes disclosed herein,
any sample cell wall may be used that at least partially contains,
holds or supports a material sample, such as a biological fluid
sample, and which is transmissive of at least some bands of
electromagnetic radiation, and which may but need not be
transmissive of electromagnetic radiation in the visible range. The
pierceable portion 249 is an area of the sample supply passage 248
that can be pierced by suitable embodiments of the sample extractor
280. Suitable embodiments of the sample extractor 280 can pierce
the portion 249 and the appendage 290 to create a wound in the
appendage 290 and to provide an inlet for the blood or other fluid
from the wound to enter the cuvette 240. (The sample extractor 280
is shown on the opposite side of the sample element in FIG. 14, as
compared to FIG. 13, as it may pierce the portion 249 from either
side.)
[0156] The windows 244, 246 are preferably optically transmissive
in the range of electromagnetic radiation that is emitted by the
source 220, or that is permitted to pass through the filter 230. In
one embodiment, the material that makes up the windows 244, 246 is
completely transmissive, i.e., it does not absorb any of the
electromagnetic radiation from the source 220 and filter 230 that
is incident upon it. In another embodiment, the material of the
windows 244, 246 has some absorption in the electromagnetic range
of interest, but its absorption is negligible. In yet another
embodiment, the absorption of the material of the windows 244, 246
is not negligible, but it is known and stable for a relatively long
period of time. In another embodiment, the absorption of the
windows 244, 246 is stable for only a relatively short period of
time, but the whole-blood system 200 is configured to observe the
absorption of the material and eliminate it from the analyte
measurement before the material properties can change
measurably.
[0157] The windows 244, 246 are made of polypropylene in one
embodiment. In another embodiment, the windows 244, 246 are made of
polyethylene. Polyethylene and polypropylene are materials having
particularly advantageous properties for handling and
manufacturing, as is known in the art. Also, polypropylene can be
arranged in a number of structures, e.g., isotactic, atactic and
syndiotactic, which may enhance the flow characteristics of the
sample in the sample element. Preferably the windows 244, 246 are
made of durable and easily manufactureable materials, such as the
above-mentioned polypropylene or polyethylene, or silicon or any
other suitable material. The windows 244, 246 can be made of any
suitable polymer, which can be isotactic, atactic or syndiotactic
in structure.
[0158] The distance between the windows 244, 246 comprises an
optical pathlength and can be between about 1 .mu.m and about 100
.mu.m. In one embodiment, the optical pathlength is between about
10 .mu.m and about 40 .mu.m, or between about 25 .mu.m and about 60
.mu.m, or between about 30 .mu.m and about 50 .mu.m. In still
another embodiment, the optical pathlength is about 25 .mu.m. The
transverse size of each of the windows 244, 246 is preferably about
equal to the size of the detector 250. In one embodiment, the
windows are round with a diameter of about 3 mm. In this
embodiment, where the optical pathlength is about 25 .mu.m the
volume of the sample cell 242 is about 0.177 .mu.L. In one
embodiment, the length of the sample supply passage 248 is about 6
mm, the height of the sample supply passage 248 is about 1 mm, and
the thickness of the sample supply passage 248 is about equal to
the thickness of the sample cell, e.g., 25 .mu.m. The volume of the
sample supply passage is about 0.150 .mu.L. Thus, the total volume
of the cuvette 240 in one embodiment is about 0.327 .mu.L. Of
course, the volume of the cuvette 240/sample cell 242/etc. can
vary, depending on many variables, such as the size and sensitivity
of the detectors 250, the intensity of the radiation emitted by the
source 220, the expected flow properties of the sample, and whether
flow enhancers (discussed below) are incorporated into the cuvette
240. The transport of fluid to the sample cell 242 is achieved
preferably through capillary action, but may also be achieved
through wicking, or a combination of wicking and capillary
action.
[0159] FIGS. 15-17 depict another embodiment of a cuvette 305 that
could be used in connection with the whole-blood system 200. The
cuvette 305 comprises a sample cell 310, a sample supply passage
315, an air vent passage 320, and a vent 325. As best seen in FIGS.
