U.S. patent application number 12/885379 was filed with the patent office on 2011-01-06 for method of calibrating an analyte-measurement device, and associated methods, devices and systems.
This patent application is currently assigned to Abbott Diabetes Care Inc.. Invention is credited to Benjamin J. Feldman, Geoffrey V. McGarraugh.
Application Number | 20110004084 12/885379 |
Document ID | / |
Family ID | 34556184 |
Filed Date | 2011-01-06 |
United States Patent
Application |
20110004084 |
Kind Code |
A1 |
Feldman; Benjamin J. ; et
al. |
January 6, 2011 |
Method of Calibrating an Analyte-Measurement Device, and Associated
Methods, Devices and Systems
Abstract
The invention relates to a method for calibrating an
analyte-measurement device that is used to evaluate a concentration
of analyte in bodily fluid at or from a measurement site in a body.
The method involves measuring a concentration, or calibration
concentration, of an analyte in blood from an "off-finger"
calibration site, and calibrating the analyte-measurement device
based on that calibration concentration. The invention also relates
to a device, system, or kit for measuring a concentration of an
analyte in a body, which employs a calibration device for adjusting
analyte concentration measured in bodily fluid based on an analyte
concentration measured in blood from an "off-finger" calibration
site.
Inventors: |
Feldman; Benjamin J.;
(Oakland, CA) ; McGarraugh; Geoffrey V.; (Oakland,
CA) |
Correspondence
Address: |
JACKSON & CO., LLP
6114 LA SALLE AVENUE, #507
OAKLAND
CA
94611-2802
US
|
Assignee: |
Abbott Diabetes Care Inc.
Alameda
CA
|
Family ID: |
34556184 |
Appl. No.: |
12/885379 |
Filed: |
September 17, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11929149 |
Oct 30, 2007 |
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12885379 |
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10975207 |
Oct 27, 2004 |
7299082 |
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11929149 |
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60516599 |
Oct 31, 2003 |
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Current U.S.
Class: |
600/347 ;
600/309; 600/345; 600/365 |
Current CPC
Class: |
A61B 5/746 20130101;
A61B 5/742 20130101; A61B 5/6898 20130101; A61B 5/0024 20130101;
A61B 5/1486 20130101; A61B 5/1495 20130101; A61B 5/0004 20130101;
A61B 5/14865 20130101; A61B 5/7475 20130101; A61B 5/7246 20130101;
A61B 5/14532 20130101 |
Class at
Publication: |
600/347 ;
600/309; 600/365; 600/345 |
International
Class: |
A61B 5/1473 20060101
A61B005/1473; A61B 5/145 20060101 A61B005/145 |
Claims
1. An apparatus for use in calibrating a signal from a subcutaneous
sensor, the apparatus comprising: one or more processors; a memory
for storing instructions which, when executed by the one or more
processors, causes the one or more processors to receive a
calibration measurement from a calibration sensor placed in contact
with capillary blood from an off-finger calibration site within a
body, to evaluate whether the calibration measurement is within a
predetermined range of analyte concentration, and to determine that
the calibration measurement is suitable for use in converting an
analyte signal from the subcutaneous sensor into an analyte
concentration if the calibration measurement is within the
predetermined range.
2. The apparatus of claim 1, wherein the analyte is glucose and the
predetermined range is from about 60 mg/dL to about 350 mg/dL.
3. The apparatus of claim 1, wherein the analyte is glucose.
4. The apparatus of claim 1, wherein the calibration site is
located in an arm of the body.
5. The apparatus of claim 1, wherein the calibration site is
located in a leg of the body.
6. The apparatus of claim 1, wherein the subcutaneous sensor is
located in an arm of the body.
7. The apparatus of claim 1, wherein the subcutaneous sensor is
located in the abdomen of the body.
8. The apparatus of claim 1, wherein the subcutaneous sensor is
located in one region of the body and the calibration site is
located in another region of the body.
9. The apparatus of claim 1, wherein each of the subcutaneous
sensor and the calibration site is located in substantially one
region of the body.
10. The apparatus of claim 1, wherein the subcutaneous sensor is
sufficient for electrochemically determining a concentration of an
analyte.
11. The apparatus of claim 1, wherein the instructions for
receiving the calibration measurement comprises instructions for
determining the calibration measurement electrochemically.
12. The apparatus of claim 1, wherein the instructions for
receiving the calibration measurement comprises instructions for
determining the calibration measurement in less than or equal to
about 1 .mu.L of blood.
13. The apparatus of claim 1, wherein the instructions for
receiving the calibration measurement comprises instructions for
determining the calibration measurement in less than or equal to
about 0.5 .mu.L of blood.
14. The apparatus of claim 1, wherein the instructions for
receiving the calibration measurement comprises instructions for
determining the calibration measurement in less than or equal to
about 0.2 .mu.L of blood.
15. The apparatus of claim 1, wherein the instructions for
receiving the calibration measurement comprises instructions for
determining the calibration measurement within about five minutes
after the subcutaneous sensor is inserted at a measurement
site.
16. The apparatus of claim 1, wherein the instructions for
receiving the calibration measurement comprises instructions for
determining the calibration measurement within about one hour after
the subcutaneous sensor is inserted at a measurement site.
17. The apparatus of claim 1, wherein the instructions for
receiving the calibration measurement comprises instructions for
determining the calibration measurement within about three hours
after the subcutaneous sensor is inserted at a measurement
site.
18. The apparatus of claim 1, wherein the instructions for
receiving the calibration measurement comprises instructions for
determining the calibration measurement within about twenty-four
hours after the subcutaneous sensor is inserted at a measurement
site.
19. The apparatus of claim 1, further comprising instructions
which, when executed by the one or more processors, causes the one
or more processors to receive at least one analyte signal from the
subcutaneous sensor.
20. The apparatus of claim 19, further comprising instructions
which, when executed by the one or more processors, causes the one
or more processors to evaluate the analyte signal based on a
predetermined range for a rate of change in analyte concentration
over a predetermined period.
21. The apparatus of claim 20, wherein the analyte is glucose and
the predetermined range is up to about 2 mg/dL per minute in any
direction.
22. The apparatus of claim 20, further comprising instructions
which, when executed by the one or more processors, causes the one
or more processors to repeat receiving an analyte signal, receiving
a calibration measurement or evaluating, or any combination
thereof, until the analyte signal, the calibration measurement or
both are suitable for use in converting an analyte signal from the
subcutaneous sensor into an analyte concentration.
23. The apparatus of claim 22, further comprising instructions
which, when executed by the one or more processors, causes the one
or more processors to determine a sensitivity based on a ratio of
the analyte signal and the calibration measurement when the analyte
signal, the calibration measurement or both are suitable for use in
converting an analyte signal from the subcutaneous sensor into an
analyte concentration.
24. The apparatus of claim 23, wherein the ratio falls within a
predetermined range associated with a code associated with the
subcutaneous sensor.
25. The apparatus of claim 23, further comprising instructions
which, when executed by the one or more processors, causes the one
or more processors to convert an analyte signal from the analyte
sensor to an analyte concentration based on the sensitivity.
26. The apparatus of claim 1, wherein the subcutaneous sensor
comprises a working electrode and a counter electrode.
27. The apparatus of claim 26, wherein the working electrode
comprises a glucose-responsive enzyme.
28. The apparatus of claim 26, wherein the working electrode
comprises a redox mediator.
29. The apparatus of claim 28, wherein the redox mediator comprises
a complex selected from the group consisting of a
ruthenium-containing complex and an osmium-containing complex.
30. The apparatus of claim 28, wherein the redox mediator is
non-leachable with respect to the working electrode.
31. The apparatus of claim 28, wherein the redox mediator is
immobilized on the working electrode.
32. The apparatus of claim 1, wherein the subcutaneous sensor and
the calibration sensor are physically or wirelessly associated.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 11/929,149 filed Oct. 30, 2007 of
Benjamin J. Feldman, et al., which is a continuation of U.S. patent
application Ser. No. 10/975,207 filed Oct. 27, 2004, now U.S. Pat.
No. 7,299,082, which is related to, and claims priority based on,
U.S. Patent Application No. 60/516,599 of Feldman et al.
(hereinafter, the "Feldman et al. Application") filed on Oct. 31,
2003, which is the subject of Feldman et al., A Continuous Glucose
Sensor Based on Wired Enzyme Technology-Results from a 3-Day Trial
in Patients with Type I Diabetes, Diabetes Technology &
Therapeutics, Vol. 5, No. 5, pp. 769-779 (2003) (hereinafter, the
"Feldman et al. Publication"). This application is also related to
U.S. Pat. No. 6,881,551, which issued on Apr. 19, 2005; U.S. Pat.
No. 6,551,494, which issued on Apr. 22, 2003; U.S. Pat. No.
6,514,718, which issued on Feb. 4, 2003; U.S. Pat. No. 6,175,752,
which issued on Jan. 16, 2001; and U.S. Pat. No. 6,565,509, which
issued on May 20, 2003. Each of the aforementioned applications,
publications, and patents are incorporated herein in their entirety
and for all purposes by this reference.
TECHNICAL FIELD
[0002] The invention relates to the calibration of an
analyte-measurement device adapted to determine the concentration
of an analyte in a fluid from a measurement site within a body,
such as an animal body, a mammalian body, or a human body. The
invention further relates to the use of a calibration standard that
is based on a concentration of an analyte in blood from a
calibration site that is not accessed through a surface of a
fingertip, or is not accessed through a surface of the finger, or
is not on or within a finger. The invention is particularly suited
for calibrating partially or fully implantable glucose-monitoring
devices, such as transcutaneous or subcutaneous glucose-monitoring
devices. Devices, systems and kits making use of the aforementioned
method are provided as well.
BACKGROUND
[0003] There are a number of instances when it is desirable or
necessary to monitor the concentration of an analyte, such as
glucose, lactate, or oxygen, for example, in a fluid of a body,
such as a body of an animal. The animal may be a mammal, such as a
human, by way of example. For example, it may be desirable to
monitor the level of various analytes in bodily fluid, such as
blood, that may have detrimental effects on a body.
[0004] In a particular example, it may be desirable to monitor high
or low levels of glucose in blood that may be detrimental to a
human. In a healthy human, the concentration of glucose in the
blood is maintained between about 0.8 and about 1.2 mg/mL by a
variety of hormones, such as insulin and glucagons, for example. If
the blood glucose level is raised above its normal level,
hyperglycemia develops and attendant symptoms may result. If the
blood glucose concentration falls below its normal level,
hypoglycemia develops and attendant symptoms, such as neurological
and other symptoms, may result. Both hyperglycemia and hypoglycemia
may result in death if untreated. Maintaining blood glucose at an
appropriate concentration is thus a desirable or necessary part of
treating a person who is physiologically unable to do so unaided,
such as a person who is afflicted with diabetes mellitus.
[0005] Certain compounds may be administered to increase or
decrease the concentration of blood glucose in a body. By way of
example, insulin can be administered to a person in a variety of
ways, such as through injection, for example, to decrease that
person's blood glucose concentration. Further by way of example,
glucose may be administered to a person in a variety of ways, such
as directly, through injection or administration of an intravenous
solution, for example, or indirectly, through ingestion of certain
foods or drinks, for example, to increase that person's blood
glucose level.
[0006] Regardless of the type of adjustment used, it is typically
desirable or necessary to determine a person's blood glucose
concentration before making an appropriate adjustment. Typically,
blood glucose concentration is monitored by a person or sometimes
by a physician using an in vitro test that requires a blood sample
that is relatively large in volume, such as three microliters
(.mu.L) or more. The person may obtain the blood sample by
withdrawing blood from a blood source in his or her body, such as a
vein, using a needle and syringe, for example, or by lancing a
portion of his or her skin, using a lancing device, for example, to
make blood available external to the skin, to obtain the necessary
sample volume for in vitro testing. (See U.S. Provisional Patent
Application No. 60/424,414 of Saikley et al. filed on Nov. 6, 2002;
and U.S. Patent Application Publication No. 2004/0138588 A1 of
Saikley et al. filed on Nov. 4, 2003.) The person may then apply
the fresh blood sample to a test strip, whereupon suitable
detection methods, such as calorimetric, electrochemical, or
photometric detection methods, for example, may be used to
determine the person's actual blood glucose level. The foregoing
procedure provides a blood glucose concentration for a particular
or discrete point in time, and thus, must be repeated periodically,
in order to monitor blood glucose over a longer period.
[0007] Since the tissue of the fingertip is highly perfused with
blood vessels, a "finger stick" is generally performed to extract
an adequate volume of blood for in vitro glucose testing. By way of
example, a finger stick may involve lancing the fingertip and
"milking" the adjacent tissue, such that an adequate volume of
blood is available on the fingertip surface. Unfortunately, the
fingertip is also densely supplied with pain receptors, which can
lead to significant discomfort during the blood extraction process.
Thus, conventional extraction procedures are generally inconvenient
and often painful for the individual, particularly when frequent
samples are required.
[0008] A less painful method for obtaining a blood sample for in
vitro testing involves lancing an area of the body having a lower
nerve ending density than the fingertip, such as the hand, the arm,
or the thigh, for example. Such areas are typically less supplied,
or not heavily supplied, with near-surface capillary vessels, and
thus, blood. For example, a total blood flow of 33 AO mL/100 gm-min
at 20.degree. C. has been reported for fingertips, while a much
lower total blood flow of 6 to 9 mL/100 gm-min has been reported
for forearm, leg, and abdominal skin. (See: Johnson, Peripheral
Circulation, John Wiley & Sons, p. 198 (1978).) As such,
lancing the body in these regions typically produces sub-microliter
samples of blood that are not sufficient for most in vitro blood
glucose-monitoring systems.
[0009] Glucose-monitoring systems that allow for sample extraction
from sites other than the finger and that can operate using small
samples of blood, have been developed. For example, U.S. Pat. No.
6,120,676 to Heller et al. describes devices that permit generally
accurate electrochemical analysis of an analyte, such as glucose,
in a small sample volume of blood. Typically, less than about one
.mu.L of sample is required for the proper operation of these
devices, which enables glucose testing through "arm sticks" rather
than finger sticks. Additionally, commercial products for measuring
glucose levels in blood that is extracted from sites other than the
finger have been introduced, such as the FreeStyle.RTM. blood
glucose-monitoring system (Abbott Diabetes Care, formerly known as
TheraSense, Inc., Alameda, Calif.) that is based on the
above-referenced U.S. Pat. No. 6,120,676.
[0010] However, differences between the circulatory physiology of
finger sites and "off-finger" sites have led to differences in the
measurements of blood glucose levels associated with those
different sites, as reported in McGarraugh et al., Glucose
Measurements Using Blood Extracted from the Forearm and the Finger,
TheraSense, Inc., Alameda, Calif. (2001), and McGarraugh et al.,
Physiological Influences on Off-Finger Glucose Testing, Diabetes
Technology & Therapeutics, Vol. 3, No. 3, pp. 367-376 (2001).
The former study indicates that stimulating blood flow at the skin
surface of the arm may reduce these differences in certain
circumstances when the off-finger site is the arm. In the latter
study, the differences between blood glucose measurements using
capillary blood from the finger and those using capillary blood
from the arm were attributed to a time lag in the glucose response
on the arm with respect to the glucose response on the finger that
was observed when the glucose concentration was changing. This time
lag varied from subject-to-subject in a range of five to twenty
minutes. The study found that when glucose concentration is
decreasing rapidly into a state of hypoglycemia, this time lag
could delay the detection of hypoglycemia. Thus, it was determined
that relative to the arm, the finger was a preferable test site for
testing for hypoglycemia.
[0011] It follows that while it may be desirable to move away from
the finger as a site for obtaining blood samples for discrete or
periodic in vitro blood glucose determinations, in view of the pain
involved, for example, it has not heretofore been deemed practical
to do so to effectively monitor for low blood glucose levels that
may be detrimental to an individual.
[0012] In addition to the discrete or periodic, in vitro, blood
glucose-monitoring systems described above, at least partially
implantable, or in vivo, blood glucose-monitoring systems, which
are designed to provide continuous in vivo measurement of an
individual's blood glucose concentration, have been described.
(See, e.g., U.S. Pat. Nos. 6,248,067 to Causey et al.; 6,212,416 to
Ward et al.; 6,175,752 to Say et al.; 6,119,028 to Schulman et al.;
6,091,979 to Pfeiffer et al.; 6,049,727 to Crothall et al.; and
5,791,344 to Schulman et al.; and International Publication No. WO
00/78992.) Although optical means or devices may be employed to
monitor glucose concentration, a number of these in vivo systems
are based on "enzyme electrode" technology, whereby an enzymatic
reaction involving glucose oxidase is combined with an
electrochemical sensor for the determination of an individual's
blood glucose level. By way of example, the electrochemical sensor
may be inserted into a blood source, such as a vein or other blood
vessel, for example, such that the sensor is in continuous contact
with blood and can effectively monitor blood glucose levels.
Further by way of example, the electrochemical sensor may be placed
in substantially continuous contact with bodily fluid other than
blood, such as dermal or subcutaneous fluid, for example, for
effective monitoring of glucose levels in such bodily fluid.
Relative to discrete or periodic monitoring, continuous monitoring
is generally more desirable in that it may provide a more
comprehensive assessment of glucose levels and more useful
information, such as predictive trend information, for example.
Subcutaneous continuous glucose monitoring is also desirable for a
number of reasons, one being that continuous glucose monitoring in
subcutaneous bodily fluid is typically less invasive than
continuous glucose monitoring in blood.
[0013] While continuous glucose monitoring is desirable, there are
several drawbacks associated with the manufacture and calibration
of continuous glucose-monitoring devices. By way of example, based
on current manufacturing techniques, it may be impossible to
account for sensor-to-sensor or subject-to-subject variability in
performing accurate factory calibration. Further by way of example,
individual-specific calibration may be desirable or required to
account for subject-to-subject variability, such as
subject-to-subject physiological variability. If an
individual-specific calibration is called for, a sample of the
individual's blood may be required in order to calibrate a glucose
monitor for that individual's use.
[0014] Further development of calibration methods, as well as
analyte-monitoring devices, systems, or kits employing same, is
desirable.
SUMMARY OF THE INVENTION
[0015] The concentration of a specific analyte at one area of a
body may vary from that at another area. Herein, a body refers to a
body of an animal, such as a mammal, and includes a human. Such a
variation may be associated with a variation in analyte metabolism,
production, and/or transportion from one area of the body and
another. When data obtained from one area of the body is used to
calibrate an analyte-measurement or monitoring device for a
particular individual, such a variation may result in improper
calibration of the device for that individual. According to one
aspect of the present invention, a method of calibrating such a
device that accounts for such a variation, is provided.
[0016] For example, one aspect of the invention relates to a method
for calibrating an analyte-measurement device that is adapted to
evaluate the analyte concentration in a bodily fluid from a
specific measurement site in a body. The method involves
determining the concentration of the analyte in blood from a
calibration site within the body that is not accessed through a
surface of a fingertip, and, based on that determination,
calibrating the analyte-measurement device. Preferably, the
calibration site is not accessed through a surface of a finger.
Most preferably, the calibration site is not on or within a finger.
By way of example, but not limitation, the calibration site may be
accessed through a surface of a palm, a hand, an arm, a thigh, a
leg, a torso, or an abdomen, of the body, and may be located within
a palm, a hand, an arm, a thigh, a leg, a torso, or an abdomen, of
the body. An in vitro blood glucose-monitoring device, such as the
above-mentioned FreeStyle.RTM. blood glucose-monitoring device, may
be used for determining the concentration of the analyte in the
blood from the calibration site, or an in vivo measurement device
or sensor may be used. The analyte-measurement device undergoing
calibration may be, and preferably is, an in vivo
glucose-monitoring device, such as that described in U.S. Pat. No.
6,175,752 of Say et al. filed on Apr. 30, 1998, U.S. Pat. No.
6,329,161 of Heller et al. filed on Sep. 22, 2000, U.S. Pat. No.
6,560,471 of Heller et al. filed on Jan. 2, 2001, U.S. Pat. No.
6,579,690 of Bonnecaze et al. filed on Jul. 24, 2000, U.S. Pat. No.
6,654,625 of Say et al. filed on Jun. 16, 2000, and U.S. Pat. No.
6,514,718 of Heller et al. filed on Nov. 29, 2001, for example. It
is contemplated that the analyte-measurement device may be an in
vivo FreeStyle Navigator.RTM. glucose monitoring device (Abbott
Diabetes Care Inc.), based on the foregoing U.S. Pat. Nos.
6,175,752, 6,329,161, 6,560,471, 6,579,690, 6,654,625, and
6,514,718, that is currently in clinical trials, though not now
commercially available.
[0017] Another aspect of the invention relates to a method for
monitoring the concentration of an analyte in a body. The method
involves determining a concentration of the analyte in blood from a
calibration site, such as that described above; inserting a sensor
into the body at a specific measurement site; obtaining at least
two signals indicative of the concentration of the analyte in the
bodily fluid at that measurement site via the sensor; and adjusting
those signals based on the concentration of the analyte in blood
from the calibration site. An in vitro blood glucose-monitoring
device, such as the above-mentioned FreeStyle.RTM. blood
glucose-monitoring device, may be used for determining the
concentration of the analyte in the blood from the calibration
site, although in vivo measurement devices or sensors may also be
used. The sensor is chosen as one that is sufficient for
determining the concentration of the analyte in the bodily fluid at
the measurement site, or providing a signal indicative of such
analyte concentration, such as that associated with an in vivo
glucose monitoring device, as described above. Preferably, the
sensor is exposed to the bodily fluid in a thorough or
substantially continuous manner. Preferably, obtaining the signals
indicative of the concentration of the analyte in the bodily fluid
at the measurement site occurs over a period of time, such as from
about one day to about three days or more, for example.
[0018] According to yet another aspect of the invention, a surface
of the body adjacent to the calibration site may be rubbed prior to
the determination of analyte concentration in blood from the
calibration site. Preferably, the rubbing is sufficient to enhance
mobility of fluid at the calibration site. Typically, manually
rubbing the surface of an arm, leg, or abdomen, for example, with a
comfortable or moderate amount of pressure for a few seconds, up to
a minute or more, will suffice to enhance mobility of fluid at a
nearby calibration site within the arm, leg, or abdomen,
respectively. Rubbing pressure and time can be varied
appropriately, for example, less pressure can be applied for
longer, and more pressure can be applied more briefly, and either
or both can be varied as desirable or necessary for a particular
calibration site. Any appropriate means or devices, manual or
otherwise, may be used to rub the surface or to enhance mobility of
the fluid at the calibration site.
[0019] A method according to the present invention is well suited
for use in connection with a device that allows for the
self-monitoring of glucose levels. Such a method may involve
determining or measuring an analyte concentration in subcutaneous
fluid, or in dermal fluid, or in interstitial fluid, for example.
Any of the above-described methods may utilize any of a number of
calibration sites in a body, such as those in the arms, the legs,
the torso, the abdomen, or any combination thereof, merely by way
of example. In humans, arms and legs are particularly convenient
calibration sites. The measurement and calibration sites may be
located in different parts of a body, or in the same region or
regions of the body. The same or different types of devices may be
used to measure analyte concentration in the bodily fluid and in
the blood. Depending on the particular physiological conditions of
the calibration site or sites, it may be desirable to rub a surface
of the body adjacent the calibration site, such as arm skin that is
above or near a calibration site within an arm, as previously
described. (See: U.S. Pat. No. 6,591,125 of Buse et al. filed on
Jun. 27, 2000.)
[0020] According to yet another aspect of the present invention, a
system or kit for measuring the concentration of an analyte in a
body is provided. The system comprises a measurement sensor for
providing a signal indicative of a concentration of the analyte in
the bodily fluid at the measurement site, a calibration sensor for
determining a concentration of the analyte in blood from the
calibration site, and a calibration device in operative
communication with the measurement sensor and the calibration
sensor for receiving data therefrom. The measurement sensor may be
a disposable device, and may be independent, separate, separable or
detachable relative to the calibration device, and may be
wirelessly or physically associated with the calibration device
when in use. Appropriate measurement sensors include the various in
vivo measurement devices or sensors described above. The
calibration sensor may be any sensor sufficient for determining the
concentration of the analyte in blood at the calibration site.
Appropriate calibration sensors include the various in vitro
measurement devices or sensors described above, although in vivo
measurement devices or sensors may also be used. The calibration
device comprises a receiving element for receiving at least one
signal obtained via the measurement sensor, a receiving element for
receiving at least one concentration value obtained via the
calibration sensor, and calibration element for calibrating the
signal obtained via the measurement sensor based on the value
obtained via the calibration sensor. The receiving element may
comprise a storage element for storing any value received. The
calibration element may comprise an algorithm for making the
calibration or adjustment, which algorithm may be embodied in
software.
[0021] Preferably, the measurement sensor is sufficient for
electrochemically determining the concentration of the analyte in
the bodily fluid. When an electrochemical measurement sensor is
used, the sensor generally comprises a working electrode and a
counter electrode. When the analyte of interest is glucose, the
working electrode generally comprises a glucose-responsive enzyme
and a redox mediator. The redox mediator may comprise an osmium
(Os)- or a ruthenium (Ru)-containing complex, by way of example,
preferably, the former. Preferably, the redox mediator is
non-leachable relative to the working electrode, such that it does
not leach from the working electrode into the body over the
lifetime of the sensor. Most preferably, the redox mediator is
immobilized on the working electrode.