16, 16A and 17, the cuvette also comprises a first sample cell
window 330 having an inner side 332, and a second sample cell
window 335 having an inner side 337. As discussed above, the
window(s) 330/335 in some embodiments also comprise sample cell
wall(s). The cuvette 305 also comprises an opening 317 at the end
of the sample supply passage 315 opposite the sample cell 310. The
cuvette 305 is preferably about 1/4-{fraction (1/8)} inch wide and
about {fraction (3/4)} inch long; however, other dimensions are
possible while still achieving the advantages of the cuvette
305.
[0160] The sample cell 310 is defined between the inner side 332 of
the first sample cell window 330 and the inner side 337 of the
second sample cell window 335. The perpendicular distance T between
the two inner sides 332, 337 comprises an optical pathlength that
can be between about 1 .mu.m and about 1.22 mm. The optical
pathlength can alternatively be between about 1 .mu.m and about 100
.mu.m. The optical pathlength could still alternatively be about 80
.mu.m, but is preferably between about 10 .mu.m and about 50 .mu.m.
In another embodiment, the optical pathlength is about 25 .mu.m.
The windows 330, 335 are preferably formed from any of the
materials discussed above as possessing sufficient radiation
transmissivity. The thickness of each window is preferably as small
as possible without overly weakening the sample cell 310 or cuvette
305.
[0161] Once a wound is made in the appendage 290, the opening 317
of the sample supply passage 315 of the cuvette 305 is placed in
contact with the fluid that flows from the wound. In another
embodiment, the sample is obtained without creating a wound, e.g.
as is done with a saliva sample. In that case, the opening 317 of
the sample supply passage 315 of the cuvette 305 is placed in
contact with the fluid obtained without creating a wound. The fluid
is then transported through the sample supply passage 315 and into
the sample cell 310 via capillary action. The air vent passage 320
improves the capillary action by preventing the buildup of air
pressure within the cuvette and allowing the blood to displace the
air as the blood flows therein.
[0162] Other mechanisms may be employed to transport the sample to
the sample cell 310. For example, wicking could be used by
providing a wicking material in at least a portion of the sample
supply passage 315. In another variation, wicking and capillary
action could be used together to transport the sample to the sample
cell 310. Membranes could also be positioned within the sample
supply passage 315 to move the blood while at the same time
filtering out components that might complicate the optical
measurement performed by the whole-blood system 200.
[0163] FIGS. 16 and 16A depict one approach to constructing the
cuvette 305. In this approach, the cuvette 305 comprises a first
layer 350, a second layer 355, and a third layer 360. The second
layer 355 is positioned between the first layer 350 and the third
layer 360. The first layer 350 forms the first sample cell window
330 and the vent 325. As mentioned above, the vent 325 provides an
escape for the air that is in the sample cell 310. While the vent
325 is shown on the first layer 350, it could also be positioned on
the third layer 360, or could be a cutout in the second layer, and
would then be located between the first layer 360 and the third
layer 360 The third layer 360 forms the second sample cell window
335.
[0164] The second layer 355 may be formed entirely of an adhesive
that joins the first and third layers 350, 360. In other
embodiments, the second layer may be formed from similar materials
as the first and third layers, or any other suitable material. The
second layer 355 may also be formed as a carrier with an adhesive
deposited on both sides thereof. The second layer 355 forms the
sample supply passage 315, the air vent passage 320, and the sample
cell 310. The thickness of the second layer 355 can be between
about 1 .mu.m and about 1.22 mm. This thickness can alternatively
be between about 1 .mu.m and about 100 .mu.m. This thickness could
alternatively be about 80 .mu.m, but is preferably between about 10
.mu.m and about 50 .mu.m. In another embodiment, the second layer
thickness is about 25 .mu.m.
[0165] In other embodiments, the second layer 355 can be
constructed as an adhesive film having a cutout portion to define
the passages 315, 320, or as a cutout surrounded by adhesive.