[0022] Preferably, the calibration sensor is sufficient for
electrochemically determining the concentration of the analyte in
blood based on any suitable volume of blood. While this volume may
be about 3 .mu.L for some measurement sensors, as described above,
it is preferably less than or equal to about 1 .mu.L of blood, more
preferably, less than or equal to about 0.5 .mu.L of blood, and
still more preferably, less than or equal to about 0.2 .mu.L of
blood, such as the smallest amount sufficient for a meaningful
measurement. The calibration sensor may be an in vitro
electrochemical sensor, as described above, or an in vivo
electrochemical sensor, as also described above, designed for
sensing in blood, typically and preferably the former.
[0023] These and various other aspects, features and embodiments of
the present invention are further described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] A detailed description of various aspects, features and
embodiments of the present invention is provided herein with
reference to the accompanying drawings, which are briefly described
below. The drawings are illustrative and are not necessarily drawn
to scale. The drawings illustrate various aspects or features of
the present invention and may illustrate one or more embodiment(s)
or example(s) of the present invention in whole or in part. A
reference numeral, letter, and/or symbol that is used in one
drawing to refer to a particular element or feature may be used in
another drawing to refer to a like element or feature.
[0025] Each of FIG. 1A (FIG. 1A) and FIG. 1B is a schematic
illustration of a system or portions thereof for measuring a
concentrate of an analyte in a bodily fluid that may be employed,
according to various aspects of the present invention. These two
figures may be collectively referred to as FIG. 1 (FIG. 1)
herein.
[0026] FIG. 2A (FIG. 2A), FIG. 2B (FIG. 2B), and FIG. 2C (FIG. 2C),
collectively and sequentially illustrate a calibration process or
algorithm that may be employed, according to various aspects of the
present invention. These three figures may be collectively referred
to as FIG. 2 (FIG. 2) herein.
[0027] FIG. 3 (FIG. 3) is a schematic illustration of an
analyte-measuring or monitoring device, a portion of which is
enlarged for illustration purposes, that may be employed, according
to various aspects of the present invention.
[0028] FIG. 4A (FIG. 4A) is a schematic illustration of a sensing
layer that is associated with a working electrode of an
analyte-measuring or monitoring device, such as that illustrated in
FIG. 3. FIG. 4B (FIG. 4B) is an illustration of the structure of a
redox polymer component of a sensing layer, such as that
illustrated in FIG. 4A. FIGS. 4A and 4B may be collectively
referred to as FIG. 4 (FIG. 4) herein.
[0029] FIG. 5 (FIG. 5) is a overlay plot of representative data (-)
from an abdominally implanted analyte-measuring or monitoring
device in raw, uncalibrated current (nA) on the left axis versus
time (days) and venous plasma data (.DELTA.) in glucose
concentration (mg/dL) on the right axis versus time (days),
according to an Experimental Study described herein.
[0030] FIG. 6 (FIG. 6) is a plot of representative data (-) from an
arm-implanted analyte-measuring or monitoring device, as
calibrated, venous plasma data (.DELTA.), and arm-capillary blood
data (.quadrature.), in glucose concentration (mg/dL) versus time
(days), according to an Experimental Study described herein.
[0031] FIG. 7 (FIG. 7) is a plot of representative data (-) from an
arm-implanted analyte-measuring or monitoring device, as
calibrated, representative data (-) from an abdomen-implanted
analyte-measuring or monitoring device, as calibrated, and venous
plasma data (.DELTA.), in glucose concentration (mg/dL) versus time
(days), according to an Experimental Study described herein.
[0032] FIG. 8 (FIG. 8) is a plot of glucose concentration data
(mg/dL) from arm- or abdomen-implanted analyte-measuring or
monitoring devices, as calibrated, versus that data from venous
blood, in the form of a Clarke error grid, according to an
Experimental Study described herein.
DETAILED DESCRIPTION OF THE INVENTION
[0033] In the description of the invention herein, it will be
understood that a word appearing in the singular encompasses its
plural counterpart, and a word appearing in the plural encompasses
its singular counterpart, unless implicitly or explicitly
understood or stated otherwise. Merely by way of example, reference
to "an" or "the" "analyte" encompasses a single analyte, as well as
a combination and/or mixture of two or more different analytes,
reference to "a" or "the" "concentration value" encompasses a
single concentration value, as well as two or more concentration
values, and the like, unless implicitly or explicitly understood or
stated otherwise. Further, it will be understood that for any given
component described herein, any of the possible candidates or
alternatives listed for that component, may generally be used
individually or in combination with one another, unless implicitly
or explicitly understood or stated otherwise. Additionally, it will
be understood that any list of such candidates or alternatives, is
merely illustrative, not limiting, unless implicitly or explicitly
understood or stated otherwise.
[0034] Various terms are described below to facilitate an
understanding of the invention. It will be understood that a
corresponding description of these various terms applies to
corresponding linguistic or grammatical variations or forms of
these various terms. It will also be understood that the invention
is not limited to the terminology used herein, or the descriptions
thereof, for the description of particular embodiments. Merely by
way of example, the invention is not limited to particular
analytes, bodily or tissue fluids, blood or capillary blood, or
sensor designs or usages, unless implicitly or explicitly
understood or stated otherwise, as such may vary.
[0035] The terms "amperometry" and "amperometrically" refer to the
measurement of the strength of a current and include steady-state
amperometry, chronoamperometry, and Cottrell-type measurements.
[0036] The term "bodily fluid" in the context of the invention
encompasses all non-blood bodily fluid that can be found in the
soft tissue of an individual's body, such as subcutaneous, dermal,
or interstitial tissue, in which the analyte may be measured. By
way of example, the term "bodily fluid" encompasses a fluid such as
dermal, subcutaneous, or interstitial fluid.
[0037] The term "blood" in the context of the invention encompasses
whole blood and its cell-free components, such as plasma and serum.
The term "capillary blood" refers to blood that is associated with
any blood-carrying capillary of the body.
[0038] The term "concentration" may refer to a signal that is
indicative of a concentration of an analyte in a medium, such as a
current signal, for example, to a more typical indication of a
concentration of an analyte in a medium, such as mass of the
analyte per unit volume of the medium, for example, or the
like.
[0039] "Coulometry" refers to the determination of charge passed or
projected to pass during complete or nearly complete electrolysis
of a compound, either directly on the electrode or through one or
more electron-transfer agents. The charge is determined by
measurement of electrical charge passed during partial or nearly
complete electrolysis of the compound or, more often, by multiple
measurements during the electrolysis of a decaying current over an
elapsed period. The decaying current results from the decline in
the concentration of the electrolyzed species caused by the
electrolysis.
[0040] A "counter electrode" refers to one or more electrodes
paired with the working electrode, through which passes an
electrochemical current equal in magnitude and opposite in sign to
the current passed through the working electrode. The term "counter
electrode" is meant to include counter electrodes that also
function as reference electrodes (i.e., a counter/reference
electrode) unless the description provides that a "counter
electrode" excludes a reference or counter/reference electrode.
[0041] The term "electrolysis" refers the electrooxidation or
electroreduction of a compound either directly at an electrode or
via one or more electron-transfer agents, such as redox mediators
and/or enzymes, for example.
[0042] An "immobilized" material refers to a material that is
entrapped on a surface or chemically bound to a surface.
[0043] An "implantable" device refers to a fully implantable device
that is implanted fully within a body and/or an at least partially
implantable device that is at least partially implanted within a
body. An example of an at least partially implantable sensing
device is a transcutaneous sensing device, sometimes referred to as
a subcutaneous sensing device, that is associated with a portion
that lies outside of a body and a portion that penetrates the skin
from the outside of the body and thereby enters the inside of the
body.
[0044] The term "measure," as in "to measure the concentration," is
used herein in its ordinary sense and refers to the act of
obtaining an indicator, such as a signal, that may be associated
with a value, such as concentration, for example, and to the act of
ascertaining a value, such as a concentration, for example. The
term "monitor," as in "to monitor the concentration," refers to the
act of keeping track of more than one measurement over time, which
may be carried out on a systematic, regular, substantially
continuous, and/or on-going basis. The terms measure and monitor
may be used generally herein, such as alternately, alternatively,
or interchangeably, or more specifically, as just described.
[0045] The term "measurement" may refer to a signal that is
indicative of a concentration of an analyte in a medium, such as a
current signal, for example, to a more typical indication of a
concentration of an analyte in a medium, such as mass of the
analyte per unit volume of the medium, for example, or the like.
The term "value" may sometimes be used herein as a term that
encompasses the term "measurement."
[0046] The term "patient" refers to a living animal, and thus
encompasses a living mammal and a living human, for example. The
term "subject" may sometimes be used herein as a term that
encompasses the term "patient."
[0047] The term "redox mediator" refers to an electron-transfer
agent that transfers electrons between a compound and a working
electrode, either directly or indirectly.
[0048] The term "reference electrode" encompasses a reference
electrode that also functions as a counter electrode (i.e., a
counter/reference electrode), unless the description provides that
a "reference electrode" excludes a counter/reference electrode.
[0049] The term "working electrode" refers to an electrode at which
a candidate compound is electrooxidized or electroreduced with or
without the agency of a redox mediator.
[0050] The invention generally relates to the calibration of a
device adapted to measure or monitor a concentration of an analyte
in a body. The invention exploits a correspondence that exists
between a concentration of an analyte found in a bodily fluid of an
individual and a concentration of the same analyte found in blood
of that individual. For example, according to the present
invention, a concentration of an analyte in blood from a particular
calibration site within the body of an individual is used to
calibrate a device that is adapted to measure or monitor a
concentration of the analyte at a measurement site in the body of
that individual.
[0051] As previously described, it is often undesirable or painful
to obtain blood from a fingertip or finger. The calibration method
of the present invention does not demand this. That is, according
to the present invention, a calibration site may be selected as one
that is not accessed from a surface of a fingertip, one that is not
accessed from a surface of a finger, or one that is not on or
within a finger, preferably the latter. Merely by way of
convenience, but not limitation, such a calibration site may be
referred to as an "off-finger" calibration site. By way of example,
but not limitation, the calibration site may be accessed through a
surface of a palm, a hand, an arm, a thigh, a leg, or an abdomen,
of the body, and may be located within a palm, a hand, an arm, a
thigh, a leg, or an abdomen, of the body, or any other bodily site
wherein the blood or capillary blood at the site generally tracks
bodily fluid in terms of glucose concentration. The off-finger
calibration site is typically located up to about 2 mm beneath the
exterior surface of the epidermis, or up to the maximum depth
appropriate for a "stick" by a lancet or other appropriate means or
device.
[0052] As previously described, there are a number of different
systems that can be used in the measuring or monitoring of glucose
levels in a body, including those that comprise a glucose sensor
that is adapted for insertion into a subcutaneous site within the
body for the continuous monitoring of glucose levels in bodily
fluid of the subcutaneous site. For example, U.S. Pat. No.
6,175,752 to Say et al. employs such a sensor that comprises at
least one working electrode that is associated with a redox enzyme,
wherein the redox enzyme is sufficient to catalyze a reaction that
is associated with the detection of glucose. This sensor further
comprises a counter electrode and a reference electrode, or a
combined counter/reference electrode, and may further comprise a
temperature probe. Such a sensor is further described in the
Experimental Study below.
[0053] A suitable sensor may work as now described. The sensor is
placed, transcutaneously, for example, into a subcutaneous site
such that subcutaneous fluid of the site comes into contact with
the sensor. The sensor operates to electrolyze an analyte of
interest in the subcutaneous fluid such that a current is generated
between the working electrode and the counter electrode. A value
for the current associated with the working electrode is determined
periodically. If multiple working electrodes are used, current
values from each of the working electrodes may be determined
periodically. A microprocessor may be used to collect these
periodically determined current values or to further process these
values.
[0054] The periodically determined current values may be processed
in various ways. By way of example, current values may be checked
to determine whether they are within a predetermined range. If the
current values are within the predetermined range, one of the
current values is converted to an analyte concentration by way of a
calibration. Further by way of example, in the case of multiple
working electrodes, current values from each of the working
electrodes may be compared to determine whether they differ by a
predetermined threshold amount. If the current values are within
the predetermined range and do not differ by more than the
predetermined threshold amount, one of the current values is
converted to an analyte concentration by way of a calibration.
Sensor-specific calibration may be performed during the manufacture
of the sensor, as described elsewhere herein. Alternative or
additional individual-specific calibration may be performed on an
individual basis, as also described herein. Further calibration may
be needed when the current values from a working electrode or from
each of multiple working electrodes are not within the
predetermined range, or when the current values from each of
multiple working electrodes differ by more than the predetermined
threshold amount. If the current values do not meet one or more of
the established criteria, none of the current values may be
acceptable for conversion into an analyte concentration. An
indication, such as a code, may be displayed or otherwise
transmitted, such as via audio, visual, vibrational, sensory, or
other suitable notification means or device, to indicate this fact.
If analyte concentration is successfully determined, it may be
displayed, stored, and/or otherwise processed to provide useful
information. By way of example, analyte concentrations may be used
as a basis for determining a rate of change in analyte
concentration, which should not change at a rate greater than a
predetermined threshold amount. If the rate of change of analyte
concentration exceeds the predefined threshold, an indication may
be displayed or otherwise transmitted to indicate this fact.
[0055] The sensor may have undergone calibration during the
manufacturing process. However, as previously described, such
calibration may be insufficient in terms of accounting for
sensor-to-sensor or subject-to-subject variability. Thus,
individual-specific calibration may be desirable or required to
account for subject-to-subject variability, such as
subject-to-subject physiological variability. In such a
calibration, a sample of blood may be extracted from a calibration
site within the individual and measured to obtain a glucose
concentration for use as a calibration point. The measurement may
be carried out using any of various known means, devices and
methods, such as via the FreeStyle.RTM. blood glucose-monitoring
system. The resulting glucose concentration can be entered into an
analyte-monitoring device as a calibration code, as desirable or
needed, for example, immediately after sensor implantation or
following notification of an invalid result. The sensor may be
calibrated manually, periodically, or as desirable or necessary,
during use.
[0056] As described above, blood samples are often obtained from
sites within highly perfused areas of the body, such as sites
within the fingertips. Blood-sampling from these sites is quite
painful. Alternative sites, however, have not previously been
thought to be sufficiently practical or useful as sources for
calibration samples. By way of example, in a previous study, it was
reported that capillary blood obtained simultaneously from
different body sites have different glucose concentrations, and
that the blood glucose levels obtained from the arm and the finger
were not perfectly correlated. (See: McGarraugh et al., Glucose
Measurements Using Blood Extracted from the Forearm and the Finger,
TheraSense, Inc., Alameda, Calif. (2001); and McGarraugh et al.,
Physiological Influences on Off-Finger Glucose Testing, Diabetes
Technology & Therapeutics, Vol. 3, No. 3, pp. 367-376 (2001).)
Thus, it has previously been thought that alternative sites are not
suitable for blood-sampling for calibration purposes.
[0057] According to the present invention, blood-sampling at
alternative sites is used for calibration purposes. As demonstrated
in the Experimental Study described herein, the use of alternative
sites for calibration purposes is advantageous for a number of
reasons beyond pain reduction, such as allowing for the
concentration of calibration points early on in the period of use,
allowing for the refinement of calibration as multiple calibration
points are obtained, allowing for the use of real-time data, and
providing clinically accurate or acceptable results.
[0058] According to an embodiment of the present invention, a
method for calibrating a device sufficient for determining a
concentration of an analyte of interest at a measurement site
within a body, comprises providing the device at the measurement
site within the body, determining a concentration of the analyte in
blood from an off-finger calibration site within the body, and
calibrating the device using the resulting analyte concentration.
According to this method, the resulting analyte concentration may
serve as a baseline concentration of analyte in the blood for
calibration purposes. There is no particular limitation on the
location of the measurement site. By way of example, any
measurement site of practical utility may be used. Preferably, the
measurement site is also an off-finger measurement site, such as an
arm, a leg, a torso, or an abdomen, for example. The measurement
site is typically located up to about 8 mm beneath the exterior
surface of the epidermis, preferably located from about 2 mm to
about 6 mm beneath the exterior surface, and more preferably
located from about 3 mm to about 5 mm beneath the exterior
surface.
[0059] According to another embodiment of the present invention, a
method for determining a concentration of an analyte, such as
glucose, in a bodily fluid at a measurement site within a body,
comprises inserting a device, such as those described herein, at
the measurement site within the body, determining the concentration
of an analyte of interest, such as glucose, in blood from an
off-finger calibration site within a body, and calibrating the
device using the resulting analyte concentration. In this method,
the sensor is used to determine at least two values for the
concentration of the analyte in the bodily fluid at the measuring
site. Further, calibrating the device comprises adjusting the at
least two values based on the concentration of the analyte in blood
from the calibration site. According to this method, the
concentration of the analyte in blood from the calibration site may
be determine at least once, or at least twice, during the
determination of the at least two values for the concentration of
the analyte in the bodily fluid at the measurement site. Here
again, there is no particular limitation on the location of the
measurement site, although preferably it is an off-finger site,
such as an arm, a leg, a torso, or an abdomen, for example.
[0060] As demonstrated herein, the methods of the present invention
are particularly useful in connection with a device that is used to
measure or monitor a glucose analyte, such as any such device
described herein. These methods may also be used in connection with
a device that is used to measure or monitor another analyte, such
as oxygen, carbon dioxide, proteins, drugs, or another moiety of
interest, for example, or any combination thereof, found in bodily
fluid, such as subcutaneous fluid, dermal fluid (sweat, tears, and
the like), interstitial fluid, or other bodily fluid of interest,
for example, or any combination thereof. Preferably, the device is
in good contact, such as thorough and substantially continuous
contact, with the bodily fluid.
[0061] According to yet another embodiment of the present
invention, a system or kit for measuring a concentration of an
analyte in a bodily fluid at a measurement site within the body is
provided. An example of such a system 100 is schematically
illustrated in FIG. 1A and FIG. 1B. The system 100 comprises a
measurement sensor 102, a calibration sensor 104, and a calibration
device 106. The measurement sensor 102 is any suitable sensor that
is sufficient for determining the concentration of the analyte in
the bodily fluid at a measurement site within the body, such as any
described herein. The calibration sensor 104 is any suitable sensor
that is sufficient for determining a calibration concentration of
the analyte in blood at an off-finger calibration site within the
body. The location of the measurement sensor within the body is
unrestricted, although some locations may be more desirable or
practical, as described above. Preferably, the measurement site is
an off-finger site.
[0062] The two sensors 102 and 104 may be completely independent,
such as an independent in vivo, continuous, glucose monitoring
sensor and an independent in vitro, discrete, glucose-testing
strip, that are physically separate, merely by way of example. The
sensors 102 and 104 may be provided in a system or kit 100 that
comprises elements sufficient for calibration and use of the
measurement sensor according to the present invention, such as the
elements described below.
[0063] The measurement sensor 102 and the calibration device 106
may be physically associated with one another, whether temporarily,
detachably, or permanently. The measurement sensor 102 and the
calibration device 106 may be wirelessly associated, whether
directly (not shown) or indirectly, as shown via transmission
element 108 in FIG. 1A. The measurement sensor 102 may include a
transmission element or device 108 as a component (not shown), or
may be operatively coupled to a transmission element or device 108,
as shown in FIG. 1A and FIG. 1B. The coupling may be wireless or in
the form of a direct physical connection, as shown in FIG. 1A,
merely by way of example. The transmission element or device 108 is
of a construction sufficient for receiving a raw analyte signal
(represented by an encircled .about.symbol) from the measurement
sensor 102 and transmitting a raw analyte signal, such as a
current, for example, to the calibration element or device 106. The
transmission device 108 and the calibration device 106 are
operatively coupled for communication therebetween. The coupling
may be in the form of a wireless connection, as shown in FIG. 1A,
any other suitable communicative connection, or any combination
thereof.
[0064] The calibration sensor 104 may include the calibration
device 106 as a component (not shown), or may be operatively
coupled to the calibration device 106, as shown in FIG. 1A and FIG.
1B. The coupling may be wireless (not shown) or in the form of a
direct physical connection, as shown in FIG. 1A, merely by way of
example. Preferably, the calibration device 106 is designed to
receive calibration data from the calibration sensor 104
automatically, rather than manually via the user, so as to reduce
the chances of data entry error, for example.
[0065] As shown in FIG. 1B, the calibration device 106 comprises an
element 110 for receiving at least one signal or concentration
value obtained via the measurement sensor 102 and an element 112
for receiving at least one concentration value obtained via the
calibration sensor 104, and a calibration element 114 for
evaluating data, such as a signal or value from the measurement
sensor 112, and/or a value from the calibration sensor 104. The
receiving elements 110 and 112 may comprise any suitable electronic
circuitry, componentry, storage media, such as temporary storage
media or rewriteable storage media, a signal- or data-processing
element, a software element, or any combination thereof, merely by
way of example, and may be physically (wired, for example) or
wirelessly associated with sensors 102 and 104, respectively. The
calibration element 114 may comprise any suitable electronic
circuitry, componentry, storage media, an algorithmic element, a
data-processing element, a software element, or any combination
thereof, for making the adjustment or calibration. The calibration
element 114 may comprise any suitable means or device for storing
any suitable algorithm or software, such as any suitable storage
media, for example, non-rewriteable electronic storage media and/or
read-only electronic storage media. As output 110, the calibration
element 114 may provide an indication of operating sensitivity 116,
as shown in FIG. 1B, by way of example, for use in another part of
the system, such as a microprocessor (".mu.P") 118, for calibrating
an analyte signal or value from the measurement sensor based on the
value from the calibration sensor, or calculating analyte
concentration. The calibration, or calculation of analyte
concentration, may be found by dividing the raw analyte signal by
the operating sensitivity, when the sensitivity is expressed in
appropriate units of current/concentration, such as nA/(mg/dL), for
example. The system 100 may further comprise any suitable
communication means or device (not shown), operatively connected to
the microprocessor 118, for communicating the analyte sensitivity
to the user, to another system, and/or the like.
[0066] Preferably, the measurement sensor 102 is designed,
constructed, or configured for ease in self-monitoring analyte
concentration in bodily fluid. Merely by way of example, the
measurement sensor 102 may be any suitable sensor described in U.S.
Pat. No. 6,175,752 to Say et al. The measurement sensor 102 may be
one suited for an in vitro measurement of analyte concentration in
solution, or one suited for in vivo measurement of analyte
concentration of a bodily fluid. Merely by way of example, the
measurement sensor 102 may be one suited for partial or full
implantation within a body, such as an in vivo sensor suited for
continuous monitoring of an analyte concentration in a bodily fluid
with the body. The measurement sensor 102 may comprise an
analyte-diffusion-limiting membrane, as further described in
relation to the Experimental Study herein, although such a membrane
is not required. (See: U.S. Pat. No. 6,932,894 of Mao et al. filed
on May 14, 2002 (may include a membrane); and U.S. Pat. No.
7,052,591 of Gao et al. filed on Sep. 19, 2000 (may not include a
membrane).)
[0067] According to a preferred embodiment of the present
invention, the measurement sensor 102 is one suited for
electrochemical measurement of analyte concentration, and
preferably, glucose concentration, in a bodily fluid. In this
embodiment, the measurement sensor 102 comprises at least a working
electrode and a counter electrode. It may further comprise a
reference electrode, although this is optional. The working
electrode typically comprises a glucose-responsive enzyme and a
redox mediator, as further described below in the Experimental
Study, both of which are agents or tools in the transduction of the
analyte, and preferably, glucose. Preferably, the redox mediator is
non-leachable relative to the working electrode. Merely by way of
example, the redox mediator may be, and preferably is, immobilized
on the working electrode.
[0068] According to a most preferred embodiment of the present
invention, the measurement sensor 102 is one suited for in vivo,
continuous, electrochemical measurement or monitoring of analyte
concentration, and preferably, glucose concentration, in a bodily
fluid. In this embodiment, the measurement sensor 102 is
sufficiently biocompatible for its partial or full implantation
within the body. By way of explanation, when an unnatural device is
intended for use, particularly long-term use, within the body of an
individual, protective mechanisms of the body attempt to shield the
body from the device. (See co-pending U.S. application Ser. No.
10/819,498 of Feldman et al. filed on Apr. 6, 2004, published as
U.S. Publication No. 2005/0173245.) That is, such an unnatural
device or portion thereof is more or less perceived by the body as
an unwanted, foreign object. Protective mechanisms of the body may
encompass encapsulation of the device or a portion thereof, growth
of tissue that isolate the device or a portion thereof, formation
of an analyte-impermeable barrier on and around the device or a
portion thereof, and the like, merely by way of example.
Encapsulation and barrier formation around all or part of the
implantable sensor may compromise, significantly reduce, or
substantially or completely eliminate, the functionality of the
device. Preferably, the measurement sensor 102 is sufficiently
biocompatible to reduce, minimize, forestall, or avoid any such
protective mechanism or its effects on the sensor functionality, or
is associated with or adapted to incorporate a material suitable
for promoting biocompatibility, such as a
superoxide-dismutase/catalase catalyst. (See co-pending U.S.
application Ser. No. 10/819,498 of Feldman et al. filed on Apr. 6,
2004.) Preferably, the measurement sensor 102 is sufficiently
biocompatible over the desired, intended, or useful life of the
sensor.