[0166] Further information can be found in U.S. patent application
Ser. No. 10/055,875, filed Jan. 22, 2002, titled REAGENT-LESS
WHOLE-BLOOD GLUCOSE METER. The entire contents of this patent
application are hereby incorporated by reference herein and made a
part of this specification.
II. Sample Adapter
[0167] A method and device for reducing measurement error in a
noninvasive monitor (such as, but not limited to, the noninvasive
system 10) when measuring the concentration of an analyte, e.g.,
glucose, in the tissue of a patient is disclosed. The method
involves measuring properties of the analyte in a sample of blood,
whole blood or any other suitable body fluid(s) withdrawn from the
patient. The method can also involve using the analyte property
measurements to reduce patient-specific calibration error of the
noninvasive monitor. In another variation, the noninvasive monitor,
in combination with an adapter, measures analyte concentration in a
sample of blood, whole blood or any other suitable body fluid(s)
withdrawn from the patient, i.e., a makes an invasive or "whole
blood" measurement. An apparatus for calibrating the noninvasive
monitor is also disclosed.
[0168] In the remainder of this section and in the drawings related
thereto, various methods and devices will be described or depicted
in the context of withdrawing, handling, containing, analyzing,
etc. samples of blood or whole blood withdrawn from a patient. It
should be understood, however, that the methods and devices
disclosed herein are not limited to withdrawing, handling,
containing, analyzing, etc. blood or whole blood, and that the
disclosed methods and devices can be used with any suitable body
fluid or sample withdrawn from a patient, such as whole blood,
blood component(s), interstitial fluid or intercellular fluid
obtained invasively, or saliva or urine obtained noninvasively, or
any collection of organic or inorganic material. Therefore any
mention of "blood" or "whole blood" should not be construed as
limiting the device or method in question use with blood or whole
blood.
[0169] Monitor calibration error can arise from several sources,
including physiological variation across the patient population.
Patient-specific monitor calibration error can arise from, for
example, the skin condition or the physical condition of the
patient. This error can be estimated and corrected by performing an
invasive or whole blood measurement of analyte concentration in
each patient, comparing the result to a measurement by the
noninvasive monitor, and correcting the noninvasive monitor for any
observed differences between the two measurements. In one
embodiment, the traditional analyte concentration measurement is
performed on blood withdrawn from the patient by using, for
example, a needle, laser, lancet, finger-stick, or any other
suitable sample extractor, including any of those disclosed herein.
The traditional or invasive measurement selected is any of a number
of highly accurate techniques well known to those skilled in the
art. For example, a calorimetric, amperometric or coulombometric
technique could be employed. In one embodiment, the invasive
measurement is performed with the whole-blood system 200.
[0170] As shown in FIG. 18, the monitor 1100 comprises a
noninvasive detection unit 1102 and a traditional measurement
system 1116. In the illustrated embodiment, the noninvasive
detection unit 1102 comprises an analyzer window 1108, a thermal
element 1110 capable of inducing a thermal gradient at the surface
of the patient's skin 1112, and an infrared radiation detector
system 1114 capable of measuring radiation emitted from the
patient's skin or body at wavelengths selected to highlight or
isolate the absorptive effects of the analyte of interest, for
example, at one or more analyte absorbance wavelength peaks and at
one or more reference wavelengths. However, one of skill in the art
will appreciate that the noninvasive detection unit 1102 can
comprise any instrument, such as but not limited to the noninvasive
system 10, which has the capability to determine the concentration
of an analyte in in-vivo tissue samples or bodily fluids.
[0171] In one embodiment, the traditional measurement system 1116
has a blood-withdrawal portion 1118 and an analysis portion 1120.
The traditional measurement system 1116, via the analysis portion
1120, is capable of analyzing whole blood (or other body fluid(s))
withdrawn from the patient with the withdrawal portion 1118 and
providing a value or values to the monitor indicating analyte
concentration in the blood (or other fluid(s)) withdrawn.