[0069] It is also preferable that the measurement sensor 102 be
relatively inexpensive to manufacture and relatively small in size.
It is particularly preferable that the measurement sensor 102 be
suitable for being treated as a disposable device, such that the
measurement sensor may be disposed of and replaced by a new
measurement sensor, for example. As such, the measurement sensor
102 is preferably physically separate from, or separable from, the
calibration device 106 or calibration sensor 104. A measurement
sensor suitable for operating over a period of about 1 to 3 days,
is desirable. A measurement sensor suitable of operating over a
longer period is contemplated, provided it provides no significant
ill effect in the body.
[0070] The calibration device 106 may comprise suitable electronic
and other components and circuitry such as those described in U.S.
Pat. No. 6,175,752 to Say et al. By way of example, the calibration
device 106 may comprise a potentiostat/coulometer suitable for use
in connection with an electrochemical measurement sensor. The
calibration device 106 may be a device that is suitable for
repeated or on-going use, even if the measurement sensor 102 is
disposable. As such, the measurement sensor 102 and the calibration
device 106 may be physically separate or capable of physical
separation or detachment.
[0071] According to embodiments of the present invention, the
calibration site may be any off-finger site within a body that is a
suitable source of blood or capillary blood. Convenient calibration
sites may be those that are close to an exterior surface of the
body. Preferred calibration sites are those that have a sufficient
supply of blood or capillary blood for drawing a suitable sample
and have a low density of pain receptors. Suitable calibration
sites are located in an arm, a forearm, a leg, or a thigh, for
example. Any suitable way or means of, or device for, measuring
analyte concentration in blood or capillary blood at such a
calibration site, such as any of those described herein, is
contemplated as being of use according to the present invention.
However, as obtaining a sufficient volume of blood for measurement
may be more difficult at an off-finger calibration site than at a
fingertip or finger calibration site, a suitable way or means of,
or device for, measuring analyte concentration in a small volume of
blood or capillary blood from an off-finger calibration site is
preferred. A suitable way or means or device may be any of those
associated with a small volume, in vitro, analyte sensor, such as
any of those described in U.S. Pat. No. 6,120,676 to Heller et al.;
or any of those suitable for measuring analyte concentration in
preferably less than or equal to about 1 .mu.L of blood or
capillary blood, more preferably, less than or equal to about 0.5
.mu.L of blood, and most preferably, less than or equal to about
0.2 .mu.L of blood is used for calibration, such as any amount
sufficient for obtaining a meaningful or useful measurement. In a
preferred embodiment, such a way or means or device is
electrochemical, such as amperometric or coulometric, for
example.
[0072] According to embodiments of the present invention, the
measurement site may be any site within a body that is a suitable
source of bodily fluid. A suitable measurement sites is any such
site that is suitable for operation of the analyte-measurement or
monitoring device. By way of example, suitable measurement sites
include those in an abdomen, a leg, a thigh, an arm, an upper arm,
or a shoulder, as described in U.S. Pat. No. 6,175,752 to Say et
al. Preferably, the measurement site is in the upper arm or in the
abdomen. The measurement site and the calibration sites may be
located in substantially the same region or part of the body or in
different regions or parts of a body.
[0073] The analyte-monitoring device may be calibrated a particular
point or at various points in the analyte-monitoring process. The
device is typically calibrated before it is used to monitor analyte
concentration in a body. As such, analyte concentration in blood or
capillary blood from the calibration site is typically measured
within about five minutes to about one hour of sensor use or
insertion within a body. In some cases, it may be desirable or
necessary to calibrate the device during a period of analyte
monitoring. As such, analyte concentration in blood or capillary
blood may be measured once or more during such a period. Any
suitable way or means of, or device for, measuring analyte
concentration in a bodily fluid at a measurement site may be used.
A suitable way or means or device may be electrochemical, as
described above in connection with calibration measurements, albeit
adapted as desirable or necessary for the measurement of analyte
concentration in the bodily fluid rather than in blood.
[0074] Calibration may be described as a process by which a raw
signal from an analyte-measuring or monitoring sensor is converted
into an analyte concentration. By way of example, when an optical
analyte sensor is used, the raw signal may be representative of
absorbance, and when an electrochemical analyte sensor is used, the
raw signal may be representative of charge or current. Calibration
may generally be described in terms of three parts or phases, as
described below.
[0075] In one phase, or a first phase, a calibration measurement
may be made via a calibration sensor and a raw signal may be
gathered via an analyte sensor more or less simultaneously. By more
or less simultaneously, or substantially simultaneously, is meant
within a period of up to about 10 minutes; preferably, up to about
5 minutes; more preferably, up to about 2 minutes; and most
preferably, up to about 1 minute, in this context. In general, the
calibration measurement is deemed or trusted as accurate because
the performance of the calibration sensor has been verified through
its own calibration process. Ideally, the calibration measurement
and the raw signal are obtained from identical samples.
Practically, this is often not possible. In the latter case, the
relationship between the calibration sample and the test sample
must be sufficiently strong to provide accurate or reliable
results. By way of example, when blood glucose test strips are
calibrated, the test sample may be capillary blood, while the
calibration may be capillary plasma. Further by way of example,
when subcutaneous glucose sensors are calibrated, the test sample
may be subcutaneous fluid, while the calibration sample may be
capillary blood.
[0076] In another phase, or a second phase, the quality of the raw
analyte signal and the calibration measurement data are evaluated
to determine whether to accept or decline a particular data pair
for use in calibration. By way of example, dual calibration
measurements may be made, and acceptance may be based upon adequate
agreement of the dual measurements. Further by way of example,
acceptance of the raw analyte signal may be predicated on some
feature of that signal, such as magnitude or variability, for
example. In the simplest manifestation of this phase of the
calibration process, raw analyte signal and calibration measurement
data pairs may be accepted without further discrimination.
[0077] In yet another phase, or a third phase, the raw analyte
signal is converted into an analyte concentration. By way of
example, when an electrochemical glucose sensor is used, a raw
current signal (in nanoAmperes (nA), for example) may be converted
into a glucose concentration (in units of mg/dL, for example). A
simple way of performing this conversion is by simply relating or
equating the raw analyte signal with the calibration measurement,
and obtaining a conversion factor (calibration measurement/raw
analyte signal), which is often called the sensitivity. Another
simple way of performing this conversion is by assuming a
sensitivity, such as a sensitivity based on a code associated with
the measurement sensor, as described above. The sensitivity may be
used to convert subsequent raw analyte signals to analyte
concentration values via simple division ((raw analyte
signal)/(sensitivity)=analyte concentration). For example, a raw
analyte signal of 10 nA could be associated with a calibration
analyte concentration of 100 mg/dL, and thus, a subsequent raw
analyte signal of 20 nA could be converted to an analyte
concentration of 200 mg/dL, as may be appropriate for a given
analyte, such as glucose, for example. This is often called
one-point calibration.
[0078] There are many variations of the conversion phase of the
calibration process, as will be appreciated. Merely by way of
example, the sensitivity can be derived from a simple average of
multiple analyte signal/calibration measurement data pairs. Further
by way of example, the sensitivity can be derived from a weighted
average of multiple analyte signal/calibration measurement data
pairs. Yet further by way of example, the sensitivity may be
modified based on an empirically derived weighting factor, or the
sensitivity may be modified based on the value of another
measurement, such as temperature. It will be appreciated that any
combination of such approaches, and/or other suitable approaches,
is contemplated herein.
[0079] Ideally, the calibration measurement of the first phase
described above is performed at the time of the analyte sensor is
manufactured. Typically, representative sensors from a large batch
or "lot" of analyte sensors are tested at the site of manufacture,
and a calibration code is assigned to the sensor lot. The
calibration code may then be used in association with the
analyte-measuring device to convert the raw analyte signal into an
analyte concentration. By way of example, a manufacturer or user of
the device may enter the code into the device, or a data processor
of the device, for such data conversion. Blood glucose test strips
are typically calibrated in this manner, at the site of
manufacture.
[0080] For other types of sensors, including subcutaneous glucose
sensors, calibration at the site of manufacture is typically not
feasible. This infeasibility may be based on any of a number of
factors. Merely by way of example, variations in the within-lot
performance of the analyte sensors may be too large, and/or
variations in person-to-person response to a given sensor lot may
be too large. When calibration at the site is not feasible, the
calibration measurement must be performed upon fluid, often
capillary blood, drawn from or within the wearer of the
subcutaneous sensor. Such a calibration process is often called in
vivo calibration.
[0081] An example of a calibration process 200 is now described in
relation to a flow-chart illustration shown in FIGS. 2A, 2B, and 2C
(collectively, FIG. 2). The process 200 comprises the selection 202
of at least one possible calibration point and the starting 204 of
the process with the first possible calibration point. Merely by
way of example, one may select three different calibration points
and choose the first calibration point in time for further
processing, such as a calibration point that is taken within or up
to about one hour from the implantation of a measurement sensor,
for example.
[0082] The first calibration point is then evaluated in at least
one of several possible processes. For example, the calibration
point may be evaluated as to whether or not (1) a predetermined
time has elapsed since implantation or since a prior calibration
206, such as a predetermined time of about one hour after
implantation, or a predetermined time of about 2 hours after a
prior calibration, for example; (2) an analyte concentration ("[G]"
in FIG. 2)) associated with the calibration point, such as an
analyte concentration from a calibration sensor (for example, from
an in vitro measurement of blood from the calibration site) falls
within a predetermined range 208, such as a predetermined glucose
concentration range of from about 60 to about 350 mg/dL, for
example; (3) a rate of change in analyte concentration from an
analyte sensor (for example, from an in vivo measurement of bodily
fluid at the measurement site) since a prior calibration, over a
predetermined period, such as about 10 minutes, or about 30
minutes, for example, falls within a predetermined range 210, in
any direction (i.e., positive or negative, up or down), such as a
predetermined range for a rate of change in glucose concentration
change of up to about 2 (mg/dL)/minute, for example; (4) a
temperature measurement, such as a measurement of skin temperature,
for example, is within a predetermined range 212, such as a
predetermined range of from about 28.degree. C. to about 37.degree.
C., for example; and/or (5) the sensitivity falls within
predetermined limits 214, such as within a preset range associated
with an analyte sensor production lot 216 (for example, a preset
range of percentage determined by a code assigned to a glucose
sensor production lot). The evaluations associated with the rate of
change in analyte concentration and the sensitivity are deemed of
particular relevance for applications in which glucose is the
analyte of interest.
[0083] If any of the evaluation standards is not met, the
calibration point is deemed unacceptable 218, the next possible
calibration point, if any, is selected 220, and that calibration
point is then evaluated, as described above. If there is no next
possible calibration point, the calibration process has failed to
provide an acceptable calibration point and ends (not shown). If
all of the evaluation standards are met, the calibration point is
deemed acceptable 222. If there are more calibration points to
evaluate 224, the next possible calibration point is selected 220,
and that calibration point is then evaluated, as described above.
If there are no more calibration points to evaluate 224, the
sensitivity factor or factors are calculated 226, in any of a
number of ways. Merely by way of example, an unweighted sensitivity
factor (SN), such as the current from an analyte sensor (for
example, from an in vivo measurement of bodily fluid at the
measurement site) divided by the analyte concentration from a
calibration sensor (for example, from an in vitro measurement of
blood from the calibration site), may be determined for each
calibration point 228; an adjusted weighting factor (AXM,N), based
on a raw weighing factor (XM,N) and a sensitivity weighing factor
(SWF), for example, may be determined for each calibration point
230; and/or a weighted sensitivity (WSN), based on a sensitivity
fudge factor (FN), for example, may be determined for each
calibration point 232, wherein N is the number associated with the
calibration point (i.e., N=1 for the first calibration point 1, N=2
for next calibration point 2, N=3 for the next calibration point 3,
etc.) and M is a number from 1 to N, inclusive (i.e., when N=1,
M=1; when N=2, M=1 and M=2, such that there are two raw weighing
factors and two adjusted weighting factors; when N=3, M=1, M=2, and
M=3, such that there are three raw weighing factors and three
adjusted weighting factors, etc.).