Generally, the blood-withdrawal portion 1118 comprises a needle,
laser, lancet, finger-stick, etc. (or any other suitable sample
extractor, including any of those disclosed herein), and/or any
supporting hardware used for holding a withdrawn sample and/or
placing the sample on or in the analysis portion 1120. In one
embodiment, the whole-blood system 200 comprises at least part of
the traditional measurement system 1116.
[0172] In one embodiment, shown in FIG. 18, the analysis portion
1120 (in one embodiment, the whole-blood system 200) is a separate
unit connected to the noninvasive detection unit 1102 through a
data communication line 1122 to facilitate communication of
analyte-concentration information to the noninvasive detection unit
1102. The analysis portion 1120 can also be made as an integral
component of the monitor 1100. In one preferred variation of the
monitor 1100, the analysis portion 1120 of the traditional
measurement system 1116 is an electro-chemical monitor. In this
embodiment, the monitor 1100 is configured to receive a
conventional whole blood electro-chemical test strip with blood
added thereto. The analysis portion 1120 of the traditional
measurement system 1116 can then perform the electro-chemical
analyte measurement.
[0173] Both the integral construction of the monitor 1100 and the
use of the data link 1122 advantageously eliminate human
transcription, which would otherwise be a source of human
transcription error. Human transcription involves the manual entry,
using an input device, such as a dial, keyboard, or other similar
manual input device, of a value into a measurement device, such as
the monitor 1100. The transcription error avoided by the
construction of the monitor 1100 would occur if the user entered a
wrong value using the input device. Such errors, which would
ordinarily cause all subsequent measurements to be inaccurate,
would otherwise be very difficult to eliminate.
[0174] Advantageously, at least the blood withdrawal portion 1118
of the device 1116 may be configured as a single use item. In one
embodiment, the blood withdrawal portion 1118 of the device 1116 is
a single use device, i.e., one configured to be used only once.
[0175] FIG. 19 is a flow chart of a method of operation of the
monitor 1100. In one embodiment of this method, the noninvasive
detection unit 1102 comprises a thermal element 1110 capable of
inducing a thermal gradient at the surface of the patient's skin
1112, as described above. The method may comprise switching the
monitor 1100 to a patient calibration mode in a step 1210. Then in
a step 1212, the operator performs a traditional or invasive
measurement using the analysis device 1116. This is done by
withdrawing a sample of whole blood or any other suitable body
fluid(s) from the patient and analyzing the sample in the device
1116 to determine the analyte concentration in the sample. In
another embodiment, the step 1212 comprises performing multiple
measurements to produce a series of data. These data can be
manipulated to yield numerical values relating to the analyte
concentration in the sample.
[0176] In a step 1216, the operator uses the noninvasive detection
unit 1102 to measure the analyte concentration in the patient's
blood/tissue. In one embodiment of the method shown in FIG. 19, the
step 1216 comprises placing the thermal gradient inducing means of
the monitor 1100 in contact with the patient's skin 1112 at a
measurement site, inducing a thermal gradient in the patient's
skin, and performing an analyte measurement by detecting and
analyzing infrared radiation at selected wavelengths. As in the
step 1212, another embodiment of the step 1216 comprises performing
multiple measurements to produce a series of data representing the
analyte concentration. As mentioned above, one of skill in the art
will appreciate that the noninvasive detection unit 1102 can
comprise any instrument, such as the noninvasive system 10, which
has the capability to determine the concentration of an analyte in
in-vivo tissue samples or bodily fluids.
[0177] Next in a step 1220, the analyte measurements performed in
the step 1212 and the step 1216 are compared to estimate the
calibration error. Finally, in a step 1222 the measurement output
of the monitor is corrected using the calibration error estimated
in step 1220 to correct for the patient-specific monitor
calibration error.
[0178] FIG. 20 is a flow chart of another variation of the method
of operation of the monitor 1100. This variation addresses where
and when measurements are to be taken. More particularly, the
method involves the choice of a location on a subject's body at
which to take the analyte measurement, preferably based on the
amount of time that has elapsed since the last time the subject
ate. A restricted period commences after the subject eats. This
restricted period is characterized by a restriction on where the
subject may take analyte measurements; specifically, the subject is
restricted to taking measurements "on-site" (on a finger or
fingertip) during a restricted period.