[0084] Based on at least one sensitivity factor, the analyte
concentration value or values, such as a glucose concentration
value, for example, is determined 234. By way of example, a raw
glucose value (G-raw) may be calculated 236, where the raw glucose
value equals the raw analyte signal (I), which may be a current
from an analyte sensor, as described above, divided by an
applicable weighted sensitivity (WS) value. Further by way of
example, a temperature-compensated glucose value (G-temp) may be
calculated 238, where this value equals the raw glucose value
(G-raw), as just described, multiplied by a temperature
compensation factor (TCF) raised to a power equal to the
temperature at the time associated with the calibration point
(T,cal) minus the temperature at the time associated with the raw
analyte signal reading (T,m). Still further by way of example, a
lag-compensated glucose value (G-final) may be calculated 240,
where this value equals the temperature-compensated glucose value
(G-temp), as just described, plus a lag factor (k) multiplied by
the change in the temperature-compensated glucose value
(.DELTA.G-temp) over a period between two acceptable or consecutive
calibration points and divided by the change in time (.DELTA.T)
over a period between two acceptable or consecutive calibration
points.
[0085] The foregoing description provides various calibration or
correction algorithms that may be used to convert an analyte
concentration obtained from bodily fluid to an analyte
concentration obtained from blood. It will be understood that any
of a variety of calibration or correction processes or algorithms
may be used, such as any suitable means or devices described in any
of the above-mentioned U.S. Pat. Nos. 6,175,752, 6,514,718,
6,565,509, and 6,881,551; U.S. Patent Application Publication No.
2003/0187338 filed Apr. 18, 2003, Schmidtke et al., Measurement and
Modeling of the Transient Difference Between Blood and Subcutaneous
Glucose Concentrations in the Rat after Injection of Insulin, Proc.
Of the Nat'l Acad. Of Science, 92, pp. 294-299 (1998); and Quinn et
al., Kinetics of Glucose Delivery to Subcutaneous Tissue in Rats
Measured with 0.3 mm Amperometric Microsensors, Am. J. Physiol.,
269 (Endocrinol. Metab. 32), E155-E161 (1995). Once an analyte
concentration is appropriately calibrated, it may be used as a
basis for suitable administration of a suitable amount of a drug,
such as insulin, for example, to the patient or subject.
[0086] Any of various statistical analyses of the data may follow,
such as those exemplified in the Experimental Study described
below, for example. By way of example, a Clarke error analysis 242
may be conducted to determine values that may be plotted on a
Clarke error grid. Suitable data for such a plot includes analyte
concentration values from an implanted analyte sensor and analyte
concentration values from venous blood. Further by way of example,
root mean square error, average error, slope, intercept,
correlation coefficient, and/or the like, may be determined 244.
Suitable data for such a determination includes analyte
concentration values from an implanted analyte sensor and analyte
concentration values from venous blood. Merely by way of example,
analyte concentration values from venous blood (YSI) may be
measured on a YSI 2300 instrument (Yellow Springs Instruments,
Yellow Springs, Ohio), as described in the Experimental Study that
follows. Other statistical determinations may be made as desired or
useful.
[0087] As indicated above, this application is related to, and
claims priority based on, the Feldman et al. Application, which is
the subject of the Feldman et al. Publication. The Feldman et al.
Application and the Feldman et al. Publication described Wired
Enzyme.TM. sensing technology (Abbott Diabetes Care) for the
continuous measurement of in vivo glucose concentrations. Such
Wired Enzyme.TM. sensing technology offers excellent sensor
stability, reduced sensor susceptibility to variations in in vivo
oxygen concentration, and minimized sensor response to common
electroactive interferents, as demonstrated in the Experimental
Study described below.
Experimental Study
[0088] In a sensor-response study, 48 subcutaneous sensors based on
Wired Enzyme.TM. sensing technology were implanted in patients with
Type 1 diabetes (25 in the upper arm, and 23 in the abdomen). These
implanted sensors were prospectively calibrated using capillary
blood. When glucose concentration values from the sensors were
compared with those from venous plasma obtained at 15-minute
intervals, ninety-eight percent of the values fell in a zone
consisting of the clinically accurate Clarke error grid zone A and
the clinically acceptable zone B. Neither the site of the implanted
sensor (upper arm versus abdomen) nor the site of the capillary
blood extraction (arm versus finger) affected system accuracy. The
foregoing study and results are further described herein, following
the introduction below.
Introduction
[0089] Evidence suggests that improved glycemic control can
minimize many of the complications associated with Type 1 diabetes.
(See, Diabetes Control and Complications Trial Research Group: The
Effect of Intensive Treatment of Diabetes on the Development and
Progression of Long-Term Complications in Insulin-Dependent
Diabetes Mellitus, N. Engl. J. Med., 329, pp. 977-986 (1993).)
Frequent self-monitoring of blood glucose, in concert with
intensive insulin therapy, greatly improves glycemic control.
[0090] Continuous glucose sensing provides all of the advantages of
high-frequency, discrete testing. It also provides advantages of
its own. By way of example, continuous glucose sensing may provide
valuable information about the rate and direction of changes in
glucose levels, which information may be used predictively or
diagnostically. Further by way of example, as continuous glucose
sensing occurs at times when discrete testing does not usually
occur, such as post-prandially or during sleep, for example,
continuous glucose sensing may provide sensitive alarms for
hyperglycemia and hypoglycemia that may be associated with
post-prandial or resting conditions.
[0091] The above-mentioned FreeStyle Navigator.RTM. continuous
glucose sensor is a subcutaneous, electrochemical sensor, which
operates for three days when implanted at a site in the body. This
sensor is based on the above-mentioned Wired Enzyme.TM. sensing
technology, a mediated glucose-sensing technology that offers a
number of advantages over conventional oxygen-dependent,
electrochemical, glucose-sensing technologies, which utilize
hydrogen peroxide (H.sub.2O.sub.2) detection at high applied
potential (.about.500 mV vs. a silver/silver chloride (Ag/AgCl)
reference electrode). (See, Csoregi, E., Schmidtke, D. W., and
Heller, A., Design and Optimization of a Selective Subcutaneously
Implantable Glucose Electrode Based on "Wired" Glucose Oxidase,
Anal. Chem., 67, pp. 1240-1244 (1995).)
[0092] Wired Enzyme.TM. technology works at a relatively gentle
oxidizing potential of +40 mV, using an osmium (Os)-based mediator
molecule specifically designed for low potential operation and
stably anchored in a polymeric film for in vivo use. The sensing
element is a redox active gel that comprises Os-based mediator
molecules, attached by stable bidentate anchors to a polymeric
backbone film, and glucose oxidase (GOx) enzyme molecules,
permanently coupled together via chemical cross-linking This redox
active gel is a glucose-sensing gel, which accurately transduces
glucose concentrations to a measured current over a glucose range
of 20-500 mg/dL.
[0093] Wired Enzyme.TM. sensing technology offers three primary
advantages over conventional H.sub.2O.sub.2-based detection
systems, which rely on oxygen for signal generation. One advantage
is that this Wired Enzyme.TM. technology affords electrochemical
responses that are extremely stable. This is not the case with many
other implanted, or in vivo, glucose sensors, which have been
associated with drifts in sensitivity (output per unit glucose
concentration) over their lifetimes. (See: Roe, J. N., and Smoller,
B. R., Bloodless Glucose Measurements, Crit. Rev. Ther. Drug
Carrier Syst., 15, pp. 199-241 (1998); and Wisniewsky, N., Moussy,
F., and Reichert, W. M., Characterization of Implantable Biosensor
Membrane Biofouling, Fresenius J. Anal. Chem., 366, pp. 611-621
(2000).) Because of these drifts, many other implanted glucose
sensors require frequent and/or retrospective calibration. By
contrast, after an initial break-in period, Wired Enzyme.TM.
implanted glucose sensors have extremely stable in vivo
sensitivities, typically losing no more than 0.1% sensitivity per
hour.
[0094] Another advantage is that Wired Enzyme.TM. technology does
not rely on oxygen for signal generation. Although oxygen can
compete for electrons with the Os-based mediator molecules, and
thereby modestly reduce the sensor output, the overall effect is
much smaller than exists in conventional H.sub.2O.sub.2-measuring
systems, which can generate no signal in the absence of oxygen.
This reduced oxygen dependency results in minimal sensitivity to in
vivo oxygen variations and good linearity at high glucose
concentrations. Yet another advantage is that Wired Enzyme.TM.
implanted glucose sensors operate at an applied potential of only
+40 mV, which is much gentler than the .about.500 mV required by
H.sub.2O.sub.2-sensing systems. Oxidation of many interferents
(acetaminophen, uric acid, etc.) and subsequent, false, high
glucose readings, are minimized at the comparatively low operating
potential of +40 mV associated with Wired Enzyme.TM. sensors.
[0095] The Feldman et al. Application presented preliminary results
from an accuracy study conducted in 30 patients with Type 1
diabetes, using frequent venous blood glucose measurements (at
15-min intervals, for 3 days), as reference values. The study was
performed with a corded system, although use of a wireless system
or radio-frequency based system is contemplated according to the
present invention. (See: U.S. Pat. Nos. 6,175,752 and 6,565,509 to
Say et al. filed on Apr. 30, 1998 and Sep. 21, 2000, respectively;
and U.S. Patent Application Publication No. 2004/0186365 A1 of Jin
et al. filed on Dec. 26, 2003.) The study and its results are
further described below.
Sensor Description
[0096] A continuous glucose sensor 300, as schematically shown in
FIG. 3, was used in the study described above. This continuous
glucose sensor 300 is the FreeStyle Navigator.RTM. continuous
glucose monitoring device that is based on Wired Enzyme.TM.
technology, as described above. The sensor 300 is an amperometric
sensor that comprises three electrodes, a working electrode 302, a
reference electrode 304, and a counter electrode 306, contacts of
which are shown in FIG. 3. Each of the working electrode 302 and
the counter electrode 306 is fabricated from carbon. The reference
electrode 304 is an Ag/AgCl electrode. The sensor 300 has a
subcutaneous portion 308 having dimensions of about 5 mm in length,
0.6 mm in width, and 0.25 mm in thickness, as further detailed in
the enlarged portion of FIG. 3.
[0097] The working electrode 302 has an active area 310 of about
0.15 mm.sup.2. This active area 310 is coated with the Wired
Enzyme.TM. sensing layer 312, which is a cross-linked,
glucose-transducing gel. As this sensing layer or gel 312 has a
relatively hydrophilic interior, glucose molecules surrounding the
subcutaneous portion 308 of the sensor 300 are free to diffuse into
and within this glucose-transducing gel. The gel 312 is effective
in the capture of electrons from these glucose molecules and the
transportation of these electrons to the working electrode 302. A
schematic illustration of the Wired Enzyme.TM. sensing layer 312,
showing various of its components (as further described below), as
well as the path of electron flow in the direction depicted by
arrows 314, from the glucose to the working electrode 302, is shown
in FIG. 4A.
[0098] The sensing layer or gel 312 comprises a redox polymer
mediator 316 of high molecular weight, glucose oxidase ("GOx") 318,
and a bi-functional, short-chain, epoxide cross-linker (not shown),
the former two of which are shown in FIG. 4A. The sensing layer 312
has a mass of 300 ng (at a dry thickness of about 2 .mu.m) and
comprises about 35% by weight redox polymer 316, 40% by weight GOx
enzyme 318, and 25% by weight cross-linker. The redox polymer 316,
the structure of which is illustrated in FIG. 4B, comprises a
modified poly(vinylpyridine) backbone, which is loaded with
poly(bi-imidizyl) Os complexes that are securely anchored to the
backbone via bidentate linkage. (See: U.S. Provisional Patent
Application No. 60/165,565 of Mao et al. filed on Nov. 15, 1999;
U.S. Pat. No. 6,605,200 of Mao et al. filed on Nov. 14, 2000; U.S.
Pat. No. 6,605,201 of Mao et al. filed on Nov. 14, 2000; U.S. Pat.
No. 7,090,756 of Mao et al. filed on Aug. 11, 2003; U.S. Pat. No.
6,676,816 of Heller et al. filed on May 9, 2002; and U.S. Pat. No.
7,074,308 of Mao et al. filed on Nov. 14, 2003.) This polymer 316
is an effective mediator or facilitator of electron transport in
the sensing layer.
[0099] As shown in FIG. 3, the sensor 300 also comprises an
analyte-restricting membrane 320, here, a glucose-restricting
membrane, disposed over the sensing layer 312. (See: U.S. patent
application Ser. No. 10/146,518 filed on May 14, 2002 and issued as
U.S. Pat. No. 6,932,894.) The membrane 320 comprises a
poly(vinylpyridine)-poly(ethylene glycol) co-polymer of high
molecular weight, that is cross-linked using a tri-functional,
short-chain epoxide. The membrane 320, which is about 50 .mu.m
thick, serves to reduce glucose diffusion to the active sensing
layer 312 by a factor of about 50. The hydrophilic membrane 320
provides a surface that is biocompatible, such that bodily
irritation from the subcutaneous portion 308 of the sensor 300 is
reduced.
[0100] The sensor 300 is associated with an in vivo sensitivity of
about 0.1 nA/(mg/dL) and a linear response over a glucose
concentration range 20-500 mg/dL. Additionally, in terms of
response to an instantaneous change in glucose concentration, the
sensor 300 is associated with a response time of about three
minutes.
Sensor Configuration
[0101] For each sensor 300 that was used in the study, the
subcutaneous portion 308 of the sensor was placed into the
subcutaneous tissue of the upper arm or the abdomen of a subject or
patient using a spring-actuated insertion mechanism. (See: U.S.
Provisional Patent Application No. 60/424,099 of Funderburk et al.
filed on Nov. 5, 2002; and U.S. Pat. No. 7,381,184 of Funderburk et
al. filed on Nov. 5, 2003.) The sensor 300 was connected via cord
(not shown) to a portable, potentiostat-data logger device (not
shown), which was used to maintain the glucose-sensing working
electrode 302 at a potential of +40 mV versus the Ag/AgCl reference
electrode 304, while obtaining and storing instantaneous current
values at 10-second intervals. Each subject was also fitted with a
small (about 1 cm.sup.2), insulated, transdermal skin-temperature
sensor, in the immediate vicinity of the continuous glucose sensor
300.
In Vitro Continuous Glucose Sensor Evaluations
[0102] In vitro continuous glucose sensor evaluations were carried
out at 37.degree. C. in 0.1 M phosphate-buffered saline (PBS)
contained in a 2-L jacketed beaker with gentle stirring. Oxygen
dependence experiments were conducted under two gas mixtures: 95%
N.sub.2/5% O.sub.2 and 98% N.sub.2/2% O.sub.2. Interferent
evaluations were conducted in separate experiments using 0.2 mM
acetaminophen, 0.085 mM ascorbate, or 0.5 mM uric acid, also in
PBS. In long-term stability experiments, Proclin 500 (Supelco,
Bellefonte, Pa.) was added to the interferent evaluation solution
at 5 .mu.L/L to retard bacterial growth.
Biocompatibility Testing
[0103] Biocompatibility testing was performed on large-scale
assemblies consisting of all sensor components (substrate,
electrode inks, membrane, and sensing layer formulations) in
proportions corresponding exactly to the actual composition of the
continuous glucose sensors 300. (See U.S. Pat. No. 6,175,752 to Say
et al.) Cytotoxicity was assessed by ISO elution test (minimum
essential medium extract) in vitro. Sensitization was assessed with
a maximization test (Magnusson Kligman method) in guinea pigs.
Irritation was assessed with an ISO intra-cutaneous reactivity test
in rabbits. Systemic toxicity was assessed by a USP systemic
injection test in rabbits. Sub-chronic sensitization was assessed
by a 30-day implantation test in rabbits. Genotoxicity was assessed
by Ames mutagenicity test in vitro. Hemocompatibility was assessed
by a hemolysis test (extract method) in vitro. All tests were
passed.
Clinical Trial Procedure
[0104] In a clinical trial, thirty subjects were tested, as
described below, over a 3-day trial period. Each subject was fitted
with either one continuous glucose sensor or two such sensors, and
correspondingly, one transdermal skin temperature sensor or two
such sensors, as described above. Sensor implant depth was about 5
mm. Each subject was also fitted with a heparin lock for obtaining
venous blood samples. Glucose and temperature data were obtained at
10-second intervals over the 3-day trial period, while venous blood
samples were obtained at 15-minute intervals over the trial period.
Venous plasma blood glucose values were measured on a YSI 2300
(Yellow Springs Instruments, Yellow Springs, Ohio). Capillary blood
measurements were also made using the above-mentioned
FreeStyle.RTM. blood glucose-monitoring system to enable
development of a prospective calibration algorithm. Arm capillary
blood was obtained hourly at hours 0-12, 24-30, and 48-54, for all
of the subjects. Finger capillary blood was also obtained at the
same times for 10 subjects wearing 19 continuous glucose
sensors.
[0105] Glycemic challenges were performed daily for all subjects.
Subjects were given intravenous insulin once (0.15 U/kg, followed
by 0.10 U/kg if necessary to achieve hypoglycemia), and oral
glucose (75 g) on two separate occasions. Vital signs were
monitored at 15-minute intervals during administration of
intravenous insulin.
[0106] An institutional review board approved the trial protocol.
Inclusion criteria for the study were the following: presenting
Type 1 diabetes, having a C-peptide concentration of less than 0.5
ng/mL, and being 18 years old or older. Thirty subjects were
enrolled at three clinical trial sites (Renton, Wash.; San Antonio,
Tex.; and Walnut Creek, Calif.). Subjects ranged in age from 20 to
85 years, with a mean of 40 years. There were eight females and 22
males, comprising three African Americans, 26 Caucasians, and one
Hispanic.
Calibration Procedure
[0107] A prospective calibration algorithm was developed in an
earlier study consisting of 20 sensors (15 arm, 5 abdominal)
implanted into subjects with Type 1 diabetes. The 48 sensors, whose
performance is described here, were implanted in a separate study
conducted sequentially following the calibration development set.
Therefore, none of the data sets described in the present study was
used in development of the calibration algorithm. For each implant,
three capillary blood glucose measurements, obtained using the
FreeStyle.RTM. blood glucose-monitoring system, were used as
calibration bases, subject to exclusion criteria based on time,
glucose concentration range, rate of glucose concentration change,
sensitivity, and temperature, as further described below.
[0108] As to time, calibration point 1 occurred a minimum of 1 hour
after insertion, calibration point 2 occurred a minimum of 2 hours
after a successful calibration point 1, and calibration point 3
occurred a minimum of 21 hours after a successful calibration point
2. As to glucose concentration range, calibration was allowed
within a capillary blood glucose concentration range of 60-350
mg/dL. As to rate of glucose concentration change, calibration was
restricted to rates of change of 2 (mg/dL)/min or less. (A separate
study in 20 patients with Type 1 diabetes performing normal daily
routines (i.e., not performing daily glucose challenges) showed
that the rate of 2 (mg/dL)/min was exceeded only 4% of the time,
consistent with other published data. See Jungheim, K., Kapitza,
C., Djurhuus, C. B., Wientjes, K. J., and Koschinsky, T., How Rapid
Does Glucose Concentration Change in Daily-Life of Patients with
Type 1 Diabetes?, Abstract, Presented at the Second Annual Diabetes
Technology Meeting, Diabetes Technology Society, Atlanta, Ga.
(November 2002).) As to sensitivity, calibration was allowed only
if the resulting nominal sensitivity (in nA/mM glucose) was within
a preset range as determined by a code assigned to each continuous
glucose sensor production lot. As to temperature, calibration was
allowed over a skin temperature range of 28-37.degree. C.
[0109] The operating sensitivity for the first 2 hours of operation
was based entirely on calibration point 1. However, subsequent
operating sensitivities (after the second calibration point was
obtained) were based on a weighted average of all previously
obtained calibration points. This had the effect of refining, and
increasing the accuracy of, the calibration as the implant
proceeded. This refinement process was made possible by the
near-negligible drift of the continuous glucose sensor sensitivity
with time.
[0110] The calibration process also involved a correction for
changes in skin temperature underneath the insulated skin
temperature probe. An adjustment of 7% per .degree. C., relative to
the skin temperature at the time of the operative calibration
point, was performed. One sensor (of 49 implanted) did not achieve
calibration, because of violation of the sensitivity restriction
described above. That sensor was excluded from the statistical
analysis.
Results
[0111] The continuous glucose sensor was found to have excellent in
vitro stability. This was demonstrated by a plot that showed the
responses (current, in nA) of three separate sensors in glucose at
500 mg/dL (in PBS, at 37.degree. C.) versus time (days) over a
period of 7 days, as shown in the Feldman et al. Application and
Feldman et al. Publication (see FIG. 3). The average total decay in
glucose signal over the 7-day test period was 1.7%. The mean hourly
rate of decay, at 0.011% per hour, is insignificant. Similar
stabilities have been observed in vivo (vide infra).
[0112] In vitro testing was also performed to determine the effect
of oxygen on the linearity of the continuous glucose sensors. This
results were displayed in a plot of the averaged response (current,
in nA) versus glucose concentration (mg/dL) of eight continuous
glucose sensors that were maintained under an oxygen tension of 15
ton, and a plot of the same, but with the sensors maintained under
an oxygen tension of 38 ton, as shown in the Feldman et al.
Application and Feldman et al. Publication (see FIG. 4). (The
lowered O.sub.2 levels reflect the reduced levels found in
subcutaneous tissue. See Burtis, C. A., and Ashwood, E. R., eds.,
Tietz Textbook of Clinical Chemistry, W.B. Saunders Co.,
Philadelphia, Pa. (1999).) Curves drawn for the two plots exhibit
excellent linearity (R.sup.2=0.9999 for both curves) over the
glucose range of from 18 to 540 mg/dL. The curves differ in slope
by only 4%, with differences varying from 0.4% at 36 mg/dL to 3.5%
at 540 mg/dL. These results indicate that the continuous glucose
sensors are only minimally oxygen dependent.
[0113] In vitro testing was performed to determine the effect of
three interferents, namely, acetaminophen, ascorbate, and uric
acid, at the top of their normal physiological or therapeutic range
(0.2 mM, 0.085 mM, and 0.5 mM, respectively (see Burtis, C. A., and
Ashwood, E. R., eds., Tietz Textbook of Clinical Chemistry, W.B.
Saunders Co., Philadelphia, Pa. (1999)), on continuous glucose
sensors. The glucose-equivalent interferences were 3 mg/dL for
acetaminophen, 19 mg/dL for ascorbate, and 3 mg/dL for uric acid,
tested at these levels. The interferences due to uric acid and
acetaminophen are inconsequential, which can be attributed largely
to the low operating potential (+40 mV versus Ag/AgCl) associated
with the continuous glucose sensors.
[0114] In vivo testing of continuous glucose sensors, as implanted,
was performed. Representative results of the testing are shown in
FIG. 5, in the form of an overlay plot of representative data from
an abdominally implanted continuous glucose sensor (current (in nA)
versus time (in days)) and venous plasma glucose values (glucose
concentration (in mg/dL) versus time (in days)). It should be noted
that the data were raw, that is, not calibrated and not corrected
for temperature, and no time-shifting of the data was
performed.
[0115] The results are noteworthy in that they demonstrate what is
obviously an excellent correlation between the raw current values
associated with the continuous glucose sensor and the venous plasma
glucose concentrations. No substantial lag between subcutaneous and
venous glucose concentrations is evident. The results are also
noteworthy in that they demonstrate that the sensitivity of the
implanted continuous glucose sensor is essentially unchanged over
the 3-day implantation period. Given this stability in signal
sensitivity, it is possible to schedule three calibration points in
the first 24 hours of the implantation, with no additional
calibration points during the final 48 hours. Additionally, given
nearly negligible sensor drift, it is possible to use a weighted
average of multiple calibration points as a basis for accounting
for the operating sensitivity of the implanted sensor. Such use of
a weighted average is helpful reducing any error inherent in the
capillary blood glucose measurement that is used for
calibration.
[0116] In vivo testing of continuous glucose sensors, as implanted
in the arms of the subjects, was performed. Representative results
of the testing are shown in FIG. 6 in the form of a plot (glucose
concentration (in mg/dL) versus time (in days)) of representative
data from an arm-implanted continuous glucose sensor (one of the 48
calibrated sensors), venous plasma, and capillary blood from an
arm-stick. It should be noted that the current data obtained from
the arm-implanted continuous glucose sensor was converted to
glucose concentration data, by way of a prospective calibration
that was based on the arm-capillary blood measurements that were
obtained using the FreeStyle.RTM. blood glucose-monitoring system.
No time-shifting of the data was performed.
[0117] The results are noteworthy in that they demonstrate an
excellent correlation between subcutaneous and venous plasma
glucose values, which is indicative of both reliable sensor
function and accurate calibration. As noted above, the
representative data set shown in FIG. 6 was calibrated using
arm-capillary blood measurements. The results are also noteworthy
in that no significant change in accuracy was found (vide infra)
when the data were calibrated using finger-capillary blood
measurements.
[0118] In vivo testing of continuous glucose sensors, as
simultaneously implanted in the arm and in the abdomen of a single
subject, was performed. Representative results of the testing are
shown in FIG. 7, in the form of a plot (glucose concentration (in
mg/dL) versus time (in days)) of representative data from an
arm-implanted continuous glucose sensor, an abdomen-implanted
continuous glucose sensor, and venous plasma. The results
demonstrate good agreement between the glucose values measured at
subcutaneous sites in the arm and in the abdomen.