[0179] In contrast, when no restricted period is in effect (i.e.,
the designated time interval has elapsed since the last time the
subject ate) the subject may take analyte measurements either
on-site or at an alternative site such as, for example, the
forearm. It is to be understood, however, that "alternative site"
refers to any location other than the on-site positions.
[0180] The method shown in FIG. 20 may comprise switching the
monitor 1100 to a patient calibration mode in a step 1250. Then in
a step 252, the operator determines whether there is a restricted
period in effect. In one embodiment, the restricted period lasts
from about 0.5 to about 3 hours after the subject eats. In another
embodiment, the restricted period lasts from about 1.0 to about 2
hours. In another embodiment, the restricted period lasts from
about 1.5 to about 2 hours. In a presently preferred embodiment,
the restricted period lasts about 2 hours. If there is a restricted
period in effect, then in a step 1254, the operator performs a
traditional or invasive measurement on-site using the analysis
device 1116. This is done by withdrawing a sample of blood, whole
blood or any other suitable body fluid(s) from the patient and
analyzing the sample in the device 1116 to determine the analyte
concentration in the sample.
[0181] Then in a step 1256, the noninvasive detection unit 1102
measures the analyte concentration on-site. The step 1256 may
comprise placing the thermal gradient inducing means of the monitor
1100 in contact with the patient's skin 1112 at a measurement site,
inducing a thermal gradient in the patient's skin, and performing
an analyte measurement by detecting and analyzing thermal radiation
at selected wavelengths. As mentioned above, however, one of skill
in the art will appreciate that the noninvasive detection unit 1102
can comprise any instrument, such as the noninvasive system 10,
which has the capability to determine the concentration of an
analyte in in-vivo tissue samples or bodily fluids.
[0182] Next in a step 1260, the analyte measurements performed in
the step 1254 and the step 1256 are compared to estimate the
calibration error. Finally, in a step 1262 the measurement output
of the monitor is corrected using the calibration error estimated
in step 1260 to correct for the patient-specific monitor
calibration error.
[0183] If no restricted period in effect, then in a step 1274, the
operator performs a traditional or invasive measurement at an
alternative site measurement location using the analysis device
1116. As mentioned above, the traditional or invasive measurement
at the alternative site measurement location is done by withdrawing
a blood sample from the patient and analyzing the blood sample in
the device 1116 to determine the analyte concentration of the blood
sample.
[0184] In a step 1276, the noninvasive detection unit 1102
measures, at an alternative site measurement location, the analyte
concentration of the blood. As above, the step 1276 may comprise
placing the thermal gradient inducing means of the monitor 1100 in
contact with the patient's skin 1112 at a measurement site,
inducing a thermal gradient in the patient's skin, and performing
an analyte measurement by detecting and analyzing thermal radiation
at selected wavelengths. Again, the noninvasive detection unit 1102
can comprise any instrument, such as the noninvasive system 10,
which has the capability to determine the concentration of an
analyte in in-vivo tissue samples or bodily fluids.
[0185] Next in a step 1280, the analyte measurements performed in
the step 1274 and the step 1276 are compared to estimate the
calibration error. Finally, in a step 1282 the measurement output
of the monitor is corrected using the calibration error estimated
in step 1280 to correct for the observed patient-specific monitor
calibration error.
[0186] In any of the methods described herein, calibration can also
be performed by using the noninvasive monitor to analyze analyte
concentration in withdrawn blood. In this embodiment, the analysis
portion 1120 of the analysis device 1116 could be omitted. Instead,
the monitor 1100 performs the analyte concentration measurement on
a blood sample withdrawn from the patient, i.e., whole blood
analysis. This process is described in more detail below in
connection with FIGS. 29 and 30.
[0187] FIGS. 21 and 22 depict one embodiment of an adapter 1300
which can be used to facilitate analysis of samples of body fluids
(such as blood, whole blood or any other suitable body fluid(s)
withdrawn from a patient) by any noninvasive monitor (such as but
not limited to the noninvasive system 10) having a window, lens, or
other opening for passing or receiving energy to or from a sample
or living tissue. In one embodiment the adapter 1300 comprises a
base material 1310. The material 1310 is preferably a hydrophobic
material, e.g., Kapton. The adapter 1300 is configured to be
applied to the analyzer window 1108 of the monitor 1100 and sized
to cover a large portion of the window 1108. The adapter 1300 also
has a sample accommodating volume 1314 configured to receive a
small sample of blood, whole blood or other body fluid(s) that
extends between openings positioned on opposite sides of the base
material 1310. In one embodiment, the sample accommodating volume
1314 is about 250 microliters.
[0188] In another embodiment, the adapter 1300 also comprises an
adhesive backing 1312. The adhesive backing 1312 is selected from
materials that do not give any analyte absorption signature, i.e.,
those materials that do not emit thermal radiation in the same
spectra as the analyte. This has the effect of "passivating" the
portions of the window covered by the adhesive 1312. In still
another embodiment, an anti-clotting agent (such as heparin) is
added to a blood sample before placement in the adapter.
[0189] In still another embodiment, the control software and/or
electronics of the noninvasive unit 1102 is configured to account
for any observed rate of consumption of the analyte in the sample
after placement of the sample in the adapter 1300. For example, the
software/electronics may accept input of an observed consumption
rate and use a time measurement (taken from any of (i) elapsed time
since placement of the adapter on the window; (ii) elapsed time
since initiation of an analyte-concentration measurement; or (iii)
elapsed time since sample withdrawal) to calculate a consumption
adjustment. The software/electronics may then adjust its initial
measurement of analyte concentration by the consumption adjustment,
to arrive at a consumption-adjusted analyte concentration
measurement. In another embodiment, the software/electronics
assumes a consumption rate based on input of the sample type and
analyte(s) measured. For example, if the user desires to measure
the concentration of glucose in whole blood, upon input of the
analyte and sample type, a consumption rate of about 0.16 mg/dL/min
could be assumed and employed in calculation of the consumption
adjustment.
[0190] In operation, the adapter 1300 is applied to the analyzer
window 1108. Then a drop of the withdrawn sample is placed in the
sample accommodating volume 1314. Once the sample is applied to the
sample accommodating volume 1314, the analyte concentration in the
sample is measured in the usual manner. After the monitor 1100
performs the measurement, the adapter 1300 is removed from the
window 1108 of the monitor 1100, and any of the sample left on the
window is removed. In one embodiment, the adapter 1300, with the
sample placed therein, is shaken before placement on the window
1008; it is believed that shaking counteracts any settlement and
separation of the components of the sample, thereby promoting
increased measurement accuracy. This can be done using a
sterilizing solution, such as isopropyl alcohol or other well known
sterilizing solutions.
[0191] In one variation shown in FIGS. 23 and 24, an adapter 1400
similar to the adapter 1300 has a wicking medium 1420 that captures
the sample using capillary forces. Capillary forces cause the
sample to be drawn into the wicking medium. In operation, after the
adapter 1400 is removed from the window 1108 of the monitor 1100,
the sample remains captured in the wicking material 1420. This
reduces the amount of the sample remaining on the window 1108 after
the adapter 1400 is removed. Thus, a simple wipe with an alcohol
soaked pad is sufficient to clean the window.
[0192] In another embodiment shown in FIGS. 25 and 26, an adapter
1500 comprises a thin optically transparent material layer 1530 to
prevent the sample from coming into contact with the analyzer
window 1108. Suitable materials for the layer 1530 include mylar,
vinyl, and polypropylene. After the measurement is made the adapter
1500, including the thin layer 1530, is removed and discarded.
There is no need to clean the window 1108 as the sample did not
contact the window. In the embodiments illustrated in FIGS. 21-26,
a column of the sample fluid(s) is captured in the sample
accommodating volume having an outer diameter approximately equal
to the diameter of the opening in the base material and a height
approximately equal to the thickness of the base material. The
amount of the sample required is limited by the diameter of the
opening in the base material.