[0119] These results also demonstrate good agreement between the
subcutaneous glucose values associated with the arm and abdomen and
those associated with the venous plasma, although some deviations
from the latter were observed on the first night of implantation,
when the subcutaneous values fell intermittently below the venous
plasma values. Based on data (not shown) for spatially adjacent
sensors implanted at a single site, it is believed that these
deviations result from interactions between the sensor and the
insertion site, not from systematic differences between venous and
subcutaneous glucose in the body. The deviations are virtually
always negative (that is, the glucose value from the implanted
continuous glucose sensor is lower than the glucose value from the
venous plasma) and tend to occur at night and early in the course
of the 3-day implantation.
[0120] The cause of the negative deviations described above is
unknown, although some possible causes may be put forward, as
follows. It may be that cells or other subcutaneous structures
adhere to the sensor surface, blocking glucose ingress. It may be
that blood clots form upon sensor insertion, exerting a similar
glucose-blocking effect. (Blood clots were not observed to adhere
to the active areas of explanted sensors (that is, sensors that
were removed from the body after implantation), but that does not
preclude their presence prior to explantation.) It may be that
constriction of local blood vessels, due to external pressure
effects, restrict glucose delivery to the sensor site.
[0121] It should be noted that the deviations described above are
not frequent. Sensitivity was reduced by 40% or more for only 4% of
the roughly 3,500 sensor-hours represented by this study. Overall,
the system performed well, as demonstrated by statistical data
described below.
[0122] A Clarke error grid of data (glucose concentration from the
continuous glucose sensor versus that in venous plasma (mg/dL))
from all of the 48 continuous glucose sensors (25 in the arm and 23
in the abdomen) that were inserted in the 30 subjects, is shown in
FIG. 8. These data were prospectively calibrated, with no
time-shifting, using arm-capillary blood data. The grid represents
12,667 data pairs. Approximately 98% of the data fall within a zone
consisting of the clinically accurate "A" region and the clinically
acceptable "B" region of the Clarke error grid.
[0123] A tabular summary of statistical data from the Clarke error
grid and from the implanted continuous glucose sensors is presented
in Table 1 below. In Table 1, the data are categorized according to
the implantation site, either arm or abdomen, and/or the
calibration site, either arm or finger.
TABLE-US-00001 TABLE 1 Summary of Statistical Data Calibration
Clarke error grid Subset Description Site N.sup.a % A % B % C % D %
E ARE (%) A All sensors Arm 12,667 67.9 29.7 1.2 1.1 0.0 17.3 (25
arm, 23 abdominal) B 25 sensors Arm 6,656 67.0 30.3 1.8 1.0 0.0
17.7 (arm) C 23 sensors Arm 6,011 69.0 29.1 0.6 1.3 0.0 17.2
(abdominal) D.sup.b 19 sensors Arm 4,987 67.7 29.3 1.8 1.1 0.0 17.4
(arm, finger calibration available) E.sup.b 19 sensors Finger 4,922
68.2 29.8 1.1 0.8 0.0 17.0 (arm, finger calibration available)
.sup.aNumber of continuous sensor/venous plasma data pairs.
.sup.bSubsets D and E have slightly different n values, since there
were small variations in the time at which calibrated operation
(and hence meaningful venous/subcutaneous glucose pairs) began.
[0124] More particularly, the data described above in relation to
FIG. 8 appears in Table 1 in association with a Subset A,
representing arm-based calibration, for the data from the 48
continuous glucose sensors (25 in the arm and 23 in the abdomen).
This data is further broken down in Table 1 for the 25 sensors that
were implanted in the arm (Subset B) and the 23 sensors that were
implanted in the abdomen (Subset C). The data demonstrates that
when arm-capillary blood calibration was employed, there was no
significant difference between the use of an insertion site in the
arm, associated with an absolute relative error ("ARE") of 17.7%
(for 25 sensors, Subset B), and use of an insertion site in the
abdomen, associated with an ARE of 17.2% (for 23 sensors, Subset
C).
[0125] The other data appearing in Table 1 were obtained from 19
sensors that were used to simultaneously determine glucose values
using calibration samples withdrawn from both the arm (Subset D)
and the finger (Subset E) of a subject on an hourly basis for hours
0-12, 24-30, and 48-54. The data were obtained in this manner from
10 subjects. The data show that of 4,987 continuous sensor/venous
plasma data pairs in Subset D, representing arm-based calibration,
67.7% were found to be in region A of the Clarke error grid, 29.3%
in region B, 1.8% in region C, 1.1% in region D, and 0.0% in region
E. The data further show that of the 4,922 continuous sensor/venous
plasma data pairs in Subset E, representing finger-based
calibration, 68.2% were found to be in region A of the Clarke error
grid, 29.8% in region B, 1.1% in region C, 0.8% in region D, and
0.0% in region E. The data in Table 1 demonstrate that there is no
significant difference between arm-capillary blood calibration
(ARE=17.4%) and finger-capillary blood calibration (ARE=17.0%).
Accordingly, arm-capillary blood may be used more or less as
effectively as finger-capillary blood as the basis for one-point in
vivo calibration.
CONCLUSIONS
[0126] All of the continuous glucose sensor data presented above
(with the exception of the raw data overlay of FIG. 5) were derived
using a prospective calibration based on nominal calibration times
of 1, 3, and 24 hours after implantation. The calibration algorithm
was developed using a separate data set for 20 similar implanted
continuous glucose sensors. None of the data reported here was used
in development of the calibration algorithm.
[0127] As demonstrated herein, the continuous glucose sensor used
in the study is extremely stable in terms of in vivo sensitivity
after a modest acclimation process (during which sensitivity may
rise by a few percent) that is generally complete in a few hours.
Because sensor output is so stable, calibration points may be
concentrated in the first 24 hours of use and calibration may be
periodically or continuously refined as multiple calibration points
are obtained. Both of these strategies may be advantageous for a
number of reasons. By way of example, the concentration of
calibration points in an early portion of the implantation period,
such as the first 24 hours, for example, may be advantageous in
that no calibration is required over the remaining portion of the
implantation period, such as the final 48 hours of a 72-hour period
of implantation, for example. Further by way of example, either
this concentration of calibration points early on, or the
above-described refinement of the calibration, as opposed to the
use of the most recent calibration point as a basis for calibrating
the sensor, or both, may be advantageous in the reduction or
minimization of calibration error.
[0128] It is noteworthy that no time-shifting of data was used in
the study described herein. That is, all of the data are real-time
data. Time-shifting of data has been used frequently in the
literature to compensate for any error associated with
physiological time lags between the subcutaneous and reference
glucose measurements or associated with slow system response times.
As it is believed that time-shifting of glucose values and
prospective calibration are incompatible concepts, time-shifting of
data, such as glucose values, may be avoided according to the
present invention.
[0129] Based on the statistical data provided herein, the average
physiological time lag (subcutaneous-venous) associated with the
continuous glucose sensors tested was found to be about 8 minutes.
This value was determined by the theoretical exercise of finding
the minimum in absolute relative error as reference and
subcutaneous values were time-shifted. Of this 8-minute lag, about
3 minutes and 5 minutes can be attributed to the response time of
the sensor, and to physiology, respectively. In a recent review
(see Roe, J. N., and Smoller, B. R., Bloodless Glucose
Measurements, Crit. Rev. Ther. Drug Carrier Syst., 15, pp. 199-241
(1998)) of various subcutaneous glucose measurement strategies, lag
times ranging from 2 to 30 min, with an average lag of 8-10
minutes, were reported, which is in good agreement with the
findings of this Experimental Study. A more complete study of
physiological glucose lags based on the raw data of this study has
been presented at the 39.sup.th Annual Meeting of the German
Diabetes Association, in Hannover, Germany, May 19 to May 22, 2004,
by Feldmen, B., and Sharp, C., under the title, Correlation of
Glucose Concentrations in Intersitital Fluid and Venous Blood
during Periods of Rapid Glucose Change.
[0130] The data for the continuous glucose sensor tested, as shown
in FIGS. 5-7, demonstrate excellent linearity at both high and low
glucose values induced by glycemic challenges. The continuous
glucose sensor faithfully tracks in vivo glucose values over the
physiologically relevant range. Overall, for the complete data set,
98% of readings fall within a zone that consists of the clinically
accurate Clarke error grid zone A and the clinically acceptable
zone B, as shown in FIG. 8 and Table 1. This represents excellent
performance. It should be noted that no only does the continuous
glucose sensor perform outstandingly, it provides directional trend
information, a very desirable predictive or diagnostic tool.
[0131] The data summarized in Table 1 demonstrates that there was
no significant difference between arm-capillary blood calibration,
associated with an ARE of 17.4%, and finger-capillary blood
calibration, associated with an ARE of 17.0%. Thus, arm-capillary
blood served as an almost equally accurate, and less painful,
calibration tool, relative to finger-capillary blood. While not
studied here, it is contemplated that rubbing of skin adjacent to a
calibration site (see the FreeStyle.RTM. Blood Glucose Testing
System, Test Strip Package Insert, TheraSense, Inc., Alameda,
Calif. (2000)), such as a calibration site in the arm, may improve
the efficacy of the capillary blood from that site as a calibration
tool. The data summarized in Table 1 also demonstrates that when
arm-capillary blood calibration was employed, there was no
significant difference between the use of an insertion site in the
arm, associated with a ARE of 17.7% (for 25 sensors), and use of an
insertion site in the abdomen, associated with a ARE of 17.2% (for
23 sensors).
[0132] The possibility of a large variation between arm- and
finger-capillary blood values has been put forth in various studies
conducted under the extreme conditions of glucose loading, followed
by intravenous delivery of insulin. (See Koschinsky, T., and
Jungheim, K., Risk Detection Delay of Fast Glucose Changes by
Glucose Monitoring at the Arm, Diabetes Care, 24, pp. 1303-1304
(2001).) In fact, under normal use conditions, these differences
are not significant unless glucose is changing very rapidly. (See
Bennion, N., Christensen, N. K., and McGarraugh, G., Alternate Site
Glucose Testing: A Crossover Design, Diabetes Technol. Ther., 4,
pp. 25-33 (2002).) Restriction of calibration to rates of less than
2 mg/dL per min virtually eliminates this possible source of
error.
[0133] The present invention is applicable to corded or cabled
glucose-sensing systems, as described above, as well as other
analyte-sensing or glucose-sensing systems. For example, it is
contemplated that suitable results, along the lines of those
described herein, may be obtained using a wireless glucose-sensing
system that comprises a pager-sized, hand-held, informational
display module, such as a FreeStyle Navigator.RTM. wireless
glucose-sensing system. The FreeStyle Navigator.RTM. system
employed herein is capable of providing real-time glucose
information at 1-minute intervals and information regarding rates
and trends associated with changes in glucose levels. This system
is further capable of providing a visual indication of glucose
level rates, allowing users to discriminate among glucose rate
changes of less than 1 mg/dL per minute, 1-2 mg/dL per minute
(moderate change), and greater than 2 mg/dL per minute (rapid
change). It is contemplated that sensors having features such as
these will be advantageous in bringing information of predictive or
diagnostic utility to users. The FreeStyle Navigator.RTM. system is
also designed to provide hypoglycemic and hyperglycemic alarms with
user-settable thresholds.
[0134] Each of the various references, presentations, publications,
provisional and/or non-provisional United States patent
applications, United States patents, non-U.S. patent applications,
and/or non-U.S. patents that have been identified herein, is
incorporated herein in its entirety by this reference.
[0135] Other aspects, advantages, and modifications within the
scope of the invention will be apparent to those skilled in the art
to which the invention pertains. Various modifications, processes,
as well as numerous structures to which the present invention may
be applicable will be readily apparent to those of skill in the art
to which the present invention is directed upon review of the
specification. Various aspects and features of the present
invention may have been explained or described in relation to
understandings, beliefs, theories, underlying assumptions, and/or
working or prophetic examples, although it will be understood that
the invention is not bound to any particular understanding, belief,
theory, underlying assumption, and/or working or prophetic example.
Although various aspects and features of the present invention may
have been described largely with respect to applications, or more
specifically, medical applications, involving diabetic humans, it
will be understood that such aspects and features also relate to
any of a variety of applications involving non-diabetic humans and
any and all other animals. Further, although various aspects and
features of the present invention may have been described largely
with respect to applications involving partially implanted sensors,
such as transcutaneous or subcutaneous sensors, it will be
understood that such aspects and features also relate to any of a
variety of sensors that are suitable for use in connection with the
body of an animal or a human, such as those suitable for use as
fully implanted in the body of an animal or a human. Finally,
although the various aspects and features of the present invention
have been described with respect to various embodiments and
specific examples herein, all of which may be made or carried out
conventionally, it will be understood that the invention is
entitled to protection within the full scope of the appended
claims.
* * * * *