[0193] In yet another embodiment shown in FIG. 6, an adapter 1600
is configured to further limit the minimum amount of the sample by
further reducing the height of the sample column and by reducing
the diameter of the opening in the base material. As a result, the
sample accommodating volume is reduced. Under normal operating
conditions the noninvasive monitor disclosed in U.S. Pat. No.
6,198,949 will sense an analyte to a depth of several hundred
microns in the sample under analysis. If the height of the sample
is reduced, the measurement will be made on only the available
height. Such a measurement can be performed by incorporating a
neutral absorption material 1640 such as polyethylene or silicon
into the adapter 1600. The material 1640 is positioned in the
adapter 1600 so that when the sample is within the adapter 1600 and
when the adapter is positioned on the window 1108, the sample is
between the material 1640 and the window 1108. The material 1640
must not absorb infrared energy in the wavelength ranges absorbed
by the analyte, the sample, or the normal body tissues.
[0194] FIG. 29 is a flow chart of a method of operation of the
noninvasive detection unit 1102 of the monitor 1100. (As mentioned
above, the noninvasive detection unit 1102 may, but need not,
comprise the noninvasive system 10.) In one embodiment of this
method, the noninvasive detection unit 1102 comprises a thermal
element 1110 capable of inducing a thermal gradient at the surface
of the patient's skin 1112, as described above. The method may
comprise switching the monitor 1100 to a patient calibration mode
in a step 1710. Then in a step 1712, the operator performs with the
noninvasive detection unit 1102 an analysis of a sample of body
fluid(s) withdrawn from a patient. This is done by withdrawing the
sample from the patient and positioning the sample over the
analyzer window 1108. The sample may be positioned over the window
1108 by placing the sample in an adapter (e.g., adapter 1300,
adapter 1400, adapter 1500, or adapter 1600) and positioning the
adapter on the window 1108. In another embodiment, the step 1712
comprises performing multiple measurements to produce a series of
data. The data obtained from analysis of the sample can be
manipulated to yield numerical values, or an invasive-measurement
output, relating to the concentration of the analyte of
interest.
[0195] In a step 1716, the operator performs noninvasive
measurements with the noninvasive detection unit 1102 to measure
the analyte concentration within the patient's blood/tissue. In one
embodiment of the method shown in FIG. 29, the step 1716 comprises
placing the thermal gradient element 1110 of the noninvasive
detection unit 1102 in contact with the patient's skin 1112 at a
measurement site, inducing a thermal gradient in the patient's
skin, and performing an analyte measurement by detecting and
analyzing thermal radiation at selected wavelengths. As in the step
1712, another embodiment of the step 1716 comprises performing
multiple measurements to produce a series of data representing the
analyte concentration. The obtained from the noninvasive
measurement(s) then become a noninvasive-measurement output. As
mentioned above, the noninvasive detection unit 1102 can comprise
any instrument which has the capability to determine the
concentration of an analyte in in-vivo tissue samples or bodily
fluids.
[0196] Next in a step 1720, the invasive-measurement output
generated in the step 1712 and the noninvasive-measurement output
generated in the step 1716 are compared to estimate the calibration
error. Finally, in a step 1722 the measurement output of the
monitor 1100 is corrected using the calibration error estimated in
step 1720 to correct for the patient-specific monitor calibration
error.
[0197] FIG. 30 is a flow chart of another variation of the method
of operation of the monitor 100. This variation addresses where and
when measurements are to be taken. More particularly, the method
involves the choice of a location on a subject's body at which to
take the analyte measurement, preferably based on the amount of
time that has elapsed since the last time the subject ate. A
restricted period commences after the subject eats. This restricted
period is characterized by a restriction on where the subject may
take analyte measurements; specifically, the subject is restricted
to taking measurements at an on-site location during a restricted
period.
[0198] In contrast, when no restricted period is in effect (i.e.,
the designated time interval has elapsed since the last time the
subject ate) the subject may take analyte measurements either
on-site or at an alternative site measurement location such as, for
example, the forearm. It is to be understood, however, that
"alternative site" refers to any location other than the on-site
positions.
[0199] The method shown in FIG. 30 may comprise switching the
noninvasive detection unit 1102 to a patient calibration mode in a
step 1750. Then in a step 1752, the operator determines whether
there is a restricted period in effect. In one embodiment, the
restricted period lasts from about 0.5 to about 3 hours after the
subject eats. In another embodiment, the restricted period lasts
from about 1.0 to about 2 hours. In another embodiment, the
restricted period lasts from about 1.5 to about 2 hours. In a
presently preferred embodiment, the restricted period lasts about 2
hours. If there is a restricted period in effect, then in a step
1754, the operator performs an invasive or whole blood measurement
"on-site" using the noninvasive detection unit 1102. This is done
by withdrawing a sample from the patient, placing the sample in an
adapter (e.g., adapter 1300, adapter 1400, adapter 1500, or adapter
1600) and analyzing the blood sample in the noninvasive detection
unit 1102 to determine the analyte concentration in the sample.
[0200] In a step 1756, the operator uses the noninvasive detection
unit 1102 to measure analyte concentration on-site. The step 1756
may comprise placing the thermal gradient inducing means of the
monitor 1100 in contact with the patient's skin 112 at an on-site
measurement location, inducing a thermal gradient in the patient's
skin, and performing an analyte measurement by detecting and
analyzing thermal radiation at selected wavelengths. As mentioned
above, however, one of skill in the art will appreciate that the
noninvasive detection unit 1102 can comprise any instrument, such
as the noninvasive system 10, which has the capability to determine
the concentration of an analyte in in-vivo tissue samples or bodily
fluids.
[0201] Next in a step 1760, the analyte measurements performed in
the step 1754 and the step 1756 are compared to estimate the
calibration error. Finally, in a step 1762 the measurement output
of the monitor 1100 is corrected using the calibration error
estimated in step 1760 to correct for the patient-specific monitor
calibration error.
[0202] If no restricted period in effect, then in a step 1774, the
operator performs an invasive or whole blood measurement at an
alternative site using the noninvasive detection unit 1102. As
mentioned above, the invasive or whole blood measurement at the
alternative site measurement location is done by withdrawing a
sample from the patient, placing the withdrawn sample in an adapter
(e.g., adapter 1300, adapter 1400, adapter 1500, or adapter 1600),
and analyzing the sample with the noninvasive detection unit 1102
to determine the concentration of the analyte of interest in the
withdrawn sample.
[0203] In a step 1776, the noninvasive detection unit 1102 measures
at an alternative site the analyte concentration in the patient's
blood/tissue. As above, the step 1776 may comprise placing the
thermal gradient inducing means of the monitor 1100 in contact with
the patient's skin 1112 at an alternative site, inducing a thermal
gradient in the patient's skin, and performing an analyte
measurement by detecting and analyzing thermal radiation at
selected wavelengths. In another variation, the analyte measurement
of the step 1776 may be performed on-site. As above, the
noninvasive detection unit 1102 can comprise any instrument, such
as the noninvasive system 10, which has the capability to determine
the concentration of an analyte in in-vivo tissue samples or bodily
fluids.
[0204] Next in a step 1780, the analyte measurements performed in
the step 1774 and the step 1776 are compared to estimate the
calibration error. Finally, in a step 1782 the measurement output
of the monitor is corrected using the calibration error estimated
in step 1780 to correct for the observed monitor error.
[0205] Although this invention has been disclosed in the context of
certain preferred embodiments and examples, it will be understood
by those skilled in the art that the present invention extends
beyond the specifically disclosed embodiments to other alternative
embodiments and/or uses of the invention and obvious modifications
and equivalents thereof. Thus, it is intended that the scope of the
present invention herein disclosed should not be limited by the
particular disclosed embodiments described above, but should be
determined only by a fair reading of the claims that follow.
* * * * *